Transcript drug

General pharmacology&
pharmacology of the Eye
By
Dr. MOHAMED A.ETARSHAWI
Optometry department
Faulty of Health Sciences-IUG
2015-2014
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DEPARTMENT OF
OPTOMETRY
PART I
General Pharmacology
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Contents
I- Drug definition, sources and preparation. SLIDE6
II- Drug absorption , distribution , and excretion
-metabolism SLIDE 35
III- Drug action , activity and dosage Slide- 62
IV-Channels of Drug Administration Slide- 79
V- How do drugs work? Slide 90
VI- Side effects and drug toxicity Slide 95
VII- General guidelines for handling medications Slide
110
VIII-
PHARMACODYNAMICS PHARMACOKINETICS
IX- CLASSES OF ANTIBACTERIAL AGENTS Slide
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116
121
PART II
Pharmacology Of the Eye
X- Entry of drugs into the eye. Slide -129
XI- Diagnostic drugs and products used in
optometry Slide 174.
XII- Mydriatics. Slide 242
XIII- Miotics. Slide 277
XIIII- Stains . Slide 294
XV- Contact solutions Slide .315
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Contents
XVI-Therapeutic drugs of eye diseases and their uses
Slide 353
XVII-Topical Eye Medication in Infants and Children .
Slide 393
XVIII-VERNAL KERATOCONJUNCTIVITIS ( VKC)Slide
413
XVIIII-Pharmacology of Ocular Beta- Adrenoceptor
Antagonists (Antiglaucoma drugs) Slide 446
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CHAPTER ONE
Drug definition, sources action and
preparations
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General Pharmacology
Pharmacology:
Pharmacology is a Latin word meaning
drug knowledge.
Pharmaco = drug .
Ology = science or knowledge.
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General Pharmacology
Drug : is defined by the United States food and
drug administration (FDA) as “ A
substance or agent used in diagnosis,
cure, prevention, mitigation ‫التخفيف‬, or
treatment of a disease condition.”
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General Pharmacology
1.
2.
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The FDA definition of drug also includes
any substance listed in USP (the United
States pharmacopia) and BP (British
pharmacopia) and all substances other
than food or devices capable of altering
body structure.
Pharmacopia : is a book containing
formulas ‫الصيغ‬, which are standard for
preparation and dispensation of drug
(distribution) .
Branches of pharmacology
I- Pharmacotherapeutic: ( Clinical
pharmacology)
‫دراسة التأثير العالجي لألدوية داخل جسم اإلنسان‬
• It deals with relative effect of drugs in the
human system for various disorders.
• Or it deals with the effect of a drug that the
Dr. orders for treating a human patient .
• Or “The study of drug action in diseased
man”.
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General Pharmacology
II- Pharmacodynamic: ‫علم الدواء التجريبي‬
•Which deals with experimental pharmacology.
•Or it deals with the interactions between
components of living system and foreign
chemical including drugs that enter living
organism in experiment.
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General Pharmacology
III-Pharmacokinetics: is the study of drug’s
‫دراسة‬alteration during its way through the
body. ‫التغييرات التي تطرأ على الدواء داخل الجسم‬
•Or it is the study of the fate of drug in the
body as it is absorbed, distributed, bound to or
localized in tissues, biotransformed and
excreted .‫دراسة مصير الدواء بعد عمله داخل الجسم‬
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Parameters of drug action
The parameters of drug action are :
1. Drug absorption and distribution.
2. Drug plasma concentration.‫تركيز الدواء داخل بالزما الدم‬
3. Therapeutic plasma levels. ‫التركيز العالجي للدواء‬
‫داخل البالزما‬
4. Concentration of the active drug at the target
site. ‫تركيز الدواء داخل العضو المريض‬
5. Rate of metabolism.
6. Rate of excretion.
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Factors affecting the
Parameters of drug action
These parameters in turn are affected by:
1. Physiochmeical nature of the drug e.g. lipid or
water solubility of the drug.
2. Formulation ‫ تركيب‬of the drug.
3. Route of administration of the drug .
4. Binding of the drug to plasma and/or body
tissues (bioavailability).
5. Individual characteristics of the patient.
6. Concomitant diseases.‫األمراض المصاحبة لتناول الدواء‬
7. Concomitant administration of food or other
drugs. ‫المصاحبة لتناول الدواء‬
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Sources of drugs
Drugs and biologic products are derived
from 4 main sources:
I- Plants: are the major source of drugs
examples of which are digitalis.
II- Animals : from which drugs such as
insulin, epinephrine are obtained.
III- Minerals‫ المعادن‬: examples such as
iodine and iron.
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IVChemicals: made in laboratories.
General Pharmacology
Active constituents of plant drugs:
The ‫االوراق‬leaves, ‫الجذور‬roots, ‫ البذور‬seeds
and other parts of plants may be dried or
otherwise processed ‫ تصنع‬for use as
medicine and they are known as crude
drugs.‫دواء خام‬
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General Pharmacology
On separation of these active plant
constituents, the resulting pure drug
form are:
1. More potent. ‫أكثر قوة‬
2. Usually produce effects more reliable
‫ فعال‬than those of the crude drugs.
3. More poisonous and the dose must be
smaller .
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General Pharmacology
These plant active constitutes are:
1.Alkaloids ‫القلويات‬: examples are atropine,
morphine, codeine and heroine. They are
toxic, have bitter taste, potent in small doses,
insoluble in water (but their salts are soluble
in water) and they usually end with “ine” suffix
2.Glycosides ‫ سكريات نباتية‬: such as Digoxin ‫دواء‬
‫لعضلة القلب‬.
3.Gums ‫ األصماغ‬: Such as Agar.
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General Pharmacology
4.Resins ‫ الدهون النباتية‬: they are fatty-like
substances that are greasy and irritant
such as cathartics ‫الملينات النباتية‬. (laxatives)
5.Oils: they are 2 types:
a - Volatile ‫ طيار‬such as peppermint oil ‫زيت‬
‫ النعنع‬and clove oil. ‫زيت القرنفل‬
b –Nonvolatile (Fixed ) oils such as olive oil
‫ زيت الزيتون‬and castor oil. ‫زيت الخروع‬
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General Pharmacology
Common Drug Preparations:‫التراكيب الدوائية الشائعة‬
I-Solutions and suspensions : ‫ معلقات‬, ‫محاليل‬
• Aqueous solutions: have one or more
substance dissolved in water e.g. epinephrine
nasal solution.
• Aqueous suspensions: are preparations of
finally divided drugs (undissolved) either
intended for suspension or already in
suspension in some suitable liquid vehicle.
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Common Drug Preparations:
• Sterile suspensions are intended for
intramuscular or subcutaneous injections but
they can’t be given intravenously .
• Oral suspensions are NOT sterile and must
NOT be injected.
• N.B : Suspensions tend to settle slowly and
should be SHAKED WELL before use to
provide uniform distribution of the drug.
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Common Drug Preparations:
II-Elixir :‫ إكسير‬clear fluid containing the drug
,water and alcohol designed for oral use,
usually has a sweetener added ,e.g most
cough drugs. ‫شراب الكحة‬
III-Syrup ‫شراب‬: drug dissolved in a
concentrated sugar solution.
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Common Drug Preparations:
IV-Capsules:
are a convenient way of giving drugs that have
unpleasant taste. Capsules are solid dosage
form for oral use medication in a powder,
liquid or oil form are incased in gelatin shell,
capsule colored to avoid mistakes in product
identification. Capsules may be controlledrelease or sustained- release capsules.
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Common Drug Preparations:
V-Coated tablets‫االقراص المغلفة‬
“Enteric coating” drugs are used for the
following reasons:1.To prevent decomposition of chemically
sensitive drugs by gastric secretions.
2.To prevent dilution of the drug before it
reaches the intestine.(giving weak action)
3.To prevent nausea and vomiting due to
gastric irritation.
4.To provide delayed action of the drug .
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Capsules
N.B. : Capsule forms are absorbed more
rapidly than tablets because the powder
inside capsules affords ‫ تغطي‬a larger
surface area of stomach mucosa than the
compressed tablets.
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General Pharmacology
VI-Tablets ‫أقراص‬: are powdered dosage form
compressed into hard disks or cylinders. In
addition to primary drug , they contain binders
(adhesive to allow powder to stick together).
VII-Pills :‫ برشامة دواء‬are solid round dosage form
containing one or more drug. Pills are used to
provide a drug or mixture of drugs into definite
doses and avoid the inconvenience ‫اإلزعاج‬of
preparing the dose from dry powder.
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General Pharmacology
NOTES:1-Some gelatin capsules and coated tablets may
be coated with substances that resist the action
of gastric juice so that will not disintegrate until
they reach the alkaline secretions of mall
intestine.
2-Sustained – release dosage capsules and
tablets forms contain small particles of the drug
coated with materials that require a varying
amount of time to dissolve. This provides for a
long
continuous period of absorption and effect.
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General Pharmacology
VIII-Ampoules and vials:- Ampoules and vials
contain powder or
liquid drug usually
intended for injection.
VIIII-Disposable syringes:Disposable syringes containing single dose of
drug preparations are widely used today.
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Disposable syringes
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General Pharmacology
X-Large volume intravenous solutions:In glass, flexible plastic or semi-rigid plastic
bag usually of 250, 500, 1000 ml e.g.
0.9% sodium chloride for I.V. injection.
XI-Intermittent I.V Solution:- These solutions
are similar to the I.V. solutions except
they come in smaller volumes .
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General Pharmacology
X11- Additional Formulations:A- Drops:- are aqueous solutions that
anesthetize, soothe or medicate (treat) eyes,
ears, or nose.
Drops are aqueous solution instilled into the
body cavities like eyes , nose or ears allowed
to stay there in contact with tissue to treat
certain disorders.
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General Pharmacology
B- Foams ‫ أبخرة‬and aerosols ‫رذاذ‬:- are
powders or solutions for spraying skin as
topical anesthesia to soothe or protect skin
or inhalation for bronchodilation in cases of
bronchial asthma.
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General Pharmacology
XIII-Other Formulations :A-Lotions:- Liquid suspensions used for external
applications e.g. calamine lotion as antipruiritic.
B-Creams:- aqueous and oily emulsions to soothe skin.
َ ‫ َمرا‬semisolid preparations of
C- Skin ointments: ‫هم‬
medical substances in some type of base such as
petrolatum lanolin used for skin soothing or have a
bacteriostatic effect.
D- Ophthalmic ointments: are sterile (e.g. antibiotics )
ophthalmic ointment.
E-Pasts:- Ointment- like preparations suited for only
external skin application. e.g. Zinc oxide past.
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General Pharmacology
XIIII- Suppositories:- are mixtures of drugs with
a firm base that can be molded in shapes
suitable for insertion manually or with an
applicator into certain body cavity or orifice
rectal or vaginal e.g. aminophylline
suppositories in bronchospasm (bronchial
asthma).
N.B. :- They should be kept cool.
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Suppositories
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CHAPTER TWO
Drug absorption , distribution,
metabolism and excretion
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Drug Absorption, Distribution
metabolism and Excretion
Absorption
Is the process that involves the movement
of drug molecules from the site of entry
into the body to the circulating body
fluids (blood or lymph).
The process of absorption begins at the site
of administration and is essential to the
subsequent processes (distribution,
metabolism and excretion).
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Absorption
Absorption as a process varies according to:
1. The route of administration.
2. Drug form (preparation ).
3. The dose of the drug.
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Factors Affecting Drug
Absorption
1-Nature of the absorbing surface:
Cell membrane through which the drug must traverse.
The drug molecule may pass through a single layer
of cells (intestinal epithelium of villi) faster than
several layers of cells (skin). Inverse
proportion
2-Surface area of the absorbing surface:
N.B. : The more extensive the absorbing surface,
the greater the absorption rate and more
rapid effect of the used drug. Direct proportion
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Blood flow to the site of
administration
3-Blood supply of the absorbing area:
Rich blood supply (sublingual) enhances
absorption where as, poorly vascular site
(subcutaneous) delays it. (Direct proportion).
For example, patient in shock may not respond to
(I.M) administration of drugs because of poor
peripheral circulation.
N.B. :- Drugs injected (I.V) are placed directly into
the circulatory system leading to rapid drug
absorption.
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4-Solubility of the drug
- In
order to be absorbed drug must be soluble in
solutions. The more soluble the drug, the more
rapidly it will be absorbed.
N.B : Chemicals and minerals that form insoluble
precipitates in the G.I.T or drugs that are
insoluble in water or lipids can’t be absorbed.
- Parenterally ‫غير معوي‬administered drugs(injections )
prepared in oily vehicle will be more slowly
absorbed from the muscle than drugs dissolved in
water or isotonic sodium chloride solution.
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5-Influence of pH
• Drugs that are acidic (e.g. Aspirin) the medical
substance becomes relatively undissociated
( remain active) in an acidic environment such
as the stomach , and therefore can readily
diffuse across the intestinal cell membrane
into the circulation.
• In contrast, an alkaline drugs (antacid) tends to
dissociate (inactivated) in the stomach acid
environment and not absorbed through the
gastric
mucosa.
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5-Influence of pH
• The reverse occurs when these drugs are
in an alkaline media. ( like Duodenum).
• N.B. : The unionized (undissociated ) drug in
water is lipid soluble readily diffuses across
the cell membrane of intestine , while the
ionized water soluble (dissociated ) drug is
lipid insoluble and nondiffusable across the
cell membrane of intestine .
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6-Drug concentration
• Drug administered in high concentration tend to be
more rapidly absorbed than drugs administered in
low concentration.
• In certain situations, drug may be initially
administered in large doses that temporarily
exceeds the body capacity for exertion of the drug
High concentration tend to be more rapidly
absorbed than drugs administered in low doses.
• In this way (high concentration) the active drug
therapeutic levels are rapidly reached at the
receptor site.
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6-Drug concentration
Once active drug level is established by such
cumulating effects, smaller doses of the
drug can be administered to replace only the
amount of the drug excreted since the
previous dose.
N.B. :- The initial large dose temporary
overloading doses of the drug are Priming
or Initial doses, while the smaller daily
doses are Maintenance doses .
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Distribution of drugs
• Is defined as the transport of a drug in body
fluids from the blood stream to various tissues
of the body and ultimately to its site of action.
1. Most of drugs are distributed initially to organs that
have rich blood supply as the heart, liver and kidney.
2. Delivery of the drug to extremities, skin and adipose
tissue is slower due to poor blood supply.
3. The distribution phase can be extremely slow for
drugs that bind strongly to serum proteins, because
the drug- protein complex is unable to pass out of the
plasma to different tissues due to its large size.
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Distribution of drugs
Distribution barriers:Specialized structures which are made up of
biologic membranes can serve as barriers to
passage of drugs at certain sites in the body:1- Blood- Brain Barrier (B.B.B) :Is a special anatomic arrangement that aims to
distribute only lipid- soluble drugs into the
brain and CSF e.g. General anesthesia.
- Drugs that are water soluble & poorly soluble in
fat are prevented from easy entry into the
brain.
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Distribution barriers
- Antibiotics that cross the B.B.B with difficulty
can NOT be used for treatment of central
nervous system infections.
-The instillation of the water soluble drugs
INTRATHECALY is done to bypass the
B.B.B and provides direct effect against
bacterial brain infection.
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Distribution barriers
2- Placental Blood Barrier: (P.B.B)
• Is the membrane layers that separate the
blood vessels of the mother from those of
the featus.
• Unlike B.B.B, the non-selective passage
of drugs across the placenta to the featus
is well-established fact ,resulting in some
hazards on faetal life.(AIDS and German
measles and malarial infection)
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Distribution barriers
Major types of drug effects occur in the
fetus:In the first trimester:One type of drug may induce harmful
development of organs & systems
(teratogenesis) during the formation of these
structures. These are known as a
teratogenic drugs, which are defined as
“agents that cause physical defects in
developing embryo like heart septal defect”.
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Distribution barriers
In the second half of pregnancy
• The second type of drugs affect the
second half of pregnancy as well as
delivery, when respiratory depression
and death may occur in the newborn
because of its inability to biotransform &
excrete the drug given to the mother.
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Metabolism
Biotransformation “Metabolism”
• Is a process that chemically inactivates a
drug by converting it to a more soluble
compound or metabolite products for
excretion from the body.
• Liver is the primary site of drug metabolism,
but other tissues also may be involved in
this process as plasma, kidney, lungs, and
the intestinal mucosa.
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Metabolism
Chemical alterations produced by enzyme
system located largely in the liver.
By this process the drug is converted to more
polar ‫ & قابل لدخول الخاليا‬more water soluble.
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Metabolism
Prolonged drug metabolism may be expected in the
following cases:1. Liver disease. (loss of hydrolyzing enzymes).
2. Renal problems. (delay of drug excretion).
3. Sever cardiovascular dysfunction. (slow blood
circulation with delayed drug removal).
4. Infant due to immature metabolizing system.
5. Old - aged persons with degenerative enzyme
function.
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EXCRETION
Is the process by which drugs and
pharmacologically active or inactive drug
metabolites are eliminated from the body,
so this process decreases the drug level in
the body gradually.
The routes of drug elimination are :1) Kidneys : The majority of drugs and/or their
metabolites are excreted through urine.
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Excretion
2) Lungs : The gases and volatile liquids as
general anaesthetics are excreted across the
lungs in the expired air.
3) Intestine: Many agents are eliminated
through the intestine in the faeces by biliary
excretion.
4) Sweat and salivary glands secretions (in
saliva , sweat and arena ‫) الحلبة‬.
5) Mammary glands transfer drugs with milk
from mother to baby.
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EXCRETION
N.B. : In renal disease, the risk of drug
accumulation and drug toxicity is increased
(some drugs and urea).
In such cases dosage is reduced for most
drugs in the presence of impaired renal
function, while “some drugs must not be
given”.
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CHAPTER THREE
Drug Onset of action ,
activity and dosage
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Onset of action
Refers to the time interval between administration
and notation of the first therapeutic effect in
body fluids.
It depends on :
1.The route of administration e.g I.V injection
has the most rapid onset of drug action.
2.The characteristics of the drug e.g solubility
of the drug and size of molecule.
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Onset of action
3. The drug’s rate of absorption through
various body membranes.
4. The formulation ‫ تركيب‬of the dose e.g fluid
form of the drug has a more rapid onset of
action than the tablet form.
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Onset of action
N.B. : The onset of action of drug is especially
variable after oral administration depending
on the:1- presence of food in the stomach.
2- motility of the G.I tract and
3- other factors ( health state of intestinal villi).
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Peak of activity
Peak of activity :
When the drug reaches its maximum effect
coincides often with peak serum concentration
High drug dose causes this peak to exceed the
optimally effective level but the concentration
can fall rapidly below this level as a result of
drug excretion.
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Peak of activity
This drop occurs especially often when a short
acting drug is given initially or intermittently.
Example : In treatment of diabetes, insulin with
various lengths of action ( short and long
acting) are mixed to keep insulin levels at a
therapeutically effective level around the clock.
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Duration: is the period between the
administration of the drug and the excretion
of the entire dose of that drug or its
metabolites.
Biologic Half-life :The time in which half the drug has been
eliminated.
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Bioavailability
It measures the concentration of the
pharmacologically active substance at the
target site and / or in the serum.
It is the function of :1. The drug itself.
2. The metabolism of the patient .
3. The rate at which the drug is liberated from
its dosage form .
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Bioavailability
Example : many drugs bind to serum protein
(albumin) from which they are released
gradually, others stored at specific site as bone
(tetracycline) from which also it is released
gradually.
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Bioavailability
Drug isn’t to be bioavilable ready for use
(unready for use) if :1. Bound to protein or to any other substance
that renders the drug permanently inactive.
2. Not released from its dosage form or site of
administration.
3. Partially or totally drug degradation.
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Factors that influence drug dosage and action
It is important for the user to be oriented of the
characteristics that modify cell conditions and therefore
modify the activity of a drug. These characteristics
include the following: 1- Age :Children and adult persons are highly responsive to
drug. Infants often have immature hepatic and renal
systems and therefore incomplete metabolic &
excretory mechanisms.
N.B. :-Old aged individuals may demonstrate different
responses to drug therapy because of deterioration of
hepatic and renal function which is often accompanied
by concurrent ‫متزامن‬disease process such as C.V.D.
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(cardiovascular disease).
Factors that influence drug dosage and action
2- Weight :The greater the weight, the greater must be
the dose.
However, body weight due to fat or edema
fluid should not be taken into consideration.
For very lean and very obese individuals,
drug dosage is frequently determined on the
basis of drug/kg of body weight or body
surface area.
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Factors that influence drug dosage and action
3- Sex :-Females don’t always respond to the action of drugs in
the same manner as do men. Women are usually smaller in weight
than men, which lead to high drug concentration if dosage is
prescribed indifferently. Female’s body is composed of higher % of
adipose tissue than males, absorption rate of drug are slower in
fatty tissue than in skeletal muscle, so the effect of drug will be
more pronounced and prolonged.
N.B. :- During pregnancy, lactation, and menstruation many drugs
are stopped like:1)Aspirin: not used during menstruation as it increases blood
fluidity.
2)Those excreted in milk don’t given during lactation as penicillins.
3)Uterine stimulants should be avoided during pregnancy as they
may produce abortion such as prostaglandin.
4) Drugs
that might affect development of fetus and placenta.
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Factors that influence drug dosage and action
4- Time of administration:Drug is more rapidly absorbed when the GIT is free of food,
while irritating drugs are more readily tolerated if there is
food in stomach.
Physiologic state:
Body resistance to drug is generally greater in the early
morning when the body is at its lowest point of physiologic
functioning and conversely, the body is more sensitive to drugs
effect during time of maximal physiological activity.
Pathologic state :Diseases alter the functional activity of tissue and accordingly
its response to drug. e.g. sever pain tends to increase patient’s
requirement to opiates and other analgesics ‫املسكنات‬.
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Factors that influence drug dosage and action
5- Environmental Milieu ‫ حميط‬:Drugs affecting mood & behavior are particularly susceptible
to the influence of the patient’s environment. Example : Heat
relaxes peripheral blood vessels (vasodilation) while coldness
has the opposite effect (vasoconstriction).
With such drugs one has to consider effects in light of
‫يف ضوء‬4 FACTORS:1)The drug itself.
2)The personality of the user.
3)The environment of the user.
4)The interaction of these 3 components.1) +2) +3)
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Factors that influence drug dosage and action
6- Genetic Factors : Genetic variation in humans was
recognized as an important determinant of individual
variability of drug response from clinical observations in
late 1950s. In these cases, patients with very high or low
plasma or urinary drug concentrations that correspond to
a specific phenotype ‫ النمط الورا ثي‬of a drug response were
identified, and the biochemical traits leading to the
variation of drug concentrations were found to be
inherited. The observation that individual variation of a
drug response is often larger among members in a
population (population variability) than within the same
person at different times (intrapatient variability) further
supports
inheritance as a major determinant of drug
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response .
CHAPTER FOUR
Channels of Drug
Administration
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Channels of Drug Administration
1- The oral route : The first and most convenient mean
is the oral route i.e. the patient usually swallows the drug,
which then enters the gastrointestinal tract and absorbed
from that area.
Advantages:1. This route accounts for 80% of all medications
administered to patients.
2. Doctors usually decide the amount and frequency and the
patient administer the drug to himself.
3. The cost of medication and therapy is low.
4. Oral administration is painless and there is no necessity to
practice sterile technique .
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Channels of Drug Administration
Disadvantages of oral administration:1. Inconsistent ‫ متغير‬,‫ غير مستقر‬absorption from the gastrointestinal
tract.
2. Blood level may vary among different patients because of
different GI characteristics e.g. acidity, gastric motility &
intestinal mucosa.
Patients that can’t be given the drug by oral route:1- Drug irritation that causes nausea & vomiting.
2- Unconscious patients.
3- Some infants and children that refuse swallowing of the drug.
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Channels of Drug Administration
2- Parenteral Route ( mainly injection):The next most popular route of drug administration.
The word parenteral indicates that the drug is administered by a
route other than mouth route , common agreement has come to
indicate the injectable route.
Advantages :1. Useful for drugs that cannot be given through GIT.
2. Eliminate the unpredictability of absorption from GIT i.e. the
amount of drug will be delivered to the patient from injection site.
3. Medication can be given to an unconscious patient.
Disadvantages :1. Need sterile technique.
2. More expensive than oral preparations.
3. Patient usually not able to medicate himself especially when
medication needs to be injected deep into a muscle.
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Channels of Drug Administration
4- Accidental penetration of blood vessel , causing
extravascular haematoma and irritation.
There are a number of techniques for administration of drugs
by injection, these are related to the target area of the
injection: -
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Channels of Drug Injection
A- Subcutaneous Injection:-(S.C.I)
S.C injection is administration of a drug into the subcutaneous
tissues.
advantage :slow drug absorption (insulin injection)
Disadvantages:1-The most painful route.
2- Not effective in emergency (poor blood supply as in shock ).
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Channels of Drug Administration
B- Intramuscular Route:- IM
Administering of a quantity of medication through a needle into a
skeletal muscle . It is the second most widely used route for injectable
drugs.
Advantages :
1. Suitable for administration of both solutions and
suspensions.
2. Drugs that are very water insoluble can be given I.M in an
oily base. (Remain for an extended period of time).
3. Has greater vascular network than S.C, so drug
absorption is more quick than S.C route. Less painful
(less nerve supply than skin ).
Disadvantages:
1. Painful injection.
2. Injury to some nerves (sciatic nerve).
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3. Sometimes
bloody injection occurs.
Intramuscular Route
88
Channels of Drug Administration
C- Intravenous Injection :- I.V.I
Administering of a quantity of medication directly through a needle into the
circulation. 2 methods of intravenous injection are used :A. Administering the drug as a bolus.
B. Continuous infusion of a drug, which is called I.V drip.
Advantages of I.V.I.:1. To achieve highly, accurate and quick blood level.
2. A channel to administer drugs that irritate another sites e.g. chemotherapy.
3. Less painful during drug administration.
Disadvantages:1. Accidental overdose, and there is no way to withdraw the drug from
circulation once it is injected.
2. Infiltrating the area around the vein i.e. needle slip out of the vein .
3. Thrombophlebitis from repeated injections. To minimize this phenomena
(but doesn’t exclude it), drug should be given I.V. drip.
4. Inadvertent ‫غير متعمد‬intra-arterial injection instead of a vein.
89
Infiltrating the area around the vein
90
Thrombophlebitis
91
Channels of Drug Administration
D- & E- Intradermal (I.D) and Intrathecal
administration:a- I.D is a route of administration in which the drug is
injected just below the epidermis.
- Injection is usually used for allergy tuberculin test , for
T.B tests and for penicillin sensitivity test.
b- Intrathecal route of administration involves inserting
a needle between 2 vertebrae and injecting the drug in
the subarachnoid space into the CSF.
Used frequently when anesthetist desires to produce a
spinal block for surgeries in the lower half of the body
and inject local anesthetic directly into the cerebrospinal
fluid.
92
Intrathecal route
93
Channels of Drug Administration
Rectal, urethral and vaginal suppositories:Another route of administration that is quite useful when:1) The oral route can’t be used.
2) The physician desires not to use the injectable drug route .
3) When self-medication other than per mouth is desired, the
rectal route of administration is used.
Disadvantages:1) Erratic absorption from the rectal area results in an inaccurate
predicted blood level of drug so the dosage must be adjusted.
2) Rectal route is ineffective when the patient suffers from diarrhea.
Examples:1) Rectal supp. ___ used to treat hemorrhoids.
2) Vaginal supp.____ used to treat vaginitis.
3) Urethral supp.___ used to treat urinary bladder conditions.
94
suppositories
95
Channels of Drug Administration
Topical route
Is intended for use at the site of administration . Two topical
preparations are frequently confused with each other ( ointment and
creams).
Ointments:Are usually made up of a petrolatum type of base.
They are quite greasy, as they intended for prolonged contact with the
skin.
They don’t disappear or penetrate the skin, but remain on the surface.
Creams:Made of viscous water-soluble chemicals, which usually disappear after
being placed to the skin.
Patient prefers cream to ointment, as creams don’t discolor clothing.
96
CHAPTER FIVE
How do drugs work?
97
How do drugs work?
In spite of a great deal of research, it is still not known how some drugs
produce their effect, but it is possible to describe the way in which some of
them act.
1-The receptor theory:It is believed that the cells in certain tissues contain structures
(called receptors). These receptors combine with substances, which
are produced naturally in the body as well as certain drugs.
The drugs stimulate the receptors which will cause the cells to be
stimulated. The contraction of muscle fibers produced by
acetylcholine is an example.
The drug is thought to fit into a receptor rather as a key fits a lock.
It may then either stimulate the receptor and produce an effect
similar to that of the naturally occurring substance or it may occupy
the receptor without producing any effect but preventing any
naturally occurring stimulation to take place (the blocking of
acetylcholine by atropine is a good example).
98
Receptors
99
100
How do drugs work?
2- Antimetabolites:These drugs closely resemble substances which are used
by the cells for nutrition and when absorbed, the cells
cannot use them and so fail to multiply.
The sulfonamides which are used to stop the multiplication
of bacteria are a good example.
They are very similar in structure to para-aminobenzoic acid
and certain bacteria can’t distinguish between them, and
absorb the sulfonamide so bacterial growth and
multiplication is stopped.
101
How do drugs work?
3- Enzyme Inhibitors:Enzymes are substances that speed up many chemical processes within
the body. Some of these enzyme-activated processes are concerned
with the transport of chemicals in and out of the cells. Certain drugs
have the property of inhibiting their action and thus interfere with some
of these processes.
Diuretics are a good example , as normally salt and water is transported
out of the renal tubules back into the body, but this action requires
certain enzymes which if are inhibited by a diuretic, salt and water are
not reabsorbed and pass out of the kidney with a resulting diuresis that
results in lowering of arterial blood pressure.
4-Action on cell membranes:The function of nerves and muscles depends on ions passing across the
membranes surrounding these cells. Certain drugs interfere with
movement of these ions and thus prevent nerve or muscle function as
demonstrated by local anesthetics which block impulses passing up a
102
sensory
nerve.
103
104
How do drugs work?
5-Cytotoxic Effect:Drugs may be used to kill bacteria
or malignant cells without undue
‫ غير ضروري‬damage to the patient’s
cells. These are just a few of the
ways in which drugs may work. It is
probable that all drug action
depends on their interference with
cell activity and when more is
known about the processes within
the cell, then more will be
discovered about how do drugs
work.
105
CHAPTER SIX
Side effects and drug toxicity
106
Side effects and drug toxicity
1- Serious Side Effects
In addition to common side effects, many drugs cause dangerous
side effects. If a drug has numerous problems, the FDA can add
warnings to the drug’s label, including its stringent ‫صارم‬black-box
warning. In rare cases, the drug is recalled or removed from the
market.
Death from deadly cancer or fatal heart attacks, some prescription
drugs have been known to cause either slow or immediate death.
Sometimes prescription drugs such as penicillin stimulate allergic
reactions that cause anything from itching to an anaphylactic
response, which can lead to death. Other drugs may cause patients
to do things they wouldn’t ordinarily consider, including suicide.
Drugs such as Accutane and some antidepressants have been linked
to suicidal thoughts or actions .
107
Side effects and drug toxicity
2- Physical Debilitation ‫الوهن الجسدي‬
Many drugs can be physically and emotionally debilitating,
including causing total or partial paralysis or severe pain.
This includes headaches, stomachache, joint and muscle
pain and decreased control over bodily functions.
Sometimes these side effects are caused by the drug’s
numbing effect on the area of the brain responsible for pain
perception. Lipitor, a commonly prescribed
hypocholesteraemic medication, is linked to unexpected
muscle pain and loss of muscle coordination.
108
Side effects and drug toxicity
3- Heart Conditions
Problems related to the heart, including heart
attacks, congestive heart failure, lifelong heart
damage and cardiomyopathy, have been linked to
many prescription drugs. Sometimes, the drugs
cause an increase in water-weight gain, which
causes heart failure or a heart attack. Such is the
case with Avandia and its sister drug, Actos.
Other drugs, including the painkiller Celebrex,
have been proven to be so risky that doctors
refuse to prescribe it for long-term use.
109
Side effects and drug toxicity
4- Stroke
‫السكتة الدماغية‬
Described as the rapid loss of brain function due to a blood
flow disturbance, strokes have been linked to several kinds
of prescription drugs. In some cases, the drugs cause
blood clots to form. When these clots move through the
body, they can block the blood flow to the
brain(embolism).
Some antipsychotic drugs, including drugs used in
Alzheimer’s treatment such as Risperdal, are linked to
strokes. Other drugs, including the painkiller Vioxx, are
also linked to stroke.
110
5- Cancer
Side effects and drug toxicity
Probably one of the most shocking and overwhelming ‫ساحق‬
side effects of prescription drugs is cancer. Perhaps that’s
because most people spend their lives avoiding known
carcinogens, such as cigarette smoking. When patients
learn that their prescription drugs can be carcinogenic, they
feel angry and mislead.
1- One of the most shocking medication-cancer connections
came when Tamoxifen, a drug used to treat breast cancer,
was found to increase the risk of uterine cancer.
2- In addition, Actos a drug that is supposed to alleviate
diabetes symptoms, is linked to an 80 percent increased risk
of bladder cancer in those taking the drug two years or
longer.
111
Side effects and drug toxicity
6- Other significant side effects : Some drugs have
been linked to other significant side effects, including
losing the sense of taste, amnesia,‫ فقدان الذاكرة‬sight loss
and hallucinations. For all patients, the best way to
combat all of these problems is to carefully read the
drug’s label.
7- gastrointestinal effects :Possibly the most
common side effects of any prescription drug is
gastrointestinal issues, including nausea, vomiting ‫و‬
constipation and diarrhea, because most drugs go
through the digestive system to be absorbed. Other
common after effects include drowsiness, pain and skin
reactions.
112
Side effects and drug toxicity
6- Other significant side effects : Some drugs have
been linked to other significant side effects, including
losing the sense of taste, amnesia,‫ فقدان الذاكرة‬sight loss and
hallucinations. For all patients, the best way to combat all
of these problems is to carefully read the drug’s label.
7- Gastrointestinal effects :Possibly the most common
side effects of any prescription drug is gastrointestinal
issues, including nausea, constipation and diarrhea,
because most drugs go through the digestive system to
be absorbed. Other common aftereffects include
drowsiness, pain and skin reactions.
113
Common Side Effects
8- Dizziness ‫الدوخة‬
While dizziness may not seem like a serious side
effect, it can have grave consequences. For
elderly patients or those already unsteady on their
feet, random dizziness can cause a fall that could
lead to broken bones.
For the elderly, especially those who are already
battling other medical problems, a broken hip can
take a deadly fracture of neck femur .‫الكسر القاتل‬
Because dizziness is a common side effect of
most prescription drugs, patients should be acutely
aware of any vertigo-like ‫تشبه الدوار‬feelings.
114
115
Common Side Effects
9- Nausea
While nausea and vomiting aren’t considered
deadly side effects, they can cause a cascade
of‫ تتالي‬medical problems, especially in the elderly
or those already weakened by a disease. The
resulting dehydration, internal bleeding and
esophageal rupture can result in death.
Chemotherapy drugs, which are aimed at
treating cancer, are known to cause severe
nausea and vomiting as like as antirheumatics .
116
Side effects and drug toxicity
10- Allergic reactions can happen with any
drug or food and can range from itching and rash.
up to a life-threatening anaphylactic shock.
Penicillins, aspirin, and sulfonamides account for over
80 percent of allergic drug reactions.
Approximately 1 to 3 percent of patient courses of
penicillin are complicated by allergic reactions.
117
11- Appetite Loss
Loss of interest in eating can come from many different
drugs when they either directly suppress appetite or create
changes in the sense of smell or taste which indirectly
cause the disinterest. It can also occur when drugs are
causing nausea that makes the very thought of eating
impossible . Although discontinuing the offending drug will
usually quickly solve the problem, this is often not a
possibility so other approaches are needed . First, consider
the other causes that might also be contributing:
1. Infections and fever (treat them).
2. Abnormal levels of hormones (especially testosterone
which can be replaced if testing determines that its levels
are low).
‘
118
12- Diarrhea
Diarrhea an increase in the frequency and decrease in
consistency of stools can be caused by many antiretrovirals
drugs.
This is an important side effect to keep in check, and any
diarrhea that is frequent, watery or lasts for more than a
couple of days should always be reported to your doctor.
The two medications most commonly reported to cause
diarrhea are the protease inhibitors nelfinavir (Viracept) and
ritonavir anti-herpes drug acyclovir (Zovirax) many
antibiotics and other medicatons.
In other words, a large number of medications can be
implicated in the problem of diarrhea. If the onset or sudden
worsening of diarrhea is tied closely to beginning a medicine,
it’s a likely suspect.
119
Side effects and drug toxicity
13- Gas and Bloating :The smelly intestinal
gas and abdominal bloating that any of the
protease inhibitors can cause will usually
disappear quickly if the offending drugs are
discontinued, but often continue unabated ‫دون‬
‫ إنقطاع‬for as long as the drugs are taken. Where
discontinuation is not desirable or possible, it
was found that taking pancreatic enzymes (one
or more, taken with every meal or snack) can
often eliminate the problem.
120
Side effects and drug toxicity
14- Headaches
Some people develop headaches as a result of drug side
effects. In some cases, these will only occur during the
beginning of drug therapy, and will gradually disappear
over the next few weeks. In others, they may remain longterm, and the only solution may be a drug switch.
Medications should be particularly suspected as a
headache cause when a new drug treatment has recently
been started, but note that such reactions can occur even
after months of using a particular drug. Headaches can
also be a symptom of many different infections and
conditions, some of which could be fatal if undiagnosed.
121
Side effects and drug toxicity
14- Headaches
Many drugs can induce acute headache, including
nitroglycerin,(Nitroglycerin spray and tablets are used to
treat episodes of angina (chest pain) in people who have
coronary artery disease) , antihypertensive agents ,
histamine receptor antagonists (e.g., cimetidine and
ranitidine), Non Steroidal Anti-inflammatory Drugs
(especially indomethacin), cyclosporine, and antibiotics
(especially griseofulvin, tetracycline, and
sulfonamides).
122
Side effects and drug toxicity
15- Muscle aches and pains :
Symptoms that can develop in the musculoskeletal
system of Human Immunodeficiency Virus (HIV) infected
persons include:
1. muscle pains (myalgias).
2. joint pains (arthralgias).
3. muscle damage that can result in aches, pains, and
weakness (myopathy).
4. muscle cramping.
123
Side effects and drug toxicity
16- Sexual Difficulties
1. Loss of sexual interest (decreased libido).
2. Erectile difficulties in men.
3. Difficulties in reaching orgasm in both men and women
are frequently ignored side effects of some medications.
Sexual difficulties have been reported in some people taking
protease inhibitors,(‫ )مضادات فيروس األيدز‬although more research
is needed to show whether the drugs are really the cause of
the problems.
124
CHAPTER NINE
General Guidelines For
Handling Medications
125
General Guidelines For Handling Medications
1. When preparing or giving medicines, concentrate your whole
attention on what you are doing.
2. Make certain that you have a written order for every medication
you will dispense.
3. Read the label before taking, using and returning the drug to its
place.
4. All medicines should be labeled and the label should be clear.
5. Never give medicine from unlabeled container.
6. Measure quantities and calculate doses as ordered in proper
way.
7. Handling tablets, capsules and pills properly and DO’NOT
touch with fingers. Use the cap of the container to guide or from
126 container to the cup directly.
the
General Guidelines For Handling Medications
8. Avoid wastage of medicine.
Some preparations as insulin, vaccines & suppositories need to be kept in
the refrigerator.
10. Stay with the patient until he takes his medicine.
11. All mixtures should be made immediately before use.
12. NEVER return unused drug to a stock bottle.
13. Don’t use any sterile article become unsterile by any way.
14. Don’t use clear solutions which has became cloudy or has a
9.
sediment.
15.
16.
17.
18.
Don’t use a drug that is out date.
Don’t use a drug that has change its color.
Don’t use a drug which arise doubt in mind.
All medicines should be kept in cupboard ‫ الدوالب‬NARCOTICS in a
127
locked one.
General Guidelines For Handling Medications
19. Narcotics has a rule controlling their ordering , giving , and their
registration.
20. Many liquids should be diluted with water or other liquids. “this is
especially in powdered drugs before use.
21. Exception to this rule, cough medicines are not diluted, or the
patient not allowed to drink water after taking cough syrup.
22. Never chart a medicine as having been given, until it has been
administered.
23. Follow up the five rights
A.
B.
C.
D.
E.
Right patient.
Right drug.
Right dose.
Right route of administration.
Right time.
128
Part II
EYE DRUGS DIAGNOSTIC
AND THERAPEUTIC
129
CHAPTER TEN
Ocular Pharmacology of
PHARMACODYNAMICS
PHARMACOKINETICS
CLASSES OF ANTIBACTERIAL
AGENTS
130
Ocular Pharmacology of
Antibacterial Agents
The selection of an antibiotic to treat an ocular
infection is based on several factors
including:1-The likely ‫ المحتملة‬organisms and their historic
susceptibilities. ‫س ِت ْعداد‬
ْ ِ‫أ ُ ْهبَة ; ا‬
2-The host immunity.
3-The properties of the drug.
In all serious infections, attempts to identify
the organism through culturing, or other
methods should be completed before initiating
treatment.
131
Ocular Pharmacology of
Antibacterial Agents
Features of the host include:
1.
2.
3.
4.
5.
The immune status,
Site of the infection,
History of drug allergies,
Drug interactions ‫تَفَاعُل االدوية‬,
Special concerns ‫ المخاوف‬such as age or
pregnancy, and
6. The host's ability to absorb and metabolize
the drug.
132
Ocular Pharmacology of
Antibacterial Agents
Features of the drug include:
1. Its pharmacodynamics or interaction between the
drug and the infecting organism.
2. Its pharmacokinetics or interaction between the
host and the drug.
3. Its effects on immunity.
4. Its adverse ‫ار‬
ّ ‫ ِض‬effects.
5. Treatment costs.
6. Concerns for antibiotic resistance .
133
Ocular Pharmacology of
Antibacterial Agents
Features of the organism:
1.Bacterial resistance is due to a variety of
mechanisms that aim at disrupting the antimicrobial
mechanism of action increasing resistance of ocular
pathogens represents an important therapeutic
challenge.
Antibiotic resistance is caused, paradoxically, by
both overuse and underuse.
Example of overuse :The result of the overuse of
antibiotics for systemic use, ophthalmic use, and in
poultry and livestock ‫ أَ ْنعام‬feed, is an increasing
number of bacterial strains that are stronger than the
antibiotics being used against them. (overuse).
134
Ocular Pharmacology of
Antibacterial Agents
• Example of underuse : especially in
developing countries, resistance often
develops when people stop taking their
medication as soon as they feel better.
(underuse).
135
The minimal inhibitory
concentration (MIC)
• Is the lowest concentration of an antimicrobial agent
that prevents (inhibits) visible growth of bacteria after
a period of incubation in vitro ( an artificial
environment i.e. test tube) .
•
The MIC90 is the concentration at which 90% of the
isolates by genus ‫الجنس‬and species ‫األنواع‬are inhibited
(not killed).
• For antimicrobial therapy to be effective , it is believed
that a drug should, at a minimum, reach a
concentration that at least exceeds the MIC90 of the
target organism.
136
The minimal inhibitory concentration
breakpoint (MICBP)
• The MIC breakpoint ‫( نقطة الحسم‬MICBP) of a drug
is a yardstick ‫المقياس‬against which the MIC for
an infecting organism can be compared.
• The MICBP ‫ نقطة الحسم‬is that MIC separating
susceptibility from resistance and is typically
the concentration of a drug that is achieved
reasonably ( rationally, logically) in the serum
or tissue.
137
The minimal inhibitory
concentration (MIC)
• An organism is considered susceptible (S) if its MIC is
one fourth (1/4) the peak drug concentration that will
be achieved using the recommended dose ( full dose )
of a drug.
• If the MIC of the organism equals 1/16 the peak drug
concentration that will be achieved using the
recommended dose of a drug the organism is
considered resistant (R).
• The breakpoints in defining bacterial resistance
are based on what can be achieved with systemic
therapy, and therefore they may not always reflect
ocular levels.
138
139
The minimal bactericidal
concentration (MBC)
• The minimal bactericidal concentration
(MBC) is the lowest concentration of
antimicrobial that totally suppresses
growth on antibiotic-free media or that
results in a 99.9% reduction or greater
decline ‫سار‬
َ ‫ اِ ْن ِح‬in colony counts after
overnight incubation.
140
• Bactericidal drugs : Are defined as drugs
whose MIC is very close to the MBC. However,
the bactericidal effects of a drug depend on
achieving sufficient concentration of the drug at
the antimicrobial target tissue.
• Bacteriostatic : drug is a drug whose MBC is
more than 16-fold greater than the MIC.
• It is important to note that bactericidal drugs
can be rendered bacteriostatic should
insufficient concentrations be reached.
141
‫من هنا‬
‫‪142‬‬
CHAPTER NINE
Entry of drugs into the eye
143
Drugs and Eye
The eye is one of the few structures that can
be considered pharmacokinetically separate
from the body. This separation is possible
because of two main factors:
(1) Absorption occurs directly into the eye
before reaching the systemic circulation.
(2) Elimination occurs directly into the body,
which can be considered a large reservoir that
can dilute drug concentration in plasma below
a therapeutic threshold. ‫تحت المستوى المطلوب‬
144
There are five barriers to the
entry of drugs into the eye
1-Corneal epithelium restricts the entry of
water-soluble drugs into the cornea and
aqueous humour. The barrier is breached
by ‫ترق‬
ْ ‫( ي َخ‬overcome) epithelial defect or, if
the epithelium is intact , it is bypassed by
a-subconjunctival injection , or
b- adding the drug to lipid base as vehicle.
145
barriers to the entry of drugs into
the eye
2-Conjunctiva/sclera
• Compared to the cornea, the conjunctiva and
the anterior sclera have a much larger area
and are more permeable to water-soluble
drugs.
• However, drug loss by uptake into the
conjunctiva in the blood stream is important
in reducing the fraction of drug available for
corneal absorption.
146
barriers to the entry of drugs into
the eye
3-Aqueous-vitreous barrier (intact
lens
and zonules )
Bulk flow of aqueous humor from the eye
and the presence of an intact lens and
zonules retard the diffusion of drugs from
the anterior chamber into the vitreous
humor.
147
148
barriers to the entry of drugs into
the eye
4- Blood-aqueous barrier
Tight junctions of the iridal vasculature
endothelial cells limit entry into the
aqueous from the blood for systemic
taken drugs.
The epithelium of the iris and ciliary body
pump anionic drugs ( ion with negative
charge) from the aqueous into the
blood stream.
149
150
barriers to the entry of drugs into
the eye
5-Blood-retinal barrier
• Tight junctions of the retinal vasculature limit the
entry of drugs into the eye from the systemic
circulation (internal).
• The pigment epithelial barrier also limits flow
into the eye i.e from choroid to retina (external).
• There is an outward pumping of ions with
positive charge (cations) across the retina to
blood stream by the retinal pigment epithelium
and the endothelial cells of the retinal vessels.
151
152
Retina
Diagram B Layers
•
Internal
Limiting
membrane
External
Limiting
membrane
153
Drug target sites inside the eye(4)
‫المناطق التي يعمل عليها الدواء داخل العين‬
In terms of drug delivery, the eye can
be considered to have four target sites:
(1)the pre-ocular structures of the front of
the eye, such as the conjunctiva and
eyelids.
(2) the cornea.
(3) the anterior and posterior chambers
and associated tissues.
(4) the vitreous cavity.
154
Four target sites
• Topical administration to the front of the eye
can be used to deliver pharmacologic agents
to the preocular, corneal, and
anterior/posterior chambers, but this method
is presently rarely used to deliver drugs to the
vitreous cavity.
• Systemic administration or more commonly,
intraocular injection is used to deliver drugs
to treat disorders associated with the vitreous
cavity.
155
Four target sites
A factor that influences drug availability to the
three anterior ocular target sites following
topical ocular administration is retention of
the antibiotic in the preocular area.
The volume of tears in the eye is approximately
9 μL, most of which resides in the
conjunctival sacs, with approximately 1 μL
covering the cornea with the tear film .
156
TOPICAL ANTIBIOTICS
• The antibiotic must be present in the tear film
in amounts above the Minimal Inhibitory
Concentration (MIC) values of the pathogen
for a significant amount of time to produce
microbiological and clinical improvement or
cure.
• When the target site is intraocular, drug
must be absorbed from the preocular region
into the eye via the cornea.
157
TOPICAL ANTIBIOTICS
For drug delivery, the cornea can be considered to
be composed of three layers:
• The epithelium,
• stroma, and
• endothelium.
Bowman's layer and Descemet's membrane are
important anatomically but not significant ratedetermining barriers.
Drugs penetrate the outer epithelium either by
partitioning through the cells (intracellular) or by
passing between the cells (intercellular).
158
159
TOPICAL ANTIBIOTICS
Most drugs penetrate the cornea via the
intracellular route, although the
intercellular route predominates for
hydrophilic drugs.
It has been shown that for lipophilic
compounds, the lipophilic epithelium
offers little resistance to absorption and
the major barrier is passage across the
hydrophilic stroma and the
endothelium.
160
TOPICAL ANTIBIOTICS
For hydrophilic compounds, the major
barrier is the outer lipophilic epithelium,
whereas the hydrophilic stroma offers
little resistance to drug absorption.
In reality, a gradient is established
across the cornea, with different
concentrations of drug in the different
layers of the cornea.
161
Drug gradient is established across the cornea
162
TOPICAL ANTIBIOTICS
Antibacterial concentrations at the site of
infection of the cornea may, be either
considerably higher than corneal
concentrations (if organisms are
superficially located in the cornea) or
significantly lower corneal concentrations if
organisms are deeply located.
163
TOPICAL ANTIBIOTICS
The corneal route has always been
assumed to be the major route of entry
into the eye; however, recent evidence
suggests that penetration across the
conjunctiva and sclera may also
contribute significantly to penetration
into the anterior chamber. (minor route(
164
Factors Affecting Absorption
of TOPICAL ANTIBIOTICS
1- The solubility :Lipophilic antibiotics, such
as chloramphenicol, penetrate the intact
corneal epithelium more easily than do nonlipophilic antibiotics ,such as gentamicin.
2- pH of a topical antibiotic preparation are
important factors affecting drug absorption.
For example, when ciprofloxacin, more soluble at pH
4.5, comes into contact with tear film at neutral pH
(7), its solubility equilibrium is decreased, and
there is a tendency for the drug to precipitate in
the conjunctival sac.
165
Factors Affecting Absorption of
TOPICAL ANTIBIOTICS
3-Increasing the concentration (but not the
volume) of an antimicrobial eye drop will
increase the level of drug in the precorneal
tear film and, therefore, in the aqueous and
internal ocular tissues. Hypertonic eyedrops
dilute drug from the tear film more rapidly than
do less concentrated ones as a result of the
osmotic effect through the conjunctiva.
4- Abrasion or inflammation of the cornea
Higher corneal concentrations of drug are
َ ‫ش‬
achieved in abraded ‫ط‬
َ ‫ ; َك‬or inflamed corneas
than in normal ones.
166
Factors Affecting Absorption of
TOPICAL ANTIBIOTICS
However, with epithelium absent, as is the case
with most infectious corneal ulcers, the
epithelial barrier is eliminated, and
hydrophilic antibiotics may enter the corneal
stroma more easily.
For instance, topical ciprofloxacin (hydrophilic
antibiotic ) drops achieve anterior chamber
levels 2 to 3 times greater if the epithelium is
compromised (defective) than if it is intact.
167
Corneal ulcers
Viral
168
Bacterial
Distribution of TOPICAL ANTIBIOTICS
Factors interfering with distribution of drugs
inside the eye include:
1. Binding to melanin in the iris and the ciliary
body.
2. Binding to protein in the aqueous humor .
3. Rapid elimination of drug to an inactive site that
can act as a biological reservoir‫ح ْوض‬
َ , releasing
drug slowly over time like conjunctival sac
fornices.
169
Ocular drug metabolism and
elimination
• The time between drug instillation and its
appearance in the aqueous humor is the lag ;
ُ ‫ تَبَا‬time.
‫طؤ‬
• Once drugs are absorbed into the anterior
chamber, they are eliminated primarily by
aqueous humor turnover ‫( االستبدال‬through the
trabecular meshwork in the angle of A.C),
which is 1.5% per minute of the anterior
chamber volume.
• When expressed as a half-life, aqueous
170 turnover is 46.2 minutes, or 0.77 hours.
171
Metabolism and Elimination
1.Therefore, if drugs with a half-life of approximately
45 minutes (e.g., tobramycin) are eliminated from
the eye, their elimination can be explained as
normal elimination.
2.For drugs with a half-life of longer than 45
minutes, strong tissue binding is likely responsible
for the longer half-life. (slow elimination).
3. If the half-life for a drug is less than 45 minutes,
metabolism and uptake by blood vessels in the
anterior uvea or iris are other likely pathways for
elimination of drugs. (rapid elimination).
172
Metabolism and Elimination
4. Several antibacterials, including chloramphenicol and
fluoroquinolones, penetrate the cornea sufficiently
rapidly to achieve potentially therapeutic concentrations
in the aqueous humour if applied frequently.
5. However, the constant flow of aqueous from the
ciliary processes, where it is secreted, through
the posterior and anterior chambers and out of
the eye via Schlemm's canal, prevents the
accumulation of high concentrations of
antibacterials at this site i.e the drug undergoes
turnover with the aqueous.
173
Metabolism and Elimination
6. Some absorption of antibacterials from the
aqueous by the anterior uvea and lens is
inevitable but not well characterized.
7. Concentrations achieved in the vitreous body
following topical administration are generally
subtherapeutic , necessitating the administration
of antibacterials by local intravitreal injection for
patients with infectious endophthalmitis.
174
PERIOCULAR INJECTION
‫الحقن تحت الملتحمة‬
In general, hydrophilic drugs are more effective
when given by the subconjunctival route.
Absorption occurs from the reservoir of drugs
at the conjunctival depot, which is not
subject to precorneal factors as in topical
application.
Also, a subconjunctival drug bypasses the
conjunctival epithelium, a significant ratedetermining barrier for water-soluble drugs.
175
ADVANTAGES OF PERIOCULAR
INJECTION
1-Conjunctival route of administration often
provides therapeutically effective drug
levels in aqueous for 8 to 12 hours after a
single injection.
2-In studies of subconjunctival injections of
third-generation cephalosporins, the
corneal levels achieved were fourfold
higher than levels in aqueous concentrations.
Corneal 4 :
176
Aqueous 1
Periocular injection
Intravitreal
injection
177
PERIOCULAR INJECTION
3-Concentrations in the choroid were fivefold
to 15-fold higher than for the retina.
Choroid 15 : retina 1
4- Retinal concentrations were about tenfold
higher than vitreous cavity.retina10: vitreous 1
5-Thus, there is a significant concentration
gradient ‫ تدرج‬from choroid to retina and from
retina to vitreous.
178
PERIOCULAR INJECTION
This report suggested that subconjunctival
injections cannot replace intravitreal injections
in the treatment of endophthalmitis.
Similarly, subconjunctival injections are not
as efficient as frequent topical application in
treating keratitis and should be limited to
situations where topical therapy is limited (eg,
when the eye is patched ‫مغطاة‬or in
uncooperative or noncompliant ‫غير‬
‫مطاوع‬patients .
179
The selection of a periocular or
topical route
The selection of a periocular or intraocular route of
administration depends on the:
1- Ability of the drug to penetrate the cornea.
2- The location of the target site.
a.In general, lids and lid margins are best treated
with ointments ,
b.whereas the conjunctiva , limbus, cornea, and
anterior chamber are treated most effectively
by topical instillation of solutions or
suspensions eye drops.
c. if unresponsive, by subconjunctival injection.
180
SYSTEMIC ADMINISTRATION
Drugs administered systemically penetrate
the aqueous and vitreous humour with difficulty
because of anatomic blood aqueous(BAB) and
retinal barriers (BRB).
Penetration into the aqueous humour is
restricted by the blood-aqueous barrier (BAB),
which exists because the endothelium overlying
the capillaries of the iris and ciliary body has
tight intracellular junctions.
181
SYSTEMIC ADMINISTRATION
Penetration into the vitreous humour is
limited because the endothelial cells of the
retinal capillaries and the retinal pigment
epithelium (RPE) cells overlying the
choroidal capillaries have tight junctions;
together, these constitute the blood-retinal
barriers.
182
SYSTEMIC ADMINISTRATION
By removing the lens and vitreous,
topically administered drugs can readily
enter the vitreous cavity through both the
anterior and posterior chambers.
Inflammation can also increase the
antimicrobial penetration into the vitreous
cavity.
183
Chapter TEN
Factors affecting the
choice of diagnostic drugs
184
CLASSIFICATION OF OPHTHALMIC
DRUGS
• Cycloplegics : this group has suffered some
attrition and, from an original list of seven
agents, only four now remain, and one of these
has little to recommend it.
• Mydriatic : from a long list of agents that have
been used to dilate the pupil, only two are now
seriously considered for optometric use. More
potent mydriatics are used prior to surgery.
• Miotics : the greatest losses have occurred from
this group. Miotics have a dual use, being
therapeutic and diagnostic.
185
CLASSIFICATION OF OPHTHALMIC
DRUGS
• Local anaesthetics : despite the use of the noncontact tonometer, the range of local anaesthetics has
remained fairly steady. Cocaine, which was never
really an option as far as the optometrist was
concerned, is now rarely used medically because
better agents are available.
• Stains: this is one area that, at one time, appeared to
have growth. Nowadays, two stains are used routinely,
and the use of one far exceeds the other.
186
ADVANTAGES AND DISADVANTAGES OF
USING DIAGNOSTIC DRUGS
There are three possible advantages of using
diagnostic drugs. If none of these applies, the
optometrist should seriously question whether
it is necessary to use a drug at all:
1- Easier on the patient : this certainly applies
when the procedure involves a local
anaesthetic. However, for other agents, if the use
of a diagnostic drug will allow the examination to
be carried out quicker and more efficiently, then
this will be to the patient’s advantage.
187
CHOICE OF OPHTHALMIC DRUGS
2- Easier for the practitioner : the use of an agent
will often facilitate the examination, especially
in the case of mydriatics and cycloplegics.
3- Better examination : again, in the case of
mydriatics and cycloplegics, the results
obtained will often be more valuable.
188
CHOICE OF OPHTHALMIC DRUGS
Against these advantages, must be weighed
several disadvantages:
1- The eye is in an artificial state : this must be
allowed for when carrying out certain tests.
2-The latent period : this can be short (e.g. local
anaesthetics) but sometimes long enough to
inconvenience ‫إزعاج‬the patient and, in the case of
atropine, would require the drug’s administration
at home by the parent.
3- Prolonged duration of action : prolonged
cycloplegia for a child at school, or mydriasis
for a driver, can seriously inconvenience the
patient.
189
Adverse effects of ophthalmic drugs
Adverse effects of ophthalmic drugs :
1- Local adverse effects : these can be as mild as
stinging on instillation or as severe as angleclosure glaucoma. Only acute problems need be
considered as the drugs are not used chronically.
2- Systemic adverse effects : many diagnostic
drugs are potent modifiers of the autonomic
nervous system and are capable of causing
effects on autonomically innervated structures.
190
IDEAL PROPERTIES OF DIAGNOSTIC DRUGS
In light of the preceding discussion, the ideal diagnostic
drug would have the following properties:1.It should be available: unfortunately excellent drugs,
such as atropine ointment, are no longer commercially
produced .
2.It should produce the desired depth of effect: for some
indications the maximum effect would be excessive and
inconvenience the patient unnecessarily,
3.Its action should be fast in onset : time waiting for the
drug to become effective is time wasted for both the patient
and practitioner.
4.Its action should be short in duration.
5.The drug should have no unwanted pharmacological
effects.
191
IDEAL PROPERTIES OF DIAGNOSTIC DRUGS
6. It should have no local or systemic toxic effects.
7. It should be pleasant and easy to use.
8.It should be capable of being produced in stable and
sterile ophthalmic form that is appropriate to the use for
which it is intended: a cycloplegic ointment would make
retinoscopy difficult if it was used.
Every patient is different and the advantages and
disadvantages of a proposed drug must be weighed in
the light of the particular patient immediately prior to
the examination.
192
SELECTION OF PATIENTS
In particular, the following questions should be
addressed:
1. Will the patient benefit from the use of a particular
diagnostic drug?
2.Has the particular drug been applied to this patient
before?
3. If so, were there any adverse reactions or allergic
responses?
4. Is the patient suffering from any ocular condition that
would make the use of this drug inadvisable? high I.O.P
5. Are there any systemic conditions that would be
contraindications for the drug’s use? like systemic
hypertension or diabetes mellitus.
6.Is the patient currently taking any medicine that could
interact with the diagnostic drug? Drug interaction.
193
Chapter-Eleven
Diagnostic drugs and
products
used in optometry
194
Diagnostic drugs and products
used in optometry
Cycloplegics
Cycloplegics are drugs that paralyze the ciliary muscle by blocking
the muscarinic receptors that are normally stimulated by the release of
acetylcholine from the nerve endings of the parasympathetic system.
As the parasympathetic nervous system also innervates the pupil
sphincter muscle, cycloplegia must be accompanied by mydriasis. It
should be noted that mydriasis is not always evidence of an
accompanying cycloplegia and merely indicates paralysis of the pupil
sphincter. Cycloplegics are used to prevent or reduce accommodation
during refraction, thus making latent refractive errors manifest.
195
196
INDICATIONS FOR CYCLOPLEGIC EXAMINATION
Cycloplegics are also used as adjunctive therapy in the
treatment of certain diseases of the anterior segment of the
eye like acute anterior uveitis.
Cycloplegic examination can be desirable in some
children and young adults but is most unlikely to be
necessary in presbyopic adults. Use of a cycloplegic is
indicated in the following cases:
1. in children with constant or intermittent esotropia, on
and sometimes subsequently initial examination .
2. in children and young adults with asthenopia and
esophoria, especially when a latent refractive error is
suspected .
3. when retinoscopy suggests that accommodation is
fluctuating significantly .
197
CYCLOPLEGIC EXAMINATION
4.When the retinoscopy findings differ significantly
from the results of subjective refraction in cases
of anomalies of accommodation such as
accommodative insufficiency, accommodative
fatigue, accommodative inertia and spasm of
accommodation .
5.in cases where retinoscopy along the visual axis
is very difficult due to lack of patient’s
cooperation as in children or mental handicap
candidates ‫المتخلفين عقليا‬.
198
CONTRAINDICATIONS FOR CYCLOPLEGIC EXAMINATION
In optometric practice, cycloplegic examination is
usually confined to children and young adults and there are
unlikely to be any contraindications in this age group apart
from:1- abnormally shallow anterior chamber and
2-dislocation or subluxation of the crystalline lens.
3-If it is considered necessary to undertake cycloplegic
refraction in a presbyopic adult, the contraindications are
those relevant to the mydriasis that is a concomitant ‫مصاحب‬
of cycloplegics as narrow angle of A.C .
199
IDEAL PROPERTIES OF CYCLOPLEGICS
1. Quick in onset (the delayed onset of atropine puts
special requirements on its dosing).
2. Provides adequate depth of cycloplegia.
3. Provides adequate duration of cycloplegia.
4. Does not cause mydriasis (as mentioned earlier, this is
unattainable so the mydriasis that invariably
accompanies cycloplegia must be considered an
unwanted side-effect that can cause photophobia).
5. Causes no other pharmacological effect.
6. Results in no local toxicity.
200
ADVANTAGES OF CYCLOPLEGIC REFRACTION
Under cycloplegia, full static refraction can be
estimated without interference from a tonic or clonic
(fluctuating) contraction of the ciliary muscle.
This is particularly important in the very young
because of their large amplitude of accommodation, the
latency resulting from this masking a large part of their
full refractive error if it is of the hypermetropic type.
201
CYCLOPLEGIC REFRACTION – ADVANTAGES
The unreliability ‫عدم موثوقية‬of subjective findings in the
very young children makes the retinoscopy results of
paramount ‫أساسي‬importance .
202
INDICATIONS OF CYCLOPLEGIC REFRACTION
The full cycloplegic correction found is not necessarily
given in any subsequent prescription that is deemed to
be necessary. Knowledge of the cycloplegic findings is
nevertheless of great importance, especially in:
1)Children and young people and particularly where
intermittent or constant manifest strabismus.
2) medium to high heterophoria or pseudomyopia are
present.
203
3) where marked accommodative asthenopic symptoms.
OF CYCLOPLEGIC REFRACTION
1-Refraction under cycloplegia is unnatural because the
shape of the lens has been changed. As this will
resume its normal form when the effects of the drug
have worn off, cycloplegic findings must be compared
with those obtained at either a pre- or postcycloplegic
test, whichever is appropriate in a given case.
2-The optical aberrations present with the widely dilated
pupil are then very much reduced.
204
CYCLOPLEGIC REFRACTION – DISADVANTAGES
Additional disadvantages include:
1-making an allowance ‫ السماح‬for the dependent tone of the
ciliary muscle, ‫تصبح العضلة الهدبية معتمدة على غيرها‬
2- the dangers of cycloplegia, but as these can be
successfully overcome, the advantage of cycloplegic
refraction (when it is indicated) far outweigh the ‫المخاطر تعادل‬
‫المزايا لهذه القطرات‬disadvantages.
205
PRECYCLOPLEGIC EXAMINATION
Such an examination will include the following:
1.Symptoms of the disease.
2.Ocular and medical history: if the need for cycloplegia is
anticipated, ‫ سيتم استعمالها‬enquire about any current or
previous drug therapy local or systemic and any adverse
reactions to medications.
3.Establish any history of allergy in the eye .
4.Manifest refraction with vision and visual acuity at
distance and near.
5.Determination of binocular status (B.S.V) with tests
appropriate to patient’s age, in all cases, these will
include prism/cover test and a test of ocular motility.
206
PRECYCLOPLEGIC EXAMINATION
External eye examination including :
1.Tests of pupil function.
2.Using slit lamp microscope or hand-held slit lamp
and loupe (as appropriate to patient's age).
3.Internal ocular examination: if cycloplegia is to be
undertaken, ophthalmoscopic findings of the eye
fundus can be verified later with the benefit of the
dilated pupil.
4.Test of accommodative function (range and
amplitude ).
207
In those cases in which the non-cycloplegic examination has
indicated the need for cycloplegia it is helpful to offer
advice to the patient or the parent of a young child on the
following: ‫النصائح للمريض قبل وضع قطرة السيكلو في عيون المريض‬
1.How long it will take before near vision becomes clear
again?
2.That associated mydriasis can cause photophobia, which
can be alleviated ‫ يخفف‬by the temporary use of miotics .
3.Adult patients should be advised that because distance
visual acuity may be slightly reduced (as a consequence of
the mydriasis) it would be advisable to avoid riding a
motorcycle or driving a car immediately after the
cycloplegic examination.
208
EFFECTS OF CYCLOPLEGIA ON OCULAR COMPONENTS
Cycloplegia in children has been reported to:
1. Increase anterior chamber depth .
2. Decrease crystalline lens thickness .
3. Decrease vitreous chamber length irrespective of the
nature of the refractive error.
4.Axial length increased in hyperopic eyes and decreased in
myopes.
5. Using a computerized video keratoscope , corneal power
increased in hyperopes
and decreased in myopes.
The cause is change in
corneal curvature.
209
210
CHOICE OF CYCLOPLEGIC
Many antimuscarinic agents were used in the past
but today only three are used regularly (Table 6.1).
Arranged alphabetically, and in descending order of
efficacy, they are:
1. atropine,
2. cyclopentolate and
3. tropicamide.
Of the others , homatropine is still used infrequently,
whereas hyoscine is hardly ever employed at all.
211
CHOICE OF CYCLOPLEGIC
The principle of as little as possible but as
much as necessary should apply to the use of
drugs by doctors, optometrists and patients
alike. Having decided that a particular patient
will benefit from a cycloplegic.
212
ATROPINE
Atropine is an alkaloid extracted from a variety of plant
species, such as Atropa belladonna and Hyoscyamus
niger . It was the first antimuscarinic agent used in
medicine and is the most toxic substance available for
use by optometrists. It is available as 1% eye drops , both
in multidose and single-use units .
213
ATROPINE
Because of the systemic toxic reactions that can occur,
the ointment form is most often favoured . However,
Aurfarth &Hunold (1992) carried out refractions on 90
strabismic children :
1- 90 minutes after administering two drops of atropine
eye drops ( 0.5 or 1.0%, depending on age), and found
small differences between results obtained by this method
2- and those after a 3-day of later atropinization, the latter
producing only an extra 0.5D of cycloplegia .
214
ATROPINE
When atropine is used as an ointment, it is usually
applied in the child’s eyes by the parent at home twice a
day for 3 days ( 1x2x3 ) prior to refraction but not on the
day of refraction because the unabsorbed ointment may
interfere with refractive ‫يعمل كطبقة عازلة على القرنية‬
procedures.
The technique for application of eye ointment should
be carefully demonstrated to the parent by the
practitioner, either using a simple eye ointment or the
first dose of atropine.
Parents must be warned that very great care must be
taken in handling atropine and that hands must be
washed thoroughly before and after its application.
215
RESULTS OF ATROPINE
Time scale after one instillation of the usual 1% strength
solution,
1- Mydriasis : commences ‫يبدأ‬in 10–15 minutes and is
maximal in 30–40 minutes.
2- Recovery from mydriasis following a single instillation
might take as long as 3–7 days .
3- Pupillary recovery from mydriasis when atropine is
used in children, and this necessitates twice daily
application for 3 days, then usually takes from 10 to 14
the action is slow and full pupil recovery may take 7–10
days .
216
RESULTS OF ATROPINE
4- Cycloplegia after single drop commences in half an
hour, although adequate accommodation for near work
has usually returned within 4–5 days (after the usual six
applications).
Even with one application, full ciliary muscle recovery
might take 3–7 days; the resulting cycloplegia reached
in 1–3 hour, although marked, is not complete.
Because of the different time courses of mydriasis
and cycloplegia, the size of the pupil is a poor indicator
of cycloplegic effect induced by atropine .
217
ATROPINE
5- Wide dilation of the pupil causes photophobia and
sometimes the patient complains of micropsia.
Normal pupillary reflex constrictions to light and to
accommodation-convergence are completely
abolished.
Very powerful miotics (such as ecothiopate 0.3%) will
overcome the mydriatic effects of atropine 1% but
this drug is not readily available in the U.K .
It has been withdrawn and is now available on a limited
basis.
218
RESULTS OF ATROPINE
The ciliary muscle, like all other smooth muscles in the
body, has both a dependent and an independent tone, the
former being conditional‫ شرطي بوجود العصب سليما‬on an intact
nerve supply whereas the latter is not.
The independent tone in the ciliary muscle is very small
and does not give rise to symptoms, neither is it affected by
cycloplegics. On the other hand, the dependent tone of the
ciliary muscle is totally abolished by complete atropine
cycloplegia, but not by the full effects of other cycloplegics .
An allowance of tone therefore has to be considered only
in the return of the dependent tone of the ciliary muscle on
its recovery from the effects of atropine paralysis.
219
ATROPINE
This tonus allowance is an adjustment of the
spherical element only of the retinoscopic findings in
such cases, to take into account the fact that the
eyes, when fully returned to normal , will once more
usually have their overall refractive power increased
slightly in a positive direction by the constant effect
of the (dependent) tone of the recovered ciliary
muscle. The quantitative effect of this tone will vary
slightly, depending on the nature of the refractive
condition of the eye being considered.
220
Uses of atropine
1- Refraction: atropine has become the standard to
which all other cycloplegic agents have been
compared. Because atropine is the most potent
cycloplegic agent currently available, it is often
used for cycloplegic refractions in young actively
accommodating children with suspected latent
hyperopia or accommodative esotropia.
Because of prolonged paralysis of
accommodation that renders patients visually
handicapped in near vision, atropine is not
typically used for routine cycloplegic refractions in
school-aged children or adults.
221
Uses of atropine
Other shorter acting agents are becoming more
widely used for refraction in almost all patients
when a cycloplegic refraction is deemed
necessary, so that the inconvenience of a
prolonged accommodative loss is avoided.
Use of atropine often reveals more hyperopia
,however, and thus may be warranted ‫مضمون‬in
cases of esotropia with a suspected accommodative
component.
222
Uses of atropine
2- Treatment of Uveitis : Atropine is extremely
useful in the treatment of anterior uveal
inflammation.
A- Atropine relieves the pain associated with the
inflammatory process by relaxing the ciliary
muscle spasm and
B- helps prevent posterior synechiae by dilating
the pupil. With the pupil dilated, the area of
posterior iris surface in contact
with the anterior lens capsule
decreases
223
C-Moreover, the cycloplegia produced by
atropine is of additional value in reducing both
the thickness and convexity of the lens.
If posterior synechiae should develop even
when the pupil is dilated, there is less chance of
iris bombé.
D- Atropine may also help decrease the
excessive permeability of the inflamed vessels in
iris and thereby reduce cells and protein in the
anterior chamber.
224
iris bombé
225
Change in thickness and convexity of the lens
226
Uses of atropine
3- Treatment of Amblyopia: Atropine cycloplegia of
the fixing eye of strabismic infants and children as an
‘occluder’ has been used to encourage the use of the
amblyopic eye in near vision. Use of this technique,
which is sometimes described as penalization, during
the period of visual immaturity might induce amblyopia
in the eye subjected to cycloplegia.(Reversed amblyopia)
227
4- Treatment of Myopia : It has been suggested that
topical biocular use of atropine may prevent or slow the
progression of myopia . By placing the ciliary muscle at rest
accommodation is relaxed, and the tension that produces
elongation of the eye may be reduced. With administration
of 1% atropine for 1 to 8 years, the decrease in myopia in
treated eyes of children has usually been less than 0.5 D.,
the nontreated eye showed an increase in myopia that
averaged approximately 0.91 D per year.
Treatment of Myopia
A study showed significant reduction in myopia progression with
atropine in patients who presented good compliance ‫ جيد االمتثال‬.
Another uncontrolled study reported that topical instillation of 1%
atropine for 6 to 12 months in children 7 to 14 years of age seemed to
prevent the progression of myopia, but on discontinuation of the
drops only 12% of children maintained improvement for more than 6
months. In a more recent study , 20 children with 6.0 D or more of
myopia were treated with 0.5% atropine once at bedtime and followed
for up to 5 years.
The myopic progression that occurred under atropine treatment was
significantly slower than the progression observed before atropine
treatment was initiated or under treatment with tropicamide.
229
Side Effects Of Atropine
Ocular Effects: Ocular reactions include :
1.direct irritation from the drug preparation itself, ‫تهيج العين‬
2.allergic contact dermatitis, ‫تهيج جلد الجفون‬
3.risk of angle-closure glaucoma, In general, topical
atropine, as well as other cholinergic antagonists,
increases patients’ risk for angle-closure glaucoma.
However, the risk of inducing angle closure in eyes
without a previous history of attack is remote.
4.elevation of IOP in patients with open angles.
5.Wide dilation of the pupil causes photophobia and
6.sometimes the patient complains of micropsia.
7.The allergic reaction to atropine generally involves the
eyelids and manifests itself as an erythema, with edema.
8.Allergic papillary conjunctivitis and keratitis have also
been reported.
230
allergic contact dermatitis
231
angle-closure glaucoma
Allergic papillary conjunctivitis and
keratitis
232
Systemic Reactions to Atropine in
Children
1. Diffuse cutaneous flush.
2. Depressed salivation/thirst.
3. Fever.
4. Urinary retention.
5. Tachycardia.
6. Somnolence.‫نعاس‬
7. Excitement/restlessness and hallucinations.
8. Speech disturbances.
9. Ataxia ‫ترنح‬.
10. Convulsions.
233
CYCLOPENTOLATE
Cyclopentolate is the most widely used cycloplegic today,
and is now the one of choice. The paralysis of
accommodation is not complete but it gives a depth of
cycloplegia that is sufficient for the majority of cases.
Havener (1978) aptly sums the great value of cyclopentolate
when he describes its effects in the field of cycloplegia as
superior to homatropine (even the 5% concentration of the
latter) in its rapidity of onset , shortened duration of action
and greater intensity of effect.
234
Cyclopentolate
Cyclopentolate is available in single-dose form (‘Minims’)
and in multidose containers in two strengths for
cycloplegia, 0.5% and 1.0% . An interesting alternative
application method for cyclopentolate has been evaluated
by Ismail et al (1994), who used a spray application to the
closed eye and compared it with conventional eye drop
administration. They found that the resulting refractions
using the two applications were not significantly different
but that the spray application was easier to administer
and was more acceptable to the patient.
235
Cyclopentolate
Aged up to 12 years (before 12 ) : Only one drop of the
1% solution is usually necessary but a further drop
should be instilled if little effect is measurable after 15
minutes. A further factor in determining the appropriate
concentration is the degree of iris pigmentation and ,
when this is very light , the 0.5% solution might be
suitable. Retinoscopic refraction can then be performed
in 40–60 minutes .
236
Cyclopentolate
Aged 12 years : One drop of the 0.5% solution,
repeated only if – within 15–20 min – and above there is no
significant measurable reduction in the amplitude of the
accommodation. This second drop 0.5% solution is
sometimes necessary in fair skinned ‫ بشرة فاتحة اللون‬patients
with dark hair and irides. Where it is considered necessary
to administer two drops of cyclopentolate, it has in the
past been accepted procedure to allow a 5- minutes
interval between drops so that the conjunctival sac can
drain and allow space for the second drop.
237
Cyclopentolate
For dark-skinned adults, one drop of the 1% solution
should be instilled and the dose repeated only if the
amplitude of accommodation is not falling at a
satisfactory rate. Again, retinoscopy is generally
carried out in 40–60 minutes, that is, the average
time taken for the maximum effect of the drug to
reduce the accommodation to less than 2.0D.
238
Cyclopentolate
Time course : One or two drops of the cyclopentolate
solution instilled into the conjunctival sac produces a
cycloplegia commencing in a few minutes and becoming
maximal in 30–60 minutes, but sometimes as rapidly as in
15 minutes or (on rare occasions) even in 10 minutes,
especially in patients with light irides . Because of the
variation in the time taken to produce maximum
cycloplegia, and also in view of the fact that the duration of
this condition varies from 10 to 60 minutes (averaging
about 40 minutes).
239
Cyclopentolate
The amplitude of accommodation should be measured every
10 minutes after a time lag of 20 minutes following
instillation, until no further fall in the accommodation is
recorded . In very young children and others unable to
respond to this test, the accommodative state can be
assessed using dynamic retinoscopy . Like most drugs
that affect accommodation and the pupil, the time course
of the mydriasis is different to that of the cycloplegia and
pupil diameter should not be relied on to give a measure of
the remaining accommodation.
240
Cyclopentolate
Depth of cycloplegia as in nearly all cases the residual
accommodation is 1.50D or less around 40–60 minutes
after instillation (although not infrequently a second drop
of the solution might be necessary to reduce the
accommodation to this level) , a period during this
interval is the most usual time for retinoscopic refraction.
Considered that cyclopentolate more closely
approximated their ideal criteria for a cycloplegic or
mydriatic than any other drug discovered up to that time.
Priestley & Medine compared the depth of cycloplegia
241
reached
1 hour after instillation of :
Cyclopentolate
1-two drops of a 0.5% solution of cyclopentolate in the right
eye with the
2-same dosage as a 5% solution of homatropine in the left
eye. in a group of over 50 patients, which included
children and young adults .
Their results showed that the residual accommodation for
cyclopentolate ranged between 0.50 and 1.75D ,with an
average of (1.25D), whereas with homatropine this range
and 3.0 D, with an average of (2.0 D. (was between 1.0
242
Cyclopentolate
1-Full recovery of the accommodation without the
instillation of a miotic usually occurred between
4 and 12 hours, but in a few cases this was delayed
for 24 hours.
2-Reading, in practice a more important consideration
than full restoration of accommodation, was usually
possible after 3–4 hours.
3- Recovery from mydriasis was shown as occurring
between 24 and 48 hours, in all instances without
the aid of a miotic.
243
Therapeutic uses cyclopentolate
Cyclopentolate can be used in :
1- the treatment of corneal ulceration.
2- anterior uveitis.
3- and keratitis.
One or two drops of the 0.5% solution being instilled
every 6–8 hour, to prevent the formation of posterior
synechiae and ‘rest’ the painful ciliary and pupil
sphincter muscles. By relaxing the ciliary muscle and
immobilizing the iris, cyclopentolate alleviates the
patient’s discomfort. For long-term treatment in these
conditions, cyclopentolate does not compared favorably
with the longer-acting drugs such as atropine and
homatropine.
244
Therapeutic uses Cyclopentolate
When breaking down lenticular adhesions,
(posterior synechiae ) one or two drops of
the 0.5% cyclopentolate solution are instilled,
followed 6 hour later by one or two drops of a
2% solution of pilocarpine nitrate; this
alternating treatment is repeated daily.
245
TROPICAMIDE (MYDRIACYL)
Tropicamide is another rapidly acting synthetic
antimuscarinic drug. It is used as a mydriatic in a
0.5% solution and a cycloplegic in a 1.0%
solution.
As a mydriatic , two drops of the weaker solution
instilled into the conjunctival sac produce a full
mydriasis in about 15 minutes , the pupil returning
to normal in 8–9 hours if no miotic is used to
counteract the pupillary dilatation.
246
TROPICAMIDE
To produce cycloplegia, two drops of the 1%
solution are instilled into the eye, allowing a 5minutes interval between each drop.
The full cycloplegic effect is achieved in about
30 minutes , when the retinoscopy is
performed.
If the examination has to be delayed beyond
35 minutes , because of the very brief maximal
effect of the cycloplegia, a further (third) drop
of the 1% solution should be used.
247
TROPICAMIDE
Complete recovery of the accommodation usually
occurs within 6 hour and reading is generally
possible after 2–4 hours from the time of the initial
instillations.
Excellent cycloplegia (with residual accommodation
below 2.0 D) is usually obtained, according to ,
following the procedures outlined above.
However, due to the very brief duration of maximum
effect, a third drop is not infrequently necessitated
in routine practice.
248
TROPICAMIDE
In a series of 193 patients, Gettes & Belmont
(1961) were able to examine only 60% of these
during the 20 to 35 minute interval when
cycloplegia was maximal, and 40% had to receive
the third drop .
However, as Havener (1978) emphasizes, the
great advantage of:
1- tropicamide is its rapid action and short duration,
2- the patient having fully recovered from
cycloplegia in 2–6 hour, and these very qualities
also make it a most useful mydriatic in its weaker
concentration of 0.5% .
249
TROPICAMIDE
The speed of onset of tropicamide allowed Harding
(1970) to see more patients in his working day and the
short duration of action allowed patients to return to
work within 2 hours.
However, Milder (1961) did not find using two drops of
tropicamide 1% solution to be as satisfactory a
cycloplegic as the same number of drops of a 1%
cyclopentolate or a 5% homatropine solution.
He instilled tropicamide in one eye and cyclopentolate or
homatropine in the other.
250
TROPICAMIDE
In a series of 50 consecutive ‫ على التوالي‬cases
(100 eyes) he found better cycloplegia produced by
the cyclopentolate in 23 out of the 25 cases and
homatropine in 20 out of 25 cases in comparison to
the tropicamide instilled in the second eye in each
case. Thus, in only seven (five with homatropine in
the other eye and two with cyclopentolate in the
other eye) of the 100 eyes was tropicamide superior
in its cycloplegic effect to these other drugs.
251
TROPICAMIDE
In children in particular, Milder’s of
tropicamide results indicated a poor paralysis
of the ciliary muscle; in the six 6 cases in this
series up to the age of 9 years an average of
6.25 D of residual accommodation was present
after 30 minutes , and in 20 cases from 10 to 14
years this reading was still averaging 3.65 D.
Conclusion: Tropicamide would therefore
appear to be a relatively inadequate cycloplegic
for use with children.
252
OTHER CYCLOPLEGICS
Homatropine is a semisynthetic alkaloid prepared
from atropine; the homatropine base tropine obtained by
hydrolysis of atropine is chemically combined with
mandelic acid. Homatropine Hydrobromide Eyedrops, the
standard solution, contains up to 2% homatropine
hydrobromide.
At one time, ‫ في الماضي‬this drug was quite popular as a
routine mydriatic and cycloplegic, but its use has declined.
It does not produce a satisfactory cycloplegia in children
and its use for this purpose is therefore usually restricted to
those over 15 years. ‫ال يستعمل لألطفال قبل سن الخامسة عشرة‬
253
Homatropine
Conventional dosage of the eyedrops is one drop
of the 2% solution repeated twice at 10-minute
intervals (i.e. a total of three drops).
• Mydriasis commences in 15 minutes and is
maximal in about 30–40 minutes, with complete
abolition of pupillary reflex to light and
accommodation.
• Complete recovery of the pupil can take between 24
and 48 hour, depending on dosage.
254
Cycloplegic retinoscopy -
Homatropine
The amplitude of accommodation begins to fall in 15
minutes and is usually at its lowest between 45 and 90
minutes. Therefore, cycloplegic retinoscopic refraction
should not commence until about 60 minutes after
instillation, and the residual accommodation should be
measured to ensure that it is below 2.0D.
Refraction should be completed before 90 minutes has
elapsed from the time of instillation of the drops. Not
infrequently, the depth of cycloplegia in the under 20
years age group is not reduced much below 2.0D, but a
lower amount is recorded (the first reading being taken
after half an hour and then every 10 minute until no
further fall of accommodation is noted).
255
Cycloplegic retinoscopy-Homatropine
Cycloplegic retinoscopy can usually be
adequately performed with the patient gazing at
a distant target to relax the small amount of
accommodation left unparalysed. Koyama et al
(1995) used a combination of homatropine (4%)
and cyclopentolate (1%) to examine myopic
children and compared the refractions obtained
under cyclopentolate (1%) alone. Not
surprisingly, they found no difference between
the two cycloplegic drops.
256
PRESCRIBING FOLLOWING CYCLOPLEGIA
•When cycloplegia discloses ‫ يكشف‬a significant difference
in refractive findings compared to the pre-cycloplegic
examination , it will be beneficial to arrange a further
post-cycloplegic visit.
• At this further consultation , it is particularly important to
assess the effect of the proposed correction on the
patient’s binocular status.
• Each prescription issued will be determined by the
individual circumstances of the case, and it is therefore
only possible to offer general guidelines on prescribing.
257
PRESCRIBING FOLLOWING CYCLOPLEGIA
• In the case of esophoria accompanied by hyperopia,
the aim would be to prescribe the minimum plus
which would allow this heterophoria to become
compensated.
• In esotropia accompanied by hyperopia, the ideal is
to prescribe that (maximal) plus power that permits
binocular fixation as demonstrated by the cover
test.
258
PRESCRIBING FOLLOWING CYCLOPLEGIA
Both esophoria and esotropia might be of the
convergence excess type and, as the degree of plus
power required at near is greater than that for distance,
it is likely to impair distance visual acuity.
In such cases, bifocal or multifocal spectacles lenses
might be appropriate.
It is unlikely that cycloplegia would be considered
necessary in patients with exophoria or
exotropia.
Generally, the aim in these cases is
to prescribe the minimum plus correction or a full
minus correction.
259
PRESCRIBING FOLLOWING CYCLOPLEGIA
• In some younger patients, a minus overcorrection
might allow the compensation of the heterophoria or
the attainment of binocular fixation in exotropia.
• In every case, consideration must be given as to
whether the patient will be able to tolerate the
proposed prescription when it is compared to the
present correction, if any.
260
USE OF CYCLOPLEGICS IN MYOPIA
Estimates suggest that the prevalence of myopia in
young adolescents has increased in recent decades and is
now in the region of 10–25% in industrialized Western
societies and significantly higher (60–80%) in Asian
populations (Gilmartin 2004). These findings have
stimulated various attempts to reduce the rate of
progression of myopia in children including the use of
topical ocular pharmaceutical agents. The role of other
approaches, such as varifocal (bifocal or progressive
addition) spectacle lenses and rigid contact lenses, lies
beyond the scope of this text.
261
USE OF CYCLOPLEGICS IN MYOPIA
The view that myopia develops as the consequence of
prolonged exposure to nearpoint activities has prompted
‫دفع‬the regular application, over an extended period, of
(cycloplegics) muscarinic antagonists.
Many investigations have used animal models and, in
1965, Young studied the effect of atropine on the
development of myopia in monkeys. Subsequently, the
daily administration of atropine sulphate 1% in children
was reported to reduce the rate of myopic progression
(Bedrossian 1979, Dyer 1979).
262
USE OF CYCLOPLEGICS IN MYOPIA
Atropine has been shown to retard growth in the axial
length of the eye and it was suggested that this was the
consequence of deep cycloplegia and reduction of
fibroblast proliferation in the sclera (Shimmyo et al 2005).
Pirenzepine is a selective M1 muscarinic antagonist that
has been prescribed for the treatment of gastric and
duodenal ulcers but is no longer used in these conditions.
It has been shown to be effective in preventing axial
elongation of the eye associated with experimental myopia
in chickens. ‫في الدجاج‬
263
ADVERSE EFFECTS OF CYCLOPLEGICS
Antimuscarinic drugs are potent agents that can
produce effects on several structures in the body.
Atropine was a favourite of the medieval ‫من القرون الوسطى‬
professional poisoners and is probably the most toxic
compound that is used routinely as a diagnostic agent.
Other cycloplegics also have the potential to produce
marked side-effects.
Toxic effects from topical ophthalmic use have been
known for a long time (Wise 1904).
264
ADVERSE EFFECTS OF ATROPINE
These consisted of :
1- A high temperature .
2- The central nervous system effects of hallucinations and
ataxia ‫ ترنح‬. Confusion and restlessness after the use of
atropine.
3- Psychotic reactions to atropine eyedrops. ‫تفاعالت نفسية‬
4- Death from the use of atropine has been reported by
Heath (1950). CNS effects represent an advanced stage of
atropine poisoning.
5- Milder effects can be seen at earlier stages of poisoning.
These affect peripheral tissues, including exocrine glands
such as the salivary glands and the sweat glands. ‫عطش مع فقدان العرق‬
265
ADVERSE EFFECTS OF ATROPINE
Patients suffering from atropine poisoning are said to be:
1.blind as a bat: ‫الخفافيش‬
Patients are as blind as a bat because of the loss of accommodation
2.dry as a bone: they are as dry as a bone because of the
inhibition of the sweat glands and salivary glands – a dry
mouth is one of the earliest signs of atropine poisoning.
3. red as a beetroot: ‫ جذر الشمندر‬the inhibition of sweat glands
deprives the body of one of its methods of losing heat and, to
compensate for this, there is a dilation of skin blood vessels,
giving the patient the appearance of being ‘as red as a
beetroot’.
4. mad as a hatter: ‫ حتر‬when CNS effects occur patients
become as ‘mad as a hatter’.
ADVERSE EFFECTS OF CYCLOPETOLATE
CNS effects have also been reported following the use
of cyclopentolate. In the majority of cases these effects
followed the administration of a higher than recommended
dose or a combination with other drugs
1- 1% cyclopentolate :CNS effects manifest themselves as
confusion, difficulty in speaking hallucinations and ataxia.
Fortunately there have been no fatal reports following these
effects of 1% cyclopentolate, and the patient is back to
normal in a matter of hours. These effects would appear to
be dose related, as Cher (1959) used two drops of 0.5% with
a 10-minute interval between applications on 159 patients
without producing CNS problems.
267
ADVERSE EFFECTS OF CYCLOPETOLAE
2- 2% cyclopentolate : Beswick (1962) used (not available
in the UK) and noted hallucinations in a 9-year-old child.
Binkhorst et al (1963) found that 2% cyclopentolate elicited
reactions in four patients out of 40 years.
3- 0.2% cyclopentolate : one case has been reported in
which CNS effects were seen after the use of 0.2%
cyclopentolate but the patient had a history of chronic
dementia.‫الخرف‬
4- Bauer et al (1973) had earlier reported necrotizing
enterocolitis following the use of cyclopentolate.
268
ADVERSE EFFECTS OF CYCLOPENTOLAE
5- Problems in the gastrointestinal tract following the use of
cyclopentolate in premature babies have been reported
(Isenberg et al 1985).
It was found that cyclopentolate 0.5% decreased
gastric
acid secretion while 0.25% did not.
• From the above, it would appear that 0.5% cyclopentolate
should be used whenever possible and cyclopentolate 1%
should be used sparingly. .‫في حاالت متفرقة‬
269
ADVERSE EFFECTS OF CYCLOPENTOLAE
6- An unusual acute psychotic reaction following the instillation of two
drops of cyclopentolate 1% in a 56-year-old woman has been reported.
7- Immediately after the second instillation, the patient reported
neurological symptoms drowsiness ‫ نعس‬, dizziness ‫ دوخة‬, nausea and
fatigue.
8-Ten minutes later, stimulatory central nervous system symptoms in
the form of restlessness, cheerfulness‫ مرح‬and a 20-minutes roar ‫هدير‬of
laughter were observed, interrupted by a new sedative phase. Basic
medical and neurological examinations were unremarkable except for
gait ataxia.
270
ADVERSE EFFECTS OF HOMATROPINE
Homatropine, although less toxic than atropine, has
produced problems in the past. Hoefnagel (1961) reported
CNS effects such as ataxia and hallucinations in four
children who had received six drops of homatropine 2% at
10-minute intervals. Such a dose must be considered
excessive and it is not surprising that problems arose.
271
ADVERSE EFFECTS OF TROPIAMIDE
In comparison with other cycloplegics,
tropicamide is relatively free from adverse
reactions. Wahl (1969) reported unconsciousness
and pallor following one drop of 0.5% tropicamide .
As there have been no similar reports it would
appear that the reaction is probably not drug
related.
272
AllERGIC REACTIONS OF CYCLOPLEGICS
Allergic reactions can occur to many compounds.
Atropine is probably the most notorious ‫ مشهور‬for
producing reactions but cyclopentolate has also been
implicated.‫متورط‬
It might appear that the use of cycloplegics is
potentially hazardous.
If the precautions mentioned in this chapter are
observed by the practitioner, then the risk of an
adverse effect is minimized and will be a very rare
occurrence.
273
PRECAUTIONS OF ADVERSE EFFECTS OF CYCLOPLEGICS
The following precautions should be observed in the use of cycloplegics in
refraction:
1. Explain to the patient or parent the reason for undertaking a cycloplegic
examination.
2. Patients or parents should be forewarned ‫محذر‬that photophobia is likely and
that it can be alleviated by wearing sunglasses and/or a broad-brimmed hat.
3. They should also be warned that near, and possibly distance, vision will be
blurred.
4. Adults should also be told that riding a motorcycle or driving a car should be
avoided.
5. Evaluation of anterior chamber depth.
6. Ask whether the patient has previously undergone cycloplegia and whether
there was any adverse reaction to the drug used.
7. Issue ‫ سجل‬a note which identifies the cycloplegic used and provides advice
on what action the patient should take in the event of an adverse reaction.
274
Chapter-II
Mydriatics
275
Mydriatics
Mydriatics dilate the pupil to facilitate a more thorough examination of the
fundus, lens periphery and vitreous. They are mostly used on elderly patients,
as older pupils are usually smaller and lens opacities and abnormal retinal
conditions are not uncommon. However, the use of mydriatics can be essential
in any age group, especially where the macula or the peripheral areas of the
retina need particularly careful observations, for example, :
1- suspected macular cyst or hole,
2- location of a penetrating foreign body,
3- intraocular tumours,
4- peripheral retinal detachments.
Martin-Doyle (1967) considers the instillation of a mydriatic indispensable
for an adequate examination of the macula. Siderov et al (1996) examined
patients’ attitudes to pupil dilatation during optometric
examination and found that the majority were in favour, although a large
proportion suffered adverse effects such as glare and blurring of vision.
276
IDEAL PROPERTIES OF MYDRIATICS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
277
Quick in onset.
Adequate duration.
Fast recovery after examination.
Light reflex abolished.
No cycloplegia.
Capable of quick reversal in an emergency.
No rise in intraocular pressure.
No other pharmacological effect.
No local toxic reaction.
No systemic toxic reaction.
No adverse subjective complaints such as ‘stinging’.
INDICATIONS FOR MYDRIATIC EXAMINATION
Those occasions when there is a special need for a
thorough fundus inspection through a dilated pupil , where
the latter does not already exist, include the following :
1. Recent onset of floating vitreous opacities, especially if
accompanied by the symptoms of flashing light .
2. Relatively sudden decrease in visual acuity.
3. Unexplained loss of visual field.
4. Unexplained ocular pain, unaccompanied by raised
intraocular pressure.
5. Redness of the eye that cannot be attributed to infection,
allergy, or raised intraocular pressure.
6. After contusion, to exclude the presence of ocular damage.
278
INDICATIONS FOR MYDRIATIC EXAMINATION
7.Difficulty in observing the fundus due to reduced
transparency of the media.
8. Diabetic patients – annually as a general rule.
9. Fundus photography, although some cameras are now
designed to be non-mydriatic.
Note: as well as their diagnostic uses .
In the treatment of anterior uveitis, cycloplegics are
used as the adjunctive therapy and are sometimes
replaced at a later stage, as the condition resolves, with a
drug having only a mydriatic effect.
279
Side effects of mydriatics
Most reported that the mydriasis resulted in blurry vision and
increased sensitivity to glare, which had interfered with some aspects
of their everyday life, notably driving a motor vehicle.
These authors considered that patients should be informed about
the visual disturbances that can be associated with mydriasis.
It is especially helpful to provide information on the:1.probable duration of the mydriasis (commonly 4–6 hours) and any
expected blurred near vision
2. benefits of wearing sunglasses and/or a broad-brimmed hat to
alleviate photophobia ,
3.desirability of avoiding riding a motorcycle or driving a car
immediately after the mydriatic examination.
280
CONTRAINDICATIONS FOR A MYDRIATIC EXAMINATION
Before instillation of any mydriatic , the optometrist must
first confirm that no contraindications are present to the
dilatation of the pupil (s) are present .
Contraindications include:
1. patients using pilocarpine for the treatment of glaucoma.
2. narrow-angle glaucoma .
3. abnormally shallow anterior chamber (due to the risk of
angle-closure glaucoma) .
4. dislocation of the crystalline, or an intraocular lens .
5.an intraocular lens of the anterior chamber or irissupported type .
281
CONTRAINDICATIONS FOR A MYDRIATIC
EXAMINATION
Not only will full mydriasis in predisposed eyes result in an
increased intraocular tension by mechanical blockage of
the angle by the iris, but a state of semi-dilation of the pupil
might initiate this rise by producing pupillary block.
This can occur in semi-dilated eyes because of the shallow
anterior chamber and anteriorly placed lens, the iris being
more closely opposed to the lens capsule over a much
wider area than in the normal or deep chamber where the
pupillary iris margins lightly touch the anterior lens surface.
282
283
MODE OF ACTION OF MYDRIATICS
•Because of the presence of the two opponent muscles, the pupil
sphincter and dilator muscles, there are two different modes of action of
mydriatics: sympathetic and parasympathetic.
•The pupil dilator muscle is innervated by the sympathetic nervous
system and sympathomimetic drugs will cause a contraction of the
dilator muscle causing mydriasis.
•The parasympathetic system is largely unaffected by such
sympathomimetic drugs and thus the pupillary light reflex remains
active.
•Sympathomimetic drugs also have little effect on accommodation.
•However, the pupil sphincter muscle, which is innervated by the
parasympathetic system, can be paralysed by the same class of
drugs that causes cycloplegia ( parasympathomimetic drugs ) . With this
type of drug the pupillary light reflex is reduced or abolished .
284
MODE OF ACTION OF MYDRIATICS
Irrespective of the type of mydriatic employed, when a
mydriatic is applied unilaterally the light reflex in the other
eye is unaffected and the mydriasis in the treated eye is
accompanied by a consensual miosis in the other eye .
That this miosis is a result of the light reflex is
confirmed by the fact that the consensual miosis is not
manifest when the pupil diameters are measured in
darkness .
It is usual practice to dilate both eyes and this effect
will have little significance unless the clinician is trying to
assess the amount of anisocoria.
285
TROPICAMIDE
Tropicamide is the antimuscarinic mydriatic of choice
today. Normally available in 0.5% and 1.0% strengths, the
weaker solution is used most often for mydriasis; the 1%
strength is used for cycloplegia. Davidson (1976) states
that the mydriatic effect is greater than the cycloplegic
effect and that this propensity ‫ميل‬for mydriasis is of clinical
value.
Tropicamide is quick in onset and short in duration, and
the depth of mydriasis is adequate for most examinations
because the pupil light reflex is depressed, facilitating
indirect ophthalmoscopy and retinal photography. Pollack
et al (1981) investigated the dose/response relationships
of tropicamide’s mydriasis and cyloplegia under two levels
of illumination.
286
ANTIMUSCARINIC MYDRIATICS
TROPICAMIDE
They found that the mydriatic effect was independent of
dose (range 0.25–1.0%) and level of illumination ‫ بينما‬whereas
the cycloplegic effect was greater for the stronger
concentrations. This finding confirms that 0.5% tropicamide
should be used for mydriasis and 1% for cycloplegia. Pollack
et al studied patients with a range of eye colours but did not
collate ‫قارن‬the findings for different degrees of pigmentation.
287
TROPICAMIDE
Hence it is possible that the strength might need to be
varied with the level of pigmentation. If necessary, a
second drop can be applied 5 minute after the first.
The mydriasis caused by tropicamide can be reversed,
if necessary, with weak solutions of physostigmine.
Side effects:
1-Tropicamide can cause initial stinging.
2-Few allergic or adverse systemic reactions have been
reported .
3- if the patient is taking any systemic drug with an
antimuscarinic action, the effect of tropicamide might be
augmented (synergism).‫يزداد‬
288
Cyclopentolate
• All cycloplegics can be used as mydriatics but the effect
is usually too long lasting. The following have been used
in the past:
•Cyclopentolate :The mydriatic concentration of
cyclopentolate is 0.1% (compared with 0.5% and 1.0% for
cycloplegia). However, this strength is no longer available
and if cyclopentolate is used as a mydriatic then
significant cycloplegia will accompany its use. Mydriasis
commences in about 10 minutes and is maximal in about
30 minutes , the effect can last up to 24 hours .
• It produces similar mydriasis but more cycloplegia than
homatropine. Cyclopentolate 1% is sometimes used preoperatively to produce maximal mydriasis.
289
Homatropine
• At one time, homatropine was the principal mydriatic and was often
used in mixtures such as homatropine and cocaine or homatropine
and ephedrine.
• The mydriatic effect commences in 10–20 minutes and is maximal in
30–40 minutes. At 30 minutes , both light and accommodative
reflexes are absent and an examination may be carried out.
• Recovery takes the same time as cyclopentolate if a miotic is not
used but it can be as prolonged as 3 days (Davidson 1976).
Homatropine can be used as 0.25% or 0.5%, but these concentrations
are not available commercially.
• As would be expected, the higher strength produces a slightly larger
pupil but a much more marked effect on the ciliary muscle in
reducing accommodation.
290
SYMPATHOMIMETIC MYDRIATICS (ALPHA-1 AGONISTS)
PHENYLEPHRINE
1- Phenylephrine is the only sympathomimetic mydriatic in
regular use and the only one available in single-use units.
It is available in a variety of strengths but 2.5% and 10%
are most often used.
• Mydriasis commences in about 10 minutes and is
maximal in 30 minutes ; the mydriasis lasts for several
hours. Phenylephrine has been compared with ephedrine,
which it has replaced as the most commonly used
mydriatic.
• The light reflex is retained and it is unsuitable when
indirect ophthalmoscopy is carried out.
291
PHENYLEPHRINE
2- Phenylephrine causes vasoconstriction of the
conjunctiva. In low concentrations (0.125%) it is used as a
vasoconstrictor in some eyes brightening drops.
3- There is little doubt that phenylephrine produce less
effect on accommodation than antimuscarinic like
tropicamide , and some authors (Kanski 1969) suggest that
phenylephrine produces myriadsis without any cycloplegic
effect at all. ( controversy)
4- On the other hand, larger decreases in near-point
accommodation than can be attributed to the increase in the
size of the pupil have been reported .
5-Phenylephrine will also cause a widening of the palpebral
fissure (Munden et al 1991).
292
PHENYLEPHRINE
6- Phenylephrine is less effective in highly pigmented
patients. The disparity in mydriasis was greater for darkly
pigmented eyes as opposed to lightly coloured eyes.
7.There has been some discussion of the effectiveness of
2.5% phenylephrine relative to the 10% strength. Although
Duffin et al (1983) found a greater effect from 10%
phenylephrine than from 2.5%, it must be pointed out that
they were using a viscolized (in fat ) 10% solution against
an aqueous 2.5% solution, and that this difference in
vehicles could have influenced the mydriatic action.
• Neuhaus& Hepler (1980) found similar mydriatic effects
with 2.5% and 10% phenylephrine and recommend 2.5% for
routine dilation.
293
phenylephrine contraindications
The use of phenylephrine is contraindicated in
conditions such as:
1- hypertension,
2- coronary disease,
3- hyperthyroidism and
4- diabetes.
Adverse systemic reactions to phenylephrine
include :
1- cardiac arrythmias.
2- and hypertension.
294
Choice of mydriatics
When selecting a mydriatic, the optometrist will no doubt
invoke ‫ استخدام‬some personal preference. With the demise
‫ زوال‬of many traditional mydriatics, the probable choice will
be between phenylephrine and tropicamide.
Cyclopentolate should be considered only if these drugs fail
to produce a sufficient depth of mydriasis.
Tropicamide is the more effective mydriatic, especially if
photography ‫تصوير قاع العين‬is contemplated, ‫ تفكير‬as the
pupillary light reflex will be abolished. However,Mordi et al
(1986), when comparing 0.1% cyclopentolate and 10%
phenylephrine as mydriatics, concluded that neither was
ideal because both caused a loss of accommodation
signified by a recession of near point and a slowing of the
accommodation response.
295
Choice of mydriatics
Tropicamide can cause an increase in intraocular
pressure in eyes with a deep anterior chamber, as
opposed to phenylephrine, which causes a fall in
intraocular (like all sympathomimetics). However, the
rise in intraocular pressure is likely to be small and
transient, and unlikely to cause a problem.
Phenylephrine can have effects on blood pressure
and is contraindicated in patients with cardiovascular
problems and in those taking certain drugs.
In summary, it would appear that tropicamide 0.5% is the
first choice as a mydriatic, but special conditions
require special considerations.
296
MIXED MYDRIATICS
When the mydriasis produced by one or other of the two types
of mydriatic will not produce a sufficient depth of mydriasis,
mixtures of an antimuscarinic and a sympathomimetic can be
used. The following mixtures are some of the ones that have
been employed:
1. homatropine and cocaine.
Obselete
now
2. homatropine and ephedrine.
3. tropicamide and phenylephrine.
4. cyclopentolate and phenylephrine.
297
Available now
MIXED MYDRIATICS
The strengths of the compounds in the mixtures can be
varied according to the degree of mydriasis required.
Apt & Hendrick (1980) investigated the mydriatic effect of
three combinations:
1. Cyclopentolate 0.5% and phenylephrine 2.5%
2. Tropicamide 0.5% and phenylephrine 2.5%
3. Tropicamide 1.0% and phenylephrine 2.5%.
They found no significant difference between the mixtures.
They recorded dilation of around 7 mm within 60 min, which
must be approaching maximal effect.
298
CASES IN WHICH DILATION IS DIFFICULT
The two principal conditions that make pupils less responsive to the
action of a mydriatic are dark iris pigmentation and diabetes mellitus.
Inevitably, a number of patients present both problems.
A- IRIS PIGMENTATION:Phenylephrine , like all sympathomimetic, is less effective in highly
pigmented patients and will allow the light reflex to remain. When
mydriasis is necessary with pupils that are obviously going to be
difficult to dilate, one of the more powerful antimuscarinic mydriatics
should be used without hesitation; it is a waste of the patient’s and
practitioner’s time to attempt to dilate such pupils with one of the
weaker sympathomimetic drugs.
299
CASES IN WHICH DILATION IS DIFFICULT
For example, Barbee & Smith (1957) concluded that:
1- Phenylephrine is a relatively ineffective mydriatic when used on AfroCaribbean patients. They found that only the antimuscarinic drugs
(and these in cycloplegic concentrations) were really adequate in these
patients,
2- Cyclopentolate 1% produced only a 1.5 mm mean increase in
pupillary diameter.
3- The effect of cyclopentolate is compared to the approximately 3.0mm
additive increase in pupillary diameter obtained with atropine
1% hyoscine and 2% homatropine .
4- Phenylephrine 10% actually proved slightly more effective than the
cyclopentolate, giving an average 1.75 mm additive increased pupil
width.
300
CASES IN WHICH DILATION IS DIFFICULT
Priestley & Medine (1951) have also carried out a comparative study
of the mydriatic responses to various drugs of subjects from different
races. They found that after 20 min the speed of mydriasis
1- with cyclopentolate 0.5% was surpassed by ‫تجاوزها‬
2- homatropine (2%) and
3-phenylephrine (neosynephrine) 10% and
at the end of 60 min the latter (phenylephrine) ranked first.‫المرتبة األولى‬
4- Nevertheless, after this time the cyclopentolate drops did produce
an average 7.0 mm pupil in Afro-Caribbean subjects, compared to 7.5
mm in the white subjects.
301
CASES IN WHICH DILATION IS DIFFICULT
B - DIABETES MELLITUS
Huber et al (1985) found that diabetic patients responded poorly to
tropicamide and recommended a combination of tropicamide and
phenylephrine to give adequate mydriasis with a minimum of
accommodative paralysis.
C- SECTOR DILATION
In the presence of a narrow-angle anterior chamber, localized dilation of
the pupil can be undertaken to reduce the risk of inducing an acute
angle-closure glaucoma. Following instillation of one or two drops of
topical anaesthetic, the tip of a cotton-tipped applicator is moistened
with two or three drops of 2.5% phenylephrine and held against the
limbus for 15–20 seconds.
302
CASES IN WHICH DILATION IS DIFFICULT
D- CHILDREN
One study has demonstrated the efficacy of a novel method
of mydriatic drug delivery in children. Twenty-two healthy
children, aged 2–8 years, were given either :
1- one drop each of 1% tropicamide and 2.5% phenylephrine
in each eye
2- or one application of mydriatic spray (containing
concentrations of 0.5% tropicamide and 2.5% phenylephrine)
to each closed eyelid.
There was no statistically significant difference in pupil size
between the two methods of drug administration at 40 min.
after application . It is disappointing that this child-friendly
mode of application has not become commercially available.
303
ADVERSE EFFECTS OF MYDRIATICS
With any topically applied ophthalmic drug there is a possibility of
producing an undesirable effect, either on the eye or on the body as a
whole. Mydriatics have the ability to do both.
Many of the potential problems can be avoided by carrying out the
following precautions:
1. Explain to the patient the reason(s) for dilating the pupil(s).
2. Forewarn patients that photophobia is likely and that it can be
alleviated by wearing sunglasses and/or a broad-brimmed hat.
3. Patients should also be told that riding a motorcycle or driving a car
should be avoided for several hours because vision might be blurred.
4. Evaluation of anterior chamber depth prior to dilation.
5. As with any other drug , it is wise to ask patients whether they have
previously undergone mydriasis and whether there was any adverse
reaction to the drug used.
304
ADVERSE EFFECTS OF MYDRIATICS
It is particularly important to establish whether the patient suffers
from any illness or is taking any prescribed medication or over-the
counter ‫ من دون وصفة‬preparations, especially those that are
antimuscarinic. Carry out the following precautions to prevent
mydriatic complications:1. In general, use a single drop. However, it might be necessary to
use two or three drops with older patients and those with darkly
pigmented irides.
2.Measure intraocular pressure both before and upon completion
of the mydriatic examination.
3. Issue a note stating the mydriatic used and providing advice on
what action the patient should take in the event of an adverse
reaction.
305
ADVERSE EFFECTS OF MYDRIATICS
1- ANGLE-CLOSURE GLAUCOMA
The use of a mydriatic causes pupil dilation that, in turn,
introduces the possibility of angle block. The danger will
be dependent on the degree of dilation, not on the
mydriatic employed. The probability of inducing an attack
of closed-angle glaucoma is remote =little (figures vary
from 0.06% to 0.09% of the population) and it can be made
even more remote by careful prior examination of the
patient and detailed history taking. Keller (1975) concludes
that, providing proper precautions are taken, the risk of
precipitating angle closure is virtually nil.
306
ADVERSE EFFECTS OF MYDRIATICS
An optometrist might expect to see an attack of closed-angle
glaucoma about once in 40 years.
The classical symptoms and signs of closed-angle glaucoma are
well known but are worth repeating here.
1.The patient experiences intense pain, which might be severe
enough to induce vomiting.
2.The conjunctival blood vessels are dilated, giving an appearance
to the inexpert eye of conjunctivitis,
3.the cornea loses transparency slightly because the high
intraocular pressure causes it to imbibe water and swell.
4.The patient might report this as seeing haloes around lights.
5. Through the hazy cornea the pupil can be seen, often middilated and probably non-circular. The pupil will not constrict to
light, accommodation or to the action of miotics.
6.The intraocular pressure is very high <50mm.Hg.
307
308
2- Toxic epithelial desquamation of the cornea
Other local toxic effects from topical sympathomimetic drugs
include a toxic epithelial desquamation of the cornea similar to
that seen with local anaesthetics (Havener 1978) and a case of
allergic conjunctivitis following the use of phenylephrine (Shoji &
Watanabe 1991).
3- Liberation of iris pigment into the anterior chamber
has been reported by Aggarwal & Beveridge (1971) following the
use of 10% phenylephrine.
The pigment appeared as aqueous floaters within 45 min of the
drug being instilled, causing an aqueous flare that could be
confused with anterior uveitis.
309
4- Systemic toxic effects
• Sympathomimetic mydriatics can produce systemic effects; the
cardiovascular system is the one most sensitive to their effects.
The problem with sympathomimetic is exacerbated by the high
concentration of active agent that is used relative to the normal
systemic dose.
• Topically administered drugs can gain access to the vascular
system either by direct absorption through the conjunctival
blood vessels or via the nasolacrimal system to the alimentary
tract.
• Absorption can be very quick, with maximum levels being reached
10–20 min after instillation.
• Absorption can be markedly reduced by reducing the volume of
the drugs solution in the conjunctival sac. This in turn can be
achieved by reducing the volume of the drop administered. The
principal determinant of drop size is the diameter of the dropper
from which the drop is expelled.
310
Chapter I2 Miotics
311
Miotics
Miotics are drugs that constrict the pupil. In the hands of
the optometrist they can be used to reverse the mydriasis
produced by drugs such as phenylephrine and
tropicamide but, because of the short duration of action
the currently used mydriatics, miotics are being employed
less and less.
Providing patients are carefully screened before the use of
mydriatics, the incidence of angle-closure glaucoma is
quite low .
Should this rare event occurs then the patient should be
referred to an ophthalmologist without delay.
In exceptional circumstances it might be appropriate to
instil pilocarpine as an emergency treatment.
312
Miotics
In therapeutics, the principal use of miotics is in the
treatment of primary open-angle glaucoma. However,
their use in this condition has been markedly reduced
not only by their undesirable side-effects but also by
the advent of more modern drugs.
As the ideal properties for a glaucoma treatment vary
greatly from those of an antimydriatic miotic, this
chapter will only deal with the latter.
313
IDEAL PROPERTIES OF MIOTICS
1. Quick in onset.
2. A length of action appropriate to the mydriatic
previously employed. (duration)
3. An effect on the ciliary muscle that leaves the
patient without cycloplegia or cyclospasm.
4. An effect on the iris that allows a normal pupil light
reflex.
5. No other pharmacological effects for the drug .
6. No local toxic reactions.
7. No systemic toxic reactions.
314
MIOTICS
From the above it can be seen that there will be no
perfect miotic. Much will depend on the appropriate
selection of a miotic to follow the mydriatic.
At one time it was routine to instil a miotic after mydriatic
examination in all patients over the age of 40.
Nowadays, with the use of shortacting mydriatics such
as tropicamide, the necessity for the routine use
of miotics must be questioned and the advantages of the
miotic must be carefully weighed against its
disadvantages.
315
INDICATIONS FOR MIOTICS
Any miotic that is used should:
1.Reduce the danger of angle closure.
2. Avoid photophobia, especially on a bright, sunny day.
3 .Speed the return of accommodation.
4. Lower the intraocular pressure. This should not be too
elevated if the anterior chamber is sufficiently deep and
some mydriatics, e.g. phenylephrine, actually cause a fall in
I.O.P .
316
CONTRAINDICATIONS
1. The small pupil can lead to dimness of vision. This can
be a problem at twilight‫الشفق‬, especially if the patient is
proposing to drive a car.
2. A spasm of accommodation may be caused, leading to
pseudomyopia.
MODE OF ACTION
Mydriatics can cause mydriasis either by paralysing the sphincter
(antimuscarinic) or by stimulating the dilator (sympathomimetic).
Conversely, miotics can cause their effect either by :
1- inhibiting the dilator (alpha-blocking agents) or by
2- stimulating the sphincter (parasympathomimetics or
anticholinesterases).
Note: many of the miotic compounds are no longer commercially
available and only pilocarpine is in routine use.
317
MIOTICS ACTING ON THE PUPIL
SPHINCTER MUSCLE
The sphincter muscle is stimulated to contract by the
action of acetylcholine on muscarinic receptors, so
drugs can act by ;
A-mimicking the action of acetylcholine on the
muscarinic receptor (parasympathomimetic)
B-or by preventing the breakdown of acetylcholine by the
cholinesterase present at the cholinergic neuroeffector
junctions (anticholinesterases).
318
MIOTICS ACTING ON THE PUPIL DILATOR
MUSCLE
•As the sympathetic innervation to the dilator muscle is
stimulatory (motor), it is logical that alpha-receptors
predominate. The effect of noradrenaline on this muscle
can be blocked by an alpha-blocking agent (sympatholytic
miotics ).
1-Many alpha-blocking agents are available for use in
general medicine. They are used in the treatment of
hypertension and peripheral vasospastic conditions, .
2-Studies have been carried out with a new alpha-blocking
drug dapi-prazole (Molinari et al 1994), which is available to
eyecare practitioners in the USA and Canada under the
Trade Name: Rev-Eyes; it is not available in the UK.
319
320
321
PARASYMPATHOMIMETIC MIOTICS
• Parasympathomimetic miotics can be grouped into choline esters,
which are derivatives of acetylcholine, and cholinomimetic alkaloids,
which include pilocarpine, are coline and muscarine.
• By far the most commonly used parasympathomimetics miotic is
pilocarpine.
• PILOCARPINE
Obtained from the leaves of Pilocarpus microphyllus (the Jaborandi
plant) and other species of Pilocarpus, pilocarpine is a colourless,
syrupy, liquid alkaloid that is soluble in water. (The hydrochloride salt,
which is freely soluble in less than one part of water, is now preferred to
the nitrate (previously used) in the preparation of the eyedrops, because
it is compatible with a wide range of antimicrobial preservatives.)
322
Mechanism of action
Pilocarpine is a direct-acting parasympathomimetic agent
(compare with the indirect-acting physostigmine).
Like all such agents (including also such synthetic choline
esters as carbachol and bethanecol), its primary action is
the stimulation (or inhibition) of autonomic effector cells in
a similar manner to that accomplished by the acetylcholine
released by stimulation of postganglionic parasympathetic
nerves, that is, it acts primarily at muscarinic receptors of
autonomic effector cells.
323
CHOICE OF MIOTIC
In the past, optometrists had a choice of three miotics –
pilocarpine (a parasympathetic), physostigmine (an
anticholinesterase) and moxisylyte (an alpha-blocker) – and
would have based their choice on the mydriatic used and the
circumstances under which the patient would be placed while
the mydriatic was reversed naturally. Today, optometrists
have to choose between pilocarpine and nothing; with new
legislation ‫تشريع‬even pilocarpine will not be available.
Because of the short duration of the action of mydriatics and
the recognition of the rarity of the incidence of closed-angle
glaucoma, most patients can be safely spared the discomfort
of a miotic.
324
MIXED MIOTICS
Just as it was the practice in the past to use mixed mydriatics
Containing agents with different modes of action to produce synergy,
mixtures of miotics have also been employed. Whereas mixed
mydriatics always contain :
1- an agent acting on the pupil dilator muscle and
2-an agent acting on the pupil sphincter muscle, mixed miotics have
tended to contain a parasympathomimetic and an anticholinesterase
(e.g. pilocarpine and physostigmine), both of which are active on the
sphincter. Their use has been based on empiricism ‫ التجريبية‬rather than
pharmacological evidence.
325
ADVERSE REACTIONS TO MIOTICS
In the main, the most serious side-effects from miotics arise from their
chronic use in glaucoma or from possible overdosage during acute
glaucoma treatment rather than the single application used to reverse
mydriatics. However, miotics can cause transient effects that trouble
some patients and might therefore discourage the optometrist from
using them.
1-Moxisylyte (thymoxamine) is irritant on instillation, as are some other
miotics.
2-Miotics whose principal action is on the sphincter pupillae might also
cause a spasm of accommodation even in some presbyopic patients.
3-Abramson et al (1973) demonstrated an axial thickening of the lens
band with a decrease in anterior chamber depth in patients between
70 and 80 years of age.
4-If the miotic is much stronger than the mydriatic then the patient will
have smaller than normal pupils with some dimness of vision .
326
ADVERSE REACTIONS TO MIOTICS
This dimness of vision can be a problem, especially if combined with a
pseudomyopia from the spasm of accommodation.
5-The blood vessels of the conjunctiva will dilate in response to
parasympathomimetic agents and conjunctival injection might result.
6-Additionally, some patients might be allergic to pilocarpine, but this is
unlikely to develop after one instillation.
7- Anticholinesterases can have nicotinic as well as muscarinic effects
and these will be manifested as lid twitching.
8- Anticholinesterases have been implicated in cataract formation
(Pietsch et al 1972).
9-The parasympathetic nervous system supplies many of the visceral
structures and, theoretically, these might be affected by topically
administered agents. In particular, one could expect effects on the
respiratory, cardiovascular and gastrointestinal systems.
327
ADVERSE REACTIONS TO MIOTICS
a. Drugs that stimulate muscarinic receptors will cause
bronchoconstriction and could cause respiratory embarrassment to
asthmatic patients, but this is a theoretical possibility rather than an
actual danger.
b. Similarly, bradycardia (slowing of the heart) and vasodilation do not
appear to be problems.
c. Anticholinesterase can reduce the level of plasma cholinesterase,
leading to diarrhoea and adverse interaction with certain muscle
relaxants used in surgery, but this is only from chronic use.
Few systemic effects should therefore result from the postmydriatic
use of miotic. However, gastrointestinal symptoms such as diarrhoea
and vomiting and respiratory problems have been reported following
large doses of topical pilocarpine (Epstein & Kaufman 1965)al note
328
Precautions should be observed in the use of miotics following
mydriasis
The following precautions should be observed in the use of
miotics following mydriasis:
1.Explain to the patient or parent the reason for using a miotic.
2.Ask whether the patient has previously had a miotic instilled and
whether there was any adverse reaction to the drug used.
3.Issue a note which identifies the miotic used and provides
advice on what action the patient should take in the event of an
adverse reaction.
329
Chapter 13
Stains
330
Stains
Staining agents are some of the most useful diagnostic
agents, providing information fairly rapidly without
producing a pharmacological effect.
Their usefulness lies in their differential staining
characteristics.
Important clinical information is provided both by the
presence and the absence of staining demonstrated by the
use of these agents . Many dyes and substances have been
investigated in the past for their usefulness . Foster (1980)
lists 34 chemical substances that have been used for vital
staining of the eye, including such marvellous ‫ رائع‬names as
magadala red, safranin, brilliant black and Victorian
blue.Today only two stains are in regular use, fluorescein
sodium
and rose Bengal.
331
IDEAL PROPERTIES
1. Stains should be water soluble because vehicles other than water
will be toxic and/or interfere with staining patterns.
2. Stains should selectively stain certain cells or structures in the
eye.
3. They should not stain skin, clothes, contact lenses or any
instrument that is likely to come in contact with the eye when the
stain is present.
4. The effect should be reversible , either as a result of tear flow or
by use of an irrigating solution.
5. There should be no interference with vision.
6. There should be no other pharmacological effect.
7.They should be non-irritant to the surface of the eye.
8.They should be non-toxic, especially as one is looking for
pathological changes.
332
FLUORESCEIN SODIUM
Fluorescein is an orange–red dye that fluoresces in high dilution , used
as a topical stain, it can also be used as an injection for fluorescein
angiography. Fluorescein does not actually stain tissues, it merely
colours the tear film. The normal corneal epithelium is impermeable to
the tear film and substances dissolved in it , because the lipid
membranes at the surface of the eye act as an effective barrier against
polar, water-soluble substances. If this barrier is breached then the tear
film can gain access to deeper layers. There is a pH difference
between the surface and the deeper tissues and this causes a green
colour in the area of desquamation.
333
The factors that affect the fluorescence of fluorescein
The factors that affect the fluorescence of fluorescein have
been extensively reviewed :
1-The pH of the solution not only influences the
absorption spectrum (like any other pH indicator) but also
determines the intensity of the fluorescence, which is
highest at pH 8, and thus the area of defect is shown up.
After gaining access, the fluorescein will diffuse sideways
giving a slightly false picture.
2- Defects in the epithelium whether caused by trauma or
disease (e.g. dendritic ulcer), are disclosed ‫ كشف‬by the
stain.
334
OPTIMUM CONDITIONS FOR OBSERVATION
OF FLUORESCEIN
3- Absorption of light energy : light with a wavelength
between 485 and 500 nm is absorbed maximally. This
absorbed energy excites the fluorescein molecules and the
emitted light is in a lower energy state and of longer
wavelength. The fluorescent light appears green, having its
highest intensity at a wavelength between 525 and 530 nm.
335
INDICATIONS FOR USE
1.
2.
3.
4.
5.
6.
336
Detection of defects in the corneal epithelium.
Contact lens fitting.
Applanation tonometry.
Determination of nasolacrimal duct patency.
Assessment of tear break-up time.
Tear flow assessment.
Corneal defects
Fluorescein should be used routinely after foreign body
removal to detect any damage caused by the offending
object while it is present. If a small foreign body has
penetrated the eye, a corresponding green rivulet ‫ ممر‬will
be seen issuing from the entry hole.
Although fluorescein will also demonstrate corneal ulcers,
it might be better to use rose Bengal, which is more
selective.
Epithelial erosions due to trichiasis will be shown up but
fluorescein is of little help in the diagnosis of
keratoconjunctivitis sicca or other forms of conjunctivitis,
e.g. infective, allergic or chemical in origin.
337
338
Contact lens fitting
1- When fitting of rigid contact lenses, the dye is an aid in studying
the areas where the lens is clearing (green fluorescence) or touching
(purplish-blue) the cornea in the case of corneal lenses.
2- With scleral rigid contact lenses the same observations apply to the
optic area but a green coloration, or the absence of it will show where
there is clearance or contact, respectively, of the scleral portion of the
lens in relation to the sclera.
Textbooks on contact lens practice deal with the interpretation of
these observations in the appropriate detail.
Fluorescein sodium should not be used to study the fit of soft contact
lenses because it stains them following absorption into the polymer.
339
340
Applanation tonometry
In applanation tonometry (Fig. 10.1), the visibility of the fluorescein,
observed under cobalt-blue filter light, again assumes practical
significance.
The margin of the applanated area is delineated ‫ يرسم‬by a solution of
the dye; the ‘touch’ area (purplish-black) has a diameter of 3.06 mm
on the cornea. The concentration of the fluorescein is very important
in this technique and it should not be too low (as occurs with
excessive tearing), when the examiner’s visibility of it is impaired, or
too high. The best results are often obtained when using benoxinate
hydrochloride 0.1% as the local anaesthetic, as recommended by
Goldmann and by employing sterile fluorescein paper strips.
Because Goldmann-type applanation tonometers involve contact
with the eye, a topical anaesthetic has to be administered with the
fluorescein.
341
Applanation tonometry
342
Lacrimal patency
To demonstrate the patency of the lacrimal drainage system in
patients complaining of frequent and troublesome epiphora, a drop or
two of 2% fluorescein sodium eyedrops can be used. Alternatively, a
saline moistened fluorescein strip can be used to convey sufficient
amounts of the dye to the conjunctiva.
Then a few drops of saline solution are also instilled into the
conjunctival sac to increase the volume of liquid present and patients
are asked to blow their nose in a white tissue.
Yellow staining of the tissue proves patency of the lacrimal drainage
of this particular eye; the procedure is repeated for the other eye.
Absence of staining of the tissue does not necessarily indicate
obstruction to the passage of tears down the lacrimal passage way
until observation has shown that the lacrimal punctum is in correct
apposition to the globe of the eye.
343
344
Assessment of tear
As fluorescein colours the tear film, it can be used to assess the tear
break-up time break-up time (TBUT), which is the interval after blinking
for discontinuities to appear in the precorneal tear film. After a blink,
the tear film is formed anew ‫ من جديد‬and if the tears are coloured with
fluorescein, a uniform fluorescent layer will be seen. After some time
(usually much greater than the interblink period), convection ‫الحمل‬
‫ الحراري‬currents disrupt the normal trilaminar layer, the surface active
effect of the mucin is diluted and holes appear in the film.
1-TBUT can be lengthened by the application of viscous drops.
2- It is very much reduced in tear deficiency syndromes such as
keratoconjunctivitis sicca, .
3- Foster (1980) considers TBUTs of less than 10 seconds to be
pathognomic of dry eye.
4- If the tear film breaks up immediately, the eyes are open and breaks
appear repeatedly in the same place, there is probably some
pathological process at these sites.
345
Fluorescein
346
347
Tear flow assessment
The half-life of drops in the conjunctival sac is very
short. It will depend on the patency of the nasolacrimal
duct and the rate of tear production.
The rate at which fluorescein disappears from the
conjunctival sac can be taken as a measure of the tear
flow. Barendsen et al (1979) used fluorescein to estimate
the minimum permissible interval between the
application of drugs. Predictably, they found that
fluorescein concentration in the tear film decreased
faster in younger patients and thus viscous solutions
were cleared at a slower rate than aqueous ones.
348
STAINS
CONTAMINATION
Contamination of fluorescein eyedrops is a particularly
serious risk, even greater than that encountered with the
majority of other eyedrops. As these individual drops are
liable to become infected with bacteria and, at the same time,
are frequently used on damaged tissue that is prone to
infection, very great care must be taken in their use. Ps.
aeruginosa is an especially dangerous pathological
microorganism with which fluorescein eyedrops are inclined
to become invaded. Phenylmercuric acetate or nitrate in
0.002% strength is the best bactericide for preserving these
particular eyedrops, and this is effective against
Pseudomonas, given adequate contact time. However, the
safest method of their employment is sterile single-dose
units or sterile fluorescein-impregnated ‫ مخصب‬paper strips,
both of which are readily available and to be highly
349
recommended.
ROSE BENGAL
Rose Bengal is a brownish-red powder that is soluble in
water and is normally used as a 1% solution. Although not
approved for sale in the UK, rose bengal strips have been
prepared. This substance is a derivative of fluorescein but
has markedly different staining characteristics :
1- Crossing the cell membranes of dead cells but not living
ones.
2- Mucus threads will also be stained. Some practitioners
prefer to examine the eye after rose Bengal staining with a
green light.
3-While probably no optometric practice is without
ophthalmic fluorescein in some form, rose Bengal is
comparatively little used.
350
Rose Bengal
351
ROSE BENGAL
4- Rose Bengal also differs from fluorescein in its usage.
This is most likely due to:
(1) the initial irritation to the surface of the rose bengal (especially,
unfortunately, patients with dry eyes); and
(2) unfamiliarity with the results of rose bengal staining.
Rose Bengal is useful in the following conditions:
1.Dendritic keratitis: rose Bengal will stain the areas of the dendritic
ulcer. It is restricted to the processes of the ulcer and does not diffuse
to surrounding areas.
2. Keratoconjunctivitis sicca: the parts that are stained are the
exposed triangular areas in the interpalpebral conjunctiva. Such
staining constitutes a better diagnostic indication of dry eye than the
Schirmer tear test.
3. Keratitis neuroparalytica: extensive staining can occur in the same
regions as in keratoconjunctivitis sicca.
352
Keratitis neuroparalytica
Keratoconjunctivitis
sicca
Exophthalmos
353
Dendritic keratitis
ROSE BENGAL
4. Exophthalmos: if this is great enough to deny the eye of
the normal protection of the lids, drying will occur, which
will lead to changes in the exposed area.
5.Pressure areas due to contact lens wear: practitioners
can use rose Bengal during their initial assessment of
patients for contact lens tolerance.
6.It is equally useful in follow-up visits, when stains might
be found on the cornea or bulbar or palpebral conjunctiva
and, although not serious, provide an indication that
modification of the contact lens might be necessary.
354
MIXTURES OF FLUORESCEIN AND ROSE BENGAL
A mixed stain containing 1% fluorescein sodium and 1% rose
bengal was investigated by Norn (1964b, 1967), who concluded that
it was better than the individual stains alone. He examined normal
patients, patients with diseases of the cornea, conjunctiva and
lacrimal passages and contact lens wearers. For the latter, he
concluded that these vital stains are suitable for assessing damage
in relation to the wearing of contact lenses. He observed a punctate
red crescent on the lower bulbar conjunctiva but considered that
modification was indicated only in the presence of symptoms.
Triple staining with the above mixtures plus alcian blue has also
been examined . The three dyes stain different structures:
1.fluorescein stains epithelial lesions,
2.rose bengal stains degenerate cells and
3.alcian blue stains mucus.
alcian blue
355
OTHER STAINS
Alcian blue
• The following stains are seldom used but nevertheless
are of interest:
• Alcian blue Acomplex copper-containing compound
used in 1% solution and specific for staining mucus.
• Alcian blue is used to counterstain rose bengal ,which
, in addition to staining dead cells, also stains mucus .
• If a break in the integrity of the epithelium exists, the
exposed deeper layers will be stained a pale blue–
green colour with alcian blue which will persist for
several months (Norn 1964b).
356
Methylene blue
Dwyer-Joyce (1967) reported on methylene blue, a
bacterial stain that will also vitally stain nerve tissue. Like
rose bengal, it will outline an area of ulceration in
herpetic keratitis. Hitchen (1971) refers to its ability to
artistically ‫ فنيا‬stain corneal ulcers when combined with
fluorescein, the ulcer appearing as a dark blue area with
a green halo.
357
The following precautions should be observed when
using stains
• When an impregnated strip is used as the source of
fluorescein, it should be moistened with sterile saline and
any excess shaken off before gentle application to the
bulbar conjunctiva.
• Care should be taken not to splash ‫ تلويث‬either stain on
the patient’s face or clothing.
• To avoid discoloration, soft lenses must be removed prior
to the use of either stain. After the use of fluorescein, for
example, they can be re-inserted, having irrigated the eye
and when the stain can no longer be seen upon reexamination with the slit-lamp microscope.
358
Chapter 14
Contact solutions
359
Contact lens solutions
Commercially produced contact lens solutions date from this
Period 1950 . Initially, two types of solution were introduced,
1- one for ‘wetting’, which was intended to promote tear flow over the
PMMA surfaces, and
2- another for ‘soaking’, with which the storage case was filled to
achieve disinfection of the contact lenses.
Gas permeable rigid materials, which evolved rapidly from the 1970s,
tend to be more susceptible to deposits than PMMA but less so than
hydrogels. Soft hydrogel contact lenses were introduced in the 1960s
and became widely available a decade later.
360
Contact lens solutions
Hydrogel lenses have a greater affinity for surface deposits than
rigid lenses and this problem was addressed by means of the following,
alternative strategies:
1.The introduction of enzymatic cleaners intended for use about once a
week.
2. The development of various ‘deposit resistant’ hydrogels.
3. Limitation of the ‘lifetime’ of the lenses : originally, this option was
achieved by the planned replacement of lenses after 6 or 12 months.
4.The development of the moulding method ‫طريقة صب في القوالب‬of
manufacture permitted the low- cost production of disposable lenses that
are discarded after 1 month’s or after 1 day’s use.
5.Soft silicone hydrogel lenses with very high oxygen permeability
became available in the late 1990s and, in comparison with conventional
‫ تقليدي‬hydrogels, adsorb less protein, and exhibit greater lipid deposition.
361
Contact lens solutions
The functions of the care products required by a contact
lens patient vary according to:
1- the type of lens worn and its ‘lifetime’ and are Rigid
lenses that are worn on an extended or continuous basis
might need to be removed from time to time for cleaning,
2- the use of a comfort’ product can be especially
beneficial on waking to encourage lens movement.
3- Those hydrogel and silicone hydrogel lenses that are
worn on an
extended or continuous basis are generally discarded
after 1 month’s use, or less and might require only the use
of ‘comfort ‘ drops.
362
The reasons for the use of contact lens solutions
are to:
1. facilitate contact lens wear (e.g. wetting the
surface of rigid lenses)
2. maintain the optical and physical properties of
the contact lens (e.g. storage solutions for
hydrogel lenses)
3. reduce the risk of infection (e.g. overnight
storage of lenses in a solution that disinfects
them).
363
WETTING SOLUTIONS
Although dedicated, ،‫‘مخصص‬stand-alone’ wetting solutions are no
longer available they are mentioned here briefly to establish the
importance of the wetting function of multipurpose solutions for
rigid contact lenses.
Wetting solutions were developed in the 1950s with the specific aim
of rendering the surface of a rigid contact lens relatively hydrophilic.
They were applied to the lens following its removal from the storage
case i.e. to a disinfected lens. They contained a surface active agent
that reduced the contact angle of tears on the contact lens surface
and provided a viscous ‘coating’ that encouraged the lens to adhere
to the finger during insertion.
364
Multipurpose solutions of contact lenses
365
WETTING SOLUTIONS
The solution also acted as a lubricant between the
contact lens and cornea, thereby enhancing comfort.
Today, it remains necessary to warn patients not to lick
‫ لمس‬a lens to remove foreign matter from its surfaces.
Wetting solutions contained a wetting agent, a viscosityincreasing agent such as polyvinyl alcohol (PVA) and a
preservative. Commonly, the preservative used was
benzalkonium chloride, the efficacy of which was
enhanced by the addition of the chelating (chelating agent
in order to remove a heavy metal such as lead from the
bloodstream) agent ethylene diamine tetraacetic acid
(EDTA).
366
SURFACTANT ‫السطح‬CLEANER
• Cleaning is an important step prior to disinfection
of all contact lenses (except daily disposable
lenses, which are simply discarded after use).
• Although multipurpose solutions can perform
both of these functions, surfactant cleaners are
still available. They have a detergent action ‫عمل‬
‫المنظفات‬that enables them to emulsify‫ استحلب‬lipids
and some organic deposits.
367
Contact lenses attract a variety of contaminants, including
fats and proteins from tears. Other contaminants will occur
depending on the patient’s lifestyle (e.g. nicotine).
Deposits occur both on rigid lenses and on hydrogel lenses
of either low or high water content.
The level of deposit formation appears to be proportional to
the water content of hydrogel lenses and is also influenced
by the surface charge of the hydrogel.
1- Ionic, high-water-content lenses have a greater affinity for
protein deposits than
2- Non-ionic lenses, and non-ionic low-water-content lenses
attract the least protein.
368
369
ADVANTAGES OF DAILY CLEANING OF CONTACT LENSES
1. Improves the clarity of the lens: daily cleaning removes
endogenous contaminants (i.e. tear-film constituents such as
mucus, lipids and protein) together with exogenous
contaminants such as cosmetics and environmental
pollutants.
2. Prolongs the successful wearing time (Hesse et al 1982).
3. Reduces the level of microbiological contamination: daily
cleaning physically removes contaminated debris. The
preservatives in the solution are capable of achieving some
disinfection.
4. Improves the efficacy of subsequent disinfection by
exposing clean surfaces to this process.
5. Removes possible nutrients on which organisms can grow.
370
ADVANTAGES OF DAILY CLEANING OF CONTACT LENSES
6. Can reduce toxic effects from disinfection solutions:
daily cleaning removes contaminants to which
preservatives might bind.
7. Reduces the adherence of organisms to the lens: it has
been shown that tear components adsorbed onto the lens
surface enhance the adherence of microorganisms to
lenses but some might adhere even to clean lenses .
Failure to remove tear proteins before disinfection with
hydrogen peroxide (or heat) allows the protein to become
denatured and acts as an antigen.
8- Daily cleaners contain a surface active agent, or
detergent, which reduces the surface tension of fats and
other lipophilic substances.
371
DISINFECTING SOLUTIONS
With the exception of daily disposable hydrogel lenses, all
contact lenses need to be disinfected after their removal
and cleaning.
1- Dry storage: If rigid lenses were stored dry, any organic
contaminants on them would support the growth of
microorganisms. The surface wetting properties of some
rigid gas permeable materials would be impaired by dry
storage.
2- Wet storage of hydrogel lenses is essential not only to
ensure disinfection but also to maintain their hydration
because they have a water content that can range from 38
to 80%.
372
DISINFECTING SOLUTIONS
Two types of solution are currently used to achieve disinfection of
contact lenses:-
1- A stable solution containing a preservative that has been
formulated for use either with rigid contact lenses or with hydrogel
and silicone hydrogel lenses.
2- A transient solution containing an antimicrobial agent that is
inherently ‫بطبيعتها‬unstable and is broken down by a neutralizer until
none of the active ingredient ‫العنصر النشط‬remains. Such solutions were
originally introduced for use with hydrogel lenses but can also be
used with rigid and silicone hydrogel lenses.
Any system of disinfection should be effective not only
against commonly used challenge bacteria such as Staph.
aureus, Ps. aeruginosa and Escherichia coli, but also on
many types of bacteria and other organisms such as fungi
and acanthamoebae.
373
Multipurpose solutions
Solutions intended for both cleaning and disinfection of
hydrogel lenses were introduced in 1994 and, by 2005,
represented the care system used by 91% of patients in the
UK .
The popularity of multipurpose solutions is due to the fact
that they simplify contact lens care for the patient and this,
it is hoped, enhances compliance.‫ يعزز االمتثال‬The most
recent development in the quest for‫ البحث عن‬simplification is
the ‘no rub’ multipurpose solution, which eliminates the
rub-and-rinse ‫ شطف‬step.
Nevertheless, one study indicated that the greater the
number of steps in a regimen, the greater its disinfecting
efficacy. Rinsing the lenses prior to disinfection was
considered to assist this process .
374
Multipurpose solutions of contact lenses
375
Multipurpose solutions- preservatives
These solutions incorporate preservatives regarded as
‘novel’ in the sense that they have not been in general use in
other ophthalmic products and are of high molecular weight.
Examples are the biguanide preservative polyhexanide .
It is used in a concentration of 0.00005 to 0.0001% and
provides efficient antimicrobial action even in high dilution.
Polymeric biguanides have found use as general disinfecting
agents in the food industry and for the disinfection of
swimming pools. polyhexanide is a membrane-active agent
that also impairs the integrity of the outer membrane of
Gram-negative bacteria .
376
TRANSIENT OR OXIDATIVE DISINFECTING SOLUTIONS
Hydrogen peroxide was the first chemical means of disinfection of
hydrogel lenses to be introduced as an alternative to heat disinfection
and the extent of its usage has varied over the years.
In 2005, it was used by only 10% of patients in the UK .
Advantages of hydrogen peroxide are:
1• It is free of preservatives, to which some patients exhibit an allergic or
toxic response.
2• Its broad spectrum of antimicrobial action against bacteria, viruses
and yeast. A 3% solution can kill trophozoites of Acanthamoeba
castellanii after 3 min and cysts after 9 hours.
How to use?:
1-The original procedure involved soaking the lenses in 3% Hydrogen
peroxide for 5 min,
2- They were then exposed to sodium bicarbonate (0.5%) to accomplish
neutralization .
3- Following two changes of saline, the lenses were stored overnight in
fresh saline.
377
Hydrogen peroxide for contact lenses
378
TRANSIENT OR OXIDATIVE DISINFECTING
SOLUTIONS
The time-consuming nature of this multistep process
prevented the popular use of hydrogen peroxide until simpler
means of neutralization were developed.
Hydrogen peroxide has been used for many years as a
surface disinfectant and for its bleaching‫ التبييض‬effect.
Its strength can be described in terms of volumes (10 volume,
20 volume, etc.). A 10 volume solution possesses 10 times its
volume of oxygen when it breaks down. Tragakis et al (1973)
found that hydrogen peroxide was very effective against all
the organisms used in their tests .
379
Two-step disinfection
When used to disinfect contact lenses, it is necessary to neutralize the
peroxide after an interval of time and early products were described as
‘two-step’, which means that the patient carries out disinfection and
neutralization as separate stages in the procedure.
The advantage
of a two-step system are:
1. The extended duration of antimicrobial action that can, for
example, be overnight.
2. In hot, humid climates that favour microbial proliferation,
overnight storage in hydrogen peroxide is advantageous.
3. Suitable when contact lens wear is intermittent rather than
daily.It is important that neutralization of the peroxide is not
undertaken too rapidly.
380
Two-step disinfection
In one system, a solution containing the enzyme catalase is
added to the storage case after the hydrogen peroxide has
been discarded.
Although a two-step system is compatible with non-ionic
high water content hydrogel lenses, ionic high-watercontent lenses undergo marked hydration changes as a
consequence of the lengthy immersion in hydrogen
peroxide. Lowe et al (1993) concluded that the latter lens
type should not be used with this peroxide method.
381
Two-step disinfection
A disadvantage of some two-step processes is
the need for the patient to remember to initiate
neutralization. The pH of hydrogen peroxide is
in the range of 3.5–4.5 (McKenney 1990) and the
patient who omitted to neutralize it before
inserting a lens into the eye would make this
mistake only once due to the resultant degree of
discomfort.
382
One-step disinfection
One-step systems were introduced to simplify the procedure
for the patient and have the advantage that the vital step of
neutralization cannot be overlooked.‫التغاضي‬
The disadvantages are:
• The duration of the disinfection stage is less than with twostep products.
• Unsuitable for long-term storage of lenses.
About 90% of the hydrogen peroxide systems now used are
one-step. In one such system, a platinum disc in the storage
case is used as a catalyst to break down the peroxide into
oxygen and water. Having filled the case with 3% peroxide,
there is an initial rapid phase of neutralization resulting in a
concentration of 0.9% after 2 min,
383
One Step Disinfectant
Oxysept 1 Step Disinfecting
384
pharmacydirect.co.nz
One-step disinfection
which is followed by a slow phase to approximately 15
parts per million (ppm) after 6 hours. Such a level is
below the threshold of subjective sensitivity (50–300
ppm) and that at which adverse effects on the mitotic
activity and movement of epithelial cells occur.
Another one-step system uses a tablet coated with
hydroxypropylmethyl cellulose, which contains catalyse,
which is slowly released after 30 min. with reactive
neutralization to a final peroxide level of 1 ppm after
about 2 hours.
385
One-step disinfection
Microbiological contamination of the contact lens storage
case regularly receives attention as a possible source of
infection in wearers.
Wilson et al (1990) found that cases disinfected with
peroxide systems showed a lower level of microbial
contamination than those in which other methods of
disinfection had been used. Frequent replacement of the
storage case remains the best means of avoiding the risk of
its contamination (Devonshire et al 1993).
386
One-step disinfection
Although hydrogen peroxide was adopted for use with
hydrogel lenses, it can also be used with rigid and silicone
hydrogel lenses.
However, it has been reported that one silicone hydrogel
(PureVision) suffered parameter changes when used with a
one-step peroxide system.
Other transient alternative transient solutions have been
introduced from time to time disinfectant solutions but have
fallen into disuse. Oxidizing agents such as iodine and
chlorine have antimicrobial effects, especially against
anaerobes.
387
One-step disinfection
1- A brown-coloured iodine solution was reduced
by a neutralizing agent to the inactive colourless
iodide, the reaction producing a mixture of
electrolytes, none of which were foreign to the
eyes.
2- Chlorine, which like other halogens acts a
disinfectant and mild cleaning agent, was used in
two products one of which contained dichlorosulphamoyl benzoic acid (halozone) and the other
sodium dichloro-isocyanurate.
388
LIMITATIONS OF PRESENT METHODS OF CONTACT
LENS DISINFECTION
Two examples can serve to demonstrate the limitations of
contact lens disinfection with a multipurpose solution or
with hydrogen peroxide.
1- Bacillus cereus is a possible aetiological agent of
contact lens-associated keratitis. Heat and many types of
contact lens disinfecting solutions appear to be ineffective
in eradicating B. cereus from contaminated contact lens
cases whereas hydrogen peroxide was sporicidal.
2- Adenovirus has been shown to survive chemical and
hydrogen peroxide disinfection but not heat sterilization.
As heat sterilization is generally unavailable in a practice,
patients with adenoviral keratoconjunctivitis should simply
discard contact lenses worn at the onset of the infection.
389
Preserved saline
Preserved saline has been used to enhance the efficacy of heat
disinfection but is generally used today to rinse contact lenses. The
function of preservatives in saline solutions is to maintain solution
sterility and not to provide a means of contact lens disinfection.
Preservatives can pose the risk of allergic and toxic reactions. Shaw
(1980) demonstrated the relationship between preservatives and the
incidence of solution allergy.
In a double masked randomized crossover study, six subjects
used an unpreserved saline solution and a preserved saline solution
These subjects had a probable history of sensitivity to preserved
solutions which was confirmed in this investigation.
390
Preserved saline
Preserved saline solutions containing ethylene
diamine tetraacetic acid (EDTA ) as part of the
preservative system have a useful deposit resistant
effect compared with an unpreserved saline
solution (0.001% thiomersal and 0.1% EDTA).
Pressurized containers both buffered and
unbuffered forms of sterile saline have been made
available in aerosol-type containers. This mode of
presentation of saline requires no preservatives.
391
Preserved saline
Single-use containers available both preserved and
unpreserved, sachets ‫ كيس‬have the major advantage of
remaining sterile until opened. Their disadvantage is the
greater cost.
Non-clinical use : When a saline solution is used
specifically to undertake standardized saline for contact
tests to determine dimensions, physical, chemical and
biological lens testing characteristics of contact lenses and
contact lens materials, it should be formulated in strict
accordance with the relevant ‫ ذو صلة‬International Standard.
392
ENZYMATIC CLEANERS
Tablets containing an enzyme are dissolved in either saline
or distilled water to remove denatured protein deposits from
the surfaces of contact lenses. They were originally
introduced for use about once a week with hydrogel lenses
but, if necessary, can also be used with rigid contact
lenses. A film of protein, mainly lysozyme (Hosaka et al 1983)
but with amounts of albumin and globulin from the tears, can
build up on lenses and be difficult to remove with the
surfactants in the daily cleaning solutions is in need for
enzyme to remove this film.
393
Papain
1- Papain, one of the enzymes used in protein remover
tablets, is a thermostable endopeptidase found in the
pawpaw fruit. ‫الفاكهة الباباية‬
2- Pronase is comprised of a bacterial protease, a lipase
and pancreatin is composed of protease, a lipase and an
amylase.
3- Subtilisin is derived from the bacterium Bacillus
licheniformis.
In a comparison of the efficacy of papain and subtilisin,
the former proved to be better with medium and heavy
deposits and the latter was better with light deposits.
394
Papain
However, when chemical disinfection and enzymatic
cleaning was compared with oxidative disinfection alone
H2O2 (Lasswell et al 1986), the lenses treated by the former
method were significantly cleaner than those treated by the
latter. The use of protein-removing tablets is not an
alternative to daily cleaners because the two agents are
complementary. Lenses treated with either type of cleaner
were contaminated more than those treated with both.
395
COMFORT DROPS
These drops, which are also referred to as re-wetting, conditioning or
cushioning drops, can be instilled into the eyes of contact lens wearers
at any time during wear to enhance comfort.
The eye can tolerate adverse atmospheric conditions, and while it can
also tolerate the wearing of contact lenses, it sometimes has difficulty
in coping with both.
Factors that reduce contact lens tolerance:
1- In particular, dry, smoky environments can produce changes in the
lens–tears system, which turns an acceptable situation into an
intolerable one.
2-Certain drugs such as antihistamines, which have an antimuscarinic
effect, can reduce contact lens tolerance.
3- Hormonal changes in women can also modify the quantity or quality
of tears.
396
ALTERNATIVE METHODS OF HYDROGEL CONTACT LENS DISINFECTION
Electrical systems employing ultraviolet light and/or
ultrasound have been shown to be only partially effective
when subjected to a microbiological challenge.
However, Dolman & Dobrogowski (1989) found that a 253.7
nm ultraviolet (UV) light with an intensity of 1100 W/cm2
achieved satisfactory disinfection with short exposure
times. Acanthamoeba polyphaga was sterilized in less than
3 min. Harris et al (1993) similarly concluded that ultraviolet
radiation of this wavelength is an effective and rapid
method of disinfecting contact lenses.
397
HYGIENIC CARE OF TRIAL LENSES
In the UK, 96% of new contact lens patients are fitted with
soft lenses (Morgan & Efron 2005). The ready availability of
disposable soft lenses allows the practitioner to undertake
fitting and wearing trials with freshly opened, sterile
lenses. After assessment of the fit or a period of wear, the
lenses are discarded.
In the case of rigid lenses, it is usually considered to be
necessary to evaluate the fit of several lenses from a nondisposable fitting set to decide the specification to be
ordered.
The use of trial lenses assumes particular importance
when complex designs such as bifocals are to be supplied.
398
Chapter 15
Therapeutic drugs
and their uses
399
Drugs for the treatment of infections
The term ‘anti-infective’ covers a wide group of agents that
are effective against a variety of infections (e.g. viruses,
rickettsiae, bacteria, fungi and protozoa). The mechanism
of action of these agents varies greatly and, to some
extent, will depend on the organism on which the particular
agent acts. In the majority of cases, however, some
competitive inhibition of a biochemical process is
involved. As a result, the concentration level of the
antibacterial (and hence the dose) are fundamental to the
success or otherwise of antibacterial treatments.
400
Drugs for the treatment of infections
Minimum inhibitory concentrations (MICs) are often
published for the common anti-infective drugs. These values
will vary according to the infecting organism, the MIC for a
strain of methicillin-resistant Staphylococcus aureus is
considerably higher than that for normal Staph. aureus.
When it comes to treating ophthalmic infections, there are
many more factors to take into consideration.
1-The locus (site ) of infection will determine not only the
route of administration but also the prognosis. Infections of
the anterior eye will respond better to treatment than those
further back.
2-The level of inflammation and
3- Tear flow will similarly affect the absorption of antiinfective agents.
401
ANTIBACTERIALS
As with most ophthalmic drugs, the antibacterials used on
the eye were originally developed for systemic use.
However, in the main, it is the ones that have no , or very
restricted, systemic use that are most popular for the
treatment of the eye. Although some antibacterials are
marketed as simple ophthalmic preparations, containing
just one active ingredient, many preparations contain
either a combination of 2 or more antibacterials or a
steroid and antibacterial.
402
Drugs for the treatment of infections
Antibacterials can be divided into the following groups:
1- beta-lactams
2 - tetracyclines
3- macrolides
4 - chloramphenicols
5- fluoroquinolones
6 -aminoglycosides
7- sulfonamides
8 - miscellaneous agents.
403
BETA-LACTAMS
These agents are so called because of the
presence of a beta lactam ring in their
chemical structure. They all produce their
effect by interfering with the synthesis of
the cell wall by binding to certain enzymes
in the cell membrane that are responsible
for the building of the cell wall,
producing morphological changes in the
bacteria they affect. Long filamentous cells
are produced, which fail to divide.
Lysis of cells can occur due to the
antibacterial action of some autolysins
which normally only function during cell
division.
404
BETA-LACTAMS
They can be divided into two main groups: the penicillins and
cephalosporins. The principal agent in this group is penicillin, the original
antibiotic.
Although penicillin is still extensively used in systemic medicine, several
synthetic derivatives have been developed with broader spectrums (e.g.
amoxicillin and ampicillin) whereas others are resistant to penicillinase
(e.g. flucloxacillin). Some newer penicillins even have anti-pseudomonal
activity (e.g. piperacillin). They all share the danger of inducing a possible
fatal anaphylaxis in certain, susceptible patients.
Resistance to penicillins can be caused by difficulty of the compound
penetrating to the site of action. Penicillins pass across the ocular
barriers very poorly and products containing them are rarely used in the
treatment of ocular infections.
405
TETRACYCLINES
Tetracyclines are a group of broad-spectrum antibiotics that include
chlortetracycline, demethylchlortetracycline, oxytetracycline, tetracycline
and doxacycline. There is little to choose between them with the
exception of doxacycline, which has a broader spectrum and more
specific indications.
Tetracyclines are effective against Gram-positive and Gram-negative
bacteria, as well as spirochaetes, chlamydiae and other organisms.
Resistance :
Pseudomonas and Proteus are resistant to these agents.
Side effects :
1- tetracyclines taken orally can cause stomach upsets (nausea, vomiting
and diarrhoea),
2- they are best known for their effects on bone and teeth in children.
406
TETRACYCLINES
They permanently colour teeth yellow and slow bone
growth, due to their ability to chelate ‫تتحد ب‬calcium and
magnesium.
3- Adverse effects from topical application are rare due to
the low dose of drug that the patient receives in one drop
of solution compared with the systemic dose.
If a drop of 1% tetracycline solution were to be applied four
times a day, it would take 4 months for the equivalent of
one oral dose to be administered.
Penetration across the intact cornea is poor and these
compounds are best used for surface infections as
ointment .
407
Ophthalmic uses of tetracyclines
Topical tetracycline is used in treatment of :
1- trachoma (normally in ointment form).
2- for ophthalmia neonatorum prophylactic drug of choice .
Raucher & Newton (1983) recommend intramuscular
penicillin and tetracycline 1% ointment as a prophylactic
agent. If the infecting organism is chlamydial, then
tetracycline treatment is to be preferred over other
antibiotics for long term treatment.
408
THE CHLORAMPHENICOLS
Spectrum of action :Originally isolated from cultures of
Streptomyces venezuelae, chloramphenicol is effective
against a whole range of bacteria and other organisms
such as chlamydiae, rickettsiae and spirochaetes. Of the
bacteria against which chloramphenicol is effective, there
are many ocular pathogens such as Corynebacterium spp,
E. coli, Haemophilus spp and streptococci.
•It has been recommended in treatment of:1-the routine treatment of ophthalmia neonatorum .
2-Its effect against chlamydiae has led to its use in trachoma, although
its usefulness for this condition is probably in the treatment of the
secondary infections that are responsible for many of the adverse
effects of the infection.
3- However, it is not effective against most strains of Ps. aeruginosa
and Serratia marcescens.
409
THE CHLORAMPHENICOLS
•Mode of action :The bacteriostatic action of chloramphenicol is due to
the inhibition of protein synthesis by interaction with the bacterial
ribosomes.
• Resistance to chloramphenicol is brought about by the production of
inactivating enzymes (chloramphenicol acetyltransferase).
One of the reasons for the popularity of chloramphenicol as an
ophthalmic antibacterial is that it is rarely used systemically and thus
there is little chance of cross-resistance developing. In a study of 738
patients, only 6% of the organisms cultured were resistant to
chloramphenicol. This resistance rate was lower than for any other of
the antibiotics tested .
410
Chloramphenicol
Apart from its employment in the treatment of lifethreatening conditions such as typhoid, salmonella
infections and bacterial meningitis, the systemic use of
chloramphenicol is very restricted today because of the
possibility of aplastic anaemia producing agranulocytosis.
From systemic treatment, the incidence is about 1 in 50 000
patients and from topical use, the incidence is much lower.
Trope et al (1979) failed to find systemic absorption after
drops were administered every 2 hours for 5–7 days. This
has not prevented a reluctance ‫ممانعة‬by some clinicians to
use chloramphenicol. However McGhee (1996) points out
that the theoretical risk of a fatal blood dyscrasia ‫ اعتالل‬is
about the same order as that of fatal penicillin anaphylaxis.
411
Chloramphenicol Treatment uses
Treatment uses: Chloramphenicol has a high lipid solubility
and in a study on ovine ‫غنم‬eyes was found to be retained in
the cornea at higher levels than the aqueous humour.
1- Chloramphenicol remains the first-line treatment for minor
infections such as bacterial infections , chloramphenicol is
an excellent topical antibiotic, although topical use can
sometimes lead to irritation. It is available as a 0.5% solution
or a 1% eye ointment.
2- Intramuscular injections have been recommended for the
treatment of trachoma .
412
THE FLUOROQUINOLONES
This group of broad-spectrum
antibiotics includes: norfloxacin,
levofloxacin, ciprofloxacin and
ofloxacin.
The latter two have been formulated
for ophthalmic use. The precursor to
this group was nalidixic acid, which
was introduced in the early 1960s.
• Mode of action: The fluoroquinolones
interfere with the production of DNA
by inhibiting the enzyme responsible
for producing the coils of the nucleic
acid in the bacterial cell.
413
THE FLUOROQUINOLONES
• Resistance: the emergence of resistant strains is low and there is
no cross-resistance with other antibiotic groups such as the
aminoglycosides.
• Spectrum of action:
Fluoroquinolones are well absorbed after
oral administration and are used to treat many common infections,
especially those of the:
1.upper and lower respiratory tract
2.urinary tract, including gonorrhoea.
3.They are effective against a wide range of bacteria both Grampositive and Gram-negative.
4.They are active against Staphylococcus spp, including those
resistant to penicillin and some strains of those resistant to methicillin
Gram-negative bacteria include some strains of Ps. aeruginosa, even
some that are resistant to aminoglycosides
5. They are less effective against streptococci.
414
THE FLUOROQUINOLONES - Ciprofloxacin
Ciprofloxacin ophthalmic form : As a result of
these studies, an ophthalmic form of
ciprofloxacin has been introduced as a 0.3%
solution. Absorption into ocular tissues is good,
leading to aqueous humour levels that exceed
the MIC of many ocular pathogens.
It also produced least experimental damage to
rabbit corneae. Tear levels are also maintained
above MICs for many bacteria up to 4 hours
after instillation in healthy individuals .
415
THE FLUOROQUINOLONES
•Fluoroquinolones Systemically Adverse Effects:
1- gastrointestinal disturbances being the most common
adverse reaction.
2-Other reactions include dizziness and skin reactions.
The antibacterial activity on the eye
They are claimed to have better penetration of the cornea,
conjunctiva and anterior chamber together with less tissue
toxicity.
416
THE FLUOROQUINOLONES
activity on the eye
1- Dacryocystitis :In vitro toxicity of a range of
fluoroquinolone agents has been tested to ascertain which
of them was most suitable for use in the eye and
norfloxacin has been compared with gentamicin in the
treatment of congenital dacryocystitis.
2-Lomefloxacin has a wide antibacterial spectrum and is
well absorbed. It demonstrated good antipseudomonal
activity in the treatment of experimental bacterial keratitis.
3- Lomefloxacin has been shown to be as effective as
tobramycin in the treatment of bacterial conjunctivitis and
blepharitis .
417
Therapeutic drugs and their uses
AMINOGLYCOSIDES
This is a group of complex antibiotics that are alike in
activity and toxicity and include amikacin, streptomycin,
neomycin, gentamicin and tobramycin.
Mode of action : All aminoglycosides are rapidly bactericidal
and inhibit protein synthesis by combining with mRNA
leading to suppression of ribosomes function ,but this
does not explain their rapidity of action. The transport of
the antibacterial into the cell can be reduced by low pH
and aerobic conditions ..
418
AMINOGLYCOSIDES
As the antibacterial enters the cell it increases the rate
at which further amounts can pass in. This leads
eventually to disruption of the cell membrane and
rapid death of the cell.
Resistance can be brought about by the production of
enzymes low affinity of the( that protect ) ribosomes.
419
Neomycin
Neomycin, like chloramphenicol, is favoured as a topical
antimicrobial because of the relatively rare systemic
use. Neomycin is not absorbed from the gut and is too
toxic for parenteral administration. As a result, its use
is restricted to either disinfecting the gut prior to
surgery or as topical preparation for skin or mucous
membranes
Like all aminoglycosides neomycin can produce
nephrotoxicity and ototoxicity but this is not known to
occur from topical use.
420
Neomycin
However, keratoconjunctivitis can develop as a result of
hypersensitivity to neomycin after ophthalmic use.
Neomycin has a broad spectrum of activity but is not
effective against Ps. aeruginosa.
Although preparations of neomycin alone (drops or eye
ointment) are used, it is most often encountered along
with steroids to produce antibiotic cover while
treating inflammation.)dexamycin or neodex eye drops)
421
Gentamicin
Gentamicin is another aminoglycoside antibiotic with the
same toxic effects as neomycin. It is one of the more
effective agents in this group and will kill many strains of
Ps. aeruginosa. It is the treatment of choice for this
organism , although resistant strains of Pseudomonas
have been found .
Gentamicin is given by injection for serious systemic
infections when the nature of the invading organism is
not known, and therefore it should be kept for serious
infections of the eye where other antibacterial agents are
ineffective.
The large number of topical gentamicin preparations
available has resulted in gentamicin resistant
422
Pseudomonas
infections.
Absorption Gentamicin
1-Absorption across the corneal epithelium is very poor.
Hillman et al found that after application of gentamicin by
drops very little appeared in the aqueous humour.
2-Subconjunctival injection produced effective corneal concentrations in
2 hours and these were maintained for 24 hours.
3-If a deep infection (endophthalmitis) of the eye occurs,
it is best treated by a slow intravitreal injection.
4-Reversible cellular oedema has been reported in the
corneal endothelium following anterior chamber injection.
5-Systemic injection will not give rise to sufficient ocular
levels because of its poor ability to cross the
blood/aqueous barrier. It is usually applied as a 0.3%
solution but more concentrated solutions have been
recommended for the treatment of bacterial corneal ulcers.
423
.
Gentamicin-Side effects
1-Gentamicin is a very toxic compound and, like other
aminoglycosides can cause damage to the ears and
kidneys. Both parts of the ears are affected and so ataxia
‫ ترنح‬due to vestibular damage and deafness from cochlear
damage are the results of toxic doses.
2-Hypersensitivity reactions can occur after local use and
patients who are sensitized to one aminoglycoside, will
react to others.
424
FUSIDIC ACID
Fusidic acid is used extensively as a topical antibiotic as
well as to a lesser extent internally in the form of tablets.
Internally, the drug is well tolerated, although it can cause
liver damage and jaundice, which is reversible on
discontinuation. Lately it has become very popular for the
treatment of bacterial conjunctivitis in the form of a viscous
drop that needs to be applied only twice day. (Fucithalmic
eye drops)
It has potent bacteriostatic or bactericidal activity against
Gram-positive bacteria,
Mode of action: produces this effect by inhibiting protein
synthesis, although, unlike other antibiotics, it does not
bind to ribosomes.
425
426
FUSIDIC ACID
Spectrum of action: It is effective against gram positive
bacteria like Staph. Aureus (including some strains of
methicillin- resistant Staph. aureus).
Most Gram-negative bacteria are resistant but it does have
some activity against Neisseriae spp. It is used as a 1%
viscous drops and, as mentioned, requires only a twice-a
day dosage to achieve satisfactory results in the treatment
of acute conjunctivitis.
427
FUSIDIC ACID
Therapeutic uses:
It is now often used as the front-line treatment of
conjunctivitis. Compared with chloramphenicol ointment
it has a much better compliance (James et al 1991).
Resistant strains :
can develop quickly. Hovenden et al (1995) found a large
number of resistant strains , which previously sensitive
organisms become increasing from conjunctival swabs.
428
ANTIBIOTIC RESISTANCE IN BACTERIA
It appears that almost as soon as a new agent is produced a
resistant strain of bacteria develops. Due to the rapid
reproduction rates of bacteria (with divisions happening
every 20 min in some strains under ideal growing conditions),
the possibility of spontaneous mutations occurring is quite
high.
Luckily, under normal treatment conditions, the great
majority of the sensitive organisms are killed by the
antibiotic, leaving the body to cope with the few resistant
bacteria. However, by genetic information which codes for
resistance can be passed to other organisms.
429
ANTIBIOTIC RESISTANCE IN BACTERIA
The routes by which resistance can occur are as follows:
1- The production of an inactivating enzyme: penicillin can
be broken down by beta-lactamase, which is principally
produced by strains of Staph. aureus but also by some Gram
negative organisms . Chloramphenicol and aminoglycosides
can be inactivated by chloramphenicol acetyltransferase,
which is produced by some resistant strains of Gramnegative and Gram-positive organisms.
2- Alteration of the binding site: the ribosome, to which
some aminoglycosides bind, can become altered.
430
ANTIBIOTIC RESISTANCE IN BACTERIA
3-Alteration of the susceptible pathway: organisms can
become resistant to sulfacetamides by developing
pathways that do not require drug effect. (false pathways)
4- Reduction in the intracellular levels of agent: some
strains of Staph. aureus can become resistant to
fluoroquinolones by causing an efflux of the agent.
431
432
Chapter 16
OPHTHALMIC DRUGS
ANTIVIRALS
Because of the intimate relationship between the
infecting virus and the host cell, viral infections are
more difficult to treat than those caused by bacteria.
433
OPHTHALMIC DRUGS ANTIVIRALS
Many viral infections still resist treatment and only
a few will respond to therapy. Recently, much
research effort has been expended in the search
for compounds active against other viruses, in
particular the human immunodeficiency virus (HIV).
One of the earliest viruses to be treated was herpes
simplex, the causative organism of dendritic ulcer,
cold sores and genital herpes. Several agents have
been used as topical treatments for these
conditions: idox-uridine, vidarabine ,irifluorothymidine, aciclovir and ganciclovir; the last
two are the only ones in regular use.
434
ACICLOVIR
Mode of action : Aciclovir affects only virus-infected cells
because it utilizes an enzyme – thymidine kinase – whose
structure and functioning is slightly different in viruses to
that found in uninfected host cells.
Viral thymidine kinase can metabolize acycloguanosine
(Cyclovir and Zovirax among others. The chemical name is
acycloguanosine (ACV)). Acycloguanosine inhibits
replication of cytomegalovirus by a mechanism that is
independent of its phosphorylation by viral or cellular
thymidine kinase whereas cellular thymidine kinase
cannot. Some viral mutants have modified genes for the
production of thymidine kinase but these tend to have low
pathogenicity and virulence .
435
ACICLOVIR
It is effective against infections with strains of herpes
simplex which were resistant to idoxuridine .
Aciclovir was significantly more effective than the other
antivirals, even on drug-sensitive strains.
Aciclovir-treated eyes showed less corneal epithelial
involvement ( disease) and conjunctivitis and exhibited
less iritis and corneal clouding.
436
ACICLOVIR - therapeutic effects
1- McGill et al (1981) compared aciclovir and vidarabine
and found that the former had a much better rate of
healing and reduction in symptoms of corneal ulcer, but
Coster et al (1980) found no difference between aciclovir
and idoxuridine.
2- Because of its very selective action it does not interfere
with corneal wound healing, whether epithelial or stromal.
3-Aciclovir had no significant effect on the regenerating
epithelium or re-epithelialization surface wounds or on the
collagen content of stromal wounds.
4- It is effective on its own against dendritic and small
amoeboid ulcers, but larger and stromal ones require the
addition of a topical steroid for complete resolution.
437
ACICLOVIR - therapeutic effects
438
Corneal ulcers
439
CHAPTER 16
Topical Eye
Medication in Infants
and Children
440
Topical Eye Medication in Infants
and Children
• In the large number of reports concerning
adverse reactions to topical ophthalmic
drugs, it is evident that infants and children
are particularly prone to toxic reactions.
• Many topical ophthalmic drugs frequently
used in children are commonly prescribed by
ophthalmologists for infants and children are
safe , unless serious side effects specific to
the pediatric population have been reported .
441
Topical Eye Medication in Infants
and Children
Infants and children have increased potential for
ocular and systemic drug-induced adverse
reactions for several reasons:
(1) They may receive an excessive dose owing to
difficulty in instilling drops or ointment, particularly if
they are uncooperative.
(2) Administration of a drug may be continued by a parent
or nurse who does not recognize early signs of drug
toxicity.
(3) Differences exist between children and adults in their
physiologic response to the same drug .
442
Topical Eye Medication in Infants
and Children
)4( Drug absorption through the conjunctival
epithelium and skin may be more rapid in infant.
)5( Metabolic enzyme systems are immature,
especially in neonates, and may prolong the
half-life of drugs.
(6)The dose relative to blood volume, body
weight, and surface area is greater for infants
and children (blood in adults dilutes absorbed
drug 20 times more than in neonates).
443
Topical Eye Medication in Infants
and Children
This factor number (6) of the relationship of
the dose to blood volume, body weight , and
surface area is particularly important in
causing toxicity.
If drops only are considered, an approximation
‫ب‬
can be made of the total dose delivered
َ ‫تقار‬
َ
to the eyes following a routine instillation by
lessening of the children dose .
444
Topical Eye Medication in Infants
and Children
• A child weighing 20 kg receives almost twice
the usual adult parenteral subcutaneous or
intramuscular therapeutic dose or nine times
the usual adult parenteral intravenous
therapeutic dose due to sudden action.
•) blood in adults dilutes absorbed drug 20
times more than in neonates).
445
Measures to reduce excessive absorption and
toxicity of topical eye medication in pediatric
patients
Measures to reduce excessive absorption and
toxicity of topical eye medication in pediatric
patients have been based on techniques for :
1. resisting drainage into the nasolacrimal system or
2. the use of vehicles and delivery systems that
increase topical bioavailability and absorption by the
cornea while decreasing total drug concentration in
the eye.
446
These measures include the following:
1-Use of proper technique of drug
instillation, that is, correct immobilization
of the child and the eyelids to avoid
instilling more than the prescribed dose
(note that instilling multiple doses at
intervals of 30 seconds or less will
increase absorption and possibly deliver
a larger toxic systemic dose ).
447
2-Digital pressure on the periphery of the
nasolacrimal system at the medial canthus
for 3 to 5 minutes to obstruct drainage to the
vascular nasopharyngeal mucosa and thus
reduce potentially rapid systemic absorption
(67% in one study) .
3-Gentle and quiet eyelid closure for 3
minutes after drug instillation ( 65% reduction
of nasal absorption in the same study).
448
4-Quick blotting away ‫ تنشيف‬of any excess
drug to reduce the volume of drug
administered and encourage the eyelids to
stay closed for a short time .
5-Placement of an absorbent pledget ‫شاشة‬
‫ماصة‬at the punctum prior to drug
instillation to restrict absorption by the
conjunctiva and cornea .
449
6-Cutaneous drug delivery to eliminate
difficulty with instillation and reflex
washout.
Eye drops can be instilled on the inner
canthus with eyes closed followed by
immediate opening of the eyes. This
technique can deliver ocular cycloplegics
with the same ocular effect and safety as
the usual open-eye method. This may be
helpful in uncooperative children .
450
LACRIMAL APPARATUS
451
7- Occlusion of the lacrimal puncta
by collagen punctual plugs,
silicone punctual plugs ,or suture
to block drainage of eye drops
through the nasolacrimal system.
This also keeps the medication in
contact with the cornea for a
longer duration and improves the
therapeutic index of administered
I.O medication .
452
8-Decreasing dimensions of the eyedropper tip since the volume delivered by
commercial ophthalmic droppers (25.1 to
56.4 μL) is large in relation to capacity of
conjunctival sac .
The ideal volume for a drop is 10 to15 μL,
based on the amount of fluid the eye can
hold in children .
453
9- Use of a single eye drop combination of two
drugs to reduce the number of drug instillations
and the amount of drug delivered to the eye, like
cosopt (timolol and trusopt )containing timolol
and trusopt both of which is an antiglaucoma
drug , MAXITROL- neomycin sulfate, polymyxin b
sulfate and dexamethasone drops or ointment
contains two antibiotics and dexamethasone.
•10- Use of a preceding topical anesthetic such as
proparacaine to enhance the effect of drugs by
increasing transcorneal absorption and
decreasing the dilution effect of reflex tearing
caused by the stinging sensation ‫إحساس بالوخز‬
of454diagnostic or therapeutic drops .
MAXITROL
455
cosopt
11- Increasing the viscosity of the eye drop
by dissolving the drug in an oil or emulsion
base, which boosts ‫ يعزز‬retention in the tear
film , with minimal loss in the nose.
12-Employing drug suspensions instead of
drug solutions . Suspended drug particles
are retained in the conjunctival sac longer
than solutions. Note that the bottle must be
adequately shaken to suspend the particles
uniformly.
456
‫الساعة األخيرة‬
‫• و كان في بيته حين مرضه سبعة دنانير‪ ،‬فإذا أ ُ‬
‫غمي عليه ثم أفاق‪،‬‬
‫َ‬
‫صحا يقول ‪ :‬يا عائشة تصدّقي بها‪ ،‬فإذا استيقظ قال ما فعلتم بالمال‬
‫ش ِغلنا بك‪ ،‬يقول ‪ :‬ما ُّ‬
‫ظن محمد بربّه لو‬
‫؟ يقولون ‪ :‬يا رسول هللا ُ‬
‫ي هللا وعنده هذه الدنانير‪ ،‬تصدّقوا بها كلها ‪.‬ثم دعا النبي صلى هللا‬
‫لق َ‬
‫قربها‬
‫عليه و سلم سيدتنا الزهراء فاطمة‪ ،‬فل ّما دخلَت عليه ابتسم و َّ‬
‫فسارها بشيء‪،‬‬
‫فسارها بشيء‪ ،‬فبكت ثم دعاها‬
‫منه وهمس في أذنها‬
‫َّ‬
‫َّ‬
‫سر رسول هللا‬
‫فضحكت‪ ،‬فسألتها عائشة فقالت ‪ :‬ما كنتُ ألفشي َّ‬
‫صلى هللا عليه و سلم‪ .‬وكان صلى هللا عليه و سلم إذا دخلت عليه‬
‫فاطمة قام إليها و قبَّلَها وأجلسها في مجلسه فلما مرض ودخلت‬
‫عليه لم يستطع القيام فأ َكبَّت على يديه فقبَّلتهما و قبَّلته من وجنتيه‪،‬‬
‫فبكى رسول هللا صلى هللا عليه وسلم وقال ‪" :‬يا فاطمة َّ‬
‫إن جبريل‬
‫كان يعاودني القرآن كل سنة مرة‪ ،‬وإنه عاودني العام مرتين‪ ،‬وال‬
‫إنك أول أهل بيتي لحوقا بي"‪.‬‬
‫أراه إال حضر أجلي ويا فاطمة أبشري ِ‬
‫‪457‬‬
Measures to reduce excessive absorption and toxicity
of topical eye medication in pediatric patients
13-Substituting ointments for drops: ointments
can double eye contact time in blinking eyes,
quadruple ‫ي‬
ّ ‫ ُربَا ِع‬it in patched eyes, and remain in
the conjunctival sac for nearly 3 hours after
instillation, producing a controlled, prolonged
response .
Also, ointments decrease absorption through the
conjunctiva and decrease passage into the
nasolacrimal duct ,making the main absorption
through the cornea. However, parents often find
ointments difficult to instill and cause blurring of vision.
458
14- Use of gel-based systems that release small
amounts of drug continuously have proven
themselves commercially.
A gel-forming system is currently available for
timolol ( Timoptic -XE) and artificial tears like
viscotears.
459
Measures to reduce excessive absorption and
toxicity of topical eye medication in pediatric
patients
15-Use of controlled delivery systems
including hydrophilic soft contact lenses
(nondisposable and disposable(
usefulness has been demonstrated in
pediatric patients after cataract surgery
and in treating corneal ulcers.
460
16-Treating with site-specific or soft drugs
that are activated on the eye but rapidly
become inactive metabolically when
absorbed into the systemic circulation. The
result is improved bioavailability and
reduction of the potential for ocular and
systemic side effects.
17-Addition of vasoconstrictive agents
(i.e phenylephrine) to minimize systemic
absorption .
461
VERNAL
KERATOCONJUNCTIVITIS
( VKC)
462
GIANT PAPILLARY
CONJUNCTIVITIS
VERNAL KERATOCONJUNCTIVITIS ( VKC)
• Vernal keratoconjunctivitis typically begins in
children before puberty and has a tendency to
lessen in the second and third decades.
• In the majority, the onset is before age 10.
Rarely, the diagnosis is made in adults.
• Before puberty, males are affected two to three
times more frequently than females; however,
the prevalence in females, increases after
puberty and equals that of males after age 20.
463
VERNAL
KERATOCONJUNCTIVITIS VKC
•Vernal disease is commonly found in individuals
with a personal or family history of allergic
disease.
•It is usually seasonal, occurring in the spring
and summer; however, some persons are
affected year-round.
•The disease is prevalent in hot, dry climates
such as the Mediterranean area, Middle East,
West Africa, the Indian subcontinent, Mexico,
and the southwestern United States.
464
SYMPTOMS OF VERNAL
Symptoms :
1. the most important ocular symptom is
itching, often severe.
2. There can be burning, photophobia,
3. and complaints of lacrimation
4. and mucus discharge.
Signs:
1.Affected persons often rub their eyes vigorously and
exhibit blepharospasm.
2.Vernal is a bilateral disease but may be asymmetric.
465
VERNAL
KERATOCONJUNCTIVITIS VKC
It has two conjunctival forms, palpebral and limbal:A-The palpebral form
• Is characterized early by a dull, pale, thickened tarsal
conjunctiva.
• Eventually, papillae form that may be small and few
in number or may evolve into multiple giant
cobblestone (flat-topped) papillae on the superior
tarsal conjunctiva.
• There is often copious tenacious mucus draped over
these papillae.
• There may be an associated mechanical ptosis.
466
VKC
467
palpebral form
mechanical ptosis
468
VKC
VERNAL
KERATOCONJUNCTIVITIS
B-Limbal form :small, fine white dots may be
seen on the limbal papillae; these are HornerTrantas' dots and represent focal collections of
eosinophils).
• Horner-Trantas' dots are usually seen at the
superior limbus but can be seen elsewhere on
the limbus and on the bulbar and tarsal
conjunctiva. The limbal and palpebral forms of
vernal disease can coexist.
469
• The
limbal form is more common in blacks.
palpebral form
470
Limbal form
Horner-Trantas
Treatment of VKC
I- General measures include :
1. “climatotherapy” (i.e., moving to a cooler ‫ ُمبَ ِ ّرد‬and
moister climate), air-conditioning, humidification, and air
filtering to remove dust and other allergens.
2. Cold compresses are helpful to relieve itching.
3. Patching can be helpful.
4. The cornerstone‫ساس‬
َ َ ‫ َح َج ُر األ‬of medical therapy is the use
of mast cell stabilizers.
471
472
VERNAL
KERATOCONJUNCTIVITIS
• Topical cromolyn sodium 2% or 4% (Opticrom) is
given four times a day, and in severe cases up to
six times a day.
• He or she can be instructed to start cromolyn a
month or so prior to the expected onset of the
symptoms; some require cromolyn all year round
two to four times a day as maintenance therapy.
• As mentioned previously, this drug has few side
effects and is well tolerated.
473
VERNAL KERATOCONJUNCTIVITIS
II-Mild cases:
1. can be treated with artificial tears like
refresh or Optive eye drops,
2. or topical vasoconstrictor-antihistamines like
antistine drops.
3.Topical olopatadine (patanol) 0.1%, a newer
mast cell stabilizer, has been shown to be
effective in vernal, eliciting an earlier and
greater response than cromolyn sodium.
4. Also, oral antihistamines can be helpful
474
oral antihistamines
475
topical corticosteroids
VERNAL
KERATOCONJUNCTIVITIS
III-More severe cases:
(i.e., marked symptoms or corneal involvement)
will require topical corticosteroids four or more
times a day for a few weeks until cromolyn takes
effect.
• Thereafter, topical corticosteroids should be
tapered over a week or so to prevent rebound,
and then should be discontinued to minimize the
chance of side effects.
476
VERNAL
KERATOCONJUNCTIVITIS
• Oral aspirin has been reported to aid
remission of vernal; however, one must be
wary ‫ محترس‬، ‫ حذر‬of acetylsalicylic acid
(ASA) in those with asthma.
• Other nonsteroidal anti-inflammatory
agents, such as indomethacin (Indocid
drops), applied topically, have been
shown to be effective in the treatment of vernal
keratoconjunctivitis.
477
Prognosis of vernal
keratoconjunctivitis
• Fortunately, vernal keratoconjunctivitis is a
self-limited disease that resolves with age,
usually after an interval of 2 to 10 years.
• Unlike atopic keratoconjunctivitis, vernal does
not typically cause significant conjunctival
cicatricial changes.
• In some patients, vernal does not resolve and
instead transforms into adult atopic
keratoconjunctivitis which may be complicated
with keratoconus.
478
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC)
Giant papillary conjunctivitis affects
approximately 1% to 5% of the 30 million
contact lens wearers in the United States.
GPC can occur in those wearing hard,
semi-rigid, and soft hydrogel lenses;
however, soft lens wearers are by far the
most commonly affected.
479
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC)
Clinical Features
SYMPTOMS:
1. The earliest symptoms are itching on lens removal
2. mild mucus formation.
3. Later, patients complain of contact lens intolerance
4. with irritation, itching and redness,
5. tearing and mucus discharge,
6. blurriness of vision while wearing their lenses.
Symptoms usually precede signs.
480
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC)
SIGNS:
1. On examination, early there is bulbar and
palpebral conjunctival hyperemia.
2. Occasional mucus strands may be present.
3. With progression, conjunctival thickening with
loss of translucency occurs.
4. The upper tarsal conjunctiva will demonstrate
macropapillae (0.3 to 1 mm in diameter) or
giant papillae (more than 1 mm in diameter) .
481
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC) signs
a.The papillae often have a dome-shaped
appearance with fibrotic white yellow tops.
Horner-Trantas' dots may be seen.
b.Fluorescein staining of the papillae, which indicates
ulceration of the conjunctival surface, reflects
severity.
5. There may also be corneal staining, but this is
uncommon.
6. Pseudoptosis may occur in more severe cases.
7. There is often significant deposit formation on the
surface of the contact lenses.
482
CONTACT LENS-INDUCED GIANT PAPILLARY CONJUNCTIVITIS
483
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC)
Treatment
1- Asymptomatic patients with signs only or
those with minimal symptoms and signs
may not need to discontinue lens wear if
good lens hygiene is maintained; these
patients may take topical cromolyn 2% or
4% q.i.d. with their contact lenses in place to
maintain control.
484
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC)
2-Initial treatment of the symptomatic patient is
discontinuation of lens wear.
3- Ocular lubricants are helpful during this time
period.
4-Symptoms may improve within 2 or 3 days, but
lenses should not be resumed until about 1 week
after all mucus, redness, and irritation are gone.
5-Papillae may last longer, but contact lenses can
be resumed if there is no fluorescein staining.
485
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC)
6-Topical corticosteroids are usually not
required if lens wear is stopped but may
be helpful in more severe cases.
7-The nonsteroidal anti-inflammatory agent
suprofen used topically has also been
shown to be effective in GPC .
486
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC)
8-When contact lenses are resumed,
proper lens hygiene must be stressed.
This is especially important because as
a group, contact lens wearers with GPC
are neglectful with lens care. Hydrogen
peroxide cleaning systems (preferably
nonpreserved) and nonpreserved
saline are best for patients with GPC .
487
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC)
9- Cold disinfection systems increase the
possibility of exposure to sensitizing
agents and should be avoided.
10- Enzymatic cleaning, particularly papain
‫ إنزيم بابايين‬is superior to surfactant ‫فَا ِع ٌل‬
ْ ‫س‬
‫طح‬
َّ ‫ ِبال‬cleaning.
488
CONTACT LENS-INDUCED GIANT PAPILLARY
CONJUNCTIVITIS (GPC)
11-If a recurrence occurs after resumption of lens
wear, there must be at least a 1-month period off
lenses, preferably 3 months.
12-Again, a soft contact lens of a different polymer
‫ب‬
ٌ ‫ ُم َر َّك‬can be tried, or the patient can switch to a
gas-permeable semi-rigid lens.
13-Some will benefit from topical cromolyn 2%
or 4% four times a day with the contact lenses in
place to prevent recurrences.
489
CHAPTER IX
Pharmacology of Ocular
Beta-Adrenoceptor
Antagonists
490
ROLE OF BETA-BLOCKERS IN OPHTHALMIC
PRACTICE
• The introduction of the ß-adrenoceptor antagonists
completely changed the drug preference in
glaucoma drug therapy.
• The sites for receptor interaction of these drugs are
suggested to be ß-adrenergic receptors in the iris
and ciliary body.
• The pharmacologic properties of these drugs are
referred to as ß-adrenoceptor antagonism ,these
drugs are called beta-blockers.
491
beta-blockers.
• The focus of the majority of the studies have been
on aqueous fluid dynamics and intraocular
pressure (IOP), but other functions of the eye have
also been explored.
• Unlike pilocarpine, the drugs of glaucoma
treatment for the last 100 years, ß-blockers
generally do not contract the pupil and thus do not
interfere with vision even in patients with central
lens opacities.
• They also do not cause spasm of the ciliary
muscle, which produces transient myopia and
disturbance of accommodation.
492
BETA-BLOCKERS
• Propranolol is the prototype (ideal,
example ) of drugs that can antagonize
ß-adrenoceptors.
• The interaction of most ß-blockers with
the receptor is competitive and
reversible.
• The potency of the drug in the
cardiovascular system is not always
indicative of the ocular effect.
493
494
BETA-ADRENOCEPTOR
ß-blockers
ß-blockers are classified as relatively selective or
nonselective with respect to their actions at:ß1- and ß2-adrenoceptor subtypes.
Some drugs can block both ß1- and ß2-receptor activity
(nonselective); others predominantly or almost
exclusively block only one of the two types at low
concentrations (selective) .
The relative selectivity for either ß1 or ß2 is not
absolute; at high doses, all ß-adrenoceptors can be
antagonized (inhibited).
495
496
Pharmacologic Properties of
ß-Blocking Agents
• ß-blockers have varying degrees of
protein-binding capacity and lipid
solubility.
• Some undergo high first-pass metabolism
in the liver (e.g., propranolol); some have
active metabolites; and some are
excreted principally by the kidney (e.g.,
atenolol).
497
ß-Blocking
Potency
Ratio
(Propranol
ol = 1)
Cardioselectivity
Alprenolol
0.3
-
Cartenolol
~10
-
Levobunolol
6
-
Oxprenolol
0.5–1
-
Propranolol
1
-
Timolol
6
-
Atenolol
1
+
Betaxolol
1
+
Practolol
0.3
+
Nonselective
ß1 Selective
498
BETA-ADRENOCEPTOR
However, the deciding factors in clinical systemic
effectivity:1.differences in potency,
2.ß-receptor subtype selectivity,
3. metabolism,
4.passage through the blood-brain barrier,
5.direct effects on membranes, and
6.degrees of intrinsic sympathomimetic activity .
The suitability of various ß-blockers for topical
ophthalmic use in the treatment of glaucoma varies in
relationship to their ocular hypotensive efficacy and
ocular and systemic safety.
499
BETA-ADRENOCEPTOR
• As of 1987, three topical ß-blockers are available for
topical ocular use in the United States:
Timolol, betaxolol, and levobunolol.
• However, other ß-blockers, such as :
Atenolol, metoprolol, and propranolol, are used
systemically for mild and moderate hypertension,
angina, and arrhythmias in doses that are known to
reduce IOP.
500
BETA-ADRENOCEPTOR
Side effects
Topically applied ß-blockers can produce :
1. ON C.V.S : Bradycardia and, less rarely,
systemic hypotension.
2. On the R.S :bronchospasms in
asthmatics and patients with chronic
obstructive pulmonary disease.
3. On the eye :corneal anesthesia, dry
eyes, ocular irritation, and hyperemia .
501
OCULAR BETA-ADRENOCEPTORS
The ocular ß-blockers are considered by some to have
properties that differentiate it from the
cardiopulmonary, systemic ß-blockers.
How, then, do agents with relative ß1-blockers
selectivity lower IOP? From animal studies, Chiou and
colleagues concluded that the reduction of aqueous
humor formation by timolol may be related to a
reduction of blood flow to the ciliary body.
502
NONSELECTIVE BETA-BLOCKING
AGENTS
PROPRANOLOL
• Propranolol was the first ß-blocking agent to be
used in clinical therapeutics and has become
the standard against which other ß-blocking
drugs are measured.
• A potent agent with membrane-stabilizing
effects, the synthetic drug is a standard
treatment for systemic hypertension and
cardiac arrhythmias.
• Both oral propranolol and topical propranolol
lower IOP in humans.
503
NONSELECTIVE BETA-BLOCKING
AGENTS
PROPRANOLOL
• However, use of topical propranolol in the treatment
of glaucoma is limited because of its side effect,
which results in :
corneal anesthesia and ocular irritation.
• The mechanism of action of propranolol by which
IOP is lowered is still uncertain.
• Although propranolol has been reported to depress
aqueous humor formation, it has also been credited
(accepted) with increasing facility of outflow.
504
NONSELECTIVE BETA-BLOCKING
AGENTS
TIMOLOL
• Introduced for clinical use in the United States in
1978, topical timolol maleate (Timoptic, Timoptol)
has been rapidly adopted as a standard treatment
for open-angle glaucoma.
• Timolol is also useful in many cases of secondary
glaucoma, aphakic glaucoma, and ocular
hypertension.
• Orally, timolol is 5 to 10 times more potent than
propranolol and is relatively devoid of local
anesthetic properties.
505
TIMOLOL DROPS AND TABLETS
506
TIMOLOL ADVANTAGES
• The attraction of timolol lies in its long-term efficacy
in the treatment of various types of glaucoma, the low
incidence of ocular side-effects, and relatively long
duration of action (12–24 hours), which allows for
only once-daily or twice-daily application.
• Topical ocular administration of 0.25% to 0.5% timolol
maleate results in lowering of IOP in normal and
glaucomatous eyes .
507
TIMOLOL
• Topical timolol is effective in reducing IOP 20% to
30% compared with pretreatment values.
• The maximum ocular hypotensive effect of timolol
is reached with the dose range of 0.3% to 0.5%.
• Given twice daily for up to one year, timolol keeps
pressures down throughout the day.
• Timolol is routinely used twice daily, although
there are several reports of its efficacy on a oncedaily regimen.
508
TIMOLOL
• Oral timolol (20 mg twice daily) has also
proved effective in reducing i.o.p in
patients with open-angle glaucoma.
• Topically applied timolol is not
metabolized in the eye, but undergoes
extensive hepatic elimination once it
reaches the systemic circulation.
509
Combined treatment with timolol
• 0.5% timolol does not appear significantly more
effective than 0.25% timolol.
• Timolol can usually further reduce I.O.P when added
to parasympathomimetic agents (like pilocarpine),
as well as carbonic anhydrase inhibitors.
• Combined treatment with timolol and acetazolamide
can reduce I.O.P more than with either alone.
• Treatment with timolol plus pilocarpine also
produces a reduction of IOP greater than that with
each agent alone.
510
TIMOLOL
• In dynamic studies of aqueous humor,
using fluorophotometry, timolol was
found to reduce aqueous flow either in
single or multiple instillations.
• Timolol is without significant effect on
outflow facility, uveoscleral flow, or
episcleral venous pressure.
• Thus, it is clear that timolol is an inflow
drug.
511
Timolol Advantages
• Timolol is not associated with change in pupil size,
pupillary reaction, accommodation, or visual acuity,
and patient tolerance in most instances is excellent.
• The absence of alteration in pupil size, accommodation,
or refractive error avoids many of the unpleasant and
sometimes intolerable visual effects seen with many
other agents (e.g., pilocarpine).
512
TIMOLOL
• Timolol is thought to reduce IOP by suppressing
aqueous humor formation in the ciliary body.
• Neufeld has postulated that timolol can act on
secretion or ultrafiltration, or on both, but could
not confirm an ocular vasoconstrictor action of
timolol on the ciliary body.
• Most patients with primary open-angle glaucoma
respond initially to timolol.
513
TIMOLOL DISADVANTAGES
• But both short-term “escape” and long-term “drift”
have been reported for timolol.
1-Short-term escape refers to an acute partial loss of
therapeutic effect on I.O.P during the first few days of
timolol treatment. A possible explanation is the finding
in animal studies that the number of ß-receptors
molecules in ocular tissue increases within days of the
initiation of timolol treatment.
514
TIMOLOL
• This suggests a decreased efficacy of timolol, due
to decreased “substrate” (substance upon
َ ‫ َر‬for ß-blocker
which an enzyme acts) ‫كيزة‬
interaction.
• Other patients show a slow upward trend in I.O.P
after months of therapy.
2- long-term drift : The ocular hypotensive efficacy
of timolol may decrease by up to 25% with longterm treatment.
515
ocular side-effects of timolol
The most frequently reported ocular side-effects are :
1. Allergic blepharoconjunctivitis, allergy to topical ßblockers, as evidenced by blepharoconjunctivitis,
occurs in some patients after long-term use of
timolol.
2. conjunctival hyperemia,
3. superficial punctate keratitis,
4. blurred vision can also occur.
5. Decreased tear production in glaucoma patients
was also reported but was not deemed‫يَ ْعتَبر‬
dangerous unless the eye had abnormally low
lacrimal secretion.
516
Systemic side-effects of timolol
1. Slowing of the heart rate (BRADYCARDIA) is a
common systemic finding in clinical studies with
topical timolol.
2. Cardiac arrhythmias, and syncope ‫ إغماء‬can also
occur.
3. Timolol may exacerbate ‫يفاقم‬preexisting
asthmatic conditions .
َ and decreased libido ٌ‫شه َْوة‬
4. Impotence ‫ي‬
َ
ِ ‫ف ِج ْن‬
ٌ ‫ض ْع‬
ّ ‫س‬
‫سيَّة‬
ِ ‫ ِج ْن‬.
5. Central nervous system (CNS) complaints
reported with timolol use:-
َ ‫; د َْو‬
Headaches, fatigue, dizziness ‫خة‬
weakness, anxiety, and depression.
517
‫ د َُوار‬,
NEWER BETA-BLOCKERS
Betaxolol, levobunolol, cartenolol, and
metipranolol have also been reported to
decrease aqueous humor production.
Similar to timolol, levobunolol (Betagan)
has been reported to have no effect on
uveoscleral flow, outflow facility, or
episcleral venous pressure. Carteolol has
no effect on total outflow facility.
518
519
LEVOBUNOLOL (BETAGAN)
•Levobunolol (Betagan) is, an analogue ‫النظير‬of
propranolol, is 45 times more potent than propranolol
when given orally, and about 6 fold higher in potency
when given intravenously.
•This may be related to the activity of its metabolite.
•Levobunolol does not exhibit intrinsic sympathomimetic
activity or significant local anesthetic effects, and is
equipotent ‫متساوي التأثير‬at ß1- and ß2-adrenoceptor sites.
520
Topical Levobunolol Advantages
The pharmacology of levobunolol was recently
reviewed. Given twice daily levobunolol.
Advantages:
1. as effective as timolol for long-term use.
2. it does not reduce pupil size .
3. does not significantly reduce tear production .
4. does not reduce corneal sensitivity.
5. Levobunolol can reduce IOP 30% to 44%.
6. Tolerance does not appear to develop to the drug.
521
Levobunolol
Orally
• In humans orally administered levobunolol
has successfully been used to treat :
1. systemic hypertension,
2. cardiac arrhythmias,
3. and angina pectoris.
522
SELECTIVE
BETA1 -ANTAGONISTS
ATENOLOL, BETAXOLOL, AND METOPROLOL
ATENOLOL ACTION
Is a ß2 -blocker with no sympathomimetic or membranestabilizing activity, is currently used clinically for the
treatment of mild to moderate systemic hypertension by
mouth.
Topical ocular application of atenolol as 1%, 2%, and 4%
drops reduced IOP in patients with ocular hypertension
However, atenolol's ocular effect is relatively short-lived:
four to six times daily instillation may be necessary for a
24-hour control of IOP.
523
524
Epinephrine (adrenalin)
Adrenalin
Alpha receptors
ABP
525
Lid retraction
Mydriasis
Outflow facility
Aquous secretion
Beta receptors
B1
Heart
Tachycardia
Cardiac output
Lungs
Bronchial
dilatation
B2
Aqueous
production
ATENOLOL DOSE
• In this regard, its ocular duration of action is
shorter than its oral, antihypertensive action,
where once-daily oral therapy is the standard.
• A single oral 50-mg dose of atenolol decreases
IOP in patients with ocular hypertension, openangle glaucoma, and chronic angle-closure
glaucoma.
• However, long-term drift and short-term escape
have been reported for atenolol.
526
Acetazolamide
(Carbonic anhydrase inhibitor)
• The oral prototype ‫ ْن ُموذَج‬CAI, acetazolamide, has
been used to reduce IOP for over 40 years.
• Acetazolamide is relatively nonselective in its
inhibition of CA I and CA II.
• Acetazolamide is 93% plasma protein bound and
is excreted in the urine largely unmetabolized .
527
Acetazolamide (Trusopt)
EFFICACY:
• Oral acetazolamide reduces IOP by diminishing
aqueous production within 1 hour (onset).
• Its maximal effect is noted 2 to 4 hours after
administration, and it has a duration of action of 6 to 8
hours.
• When given intravenously (Diamox), an IOP reduction
was noted within 2 minutes, with a peak effect noted
by 10 to 15 minutes.
528
Dose of oral acetazolamide
• A dose response study suggests a submaximal peak
pressure reduction at the 63 mg dose and a maximal
reduction with a 250 mg dose,
• After a 500 mg sustained-release capsule, which also
extends duration a maximum IOP reduction of 30% to
41% was seen.
• Once-daily 500 mg sustained - release acetazolamide
resulted in a decreased pressure response compared
with twice-daily dosing.
• Acetazolamide (Diamox) is available in 125- and 250-mg
tablets and 500mg sustained- release capsules (Diamox
Sequels ‫) ت َ ْك ِملَة‬.
529
CONCENTRATION AND DOSE
• The dose for chronic clinical use ranges from 125mg by
mouth twice daily minimum to 250mg by mouth four
times daily maximum.
• Alternatively,500-mg sustained- release capsules can
be given one or two times daily.
• One study compared 250 mg four times daily and 500
mg twice daily and found similar IOP reduction and
side effects .
• Intravenous acetazolamide is available in a 500mg vial
in powder form and should be reconstituted with at
least 5 ml of sterile water.
530
CONCENTRATION AND DOSE
• The recommended dose is 250 to500 mg tablets initially
followed by 250 mg every 4 hours up to 1 gm per day.
• In children, the dose is 5 to10 mg/kg every 6 hours.
• After a 500mg sustained-release capsule, a maximum
IOP reduction of 30% to 41% was seen.
• Once-daily 500-mg sustained- release acetazolamide
resulted in a decreased pressure response compared
with twice-daily dosing.
531
ACETAZOLAMIDE ADDITIVITY
• As adjunctive ‫ ; إِضَافَة‬therapy, dorzolamide 2%
twice daily produced a 13% to 21% additional
pressure reduction when given to 16 patients
receiving timolol 0.5% twice daily .
•
In a study of the additivity of dorzolamide 2%
twice daily added to timolol 0.5% twice daily
compared with pilocarpine 2% four times daily
added to timolol 0.5% twice daily, comparable IOP
532
lowering
was seen in each group.
ACETAZOLAMIDE ADDITIVITY
•Patients preferred dorzolamide to pilocarpine in a
quality-of-life questionnaire ‫ستِ ْطالع‬
ْ ‫ ا‬. ‫ستِ ْفتاء‬
ْ ‫ ا‬in a ratio
greater than 7:1
•Most patients treated with oral CAIs in addition to
other classes of topical hypotensive agents have
switched from the oral CAI to topical dorzolamide
without IOP increases.
533
ACETAZOLAMIDE ADDITIVITY
• Other studies suggest that giving 2% dorzolamide
drops twice daily or three times daily by mouth to
patients receiving maximally tolerated topical
therapy of dorzolamide can produce additional
pressure lowering.
• The addition of dorzolamide to timolol does not
lower IOP as well as latanoprost .
534
SYSTEMIC ADVERSE REACTIONS OF
CAIs (oral)
1. GIT irritation in the form of nausea
,vomiting and abdominal colic.
2. Paraesthesia ‫ ت َ َخدُّر ; تَنَ ُّمل‬due to its effect
on the peripheral nerves.
3. Dorzolamide binding to red blood
cells may have a half-life of several
months )Prolonged action).
535
INDICATIONS OF TOPICAL
ACETAZOLAMIDE
1. Dorzolamide is indicated to (acutely or chronically)
lower IOP in patients with open- or closed-angle
glaucoma and patients at risk for elevated pressure.
2. Dorzolamide drops produces much of the IOP
lowering effect while eliminating most of the systemic
tolerability problems seen with (tablets ) oral CAIs.
3. As the risks of idiosyncratic blood dyscrasias have
faded, topical dorzolamide, and prostaglandin
analogues have replaced miotics as second-line
therapy given to patients on topical β-blockers.
536
Latanoprost (PGA)
• It is a prostaglandin analogue ‫اظر‬
ِ َ‫ ُمتَن‬recently detected.
• Latanoprost, is a powerful ocular hypotensive agent that
produces minimal systemic side effects.
• Although the drug may change the iris color, aggravate
cystoid macular edema (CME), and induce herpes
simplex keratitis, latanoprost use to treat glaucoma has
grown rapidly over the past several years, and it now
vies ‫ يتنافس‬with nonselective β blockers as a first-line
drug.
537
538
Latanoprost (Xalatan)
• In humans, latanoprost does not affect aqueous flow
and shows either no effect or a slight increase in
conventional outflow facility.
• With use of a fluorophotometric technique,
latanoprost was found to elevate uveoscleral outflow.
• The mechanism underlying the enhanced uveoscleral
outflow remains unclear.
• One hypothesis is that PGs may stimulate collagenase
and other metalloproteinases to degrade the
extracellular matrix between ciliary muscle bundles.
One study has noted such dilated spaces.
539
EFFICACY of latanoprost
• The initial human latanoprost studies in
normotensive volunteers used a 0.005%
concentration once or twice daily for up
to 1 month.
• A reduction in IOP of 20% to 40% was
noted as long as 24 hours after dosing
• Latanoprost 0.005% once daily has
since been compared with timolol 0.5%
twice daily in three studies performed in
the United States ,the United Kingdom ,
and Scandinavia .
540
Latanoprost (PGA)
• Two of these studies (those conducted in the
United States and Scandinavia) found a
substantially greater efficacy with latanoprost than
with timolol, whereas the United Kingdom study
found similar results with the two agents.
• All three studies found that latanoprost decreased
IOP by 25% to 30% compared with baseline.
541
EFFICACY
Latanoprost has been studied in several glaucoma
subtypes.
1. One study found latanoprost more effective than
timolol in chronic angle closure glaucoma .
2.Another found the drug effectively lowered IOP in
steroid induced glaucoma.
3.A one year comparison of latanoprost versus timolol
in pigmentary glaucoma found a better IOP reduction in
the latanoprost group .
4.Several studies of latanoprost efficacy in childhood
glaucomas have been published. .
542
EFFICACY
These all reported the results of latanoprost when added to
other therapies.
• In a study of 31 eyes with pediatric glaucoma only six
eyes were conisdered to have responded to latanoprost
treatment .
• A successful response to latanoprost treatment in
Sturge-Weber glaucoma was noted in only 17% of eyes
at 6 months .
• Another report of treating Sturge-Weber glaucoma with
latanoprost noted two patients with juvenile onset
glaucomas responding whereas four congenital onset
patients did not respond.
543
Sturge-Weber Syndrome
544
CONCENTRATION AND DOSE
• Latanoprost (Xalatan) has been tested in doses of
0.005% and is more effective with once daily than with
twice daily dosing.
• Peak effect takes at least 12 hours, and one study
suggests that evening dosing provides better daytime
pressure reduction compared with morning dosing .
545
Additivity of latanoprost
1-When added to a nonselective β blocker (atenolol),
latanoprost lowered IOP more than dorzolamide
2-In patients inadequately controlled on timolol,
switching to latanoprost alone was as effective as
adding pilocarpine or switching to a timolol-dorzolamide
combination.( Latanoprost= timolol-dorzolamide)
3-Latanoprost twice daily added to pilocarpine 2% three
times daily resulted in an additional reduction in IOP of 2.7
to 3.3 mmHg (14% to 18%) compared with pilocarpine alone.
546
LOCAL ADVERSE REACTIONS
1. Earlier PG preparations demonstrated a
propensity‫ نزوع‬، ‫ ميل‬toward stinging, hyperemia, and
irritation.
2. There have been several case series of Cystoid
Macular Edema (CME)associated with latanoprost
use .
3. One study of patients undergoing cataract surgery
found more angiographic CME in latanoprost treated
eyes compared with placebo.
547
LOCAL ADVERSE REACTIONS
4- Initial concerns that the iris color changes were
precursors of more ominous side effects have
been mostly resolved ‫تم التغلب عليها‬and the drug is
currently widely used as a first- or second-line
agent.
5-Patients with iris color susceptible to change
should be warned of the possibility of permanent
iris darkening or heterochromia.
6-The drug should be used with caution in patients
with previously demonstrated iritis, CME, or
herpes simplex keratitis.
548