Drug interactions

Drug interactions

A drug interaction has occurred when the administration of one drug alters the clinical effects of another. The result may be an increase or decrease in either the beneficial or harmful effects of the second agent. Although the number of potential interacting drug combinations is very large only a small number are relevant in clinical practice.

Harmful drug interactions are most likely to occur when the affected drug has a:

  • Low therapeutic index meaning that only a small increase in plasma concentration may cause toxic effects
  • Steep dose-response curve meaning that a small change in plasma concentration leads to a significant increase in pharmacodynamic effect  (where a small increase in dose results in a large increase in plasma level)
  • High first-pass metabolism because these are drugs that are extensively metabolised in the liver or gastrointestinal tract and are therefore sensitive to the effects of metabolic inhibition or induction
  • Single mechanism of elimination (e.g. renal clearance, cytochrome metabolism) meaning that the interacting drug can cause a significant increase in plasma concentration.

Drug interactions - Absorption

Absorption interactions involve changes in either the rate or extent of absorption. The rate of absorption of most drugs is dependent on gastric emptying into the small bowel. Drugs that either delay (e.g. anticholinergic drugs) or enhance (e.g. prokinetic drugs) the rate at which this occurs will influence the rate of rise in plasma concentration but not the total amount of drug absorbed. The extent of absorption can be influenced by second drugs that bind to form insoluble complexes or chelates (e.g. aluminium containing antacids binding with ciprofloxacin). Drug transport systems, notably the P-glycoprotein (the product of the multidrug resistance gene), are responsible for limiting or enhancing absorption of drugs. It is very likely that these will be the site of drug-drug interactions although most are uncharacterised.

Drug interactions - Distribution

Distribution interactions occur when drugs are extensively protein-bound and the co-administration of a second can displace it to the non-bound active form. This increases the amount of (unbound) drug available to cause an effect. For example, diazepam displaces phenytoin from plasma proteins, resulting in an increased plasma concentration of free phenytoin and an increased risk of toxicity. The effects of protein displacement are usually short-lived because the metabolism of the affected drug usually increases in parallel with the increased free drug concentration. Distribution interactions can however be significant for drugs that have extremely rapid distribution or narrow therapeutic indices, such as lithium or digoxin.

Drug interactions - Excretion

Excretion interactions primarily involve changes in renal excretion. This might be due to drug-induced reduction in glomerular filtration rate (e.g. diuretic-induced dehydration, ACE inhibitors, NSAIDs). This can reduce the clearance and increase the plasma concentration of many drugs, including some with a low therapeutic index (e.g. digoxin, lithium, aminoglycoside antibiotics). Less commonly, interactions may be due to competition for a common tubular organic anion transporters (e.g. methotrexate excretion may be inhibited by competition with NSAIDs). In some cases this kind of interaction can be used for therapeutic benefit (e.g. probenecid prolongs the half life of penicillin be competing for tubular excretion). The likelihood of clinically significant excretion interactions increases if a patient has renal impairment.

Drug interactions - Metabolism

Many drugs rely on metabolism by different isoenzymes of cytochrome P450 (CYP) in the liver, especially 3A, 2D6, 2C9, 2C19, and 1A2. Interacting drugs have the potential to either increase the rate of metabolism by inducing the formation of more CYP isoenzyme or decrease metabolism by inhibiting isoenzyme activity. Enzyme inducers (e.g. phenytoin, rifampicin) generally reduce plasma concentrations although may enhance conversion of a pro-drug to its active form. Enzyme inhibitors (e.g. clarithromycin, cimetidine, grapefruit juice) have the opposite effect. Enzyme induction effects usually take at least a few days to manifest because of the need to synthesise new CYP enzyme. In contrast, the effects of enzyme inhibition may be rapid with the affected drug quickly reaching a new higher steady state concentration.