When two or more drugs are used simultaneously, there may occur drug interaction between them. Drug interaction may lead to:

a. Enhancement of intended effect of one or both drugs

b. Diminished effect of one or both drugs and

c. An unintended and potentially harmful reaction

Unfortunately harmful drug interaction are more numerous and the incidence of such reactions has increased due to:

  • Availability of potent drugs
  • Drug explosion and Irrational poly pharmacy

Drug interaction may occur outside or inside the body.

I. Drug interaction outside the body: These interactions (incompatibility) may occur during formulation and mixing of drugs. They may be due to:

1. Physical drug interaction: There occurs alteration in physical state of either drug, e.g. amphotericine is precipitated if mixed with normal saline instead of 5% dextrose solution.
2. Chemical drug interaction: In this case, interaction between the components of two drugs in solution leads to the formation of chemically altered product, e.g. dopamine and sodium bicarbonate; furosemide and ascorbic acid.

To avoid such in vitro drug interaction, a physician must follow general guidelines such as:

i. Do not add drugs to blood, plasma or amino acid solutions.
ii. Mix drugs with the infusion fluid immediately before use.
iii. In absence of special information, add the drug to simple solutions (normal saline, dextrose, dextrose-saline).
iv. Add single drug to simple solution (more safe).
v. Consult drug firm package inserts.

II. Drug interaction in the body: These interactions can be grouped as either pharmacokinetic or pharmacodynamic interactions:

Phormacokinetic drug interaction

A. Altered absorption from gastrointestinal tract due to interaction may lead to decrease/increase response of a therapeutic agent. Examples are:

i. Anticholinergic agents (e.g. atropine) decrease gut motility, so they increase the total absorption of drugs.
ii. Purgatives increase gastric emptying time and gut motility, so they decrease the total absorption of drugs.
iii. Antacids decrease the absorption of dicoumarol, warfarin, sulfonamides, and nalidixic acid, nitrofurantoin and tetracycline.
iv. Sorbital increases the absorption of paracetamol.

B. Drug Interaction during distribution: Some drugs are highly bound to plasma proteins. In the bound form, the drug is pharmacologically inactive. Free molecules of a drug in plasma are transported to tissues and exert their effect. Certain group of drugs seems to share a limited number of protein binding sites.

So they compete with each other for these sites and can displace each other in this process if administered simultaneously. This results in an increase in the free pharmacologically active form of one of the drugs and leads to toxicity. Usually drugs with higher binding affinity to plasma proteins displace agents with lower binding affinity. Some examples are:

i. Salicylates and sulfonamides displace tolbutamide and methotrexate from protein binding sites.
ii. Salicylates, clofibrate, phenytoin displace warfarin from protein binding site.

C. Interaction during biotransformation:

• Drugs are metabolized by liver microsomal enzymes. These enzymes can be stimulated by number of commonly used drugs, insecticides and polycyclic hydrocarbons. Due to this, there occurs reduced therapeutic response to those drugs which are metabolized by microsomal enzymes. A few important examples are:

a. Phenobarbitone stimulates the metabolism of phenytoin and griseofulvin.

b. The metabolism of steroid hormones is increased by phenylbutazone, DDT and phenytoin.

c. Rifampicin accelerates the metabolic degradation of glucocorticoid and oral contraceptive pill.

At present numerous cases of drug toxicity are due to inhibition of its metabolism in the body.

A few examples are:

a. Metabolism of cyclophosphamide is inhibited by chioramphenicol.

b. Tolbutamide metabolism is depressed by salicylates, disulfiram, MAO inhibitor, chloramphenicol and probenecid. Due to this, a dangerous hypoglycaemia may result if any of these drugs is given along with tolbutamide.

c. Allopurinol inhibits the metabolism of 6-mercaptopurine and leads to bone marrow toxicity.

d. Oral contraceptives inhibit the metabolism of pethidine.

e. The p-hydroxylation of phenytoin is inhibited by p-aminosalicylic acid, disulfiram, dicoumarol, isoniazid and cycloserine.

D. Interaction during excretion: Any of the renal excretory processes may be involved in drug interaction occurring during excretion of drugs. However, most important drug interaction occurs due to either change in urinary pH or through competition for active tubular mechanisms. A few examples are:

a. Acidification of urine reduces the effectiveness of basic drugs (quinine, ganglionic blocking agents) as they will be largely ionized in acidic pH and readily excreted.

b. Alkalinization of urine with sodium bicarbonate, potassium citrate or acetazolamide enhances the excretion of acidic drugs (salicylates, barbiturates, anticoagulants).

c. Probenecid inhibits the tubular secretion of penicillin, indomethacin, thiazides and oral hypoglycaemics due to competition for the active secretory mechanisms.

d. Changes in electrolyte and fluid balance: Hypokalaemia produced by diuretics and corticosteroids increases digitalis toxicity. On the other hand, it antagonizes the antiarrhythrnic activity of quinidine, lidocaine, procainamide, phenytoin and disopyramide.

Pharmacodynamic drug interaction

1. Drugs acting on the same receptor site or at different active receptors may enhance or decrease the response, e.g. propranolol blocks the response of isoprenaline on vessel beta receptors; d-tubocurarine and aminoglycoside antibiotics may accentuate the block at neuromuscular junction; marked CNS depression by morphine and barbiturates; severe ototoxicity by aminoglycoside and frusemide.

2. Guanethidine and the related adrenergic neuron blocking drugs are actively transported into adrenergic neurons. This transport system is same that is responsible for the noradrenaline uptake into the neuron. Imipramine inhibits this system and interferes with the antihypertensive activity of guanethidine.

3. Bronchial relaxation depends upon the formation of cyclic 3! 5’AMP (cAMP). Catecholamines increase the formation of this ‘second messenger’ by stimulating adenylcyclase while aminophylline inhibits the breakdown of cAMP. So when two drugs are combined, the combination will be useful in the treatment of bronchial asthma.

4. Bradycardia produced by beta-adrenoceptor blockers due to unopposed action of the vagus nerve can be checked by concurrent administration of atropine.

Prevention of Adverse drug interaction

Unfortunately adverse drug interaction can not be predicted on the basis of animal studies. These drug interaction may cause life- threatening emergencies like hypertensive crisis, cardiac arrhythmias, hypoglycaemic coma, convulsions or, hemorrhage. So it is better to recognize and prevent such catastrophes. To achieve this goal, certain guidelines would be helpful:

1. Avoid irrational poly-pharmacy.

2. Inquire about alcohol consumption by the patient, because potentially severe reaction can occur when alcohol is consumed concomitantly with analgesics, hypnotics, tranquilizers, antihistaminics, anticonvulsants, antidiabetics, or oral anticoagulants.

3. For proper and safe use, adjust the dosages of combined drugs which are highly protein bound.

4. Appropriately adjust the dosage of any drug that is lipid-soluble at physiological pH because usually it is capable of causing enzyme induction.

[Source: Principles of Pharmacology for Dental Students]