9 Drug Interactions

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Drug interactions


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Overview

IntroductionIncidencePredisposing factors

In vitro ( outside the body) interactionsIn vivo ( inside the body): drug-food and drug-drug

interactionsDrug herb interactionsDrug-laboratory test interactions

Beneficial interactionsPrevention of interactionsConclusion


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Alteration in duration or magnitude or both inpharmacological effect of drug produced by any other substance(drug/ food substance/ environmental chemical agent) are

termed as drug interactions.

Outcome can be harmfuli.e. in toxicity of drug or intherapeutic efficacy OR

Beneficiali.e. in therapeutic efficacy or in toxicity of drug


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Predisposing factors

Insufficient knowledge of physician leading toirrational polypharmacy

Patientbehaviors such as consulting more than onephysician at a time, self medication ( over the counterOTC drugs) or smoking and alcohol consumption.Geriatric patients are predisposed to interactions dueto reduced liver and kidney functions.

Exposure to Environm entalfactors like insecticides,industrial wastes, pesticides


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Incidence

One hospital study found that the rate was 7% inthose taking 6 to 10 drugs but 40% in those taking 16to 20 drugs which represents a disproportionateincrease.

When only clinically significant interactions wereseen, the incidences reported were 4.7%, 6.3% and8.8%

Even if the incidence is as low, it still represents avery considerable number of patients who appear to

be at risk when one thinks of the large numbers ofdrugs prescribed and handled everyday by doctorsand pharmacists


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Drugs most likely to be involved in clinicallyimportant interactions

Drugs with narrow safety margin e.g. aminoglycoside antibiotics, digoxin, lithium

Drugs affecting closely regulated body functions e.g. antihypertensives, antidiabetics, anticoagulants

Highly plasma protein bound dugs e.g. oral anticoagulants, sulfonylurea

Drugs metabolized by saturation kinetics e.g. Phenytoin, theophylline


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In vitro ( outside the body)

In a syringe or IV drip leading to inactivation or precipitationdue to changes in pHE.g. penicillin G or ampicillin inactivates gentamicin if mixed insame syringe

Nor adrenaline and Amphotericin are unstable if added toisotonic saline(NS) due to its neutral or slightly acidic pH

Dextrose ( highly acidic) is not suitable as vehicle for mostdrugs.

No drug should ever be added to : blood, plasma or mannitol


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In vivo (inside the body) interactions

In vivo interactions can occur between two drugs or betweendrug and food

Drug Food interaction

E.g. hypertensive crisismay occur if patient takingMonoamine oxidase inhibitors(MAOI) consumes tyramine containing

food.

Therapeutic effect of oral anticoagulants may decrease ifpatients consumes Vitamin K rich foods such as spinach,broccoli.


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Drug food interaction( cont)

Food may delay or reduce the absorption of many drugs by slowing gastric emptying or binding with drugs & thus

decreasing their access to absorption sites or by altering theirdissolution rates or by altering the pH of the GI contents.

Food decreases the absorption of astemizole, captopril, andpenicillamine. Milk & milk products decrease absorption of tetracycline

On some occasions, food especially fatty meals may increaseabsorption of drugs like itraconazole, albendazole, griseofulvin.


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Drug food interaction( cont)

Cruciferous vegetables & charcoal broiledmeat induce CYP 450 isoenzyme

Grape fruit juice/ oranges inhibits CYP45

0isoenzyme as well as P-glycoprotein effluxtransporters thus increasing plasma levels ofdrugs like indinavir, saquinavir, midazolam,

carbamazepine, verapamil, albendazole


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Drug-drug interaction

Many drugs interact with each other by twoor more mechanisms. Two most importantare

Pharmacokinetic interactions are those whichcan affect the processes by which drugs areabsorbed, distributed, metabolised andexcreted (the so-called ADME interactions).

Pharmacodynamic interactions are thosewhere the effects of one drug are changed bythe presence of another drug at its site ofaction.


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Drug absorption interactions

A clear distinction must be made between those that decreasethe rateof absorption and those that alter the totalamountabsorbed.

For drugs that are giv

en chronically on a multiple dose regimen(e.g. the oral anticoagulants) the rate of absorption is usuallyunimportant, provided the total amount of drug absorbed is notmarkedly altered.

On the other hand for drugs which are given as single dosesintended to be absorbed rapidly (e.g. hypnotics or analgesics)where a rapidly achieved high concentration is needed, a

reduction in the rate of absorption may result in failure toachieve an adequate effect


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Absorption interactions cont..

Absorption of drug from GI tract may beaffected by concurrent use of drugs that

bind or chelate

have large surface area upon which drugs canbe adsorbed

alter gastric pH

alter gastric motility or affect transport proteins such as P-glycoprotein


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Adsorption, chelation and other complexing mechanismsTetracycline can chelate with a number of divalent and trivalentmetallic ions such as calcium, aluminium, bismuth and iron toform complexes, which not only are poorly absorbed, but havereduced antibacterial effects.

Colestyraminebinds to a considerable number of drugs if co-administered (e.g. digoxin, warfarin, levothyroxine) therebyreducing their absorption.

Sucralfateadsorbsmany drugs and interferes with absorption oftetracycline, fluoroquinolones, cimetidine, Phenytoin anddigoxin.Some antidiarrheals (e.g.,thosecontaining kaolin andpectin), may adsorb other drugs, resulting in decreasedabsorption


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Alteration in gastrointestinal pH: Rises in pH due toH2-blockers and antacids that affect dissolution &can markedly reduce the absorption of ketoconazole&fluoroquinolone derivatives such as ciprofloxacin

Changes in gastric motility: Drugs are largelyabsorbed in upper part of the small intestine, so otherdrugs which alter gastric emptying can affectabsorption.

Anticholinergic drugs delay gastric emptying &

reduce rate of absorption of many drugs. At the same time they increase the time available for

dissolution and absorption for tetracycline anddigoxin and increase their absorption.


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Prokinetic drugs like metoclopramidefacilitating gastric emptying hastensabsorption of aspirin, diazepam whilereduces extent of absorption of digoxin

Neomycin on prolonged treatment,causes amalabsorption syndromesimilar to non-

tropical sprue & impair the absorption ofdigoxin and phenoxymethylpenicillin


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Drug displacement (protein-binding) interactions

Depending on concentrations & relative affinities for thebinding sites, one drug may compete with another and displaceit from the sites. So the concentration of free form which is theactive form rises.

E.g. a drug which reduces the binding from (say) 99 to 95% willincrease the unbound concentration of free and active drug from1 to 4% (a fourfold increase).

Stockleys Drug Interactions 17thEd, Pg3

The clinical importance of protein binding displacement hasbeen overemphasized as displaced drug will diffuse in tissuesas well as get metabolized or excr


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Drug displacement interactions cont..

Moreover, two highly bound drugs do not necessarily displaceeach other-their binding sites may not overlape,g, Probenecid and Indomethacin are highly bound to albuminbut do not displace each other.

Similarly acidic drugs do not displace basic drugs and viceversa as acidic drugs bind to albumin while basic drugs to1acid glycoprotein.

Clinically important displacement interactions are

Salicylates displace sulfonylurea and methotrexate Indomethacin, Phenytoin displace warfarin


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Drug metabolism

(biotransformation) interactions Certaindrugscanenhanceorreducemetabolismofother

drugsbyrespectivelyinducingorinhibitinglivermicrosomalenzymes.

Enzymeinductionresultsinenhancedmetabolismofotherdrugs,therebyreducingtheirserumlevelsandeffects

Theextentoftheenzymeinductiondependsonthedruganditsdosagebutitmaytakedaysoreven2to3weekstodevelopfully,andpersistforasimilarlengthoftimewhenthei

nducingagentisstopped. Soenzymeinductioninteractionsaredelayedinbothstar

tingandstopping.


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Drug metabolism interactions

cont..


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Rifampicin (600mg daily plus isoniazid) increased the metabolism ofcyclosporin in this patient, thereby reducing the serum levels.He subsequently died because his heart transplant was rejected


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After the subject was giv

en rifampicin (600 mg daily for a few days),the plasma half-life of warfarin decreased from 47 hours (red curve)to 18 hours (green curve).


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cont.. Enzyme inhibition results in reduced metabolism of

other drugs given concurrently,which startaccumulating within the body, the effect beingessentially the same as when the dosage is increased.

It attains clinical significance mostly for the drugsthat are metabolized by saturation kinetics or in casedrugs having affinity for the same CYP450isoenzyme or cofactor.

Inhibition of metabolism generally take place morequickly (within hours) than enzyme induction.


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The chloramphenicol inhibited the metabolism of thephenytoin in this patient so that the serum levels climbedinto the toxic range and intoxication developed (indicated by nystagmus)


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cont.. Changes in blood flow through the liver: Number of

highly lipid-soluble drugs undergo substantialbiotransformation during this first pass through thegut wall and liver. Some concurrently administered

drugs can have a marked effect on the extent of firstpass metabolism by altering the blood flow throughthe liver.

Cimetidine (but not ranitidine) decreases hepaticblood flow and thereby increases the bioavailability

of propranolol.

Propranolol also reduces both its own clearance andthat of other drugs such as lidocaine (lignocaine)


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Interactions due to changes in excretion

Interference by drugs with kidney tubule fluid pH, with activetransport systems and with blood flow to the kidney can alterthe excretion of other drugs.

Changes in urinary pH: only non-ionised form is lipid-solubleand able to diffuse back through tubule cells.

If change in pH increases the amount in the ionised form, itincrease the loss of the drug, whereas moving the pH in theopposite directions will increase their retention.

Clinical significance is small as most of drug are metabolizedto inactive form in liver

Deliberate urinary pH changes have been used to increase theloss of drugs such as Phenobarbital and salicylates.


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Interactions due to changes in

excretion cont.. Changes in active kidney tubule excretion:

Drugs that use the sameactive transport systems

in the kidney tubules cancompete with oneanother for excretion.Probenecid( ) is able successfullyto compete with some ofthe other drugs ( o ) foractive secretorymechanisms in thekidney tubules whichreduces their loss in theurine and raises serumlevels.


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Interactions due to changes in excretion cont..


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Interactions due to changes in excretion cont

Changes in kidney blood flow: The flow of bloodthrough the kidney is partially controlled by theproduction of renal vasodilatory prostaglandins. Ifthe synthesis of these prostaglandins is inhibited (e.g.by indomethacin), the renal excretion of lithium is

reduced.

Biliary excretion and the entero-hepatic shunt:number of drugs are excreted in the bile. eitherconjugated or unconjugated. Some undergo

enterohepatic recirculation after deconjugation bygut flora. Penicillins or tetracyclines diminish gutflora and cause oral contraceptive failure.


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P-glycoprotein interactions

The pumping actions of P-glycoprotein can beinduced or inhibited by some drugs.

Rifampicin induces P-glycoprotein within the liningcells of the gut ,causes digoxin efflux, resulting in afall inthe levels of digoxin in the plasma.

Verapamil & quinidine inhibit the activity of P-glycoprotein within the kidney tubule cells so that

the amount of digoxin pushed out into the urine isreduced, thereby causing a rise in plasma digoxinlevels.


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Pharmacodynamic interactions

Effects of one drug are changed by the presence of another drug at itssite of action. Which can beAdditive or synergistic interactions: If two drugs with samepharmacological effect are given together, the effects can beadditive.


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Pharmacodynamic interactions cont

Antagonistic or opposing interactions: In contrast to additiveinteractions, there are some pairs of drugs with activities


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Drug-Herb interactions

The market of herbal medicines in western worldshas markedly increased in recent years and reports ofinteractions with conventional drugs have arisen.

St Johns wort ( Hypericumperforatum) can induceCYP450 isoenzyme and also P-glycoprotein hencedecreases levels of cyclosporin and digoxinrespectively.

St Johns wort has serotonergic properties resultingin Pharmacodynamic interaction with SSRIs namelydevelopment of serotonin syndrome


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Drug-Laboratory test interactions

Drugs may interfere with laboratory test resulting inwrong diagnosis

False positive urinary glucose test withcephalosporin administration

Diuretics can affect electrolyte test results

Use of estrogen causes increase in serum thyroxinelevel

Salicylates, nalidixic acid, VitC cause false positiv

etest for urine sugar if performed by Benedict'ssolution


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Beneficial interactions

Cotrimoxazole, a combination of sulfamethoxazole and trimethoprim.Individual drugs are bacteriostatic while combination is cidal.

Carbidopa inhibits peripheral degradation of levodopa, socombination is beneficial in parkinsonism.

T

hiazide diuretics can be combined with blockers in treatment ofhypertension.

Amoxicillin with lactamase inhibitor to prevent degradation ofamoxicillin by lactamase producing bacteria.

Vitamin C increase absorption of iron from GIT, while adrenaline

injected with lignocaine reduces absorption but prolongs duration ofaction.


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Preventionofinteraction

Avoid irrational polypharmacy

Maintain a detailed drug history &medical record of patient

Selection of right drug i.e.to choose a

non-interacting alternativeProper dose adjustmentSome interactions can be accommodatedby using another member of the samegroup of drugs.


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Conclusions

Its impossible to remember all clinically importantinteractions but there are some broad generalprinciples which need little memorising:

Be alert with drugs having narrow therapeutic

window Remember microsomal enzyme inducing as well as

inhibiting agents

Think of basic pharmacology of drug to avoid

Pharmacodynamic interactions Remember the elderly are most at risk because ofreduced liver and kidney function.

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