Transcript GENERAL PHARMACOLOGY (absorption)

General pharmacology
(Pharmacokinetics)
Grade I
Prof. Hanan Hagar
Pharmacology Department
Recommended books
Basic and Clinical Pharmacology
by Katzung
Pharmacology
by Rang
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Pharmacokinetics of drugs
(ADME)
Are studies of
Absorption
Distribution
Metabolism
Excretion of drugs
Is the passage of drug through cell
membranes to reach its site of action.
Mechanisms of drug absorption
1. Simple diffusion = passive diffusion.
2. Active transport.
3. Facilitated diffusion.
4. Pinocytosis (Endocytosis).
water soluble drug (ionized or polar) is readily
absorbed via aqueous channels or pores in cell
membrane.
Lipid soluble drug (nonionized or non polar) is
readily absorbed via cell membrane itself.
Characters
 common.
Occurs along concentration gradient. Non
selective
 Not saturable
 Requires no energy
 No carrier is needed
Depends on lipid solubility.
 Depends
pka of drug - pH of medium.
Drugs exist in two forms ionized (water soluble &
nonionized forms (lipid soluble) in equilibrium.
Drug
ionized + nonionized
Only nonionized form is absorbable.
Nonionized / ionized fraction is determined
by pH and pKa according to HendersonHasselbach
pKa- pH= log protonated / non-protonated
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.
– 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
 Relatively unusual.
Occurs against concentration gradient.
Requires carrier and energy.
Specific
Saturable.
 Iron absorption.
Uptake of levodopa by brain.
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Occurs along concentration gradient.
Requires carriers
Selective.
Saturable.
No energy is required.
Active transport
Against concentration
gradient
(From low to high)
Carrier-mediated
facilitated diffusion
along concentration
gradient
(From high to low)
Needs carriers
Needs carriers
Selective, saturable
Selective, saturable
Energy is required
No energy is required
Passive transport
Along concentration
gradient
(From high to low)
No carriers
Active transport
against concentration
gradient
(From low to high)
Needs carriers
Not selective
Not saturable
Selective, saturable
No energy
energy is required
Endocytosis: uptake of membrane-bound
particles.
Exocytosis: expulsion of membrane-bound
particles.
High molecular weight drugs or
Highly lipid insoluble drugs
Enteral
via gastrointestinal tract (GIT).
– Oral
– Sublingual
– Rectal
Parenteral administration = injections.
Topical application
Advantages
Easy
Self use
Safe
Convenient
cheap
No need for
sterilization
Disadvantages
Slow effect
No complete absorption
(Low bioavailability).
Destruction by GIT
First pass effect
GIT irritation
Food–Drug interactions
Drug-Drug interactions
Not suitable for vomiting,
unconscious, emergency.
First pass Metabolism
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
Result ?
Low bioavailability.
Short duration of action (t ½).
First pass effect
Dosage forms
Capsules
Tablets
Syrup
Suspension
Tablets
Hard- gelatin
capsule
Soft- gelatin
Spansule
capsule
Advantages
• Rapid effect (Emergency)
• No first pass metabolism.
• High bioavailability
• No GIT destruction
• No food drug
interaction
Dosage form: friable tablet
Disadvantages
Not for
irritant drugs
Frequent use
Advantages
Disadvantages
Suitable for
–Vomiting & children.
&unconsciousness
– Irritant & Bad taste drugs.
– less first pass metabolism
(50%)
Not for
– Irregular
absorption &
bioavailability.
– Irritation of
rectal mucosa.
Dosage form:
suppository or enema
Intradermal (I.D.) (into skin)
Subcutaneous (S.C.)
Intramuscular (I.M.)
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
• high bioavailability
• Rapid action (emergency)
• No first pass metabolism
Suitable for
–Vomiting &unconsciousness
– Irritant & Bad taste drugs.
– No gastric irritation
– No food-drug interaction
Dosage form:
Vial or ampoule
Disadvantages
– Infection
– Sterilization.
– Pain
– Needs skill
– Anaphylaxis
– Expensive.
Ampoule
Vial
 Produce local effect to
 Skin (percutaneous) e.g. allergy testing,
topical 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
• Low bioavailability
• Less side effects.
• No first pass effect
Dosage form: aerosol, nebulizer
Disadvantages
Only few
drugs can be
used
Nebulizer
Atomizer
a medicated adhesive patch applied to skin
* Slow effect (prolonged drug action)
* produce systemic effect
e.g. the nicotine patches
Is the fraction of unchanged drug that enters
systemic circulation after administration and
becomes available to produce action
I.V. provides 100% bioavailability.
Oral usually has less than I.V.
Bio = AUC oral / AUC IV X 100
Factors Affecting Bioavailability:
 Molecular weight of drug.
Drug Formulation (ease of dissolution).
(solution > suspension > capsule > tablet)
 Drug solubility of the drug
 Chemical instability in gastric pH
(Penicillin & insulin )
 First pass metabolism reduces bioavai
Factors Affecting Bioavailability (BAV):
 Blood flow to absorptive site
Greater blood flow increases bioavailability
Intestine has greater blood flow than stomach
 Surface area available for absorption.
Intestinal microvilli increases it
Rate of gastric emptying
rapid gastric emptying
fast transit to
intestine
 pH of gut
Intestinal motility (Transit Time)
Diarrhea reduce absorption
Drug interactions
Food
slow gastric emptying
generally slow absorption
Tetracycline, aspirin, penicillin V