Drug interactions can be classified according to the precipitant agent. A precipitant agent is the agent that alters the effect of another drug, called the object drug. These include:
- Drug-drug interactions, for example increased plasma level of penicillin by coadministration of probenecid due to interference of the latter with tubular secretion of the former.
- Drug-food interactions, for example the hypertensive crisis induced by administration of tyramine-rich food with MAO inhibitors (cheese reaction).
- Drug-chemical interactions, for example atropine which antagonizes the toxicity of organophosphate pesticides through blockade of muscarinic receptors.
- Drug-herb interactions, for example the reduced absorption of iron administered with tannin-rich herbs (tea).
- Drug-laboratory test interactions, for example interference of vitamin C with some glucose tests in urine.
- Drug-disease interactions, for example exaggeration of peptic ulcer with NSAID's.
Pharmacogentic interactions, for example the prolonged muscle relaxant effect of succinylcholine in patients with pseudocholinesterase deficiency.
Drug-life style intertactions, for example the increased carcinogenic effect of procarcinogens by administration to patients who are heavy smokers due to liver microsomal enzyme induction by tobacco smoke.
Alternatively, drug interactions can be classified according to the nature of the interaction. These include four categories; pharmacokinetic, pharmacodynamic, pharmacogenetic and pharmaceutical interactions.
A) pharmacokinetic interactions: In this type of interactions, the absorption, distribution, metabolism or excretion pattern of a drug are affected by the precipitant resulting in altered drug effect.
Drug absorption may be decreased by complexation or chelation, for example divalent cations like calcium can impair gastrointestinal absorption of tetracycline and levofloxacin by forming poorly absorbable complexes. Another cause of impaired drug absorption is adsorption. For example, cholestyramine adsorbs digoxin and levothyroxine. Increased gastrointestinal motility by laxatives and cathartics will decrease the bioavailability of slowly absorbed and controlled release drugs. Decreased gastrointestinal motility by anticholinergics will decrease absorption of drugs that are optimally absorbed from the intestine like acetaminophen because of decreased gastric emptying. Incresaed gastric pH by antacids will decrease the availability of drugs that need gastric acidity to dissolve, like ketoconazole. Antibiotics increase oral bioavailability of digoxin by alteration of intestinal flora thus decreasing digoxin inactivation by intestinal bacteria. Absorption of albuterol and levalbuterol from the intestine is increased by inhibition of intestinal metabolism of these drugs by MAO inhibitors like phenelzine and tranylcypromine due to inhibition of intestinal MAO enzyme activity. Digoxin improves the intestinal absorption of orally administered drugs in patients with congestive heart failure by improved intestinal blood flow.
Drug distribution is also affected by some precipitants. A very important mechanism is alteration of plasma protein binding. For example, salicyaltes bind to plasma proteins and compete with other drugs that bind to plasma proteins like digoxin. This increases free digoxin level and increases drug toxicity. Metabolic acidosis and alkalosis may affect tissue penetration by some objects. For example, carbonic anhydrase inhibitors cause metabolic acidosis that represents an optimal condition for salicylate penetration into CNS and toxicity.
Drug metabolism is massively affected by some precipitants. Induction of a liver microsomal enzyme subfamily by a precipitant will decrease the effect of an object drug that is inactivated by this subfamily. For example, polycyclic aromatic hydrocarbons in cigarette smoke will increase theophylline metabolism and decrease its plasma level and effect. The opposite is true for liver microsomal enzyme inhibitors. For example, grapefruit juice is a potent inhibitor of the liver microsomal enzyme subfamily CYP3A4. This effect will increase the plasma level of the anti-HIV protease inhibitor drug saquinavir. Drugs that share the same liver metabolizing enzymes have a potential for interaction. For example, fluconazole shares the same metabolic enzymes with warfarin, therefore concurrent administration of the two drugs will increase the risk of bleeding with warfarin. Inhibition of non-hepatic enzymes may also represent an important mechanism of interaction. For example, antidepressants like citalopram may cause serotonin syndrome if combined with MAO inhibitors due to impaired metabolism of serotonin.
Drug excretion of many objects is affected by a number of precipitants. Changes in urinary pH will affect tubular reabsorption of weakly acidic and weakly basic drugs. Urinary alkalinization will increase renal elimination of weakly acidic drugs, like barbiturates and salicylates, and will decrease renal elimination of weakly basic drugs, like atropine. The opposite is true for urinary acidifiers like vitamin C and citric acid. Competition for active tubular secretion, like that produced by probenecid, will interfere with renal elimination of actively secreted drugs like penicillin.
B) Pharmacodynamic interactions: There are several subtypes under this category. Drugs with similar pharmacological effects will lead to an exaggerated effect when given together. For example, combination of antihistamines with opioids will increase the CNS depressant effect of opioids causing drowsiness. Alternatively, the effect of an object drug may be ameliorated by concurrent administration of another drug with an opposite pharmacological action. For example, the antihypertensive effect of beta blockers is antagonized by the concurrent administration of vasopressor agents used for the symptomatic treatment of common cold. An adverse effect of a drug may sensitize the body to the effect of another drug. For example, thiazide diuretics cause hypokalemia that sensitizes the body to the toxic effects of digoxin.
C) Pharmacogenetic interactions:
These occur when drug disposition is affected by genetic
differences between individuals. For example, chloroquine administration
in people with glucose-6-phosphate dehydrogenase deficiency results in
hemolysis.
D) Pharmaceutical interactions:
These are interactions caused by chemical or physical
incompatibilities when two or more drugs are mixed together. For
example, an intravenous solution of aminophylline has an alkaline pH
and so should not be mixed with solutions of epinephrine, erythromycin
or cephalosporins that decompose in alkaline medium. Solutions with
acidic pH, like 5% dextrose, will precipitate drugs like phenytoin sodium.
