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Clinical Pharmacokinetics

Dr. Norul Badriah Hassan


Jabatan Farmakologi
Pusat Pengajian Sains Perubatan
Universiti Sains Malaysia

Objectives
1. Drug-Response Relationship
2. Why we need to study pharmacokinetics?
3. Absorption
4. Sites of Drug Administration
5. Bioavailability and factors affecting bioavailability
6. Absorption in children and elderly
7. Distribution
8. Distribution in children and elderly
9. Metabolism
10. Metabolism in children and elderly
11. Excretion
12. Excretion in children and elderly

Pharmacokinetics
Study of the movement of drugs through
the body.
Pharmacokinetics determine the time
course of drug concentrations in serum
or plasma as well as in tissues and body
fluids

Pharmacokinetics

Absorption
Distribution
Metabolism
Excretion

Dosage

Plasma Site of
Concen. Action

Pharmacokinetics

what the body does


to the drug

Effects

Pharmacodynamics

what the drug


does to the body

Drug-Response Relationship
Relationship between dose of a drug
and response produced by that drug
Generally if there is more dose, then
there will be more drug-receptor
complex and more response
But when the maximum response is
produced by the drug, then there will
be no more increase of response even
after administration of more dose.

Drug Concentration

Dose & Response

Therapeutic Window

Therapeutic Response

Adverse Effects

Dose-Response Relationship
Potency of A is more than B (less dose is needed
to produce same response)
Efficacy of both same (max response same).

Pharmacokinetics

Why we need to study


pharmacokinetics?
Compare and select appropriate drugs
Mode of administration
Dosage adjustment

Sites of Drug Administration

GI tract
Artery
Peripheral vein
Muscle
Subcutaneous tissue
Lung

Bioavailability
Percentage or fraction of
administered dose that
reaches systemic
circulation of patient.

Bioavailability = AUC (oral)


AUC (intravenous)

Bioavailability
1. Dissolution

2. Absorption
3. Chemical form (e.g. salt)
4. Dosage form (tablet, solution)
5. Route of administration
6. Stability of active ingredient in GI tract
7. Extent of drug metabolism

Oral Bioavailability
Destroyed
in gut

Dose

Not
absorbed

Destroyed
by gut wall

Destroyed
by liver

to
systemic
circulation

Oral bioavailability
Drug
Gentamicin
Verapamil
Lignocaine
Propranolol
Digoxin
Phenytoin
Valproate

Foral (%)
<5
22
35
36
75
98
100

Plasma concentration-time
relationship after a single oral dose

Effect of Food on Bioavailability


Grapefruit juice:
increases bioavailability:
felodipine - 200%
nifedipine - 57%

verapamil - 36%

Effect of Food on Bioavailability


Grapefruit juice:
Alter the pharmacokinetics of oral medications by different
mechanisms:
inhibit CYP3A4 irreversibly in intestinal apical enterocytes
and hepatocytes.
Inhibition of the P-glycoprotein in intestinal enterocytes.
drug amount in systemic circulation.
This inhibitory effect can last up to 72 hours after final
consumption of the grapefruit juice.

Effect of Food on Bioavailability


Other fruits which inhibit
the CYP3A4 enzyme
system:
Seville orange juice
Pimelo
common orange juice
(30% of the inhibitory
effect compared to
grapefruit)

Drugs Known to Have Potentially


Serious Interactions with
Grapefruit Products
Antiepileptics

Carbamazepine

Antidepressants

Sertaline, buspirone,
clomipramine

Benzodiazepines

Diazepam

Calcium channel blocker

Felodipine, nifedipine,
nimodipine, verapamil

Antiretroviral agents

Saquinavir, indinavir

Statins

Simvastatin, lovastatin,
atorvastatin

Cytotoxic drugs

Cyclosporin, tacrolimus,

Antiarrhythmics

Amiodarone

Miscellaneous

Methadone, sildenafil
Pillai et al, South Med J. 2009

Absorption in Children
Infant- slower compared to older children
and adults:

Prolong GI emptying time


Unpredictable gastric peristalsis
Delayed time to peak concentrations

Absorption in Children

Gastric pH values:
1 to 3 within 24 hours after birth
neutral by 1 week of age
slowly decline over 2 to 3 years to adult values.

These changes may result in:


greater absorption of basic drugs,
e.g amoxicillin, erythromycin, and penicillin
G.
reducing absorption of weak acidic drugs,
including phenobarbital.

Cmax

Distribution
Refers to transport of drugs to body
compartment and the time required
for the drug to reach those locations.
Vd : Volume of distribution
(liters or L/kg).

Distribution
Factors affecting drug transport:

Protein binding
Body fluids
Membrane transport/permeability
Blood and tissue hemodynamics

Distribution
Determinants of drug movement to
maintain equilibrium:
Disease states
Drug lipid solubility
Characteristics of body tissues
Regional pH differences
Protein binding

Volume of Distribution
A measure of the tendency of
a drug to move out of the
blood plasma to some other
site.

Volume of Distribution
C = D/V
D
V

V = D/C
Total amount of
the drug in the
body

Concentration of
a drug in the
plasma

Volume of Distribution
Vd (L/Kg) =Amount of drug (mg)
Css (mg/L)

D
V

Average population Vd = 1 L/kg Desired


Plasma concentration = 15 mg/L
Required loading dose = 15 mg/kg.

Drugs with extensive extraplasma


distribution seem to have large Vd values.

Volume of Distribution
Vd (L/Kg) =Amount of drug (mg)
Css (mg/L)

D = 50 mg
C = 2.5 mg/L

V = D/C
= 50mg /
2.5mg/L
= 20 Litres

Loading Dose
As with infusions, a loading dose may be required to produce
therapeutically effective blood levels without delay.

With loading dose (extra large initial dose)

Immediately effective treatment

Divided doses

Volumes of distribution
(In litres for average 70 Kg adult)

Warfarin
7
Gentamicin
16
Theophylline 35
Cimetidine
140
Digoxin
510
Mianserin
910
Quinacrine
50,000

Small vol. Mainly in


plasma little in
tissues.

Medium volume.
Similar concent in
plasma and tissues
Large volume.
Mainly in tissues,
little in plasma.

Steady state

Amount
eliminated = 1
dose

Amount
eliminated << 1
dose

Amount
eliminated < 1
dose

36

Concentrations at
Steady State
Css,max = Peak
Css (Average)
Css,min = Trough

Free Vs Bound Drug


Drug bound to protein
is inactive
Only unbound or free
drug is
pharmacologically
active.

Free Versus Bound Drug


Major drug binding proteins in serum:
Albumin,
1-acid glycoprotein
Lipoproteins
In uremia

free drug concentration


liver disease

hypoalbuminemia

Protein Binding of Commonly Monitored


Therapeutic Drugs
Drug

Protein Binding
(%)

Protein Type

Amikacin

<5

No

Kanamycin

<5

No

Ethosuximide

No

Procainamide

1015

Albumin

Theophylline

40

Albumin

Phenobarb

40

Albumin

Phenytoin

90

Albumin

Carbamazepine

80

Albumin

9095

Albumin

Primidone

15

Albumin

Digoxin

25

Albumin

Quinidine

80

1-acid glycoprotein

Lidocaine

6080

1-acid glycoprotein

98

Lipoproteins

Valproic acid

Cyclosporine

A. Dasgupta Handbook of Drug Monitoring Methods Humana Press Inc., Totowa, NJ

Pathophysiological Conditions that Reduce


Albumin Concentration Leading to an Increase
in Free Fraction of Acidic Drugs
Reduced Albumin Concentrations
Uremia
Pregnancy
Intensive care unit patients
Trauma patients
Liver disease
Hyperthyroidism
Burn patient
Elderly (> 75years)
Cirrhosis
Malnutrition
AIDS patients
A. Dasgupta Handbook of Drug Monitoring Methods Humana Press Inc., Totowa, NJ

Distribution in Elderly
Fat soluble (lipophilic)
Increased Vd in older persons because they have
greater fat stores.
Longer time to reach a steady-state
Longer elimination from the body.

Examples of fat-soluble drugs:


diazepam,
thiopental

Distribution in Elderly
Vd also influenced by protein binding.
Albumin is often decreased in older patients

Higher proportion of drug is unbound (free)


and pharmacologically active.
eg. ceftriaxone, diazepam, lorazepam,
phenytoin, valproic acid, and warfarin.

Distribution in Children
Total Body Water and Extracellular Fluid Volume

Expanded total body water values relative to body weight are


observed in newborns,infants, and children compared with adults:
80% total body weight in premature infants
70 to 75% in newborns
50 to 60% in adults

Neonates and young infants also have a greater extracellular fluid


compartment relative to body weight compared with adults.

For watersoluble drugs demonstrating distribution through total


body water, larger doses will be required in infants to achieve
comparable serum concentrations to those achieved in adults.

e.g aminoglycosides, penicillins, and cephalosporins,

Metabolism
Defined as chemical modification
of a drug in a biologic environment.
Also referred as drug
biotransformation or drug
detoxification.

Metabolism
Liver - most common
site of drug
metabolism

Metabolic
conversion also can
take place in:
intestinal wall
lungs
skin
kidneys
other organs

Metabolism
Most drugs undergo
metabolism.
Only few excreted
unchanged in urine.
e.g. Acetazolamide
Penicillin G

First-Pass Effect
Some drugs may be extensively
metabolised by the liver before
reaching systemic circulation
First pass refers to metabolism by the
liver as a drug passes through the liver
via portal vein following absorption

Metabolism in Children
Both Phase I and II reactions mature over time.
Phase I reactions generally mature by 1 year of
age.

Phase II processes mature at a slower rate,


E.g - glucuronidation activity by 3 to 4 years of age.
CYP activity is present at 30 to 60% of adult values
in infancy.

Metabolism in Elderly
Aging affects the liver by
decreasing liver blood flow,
liver size & mass.
Consequently, in the older
patient the metabolic
clearance of drugs by the liver
may be reduced.

Excretion
Excretion refers to a drugs final route(s) of exit
from the body.
For most drugs, this involves elimination by the
kidney as either the parent compound or as a
metabolite or metabolites.

Terms used to express excretion are drugs


half-life (t1/2) and its clearance.

Half-Life
A drugs half-life is the time it takes for its plasma or
serum concentration to decline by 50%,
e.g. from 20 g/mL to 10 g/mL.
Expressed in hours.
Steady state is reached when the amount of drug
entering the systemic circulation is equal to the amount
being eliminated.
For a drug administered on a regular basis, 95% of
steady state in the body is achieved after five half-lives
of the drug.

Half-Life

Linear vs non-linear pk
First order kinetics = linear
Rate of change in drug concentration is
proportional to drug concentration

Zero order kinetics = non-linear


Michealis-Menten Equation- capacity limited
kinetics

For most drugs


[Expansion of the relevant part of the graph]

Elimination
rate
Graph would start to curve if
we went to much higher
concentrations and began to
saturate the enzyme.

Drug concentration

For CERTAIN drugs


Elimination
rate

Highest concentrations actually seen in


real therapeutic use.
Too little to saturate the enzyme.
Almost no curvature.
Drug concentration

Linear kinetics
(most drugs)

Non-linear
kinetics
(e.g. phenytoin)

Rate of
eliminatn

Rate of
eliminatn

Blood drug conc

Blood drug conc

NON-LINEAR KINETICS
There are a small number of drugs where
concentrations seen in real life use are high
enough to saturate the eliminating enzymes.

Phenytoin - The only case of real clinical


significance
Salicylates
Ethanol
Theophylline may approach saturation but, in
practice, it can be treated as following linear
kinetics.

Factors Causing Non-Linear Kinetics


Absorption
Poor aqueous solubility/slow dissolution
(griseofulvin)
Site specific absorption along GI tract (phenytoin)
Carrier mediated absorption (riboflavin)

Factors Causing Non-Linear Kinetics


Absorption
P-glycoprotein efflux in intestinal epithelial cells
(cyclosporin A)
Saturable first pass effect by the intestine and/or
liver (propranolol).
Dose/time-dependent changes in GI physiology
including gastric emptying, GI motility & GI blood
flow rate.

Factors Causing Non-Linear Kinetics


Distribution
Non-linear plasma protein binding (valproic
acid)
Carrier-mediated membrane transport
(thiamine)
Non-linear tissue binding (prednisolone)

Factors Causing Non-Linear Kinetics


Metabolism
Saturable metabolism (ethanol)
Product inhibition (dicoumarol)
Co-substrate depletion (acetaminophen)

Nonlinear plasma protein binding (prednisolone)


Autoinduction

Factors Causing Non-Linear Kinetics


Excretion
Nonlinear protein binding and/or glomerular
filtration (naproxen)
Carrier-mediated tubular excretion
(cimetidine)/reabsorption (riboflavin)
Carrier-mediated biliary excretion (iodipamide)

Excretion in Children

Glomerular filtration function is dramatically reduced in newborns

Greater immaturity in premature infants when compared with fullterm infants

Increases in glomerular filtration rate (GFR) occur in the first weeks


of life, reaching 50 to 60% of adult function by the third week of
life, and adult values by 8 to 12 months of age.

By 3 to 6 years of life, GFR values exceed adult values.

Therefore, drugs dependent on glomerular filtration will show


reduced drug clearance through early infancy, more evident in
premature infants, and likely require dosage reduction.

During early childhood, higher daily doses are likely when


corrected for weight and in comparison with adult doses because
of increased GFR.

Clearance in the Elderly


Decline in renal function with age, even in the
absence of renal disease
Increased Vd
Larger drug storage reservoirs
Decreased drug clearance
Prolong drug half-lives and lead to increased
plasma drug concentrations in older people.

Creatinine in Elderly
Serum creatinine - not accurate
reflection of creatinine clearance in
elderly patients.
Decline in lean muscle mass cause
reduced production of creatinine.

Acknowledgements
Dr. Mohd Suhaimi Ab Wahab
Dr. Ruzilawati Abu Bakar

Suggested Readings
Michael E. Winter, Basic Clinical Pharmacokinetics,
4th ed. Lippincott Williams & Wilkins, Philadelphia
Thomas N. Tozer & Malcolm Rowland, Introduction to
Pharmacokinetics and pharmacodynamics:
The quantitative basis of drug therapy.
Lippincott Williams & Wilkins, Philadelphia