k - 19 basic principle of pharmacokinetic.ppt...
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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
RZH & DSH Faculty of Medicine, USU, Medan.
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
RZH & DSH Faculty of Medicine, USU, Medan.
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
RZH & DSH Faculty of Medicine, USU, Medan.
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
RZH & DSH Faculty of Medicine, USU, Medan.
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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