Curriculum VitaeCurriculum VitaeN a m a : Prof. Dr. dr. Rozaimah Zain-Hamid, MS, SpFKPekerjaan : * Guru Besar Tetap Bagian Farmakologi dan

Terapeutik, Fakultas Kedokteran, USU, Medan* Staf Pengajar Program S2 Biomedik &

Program S3 Kedokteran, Sekolah Pascasarjana,USU, Medan

* Sekretaris Komite Etik Penelitian Bidang Kesehatan Sekretaris Komite Etik Penelitian Bidang Kesehatan Fakultas Kedokteran USU

Riwayat Pendidikan:* Dokter (dr) dari Fak ltas Kedokteran USU Medan* Dokter (dr), dari Fakultas Kedokteran, USU. Medan* Magister Sains (MS), Ilmu Kedokteran Dasar (‘Basic Medical

Sciences’), dari Fakultas Pascasarjana, Univ. Indonesia, Jakarta* Ph D (D ) F k l i Kli ik (‘Cli i l Ph l ’)* Ph.D (Dr), Farmakologi Klinik (‘Clinical Pharmacology’),

dari Institute of Postgraduated Studies, Univ. Sains Malaysia, Malaysia

* Spesialis Farmakologi Klinik (Sp.FK), dari Dewan Penilai Kepakaran Persatuan Dokter Ahli Farmakologi Klinik Indonesia(PERDAFKI) Pusat, Jakarta.

Rozaimah Zain-Hamid & D.S. Hidayat

Department of Pharmacology & TherapeuticsDepartment of Pharmacology & TherapeuticsFaculty of Medicine

Universitas Sumatera Utara

Basic Principles of Pharmacokinetics

OUTLINES OF DISCUSSIONOUTLINES OF DISCUSSION

* Water & Lipid Solubility of Drugs- Aquous diffusion- Aquous diffusion- Lipid diffusion

* Fick’s Law of Diffusion

* Ionization of Weak Acids and Weak Bases

- The Henderson-Hesselbach EquationRZH & DSH Faculty of Medicine, USU, Medan.

&Water & lipid solubilityof drugsof drugs

RZH & DSH Faculty of Medicine, USU, Medan.

Aqueous diffusion

Within the larger aqueous compartmentsWithin the larger aqueous compartments of the body

(interstitial space cytosol etc)(interstitial space, cytosol, etc)

Across epithelial membrane tight junctions & p g jendothelial lining of blood vessels

(through aqeous pores MW 20 000 − 30 000)

RZH & DSH Faculty of Medicine, USU, Medan.

(through aqeous pores MW 20,000 − 30,000)

(Aqueous diffusion)(Aqueous diffusion)

The passive flux of molecules down a concentration gradientdown a concentration gradient

(Fick’s Law Diffusion)( )

RZH & DSH Faculty of Medicine, USU, Medan.

Lipid diffusionLipid diffusion

The most important limitingThe most important limitingfactor for drug permeation

(large number of lipid barriers separates the compartments of the body)p p y)

RZH & DSH Faculty of Medicine, USU, Medan.

Lipid diffusionLipid diffusion

The lipid : aqueous partition coefficient

Major determinant of drug’s mobility(How the drugs molecule moves between(How the drugs molecule moves between aqueous and lipid media / enters the lipid

membrane from aqueous medium)

RZH & DSH Faculty of Medicine, USU, Medan.

membrane from aqueous medium)

Drug’s movement from gaqueous to lipid or vice versa

I fl d b H f th diInfluenced by pH of the medium

Charged molecules attract water molecules

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water molecules

Professionalism means consistency of quality

(Frank Tyger)(Frank Tyger)

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Fick’s Law Diffusion

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Fick’s Law DiffusionFick s Law Diffusion

Flux (molecules per unit time) =

Area × Permeability coeff.C1 − C2 ×

Thickness

RZH & DSH Faculty of Medicine, USU, Medan.

Permeability coefficient

A measure of the mobility (drug molecules)

in the medium of diffusion path

RZH & DSH Faculty of Medicine, USU, Medan.

Ionization of weak acids and weak basesweak bases

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I i ti f dIonization of drugs

May markedly ability y y yto permeate membranes

Relatively water soluble and lipid insoluble complex

RZH & DSH Faculty of Medicine, USU, Medan.

p p

Weak acids(aspirin, acetaminophen, ampicillin,

furosemide, phenobarbital, phenytoin, warfarin theophylline tolbutamide etc)warfarin, theophylline, tolbutamide, etc)

DDrugs

Weak bases(salbutamol amphetamine atropine(salbutamol, amphetamine, atropine,

clonidine, diazepam, diphenhydramine,methadone, physostigmine, quinidine, etc)

RZH & DSH Faculty of Medicine, USU, Medan.

Weak acid drugs(aspirin)(aspirin)

C8H7O2COOH C8H7O2COO- + H+

neutral aspirin aspirin anion proton

* Protonated form of weak acids is neutralProtonated form of weak acids is neutral(more lipid soluble)

* Reaction to the left, in acidic environment (low pH, excess protons available)

** Reaction to the right, in a basic environ.RZH & DSH Faculty of Medicine, USU, Medan.

Weak base drugs(pyrimethamine)(pyrimethamine)

C12H11CIN3NH3+ C12H11CIN3NH2 + H+

i th ti t l i th tpyrimeth. cation neutral pyrimeth. proton

* Unprotonated form of weak base is neutralUnprotonated form of weak base is neutral(more lipid soluble)

* Reaction to the left, in acidic environ. (low pH, excess protons available)

** Reaction to the right, in a basic environ.RZH & DSH Faculty of Medicine, USU, Medan.

Life is not problem to be sol edLife is not problem to be solved,but a reality to be experienced

(Soren Kierkegaard)RZH & DSH Faculty of Medicine, USU, Medan.

Henderson − Hesselbalch equationequation

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Henderson-Hasselbalch equationHenderson-Hasselbalch equation

(protonated)L K HLog = pKa − pH

(unprotonated)

Equation applies to both acidic & basic drugs

RZH & DSH Faculty of Medicine, USU, Medan.

acidic & basic drugs

Henderson-Hasselbalch equation

(protonated)(protonated)Log = pKa − pH

(unprotonated)(u p oto ated)

pH <<< pKa drug fraction in the protonated form >>>>

pKa pH at which the concentration of

RZH & DSH Faculty of Medicine, USU, Medan.

the ionized & un-ionized forms are equal

Henderson-Hasselbalch equationq

Uncharged form more lipid soluble

Weak acid drugs more lipid solubleWeak acid drugs more lipid soluble at acid pH

Weak base drugs more lipid soluble at alkaline pH

RZH & DSH Faculty of Medicine, USU, Medan.

at alkaline pH

Application of Henderson-Hasselbalch equationequation

Manipulation of drug excretion kidney

Drugs in lipid soluble form reabsorptionDrugs in lipid soluble form reabsorptionby simple passive diffusion in renal tubule

To accelerate drugs excretion urine pHto make most of the drugs in ionized form

RZH & DSH Faculty of Medicine, USU, Medan.

g

To accelerate drugs excretionTo accelerate drugs excretion

Wake acid drugs alkaline urineWake acid drugs alkaline urine

Wake base drugs acidic urine

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Large number of drugs are weak basesare weak bases

Most of these bases are amineMost of these bases are amine containing molecules

The nitrogen of neutral amine has3 atoms associated with it, plus a pair of unshared electrons

RZH & DSH Faculty of Medicine, USU, Medan.

Weak base drugs amine containing moleculesamine containing molecules

RZH & DSH Faculty of Medicine, USU, Medan.

3 atoms: 1 carbon & 2 hydrogens ( i i )(a primary amine)

3 atoms: 2 carbons & 1 hydrogen y g(a secondary amine)

3 atoms: 3 carbons (a tertiary amine)3 atoms: 3 carbons (a tertiary amine)

May undergo reversible bond a proton with the unshared electrons, and vary their lipid solubility with pHy p y p

RZH & DSH Faculty of Medicine, USU, Medan.

A fourth carbon−nitrogen bond(quarternary amine)

Permanently charged and has no unshared electronsunshared electrons

(always in the poorly lipid-soluble charged form)charged form)

always in the poorly lipid-soluble charged form

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charged form

Amines containing molecules

H. .

R. .

R. .

R. .

R: N : . .

R: N :. .

R: N :. .

R: N : + R. .

H H R R

Primary Secondary Tertiary Quaternary

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Like a solid rock is not shaken by the wind, so the wise are not moved by praise or

blblame (Dhammapada)

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