I. DRUG INTERACTIONS
A. Introduction
1. Drug interactions are defined as an altered pharmacological response to one drug caused by the presence of second drug. The expected response may be increased or decreased as a result of the interaction.
a. Pharmacokinetic interactions are those in which plasma and/or tissue levels of a drug are altered by another drug.
b. Pharmacodynamic interactions are those in which the action or effect of one drug is altered by a second drug.
c. Pharmaceutic interactions or drug incompatibilities result from chemical or physical reactions of drugs mixed in vitro.
B. Pharmacokinetic interactions
1. Interactions affecting absorption
a. Gastric emptying. Drugs that increase gastric motility hasten delivery to the small intestine and increase the rate of intestinal absorption. Conversely, drugs that delay gastric emptying decrease the rate of intestinal absorption.
For example, metoclopramide and cisapride promote gastric emptying by increasing acetylcholine release from the vagus nerve. Atropine slows down gastric emptying by blocking muscarinic receptors.
b. Gastric pH. Some drugs reduce gastric acidity and slow the absorption of certain other drugs. Antacid, H2-antihistamines, and omeprazole reduce gastric acidity and thus decrease the absorption of weak acids, for example, tetracycline, salicylates, and ketoconazole.
c. Complex formation. Some drugs form insoluble complexes with divalent cations, which are poorly absorbed from the GI tract. For example, tetracycline forms a complex with Ca2+.
2. Interactions affecting distribution (plasma protein binding of drugs). Many drugs are highly bound to plasma albumin. Displacement of bound drugs may occur when a second drug with greater binding affinity is added. The resulting increase in free drug concentration may produce an exaggerated response. For example, the anticoagulant effect of coumarins is potentiated by the presence of a NSAID. The barbiturate-induced anesthesia is prolonged by the presence of a sulfonamide, NSAID, or doxycycline.
3. Interactions affecting drug metabolism
a. Inhibition of metabolism
(1) Drugs that inhibit hepatic microsomal (cytochrome P450) enzymes may prolong the action of drugs, which normally are inactivated by microsomal oxidation (phase I) reactions. Examples: chloramphenicol, enrofloxacin, ketoconazole, cimetidine, ranitidine, prednisolone, and quinidine are enzyme inhibitors.
(2) Drugs that inhibit other enzymes than hepatic microsomal enzymes may prolong the action of drugs, which normally are inactivated by the specific enzymes. For example, imipenem is metabolized by renal dihydropeptidase-1 (DHP-1) in the proximal tubule. Plasma t½ of imipenem is prolonged by cilastatin, which is a DHP-1 inhibitor.
(3) Drugs that inhibit enzymes of organisms may prolong the action of anti-infective action of the drugs. For example, clavulanate, a β-lactam, prolongs the antibacterial action of amoxicillin by inhibiting β-lactamase. Piperonyl butoxide prolongs the action of a pyrethroid ectoparasiticide by inhibiting cytochrome P450 enzymes of the ectoparasites.
b. Increased rate of metabolism
Drugs that induce hepatic microsomal enzymes diminish the efficacy and duration of action of drugs metabolized by the cytochrome P450 enzyme system. Examples include phenobarbital, phenytoin, griseofulvin, phenylbutazone, rifampin, and chlorinated hydrocarbons (lindane and methoxychlor), which can induce cytochrome P450 enzymes.
4. Interactions affecting renal excretion
a. Decreased active secretion. Acidic and basic drugs are actively secreted into urine by the renal tubular transport system. Competition for active transport between drugs may slow the rate of excretion.
(1) Acidic drugs. Examples: penicillins, cephalosporins, chlorothiazide, ethacrynic acid, furosemide, probenecid, and the following NSAIDS: aspirin, phenylbutazone, meclofenamic acid, flunixin, ketoprofen, carprofen, and etodolac.
(2) Basic drugs. Examples: histamine, serotonin, procainamide, neostigmine, trimethoprim, and atropine.
b. Increased passive excretion. Altering urinary pH increases the excretion of ionizable drugs by ion-trapping and preventing their reabsorption from tubular urine filtrate. Urinary alkalinizers (e.g., sodium bicarbonate) increase the excretion of acidic drugs and urinary acidifiers (e.g., ammonium chloride) increase the excretion of basic drugs.
c. Diuretics increase urine flow and hasten the excretion of many drugs by decreasing their reabsorption from the nephron.
C. Pharmacodynamic interactions
1. Antagonistic effects. Specific receptor antagonists are available to be used therapeutically to block or reverse agonist activity. The antagonistic effects could be pharmacological or physiological. Examples include concurrent use of the following:
a. A miotic drug and an H1-antihistamine. Most H1-antihistamines have the side effect of blocking muscarinic receptors to evoke mydriasis, which will antagonize the effect of a miotic drug (physiological antagonism).
b. An α-adrenergic agonist, for example, epinephrine, phenylephrine or phenylpropanolamine and a phenothiazine tranquilizer, for example, acepromazine or chlorpromazine. A phenothiazine can block α-adrenergic receptors to antagonize the effects of an α-adrenergic agonist (pharmacological antagonism). Blockade of the α-adrenergic action of epinephrine may produce hypotension by unmasking the β-adrenergic action of epinephrine. This effect is known as epinephrine reversal.
c. Tetracycline and a β-lactam antibiotic. A β-lactam antibiotic works most effectively in rapidly growing bacteria. Tetracycline inhibits bacterial growth, thereby reducing the antibacterial effect of a β-lactam (physiological antagonism).
2. Additive effects. Drugs that have a similar mechanism of action may exhibit additive effects in combination. The end point of the pharmacological effect is the algebraic sum of each drug’s action. Additive interactions are observed with many classes of drugs.
3. Synergistic effects. Drug combinations that produce a therapeutic or toxic effect, which is greater than the sum of each drug’s action, are termed synergistic. Examples (concurrent use of):
a. A sulfonamide and an inhibitor of dihydrofolate reductase (trimethoprim, ormetroprim) potentiate the antibacterial effect of the sulfonamide.
b. A furosemide and an aminoglycoside antibiotic may potentiate the nephrotoxic effect of the aminoglycoside.
c. A furosemide and a digitalis may potentiate the inotropic effect of the digitalis. Furosemide can induce hypokalemia.
d. An inhalant anesthetic and an aminoglycoside may potentiate the skeletal muscle-relaxing effect of the inhalant anesthetic. Aminoglycosides can inhibit acetylcholine release from the somatic nerve.
D. Pharmaceutic interactions (drug incompatibilities)
1. General. Physical and/or chemical incompatibility between drugs is common and may result in inactivation or increased toxicity. Drugs should never be mixed in a syringe or added to parenteral solutions unless the components are known to be compatible. Visual indicators of incompatibilities such as cloudiness or precipitation may or may not be evident.
2. Physical incompatibilities are usually manifested as insolubility. Examples:
a. A macrocyclic lactone diluted in water or aqueous solution will form precipitate (propylene glycol should be used as a diluent).
b. Amphotericin B is insoluble in water, but can be dissolved in sodium desoxycholate.
3. Chemical incompatibilities
a. pH. The stability of many drugs in solution is pH dependent. Alkaline solutions (sulfonamides, aminophylline, or barbiturates) are incompatible with acidic solutions (penicillin G, cephalosporins, xylazine HCl, ketamine HCl, gentamicin sulfate, etc.) or alkaloid salts such as atropine sulfate.
b. Oxidation–reduction. Redox reactions may result in loss of drug potency. Tetracyclines are oxidized by riboflavin; phenothiazine tranquilizers are oxidized by ferric salts.
c. Complex formation. Multivalent cations may form insoluble complexes with anionic drugs. Examples: Ca2+ reacts with NaHCO3, tetracyclines, cephalosporins, barbiturates, fluoroquinolones, penicillins, furosemide, and the following NSAIDS: aspirin, phenylbutazone, meclofenamic acid, flunixin, ketoprofen, carprofen, and etodolac.
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