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Pharmacokinetic interactions

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

Pharmacokinetic 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


 Alteration of pH  Many drugs are weak acids or weak bases, and the pH of the GI contents can influence absorption. Acidic drugs are usually more readily absorbed from the upper regions of the GI tract where they are primarily in a nonionized form. nonionized

Complexation and adsorption


 Tetracycline's can combine with metal ions (e.g., Ca, Mg, Al, and Fe) in the GI tract to form poorly absorbed complexes  Antacids markedly reduce the absorption of fluoroquinolone derivatives (e.g., ciprofloxacin), probably as a result of the metal ions complexion with the drug.  Antacids interfere with the absorption of other dregs like indomethacin,nitrofurantoin,diflusinal,fluoride,pheytoin and cimitidine.
Sucralfate interacts with some drugs Phenytoin and Norfloxacin in GI And reduce the absorption

 Complexation can be expected with Ion exchange resins such as cholestyramine and colestipol.They bind with anionic and neutral drugs in intestine and reduce the absorption of anticoagulants ,thyroxine  GI tract, having the greatest affinity for acidic drugs, e.g., thyroid hormone or warfarin  Some antidiarrheals e.g., kaolin,Bismuth subsalicylates and pectin may adsorb drugs like Lincomycin and promazine, 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.  decreasing GI motility by cimitidine, anticholinergics may either reduce absorption by retarding dissolution.  Some antimicrobial agents like neomycin or sulfasalazine reduce bioavailability of Digoxin

Effect of food
 Food may delay or reduce the absorption of many drugs.  by binding with drugs, decreasing their access to absorption sites,  by altering their dissolution rates, or by altering the pH of the GI contents.  e.g. astemizole, captopril, and penicillamine  Although there are some drugs their absorption increases (e.g., penicillin V potassium, amoxicillin, doxycycline, minocycline),

Alteration of Distribution
 Displacement of drugs from protein-binding proteinsites may occur when 2 drugs are given concurrently (competitive displacement).  e.g. : phenylbutazone and warfarin are extensively bound to albumin.  Other drugs like mefenamic acid, ethacrynic acid, nalidixic acid and diazoxide,thyroxine,sulphaphenazole, clofibrate are displace warfarin from albumin

Alteration of Metabolism
 Stimulation of metabolism:  E.g.: 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 occur in barbiturates 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 bloodbarrier, 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) enzymes(PBarbiturates, rifampin, digoxin, phenytoin  (decreasing levels of steroids, theophylline, warfarin, quinine). warfarin,

Inhibition of metabolism:
 One drug may inhibit the metabolism of another, causing its prolonged and intensified activity.  E.g.: disulfiram,( alcoholism) inhibits the activity of aldehyde dehydrogenises, thus inhibiting the oxidation of acetaldehyde. This results in the accumulation of excessive acetaldehyde .  Disulfiram also enhances the activity of warfarin and phenytoin by inhibiting their metabolism

 Disulfiram also enhances the activity of warfarin and phenytoin by inhibiting their metabolism .  xanthine oxidase is involved in the metabolism of such potentially toxic drugs as mercaptopurine and azathioprine.  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 like diazepam)  lorazepam, oxazepam, and temazepam undergo glucuronide conjugation and their action is not affected by cimetidine  Ranitidine also binds to the hepatic oxidative enzymes, but it have less affinity for the enzymes than cimetidine,famotidine and nizatidine .thus 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(P-450) Isoniazide, cimetidine, allopurinol, disulfiram, TCA, oral contraceptive, erythromycin, methotrexate, chloramphenicol thus (increase levels of tolbutamide, phenytoin, theophylline, benzodiazepines, barbiturates).

Alteration of Urinary Excretion


 Alteration of urinary pH: pH:  Urinary pH influences the ionization of weak acids and bases and thus affects their reabsorption and excretion  A nonionized drug more readily diffuses nonionized from the glomerular filtrate into the blood The risk of interaction is greatest in patients who are taking large doses of salicylates (e.g., for arthritis). 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.  Significantly greater serum digoxin levels are found when quinidine is administered concurrently than 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 anti(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.