Mechanism of Drug Interactions

MECHANISM OF DRUG INTERACTIONS

Drug interactions can be broadly divided into pharmacokinetic and pharmacodynamic interactions. In certain cases, however, the mechanisms are complex and may not be well understood. Few interactions take place even outside the body when drug solutions are mixed before administration.

Pharmacokinetic Interactions

These interactions alter the concentration of the object drug at its site of action (and consequently the intensity of response) by affecting its absorption, distribution, metabolism or excretion.

Pharmacokinetic Interaction

·          Alteration of absorption or first-pass metabolism

·          Displacement of plasma protein bound drug

·   Alteration of drug binding to tissues affecting volume of distribution and clearance

·          Inhibition/induction of metabolism

·          Alteration of excretion

Absorption Absorption of an orally administered drug can be affected by other concurrently ingested drugs. This is mostly due to formation of insoluble and poorly absorbed complexes in the gut lumen, as occurs between tetracyclines and calcium/iron salts, antacids or sucralfate. Phenytoin absorption is decreased by sucralfate due to binding in the g.i. lumen. Such interactions can be minimized by adminstering the two drugs with a gap of 2–3 hours so that they do not come in contact with each other in the g.i.t. Ketoconazole absorption is reduced by H₂ blockers and proton pump inhibitors because they reduce gastric acidity which promotes dissolution and absorption of ketoconazole. Antibiotics like ampicillin, tetracyclines, cotrimoxazole markedly reduce gut flora that normally deconjugates oral contraceptive steroids secreted in the bile as glucuronides and permits their enterohepatic circulation. Several instances of contraceptive failure have been reported with concurrent use of these

antibiotics due to lowering of the contraceptive blood levels. Alteration of gut motility by atropinic drugs, tricyclic antidepressants, opioids and prokinetic drugs like metoclopramide or cisapride can also affect drug absorption.

Distribution Interactions involving drug distribution are primarily due to displacement of one drug from its binding sites on plasma proteins by another drug. Drugs highly bound to plasma proteins that have a relatively small volume of distribution like oral anticoagulants, sulfonylureas, certain NSAIDs and antiepileptics are particularly liable to displacement interactions. Another requirement is that the displacing drug should bind to the same sites on the plasma proteins with higher affinity. Displacement of bound drug will initially raise the concentration of the free and active form of the drug in plasma that may result in toxicity. However, such effects are usually brief, because the free form rapidly gets distributed, metabolized and excreted, so that steady-state levels are only marginally elevated. The clinical outcome of displacement interactions is generally significant only when displacement extends to tissue binding sites as well, or is accompanied by inhibition of metabolism and/ or excretion. Quinidine has been shown to reduce the binding of digoxin to tissue proteins as well as its renal and biliary clearance by inhibing the efflux transporter P-glycoprotein, resulting in nearly doubling of digoxin blood levels and toxicity.

Metabolism Certain drugs reduce or enhance the rate of metabolism of other drugs. They may thus affect the bioavailability (if the drug undergoes extensive first pass metabolism in liver) and the plasma halflife of the drug (if the drug is primarily eliminated by metabolism). Inhibition of drug metabolism may be due to competition for the same CYP450 isoenzyme or cofactor, and attains clinical significance mostly for drugs that are metabolized by saturation kinetics. Macrolide antibiotics, azole antifungals, chloramphenicol, omeprazole, SSRIs, HIV-protease inhibitors, cimetidine, ciprofloxacin and metronidazole are some important inhibitors of metabolism of multiple drugs. Risk of statin induced myopathy is increased by fibrates, niacin, erythromycin, azole antifungals and HIV-protease inhibitors, probably due to inhibition of statin metabolism. Because lidocaine metabolism is dependent on hepatic blood flow, propranolol has been found to prolong its t½ by reducing blood flow to the liver.

A number of drugs induce microsomal drug metabolizing enzymes and enhance biotransformation of several drugs (including their own in many cases). Induction involves gene mediated increased synthesis of certain CYP450 isoenzymes; takes 1–2 weeks of medication with the inducer to produce maximal effect (contrast inhibition of metabolism which develops quickly) and regresses gradually over 1–3 weeks after discontinuation of the inducer. Barbiturates, phenytoin, carbamazepine, rifampin, cigarette smoking, chronic alcoholism and certain pollutants are important microsomal enzyme inducers. Instances of failure of antimicrobial therapy with metronidazole, doxycycline or chloramphenicol have occurred in patients who are on long-term medication with an inducing drug. Contraceptive failure and loss of therapeutic effect of many other drugs have occurred due to enzyme induction. On the other hand, the toxic dose of paracetamol is lower in chronic alcoholics and in those on enzyme inducing medication, because one of the metabolites of paracetamol is responsible for its overdose hepatotoxicity.

Excretion Interaction involving excretion are important mostly in case of drugs actively secreted by tubular transport mechanisms, e.g. probenecid inhibits tubular secretion of penicillins and cephalosporins and prolongs their plasma t½. This is particularly utilized in the single dose treatment of gonorrhoea. Aspirin blocks the uricosuric action of probenecid and decreases tubular secretion of methotrexate. Change in the pH of urine can also affect excretion of weakly acidic or weakly basic drugs. This has been utilized in the treatment of poisonings. Diuretics and to some extent tetracyclines, ACE inhibitors and certain NSAIDs have been found to raise steadystate blood levels of lithium by promoting its tubular reabsorption.

Pharmacodynamic Interactions

These interactions derive from modification of the action of one drug at the target site by another drug, independent of a change in its concentration. This may result in an enhanced response (synergism), an attenuated response (antagonism) or an abnormal response. The phenomena of synergism and antagonism are described in Chapter 4, and are deliberately utilized in therapeutics for various purposes. Of clinical significance are the inadvertent concurrent administration of synergistic or antagonistic pair of drugs with adverse consequences. Some examples are:

·   Excessive sedation, respiratory depression, motor incoordination due to concurrent administration of a benzodiazepine (diazepam), a sedating antihistaminic (promethazine), a neuroleptic (chlorpromazine), an opioid (morphine) or drinking alcoholic beverage while taking any of the above drugs.

· Excessive fall in BP and fainting due to concurrent administration of α₁ adrenergic blockers, vasodilators, ACE inhibitors, high ceiling diuretics and cardiac depressants.

·   Pronounced and asymptomatic hypoglycaemia can occur when propranolol is administered to diabetics receiving insulin/ sulfonylureas, due to blockade of β adrenoceptors which contribute to recovery from hypoglycaemia as well as some hypoglycaemic symptoms.

· Additive prolongation of prothrombin time and bleeding by administration of ceftriaxone or cefoperazone to a patient on oral anticoagulants.

· Excessive platelet inhibition resulting in bleeding due to simultaneous use of aspirin/ticlopidine/clopidogrel and carbenicillin.

·   Increased risk of bleeding due to concurrent use of antiplatelet drugs (aspirin, clopidogrel) with anticoagulants (warfarin).

·  Marked bradycardia due to administration of propranolol in digitalized patients.

·   Precipitous fall in BP and myocardial ischaemia due to use of sildenafil by patients receiving organic nitrates, because nitrates increase generation of c-GMP,while sildenafil prevents its degradation by inhibiting PDE 5.

·     Severe hyperkalaemia by concurrent use of ACE inhibitors and K+ sparing diuretics.

·   Additive ototoxicity due to use of an aminoglycoside antibiotic in a patient receiving furosemide.

· Antagonism of bactericidal action of βlactam antibiotic by combining it with a bacteriostatic drug like tetracycline, erythromycin or clindamycin.

· Mutual antagonism of antibacterial action of macrolides, clindamycin and chloram phenicol due to interference with each other’s binding to the bacterial 50S ribosome.

· Reduction in antihypertensive action of clonidine by chlorpromazine and imipramine, possibly due to blockade of central action of clonidine.

· Attenuation of antihypertensive effect of ACE inhibitors/β blockers/diuretics by NSAIDs due to inhibition of renal PG synthesis.

·    Blunting of K+ conserving action of spironolactone by aspirin, because it inhibits the tubular secretion of canrenone (an active metabolite of spironolactone).

·    Blockade of antiparkinsonian action of levodopa by neuroleptics and metoclopramide having antidopaminergic action.

Abnormal responses sometimes result from pharmacodynamic interaction between certain drugs, e.g. metronidazole and cefoperazone inhibit the enzyme aldehyde dehydrogenase resulting in bizarre distressing symptoms if the patient drinks alcohol. The basis of certain interactions is not explained, e.g. ampicillin has produced high incidence of skin rashes in patients treated with allopurinol.

Drug Interactions Before Administration

Certain drugs react with each other and get inactivated if their solutions are mixed before administration. In combined oral or parenteral formulations, the manufacturers take care that such incompatibilities do not take place. In practice situations, these in vitro interactions occur when injectable drugs are mixed in the same syringe or infusion bottle. Some examples are:

·  Penicillin G or ampicillin mixed with gentamicin or another aminoglycoside antibiotic.

· Thiopentone sodium when mixed with succinylcholine or morphine.

·    Heparin when mixed with penicillin/ gentamicin/hydrocortisone.

·    Noradrenaline when added to sodium bicarbonate solution.