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BIOPHARMACEUTICS
&
PHARAMCOKINETICS

PHARMACOKINETICS VARIATIONS
IN
DISEASE STATES

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Contents
 Definitions
 General Introduction
 Effect of Liver Disease on PK
 Effect of Kidney Disease on PK
 Effect of Cardiac Disease on PK
 Effect of Burns on

PK Biopharmaceutics
Definition:

Biopharmaceutics that consider the inter-relationship of physiochemical properties of the

drug form in which the drug is given and the route of administration on the rate and extent
of systemic drug absorption.

Pharmacokinetics vs. Pharmacodynamics

Pharmacokinetics
Definition:
Study of kinetics of absorption, distribution, metabolism and excretion.

Pharmacodynamics
Definition:
The study of biochemical & physiological effects of drugs & the mechanism of their actions
including the correlation of their action & effect with their chemical structure.

Bioavailability vs. Bioequivalence

Bioavailability
Definition:

Bioavailability means that rate and extent to which the active ingredients or active moiety
reaches the systemic circulation and becomes available at the site of action.

Bioequivalence
Definition:
Rate and extent of the absorption of test drug that do not show significant difference from
the rate and extent of absorption of the reference drug when administered at same molar
doses of therapeutic ingredient under similar experimental conditions in either single or
multiple dose.

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Structure of Pharmacokinetics
Pharmacokinetic consist of 4 major parts of its basic structure:

 Absorption
 Distribution
 Metabolism
 Excretion

Effect of Disease State on Pharmacokinetics

 Disease is the abnormal state of the body it may affect the
physiological immunological & movement of the body, also can lead to
death.
 As the functions of the body is altered so it can also effect the physic-
chemical properties of the drugs, pharmacokinetics & pharmacodynamics of
the drugs.
 The many diseases can affect the pharmacokinetics of the drugs as well as
its pharmacodynamics these are given below.
o Liver Diseases.
o Kidney Diseases.
o Cardiac Diseases.

Liver
 Acute liver impairment interferes with drug metabolism and elimination.
 Chronic liver impairment affects all parameters of pharmacokinetic.
 Because most drugs are metabolized by the liver, it is susceptible to drug toxicity.
 Impaired liver function greatly increases the risks of adverse drug effects.
 Many drugs change liver function tests without clinical signs of liver dysfunction.
 Hepatotoxicity is potentially life threatening.
 Liver is able to function with as little as 10% of undamaged hepatic cells.
 With severe hepatic impairment, extrahepatic metabolism becomes more important.
 Patient at risk for impaired liver function include:
 Primary liver disease (e.g. hepatitis, cirrhosis).
 Diseases that impair blood flow to the liver (heart failure, shock, major surgery,
or trauma).
 Hepatotoxic drugs.

Absorption & Liver

 Some oral drugs are extensively metabolized in the liver.
 This process is called the first-pass effect or presystemic metabolism.
 With cirrhosis, oral drugs are distributed directly into the systemic circulation.
 This means that oral drugs metabolized in the liver must be given in reduced doses.

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Metabolism in Liver
 Most drugs are metabolized by enzymes in the liver.
 They are called the cytochrome P450 [CYP] or the microsomal enzymes.
Drugs Effect on Liver

 With chronic administration, some drugs increase metabolizing enzymes in the liver:
enzyme induction.
 Enzyme induction accelerates drug metabolism and larger doses is required.
 Rapid metabolism also increases the production of toxic metabolites.
 Enzyme induction does not occur for 1-3 weeks because new enzymes must
be synthesized.
 Enzyme inducers consist of: phenytoin, rifampin, phenobarbital, ethanol,
and cigarette smoking.
 Tolerance and cross-tolerance are attributed to activation of liver
metabolizing enzymes.
 They also are attributed to decreased sensitivity or numbers of receptor sites.
 Metabolism can be decreased in a process called enzyme inhibition.
 It occurs with co-administration of drugs that compete for the same
metabolizing enzymes.
 In this case, smaller doses of the slowly metabolized drug is needed to avoid toxicity.
 Enzyme inhibition occurs within hours or days of starting an inhibiting agent.
 Enzyme inhibitors consist of: Cimetidine, fluoxetine, and ketoconazole.

Kidney
 Kidney is the major organ of excretion.
 Other organs also play important role in the excretion.
 If the kidney is compromised its can affect the all parameter of pharmacokinetics.
 In the presence of renal diseases some metabolic functions seem to be
impaired. What Kind Of Drugs Can Be Excreted Through Kidney!!!???

Renal route of drug elimination is the major route for drugs that are:
o Polar drugs
o Water soluble drugs
o Low molecular weight drugs
o Slowly bio transformed/metabolizing drugs

Renal Impairment

 Use of drugs in renal impairment can give rise to problems for several reasons:
 Failure to excrete a drug or its metabolites may produce toxicity.
 Sensitivity to some drugs is increased even if elimination is impaired.
 Many side effects are tolerated poorly in patients with renal impairment.

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 Some cease to be effective when renal function is reduced.

Renal Impairment &
Absorption In renal failure:
o Gastric pH increases

Result:
o Reduced absorption of many drugs

Renal Impairment & Distribution

Impaired renal function is associated with important changes in the binding of some drugs
to plasma proteins
Renal Impairment & Metabolism

 Uremia slows the rate of phase I metabolism due to this there is decreased
hydrolysis & oxidation & also in phase II metabolism.
 Even if drug is metabolized in liver the excretion of metabolites depends upon
the renal excretion.
Renal Impairment & Excretion
Renal handling of drugs depends upon:
o Glomerular Filtration
o Tubular Secretion
o Tubular Reabsorption
o GFR decrease than renal clearance decrease due to which plasma half-life increases.

Cardiac System
 Complex progressive disorder.
 Heart unable to pump sufficient amount of blood.

Cardiovascular Disease & Absorption

Effect on Absorption:
In Depressed cardiovascular state decrease perfusion to
o GIT
o Muscle

Result:
Erratic absorption of drug

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Cardiovascular Disease &

Distribution Cardiac impairment
leads to
o Diminished perfusion to organs
o Low volume of distribution
o Increase plasma drug concentration.
o Decrease blood flow to tissue.
o Presence of edema cause increase distribution of water soluble drugs

Cardiovascular Disease & Metabolism

o Cardiac impairment
o Decrease hepatic perfusion
o Hepatocellular enzyme activity diminished
o Leads to Impaired metabolism

Cardiovascular Disease & Excretion

Depressed circulatory state cause Reduction in
o Cardiac output
o Hepatic blood flow
o Renal blood flow

Result
o Decrease clearance of drugs

References

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