Drug Interactions

Drug interactions may create alarming situations. In most cases, monotherapy is preferred but sometimes drugs need to be given in combination e.g. in treatment of congestive cardiac failure, diuretics and vasodilators need to be combined, or in patients suffering from malignancy, coma, chemotherapy or tuberculosis. The aim is to:

Reduce dose
Prevent the development of resistance

Definition

When pharmacological action of a drug is altered by concurrent administration of another drug.

The adverse drug interactions may be of great clinical importance when margin of safety of drugs is small.

Sometimes clinicians allow drug interactions to occur for better actions, but adverse reactions occur with drugs having low therapeutic index.

Types

1. In Vitro

2. In Vivo

Drugs interactions can occur outside the body, e.g.

1. Incompatibilities of drug in an IV infusion

2. Use of wrong vehicle for infusion:

a) no drug should be added to blood plasma, aminoacid solutions, fat emulsions, sodium bicarbonate solution, mannitol solution (mannitol may crystalize) and to heparin infusion.

b) Mannitol should not be mixed with electrolytes, KCl or other drugs

Highly acidic solution such as dextrose, or fructorse are unsuitable as vehicle for sodium and potassium salts of weakly acidic drugs. Such as sulfonamides, barbiturates, methicillin and novobiocin

Benzyl penicillin, ampicillin, heparin and aminophylline are unstable at the pH of these solutions.

Isotonic saline is slightly acidic or neutral and is suitable vehicle for most drug like phenytoin, diazepam

Most antibiotics become unstable and deteriorate in large volumes of fluids exceptions are amphotericin B and erythromycin.

Erythromycin lactobionate is unstable in electrolyte solution but may be diluted with 5% dextrose solutions

Amphotericin B should be diluted with 5% dextrose

Calcium salts should not be added to sodium bicarbonate

Incompatibilities in syringe

Soluble and protamine zinc insulin: soluble insulin interacts with excess of zinc and protamine and its onset of action may be delayed

Barbiturates,, phenytoin, phenothiazine, frusemide should not be mixed with any other drug in solution

Penicillin is incompatible with gentamicin, tetracycline and hydrocortisone

Tetracycline is incompatible with calcium salts

Heparin sodium is incompatible with gentamicin and hydrocortisone

Thiopentone sodium is incompatible with succinylcholine

In Vivo

Pharmacokinetic Drug Interactions

Differences in plasma levels of a drug achieved by a given dose of that drug.

Pharmacodynamic Drug Interactions

Differences in pharmacological effects produced by a given plasma level of a drug

Pharmacokinetic Drug Interactions

Drug absorption e.g. antacids

Interactions due to changes in protein binding of drugs – distribution (if highly protein bound, displace other drugs, free levels increase, leading to toxicity)

Interactions affecting drug metabolism

Interactions affecting renal excretion of drugs

Interactions Affecting Absorption

Parenteral administration

Drugs + Epinephrine

Drugs + Methacholine (vasodilator –effective drug levels not achieved)

Oral administration

Chelation / Adsorption

Tetracycline + Ca⁺⁺

Cholestyramine (adsorption) + Cardiac Glycosides

Sucralfate adsorbs, cannot give other drugs

Altered Intestinal Motility

Atropine + Acetaminophen

Metoclopramide (prokinetic) + Cimetidine (anti ulcer) (increased gastric emptying, less drug absorbed)

Inhibition of Absorption

Phenytoin and oral contraceptives + Folic acid

Colchicine + Vit B₁₂

P-glycoproteins in intestinal wall can influence absorption, present in different cells of body, some drugs may be expelled out.

Influence of Diet

Food in Stomach

Fatty Meal

Griseofulvin has increased absorption with fally meal -EXCEPTION

pH Dependent Absorption

Weak acidic drugs e.g. NSAIDS

Weak basic drugs

Interactions Affecting Distribution

Competition for Plasma Protein Binding

Sulfisoxazole and Bilirubin (may lead to kernicterus)

Displacement from Tissue Binding Sites

Phenylbutazone and Warfarin (displace, also at level of metabolism, thus vitamin K dependent factors are impaired)

Methotrexate + Aspirin (efficacy decreased, PG inhibition, increased levels of methotrexate) so aspirin is stopped before treatment otherwise may cause methotrexate toxicity

Interactions Affecting Metabolism

Monoamine oxidase inhibitor –beneficial effect

Xanthine oxidase inhibitor (allopurinol) –beneficial effect

Enzyme inducers –adverse effects, therapeutic failure, diminished response

Interactions Affecting Excretion

Probenecid with penicillin and methotrexate

Aspirin with methotrexate

Agents that alkalinize urine –weak acid poisoning sodium bicarbonate given

Agents that acidify urine

Pharmacodynamic Drug Interactions

Receptor site down regulation or upregulation

Synergism

Sulfamethoxazole & Trimethoprim

Levodopa with Carbidopa

Antagonism

Rifampicin and Cloxacillin

Protamine and Heparin

Combined Toxicity

Ethanol with opioids, barbiturates and benzodiazepines