Saturday, April 09, 2005

Pharmacokinetic interactions are more complicated and difficult to predict because the interacting drugs often have unrelated actions

This article has been published by the International Biopharmaceutical Association www.ibpassociation.org

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Pharmacokinetic interactions are more complicated and difficult to predict because the interacting drugs often have unrelated actions; the interactions are mainly due to alteration of absorption, distribution, metabolism, or excretion, which changes the amount and duration of a drug's availability at receptor sites.

Alteration of Gastrointestinal Absorption
Interactions that involve a change in drug absorption from the GI tract are of variable importance.

Alteration of pH: Many drugs are weak acids or weak bases, and the pH of the GI contents can influence absorption. Since the nonionized (more lipid-soluble) form of a drug is more readily absorbed than the ionized form, acidic drugs are usually more readily absorbed from the upper regions of the GI tract, where they are primarily in a nonionized form.

Complexation and adsorption: Tetracyclines can combine with metal ions (e.g., Ca, Mg, Al, and Fe) in the GI tract to form poorly absorbed complexes. Thus, certain foods (e.g., milk) or drugs (e.g., antacids, products containing Mg, Al, and Ca salts, or Fe preparations) can significantly decrease tetracycline absorption. The increase in pH of the GI contents probably also contributes to the reduction of the tetracycline absorption.
Antacids markedly reduce the absorption of fluoroquinolone derivatives (e.g., ciprofloxacin), probably as a result of the metal ions complexing with the drug. Antacids should not be used simultaneously or <2 h (or preferably, an even longer period) after ciprofloxacin.
Complexation can be expected with cholestyramine and colestipol. In addition to binding with and preventing reabsorption of bile acids, these agents can bind with drugs in the GI tract, having the greatest affinity for acidic drugs, e.g., thyroid hormone or warfarin. To minimize the possibility of such an interaction, the interval between taking cholestyramine or colestipol and another drug should be as long as possible
Some antidiarrheals (e.g., those containing kaolin and pectin), may adsorb other drugs, resulting in decreased absorption.

Alteration of motility: By increasing GI motility, metoclopramide may hasten the passage of drugs through the GI tract, resulting in decreased absorption, particularly of drugs that require prolonged contact with the absorbing surface and those that are absorbed only at a particular site along the GI tract. Similar problems can occur with enteric-coated and sustained-release formulations.
By decreasing GI motility, anticholinergics may either reduce absorption by retarding dissolution and slowing gastric emptying, or increase absorption by keeping a drug for a longer period of time in the area of optimal absorption.

Effect of food: Food may delay or reduce the absorption of many drugs. Food often slows gastric emptying, but it may also affect absorption by binding with drugs, by decreasing their access to absorption sites, by altering their dissolution rates, or by altering the pH of the GI contents.

Food in the GI tract will reduce the absorption of many antibiotics. Although there are exceptions (e.g., penicillin V potassium, amoxicillin, doxycycline, minocycline), it is generally recommended that penicillin and tetracycline derivatives, erythromycin stearate and formulations of erythromycin base that are not enteric coated, as well as several other antibiotics, be given at least 1 h before meals or 2 h after meals to achieve optimal absorption. Food has also been reported to decrease the absorption of many other therapeutic agents including astemizole, captopril, and penicillamine.

Alteration of Distribution
Displacement of drugs from protein-binding sites may occur when 2 drugs capable of protein binding are given concurrently, especially when they are capable of binding to the same sites on the protein molecule (competitive displacement). Since the number of plasma or tissue protein-binding sites is limited, drugs can displace one another.
Both phenylbutazone and warfarin are extensively bound to plasma proteins, especially albumin, but phenylbutazone has a greater affinity for the binding sites. When the 2 drugs are taken concurrently, fewer binding sites are available for warfarin, thus increasing the amount of free anticoagulant and the risk of hemorrhage. Phenylbutazone also inhibits the metabolism of warfarin, resulting in continued enhancement of its anticoagulant effect.

Alteration of Metabolism
Stimulation of metabolism: Many drug interactions result from the ability of one drug to stimulate the metabolism of another by increasing the activity of hepatic enzymes involved in their metabolism (enzyme induction). In this manner, phenobarbital increases the rate of metabolism of coumarin anticoagulants such as warfarin, resulting in a decreased anticoagulant response. Phenobarbital also accelerates the metabolism of other drugs such as steroid hormones. Enzyme induction also is caused by other barbiturates and by various therapeutic agents (e.g., carbamazepine, phenytoin, and rifampin).
Disturbed calcium metabolism and osteomalacia are associated with the use of anticonvulsants such as phenobarbital and phenytoin. Reduced serum calcium levels are caused by vitamin D deficiency, resulting from enzyme induction by the anticonvulsants. Pyridoxine can antagonize the activity of the antiparkinsonian drug levodopa by accelerating the conversion of the levodopa to its active metabolite, dopamine, in the peripheral tissues. In contrast to levodopa, dopamine cannot cross the blood-brain barrier, where it is required for the antiparkinsonian effect. In patients receiving both levodopa and carbidopa (a decarboxylase inhibitor), the addition of pyridoxine does not reduce the action of levodopa.
Efficacy of certain drugs (e.g., chlorpromazine, diazepam, propoxyphene, theophylline) may be decreased in individuals who smoke heavily, because of increased hepatic enzyme activity from the action of polycyclic hydrocarbons found in cigarette smoke.

Drugs causing induction of hepatic mitochondrial enzymes(P-450)
Barbiturates, rifampin, digoxin, phenytoin (decreasing levels of – steroids, theophylline, warfarin, quinine).

Inhibition of metabolism: One drug may inhibit the metabolism of another, causing its prolonged and intensified activity. For example, disulfiram, used in the treatment of alcoholism, inhibits the activity of aldehyde dehydrogenase, thus inhibiting the oxidation of acetaldehyde, an oxidation product of alcohol. This results in the accumulation of excessive acetaldehyde and causes the characteristic disulfiram effect following the consumption of alcohol. Disulfiram also enhances the activity of warfarin and phenytoin by inhibiting their metabolism.
Allopurinol reduces the production of uric acid by inhibiting the enzyme xanthine oxidase. However, xanthine oxidase is involved in the metabolism of such potentially toxic drugs as mercaptopurine and azathioprine; when the enzyme is inhibited, the effect of these 2 agents can be markedly increased. Therefore, when allopurinol is given concurrently, a reduction to about 1/3 to 1/4 the usual dose of mercaptopurine or azathioprine is advised.
Cimetidine inhibits oxidative metabolic pathways and is likely to increase the action of other drugs that are metabolized via this mechanism (e.g., carbamazepine, phenytoin, theophylline, warfarin, and certain benzodiazepines). Most benzodiazepines (e.g., diazepam) are metabolized via oxidative mechanisms; however, lorazepam, oxazepam, and temazepam undergo glucuronide conjugation and their action is not affected by cimetidine. Although ranitidine also binds to the hepatic oxidative enzymes, it appears to have less affinity for the enzymes than does cimetidine,famotidine and nizatidine are not inhibit oxidative metabolic pathways.
Erythromycin inhibit the hepatic metabolism of agents such as carbamazepine and theophylline, thereby increasing their effects. The fluoroquinolones (e.g., ciprofloxacin) also increase the activity of theophylline, presumably by the same mechanism.

Drugs causing inhibition of hepatic mitochondrial enzymes (P-450)
Isoniazide, cimetidine, allopurinol, disulfiram, TCA, oral contraceptive, erythromycin, methotrexate, chloramphenicol (increase levels of tolbutamide, phenytoin, theophylline, benzodiazepines, barbiturates).
Alteration of Urinary Excretion
Alteration of urinary pH: Urinary pH influences the ionization of weak acids and bases and thus affects their reabsorption and excretion. A nonionized drug more readily diffuses from the glomerular filtrate into the blood. More of an acidic drug is nonionized in an acid urine than in an alkaline urine, where it primarily exists as an ionized salt. Thus, more of an acidic drug (e.g., a salicylate) diffuses back into the blood from an acid urine, resulting in prolonged and perhaps intensified activity. The risk of a significant interaction is greatest in patients who are taking large doses of salicylates (e.g., for arthritis). Opposite effects are seen for a basic drug like dextroamphetamine.
Alteration of active transport: Probenecid increases the serum levels and prolongs the activity of penicillin derivatives, primarily by blocking their tubular secretion. Such combinations have been used to therapeutic advantage.
Significantly greater serum digoxin levels are found when quinidine is administered concurrently than when digoxin is given alone. Quinidine appears to reduce the renal clearance of digoxin, although other nonrenal mechanisms are probably also involved in this interaction.
A number of nonsteroidal anti-inflammatory drugs (NSAIDs) increase the activity and toxicity of methotrexate. There have been reports of fatal methotrexate toxicity in patients also receiving ketoprofen, and it has been suggested that ketoprofen inhibited the active renal tubular secretion of methotrexate.

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