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A brief review on

“PHARMACOKINETIC DRUG INTERACTION”

By

Srota Dawn.

M.Pharm(Pharmacology)

VELS UNIVERSITY

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INTRODUCTION

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

substances.

A drug whose activity is affected by such interaction is called as the object drug and

the agent which precipitates such an interaction is referred to as the precipitants.

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Drug interaction includes –

1.Drug –drug interaction.

2.Food – drug interactions , for example, inhibition of several drugs by grapefruit juice.

3.Chemical – drug interactions , for example, interaction of drug with alcohol ,tobacco etc.

4.Drug – laboratory drug interactions , for example, alteration of diagnostic test results by the presence of drug.

5. Drug – disease interactions , for example, worsening of disease condition by the drug

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Factors contributing drug interactions

Some of the risk factors that lead to drug interactions include-

1. Multiple drug therapy : e.g. therapy in patient suffering from

hypertension and congestive heart failure includes antihypertensive as well as digitalis which together leads to abnormal heart rhythms.

2.Multiple prescribers : some individuals go to more than one

physician. e.g. one doctor may prescribe an anxiolytic for a patient while another doctor prescribes an antihistaminic drug having sedative properties with the possible consequences of an excessive depressant effect.

3.Multiple pharmacological effect of drug: most drug used in current therapy exhibit

more than one type of pharmacological action and have capacity to influence many physiological system

e.g. antihistamines (secondary effect is sedation) enhance the sedative effect of tranquillizers.

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4. Poor patient compliances :This results when patient does not take

medication in the manner intended by the doctor; which may be due inadequate instructions from the doctor pharmacist

5. Advancing age of patients :Increased tendency of drug instructions

episodes in elderly is generally due to decreased in liver function in such individuals.

6. Drug – related factors:Clinically significant interactions are most

likely to occur between drugs that have potent effects , a narrow therapeutic index and a steep dose response curve (e.g., cytotoxic , anti-hypertensive , and hypoglycemic drugs, digitoxin , warfarin , etc.)

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Mechanisms of drug interactions

The mechanisms by which an interaction can develop are –

The administration of one drug (A) can alter the action of another (B) by one of two general mechanisms:

1. Modification of pharmacological effect of B without altering its concentration in the tissue fluid (pharmacodyanamic interaction)

2. Alteration of the concentration of B that reaches its site of action (pharmacokinetic interaction) .

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PK InteractionsAbsorption

Distribution

Metabolism

Excretion

Piscitelli SC, Gallicano KD. N Engl J Med 2001;344:984-96

8

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D. CLASSIFICATION OF MECHANISM

1. ALTERATIONS IN ABSORPTION

I. Complexation / Chelation

Example: antacids + tetracycline

Impact: tetracycline complexes with divalent cations forming an insoluble complex

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D. CLASSIFICATION OF MECHANISM

1. ALTERATIONS IN ABSORPTION

I. Complexation/ChelationII. Altered GI Transit

Example: anticholinergics + acetaminophen

Impact: delay in absorption of acetaminophen

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D. CLASSIFICATION OF MECHANISM

1. ALTERATIONS IN ABSORPTION

I. Complexation/ChelationII. Altered GI TransitIII. Altered Gastric pH

Example: H-2 blockers + ketoconazole

Impact: dissolution of ketoconazole is decreased, resulting in reduced absorption

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D. CLASSIFICATION OF MECHANISM

1. ALTERATIONS IN ABSORPTION2. ALTERATIONS IN HEPATIC METABOLISM

I. Induction of Metabolism

Example: phenobarbital + warfarin

Impact: phenobarbital increases the metabolism of warfarin, resulting in reduced anticoagulation

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D. CLASSIFICATION OF MECHANISM

1. ALTERATIONS IN ABSORPTION2. ALTERATIONS IN HEPATIC METABOLISM3. METABOLISM INTERACTION

I. Induction of enzyme: increased rate of metabolism

II. Inhibition of enzyme: decreased rate of metabolism

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D. CLASSIFICATION OF MECHANISM

1. ALTERATIONS IN ABSORPTION2. ALTERATIONS IN HEPATIC METABOLISM 3. METABOLISM INTERACTION4. ALTERATIONS IN RENAL CLEARANCE

I. Increase in Renal Blood Flow

Example: hydralazine + digoxin

Impact: hydralazine increases the renal clearance of digoxin

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D. CLASSIFICATION OF MECHANISM

1. ALTERATIONS IN ABSORPTION2. ALTERATIONS IN HEPATIC METABOLISM3. METABOLISM INTERACTION4. ALTERATIONS IN RENAL CLEARANCE

I. Increase in Renal Blood FlowII. Inhibition of Active Tubular Secretion

Example: probenecid + penicillin

Impact: probenecid prolongs the half-life of penicillin, allowing single dose therapy

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D. CLASSIFICATION OF MECHANISM

1. ALTERATIONS IN ABSORPTION2. ALTERATIONS IN HEPATIC METABOLISM3. METABOLISM INTERACTION4. ALTERATIONS IN RENAL CLEARANCE

I. Increase in Renal Blood FlowII. Inhibition of Active Tubular SecretionIII. Alterations in Tubular Reabsorption

Example: antacids + aspirin

Impact: antacids reduce the tubular reabsorption of salicylate via an increase in

urine pH

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D. CLASSIFICATION OF MECHANISM

1. ALTERATIONS IN ABSORPTION2. ALTERATIONS IN HEPATIC METABOLISM3. METABOLISM INTERACTION4. ALTERATIONS IN RENAL CLEARANCE5. ALTERATIONS IN PLASMA PROTEIN BINDING

Example: phenytoin + valproic acid

Impact: protein binding of valproic acid is reduced and total Css decreased

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FACTORS WHICH ALTER HEPATIC BLOOD FLOW

Increased Flow•Glucagon•Phentolamine•Phenobarbital•PGE•Supine posture•High-protein meal•Viral hepatitis

Decreased Flow•Propranolol•Norepinephrine•Anesthetics•Labetalol•Upright posture•Hypovolemia•CHF•cirrhosis

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EX1., Enzyme induction

A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself e.g.,

Carbamazepine (antiepileptic drug ) increases its own metabolism

Phenytoin increases hepatic metabolism of theophyllineLeading to decrease its level

Reduces its actionand

Vice versa

N.B enzyme induction involves protein synthesis .Therefore, it needs time up to 3 weeks to reach a maximal effect

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EX2., Enzyme inhibition;

It is the decrease of the rate of metabolism of a drug by another one . This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity .

Inhibition of the enzyme may be due to the competitionon its binding sites , so the onset of action is short may be within 24h.

N.B; When an enzyme inducer (e.g.carbamazepine) is administered with an inhibitor (verapamil) The effect of the

inhibitor will be predominant

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Ex.,Erythromycin inhibit metabolism of astemazole and terfenadine

Increase the serum conc. of the antihistaminic leading to increasing the life threatening

cardiotoxicity

EX., Omeprazole Inhibits oxidative

metabolismof diazepam

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Pharmacodynamic interactions;

It means alteration of the dug action without change in its serum concentration by pharmacokinetic factors.

EX., Propranolol + verapamil Synergistic or additive effect

1. Synergism means =1+1=3

2. Additive means= 1+1=2

3. Potentiation means= 1+0=2

4. Antagonism means 1+1=0 or 0.5

Effect at the receptor site•Antiadrenegic •anticholinergic

On the other hand

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Pharmacodynamic interactions:In this case the activity of the

object drug at its site of action is altered by the precipitant . It may be direct or indirect-

1.Direct pharmacodynamic interaction: A. ANTAGONISM :

The interacting drugs drugs have opposing actions, e.g. Ach and NA have opposing action on heart rate

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B. ADDITION or SUMMATION:

The interacting drugs have similar actions and the resultant effect is the sum of individual drug responses,

e.g. CNS DEPRESSANTS like sedatives ,hyponotics,etc.

C. SYNERGISM or POTENTIATION :

It is enhancement of action of one drug by another,

e.g. alcohol enhances the analgesic activity of aspirin.

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* Prevention of drug interaction1) Monitoring therapy and making adjustments

2) Monitoring blood level of some drugs with narrow therapeutic index e.g., digoxin, anticancer agents…etc

3) Monitoring some parameters that may help to characterize the early events of interaction or toxicity e.g., with warfarin administration, it is recommended to monitor the prothrombin timeto detect any change in the drug activity.

4) Increase the interest of case report studies to report different possibilities of drug interaction

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References

1.Biopharmaceutics and Pharmacokinetics- A Treatise- D.M.BRAHMANKAR & SUNIL B. JAISWAL.

2.RANG and DALE’S Pharmacology sixth edition

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THANK YOU