General pharmacology General pharmacology ( ( Pharmacokinetics Pharmacokinetics ) ) Grade I Grade I Prof. Hanan Hagar Prof. Hanan Hagar Pharmacology Department Pharmacology Department
Jan 03, 2016
General pharmacologyGeneral pharmacology((PharmacokineticsPharmacokinetics))
Grade IGrade I
Prof. Hanan HagarProf. Hanan Hagar
Pharmacology DepartmentPharmacology Department
Recommended booksRecommended books
Basic and Clinical Pharmacology Basic and Clinical Pharmacology byby Katzung Katzung
Pharmacology Pharmacology
byby Rang Rang
Pharmacokinetics of drugs Pharmacokinetics of drugs
)ADME()ADME(
Are studies of Are studies of AAbsorptionbsorption DDistributionistribution MMetabolism etabolism EExcretion of drugsxcretion of drugs
Is the passage of drug through cell Is the passage of drug through cell membranes to reach its site of action.membranes to reach its site of action.
Mechanisms of drug absorptionMechanisms of drug absorption
1.1. Simple diffusion = passive diffusion.Simple diffusion = passive diffusion.
2.2. Active transport.Active transport.
3.3. Facilitated diffusion.Facilitated diffusion.
4.4. Pinocytosis )Endocytosis(.Pinocytosis )Endocytosis(.
water soluble drugwater soluble drug (ionized or polar) is readily (ionized or polar) is readily absorbed via aqueous channels or pores in cell absorbed via aqueous channels or pores in cell membrane.membrane.
Lipid soluble drugLipid soluble drug (nonionized or non polar) is (nonionized or non polar) is readily absorbed via cell membrane itself.readily absorbed via cell membrane itself.
CharactersCharacters common.common.Occurs along concentration gradient. Non Occurs along concentration gradient. Non
selectiveselective Not saturableNot saturable Requires no energyRequires no energy No carrier is neededNo carrier is neededDepends on lipid solubility.Depends on lipid solubility. Depends Depends
pka of drug - pH of medium.pka of drug - pH of medium.
Drugs exist in two forms ionized (water soluble & Drugs exist in two forms ionized (water soluble & nonionized forms (lipid soluble) in equilibrium.nonionized forms (lipid soluble) in equilibrium.
Drug ionized + nonionizedDrug ionized + nonionized
Only nonionized form is absorbable.Only nonionized form is absorbable.
Nonionized / ionized fraction is determinedNonionized / ionized fraction is determined
by pH and pKa according to by pH and pKa according to Henderson-Henderson-
HasselbachHasselbach
pKa- pH= log protonated / non-protonatedpKa- pH= log protonated / non-protonated
PKaPKa of the drugof the drug(Dissociation or ionization constant):(Dissociation or ionization constant):pH at which half of the substance is ionized & pH at which half of the substance is ionized & half is unionized.half is unionized.
pH of the mediumpH of the medium
Affects ionization of drugsAffects ionization of drugs..– Weak acids Weak acids best absorbed in stomach. best absorbed in stomach.– Weak bases Weak bases best absorbed in intestine. best absorbed in intestine.
Which one of the following drugs will be best absorbed in Which one of the following drugs will be best absorbed in stomach (pH=3)stomach (pH=3)??
Aspirin pka=3.0Aspirin pka=3.0
warfarin pka=5.0warfarin pka=5.0
Arrange the following drugs in ascending order from Arrange the following drugs in ascending order from least to greatest in rate of absorption in small intestine least to greatest in rate of absorption in small intestine
(pH=7.8)(pH=7.8)??
9.49.4 Propranolol pkaPropranolol pka==
Aspirin pka=3.0Aspirin pka=3.0
warfarin pka=5.0warfarin pka=5.0
Relatively unusual.Relatively unusual.Occurs against concentration gradient.Occurs against concentration gradient.Requires carrier and energy.Requires carrier and energy.Specific Specific Saturable.Saturable. Iron absorption.Iron absorption.Uptake of levodopa by brain.Uptake of levodopa by brain.
Occurs along concentration gradient.Occurs along concentration gradient. Requires carriersRequires carriers Selective. Selective. Saturable. Saturable. No energy is required.No energy is required.
Active transport Carrier-mediated facilitated diffusion
Against concentration Against concentration gradientgradient
(From low to high)(From low to high)
along concentration along concentration gradientgradient
(From high to low)(From high to low)
Needs carriersNeeds carriers Needs carriersNeeds carriers
Selective, saturableSelective, saturable Selective, saturableSelective, saturable
Energy is requiredEnergy is required No energy is requiredNo energy is required
Passive transport Active transport
Along concentration Along concentration gradientgradient
(From high to low)(From high to low)
against concentration against concentration gradientgradient
(From low to high)(From low to high)
No carriersNo carriers Needs carriersNeeds carriers
Not selectiveNot selective
Not saturableNot saturable
Selective, saturableSelective, saturable
No energyNo energy energy is requiredenergy is required
Endocytosis: uptake of membrane-bound particles.
Exocytosis: expulsion of membrane-bound particles. High molecular weight drugs orHigh molecular weight drugs or
Highly lipid insoluble drugsHighly lipid insoluble drugs
Enteral Enteral
via gastrointestinal tract )GIT(.via gastrointestinal tract )GIT(.– Oral Oral – SublingualSublingual– Rectal Rectal
Parenteral administration = injections.Parenteral administration = injections.
Topical applicationTopical application
Advantages DisadvantagesEasyEasy
Self useSelf use
SafeSafe
ConvenientConvenient
cheapcheap
No need for No need for sterilizationsterilization
Slow effectSlow effect
No complete absorption No complete absorption (Low bioavailability).(Low bioavailability).
Destruction by GITDestruction by GIT
First pass effectFirst pass effect
GIT irritationGIT irritation
Food–Drug interactionsFood–Drug interactions
Drug-Drug interactionsDrug-Drug interactions
Not suitableNot suitable for vomiting, for vomiting, unconscious, emergency.unconscious, emergency.
First pass MetabolismFirst pass Metabolism
Metabolism of drug in the gut wall or portal Metabolism of drug in the gut wall or portal circulation before reaching systemic circulationcirculation before reaching systemic circulation
so the amount reaching system circulation is less so the amount reaching system circulation is less than the amount absorbedthan the amount absorbed
Where ?Where ? LiverLiver Gut wallGut wall Gut LumenGut Lumen
Result ?Result ?
Low bioavailability.Low bioavailability.
Short duration of action (t ½).Short duration of action (t ½).
First pass effectFirst pass effect
Dosage formsDosage forms
CapsulesCapsules
TabletsTablets
SyrupSyrup
SuspensionSuspension
TabletsTabletsHard- gelatin Hard- gelatin
capsulecapsule SpansuleSpansuleSoft- gelatin Soft- gelatin
capsulecapsule
Advantages Disadvantages• Rapid effect (Emergency)Rapid effect (Emergency)• No first pass metabolism.No first pass metabolism.• High bioavailabilityHigh bioavailability• No GIT destructionNo GIT destruction• No food drug No food drug
interactioninteraction
Dosage form:Dosage form: friable tablet friable tablet
Not forNot for
irritant drugsirritant drugs
Frequent useFrequent use
Advantages Disadvantages Suitable forSuitable for–Vomiting & children. Vomiting & children. &unconsciousness&unconsciousness– Irritant & Bad taste drugs.Irritant & Bad taste drugs.– less first pass metabolism less first pass metabolism
(50%)(50%)
Dosage form:Dosage form:
suppository or enemasuppository or enema
Not forNot for – Irregular Irregular absorption & absorption & bioavailability.bioavailability.– Irritation of Irritation of rectal mucosa.rectal mucosa.
Intradermal (Intradermal (I.DI.D.) (into skin).) (into skin)Subcutaneous (Subcutaneous (S.CS.C.).)
Intramuscular (Intramuscular (I.MI.M.).)
Intravenous (Intravenous (I.VI.V.) (into veins).) (into veins)
Intra-arterial (Intra-arterial (I.AI.A.) (into arteries).) (into arteries)
Intrathecal (Intrathecal (I.TI.T.) (cerebrospinal fluids ).) (cerebrospinal fluids )
Intraperitoneal (Intraperitoneal (I.PI.P.) (peritoneal cavity).) (peritoneal cavity)
Intra - articular (Synovial fluids)Intra - articular (Synovial fluids)
Advantages Disadvantages• high bioavailabilityhigh bioavailability• Rapid action Rapid action (emergency)(emergency)• No first pass metabolismNo first pass metabolism
Suitable forSuitable for–Vomiting &unconsciousnessVomiting &unconsciousness– Irritant & Bad taste drugs.Irritant & Bad taste drugs.– No gastric irritationNo gastric irritation– No food-drug interactionNo food-drug interaction
Dosage form:Dosage form:
Vial or ampouleVial or ampoule
– InfectionInfection– Sterilization.Sterilization.– PainPain– Needs skillNeeds skill– AnaphylaxisAnaphylaxis– Expensive.Expensive.
Ampoule VialAmpoule Vial
Produce local effect to Produce local effect to Skin (Skin (percutaneouspercutaneous) e.g. allergy testing, ) e.g. allergy testing,
topical local anesthesiatopical local anesthesia Mucous membrane of respiratory tract Mucous membrane of respiratory tract
((InhalationInhalation) e.g. asthma) e.g. asthma Eye drops e.g. conjunctivitisEye drops e.g. conjunctivitis Ear drops e.g. otitis externaEar drops e.g. otitis externa Intranasal, e.g. decongestant nasal sprayIntranasal, e.g. decongestant nasal spray
Advantages Disadvantages• Mucous membrane ofMucous membrane of
respiratory system respiratory system • Rapid absorption Rapid absorption
(large surface area)(large surface area)•Provide local actionProvide local action• Minor systemic effectMinor systemic effect• Low bioavailabilityLow bioavailability• Less side effects. Less side effects. • No first pass effect No first pass effect
Dosage form:Dosage form: aerosol, nebulizer aerosol, nebulizer
Only few Only few drugs can be drugs can be
usedused
Nebulizer AtomizerNebulizer Atomizer
a medicated adhesive patch applied to skina medicated adhesive patch applied to skin
* *Slow effect (prolonged drug action)Slow effect (prolonged drug action)
* *produce systemic effectproduce systemic effect
e.g. the nicotine patchese.g. the nicotine patches
Is the fraction of unchanged drug that enters Is the fraction of unchanged drug that enters systemic circulation after administration and systemic circulation after administration and becomes available to produce actionbecomes available to produce action
I.V. provides 100% bioavailability.I.V. provides 100% bioavailability.
Oral usually has less than I.V.Oral usually has less than I.V.
Bio = AUC Bio = AUC oraloral / AUC / AUC IVIV X 100 X 100
Factors Affecting Bioavailability:Factors Affecting Bioavailability:
Molecular weight of drug.Molecular weight of drug.Drug Formulation (ease of dissolution).Drug Formulation (ease of dissolution).
(solution > suspension > capsule > tablet)(solution > suspension > capsule > tablet) Drug solubility of the drugDrug solubility of the drug Chemical instability in gastric pH Chemical instability in gastric pH
(Penicillin & insulin )(Penicillin & insulin ) First pass metabolism reduces bioavaiFirst pass metabolism reduces bioavai
Factors Affecting Bioavailability (BAV):Factors Affecting Bioavailability (BAV):
Blood flow to absorptive siteBlood flow to absorptive site
Greater blood flow increases bioavailabilityGreater blood flow increases bioavailability Intestine has greater blood flow than stomachIntestine has greater blood flow than stomach
Surface area available for absorption.Surface area available for absorption. Intestinal microvilli increases itIntestinal microvilli increases it
Rate of gastric emptyingRate of gastric emptying rapid gastric emptying fast transit to rapid gastric emptying fast transit to
intestineintestine pH of gutpH of gut
Intestinal motility (Transit Time)Intestinal motility (Transit Time) Diarrhea reduce absorptionDiarrhea reduce absorption
Drug interactionsDrug interactions Food Food
slow gastric emptying slow gastric emptying generally slow absorptiongenerally slow absorption Tetracycline, aspirin, penicillin VTetracycline, aspirin, penicillin V