PHARMACOKINETIC DRUG INTERACTION Submitted by: Vivek Paudel Ashok Bhushal

What is drug interaction? A drug interaction is a situation in which a substance (usually another drug) affects the activity of a drug when both are administered together. In other words, drug interactions are said to occur when the pharmacological activity of a drug is altered by the concomitant use of another drug or by the presence of some other substance.

This action can be synergistic (when the drugs effect is increased) or antagonistic (when the drugs effect is decreased) or a new effect can be produced that neither produces on its own. The drug whose activity is affected by such an interaction is called as the object drug and the agent which precipitates such an interaction is referred to as the precipitant.

Most of the interactions are undesirable (or harmful) whereas rare cases are found to be desirable (beneficial): for e.g., enhancement of activity of penicillins when administered with probenicid.

Types of drug interaction:

Drug-drug interactions
Food-drug interactions

Chemical-drug interactions
Drug-laboratory test interaction Drug-disease interactions

Risk Factors:
High

risk patients

-Elderly, young, very sick, multiple disease -multiple drug therapy -Renal, liver impairment
High

Risk Drugs

-Narrow therapeutic index drugs -Recognized enzyme inhibitors or inducers

Mechanism Of Drug Interactions

Pharmaceutical

Interactions Interactions Interactions

Pharmacokinetic

Pharmacodynamic

Pharmaceutical Interaction:

Also called as incompatibility, it is a physicochemical interaction that occurs when drugs are mixed in IV infusions causing precipitation or inactivation of active principles. For e.g. ampicillin, chlorpromazine and barbiturates interact with dextran in solutions in solutions and broken down or form chemical complexes.

Pharmacokinetic Interactions:

Those interaction in which absorption, distribution, metabolism, and excretion of the drug is altered.

Pharmacodynamic Interaction:

Those interaction in which the activity of the object drug at its site of action is altered by the precipitant. Such interactions may be direct or indirect.

Pharmacokinetic Interactions:
These

interactions are those in which the absorption, distribution, metabolism and/or excretion of the object drug are altered by the precipitation. also called as ADME interactions.

Hence

Pharmacokinetic interactions are those in which one drug results in an alteration (increase or decrease) of the concentration of another drug in the system. The resultant effect alters the plasma concentration of the object drug.

Classification:
Absorption Distribution

Interactions Interactions Interactions

Metabolism Excretion

Interactions

Absorption Interactions:

In this absorption of object drug is altered. This will result in a reduction in the therapeutic effect of the object drug. This may result in:
Faster or slower drug absorption.

1.

2.

More, or, less complete drug absorption.

Major Mechanisms of absorption interactions are:

Complexation and adsorption. Alteration in GI pH. Alteration in gut motility. Inhibition of GI enzyme. Alteration of GI microflora. Malabsorption syndrome.

A. Complexation/Chelation
Antacids (Mg2+, Al3+ ions) Make complex with Tetracycline, ciprofloxacin

ABSORPTION

Reduced absorption of Tetracycline, ciprofloxacin

B. Altered GI Transit

ABSORPTION
Anticholinergics Block M3 receptors

Reduce motility
Delays the absorption of Acetaminophen

C. Altered gastric pH

ABSORPTION

H2 blockers (Ranitidine, cimetidine)

Reduce acid secretion

Increase PH

Reduce dissolution of Ketoconazole Reduce absorption of ketoconazole

D. Altered GI microflora
Antibiotics

ABSORPTION

Kills the microflora of GIT

Reduce the absorption of Oral contraceptives

Unwanted pregnancy

Distribution Interactions

These are the interactions where the distribution pattern of the object drug is altered.

The major mechanism for distribution interaction is alteration in protein-drug binding.

Alteration In Plasma protein binding

Sulfonamides, Phenytoin (Highly protein bound)

DISTRIBUTION

Displaces the Warfarin from plasma protein binding

Elevates free Warfarin level

Increase anticoagulant effect

Increase the risk of bleeding

Metabolism Interactions
Metabolism interactions are those where the metabolism of the object drug is altered.

Mechanism of metabolism interactions include:1. Enzyme Induction: increased rate of metabolism 2. Enzyme Inhibition: decreased rate of metabolism

A. Enzyme Induction

Metabolism Interactions
Phenobarbital (CYP Enzyme inducer) Increase the metabolism of Warfarin Reduce the plasma level of Warfarin

Decreased anticoagulant effect

B. Enzyme Inhibition

METABOLISM

Metronidazole (CYP enzyme inhibitor)

Inhibits metabolism of Warfarin

Elevation of Plasma Warfarin levels

Raise the anticoagulant effect Increased risk of Bleeding

Excretion Interactions
In this the excretion pattern of the object drug is altered. Major mechanism of excretion interactions are

Alteration of renal blood flow : e.g. NSAIDs (reduce renal blood flow) with lithium. Alteration of urine pH : e.g. antacids with amphetamine. Competition for active secretion : e.g. probenicid and penicillin.

Forced diuresis.

A. Increase in Renal blood flow

Hydralazine (Vasodilator) Dilates the renal blood vessels Increase the renal blood flow Raise the clearance of Digoxin

EXCRETION

B. Alteration of urine pH
Antacids Reduce acid secretion Increase the PH of urine Reduced tubular reabsorption of Salicylates (Aspirin) Increased Renal clearance of Aspirin

EXCRETION

C. Competition for active secretion

Probenecid
Inhibits tubular secretion of Penicillins Increase half life of Penicillins Single dose therapy

EXCRETION

References:
1.

Biopharmaceutics and Pharmacokinetics- A Treatise

2.
3.

Katzungs Basic & clinical Pharmacology

Goodman & Gilmans The Pharmacological Basis of Therapeutics

4.
5.

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