Transcript General principles, Administration of drugs, Drug Metabolism

I. General principles of
Pharmacology
A. Pharmacology and its major
areas
• Pharmacology is the
study of drugs. It
takes into account
their composition,
uses,
characteristics/propert
ies, and effects.
The subdivisions in pharmacology
include:
• 1. pharmacy: the
science of preparing
and dispensing
medication
• 2. toxicology: the
study of the harmful
effects of medications
on living tissue
• 3.
neuropharmacology:
the study of the
effects of medication
on nervous system
and behavior
functioning
• 4. pharmacotherapeutics: the study of the
use of drugs in treating disease
• 5. pharmacokinetics: the study of the
processes involving the absorption,
distribution, metabolism and excretion of
medications.
• It is the study of what the body does to a
drug.
• 6. pharmacodynamics: the study of the
actions of medications on living tissues.
• It is the study of the biochemical and
physiological effects of drugs, the
mechanisms of drug action, and the
relationship between drug concentration
and effect.
• Pharmacodynamics is the study of what a
drug does to the body.
Example: Clomiphene citrate
• This drug induces ovulation
B. Terminology related to effects
of drugs
• 1. therapeutic effect/indication: the
intended effect of the drug; the uses of a
drug
• 2. contraindication: when the drug should
not be used (see Warnings on label)
example: celecoxib (Celebrex)
• indication: relief of
signs and symptoms
of osteoarthritis; relief
of signs and
symptoms of
rheumatoid arthritis
example: celecoxib (Celebrex)
• contraindicated in:
hypersensitivity;
history of allergic-type
reactions to
sulfonamides; history
of asthma, urticaria
(hives), or allergictype reactions to
aspirin or other
NSAIDs
• 3. undesirable effects: These are effects of
the drug, other than the therapeutic effect.
• Undesirable effects may be further
classified as side effects, adverse effects,
toxic effects, or allergic reactions.
• a. side effects:
nuisance effects (dry
mouth, altered taste,
flatulence)
• b. adverse effects:
effects that may be
harmful (diarrhea,
vomiting) or effects
that with prolonged
treatment of the drug,
may affect the
function of vital
organs such as the
liver or kidneys
• c. toxic effects:
extremely harmful,
life-threatening
• A drug may cause all 3 undesirable effects:
• example: rosuvastatin (Crestor)
• side effects: headache and insomnia
•
• as well as constipation, flatulence,
heartburn, altered taste, dyspepsia, and
nausea
• adverse effects: dizziness, diarrhea, druginduced hepatitis, elevated liver enzymes,
pancreatitis
•
• toxic effects: rhabdomyolysis (release of
muscle cell contents into the plasma)
• From rosuvastatin
• d. allergic reactions: this type of side effect
has a different underlying cause compared
to the previous types, it is due to the
systemic release of histamine.
• A hypersensitive person’s immune system
identifies a foreign substance (antigen)
and initiates a response (antibody).
• The combination of antibody-antigen
stimulates the histamine release.
• This results in a range of symptoms, from
mild (itching, swelling, redness, sneezing)
to severe or life-threatening
(bronchospasm, edema, shock, and
death).
• The severest symptoms are collectively
referred to as anaphylaxis or anaphylactic
shock.
• 4. drug idiosyncrasy: Idiosyncrasy refers
to a type of reaction that is not doserelated or allergic.
• It occurs in a small percentage of patients
given a drug. It is an individual’s unique
response and may be related to genetics.
• One example is cholinesterase deficiency,
a condition where the effects of anesthetic
agent, suxamethonium, are prolonged well
beyond the usual few minutes, because
the individual lacks the enzyme that
normally limits its effects to a short time.
• The patient’s muscles are paralyzed for
longer than normal so assistance with
breathing must be given for much longer
than usual.
• 5. LD50
• Before a drug receives approval for human
use it must undergo several years of
animal testing and evaluation.
• One of the first tests that is performed is
the lethal dose 50, (LD50) which is the
dose that will kill 50% of the animals
tested.
• The results of this test are used to predict
the safety of a drug.
• Example:
Tetrahydrocannibinol
or THC
• LD50 between
approximately 50-86
g for a 68 kg (150 lb)
person.
• This would be equivalent to 1-1.8 kg of
cannabis with a 5% THC content taken
orally.
• Example:
batrachotoxins
• These are extremely
potent alkaloids found
in certain species of
frogs (poison dart
frog) and beetles
(Melyridae beetles)
• The lethal dose of this alkaloid in humans
is estimated to be 1 to 2 µg/kg.
• For a 68 kg (150 pound) person this would
be approximately equal to the weight of
two grains of salt
• Example: botulinum
toxin
• It is generally
accepted as the most
toxic substance
known, with a median
lethal dose of about 1
ng/kg, which means
that a few hundred
grams could
theoretically kill every
human on earth.
C. Drug names
• 3 basic types: chemical, generic, and trade
• 1. chemical name: Each drug has only one
chemical name, which is assigned using
the nomenclature established by IUPAC
and is based on the chemical structure.
• Its name is usually long, very complicated,
and impossible to remember.
• 2. generic name: this is assigned by the
U.S. Adopted Names Council, and is
easier to remember.
• 3. trade name: this is assigned by the
pharmaceutical company which developed
and markets the drug. This name is
capitalized.
• 4-Chloro-N-(2-furylmethyl)-5sulfamoylanthranilic acid
• furosemide
• Lasix
• alpha'-[[(1,1-Dimethyl)amino]methyl]-4hydroxy-1,3-benzenedimethanol
• albuterol
• Proventil
D. Drug classifications
• A drug may be classified either by its
therapeutic usefulness or how it works
pharmacologically.
• The pharmacological method generally
addresses its mechanism of action and
requires an understanding of biochemistry
and physiology.
Drug
Pharmacological
Therapeutic
gentamicin
Prevacid
Atrovent
Albuterol
Propranolol
Lotensin
Diltiazem
aminoglycoside
proton pump inhibitor
anticholinergic
adrenergic
beta blocker
ACE inhibitor
Ca2+ channel blocker
anti-infective
antiulcer agent
bronchodilator
bronchodilator
antihypertensive
antihypertensive
antianginal
Corgard
beta blocker
antianginal
• Different drugs (i.e. Propranolol and
Corgard) may have the same
pharmacological actions but be prescribed
for different therapeutic uses.
• Different drugs (i.e. Atrovent and
Albuterol) may have the same therapeutic
use but different pharmacological actions.
E. Enteral administration of
drugs
• Enteral refers to
administration of a
drug through a
mucous membrane of
the gastrointestinal
tract (mouth to anus).
• They include: oral, sublingual and rectal.
1. oral route
• Administering a
drug by mouth, in
the form of tablets,
capsules and
liquids.
• Advantages: it is generally the safest,
most economical and most convenient
route.
• Disadvantages:
• a). some drugs cause irritation of the
gastric mucosa leading to nausea and
vomiting
• b). variable rates of absorption
• c). effect may be too slow for emergencies
• d). unable to use in unconscious patients
• e). 1st pass metabolism: The majority of
drugs absorbed from the GI tract enter the
portal circulation.
• They are transported to the liver before
entering the general circulation. In the liver
they may be metabolized, which might
limit their efficacy.
2. sublingual
• Administering a drug
under the tongue.
• Advantages:
• this route avoids most of the
disadvantages of oral administration,
especially 1st pass metabolism
• Disadvantages:
• a. possible unpleasant taste
• b. not all drugs can be administered by
this route.
• Examples of drugs administered
sublingually:
• nitrostat a compressed nitroglycerin tablet
(a vasodilating agent)
• buprenorphine, administered to opioid
addicts (heroin, morphine) to ease the
symptoms of withdrawal without producing
euphoria (like methadone does).
3. rectal
• Drugs administered
rectally are usually in
the form of
suppositories,
although some drugs
may be in the form of
liquids (enema).
• Advantages:
• a. may be used in unconscious or vomiting
patients
• b. it avoids 1st pass metabolism
• Disadvantage:
• irritation and inconvenience
• Patient’s dislike this route of drug
administration more than other routes.
• Examples of drugs administered rectally:
• Canasa, used to treat ulcerative colitis
• compazine, an antiemetic
• dilaudid, a hydrogenated ketone of
morphine
F. Parenteral administration of
drugs
• Parenteral means not in or through the
digestive system.
• The major routes are intravenous,
intramuscular and subcutaneous.
1. intravenous
• A needle is inserted
directly into a vein
and a solution
containing the drug is
given either in a
single dose or by a
continuous infusion.
• Advantages:
• a. drug tends to take effect more quickly
as compared to other routes
• b. more accurate in terms of dosage
• c. can be used in an unconscious or
vomiting patient
• Disadvantages:
• a. requires sterile preparations and aseptic
procedures
• b. generally patients cannot administer it
to themselves
• c. it is more difficult to administer
• d. One of the greatest disadvantages
relates to the speed of its pharmacologic
action, an overdose can not be withdrawn
nor absorption stopped.
• Examples of drugs administered IV:
• dopamine, to improve blood pressure,
cardiac output in treatment of shock
unresponsive to fluid replacement
• heparin, in the treatment of various
thromboembolic disorders
2. subcutaneous
• Here a needle is
inserted into fatty
tissue beneath the
skin.
• The drug is injected then moves into either
the capillaries or the lymphatic vessels
and enters the bloodstream.
• This route is used for many protein drugs
which would be degraded in the digestive
tract if given orally.
• Examples of drugs administered
subcutaneous:
• Insulin, in the treatment of type 1 diabetes
• Goserelin, used to treat hormone-sensitive
cancers of the prostate and breast as well
as certain benign disorders
(endometriosis, uterine fibroids).
• All live injected vaccines (MMR, varicella,
and yellow fever) are recommended to be
given subcutaneously.
3. intramuscular
• The intramuscular
route is preferred
over the
subcutaneous
when larger
volumes of the
drug are needed.
• A longer needle is
required since the
muscle lies below the
skin and fatty tissues.
• Drugs are injected into muscle in the
upper arm, thigh, or buttocks.
• Tetanus, diphtheria, and acellular
pertussis booster vaccine (Tdap) to protect
against infections caused by tetanus
(lockjaw), diphtheria, and pertussis
(whooping cough).
• Streptomycin, in combination with other
agents in the management of active TB
• Haloperidol in the treatment of acute and
chronic psychotic disorders including
schizophrenia, manic states or drug
induced psychoses
G. Skin and mucuous membrane
administration of drugs
• The major routes here are topical,
transdermal and respiratory tract
1. topical
• This route of administration usually
involves applying drugs to the skin or
membranous linings of the ear, eye, or
nose.
• These drugs tend to produce a local effect.
• Examples include:
• Antibiotic creams to treat skin infections:
Neosporin and Polysporin
• Hand sanitizers
• Calamine lotion for itching of poison ivy,
• benzocaine to relieve sunburn pain.
2. transdermal absorption
• Here absorption from
the skin produces a
systemic rather than
local effect.
• Examples:
Fentanyl patches for pain therapy
• hormone replacement therapy (for
menopausal symptoms)
3. Respiratory tract
• The respiratory
tract provides an
extensive
absorbing surface
and blood supply.
• There is good absorption for sprays,
aerosols and gases.
• The size of the particles is of great
importance.
• Generally particles greater then 10
microns are deposited in nasal passages,
less than 2 microns penetrate deeper (for
significant penetration to the alveoli, 2
microns or less).
• a. intranasal: Once
absorbed the drug
enters the
bloodstream.
• Advantage:
• Drugs taken by this route generally work
quickly.
• Disadvantage:
• They may be irritating to the nasal
passages
• Examples include calcitonin (for
osteoporosis), neosynephrine (for
congestion)
• b. inhalation: Once absorbed into the
lungs it enters the bloodstream.
• Example: dihydroergotamine (migraines),
corticosteroids (allergies, asthma)
• inhaled cyclosporine, the first drug ever to
show a decline in the incidence of chronic
rejection which is the leading cause of
death following a lung transplant
H. Pharmacokinetics
• Pharmacokinetics is what the body does to
a drug.
• It involves 4 processes: absorption,
distribution, metabolism, and excretion
1. Dissolution/absorption
• Absorption is the movement of the drug
from the site of administration into the
bloodstream (or lymphatic system)
• Drugs given orally dissolve in body fluids
(saliva, gastric juice) and are absorbed
through the tissues of the stomach and
small intestines into the blood vessels
Medications administered orally
• a. food in the stomach
• One of the factors which affects drug
dissolution is the presence of food in the
stomach.
• The presence of food in the stomach,
especially a high fat meal will delay gastric
emptying, which could slow down the
dissolution of the drug.
• In addition, the presence of food
stimulates the secretion of both enzymes
and HCl
• (the protein drug insulin cannot be
administered orally because enzymes
“digest it”)
• Nutrients in food may compete with drugs
for carrier molecules (Levodopa for
Parkinson’s is transported using the same
carriers as the amino acids leucine and
isoleucine, so it should be taken on an
empty stomach).
• Phytochemicals in fiber (i.e phytates) may
bind to medications and decrease their
absorption
• Tricyclic antidepressants (i.e. Elavil) and
digoxin shouldn’t be consumed with high
fiber foods containing wheat bran.
• Other drugs, known to cause gastric
distress, such as Erythromycin and
Augmentin should be taken with food to
alleviate the GI distress.
• b. pH
• Another factor which plays a role in drug
dissolution is pH.
• Dissolution of ketoconazole, used to treat
Candida infections is impaired if the
medium of the stomach is not acidic
enough.
• c. Interactions between medications and
dietary supplements
• vitamins and/or minerals interactions with
medications may either increase or
decrease absorption.
• Iron supplements are better absorbed if
taken with citrus juices.
• Certain drugs are chelated to minerals, for
example, Ca2+ supplements will chelate
tetracycline and levothyroxine making
these drugs unabsorbable.
• d. disease states
• Diseases that change the surface area for
nutrient absorption will also affect drug
absorption (Crohn’s disease).
medications administered
rectally or vaginally
• Following rectal or vaginal administration,
a suppository melts and releases the drug
to the mucous membranes.
• The rate of absorption with rectal
administration is rather slow and variable.
medications administered
topically
• Topical drugs are not absorbed to any
great extent, their therapeutic action is
exerted locally at the site of administration.
medications administered
through the respiratory tract
• Following administration of drugs by
inhalation, the vaporized liquid is absorbed
thru the mucous membranes lining the
alveoli and into adjacent capillaries
• Some drugs administered this way
produce a systemic effect (general
anesthetic gases) others, a topical effect
medications administered
intravenously
• Only IV injections bypass the step of
absorption as the drug is administered
directly into the blood stream.
• Subcutaneous and intramuscular
injections of liquid drugs are absorbed
from body tissues into adjacent blood
vessels
• So, with the exception of the IV (or
intraarterial) route, drugs must pass thru
mucous membranes before gaining
access to the bloodstream.
• These membranes consist of a layer of
epithelial cells that are closely connected
together.
• Molecules must traverse at least 2 cell
membranes (apical side and basal side)
• These membranes are composed of lipid
and protein, forming a semipermeable
barrier
Crossing membranes
• The mechanisms by which drugs cross
membranes are the same as those for
nutrients:
• passive diffusion
• facilitated diffusion
• active transport
• Two of the most important chemical
properties of medications related to drug
absorption include the solubility of the drug
in lipid or water and the degree of
ionization
• Cell membranes are mostly lipid, so the
more lipid-soluble a drug is, the faster it
will pass through the membrane
• With the exception of general anesthetics,
most drugs are water soluble and only
partially lipid soluble.
• Drugs are usually weak acids or weak
bases whose absorption is influenced by
their degree of ionization in body fluids
• Most drugs exist in 2 forms: ionized and
not ionized. In general, drugs that are not
ionized will be absorbed more readily
• If the drug is ionized, absorption will be
slower
Example: acidic drug
• If a drug is mildly acidic, absorption will be
enhanced in solutions that are also acidic,
because the drug will not be ionized in
these solutions.
• Aspirin (acetylsalicylic acid) is generally
not ionized in the stomach (pH of gastric
juice ranges 1-3). So its absorption here is
favored.
• In the small intestines (pH range 7-8),
acidic drugs are mostly ionized, absorption
is slower and occurs to a lesser extent
Example: basic drug
• Basic drugs (streptomycin, morphine) are
mostly ionized in the stomach, and are
absorbed more slowly and to a lesser
extent here.
• Basic drugs are not ionized in the
intestines and are more readily absorbed
here.
2. Distribution of drugs
• After absorption, distribution on the drug
occurs. It is the movement of the drug to
various tissues of the body.
• There are a number of factors which
determine how much drug reaches any
one organ or area of the body:
a. plasma protein binding
• As a drug enters the bloodstream, some of
it binds to circulating plasma proteins.
• Acidic drugs commonly bind to albumin,
while basic drugs often bind to
glycoproteins and lipoproteins.
• Many endogenous substances, such as
steroids, vitamins, and metal ions are
bound to globulins.
• Bound drugs are pharmacologically
inactive as they are carried thru
bloodstream.
• As unbound drug moves from blood into
body tissues to exert therapeutic effect,
some of the bound drug is released from
plasma protein to maintain equilibrium.
• The ratio of bound to unbound drug varies
with the drug, some are highly bound
(99%), others are not bound to any
significant degree:
• caffeine is about 10% bound
• Digoxin is about 23% bound
• Warfarin is about 99.9% bound
• Various disease states can affect drug
distribution. Specifically, liver disease may
alter the amount of albumin.
• This increases the amount of unbound
drug, which increases the concentration of
active drug within the body.
• Low albumin tends to be more common in
older patients and may lead to excessive
anticoagulation and bleeding in those on
Warfarin.
b. changes in circulation
• Physical activity and an increase in body
temperature will increase vasodilation and
theoretically increase the distribution of a
drug
c. body size and composition
• Obese individuals may accumulate fat
soluble drugs (BZ’s like valium)
d. blood-brain barrier
• This is an additional
lipid barrier that
protects the brain by
restricting the
passage of
electrolytes and other
H2O soluble
substances
(dopamine).
• Many lipid soluble drugs, such as L-dopa,
pass readily into the brain
3. Metabolism
• a. 1st pass metabolism
• Metabolism is the total of all chemical
reactions in the body
• It occurs in almost
every cell and organ,
but the liver is the
primary site
• Drugs absorbed thru
mucous membranes
of stomach or
intestines are carried
to the liver via the
portal vein
• Here the drug is subjected to metabolism
by liver enzymes before it enters into the
general circulation (this is called 1st pass
metabolism)
• The liver may actually metabolize the drug
to a less active form before it is distributed
to rest of body (including the target
organ/tissue)
• For some drugs, the 1st pass effect is so
extensive that most of the drug dose is
immediately metabolized
b. biotransformation
• Once a drug has produced its intended
therapeutic effect it needs to be eliminated
from the body.
• Biotransformation is the chemical
alteration of drugs and other foreign
compounds (xenobiotics) in the body
• Biotransformation enzyme systems
originated in ancient bacteria at least a
billion years ago,
• due to the hostile environment they had to
endure (extremes in temperature, lack of
oxygen, corrosive chemicals).
• These specialized heme-containing
enzymes are called cytochrome P450, or
CYP450, so named because they absorb
UV light at 450 nm.
• As of 7/2007 over 7,000 CYP450’s have
been identified. The very large number
necessitates a classification system (that
is based on similarity in amino acid
sequences).
• The initial division is into families,
designated by the prefix CYP followed by
a number, i.e. CYP1, CYP2. There are
over 70 of these families, but only 17 of
them in humans.
• The next division is into subfamilies which
are identified using a capital letter, i.e.
CYP1A, CYP1B.
• The final division is into individual
members of each subfamily (called
isoforms) which originate from a single
gene, i.e. CYP1A1, CYP1A2
All CYP450’s have a number of
features in common:
• They contain a heme group, therefore their
reactions with various substrates are iron
catalyzed.
• They are associated with membranes,
which are primarily lipid in composition.
• They can bind oxygen.
• They can undergo reactions (reduction)
that don’t require oxygen.
• CYP450’s are found in all tissues, but the
liver and GI tract have the highest
concentration which process and eliminate
large amounts of both endogenous and
exogenous chemicals.
• The overall aim of biotransformation is to
clear drugs and other chemicals from the
organism. Generally, biotransformation
occurs in 2 stages: phase I and phase II.
• Phase I are oxidative reactions which
insert an oxygen molecule to form an
alcohol:
• hydrocarbon—H + O2 + 2e’s + 2H1+ →
• hydrocarbon—OH + H2O
• This alcohol may now be water soluble
enough so that it is eliminated without
further metabolism. If not, it undergoes
conjugation with another water soluble
group in Phase II.
• In Phase II, a molecule destined for
elimination, either an endogenous or
exogenous substance, is attached to a
water soluble group , i.e. sulfates,
glucuronic acid, amino acids, acetate, and
glutathione
c. consequences of Phase I and
Phase II reactions
• What are the overall consequences of
these Phase I and Phase II reactions on
exogenous compounds?
i. Inactivation of a drug
• The active form of a drug is converted to
an inactive form. This is necessary so that
once it has performed its therapeutic job, it
is eliminated
• Without this reaction, it is estimated that
the barbiturate phenobarbital would
circulate for years
• This, however, is what happens to a
proportion of many drugs during their “1st
pass” through the liver.
ii. Activation of the compound
• Many drugs are biologically inactive until
metabolized by a cytochrome P450
• Codeine is activated by a cytochrome P450
to morphine
iii. formation of a toxic
metabolite
• This is obviously, not a desired effect, but
nonetheless, it happens.
• example: Benzo[a]pyrene is produced in
tobacco smoke, in charcoal grilled foods,
from burning coal, and in pollution
(resulting from various industrial
processes).
• It is metabolized by a cytochrome P450 to
a potent carcinogen which forms guanine
adducts on DNA . This may disrupt gene
function leading to mutations
• example: acetaminophen
• There are 3 major routes by which this is
metabolized, 2 of the 3 involve Phase II
reactions which produce polar, inactive
metabolites that are readily excreted
• A small amount is metabolized by a
cytochrome P450 to a highly reactive
metabolite NAPQI (N-acetyl-p-benzoquinone imine). This is usually not a
problem when normal doses of
acetaminophen are taken.
• Large quantities of acetaminophen cause
an increase in the production of NAPQI
which can cause liver damage
• In addition, consumption of alcohol
induces a cytochrome P450 , which
increases the production of NAPQI.
• The extent of liver damage depends on
the timing and amount of acetaminophen
taken.
• 41 year old white female with a diagnosis
of Tylenol overdose with liver failure
• 35% of cases involving liver failure are
caused by acetaminophen poisoning,
according to the American Liver
Foundation
d. Factors which affect drug
metabolism:
• The cytochrome P-450 system is under
genetic control and is highly sensitive to
induction (stimulation) or inhibition by
many factors (i.e., other drugs,
insecticides, herbicides, smoking, caffeine,
phytochemicals).
i. age
• A major factor in the metabolism of drugs
is age. The very young and the elderly
both have a decreased ability to
metabolize drugs due to different levels of
liver functioning. Children have smaller
livers and less circulation within the liver.
ii. genetics
• Genetics also plays a role, especially
when one considers the phenotypic
differences of metabolic enzymes. This
has been seen in various proton pump
inhibitors which may affect the treatment
for H. pylori infections.
iii. naturally occurring
ingredients in foods
Pressor agents
• Biologically active amines, or pressor
agents are commonly found in many
foods.
• These pressor agents include tyramine,
dopamine, histamine, and
phenylethylamine. Foods that contain
these agents include:
• aged cheeses (bleus, Stiltons, cheddars,
gorgonzolas), aged meats (salami,
sausages), soy sauce, fermented soy
beans or paste, tofu, miso soup, fava
beans, snowpea pods, saurkraut, Korean
beers and red wines (especially Chianti).
• The pressor agents in these foods do not
normally present a problem because they
are rapidly deaminated by MAO
(monoamine oxidase) and diamine
oxidases.
• One class of antidepressants is known as
MAO inhibitors. Patients on these drugs
should not eat foods that are high in these
pressor agents, as they are not broken
down.
• Tyramine, in particular, is a
vasoconstrictor, and can lead to a
hypertensive crisis (increased blood
pressure, increased heart rate, headache,
stroke, sometimes death).
CYP inhibitors
• Grapefruit inhibits CYP 3A4 which results
in increase in the concentration of many
drugs in the circulation, and possible
toxicity.
• The effects of grapefruit on this enzyme
can last up to 72 hours (until the body can
make more of the enzyme).
• Drugs affected include the statins, some
cardiac drugs (antiarrhythmic
amiodarone).
iv. dietary supplements
• St John’s Wort is a supplement used for
depression. It is a perennial whose
medicinal uses were first recorded in
ancient Greece.
• Preliminary studies suggest that St. John's
wort might work by preventing nerve cells
in the brain from reabsorbing the chemical
messenger serotonin.
• In Europe, St. John's wort is widely
prescribed for depression. In the United
States, it is one of the most commonly
used herbal supplements.
• Scientific evidence regarding the
effectiveness of St. John's wort for
depression is inconsistent.
• An analysis of the results of 37 clinical
trials concluded that St. John's wort may
have only minimal beneficial effects on
major depression.
• However, the analysis also found that St.
John's wort may benefit people with minor
depression; these benefits may be similar
to those from standard antidepressants.
• Research has shown that taking St. John's
wort results in an induction of CYP 3A4
which can limit the effectiveness of some
prescription medicines, including:
• antidepressant medicines, birth control
pills, cyclosporine, digoxin, and warfarin.
4. Excretion
• Drugs and their metabolites are
eliminated from the body by a number
of different routes
• The kidneys are the major organs of
excretion.
• A drug that remains bound to albumin is
too large to pass thru the glomerular
membrane in the nephron and is returned
to the general circulation
• Unbound drug is small enough to pass
through the glomerular membrane.
• Once through, distinction is made between
water-soluble and fat-soluble drugs
• Unbound water-soluble drug is excreted in
the urine
• Unbound fat-soluble drug is attracted to
lipid in membrane of renal tubule wall , is
reabsorbed into the renal tubules and
returned to the bloodstream.
•
• Eventually it is metabolized by liver into a
water-soluble form
• Without the liver’s action, it is difficult for a
fat-soluble drug to be excreted by kidneys.
• The respiratory system doesn’t generally
play a large role in drug excretion.
• An exception would be general anesthetic
gases which are not totally metabolized
and are excreted primarily by lungs
• Trace amounts of drugs are excreted in
breast milk
• May be insignificant compared with total
amount excreted by kidneys, but can be
enough of a dose to significantly affect a
nursing baby
• The rate of elimination refers to the
amount of drug removed per unit of time
from the body by normal physiological
processes
• It is an indicator of how long a drug will
produce its effect
• Half life, t1/2, is the length of time required
for a drug’s concentration in the plasma to
decrease by ½.
• The larger the ½ life, the longer it takes to
eliminate the drug
• Drugs with longer ½ lives may be given
less frequently
• With renal or hepatic disease, the ½ life of
a drug increases
•
•
•
•
•
½ life of:
minutes (nitroglycerin 1- 4 min)
several hours (metformin 17.6 hours)
days (corticosteroids)
years (Fosamax 10 yr)
I.
Pharmacodynamics
A. Introduction
• Pharmacodynamics is the mechanism of
drug action
• The receptor is the part of the cell that
interacts with a drug, and by binding with
it, initiates a specific biochemical chain of
events.
• Membrane
Receptor
embedded
in membrane
• A drug that is able to activate a receptor
and produce an effect is called an agonist.
• When present, agonists cause the tissue
to respond, resulting in a therapeutic
effect.
• Some drugs appear to fit a certain
receptor, but cannot activate the receptor
to produce an effect.
• These drugs are known as antagonists or
blockers.
• They inhibit or block the binding of body
chemicals or drugs from activating the
receptor (similar to inserting the wrong key
into a lock).
B. Mechanisms of receptor actions
• There are, generally, 3 major mechanisms
of receptor interractions.
1. binding to intracellular
receptors
• A lipid soluble drug diffuses across a cell
membrane and binds to an intracellular
receptor.
• Drugs in this class include steroid
hormones, thyroid hormones, and
corticosteroids.
Example: Corticosteroids
• Corticosteroids are taken into a target cell
and then enter the nucleus.
• Once inside the nucleus, they bind to
HRE’s (Hormone Response Elements)
and either induce or inhibit the activity of
specific genes.
• These genes control the synthesis of
various proteins, many of which are
enzymes.
• Corticosteroids are involved in the control
of the inflammatory response.
• They induce the synthesis of an inhibitory
protein called lipocortin.
• It is lipocortin that inhibits the activity of the
enzyme phospholipase A2
• This enzyme normally causes the release
of arachidonic acid from phospholipids in
cell membranes.
• Arachidonic acid is the precursor of the
prostaglandins and leukotrienes, powerful
inflammatory agents.
• Therefore, corticosteroids have the ability
to suppress the inflammatory response.
2. Secondary messengers: Activation of a
system on the cytoplasmic side of the
membrane
• A drug binds to a receptor and triggers a
cascade of reactions on the cytoplasmic
side of the membrane, leading to chemical
changes within the cell.
• There are 2 major secondary messenger
systems.
• The adenylate cyclase system which,
through the hydrolysis of ATP, leads to an
increase in cAMP.
• This results in either the activation or
inhibition of a protein kinase, ultimately
leading to some specific biochemical
activity.
• Examples of drugs and endogenous
molecules which activate protein kinases
include: a number of different growth
factors, atrial natriuretic peptide, and
insulin.
Example: insulin
• Examples of drugs which inhibit protein
kinases include: gefitinib and erlotinib.
• These drugs are tyrosine kinase inhibitors
(TKI).
• They block cell growth and division and
are used in various cancer treatments.
• The phosphatidylinositol/Ca2+ system
involves the hydrolysis of a membrane
phospholipid into a diacylglycerol (DAG)
and inositol-1,4,5-triphosphate (IP3).
• This leads to the release of intracellular
Ca2+ from storage vesicles.
• When the intracellular concentration of
Ca2+ increases, there is an increase in the
activity of various calcium-dependent
protein kinases, which again leads to
some specific biochemical reaction.
• Example: Lithium, in the treatment of
manic-depressive disorder.
3. Affect a membrane channel
• A drug binds to a receptor which controls a
membrane channel.
• The drug either mimics or blocks the
actions of some endogenous compound.
• These endogenous compounds include
acetylcholine, serotonin,
• GABA and glutamate.
Example:
• The binding of the neurotransmitter
acetylcholine will open channels that allow
the passage of Na1+, and initiate either a
nerve impulse or muscle contraction.
• Dicyclomine is an antispasmodic
anticholinergic used sometimes in the
treatment of Irritable Bowel Syndrome
(IBS)
• By preventing the binding of acetylcholine,
this antispasmodic medication decreases
muscle contractions
C. Types of receptors
• There are many types of receptors
throughout the body. Three types are
commonly involved in drug therapy:
adrenergic, cholinergic, and histaminic.
1. adrenergic receptors
• Adrenergic receptors are part of the
sympathetic nervous system.
• They are activated by the natural
neurotransmitters epinephrine,
norepinephrine and dopamine;
• as well as by many different drugs (i.e.
clonidine, dobutamine, albuterol).
• In addition, there are many drugs which
are adrenergic receptor antagonists. They
block adrenergic receptors (i.e. prazosin,
atenolol)
2. Cholinergic receptors
• Cholinergic receptors are part of the
parasympathetic nervous system and are
activated by the natural neurotransmitter
acetylcholine;
• as well as by many different drugs (i.e.
pilocarpine and neostigmine).
• In addition, there are many drugs which
are cholinergic receptor antagonists.
These block cholinergic receptors (i.e.
scopolamine, atropine)
3. Histaminic receptors
• Histaminic receptors are activated by
histamine.
• Pharmacologically, this is not a desired
effect.
• There are a number of antihistamines,
both 1st and 2nd generation (i.e. Benadryl,
Claritin) .