clinical pharmacokinetics by mubarek ahmedin adigrat university 3re year cl. pharmacy

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2. Group members
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Name id.no
1.Basa Ketema 1506/07
2. Brhane Gebrekidan 1509/07
3. Chaltu bokan 1510/07
4. Derbew Getaneh 1511/07
5. Etsay Haftom 1515/07
6. Mubarek Ahmedin 1530/07

3. CLINICAL PHARMACOKINETICS
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4. OUTLINE
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 Introduction to clinical pharmacokinetics
 Processes of pharmacokinetics
1. Absorption of drugs
2. Distribution of drugs
3. Metabolism of drugs
4. Elimination of drugs
 Applying pharmacokinetic principles

5. Learning Objectives
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 Upon completion of the chapter, the students will
be able to:
 Define the following terms: clinical
pharmacokinetics, and clearance, volume of
distribution, half-life, bioavailability.
 Calculate , a values of clearance, volume of
distribution, and half-life .
 Processes of pharmacokinetics

6. Introduction
Definition
 Pharmacokinetics ; involves the study of absorption,
distribution, metabolism (biotransformation) and drug
excretion over time.
-- refers on how the body acts on the drug
 Clinical pharmacokinetics; is the application of
pharmacokinetic principles to the safe and effective
therapeutic management of drugs in an individual patient.
- - it is the discipline that describes the absorption,
distribution, metabolism, and elimination of drugs in
patients requiring drug therapy.
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7. The question could be asked-why bother
about Pharmacokinetics ??????
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 To prevent, cure or control various disease states
adequate drug doses must be
delivered to the target tissues.
so that therapeutic yet NON – toxic levels
are obtained

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 Too much of a drug will result into toxic effects &
too little will not result into the desired therapeutic
effects.

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 Monitor medications with a narrow
therapeutic index
 Decrease the risk of adverse effects
while maximizing pharmacologic
response of medications
 Know and apply drug administration
routes.

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Pharmacokinetic paths cont..
Drug at the site of Administration
Drug in plasma
Drug & metabolites in urine, feces, or bile
1 . ABSORPTION
(INPUT)
2. DISTRIBUTION
drug in tissues
3. METABOLISM
metabolites in tissues
4. ELIMINATION
(OUTPUT)

11. 1. Absorption of drugs
Absorption
 Movement of drug from site of
administration to the systemic
circulation.
 Occurs after dissolution of a
solid drug or administration of
liquid drugs.
 Route and site of administration
affect
 Rate …… and
 Extent of
absorption
 IV delivery – absorption is complete
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12. Mechanisms of drug absorption
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There are 4 mechanisms by which drug molecules cross the cell
membrane/absorption/
 Passive diffusion
 Facilitated diffusion
 Active transport
 Bulk transport mechanisms

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Cont…
Characteristics Simple
diffusion
Facilitated
diffusion
Active transport
Incidence Commonest Less common Least common
Process Slow Quick Very Quick
Movement Along
concentratio
n gradient
Along
concentration
gradient
Against concentration
gradient
Carrier Not needed Needed Needed
Energy Not require Not required Required

14. Bioavailability
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 The bioavailability of a drug is the fraction of the
dose administered which is absorbed and reaches the
systemic circulation.
 Bioavailability of drug injected i.v. is 100%, but is
frequently lower after oral ingestion, because:
 The drug may be incompletely absorbed
 The absorbed drug may undergo first pass
metabolism in intestinal wall and/or liver or be
excreted in bile.
 For non I.V.: ranges from 0-100% (0 – 1)

15. First-Pass Metabolism
 Before the drug reaches the systemic
circulation, the drug can be metabolized in the
liver or intestine. As a Result, the
concentration of drug in the systemic
circulation will be reduced.
 Drug ⇒ Oral administration ⇒ G.I.T. ⇒ Portal
circulation ⇒Liver ( First pass metabolism ) ⇒
Systemic Circulation
 Decreases Bioavailability
 Decreases Therapeutic Response
 Can be bypassed if drug is given –
- Parenterally ( i.v. Xylocaine in Arrhythmias )
Or
- Sublingually ( Isosorbide dinitrate in Angina )
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Vena
cava

16. Factors Affecting Drug Absorption and Bioavailability
1. Physicochemical properties of the drug
– Molecular shape (Physical state)
– Particle size
– Lipid solubility and unionized form of drug
– Disintegration and dissolution time
-Formulation
2. Route of drug administration
3. pH and ionization
4. Presence of other drugs
5. Patient conditions
eg. - Disease condition
– Presence or absence of food … affect absorption from the GI
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17. 2. DISTRIBUTION OF DRUGS
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- Is a random movement drug molecules out of the central
compartment /systemic circulation/ in to the different body tissues
/fluid compartments
– Involves the delivery of drugs from the blood in to the target sites

18. Factors Affecting Distribution of
Drugs
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Physico-chemical properties of drugs
 Lipid solubility of the drug
 pKa of the drug(ionization at
physiological pH )
 Degree of plasma protein.
Physiological factors
 Rate of blood flow
Presence of barriers
 BBB
 Placental barrier

19. Drug - plasma protein binding
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 After entering the blood stream, drugs exist in two
forms [plasma protein bound & unbound form].
 Bound drugs are pharmacologically INACTIVE,
only the FREE, UNBOUND drug can act on target
sites in the tissues, elicit a biologic response & be
available to the processes of elimination.

20. CONT…
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 The major plasma proteins that bind drugs are
– Albumin
– α-acid glycoprotein
– Lipoproteins
– Globulin
– Hormone-binding factors

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The phenomenon of plasma protein binding is clinically important to
consider for drug with the following properties
– Drugs that are highly plasma protein bound (above 90% or so)
– Drugs with narrow therapeutic index
– Drugs with low excretion rate
– Examples, Warfarin, Phenytoin, Aspirin

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Redistribution
 Termination of drug effect is due to
Biotransformation and excretion, ….most
Circumstances.
 Redistribution of the drug from its site of action into
other tissues or sites.
 Highly lipid soluble drugs – distribute to brain, heart
and kidney etc. immediately followed by muscle and
Fats.

23. 3. Metabolism of Drugs
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The liver is the principal(The major site) organ for
drug metabolism.
Drugs are often eliminated by biotransformation and
or excretion into the URINE OR BILE.

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 Chemical alteration of the drug in the body.
 Aim: to convert non-polar lipid soluble compounds
to polar lipid insoluble compounds to avoid
reabsorption in renal tubules.
 Most hydrophilic drugs are less biotransformed and
excreted unchanged – streptomycin, neostigmine
and pancuronium etc.
 Biotransformation is required for protection of
body from toxic metabolites

25. Results of Biotransformation
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1. Active drug and its metabolite to inactive.
2. Active drug to active.
3. Inactive drug to active/enhanced activity
(prodrug)
4. No toxic or less toxic drug to toxic metabolites.

26. Enzymes responsible for metabolism
of drugs
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 Biotransformations are enzymatic in nature
 Microsomal enzymes:
• Located in the smooth endoplasmic reticulum of the liver, kidney & GIT.
• Cytochrome P450 monooxygenases, Dehydrogensase, Hydroxylase and
Glucuronyl transferase
• Inducible by drug,diet
 Non-microsomal enzymes:
• Present in the cytoplasm and mitochondria
• Esterases, Amidases

27. Biotransformation - Classification
2 (two) Phases of
Biotransformation:
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•Phase I or Non-synthetic –
metabolite may be active or
inactive,functionalizing.
Unmasking/addition of polar
functional group like OH,
COOH.
• Phase II or
Synthetic,conjugation –
metabolites are inactive
(Morphine – M-6 glucoronide
is exception)

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Reactions of biotransformation
1. Phase I
Also called functionalizing reaction due to the addition and/or
formation of new functional groups on to the parent drug
Result in more REACTIVE and hydrophilic metabolites
Most (not all) phase I reactions are catalyzed by a family of
microsomal enzymes called CYP 450 which are found in the
liver.
 Phase I metabolism may
– Increase
– Decrease ……..or
– leave unaltered the pharmacologic activity of the drug

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2. Phase II reactions
 Consist of conjugation reactions ( addition of polar
macromolecules to the drug molecule)
 Usually Follow the phase I reaction (not always true)
 Make the products of phase reaction more polar and water
soluble so that they can easily be excreted
Types of phase II reaction
• Glucoronide conjugation (Glucoronidation)
• Acetyl conjugation (Acetylation) etc..

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Cont…
Eg. Conjugation = addition of endogenous macromolecules to drug
molecules( substrates)
• Some drugs may undergo phase II reaction before undergoing
phase I reaction
–Isoniazide is first acetylated (phase II) and then is
hydrolyzed to isonicotinic acid (phase I)
• Phase II reactions are saturable as the conjugating
macromolecules can be exhausted

31. Microsomal Enzyme Induction
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 Enzyme inducer is a type of drug that increases the
metabolic activity of an enzyme either by binding to
the enzyme and activating it, or by increasing the
expression of the gene coding for the enzyme E.g.,
microsomal enzymes (CYP450)
 Increases metabolism of other drugs and sometimes
their own

32. Enzyme Inhibition
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 Decreases the rate of drug metabolism, thereby
increasing the amount of drug, leading to
accumulation, extended pharmacological activity, and
potential toxicity
 One drug can inhibit metabolism of other – if utilizes
same enzyme
 However not common because different drugs are
substrate of different CYPs
 A drug may inhibit one isoenzyme while being
substrate of other isoenzyme.
 Some enzyme inhibitors – Omeprazole, metronidazole,
isoniazide, ciprofloxacin and sulfonamides

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4. Drug Elimination Vs Excretion
• Elimination and excretion both signify loss of the drug from
the body though they are two different phenomena
• Drug elimination is the irreversible loss of drug from the body
through two processes:
– Metabolism
– Excretion
• Metabolism involves enzymatic conversion of one chemical
entity to another within the body
• Excretion consists of removal from the body of chemically
unchanged drug or its metabolites

34. Drug Excretion
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 The passage out of a systemically absorbed drug from the
body in the form of metabolites or unchanged drug
 Main Routes of Excretion
 Renal excretion (major organ)
 Hepatobiliary excretion
 Pulmonary excretion (for volatile/gaseous anaesthetics)
 Minor Routes of Excretion
 Saliva, sweat, milk, tears

35. Enterohepatic circulation:
•Cycle in which a drug or metabolite is excreted in bile and
then reabsorbed from the intestine either as the metabolite or
after conversion back to the parent drug
Enterohepatic recirculation
•The recirculation of highly conjugated drugs between the
liver-bile-and the GI
• Involves the release of free drug by the GI microflora and
free drug is reabsorbed back to the liver
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36. APPLYING PHARMACOKINETIC
PRINCIPLES
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 By using
1. A loading dose in one or a series of doses that may
be given at the onset of therapy with the aim of
achieving the target concentration rapidly.
 loading dose = desired concentration * VD

37. Cont…
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2. Maintenance dose- is a dose administered to
maintain the target concentration of a drug. The
dose is equivalent to the excreted amount.
 DM = DL*(1- e-K*T)
3. Drug Half-Life—Time required for amount of drug
in the body/plasma conc. to decrease by 50%.

38. Drug Half-Life
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Elimination follows either First order kinetics
or Zero order kinetics
Half-life (t1/2) is the time required for half of
the initial concentration (or amount) of
reactants to form products.
The elimination rate constant (k) is the fraction
of drug in the body which is removed per unit
time

39. Cont…
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 First order kinetics:
 Constant fraction of the drug is eliminated per
unit of time
 Most common kinetics of elimination
 Increase in dose, increases elimination
 Increase in dose, t1/2 remains unaltered

40. Cont…
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 Zero order kinetics:
 Constant amount of the drug is eliminated per unit of
time
 Rare: ethanol & high dose of phenytoin, aspirin,
dicoumarol
 Increase in dose, no increase in elimination
 Increase in dose, t1/2 is increased & chance of toxicity
is present

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 Half-life in zero-order reaction
• The half-life of zero-order reactions is directly proportional
to the initial concentration of the reactants.
 The zero-order rate constant, k1, has the units of (concentration)
time–1
 Half-life in first-order reaction
 The half-life of first order reaction are independent of the initial
drug concentration, A0 .
 The first-order rate constant, k1, has the units of time–1
0
0
1/2
2k
A
t 
1
2/1
693.0
k
t 

42. Cont…
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4. Clearance: The clearance (CL) of a drug is the
theoretical volume of plasma from which drug is
completely removed in unit time
- is fraction of the apparent volume of distribution from
which drug is removed in unit time.
 CL= Rate of elimination / Plasma Concentration of the
drug
 CL (total) = CL (renal) + CL (liver) + CL (other)
 CL total = k x Vd
CL = Rate of elimination (RoE)/C

43. CONT….
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5. Bioavailability = AUC oral / AUC IV
 AUC: reflects the actual body exposure to drug after
administration of a dose of the drug
 This area under the curve is dependent on:
• The rate of elimination of the drug from the
body
• The dose administered

44. Biovailability - AUC
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AUC – area under the curve
F – bioavailability
AUC p.o.
F = ------------ x 100%
AUC i.v.

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6. Volume of distribution (Vd)
Fluid volume that would be required to contain all of
the drug in the body at the same concentration measured
in the blood or plasma: Expressed as: in Liters
Relates the amount of drug in the body to the concentration of
drug in blood or plasma.
-- Vd = [D]/[C]
» [D] = total concentration of the drug in the body
» [C] = concentration of the drug in the plasma

46. REFERENCE
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1.GOLDMANIS CECIL MEDICINE 24TH EDITION
2.CLINICAL PHARMACOKINETICS AND
PHARMACODYNAMICS CONCEPTS AND APPLICATION
4TH EDITION.
4.CLINICAL PHARMACOKINETICS SLIDE SHARE
5. MARTINS PHYSICAL PHARMACY AND
PHARMACEUTICAL SCIENCES SIXTH EDITION
6. Pharmaceutical and clinical calculation 2nd edition

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for
listening!!!
“If you want to explain any
poison properly, what then is not
a poison? All things are poison,
nothing is without poison; the
dose alone causes a thing not to
be poison.”