Pharmacokinetic Interactions

8/6/2019 Pharmacokinetic Interactions

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Pharmacokinetic interactionsPharmacokinetic interactions

Pharmacokinetic interactions arePharmacokinetic interactions aremore complicated and difficult tomore complicated and difficult topredict because the interactingpredict because the interacting

drugs often have unrelated actionsdrugs often have unrelated actions


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PharmacokineticPharmacokinetic interactions areinteractions aremainly due to alteration ofmainly due to alteration of

absorption, distribution, metabolism,absorption, distribution, metabolism,

or excretion, which changes theor excretion, which changes theamount and duration of a drug'samount and duration of a drug's

availability at receptor sites.availability at receptor sites.


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Alteration of GastrointestinalAlteration of Gastrointestinal

Absorption

Absorption

Alteration ofAlteration ofpHpH

Many drugs are weak acids or weak bases, andMany drugs are weak acids or weak bases, and

the pH of the GI contents can influencethe pH of the GI contents can influence

absorption.absorption.

Acidic drugs are usually more readily absorbedAcidic drugs are usually more readily absorbed

from the upper regions of the GI tract where theyfrom the upper regions of the GI tract where they

are primarily in a nonare primarily in a nonionizedionized form.form.


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Complexation and adsorptionComplexation and adsorption

Tetracycline's can combine with metal ions (e.g., Ca, Mg,Tetracycline's can combine with metal ions (e.g., Ca, Mg,Al, and Fe) in the GI tract to form poorly absorbedAl, and Fe) in the GI tract to form poorly absorbedcomplexescomplexes

Antacids markedly reduce the absorption ofAntacids markedly reduce the absorption of

fluoroquinolone derivatives (e.g., ciprofloxacin), probablyfluoroquinolone derivatives (e.g., ciprofloxacin), probablyas a result of the metal ions complexion with the drug.as a result of the metal ions complexion with the drug.

Antacids interfere with the absorption of other dregsAntacids interfere with the absorption of other dregs

like indomethacin,nitrofurantoin,diflusinal,fluoride,pheytoinlike indomethacin,nitrofurantoin,diflusinal,fluoride,pheytoinand cimitidineand cimitidine..

Sucralfate interacts with some drugs Phenytoin and Norfloxacin in GISucralfate interacts with some drugs Phenytoin and Norfloxacin in GIAnd reduce the absorptionAnd reduce the absorption


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Complexation can be expected with IonComplexation can be expected with Ion exchange resins such asexchange resins such ascholestyramine and colestipol.They bind with anionic and neutral drugscholestyramine and colestipol.They bind with anionic and neutral drugsin intestine and reduce the absorption of anticoagulants ,thyroxinein intestine and reduce the absorption of anticoagulants ,thyroxine

GI tract, having the greatest affinity for acidic drugs, e.g., thyroidGI tract, having the greatest affinity for acidic drugs, e.g., thyroidhormone or warfarinhormone or warfarin

Some antidiarrheals e.g., kaolin,Bismuth subsalicylates and pectin maySome antidiarrheals e.g., kaolin,Bismuth subsalicylates and pectin mayadsorb drugs like Lincomycin and promazine, resulting in decreasedadsorb drugs like Lincomycin and promazine, resulting in decreasedabsorption.absorption.


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Alteration of motilityAlteration of motility

By increasing GI motility, metoclopramide mayBy increasing GI motility, metoclopramide mayhasten the passage of drugs through the GI tract,hasten the passage of drugs through the GI tract,resulting in decreased absorption.resulting in decreased absorption.

decreasing GI motility by cimitidine,decreasing GI motility by cimitidine,anticholinergics may either reduce absorption byanticholinergics may either reduce absorption byretarding dissolution.retarding dissolution.

Some antimicrobial agents like neomycin orSome antimicrobial agents like neomycin or

sulfasalazine reduce bioavailability of Digoxinsulfasalazine reduce bioavailability of Digoxin


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Effect of foodEffect of food

Food may delay or reduce the absorption of many drugs.Food may delay or reduce the absorption of many drugs.

by binding with drugs, decreasing their access toby binding with drugs, decreasing their access toabsorption sites,absorption sites,

by altering their dissolution rates, or by altering theby altering their dissolution rates, or by altering the pHpH ofofthe GI contents.the GI contents.

e.g. astemizole, captopril, and penicillaminee.g. astemizole, captopril, and penicillamine

Although there are some drugs their absorption increasesAlthough there are some drugs their absorption increases(e.g., penicillin V potassium, amoxicillin, doxycycline,(e.g., penicillin V potassium, amoxicillin, doxycycline,

minocycline),minocycline),


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Alteration of DistributionAlteration of Distribution

Displacement of drugs from proteinDisplacement of drugs from protein--bindingbindingsites may occur when 2 drugs are givensites may occur when 2 drugs are givenconcurrentlyconcurrently (competitive displacement).(competitive displacement).

e.g. : phenylbutazone ande.g. : phenylbutazone and warfarinwarfarin areareextensively bound to albumin.extensively bound to albumin.

Other drugs like mefenamic acid, ethacrynicOther drugs like mefenamic acid, ethacrynic

acid, nalidixic acid andacid, nalidixic acid anddiazoxide,thyroxine,sulphaphenazole,diazoxide,thyroxine,sulphaphenazole,

clofibrate are displace warfarin from albuminclofibrate are displace warfarin from albumin


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Alteration of MetabolismAlteration of Metabolism

Stimulation of metabolism:Stimulation of metabolism:

E.g.: Phenobarbital increases the rate of metabolism ofE.g.: Phenobarbital increases the rate of metabolism ofcoumarin anticoagulants such as warfarin, resulting in acoumarin anticoagulants such as warfarin, resulting in a

decreased anticoagulant response.decreased anticoagulant response. Phenobarbital also accelerates the metabolism of otherPhenobarbital also accelerates the metabolism of other

drugs such as steroid hormones.drugs such as steroid hormones.

Enzyme induction also occur in barbiturates by variousEnzyme induction also occur in barbiturates by varioustherapeutic agents (e.g., carbamazepine, phenytoin, andtherapeutic agents (e.g., carbamazepine, phenytoin, and

rifampin).rifampin). Disturbed calcium metabolism and osteomalacia areDisturbed calcium metabolism and osteomalacia are

associated with the use of anticonvulsants such asassociated with the use of anticonvulsants such asPhenobarbital and phenytoin.Phenobarbital and phenytoin.


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Reduced serum calcium levels are caused by vitamin D deficiency,Reduced serum calcium levels are caused by vitamin D deficiency,resulting from enzyme induction by the anticonvulsants.resulting from enzyme induction by the anticonvulsants.

Pyridoxine can antagonize the activity of the antiparkinsonian drugPyridoxine can antagonize the activity of the antiparkinsonian druglevodopa by accelerating the conversion of the levodopa to its activelevodopa by accelerating the conversion of the levodopa to its activemetabolite, dopamine, in the peripheral tissues.metabolite, dopamine, in the peripheral tissues.

In contrast to levodopa, dopamine cannot cross the bloodIn contrast to levodopa, dopamine cannot cross the blood--brainbrainbarrier, where it is required for the antiparkinsonian effect.barrier, where it is required for the antiparkinsonian effect.

In patients receiving both levodopa and carbidopa (a decarboxylaseIn patients receiving both levodopa and carbidopa (a decarboxylaseinhibitor), the addition of pyridoxine does not reduce the action ofinhibitor), the addition of pyridoxine does not reduce the action oflevodopa.levodopa.


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Efficacy of certain drugs (e.g., chlorpromazine, diazepam,Efficacy of certain drugs (e.g., chlorpromazine, diazepam,propoxyphene, theophylline) may be decreased in individuals whopropoxyphene, theophylline) may be decreased in individuals whosmoke heavily, because of increased hepatic enzyme activity from thesmoke heavily, because of increased hepatic enzyme activity from theaction of polycyclic hydrocarbons found in cigarette smoke.action of polycyclic hydrocarbons found in cigarette smoke.

Drugs causing induction of hepatic mitochondrial enzymes(PDrugs causing induction of hepatic mitochondrial enzymes(P--450)450)

Barbiturates, rifampin, digoxin, phenytoinBarbiturates, rifampin, digoxin, phenytoin (decreasing levels of(decreasing levels of steroids, theophylline,steroids, theophylline, warfarinwarfarin, quinine)., quinine).


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Inhibition of metabolism:Inhibition of metabolism:

One drug may inhibit the metabolism of another,One drug may inhibit the metabolism of another,

causing its prolonged and intensified activity.causing its prolonged and intensified activity.

E.g.: disulfiram,( alcoholism) inhibits the activity ofE.g.: disulfiram,( alcoholism) inhibits the activity of

aldehyde dehydrogenises, thus inhibiting thealdehyde dehydrogenises, thus inhibiting the

oxidation of acetaldehyde. This results in theoxidation of acetaldehyde. This results in the

accumulation of excessive acetaldehyde .accumulation of excessive acetaldehyde . Disulfiram also enhances the activity of warfarinDisulfiram also enhances the activity of warfarin

and phenytoin by inhibiting their metabolismand phenytoin by inhibiting their metabolism


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Disulfiram also enhances the activity of warfarinDisulfiram also enhances the activity of warfarinand phenytoin by inhibiting their metabolismand phenytoin by inhibiting their metabolism ..

xanthine oxidase is involved in the metabolism ofxanthine oxidase is involved in the metabolism of

such potentially toxic drugs as mercaptopurinesuch potentially toxic drugs as mercaptopurineand azathioprine.and azathioprine.

when allopurinol is given concurrently, a reductionwhen allopurinol is given concurrently, a reductionto about 1/3 to 1/4 the usual dose ofto about 1/3 to 1/4 the usual dose of

mercaptopurine or azathioprine is advised.mercaptopurine or azathioprine is advised.


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Cimetidine inhibits oxidative metabolic pathways and isCimetidine inhibits oxidative metabolic pathways and islikely to increase the action of other drugs that arelikely to increase the action of other drugs that aremetabolized via this mechanismmetabolized via this mechanism

(e.g., carbamazepine, phenytoin, theophylline, warfarin,(e.g., carbamazepine, phenytoin, theophylline, warfarin,and certain benzodiazepines like diazepam)and certain benzodiazepines like diazepam)

lorazepam, oxazepam, and temazepam undergolorazepam, oxazepam, and temazepam undergoglucuronide conjugation and their action is not affected byglucuronide conjugation and their action is not affected bycimetidinecimetidine

Ranitidine also binds to the hepatic oxidative enzymes, butRanitidine also binds to the hepatic oxidative enzymes, butit have less affinity for the enzymes thanit have less affinity for the enzymes thancimetidine,famotidine and nizatidine .thus not inhibitcimetidine,famotidine and nizatidine .thus not inhibitoxidative metabolic pathwaysoxidative metabolic pathways


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Erythromycin inhibit the hepatic metabolism of agents suchErythromycin inhibit the hepatic metabolism of agents suchas carbamazepine and theophylline, thereby increasingas carbamazepine and theophylline, thereby increasingtheir effects.their effects.

The fluoroquinolones (e.g., ciprofloxacin) also increase theThe fluoroquinolones (e.g., ciprofloxacin) also increase the

activity of theophylline, presumably by the sameactivity of theophylline, presumably by the samemechanism.mechanism.

Drugs causing inhibition of hepatic mitochondrial enzymesDrugs causing inhibition of hepatic mitochondrial enzymes(P(P--450)450)Isoniazide, cimetidine, allopurinol, disulfiram, TCA, oralIsoniazide, cimetidine, allopurinol, disulfiram, TCA, oralcontraceptive, erythromycin, methotrexate,contraceptive, erythromycin, methotrexate,chloramphenicol thus (increase levels of tolbutamide,chloramphenicol thus (increase levels of tolbutamide,phenytoin, theophylline, benzodiazepines, barbiturates).phenytoin, theophylline, benzodiazepines, barbiturates).


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Alteration of Urinary ExcretionAlteration of Urinary Excretion

Alteration of urinaryAlteration of urinary pHpH::

Urinary pH influences the ionization of weakUrinary pH influences the ionization of weak

acids and bases and thus affects theiracids and bases and thus affects theirreabsorption and excretionreabsorption and excretion

A nonA nonionizedionized drug more readily diffusesdrug more readily diffusesfrom the glomerular filtrate into the bloodfrom the glomerular filtrate into the blood

The risk of interaction is greatest in patientsThe risk of interaction is greatest in patientswho are taking large doses of salicylateswho are taking large doses of salicylates(e.g., for(e.g., forarthritisarthritis).).


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Opposite effects are seen for a basic drug likeOpposite effects are seen for a basic drug likedextroamphetamine.dextroamphetamine.Alteration of active transport: ProbenecidAlteration of active transport: Probenecidincreases the serum levels and prolongs theincreases the serum levels and prolongs theactivity of penicillin derivatives, primarily byactivity of penicillin derivatives, primarily byblocking their tubular secretion.blocking their tubular secretion.

Significantly greater serumSignificantly greater serum digoxindigoxin levels arelevels arefound when quinidine is administered concurrentlyfound when quinidine is administered concurrently

than digoxin is given alone.than digoxin is given alone. Quinidine appears to reduce the renal clearanceQuinidine appears to reduce the renal clearance

of digoxin, although other nonrenal mechanismsof digoxin, although other nonrenal mechanismsare probably also involved in this interaction.are probably also involved in this interaction.


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A number of nonsteroidal antiA number of nonsteroidal anti--inflammatory drugsinflammatory drugs(NSAIDs) increase the activity and toxicity of(NSAIDs) increase the activity and toxicity ofmethotrexate.methotrexate.

There have been reports of fatal methotrexateThere have been reports of fatal methotrexatetoxicity in patients also receiving ketoprofen, and ittoxicity in patients also receiving ketoprofen, and ithas been suggested that ketoprofen inhibited thehas been suggested that ketoprofen inhibited theactive renal tubular secretion of methotrexate.active renal tubular secretion of methotrexate.

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Pharmacokinetic Interactions