Transcript drug and administration and absorption

General pharmacology
(Pharmacokinetics; drug and
administration and absorption)
Prof. Hanan Hagar
Dr.Ishfaq Bukhari
Pharmacology Department
Pharmacokinetics (Drug absorption)
The student should be able to
 Discuss the different routes of drug administration
 Identify the advantages and disadvantages of various routes
of drug administration
 Know the various mechanisms of drug absorption
 List different factors affecting drug absorption
 Define bioavailability
Recommended books
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Lippincott’s illustrated reviews
(Pharmacology) by Howland and
Mycek
Basic and Clinical Pharmacology by
by Katzung
PHARMACOKINETICS:
Pharmacokinetics:It is the study of what the body
does to the drug i.e ADME
 ABSORPTION
 DISTRIBUTION
 METABOLISM
 EXCRETION
of the drug
Note: Pharmacodynamic is what the drug does to
our body
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Enteral
via gastrointestinal tract (GIT)( Oral and Rectal )
 Sublingual
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Parenteral administration = injections.
Topical application
Inhalation
Advantages
- Easy
Self use
-Safe
- convenient
- cheap
- No need for
sterilization
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Disadvantages
- Slow effect
No complete absorption
- Destruction by pH and
enzymes
- GIT irritation
- Food - Drug interactions
-Drug-Drug interactions
- First pass effect
- (low bioavailability).
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Not suitable for
 vomiting & unconscious patient
 emergency & bad taste drugs
Factors affecting absorption from
GIT
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GIT motility changed by drug / diseases
Presence of food
Blood flow/surface area
GIT juices
pH of GIT fluids
Chemical/drug interactions
dosage form of a drug
Most of the drug is absorbed with in 1-3 hours,mostly it
occurs in small intestine ,rate of absorption depends on lipid
solubility ,ionization and pH.
Factors affecting absorption from GIT
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Drugs administered in aqueous solution are
absorbed faster & completely than tablet or
suspension forms.
Drugs such as the tetracyclines, which are
highly ionized, can complex with Ca++ ions in
membranes, food, or milk, leading to a
reduction in their rate of absorption.
Factors that accelerate gastric emptying time,
permitting drugs to reach the large absorptive
surface of the small intestine sooner, will
increase drug absorption unless the drug is
slow to dissolve.
First pass Metabolism
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Metabolism of drug in the gut wall or portal
circulation before reaching systemic circulation
So the amount reaching system circulation is less than
the amount absorbed
Where ?
 Liver
 Gut wall
 Gut Lumen
Results ?
Low bioavailability.
Short duration of action of drugs (t ½).
First pass Metabolism
First pass effect
Stomach pH
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The low pH of the gastric contents (pH 1–2)
may influence absorption of drugs because it
can affect the degree of drug ionization. e.g,
the weak base diazepam (pKa 3.3) will be
highly Ioninized in the gastric juice, and
absorption will be slow.
weak acid drug, acetaminophen (pKa 9.5)
will exist mainly in its unionized form and can
more readily diffuse from the stomach into
the systemic circulation.
Small intestine
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The small intestine, with its large surface
area and high blood perfusion rate, has a
greater capacity for absorption than does the
stomach.
Conditions that shorten intestinal transit time
(e.g., diarrhea) decrease intestinal drug
absorption, while increases in transit time will
enhance absorption by permitting drugs to
remain in contact with the intestinal mucosa
longer.
Oral Dosage Forms (oral formulations)
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Tablets (enteric coated tablets)
Capsules (hard and soft gelatin capsules)
Syrup
Suspension
Emulsion
Tablets
Hard- gelatin
capsule
Spansule
Soft- gelatin
capsule
Advantages
Rapid effect (Emergency)
 No first pass metabolism.
 High bioavailability
 No GIT destruction
 No food drug
interaction
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Dosage form: friable tablet
Disadvantages
Not for
- irritant drugs
- Frequent use
Advantages
Suitable for
 children
 Vomiting or unconscious
patients
 Irritant & Bad taste drugs.
 less first pass metabolism
(50%)
Dosage form:
suppository or enema
Disadvantages
Irregular
absorption &
bioavailability.
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Irritation of
rectal mucosa.
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Intradermal (I.D.) (into skin)
Subcutaneous (S.C.) (under skin)
Intramuscular (I.M.) (into muscles)
Intravenous (I.V.) (into veins)
Intra-arterial (I.A.) (into arteries)
Intrathecal (I.T.) (cerebrospinal fluids )
Intraperitoneal (I.P.) (peritoneal cavity)
Intra - articular (Synovial fluids)
Advantages
Rapid action (emergency)
 High bioavailability
 No food-drug interaction
 No first pass metabolism
 No gastric irritation
Suitable for
Vomiting &unconsciousness
 Irritant & Bad taste drugs.
Dosage form:
Vial or ampoule
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Disadvantages
Infection
 Sterilization.
 Pain
 Needs skill
 Anaphylaxis
 Expensive.
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Not suitable for oily
solutions or poorly
soluble substance
Ampoule
Single use
Vial
Repeated use
Injection
Special Utility
Limitations
I.D.
Minute volume (0.1 ml)
Suitable for vaccinations
& sensitivity test
Not suitable for large volumes
S.C.
0.1 ml – 1 ml
Suitable for some poorly
soluble suspensions and for
instillation of slow-release
implants e.g. insulin zinc
preparation
Not suitable for large volumes
I.M.
larger volume 3-5 ml Suitable Not suitable for irritant drugs
for moderate volumes, oily
vehicles, and some irritating
substances
I.V.
Suitable for large volumes
and for irritating substances
Not suitable for oily solutions
or poorly soluble substances
Must inject solutions slowly as
a rule
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Drugs are mainly applied topically to produce
local effects. They are applied to
Skin (percutaneous) e.g. allergy test, topical
antibacterial and steroids prep and local
anesthesia
Mucous membrane of respiratory tract
(Inhalation) e.g. asthma
Eye drops e.g. conjunctivitis
Ear drops e.g. otitis externa
Intranasal, e.g. decongestant nasal spray
Advantages
Mucous membrane of
 respiratory system
 Rapid absorption
(large surface area)
 Provide local action
 Minor systemic effect
 Less side effects.
 No first pass effect
Disadvantages
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Dosage form: volatile gases
(anesthetics), aerosol, nebulizer for
asthma
Only few drugs
can be used
Nebulizer
Atomizer
a medicated adhesive patch applied to skin to
provide systemic effect (prolonged drug
action)
e.g. the nicotine patches (quit smoking)
Scopolamine
(vestibular depressant)
Is the passage of drug from its site of
administration to its site of action through
various cell membranes.
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Except for intravenous administration, all
routes of drug administration require that
the drug be transported from the site of
administration into the systemic circulation.
Is the passage of drug from its site of
administration to its site of action through
cell membranes.
Cell membrane
Sites of
Administration
Sites of
action
Sites of
Administration
Absorption & distribution
Elimination
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The transport of drugs across membranes
occurs through one or more of the
following processes:
1.
2.
3.
4.
Simple diffusion = passive diffusion.
Active transport.
Facilitated diffusion.
Pinocytosis (Endocytosis).
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water soluble drug (ionized or polar) is
readily absorbed via diffusion through
aqueous channels or pores in cell
membrane.
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Lipid soluble drug (nonionized or non
polar) is readily absorbed via diffusion
through lipid cell membrane itself.
Characters
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common.
Occurs along concentration gradient.
Non selective
Not saturable
Requires no energy
No carrier is needed
Depends on lipid solubility.
Depends on pka of drug - pH of medium.
Drugs exist in two forms ionized (water soluble)
nonionized forms (lipid soluble) in equilibrium.
Drug
ionized form + nonionized
form
 Only nonionized form is absorbable.
 Nonionized / ionized fraction is determined
by pH and pKa
As general basic drugs are more ionized and less diffusible in a
relatively acidic(less than the pka) medium, on the contrary
basic are more lipid soluble and more diffusible in a relatively
alkaline medium
PKa of the drug
(Dissociation or ionization constant): pH at which
half of the substance is ionized & half is unionized.
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The lower the pKa value (pKa < 6) of the acidic
drug the stronger the acid e.g aspirin (Pka= 3.0 ),
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The higher the pKa value (pKa >8) of a basic
drug, the stronger the base e.g propranolol (
pKa= 9.4)
PKa of the drug
(Dissociation or ionization constant):
pH at which half of the substance is ionized &
half is unionized.
pH of the medium
Affects ionization of drugs.
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Weak acids  best absorbed in stomach.
Weak bases  best absorbed in intestine.
Which one of the following drugs will be best absorbed in
stomach (pH=3)?
Aspirin
pka=3.0
warfarin
pka=5.0
Arrange the following drugs in ascending order from least to
greatest in rate of absorption in small intestine (pH=7.8)?
Propranolol pka= 9.4
Aspirin
pka=3.0
warfarin
pka=5.0
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Relatively unusual.
Occurs against concentration gradient.
Requires carrier and energy.
Specific
Saturable.
eg.
Sugar, amino acids and Iron absorption.
Uptake of levodopa by brain.
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Occurs along concentration gradient.
Requires carriers
Selective.
Saturable.
No energy is required.
Passive transport
along concentration
gradient
(From high to low)
Active transport
against concentration
gradient
(From low to high)
No carriers
Needs carriers
Not saturable
saturable
Not selective
Selective
No energy
energy is required
Active transport
Against concentration
gradient
(From low to high)
Needs carriers
Carrier-mediated
facilitated diffusion
along concentration
gradient
(From high to low)
Needs carriers
saturable
saturable
Selective
Selective
Energy is required
No energy is required
Endocytosis: uptake of membrane-bound particles.
Exocytosis: expulsion of membrane-bound particles.
Phagocytosis occurs for high molecular weight
Drugs or highly lipid insoluble drugs.
OUT
IN
IN
OUT
Factors modifying drug absorption
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GENERAL FACTORS
lipid solubility
Degree of ionization
Drug solubility (aqueous sol better than oily,susp,sol)
Dosage forms (depending on particle size and
disintegration)
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Concentration of drugs
Circulation at site of absorption
Area of absorbing surface (small intestine has large
surface area)
Route of administration.
Is the fraction of unchanged drug that
enters systemic circulation after
administration and becomes available to
produce an action
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I.V. provides 100% bioavailability.
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Oral usually has less than I.V.