Clinical Pharmacology

Peter Kabo
 Pharmacodynamic : The action of the drug on
the body

Pharmacokinetic : The study of the processes

of absorption, metabolism & excretion of
drugs as they relate to time course of the
presence of a drug in the body
 Pharmacodynamic
The actions of the drug on the body
Target of drug action :
Receptors
Enzymes :
Na+/K+ ATPase - digoxin
Xanthine-oxidase allopurinol
Acetylcholine esterase - physostigmin
PG synthetase - aspirin
Carbonic anhydrase-acetazolamide
Transport system
Molecular components
Non-specific physicochemical mechanism
 Non-specific physicochemical mechanism

Osmotic properties : laxatives, sorbitol, Mg-oxide

Acid/basic activity : Antacida
Oxidixing & reducing agents : Methylene blue
Protein precipitans : Astringent, hemostatic agents
Adsorbents : kaolin, peptin
Surfactants : antiseptics
Aneathetics
 J N Langley & P Ehrich
receptor concept (1901)
Receptros determine the
quantitative relation
between dose (concentration
of drug) & pharmacological
effect (respons).
Receptors are responsible for
selective of drug action.
Receptors mediate the action
of both pharmacologic
agonists & antagonists
(partial agonists)
 Macromolecular nature of drug Receptors
Ionotropic receptors (ion channel)
Intracellular receptors (hormone receptors)
Metabotropic (cell surface) receptors coupled to G-protein
R-PROPANOLOL L-PROPANOLOL
(Gurbel PA et al. J Am Coll Cardiol. 2005:46:1827-32)
 This is a space-filling model of the drug clopidogrel, the basic chemical structure for
which is shown in Figure 1 above. In the model shown here, green is chlorine (Cl), red is
oxygen (O), blue is nitrogen (N), and yellow is sulfur (S)
 Mengapa enantiomers menyebabkan perbedaan
farmakokinetik dan farmakodinamik obat ?
Molekul mengadakan interaksi secara stereo spesifik
receptor, enzim, molekul transporter, molekul antiporter, molekul carrier

Clopidogrel Molecule
S-enantiomer R-enantiomer

P2 Y12 Receptor P2 Y12 Receptor

 Cell unit of Clopidogrel
Crystal
Clopidogrel Form 1 Clopidogrel Form 2
S R

S-enantiomer
S-enantiomer R-enantiomer
 Kinetic analysis of drug-receptor interaction
Drug + Receptor = Drug-receptor complex

k1 k1 [D][R]
D+R DR k1 [D] + [R]= k2 [DR] = KD =
k2 k2 [DR]

[DR] [D] r
[D]=[RT] [DR] =r= [D]= KD
[RT] [D]+KD 1-r

KD = the equilibrium dissociation constant, represents the concentration of free

drug at which half-max binding is observed. The smaller the KD, the more tightly
bound the ligand.
Rate constants for muscarinic agonists KD=k1/k2 (umol/l)
Acetylcholine 0,0054
Carbachol 0,061
Arecholine 0,126
 Effectiveness of drug
LD50 is the amount of an ingested substance that kill
50% of a test animal.
EC50 is the concentration of a drug that gives half-
maximal response
Therapeutic margin/index is LD50/ED50
NNT (number need to treat) is the amount of patients
you need to treat to prevent one additional bad
outcome ( death, stroke etc).
*NNT=1/ARR ( absolute risk reduction)
ARR=CER (control event rate) EER ( experimental ER)
Drug A reduces the risk of bad outcome from 50%-30% (20%). The
NNT =1/0,2= 5
 Variation in Drug responsiveness
Idiosyncrasy :
unusual drug response (allergic reaction)
Hypo-/hyper-active :
Tolerance :
responsiveness diminished as a consequence of
continuied administration
Tachyphylaxis :
responsiveness diminished as a consequence of
rapidly after administration
 Pharmacokinetics
The study of the processes of absorption, metabolism &
excretion of drugs as they relate to time course of the presence
of a drug in the body
 Pharmacokinetics
(drug absorption)
Biologic factors:
Membrane structure & function
1. Passive aqueous diffusion (concentration gradient)
2. Passive lipid diffusion (lipid : water partition)
3. Carrier mediated transport (ATP-dependent membrane carrier protein: p-
glycoprotein, MRP1-6 etc)
Local blood flow
Gastric emptying times
Drug binding to food substance in gut
Physicochemical factors:
PH partition theory (lipid/water partition coefficient)
Ionization status
Lipophylic chemical group
Lack bulky/oxygenated side chain
Not too large size
 IMPORTANT EFFECTS OF PH
PARTITIONING:
Urinary acidification will accelerate the excretion
of weak bases and retard that of weak acids;
alkalination has the opposite effects
Increasing plasma pH (by addition of NaHCO3)
will cause weakly acidic drugs to be extracted from the
CNS into the plasma; reducing plasma pH (by
administering a carbonic anhydrase inhibitor) will cause
weakly acidic drugs to be concentrated in the CNS,
increasing their toxicity
 Pharmacokinetics
(Drug distribution)
Compartment
1. central compartment
2. peripheral compartment
3. special compartment
Condition :
Vascular permeability, regional blood flow, cardiac
output, perfusion rate of the tissue.
Ability to bind tissue & plasma protein (Covalent
bonds, Electrostatic bonds, Hydrophobic bonds)
Lipid solubility
PH partition
 Pharmacokinetics
(drug distribution)
Volume distribution (Vd) = Amount of drug in body/
concentration of drug in blood or plasma
Vd gives one as estimate of how well the drug is
distributed

Vd t1/2 target toxic

Digoxin : 500 50 1ng/ml 2ng/ml
Chloroquine : 13000 214 20 mg/ml 250mg/ml
Carbamazepine: 98 15 6mg/ml 9mg/ml
 Bioavailability
Destroyed Not Destroyed Destroyed
in gut absorbed by gut wall by liver

to
Dose systemic
circulation
 Half-life : is the time
required to change the
amount of drug in the body
by one-half during
elimination
Bioavailability : the fraction
of unchanged drug
reaching the systemic
circulation following
administration by any
route.
Area under blood
concentration-time curve
(AUC) : total amount of
drug that reaches the
circulation in given time
 Bioavailability = AUC/dose = F
Digoxin (F=0,7)
Pemberian digoxin 250 ug per oral, maka obat di
dalam darah = 250x0,7=227 ug

Bioequivalent : kesetaraan bioavailability suatu

produk terhadap produk lain yang standard.
Bioequivalent = AUC (drug A)/AUC (drug B)
= 100%
 Pharmacokinetic
(Phase I - Drug biotransformation)
A. Site of drug metabolism
at organ level
at cellular level
at biochemical level
B. Enzyme induction
Increased CYP450 activities
C. Enzyme inhibition (imidazole-containing
drugs)
Decreased CYP450 activities
 Pharmacokinetic
(Drug biotransformation)
Phase II : Conjugation by transferase :
Methylation methyltransferase
Acetylation N-acetyltransferase
Glucorunation glucorosyltrasferase
etc
Phase III : further modification & excretion
 Pharmacokinetic
(drug elimination)
Kidney, bile, sweat, saliva, exhaled air & milk
A. Renal glomerular filtration
GFR = 114 - 0,8 x age
(1 or 0,85)
Ccr
B. Renal tubular secretion
C Renal tubular absorption
D. Biliary excretion
 The enterohepatic shunt
Drug Liver

Bile Bile formation

duct
Biotransformation;
Hydrolysis by glucuronide produced
beta glucuronidase
gall bladder

Portal circulation

Gut
 Variation in pharmacodynamic &
pharmacokinetic
Pediatric pts
Elderly pts
Renal or hepatic disease pts
Pregnant women & Breast-feeding mothers
Concurrent drugs & Concurrent diseases
Pharmacogenetic phenotype
 William Osler (1849-1919)
Father of modern medicine

One of the first duties of the

physician is to educate the masses
not to take medicine.