Drug interaction is the alteration in the duration or magnitude of the pharmacological effects of one drug by another drug.
When two or more drugs are given concurrently, the response may be greater or lesser than the sum of their individual effects. Such responses may be beneficial or harmful.

For example, a combination of drugs is used in hypertension-hydralazine + propranolol for their beneficial interaction.

Drug interactions can occur:
1. In vitro in the syringe before administration i.e., mixing of drugs in syringes can cause chemical or physical interactions- such drug combinations are incompatible in solution, e.g. penicillin and gentamicin should never be mixed in the same syringe.

2. In vivo, i.e. in the body after administration.


Pharmacological Basis of Drug Interactions

The two major mechanisms of drug interactions include pharmacokinetic and pharmacodynamic interactions.

Pharmacokinetic Mechanisms
Alteration in the extent or duration of response may be produced by influencing absorption, distribution, metabolism or excretion of one drug by another.

Absorption of drugs from the gut may be affected by
1. Binding: Tetracyclines chelate iron and antacids resulting in reduced absorption. Cholestyramine is a bile acid binding resin which also binds many drugs.
2. Altering gastric pH: Antacids raise gastric pH and interfere with the absorption of drugs like iron and anticoagulants.
3. Altering Gl motility: Atropine and morphine slow gastric emptying and delay the absorption of drugs. Purgatives reduce the absorption of riboflavin.

Distribution: Competition for plasmas protein or tissue binding results in displacement interactions, e.g. warfarin is displaced by phenylbutazone from protein binding sites.

Metabolism: Hepatic microsomal enzyme induction and inhibition can both result in drug interactions.

e.g. phenytoin, phenobarbitone, carbamazepine and rifampicin are enzyme inducers while chloramphenicol and cimetidine are some enzyme inhibitors.

Excretion: When drugs compete for the same renal tubular transport system, they prolong each other’s duration of action,

e.g. penicillin and probenecid

Pharmacodynamic Mechanisms
Drugs acting on the same receptors or physiological systems result in additive, synergistic or antagonistic effects. Many clinically important drug interactions have this basis.

Examples are:
◆ Atropine opposes the effects of physostigmine.

◆ Naloxone antagonises morphine.
◆ Antihypertensive effects of β-blockers are reduced by ephedrine or other vasoconstrictors present in cold remedies.
◆ Many diuretics produce hypokalaemia which potentiate digitalis toxicity.
◆ Organic nitrates (used in angina) act by
increasing cGMP activity.

◆ Sildenafil inhibits phosphodiesterase which inactivates cGMP and thereby potentiates the effects of nitrates. Hence the combination can cause severe hypotension and even deaths have been reported.


Drug Food Interactions

Simultaneous intake of food and drugs could result in some interactions. Presence of food itself interferes with the absorption of several drugs like rifampicin, roxithromycin which need to be given on an empty stomach.

◆ Drugs also interact with constituents of food like milk (tetracycline, iron) and reduce the bioavailability of these.

◆ Tender coconut water and fruits (e.g. sweet lime) rich in potassium can add up to the hyperkalaemia caused by ACE inhibitors.
◆ Cheese reaction-consumption of tyramine- containing foods like cheese, beer, wines, yeast, buttermilk and fish by patients receiving MAO inhibitors results in hypertension-termed as cheese reaction.
Inhibition of MAO by drugs leads to raised tyramine levels which displaces NA from the adrenergic nerve terminals resulting in hypertension.

◆ Grapefruit is an enzyme inhibitor and thereby raises the levels of phenytoin.

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