DRUG INTERACTIONS

 CONTENTS:
INTRODUCTION CAUSES OF DRUG INTERACTIONS TYPES OF DRUG INTERACTIONS MECHANISMS OF DRUG INTERACTIONS TO REDUCE THE RISK OF DRUG INTERACTION

 DEFINITION:
Drug interactions are said to occur when the pharmacological activity of one drug is altered by the concomitant use of another drug or by the presence of some other substance.

The drug whose activity is affected by such an interaction is known as the object drug.

The agent which precipitates such an interaction is referred to as the precipitant drug.

 Types of Drug interactions :

1) Drug-drug interactions. 2) Food-drug interactions. 3) Chemical-drug interactions. 4)Drug-laboratory test interaction. 5)Drug-disease interactions.

The Net effect of drug interaction is:

.Genarally quantitative i.e.increased or decreased.

.Seldom qualitative i.e.rapid or slower effect. .Precipitation of newer or increased adverse effects.

 Factors contributing to drug interactions:

1.Multiple drug therapy. 2.Multiple prescribers. 3.Multiple pharmacological effects of drugs. 4.Multiple diseases/predisposing illness. 5.poor patient compliance. 6.Advancing age of patient. 7.drug related factors.

MECHANISMS OF DRUG INTERACTIONS :

 The three mechanisms by which an interaction can develop are:1) Pharmaceutical interactions 2) Pharmacokinetic interactions 3)Pharmacodynamic interactions

Drug tablet
Release
Pharmacokinetics

Sources of drug variability

Drug in gut
Absorp tion

Drug in blood

Distribution

Drug metabolites

Drug in tissues

Drug in urine/bile

Pharmacodynamics

Drug at receptor

esired response

No response Unwanted response

PHARMACEUTICAL INTERACTIONS:
Also called as Incompatibility. It is a physicochemical interaction that occurs when drugs are mixed in i.v. infusions causing precipitations or inactivation of active principles. Eg: ampicillin + dextran in solutions chemical complexes.

PHARMACOKINETIC INTERACTIONS:
 These interactions are those in which the absorption, distribution, metabolism and excretion of the object drug are altered by the precipitant drug and hence such interactions are also called as ADME interactions. The resultant effect is altered plasma concentration of the object drug.

Pharmacokinetic interactions can be classified as

a) Absorption interactions b) Distribution interactions c) Metabolism interactions and d) Excretion interactions

i)ABSORPTION INTERACTIONS:
Are those where the absorption of the object drug is altered. mechanisms of absorption interactions : complexation and adsorption. Alteration in GI pH. Altertation in Gut motility. Inhibition of GI enzymes. Alteration of GI microflora.  Malabsorption syndrome. Effect of surfactants.

i) COMPLEXATION AND ADSORPTION:

Complexation: Eg: Tetracycline + antacids: tetracyclines + divalent metal ions ( Ca, Mg, Al and Fe) poorly absorbable complexes.

Adsorption:
Eg:Anti-diarrhoeal mixtures +antacids: anti-diarrhoeal mixtures + digoxin decrease in their absorption.

ii) ALTERATION IN GASTROINTESTINAL pH:

Eg: a) Phenobarbital- Antacids: phenobarbitol + antacid delayed absorption of Phenobarbital.

ALTERATION IN GUT MOTILITY:

a )Cathartics: a cathartic, by increasing GI motility may increase the rate at which drugs pass through the GIT. This could result in a decreased absorption of drugs, particularly those that are normally slowly absorbed and require prolonged contact with the absorbing surface or those that are absorbed only at a particular site along the GIT.

INHIBITION OF GASTROINTESTINAL ENZYMES:

Eg: folic acid- phenytoin: folic acid + phenytoin Folic acid deficiency anemias because of the ability of the phenytoin to inhibit the GI enzyme.

ALTERATION OF GASTROINTESTINAL MICROFLORA:

Eg: antibiotics - oral contraceptives: antibiotics + oral contraceptives reduces the reabsorption of oestrogens from oral contraceptives, resulting in reduced effectiveness.

vi)MALABSORPTION SYNDROME:
neomycin, laxatives, colchicines + vitamins cause malabsorption problems that result in decreased absorption of vitamins and nutrients from the GIT.

EFFECT OF SURFACTANTS :
Eg: mineral oil - dioctyl sodium sulfosuccinate: DOSS + mineral oil increased absorption of mineral oil which is highly toxic.

ii) DISTRIBUTION INTERACTIONS:

Are those where the distribution pattern of the object drug is altered. The major mechanism for distribution interaction is alteration in protein- drug binding.

ALTERATION IN PROTEIN DRUG BINDING:

a)warfarin- phenylbutazone: phenylbutazone + warfarin displacement of warfarin from albumin thus increased anticoagulant effect.

iii) METABOLISM INTERACTIONS:

Are those where the metabolism of the object drug is altered. Mechanism of metabolism interactions includesi) enzyme induction ii) enzyme inhibition

i) Enzyme Induction: nduction:

Ability of drugs to stimulate the metabolism of other drugs by increasing the activity of hepatic microsomal enzymes. Eg: a) warfarin - Phenobarbital: warfarin + phenobarbital increase the rate of metabolism of warfarin by phenobarbital resulting in decreased anti cogulant effect.

ii) Enzyme Inhibition: nhibition:

One drug can inhibit the metabolism of a second drug by inhibiting the enzymes responsible for metabolism. This results in prolonged and intensified activity of the drugs. Eg: phenytoin isoniazid: isoniazid + phenytoin inhibits the metabolism of phenytoin resulting in toxic effects of phenytoin.

EXCRETION INTERACTIONS:
Are those where the excretion pattern of the object drug is altered. major mechanisms of excretion interactions arei)alteration in renal blood flow ii)alteration of urine pH iii)changes in active tubular secretion iv)changes in biliary excretion v)forced diuresis

i) ALTERATION IN RENAL BLOOD FLOW:

Eg: NSAIDs lithium: NSAIDS (indomethacin) + lithium lithium.

reduces excretion of

ii)ALTERATION OF URINE pH:

Eg: sulphonamides - methanamine: methanamine + sulphonamides precipitation of sulphonamides and development of crystallurea.

CHANGES IN ACTIVE TUBULAR SECRETION:

Eg: probenecid- penicillins: probenecid + penicillins increases the blood levels of penicillins .

iv)CHANGES IN BILIARY EXCRETION:

Eg: antibiotics - oral contraceptives: antibiotics + oral contraceptives decreased reabsorption of oral contraceptives.

II). PHARMACODYNAMIC INTERACTIONS:

Are those in which the activity of the drug at its site of action is altered by precipitant such interactions may be . direct or . Indirect

DIRECT PHARMACODYNAMIC INTERACTIONS:

Are the one in which drugs having similar or opposing pharmacological effects are used concurrently. Various mechanisms are as follows:

i) drugs having opposing pharmacological effects (antagonism). ii) drugs having similar pharmacological effects (addition). iii) Synergism or Potentiation. iv) alteration of electrolyte levels. v) interactions involving the adrenergic system. vi) alteration of receptor site interactions.

i) Antagonism: Antagonism:
The interacting drugs have opposing actions. Eg: acetylcholine and noradrenaline have opposing effects on heart rate.

ii) synergism or potentiation: ii)

It is enhancement of action of one drug by another. Eg: alcohol enhances the analgesic activity of aspirin.

iii)Addition or Summation:
The interacting drugs have similar actions and the resultant effect is the sum of individual drug responses. Eg: CNS depressants like sedatives, hypnotics, etc.

iv) Alteration of Electrolyte Levels:

Eg: digitalis glycosides + calcium to digoxin due to hypocalcemia. Decreased response

v) Interactions involving the adrenergic system: system:

Eg: MAO inhibitors-tricyclic antidepressants: MAO inhibitors + tricyclic anti-depressants like amitryptyline, imipramine severe atropine like reactions such as tremors, convulsions, hyperthermia and vascular collapse.

vi)Alteration of receptor site interactions: interactions:

Eg: warfarin- anabolic steroids: anabolic steroids (oxymethadone) + warfarin increases affinity of (warfarin)anticoagulant to the receptor sites.

INDIRECT PHARMACODYNAMIC INTERACTIONS: INTERACTIONS:

Are those in which both the object and the precipitant drugs have unrelated effects but the latter in some way alters the effects of the former. Eg: salicylates warfarin : salicylates + warfarin decreases the ability of the platelets to aggregate resulting in bleeding .

To Reduce Drug interactions:

1.Identify the patients risk factors. 2.Take thorough drug history. 3.Consider therapeutic alternatives. 4.Avoid complex therapeutic regimens . 5.Educate the patient. 6.Monitor therapy. 7.Individualize therapy.