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