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Drug DrugInteractions

By

Professor Ghada Hashem

Department of Pharmacology

Faculty of Medicine

Cairo University

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DRUG INTERACTIONS

The administration of one drug (A !an a"ter the a!tion ofanother (# $% one of t&o genera" me!hanisms'

Modification of the pharmacological effect of B without altering itsconcentration in the tissue fluid (pharmacodynamic interaction)

Alteration of the concentration of B that reaches its site of action(pharmacokinetic interaction).

1) For such interactions to be important clinically it is necessarythat the therapeutic range of drug B is narrow (i.e. that a small

reduction in effect will lead to loss of efficacy andor a smallincrease in effect will lead to to!icity).

") For pharmacokinetic interactions to be clinically important it isalso necessary that the dose#response cur$e of drug B is steep (sothat a small change in plasma concentration leads to a substantialchange in effect).

%) For many drugs these conditions are not met& e$en 'uite large

changes in plasma concentrations of relati$ely non#to!ic drugs likepenicillin are unlikely to gi$e rise to clinical problems because thereis usually a comfortable safety margin between plasmaconcentrations produced by usual doses and those resulting ineither loss of efficacy or to!icity.

) e$eral drugs do ha$e steep dose#response relationships and anarrow therapeutic margin and drug interactions can cause ma*orproblems+ for e!ample with antithrombotic+ antidysrhythmic andanti#epileptic drugs+ lithium and se$eral antineoplastic andimmunosuppressant drugs.

N.B. A third category of pharmaceutical interactions should bementioned, in which drugs interact in vitro so that one or both areinactivated. No pharmacological principles are involved, justchemistry. An example is the formation of a complex betweenthiopentone and suxamethonium, which must not be mixed in thesame syringe. Heparin is highly charged and interacts in this waywith many basic drugs; it is sometimes used to eep intravenous

lines or cannulae open, and can inactivate basic drugs! if they areinjected without first clearing the line with saline.

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)harma!od%nami! intera!tion

,harmacodynamic interaction can occur in many different ways.-here are many mechanisms+ and some e!amples of practical

importance are probably more useful than attempts atclassification. onsider the following&

#adrenoceptor antagonists diminish the effecti$eness of #receptor agonists+ such as salbutamol or terbutaline.

Many diuretics lower plasma potassium concentration+ andthereby enhance some actions of digo!in and predispose toglycoside to!icity.

Monoamine o!idase inhibitors increase the amount ofnorepinephrine stored in noradrenergic ner$e terminals andthereby interact dangerously with drugs+ such as ephedrine ortyramine that work by releasing stored norepinephrine. -his canalso occur with tyramine#rich foods/particularly fermentedcheeses such as amembert.

0arfarin competes with $itamin + pre$enting hepatic synthesis

of $arious coagulation factors. 2f $itamin production in theintestine is inhibited (e.g. by antibiotics)+ the anticoagulant actionof warfarin is increased. 3rugs that cause bleeding by distinctmechanisms (e.g. aspirin+ which inhibits platelet thrombo!ane A"biosynthesis and can damage the stomach) increase the risk ofbleeding caused by warfarin.

ulphonamides pre$ent the synthesis of folic acid by bacteria andother microorganisms4 trimethoprim inhibits its reduction totetrahydrofolate. 5i$en together the drugs ha$e a synergisticaction of $alue in treating ,neumocystis carinii.

6on#steroidal anti#inflammatory drugs (6A23s)+ such asibuprofen or indomethacin+ inhibit biosynthesis of prostaglandins+including renal $asodilatornatriuretic prostaglandins (,57"+ ,52").2f administered to patients recei$ing treatment for hypertension+they cause a $ariable but sometimes marked increase in bloodpressure+ and if gi$en to patients being treated with diuretics forchronic heart failure can cause salt and water retention and hence

cardiac decompensation.

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choreoathetosis+ characterised by in$oluntary writhing and twistingmo$ements in the child.

one displaces warfarin from binding sites onalbumin and more importantly selecti$ely inhibits metabolism of thepharmacologically acti$e isomer (see below)+ prolongingprothrombin time and resulting in increased bleeding.

B) alicylates displace methotre!ate from binding sites on albuminand reduce its secretion into the nephron by competition with theanion secretory carrier.

) ?uinidine and se$eral other antidysrhythmic drugs including$erapamil and amiodarone displace digo!in from tissue#bindingsites while simultaneously reducing its renal e!cretion+ and canconse'uently cause se$ere dysrhythmias due to digo!in to!icity.

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III) Metabolismome e!amples of drugs that inhibit or induce drug metabolism areshown in the following table&

7!amples of drugs that induce or inhibit drug#metabolising en>ymesEn/%me indu!tionDrugs modifying enzyme action Drugs whose metabolism is affected

,henobarbitone and otherbarbiturates

@ifampin

5riseoful$in

,henytoin

7thanol

arbama>epine

0arfarin

ral contracepti$es

orticosteroids

yclosporin

(as well as drugs listed in left#hand column)

En/%me inhi$itionDrugs modifying enzyme action Drugs whose metabolism is affected

3isulfiram 0arfarinAllopurinol Mercaptopurine+ a>athioprine7cothiopate and otheranticholinesterases

u!amethonium+ procaine

hloramphenicol ,henytoin

orticosteroids arious drugs+ e.g. tricyclic antidepressants+ cyclophosphamideimetidine Many drugs+ e.g. amiodarone+ phenytoin+ pethidineMA inhibitors ,ethidine7rythromycin yclosporin+ theophyllineiproflo!acin -heophylline

1 En/%me indu!tion

$er "CC drugs cause en>yme induction and therebydecrease the pharmacological acti$ity of a range of other

drugs.

2nduction (stimulation) of cytochrome iso>ymes in the li$erand small intestine can be caused by drugs such asbarbiturates+ carbama>epine+ glutethimide+ phenytoin+primidone+ rifampin+ and troglita>one.

ince the inducing agent is normally itself a substrate for theinduced en>ymes+ the process can result in slowly

de$eloping tolerance.

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Although this pharmacokinetic kind of tolerance is generallyless important clinically than tolerance that results frompharmacodynamic adaptations (e.g. to opioid analgesics)+and the lethal dose of inducing drugs such as the

barbiturates is only moderately increased in chronic users.

Many clinically important drug interactions result fromen>yme induction+ a few of which are listed in the abo$etable.

7!amples&A) -he antibiotic rifampin+ gi$en for % days+ reduces theeffecti$eness of warfarin as an anticoagulant.

B) on$ersely+ en>yme induction can increase to!icity of a drugwhose to!ic effects are mediated $ia a metabolite. ,aracetamolto!icity is the case& it is due to 6#acetyl#p#ben>o'uinone imine+which is formed by cytochrome ,:C. onse'uently the risk ofserious hepatic in*ury following paracetamol o$erdose is increasedin patients whose cytochrome ,:C system has been induced+ fore!ample by chronic use of alcohol. 2t is likely that part of the$ariability in rates of drug metabolism between indi$iduals results

from $arying e!posure to en$ironmental contaminants+ some ofwhich are strong en>yme inducers.

7n>yme induction can be e!ploited therapeutically+ byadministering phenobarbitone to premature babies to induceglucuronyl transferase+ thereby increasing bilirubincon*ugation and reducing the risk of kernicterus.

2 En/%me inhi$ition

3rugs that may inhibit hepatic microsomal metabolism ofother drugs include allopurinol+ amiodarone+ androgens+chloramphenicol+ cimetidine+ ciproflo!acin+ clarithromycin+cyclosporine+ diltia>em+ disulfiram+ erythromycin+ flucona>ole+fluo!etine+ flu$o!amine+ grapefruit *uice+ isonia>id+itracona>ole+ ketocona>ole+ metronida>ole+ me!iletine+micona>ole+ omepra>ole+ phenylbuta>one. propo!yphene+'uinidine+ ritona$ir+ sulfonamides+ $erapamil+ >afirlukast+ and>ileuton.

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-his can increase the action+ of other drugs metaboli>ed bythe en>yme+ such effects can be clinically important+e!amples include&

A) 2nteraction between the non#sedating antihistamine terfenadine

and the imida>ole antifungal drugs such as ketocona>ole and otherdrugs that inhibit the D,%A subfamily of ,:C en>ymes. -his canresult in prolongation of the ?#- inter$al on the electrocardiogramand a form of $entricular tachycardia in susceptible indi$iduals.

B) 5rapefruit *uice inhibits D,%A and reduces the metabolism ofterfenadine and other drugs+ including cyclosporin and se$eralcalcium channel antagonists.

) e$eral inhibitors of drug metabolism influence the metabolismof different stereoisomers selecti$ely. 7!amples of drugs thatinhibit the metabolism of the acti$e and less acti$e @ isomers (is times more potent) of warfarin in this way are shown in thefollowing table&

Stereose"e!tie and non-stereose"e!tie inhi$ition of &arfarinmeta$o"ism

#tereoselective inhibition of clearance of # isomer

1. ,henylbuta>one". Metronida>ole%. ulphinpyra>one. -rimethoprim#sulphametho!a>ole (o#trimo!a>ole):. 3isulfiram

#tereoselective inhibition of clearance of ( isomer

1. imetidine". mepra>ole

Non)stereoselective inhibition of clearance of ( and #$somers

Amiodarone3) -he therapeutic effects of some drugs are a direct conse'uenceof en>yme inhibition (e.g. the !anthine o!idase inhibitor+ allopurinol+used to pre$ent gout Eanthine o!idase metabolises se$eralcytoto!ic and immunosuppressant drugs+ including mercaptopurine

(the acti$e metabolite of a>athioprine)+ whose action is thuspotentiated and prolonged by allopurinol.

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7) 3isulfiram+ an inhibitor of aldehyde dehydrogenase used toproduce an a$ersi$e reaction to ethanol+ also inhibits metabolismof other drugs+ including warfarin which it potentiates.Metronida>ole+ an antimicrobial used to treat anaerobic bacterial

infections and se$eral proto>oal diseases also inhibits this en>yme+and patients are ad$ised to a$oid alcohol for this reason.

C%to!hrome )-*,3 Iso/%mes' Su$strates4 Inhi$itors4 andIndu!ers

6.B. D,%A alone is responsible for more than ;C of hheclinically prescribed drugs metaboli>ed by the the li$er

Iso/%me Su$strates Inhi$itors Indu!ers

1A2 affeinelomipramine (Anafranil)lo>apine (lo>aril)Flutamide (7nle!in)2mipramine (-ofranil)Glan>apine (Hypyre!a)-acrine (ogne!)-heophylline (-heo#3ur)@opinirole (@e'uip)

@#0arfarin (oumadin)Hileuton (Hyflo)

imetidine (-agamet)iproflo!acin (ipro)7no!acin (,enetre!)7thinyl 7stradiolFlu$o!amine (Iu$o!)2sonia>id (268)Me!iletine (Me!itil)6orethindrone-acrine (ogne!)Hileuton (Hyflo)

harcoal#broiledmeatmoking

2C eleco!ib (elebre!)3iclofenac (oltaren)3ronabinol (Marinol)Flurbiprofen (Ansaid)Flu$astatin (Iescol)5limepiride5lipi>ide (5lucotrol)J

5libenclamideJ2buprofen (Motrin)2ndomethacin (2ndocin)Iosartan (o>aar)Montelukast (ingulair)6apro!en (6aprosyn),henytoin (3ilantin),iro!icam (Feldene)-olbutamide (rinase)-orsemide (3emade!)#0arfarin (oumadin)

Hafirlukast (Accolate)

Amiodarone(ordarone)imetidine (-agamet)lopidogrel (,la$i!)o#trimo!a>ole(Bactrim)3isulfiram (Antabuse)7fa$iren> (usti$a)

Flucona>ole (3iflucan)Flu$astatin (Iescol)Flu$o!amine (Iu$o!)2sonia>id (268)tracona>ole2 (porano!)etocona>ole (6i>oral)Metronida>ole (Flagyl)ulfinpyra>one(Anturane)-iclopidine (-iclid)

Hafirlukast (Accolate)

Aminoglutethimide(ytandren)Barbituratesarbama>epine(-egretol)5riseoful$in(Ful$icin)

6afcillin (Knipen),henytoin(3ilantin),rimidone(Mysoline)@ifampin(@imactane)

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2C1

Amitriptyline (7la$il)Garisoprodol (oma)italopram (ele!a)lomipramine (Anafranil

3ia>epam (alium)G2mipramine (-ofranil)GIansopra>ole (,re$acid)Mephenytoin,antopra>ole (,rotoni!)mepra>ole (,rilosec),entamidine (,entam),henytoin (minorpathway),roguanilG@abepra>ole (Aciphe!)@#0arfarin (oumadin)

7fa$iren> (usti$a)Felbamate (Felbatol)Flucona>ole (3iflucan)

Fluo!etine (,ro>ac)GFlu$o!amine (Iu$o!)mepra>ole (,rilosec)-iclopidine (-iclid)

2D

Amitriptyline (7la$il)Gar$edilol (oreg)lomipramine (Anafranil)odeineG L Morphine3esipramine (6orpramin)3e!fenfluramine (@edu!)3e!tromethorphan3ihydrocodeineG

7fa$iren> (usti$a)7ncainideFlecainide (-ambocor)Fluo!etine (,ro>ac)GFlu$o!amine (Iu$o!)8aloperidol (8aldol)8ydrocodoneG2mipramine (-ofranil)GMaprotilineMethamphetamineMetoprolol (Iopressor)

Me!iletine (Me!itil)6ortriptyline (,amelor)!ycodone (,ercocet),aro!etine (,a!il),erphena>ine (-rilafon),ropafenone (@hythmol),ropranolol (2nderal)@isperidone (@isperdal)-hiorida>ine (Mellaril)-imolol (Blocadren)-ramadol (Kltram)G

-ra>odone (3esyrel)enlafa!ine (7ffe!or)

Amiodarone(ordarone)hloro'uine (Aralen)imetidine (-agamet)3iphenhydramine(Benadryl)Fluo!etine (,ro>ac)G

8aloperidol (8aldol)Mibefradil (,osicor),aro!etine (,a!il),erphena>ine(-rilafon),ropafenone(@hythmol),ropo!yphene(3ar$on)?uinacrine?uinidine (?uinide!)?uinine

@itona$ir (6or$ir)ertraline (Holoft)(weak)-erbinafine (Iamisil)-hiorida>ine (Mellaril)

Note& D, "3;appears relati$elyresistant toen>yme induction.

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A*

Acetaminophen (-ylenol)Alfentanil (Alfenta)Alpra>olam (Eana!)Amlodipine (6or$asc)

Amiodarone (ordarone)Astemi>oleGAtor$astatin (Iipitor)Bepridil (ascor)Bromocriptine (,arlodel)Buspirone (Buspar)arbama>epine(-egretol)isapride (,ropulsid)italopram (ele!a)larithromycin (Bia!in)yclophosphamideyclosporine (6eoral) 3apsone3ela$irdine (@escriptor)3e!amethasone3ia>epam (alium)3iltia>em (ardi>em) 3isopyramide (6orpace)3o!orubicin (Adriamycin)7fa$iren> (usti$a)7rgotamine (7rgomar)7rythromycin (7#Mycin)7thinyl 7stradiol7toposide (epesid) Felodipine (,lendil)Fentanyl (ublima>e)Finasteride (,roscar)Flutamide (7ule!in)2fosfamide (2fe!)2ndina$ir (ri!i$an)2sradipine (3ynairc)

2tracona>ole (porano!)etocona>ole (6i>oral)IidocaineIoratadine (laritin)Iosartan (o>aar)Io$astatin (Me$acor)MethadoneMethylprednisoloneMibefradil (,osicor)Micona>ole (Monistat)Mida>olam (ersed)

6efa>odone (er>one)6icardipine (ardene)

larithromycin (Bia!in)yclosporine (6eoral)3ana>ol (3anocrine)3ela$irdine

(@escriptor)3iltia>em (ardi>em)7rythromycin7thinyl 7stradiolFlucona>ole (3iflucan)(weak)Fluo!etine (,ro>ac)G(weak)Flu$o!amine (Iu$o!)5rapefruit *uice2ndina$ir (ri!i$an)2sonia>id (268)2tracona>ole(porano!)etocona>ole (6i>oral)Metronida>ole (Flagyl)MethylprednisoloneMibefradil (,osicor)Micona>ole (Monistat)6efa>odone (er>one)6elfina$ir (iracept)6orethindrone6orflo!acin (6orflo!)!icona>ole (!istat),rednisone?uinidine (?uinide!)?uinine@itona$ir (6or$ir)a'uina$ir (2n$irase)-roleandomycin (-A)erapamil (alan) Hafirlukast (Accolate)

Hileuton

Aminoglutethimide(ytandren)Barbituratesarbama>epine

(-egretol)3e!amethasone7fa$iren>(usti$a)5lutethimide5riseoful$in(Ful$icin)6e$irapine(iramune),henytoin(3ilantin),rimidone(Mysoline)@ifabutin(Mycobutin)@ifampin(@imactane)-roglita>one(@e>ulin)

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Iso/%me

A*(!ont5d

Su$strates

6ifedipine (Adalat) 6imodipine (6imotop)6isoldipine (ular)

6itrendipine,aclita!el (-a!ol) ,imo>ide (rap),rednisolone?uetiapine (ero'uel)?uinidine (?uinide!)?uinine@ifabutin (Mycobutin)@itona$ir (6or$ir)a'uina$ir (2n$irase)

ertraline (Holoft)ibutramine (Meridia)ildenafil (iagra)im$astatin (Hocor)-acrolimus (,rograf) -amo!ifen (6ol$ade!)-erfenadineG-estosterone-heophylline (minorpathway)-ria>olam (8alcion)erapamil (alan) inblastine (elban) incristine (nco$in) @#0arfarin (oumadin)Holpidem (Ambien)

6 N drugs with acti$e metabolitesNubstrate for ,#glycoprotein

7aemod%nami! effe!ts

ariations in hepatic blood flow influence the rate ofinacti$ation of drugs that are sub*ect to e!tensi$epresystemic hepatic metabolism (e.g. lignocaine orpropranolol). A reduced cardiac output reduces hepatic bloodflow+ so negati$e inotropes (e.g. propranolol) reduce the rateof metabolism of lignocaine by this mechanism.

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IV) E8!retion

-he main mechanisms by which one drug can affect the rate ofrenal e!cretion of another are& by inhibiting tubular secretion4 by

altering urine flow andor urine p84 by altering protein binding+ andhence filtration.

1 Inhi$ition of tu$u"ar se!retion' ,robenecid inhibits penicillin secretion and thus prolongs its

action. 2t also inhibits the e!cretion of other drugs+ includinga>idothymidine (AH-)

E8am9"es of drugs that Inhi$it rena" tu$u"ar se!retion

Drugs causing inhibition Drugs whose t 1/! may be affected

,robenecidulphinpyra>one,henylbuta>oneulphonamidesAspirin-hia>ide diuretics2ndomethacin

,enicillinA>idothymidine2ndomethacin

erapamilAmiodarone?uinidine

3igo!in

3iuretics Iithium

2ndomethacin FrusemideAspirin6A23s

Methotre!ate

2 A"teration of urine f"o& and 97& Ioop and thia>ide diuretics indirectly increase pro!imal

tubular reabsorption of IiO(which is handled in a similar wayas 6aO) and this can cause IiOto!icity in patients treated withlithium carbonate for mood disorders.

-he effect of urinary p8 on the e!cretion of weak acids andbases is put to use in the treatment of poisoning+ but is not acause of accidental interactions.

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Im9ortant Drug Intera!tions 8, N 8ighly predictable. 2nteraction occurs in almost all patients recei$ing the

interacting combination.

, N ,redictable. 2nteraction occurs in most patients recei$ing the combination.

6, N 6ot predictable. 2nteraction occurs only in some patients recei$ing thecombination.

67 N 6ot established. 2nsufficient data a$ailable to base estimate ofpredictability.

Drug or DrugGrou9

)ro9erties )romotingDrug Intera!tion

C"ini!a""% Do!umented Intera!tions

A"!oho" Ghronic alcoholism

results in en>ymeinduction.

GAcute alcoholicinto!ication tends toinhibit drug metabolism(whether person isalcoholic or not).

Ge$ere alcohol#inducedhepatic dysfunction mayinhibit ability tometaboli>e drugs.

G3isulfiram#like reaction inthe presence of certaindrugs.

GAdditi$e central ner$oussystem depression withother central ner$oussystem depressants.

Acetaminophen"P67Q 2ncreased formationof hepatoto!ic acetaminophen metabolites (in

chronic alcoholics).

Acitretin"PpQ increased con$ersion ofacitretin to etretinate (teratogenic).

Anticoagulants! oral"P67Q 2ncreasedhypoprothrombinemic effect with acutealcohol into!ication.

#$% depressants"P8,Q Additi$e orsynergistic central ner$ous systemdepression.

Insulin"P67Q Acute alcohol intake mayincrease hypoglycemic effect of insulin(especially in fasting patients).

3rugs that may produce a disulfiram#likereactionephalosporins"P6,Q 3isulfiram#likereactions noted with cefamandole+cefopera>one+ cefotetan+ and mo!alactam.

#hloral hydrate"P6,Q Mechanism notestablished.

Disulfiram"P8,Q 2nhibits aldehydedehydrogenase.

Metronidazole"P6,Q Mechanism notestablished.

%ulfonylureas"P67Q hlorpropamide is mostlikely to produce a disulfiram#like reaction4acute alcohol intake may increase

hypoglycemic effect (especially in fastingpatients).

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Drug or DrugGrou9

)ro9erties )romotingDrug Intera!tion

C"ini!a""% Do!umented Intera!tions

A""o9urino" 2nhibits hepatic drug#metaboli>ing en>ymes.

Anticoagulants! oral"P6,Q 2ncreasedhypoprothrombinemic effect.

Azathioprine"P,Q 3ecreased a>athioprinedeto!ification resulting in increaseda>athioprine to!icity.

Mercaptopurine"P,Q 3ecreasedmercaptopurine metabolism resulting inincreased mercaptopurine to!icity.

Anta!ids GAntacids may adsorbdrugs in gastrointestinaltract+ thus reducingabsorption.

GAntacids tend to speedgastric emptying+ thusdeli$ering drugs toabsorbing sites in theintestine more 'uickly.

Gome antacids (eg+magnesium hydro!idewith aluminum hydro!ide)alkalini>e the urinesomewhat+ thus alteringe!cretion of drugssensiti$e to urinary p8.

Digo&in"P6,Q 3ecreased gastrointestinalabsorption of digo!in.

Iron"P,Q 3ecreased gastrointestinal

absorption of iron with calcium#containingantacids.

Itraconazole"P,Q @educed gastrointestinalabsorption of itracona>ole due to increasedp8 (itracona>ole re'uires acid forabsorption).

'etoconazole"P,Q as itracona>ole.

(uinolones"P8,Q 3ecreased gastrointestinalabsorption of ciproflo!acin+ norflo!acin+eno!acin (and probably other 'uinolones).

%alicylates"P,Q 2ncreased renal clearance ofsalicylates due to increased urine p84 occursonly with large doses of salicylates.

etracyclines"P8,Q 3ecreasedgastrointestinal absorption of tetracyclines.

Anti!oagu"ants4ora"

G Metabolism inducible.

G usceptible to inhibition

of metabolism byD,"R.

G8ighly bound to plasmaproteins.

GAnticoagulation responsealtered by drugs thataffect clotting factorsynthesis or catabolism.

1 3rugs that may increase anticoagulanteffect&Amiodarone"P,Q 2nhibits anticoagulant

metabolism.Anabolic steroids"P,Q Alter clotting factordispositionJ

#hloramphenicol"P67Q 3ecreaseddicumarol metabolism (possibly alsowarfarin).

#imetidine"P8,Q 3ecreased anticoagulantmetabolism.

#iproflo&acin"P67Q 3ecreasedanticoagulant metabolismJ

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Anti!oagu"ants4ora" (!ont5d

#lofibrate"P,Q Mechanism not established.

Danazol" P67Q 2mpaired synthesis of clottingfactorsJ

De&trothyro&ine"P,Q 7nhances clottingfactor catabolismJ

Disulfiram"P,Q 3ecreased anticoagulantmetabolism.

Erythromycin"P67Q ,robably inhibitsanticoagulant metabolism.

*luconazole"P67Q 3ecreased warfarinmetabolism.

+emfibrozil"P67Q Mechanism notestablished.

,o-astatin"P67Q ,robably decreasedanticoagulant metabolism.

Metronidazole"P,Q 3ecreased anticoagulantmetabolism.

Miconazole"P67Q 3ecreased anticoagulantmetabolism.

$onsteroidal anti.inflammatory drugs"P,Q2nhibition of platelet function+ gastricerosions4 some agents increasehypoprothrombinemic response (unlikely withdiclofenac+ ibuprofen+ or napro!en).

henylbutazone" P8,Q 2nhibits anticoagulantmetabolism.

ropafenone"P67Q ,robably decreasedanticoagulant metabolism.

(uinidine"P6,Q Additi$ehypoprothrombinemia.

%alicylates"P8,Q ,latelet inhibition withaspirin but not with other salicylates4 P,Q largedoses ha$e hypoprothrombinemic effect.

%ulfinpyrazone"P67Q Mechanism notestablished.

%ulfonamides"P67Q 2nhibit anticoagulantmetabolism4 displace protein binding.

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Anti!oagu"ants4ora" (!ont5d

hyroid hormones"P,Q 7nhance clottingfactor catabolism.

rimethoprim.sulfametho&azole"P,Q2nhibits anticoagulant metabolism4 displacesfrom protein binding.

#ee also Alcohol; Allopurinol.

2 3rugs that may decrease anticoagulanteffect&

Aminoglutethimide"P,Q 7n>yme induction.

0arbiturates"P,Q 7n>yme induction.

#arbamazepine"P,Q 7n>yme induction.

#holestyramine"P,Q @educes absorption ofanticoagulant.

+lutethimide"P,Q 7n>yme induction.

$afcillin"P67Q Mechanism not established.

henytoin"P67Q 7n>yme induction4anticoagulant effect may increase transientlyat start of phenytoin therapy due to protein#

binding displacement.

rimidone"P,Q 7n>yme induction.

ifabutin"P,Q 7n>yme induction.

ifampin"P,Q 7n>yme induction.

7ffects of anticoagulants on other drugs&

2ypoglycemics! oral"P,Q 3icumarol inhibitshepatic metabolism of tolbutamide andchlorpropamide.

henytoin"P,Q 3icumarol inhibitsmetabolism of phenytoin.

Antide9ressants4tri!%!"i! andhetero!%!"i!

G2nhibition of amineuptake into postganglionicadrenergic neuron.

GAntimuscarinic effectsmay be additi$e with otherantimuscarinic drugs.

GMetabolism inducible.

0arbiturates" P,Q 2ncreased antidepressantmetabolism.

#arbamazepine"P67Q 7nhanced metabolismof antidepressants.

#imetidine"P,Q 3ecreased antidepressant

metabolism.#lonidine"P,Q 3ecreased clonidine

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Antide9ressants4tri!%!"i! andhetero!%!"i!

(!ont5d

antihypertensi$e effect.+uanadrel"P,Q 3ecreased uptake ofguanadrel into sites of action.

+uanethidine"P,Q 3ecreased uptake ofguanethidine into sites of action.

Monoamine o&idase inhibitors"P6,Q omecases of e!citation+ hyperpyre!ia+ mania+ andcon$ulsions+ especially with serotonergicantidepressants such as clomipramine andimipramine+ but many patients ha$e recei$edcombination without ill effects.

(uinidine" P67Q 3ecreased antidepressantmetabolism.

ifampin"P,Q 2ncreased antidepressantmetabolism.

%electi-e serotonin reupta3e inhibitors4%%Is)"P,QGFluo!etine S paro!etine inhibit D,"3; Sdecrease metabolism of antidepressantsmetaboli>ed by this en>yme (eg+desipramine).

Gitalopram+ sertraline+ and flu$o!amine areonly weak inhibitors of D,"3;+ but

flu$o!amine inhibits D,1A" and D,%Aand thus can inhibit the metabolism ofantidepressants metaboli>ed by theseen>ymes (e.g. imipramine4 nefa>odone).

%ympathomimetics"P,Q 2ncreased pressorresponse to norepinephrine+ epinephrine+ andphenylephrine.

#ar$iturates G2nduction of hepaticmicrosomal drug#metaboli>ing en>ymes.

GAdditi$e 6 depressionwith other central ner$oussystem depressants.

0eta.adrenoceptor bloc3ers"P,Q 2ncreased#blocker metabolism.

#alcium channel bloc3ers"P,Q 2ncreasedcalcium channel blocker metabolism.

#$% depressants"P8,Q Additi$e centralner$ous system depression.

#orticosteroids"P,Q 2ncreased corticosteroidmetabolism.

#yclosporine" P67Q 2ncreased cyclosporinemetabolism.

Dela-irdine"P,Q 2ncreased dela$irdinemetabolism.

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#ar$iturates(!ont5d

Do&ycycline"P,Q 2ncreased do!ycyclinemetabolism.

Estrogens"P,Q 2ncreased estrogenmetabolism.

Itraconazole"P,Q 2ncreased itracona>olemetabolism.

'etoconazole"P,Q 2ncreased ketocona>olemetabolism.

henothiazines"P,Q 2ncreasedphenothia>ine metabolism.

(uinidine"P,Q 2ncreased 'uinidinemetabolism.

acrolimus"P67Q 2ncreased tacrolimusmetabolism.

heophylline"P67Q 2ncreased theophyllinemetabolism4 reduced theophylline effect.

Valproic acid"P,Q 3ecreased phenobarbitalmetabolism.

#ee also Anticoagulants, oral;Antidepressants, tricyclic.

#eta-adreno!e9tor#"o!+ers

GBeta#blockade(especially withnonselecti$e agents suchas propranolol) altersresponse tosympathomimetics with #agonist acti$ity (eg+pinephrine).

GBeta#blockers thatundergo e!tensi$e first#pass metabolism may beaffected by drugs capableof altering this process.

GBeta#blockers mayreduce hepatic blood flow.

1 3rugs that may increase #blocker effect&

#imetidine"P,Q 3ecreased metabolism of #blockers that are cleared primarily by theli$er+ eg+ propranolol. Iess effect (if any) onthose cleared by the kidneys+ eg+ atenolol+nadolol.

*urosemide"P,Q 3ecreased metabolism ofpropranolol.

7%dra"a/ine'P,Q 3ecreased metabolism ofpropranolol.

2 3rugs that may decrease #blocker effect&

Enzyme inducers" P,Q Barbiturates+phenytoin+ and rifampin may enhance #blockers metabolism4 other en>yme inducersmay produce similar effects.

Nonsteroida" anti-inf"ammator% drugs'P,Q2ndomethacin reduces antihypertensi$e

response4 other prostaglandin inhibitorsprobably also interact.

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#eta-adreno!e9tor#"o!+ers(!ont5d

7ffects of #blockers on other drugs&

#lonidine"P67Q 8ypertensi$e reaction ifclonidine is withdrawn while patient is taking

propranolol.Insulin"P,Q 2nhibition of glucose reco$eryfrom hypoglycemia4 inhibition of symptoms ofhypoglycemia (e!cept sweating)4 increasedblood pressure during hypoglycemia.

,idocaine"P67Q 3ecreased clearance ofintra$enous lidocaine4 increased plasmalldocaine le$els.

razosin"P,Q 2ncreased hypotensi$e

response to first dose of pra>osin.

%ympathomimetics"P,Q 2ncreased pressorresponse to epinephrine (and possibly othersympathomimetics)4 this is more likely tooccur with nonspecific #blockers.

#i"e a!id-$inding resinse:g:!ho"est%ramine

G@esins may bind withorally administered drugsin gastrointestinal tract.

G@esins may bind ingastrointestinal tract withdrugs that undergoenterohepatic circulation+e$en if the latter are gi$enparenterally.

Acetaminophen"P67Q 3ecreasedgastrointestinal absorption of acetaminophen.

Digitalis glycosides"P67Q 3ecreasedgastrointestinal absorption of digito!in(possibly also digo!in).

*urosemide"P,Q 3ecreased gastrointestinalabsorption of furosemide.

Methotre&ate"P67Q @educed gastrointestinalabsorption of methotre!ate.

hiazide diuretics"P,Q @educedgastrointestinal absorption of thia>ides.

hyroid hormones"P,Q @educed thyroidabsorption.

#ee also Anticoagulants, oral.

Ca"!ium !hanne"$"o!+ers (CC#

Gerapamil+ diltia>em+ andperhaps nicardipine (butnot nifedipine) inhibithepatic drug#metaboli>ingen>ymes.

GMetabolism of diltia>em+nifedipine+ $erapamil+ and

perhaps other calciumchannel blockers sub*ect

#arbamazepine"P,Q carbama>epinemetabolism with diltia>em S $erapamil4possible in B metabolism.

#imetidine"P6,Q 3ecreased metabolism ofBs.

#yclosporine"P,Q 3ecreased cyclosporine

metabolism with diltia>em+ nicardipine+$erapamil.

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Ca"!ium !hanne"$"o!+ers (!ont5d

to induction and inhibition.Itraconazole"P,Q 3ecreased metabolism ofBs.

'etoconazole"P,Q 3ecreased metabolism ofBs.

henytoin"P67Q 2ncreased metabolism ofBs.

ifampin"P,Q 2ncreased metabolism ofBs.

#ee also Barbiturates, "heophylline.

Car$ama/e9ine G2nduction of hepaticmicrosomal drug#

metaboli>ing en>ymes.

Gusceptible to inhibitionof metabolism+ primarilyby D,%A.

#imetidine"P,Q 3ecreased carbama>epinemetabolism.

#larithromycin"P,Q 3ecreasedcarbama>epine metabolism.

#orticosteroids"P,Q 2ncreased corticosteroidmetabolism.

#yclosporine"P,Q 2ncreased cyclosporinemetabolism.

Danazol"P,Q 3ecreased carbama>epinemetabolism.

Diltiazem"P,Q 3ecreased carbama>epinemetabolism.

Do&ycycline"P,Q 2ncreased do!ycyclinemetabolism.

Erythromycin"P67Q 3ecreasedcarbama>epine metabolism.

Estrogens"P,Q 2ncreased estrogenmetabolism.

2aloperidol"P,Q 2ncreased haloperidolmetabolism.

Isoniazid"P,Q 3ecreased carbama>epinemetabolism.

Itraconazole"P,Q 3ecreased metabolism ofcarbama>epine.

'etoconazole"P,Q 3ecreased metabolism of

carbama>epine.$efazodone"P67Q 3ecreased

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Car$ama/e9ine(!ont5d

carbama>epine metabolism.ropo&yphene"P8,Q 3ecreasedcarbama>epine metabolism.

%electi-e serotonin reupta3e inhibitors4%%Is)" P67Q Fluo!etine and flu$o!aminedecrease carbama>epine metabolism.

heophylline"P67Q 2ncreased theophyllinemetabolism.

Verapamil"P,Q 3ecreased carbama>epinemetabolism.

#ee also Anticoagulants, oral;Antidepressants, tricyclic; *alcium channelblocers.

Ch"oram9heni!o" G2nhibits hepatic drug#metaboli>ing en>ymes.

henytoin"P,Q 3ecreased phenytoinmetabolism.

%ulfonylurea hypoglycemics"P,Q3ecreased sulfonylurea metabolism.#ee also Anticoagulants, oral.

Cimetidine G2nhibits hepaticmicrosomal drug#metaboli>ing en>ymes.(@anitidine+ famotidine+

and ni>atidine do notappear to do so.)

GMay inhibit the renaltubular secretion of weakbases.

G,urportedly reduceshepatic blood flow+ thusreducing first#passmetabolism of highlye!tracted drugs.(8owe$er+ the ability ofcimetidine to affecthepatic blood flow hasbeen disputed.)

0enzodiazepines"P,Q 3ecreasedmetabolism of alpra>olam+ chlordia>epo!ide+dia>epam+ hala>epam+ pra>epam+ andclora>epate but not o!a>epam+ lora>epam+ or

tema>epam.

#armustine"P67Q 2ncreased bone marrowsuppression.

'etoconazole"P67Q 3ecreasedgastrointestinal absorption of ketocona>oledue to increased p8 in gut4 other 8"blockersand proton pump inhibitors would bee!pected to ha$e the same effect.

Itraconazole"P67Q 3ecreasedgastrointestinal absorption of itracona>oledue to increased p8 in gut4 other 8"#receptorantagonists and proton pump inhibitors wouldbe e!pected to ha$e the same effect.

,idocaine"P,Q 3ecreased metabolism oflidocaine4 increased serum lidocaine.

henytoin"P67Q 3ecreased phenytoinmetabolism4 increased serum phenytoin.

rocainamide"P,Q 3ecreased renale!cretion of procainamide4 increased serumprocainamide le$els. imilar effect with

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Cimetidine(!ont5d

ranitidine but smaller.(uinidine"P,Q 3ecreased metabolism of'uinidine4 increased serum 'uinidine le$els.

heophylline"P,Q 3ecreased theophyllinemetabolism4 increased plasma theophylline.

#ee also Anticoagulants, oral;Antidepressants, tricyclic; Beta)adrenoceptorblocers; *alcium channel blocers,*arbama+epine.

C%!"os9orine

C%!"os9orine


Gusceptible to inhibitionof metabolism byD,%A.

(-acrolimus and sirolimusappear to ha$e similarinteractions.)

Amphotericin 0"P67Q ,ossible additi$enephroto!icity.

Androgens"P67Q 2ncreased serumyclosporine.

0arbiturates"P,Q 2ncreased yclosporinemetabolism.

#arbamazepine"P,Q 2ncreased yclosporinemetabolism.

#larithromycin"P,Q 3ecreased yclosporinemetabolism.

Diltiazem"P67Q 3ecreased yclosporinemetabolism.

Erythromycin" P67Q 3ecreased yclosporinemetabolism.

*luconazole"P67Q 3ecreased yclosporinemetabolism+ especially with large flucona>oledoses.

Itraconazole"P,Q 3ecreased cyclosporinemetabolism.

'etoconazole"P67Q 2ncreased serumcyclosporine with nephroto!icity due todecreased cyclosporine metabolism.

,o-astatin"P67Q Myopathy andrhabdomyolysis noted in patients taking bothdrugs.

$efazodone"P,Q 3ecreased cyclosporinemetabolism.

henytoin"P67Q 2ncreased cyclosporine

metabolism.ifampin"P,Q 2ncreased cyclosporine

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(!ont5d metabolism.itona-ir"P,Q cyclosporine metabolism.

Verapamil"P67Q cyclosporine metabolism.#ee also Barbiturates; *alcium channel

blocers.Digita"isg"%!osides

G3igo!in susceptible toinhibition ofgastrointestinalabsorption.

G3igitalis to!icity may beincreased by drug#induced electrolyteimbalance (eg+hypokalemia).

G3igito!in metabolisminducible.

G@enal e!cretion ofdigo!in susceptible toinhibition.

1 3rugs that may increase digitalis effect&Amiodarone"P,Q @educed renal digo!ine!cretion leads to increased plasma digo!inconcentrations.

#larithromycin"P67Q @educed renale!cretion of digo!in.

Diltiazem"P,Q 2ncreased plasma digo!in dueto reduced renal clearance.

Erythromycin"P67Q @educed renal e!cretionof digo!in.

Itraconazole"P67Q @educed renal e!cretionof digo!in.

otassium.depleting drugs"P,Q 2ncreasedlikelihood of digitalis to!icity.

ropafenone"P,Q 2ncreased plasma digo!inle$els.

(uinidine"P8,Q @educed digo!in e!cretion4displacement of digo!in from tissue bindingsites4 digito!in may also be affected.

%pironolactone" P67Q 3ecreased renaldigo!in e!cretion and interference with someserum digo!in assays.

Verapamil"P,Q increased plasma digo!inle$els.

2 3rugs that may decrease digitalis effect&'aolin.pectin"P,Q 3ecreasedgastrointestinal digo!in absorption.

enicillamine"P67Q 3ecreased plasmadigo!in.

ifampin"P67Q 2ncreased metabolism ofdigito!in and possibly digo!in.

%ulfasalazine"P67Q 3ecreasedgastrointestinal digo!in absorption.

#ee also Antacids; Bile acid)binding resins.Disu"firam G2nhibits hepatic 0enzodiazepines"P,Q 3ecreased

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microsomal drug#metaboli>ing en>ymes.

G2nhibits aldehydedehydrogenase.

metabolism of chlordia>epo!ide anddia>epam but not lora>epam and o!a>epam.

Metronidazole"P67Q onfusion andpsychoses reported in patients recei$ing thiscombination4 mechanisms unknown.

henyloin"P,Q 3ecreased phenytoinmetabolism.

#ee also Alcohol; Anticoagulants, oral.

Estrogens GMetabolism inducible.

G7nterohepatic circulationof estrogen may beinterrupted by alteration in

bowel flora (eg+ due toantibiotics).

Ampicillin"P6,Q 2nterruption of enterohepaticcirculation of estrogen4 possible reduction inoral contracepti$e efficacy. ther oralantibiotics may ha$e a similar effect.

#orticosteroids"P,Q 3ecreased metabolismof corticosteroids leading to increasedcorticosteroid effect.

Diazepam"P67Q 3ecreased dia>epammetabolism.

+riseoful-in"P67Q ,ossible 2nhibition of oralcontracepti$e efficacy4 mechanism unknown.

henytoin"P6,Q 2ncreased estrogenmetabolism4 possible reduction in oral

contracepti$e efficacy.

rimidone" P6,Q 2ncreased estrogenmetabolism4 possible reduction in oralcontracepti$e efficacy.

ifabutin"P6,Q 2ncreased estrogenmetabolism4 possible reduction in oralcontracepti$e efficacy.

ifampin"P6,Q 2ncreased estrogenmetabolism4 possible reduction in oralcontracepti$e efficacy.

roglitazone"P6,Q 2ncreased estrogenmetabolism4 possible reduction in oralcontracepti$e efficacy.

#ee also Barbiturates; *arbama+epine.

7;G-CoAredu!taseinhi$itors

7;G-CoA

GIo$astatin+ sim$astatin+and+ to a lesser e!tent+ator$astatin aresusceptible to D,%A

inhibitors S inducers.G2ncreased risk of additi$e

#larithromycin"P,Q 3ecreased statinmetabolism.

#lofibrate"P6,Q 2ncreased risk of myopathy.

Diltiazem"P67Q 3ecreased statin

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redu!taseinhi$itors(!ont5d

myopathy risk with otherdrugs that can causemyopathy.

metabolism.

#yclosporine"P,Q 3ecreased statinmetabolism.

Erythromycin"P,Q 3ecreased statinmetabolism

Itraconazole"P,Q 3ecreased statinmetabolism.

'etoconazole"P,Q 3ecreased statinmetabolism.

$efazodone"P67Q 3ecreased statinmetabolism.

Iron Binds with drugs ingastrointestinal tract+reducing absorption.

Methyldopa"P67Q 3ecreased methyldopaabsorption.

(uinolones"P,Q 3ecreased absorption ofciproflo!acin.

etracyclines"P,Q 3ecreased absorption oftetracyclines4 decreased efficacy of iron.

hyroid hormones"P,Q 3ecreased thyro!ineabsorption.#ee also Antacids.


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inhi$itors(;AOIs (!ont5d

stored norepinephrine (amphetamines+ephedrine+ phenylpropanolamine+pseudoephedrine).

ramadol"P67Q ,ossible serotoninsyndrome4 a$oid concurrent use.

Venlafa&ine"P67Q ,ossible serotoninsyndrome4 a$oid concurrent use.ee also Antidepressants+ tricyclic andheterocyclic4 Ie$odopa.

Nonsteroida"anti-inf"ammator%drugs

G,rostaglandin inhibitionmay result in reducedrenal sodium e!cretion+impaired resistance tohypertensi$e stimuli+ andreduced renal lithium

e!cretion.

GMost 6A23s inhibitplatelet function4 mayincrease likelihood ofbleeding due to otherdrugs that impairhemostasis.

GMost 6A23s are highlybound to plasma proteins.

G,henylbuta>one mayinhibit hepatic microsomaldrug metabolism (alsoseems to act as en>ymeinducer in some cases).

G,henylbuta>one mayalter renal e!cretion ofsome drugs.

A#E inhibitors"P,Q 3ecreasedantihypertensi$e response.

*urosemide"P,Q 3ecreased diuretic+natriuretic+ and antihypertensi$e response tofurosemide.

2ydralazine"P67Q 3ecreasedantihypertensi$e response to hydrala>ine.

Methotre!ate& P67Q ,ossible increase inmethotre!ate to!icity (especially withanticancer doses of methotre!ate).

,henytoin& P,Q 3ecreased hepatic phenytoinmetabolism.

-riamterene& P67Q 3ecreased renal function

noted with triamterene plus indomethacin inboth healthy sub*ects and patients.

#ee also Anticoagulants, oral; Beta)adrenoceptor blocers; ithium.

)hen%toin

)hen%toin(!ont5d

G2nduces hepaticmicrosomal drugmetabolism.

Gusceptible to inhibitionof metabolism byD,"R and+ to a lessere!tent+ D,"1R.

13rugs whose metabolism is stimulated byphenytoin&

#orticosteroids" P,Q 3ecreased serumcorticosteroid le$els.

Do&ycycline"P,Q 3ecreased serumdo!ycycline le$els.

Methadone"P,Q 3ecreased serummethadone le$els4 withdrawal symptoms.

Me&iletine"P67Q 3ecreased serumme!iletine le$els.

(uinidine"P,Q 3ecreased serum 'uinidinele$els.

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heophylline"P67Q 3ecreased serumtheophylline le$els.

Verapamil"P67Q 3ecreased serum $erapamille$els.#ee also *yclosporine, -strogens.

2 3rugs that inhibit phenytoin metabolism&Amiodarone"P,Q 2ncreased serumphenytoin4 possible reduction in serumamiodarone.

#hloramphenicol"P,Q 2ncreased serumphenytoin.

*elbamate"P,Q 2ncreased serum phenytoin.

*luconazole"P,Q 2ncreased serumphenytoin.

*luo&etine"P,Q 2ncreased serum phenytoin.

Isoniazid"P6,Q 2ncreased serum phenytoin4problem primarily with slow acetylators ofisonia>id.

Miconazole"P,Q 2ncreased serum phenytoin.

iclopidine"P6,Q 2ncreased serumphenytoin.#ee also *imetidine; %isulfiram;henylbuta+one.

3rugs that enhance phenytoin metabolism&ifampin"P,Q 3ecreased serum phenytoinle$els.

)imo/ide Gusceptible to D,%Ainhibitors4 may e!hibitadditi$e effects with otheragents that prolong ?-cinter$al.

#larithromycin"P67Q 3ecreased pimo>idemetabolism.

Erythromycin"P67Q 3ecreased pimo>idemetabolism

Itraconazole"P67Q 3ecreased pimo>idemetabolism.

'etoconazole"P67Q 3ecreased pimo>idemetabolism.

$efazodone"P67Q 3ecreased pimo>idemetabolism.

)otassium-s9aring diureti!s GAdditi$e effects withother agents increasingserum potassium

A#E inhibitors"P67Q Additi$e hyperkalemiceffect.

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(ami"oride4s9irono"a!tone4triamterene

concentration.

GMay alter renal e!cretionof substances other thanpotassium (eg+ digo!in+hydrogen ions).

otassium supplements"P,Q Additi$ehyperkalemic effect4 especially a problem inpresence of renal impairment.

#ee also %igitalis glycosides; Nonsteroidalanti)inflammatory drugs.

)ro$ene!id G2nterference with renale!cretion of drugs thatundergo acti$e tubularsecretion+ especially weakacids.

G2nhibition of glucuronidecon*ugation of otherdrugs.

#lofibrate"P,Q @educed glucuronidecon*ugation of clofibric acid.

Methotre&ate"P,Q 3ecreased renalmethotre!ate e!cretion4 possiblemethotre!ate to!icity.

enicillin"P,Q 3ecreased renal penicilline!cretion.

%alicylates"P,Q 3ecreased uricosuric effect

of probenecid (interaction unlikely with lessthan 1.: g of salicylate daily).=uinidine GMetabolism inducible.

2nhibits D,"3;.

G@enal e!cretionsusceptible to changes inurine p8.

Acetazolamide"P,Q 3ecreased renal'uinidine e!cretion due to increased urinaryp84 ele$ated serum 'uinidine.

Amiodarone" P67Q 2ncreased serum'uinidine le$els4 mechanism not established.

'aolin.pectin"P67Q 3ecreasedgastrointestinal absorption of 'uinidine.

ifampin"P,Q 2ncreased hepatic 'uinidinemetabolism.

#ee also Anticoagulants, oral;Antidepressants, tricyclic; Barbiturates;*imetidine; %igitalis glycosides; henytoin.

=uino"oneanti$ioti!s

Gusceptible to inhibitionof gastrointestinalabsorption.

Gome 'uinolones inhibithepatic microsomal drug#metaboli>ing en>ymes.

#affeine"P,Q iproflo!acin+ eno!acin+ and+ toa lesser e!tent+ norflo!acin+ inhibit caffeinemetabolism.

%ucralfate"P8,Q @educed gastrointestinalabsorption of ciproflo!acin+ norflo!acin+ andprobably other 'uinolones.

heophylline" P,Q iproflo!acin+ eno!acin+and+ to a lesser e!tent+ norflo!acin inhibittheophylline metabolism4 le$oflo!acin+lomeflo!acin+ oflo!acin+ and sparflo!acinappear to ha$e little effect.

#ee also Antacids; Anticoagulants, oral.

Rifam9in 2nduction of hepatic

microsomal drug#metaboli>ing en>ymes.

#orticosteroids"P,Q 2ncreased corticosteroid

hepatic metabolism4 reduced corticosteroideffect.

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Itraconazole"P,Q 2ncreased itracona>olemetabolism4 reduced itracona>ole effect.

'etoconazole"P67Q 2ncreased ketocona>olemetabolism4 reduced ketocona>ole effect.

Me&iletine"P67Q increased me!iletinemetabolism4 reduced me!iletine effect.

%ultonylurea hypoglycemics"P,Q 2ncreasedhepatic metabolism of tolbutamide andprobably other sulfonylureas metaboli>ed bythe li$er (including chlorpropamide).

heophylline"P,Q 2ncreased theophyllinemetabolism4 reduced theophylline effect.

#ee also Anticoagulants, oral; Beta)adrenoceptor blocers; *alcium channelblocers; *yclosporine; %igitalis glycosides;-strogens.

Sa"i!%"ates G2nterference with renale!cretion of drugs thatundergo acti$e tubularsecretion.

Galicylate renal e!cretiondependent on urinary p8

when large doses ofsalicylate used.

GAspirin (but not othersalicylates) interferes withplatelet function.

GIarge doses ofsalicylates ha$e intrinsichypoglycemic acti$ity.

Galicylates may displacedrugs from plasma proteinbinding sites.

#arbonic anhydrase inhibitors"P67Q2ncreased aceta>olamide serumconcentrations4 increased salicylate to!icitydue to decreased blood p8.

#orticosteroids" P,Q 2ncreased salicylateelimination4 possible additi$e to!ic effect on

gastric mucosa.

2eparin"P67Q 2ncreased bleeding tendencywith aspirin+ but probably not with othersalicylates.

Methotre&ate"P,Q 3ecreased renalmethotre!ate clearance4 increasedmethotre!ate to!icity (primarily at anticancerdoses).

%ulfinpyrazone"P8,Q 3ecreased uricosuriceffect of sulfinpyra>one (interaction unlikelywith less than 1.: g of salicylate daily).

#ee also Antacids; Anticoagulants, oral;robenecid.

Theo9h%""ine

Theo9h%""ine

(!ont5d

Gusceptible to inhibitionof hepatic metabolism byD,1A".


0enzodiazepines"P67Q 2nhibition ofben>odia>epine sedation.

Dlltlazem"P,Q 3ecreased theophyllinemetabolism by D,1A%.

#larithromycin"P67Q 3ecreasedtheophylline metabolism.

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Erythromycin"P,Q 3ecreased theophyllinemetabolism.

*lu-o&amine"P,Q 3ecreased theophyllinemetabolism.

%mo3ing"P8,Q 2ncreased theophyllinemetabolism.

acrine"P,Q 3ecreased theophyllinemetabolism.

iclopidine"P67Q 3ecreased theophyllinemetabolism.

Verapamil"P,Q 3ecreased theophyllinemetabolism.

6ileuton"P,Q 3ecreased theophyllinemetabolism.

#ee also Barbiturates; *arbama+epine;*imetidine; ithium; henytoin; /uinolones;(ifampin.

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SU;;AR>

,earning 7b8ecti-es

3istinguish between pharmacokinetic and pharmacodynamicdrug interactions 2dentify common and clinically significant drug interactions Formulate appropriate alternati$e treatment regimensminimi>ing the potential for drug interactions

7utline

5eneral Background 3efine $arious pharmacokinetic drug interactions 3efine $arious pharmacodynamic drug interactions 7!plore some common and clinically significant druginteractions 3iscuss patient cases

0ac3ground

3rug 2nteractions can be a significant cause of medicationerrors+ ad$erse medication reactions+ and patient morbidity andmortality Iegal ramifications possible 8077@ not all drug interactions are TbadUV ynergyV Altered metabolism or elimination -wo main categories of drug interactionsV ,harmacokineticV ,harmacodynamic ther types of drug interactions can occur such as physicalor chemical incompatibilities 3rug interactions can occur withV 7ther drugsV 8erbs 3ietary supplementsV Foods or be$erages (especially grapefruit *uice or alcohol)V moking

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ypes of Drug Interactions )harma!o+ineti! Absorption& common with ditri$alent metals and enteral feeds 3istribution

Metabolism& most common type of pharmacokinetic drug#druginteraction4 ,:C isoen>ymes V substrate $s inducer $sinhibitor

7!cretion

)harma!od%nami!V ubstance A enhances or duplicates the intended effect orad$erse effect of ubstance B i.e. agonistV ubstance A acts antagonistically with ubstance B

)harma!o+ineti! Drug Intera!tions

I) AbsorptionV ,roduct A binds with product B in the 52 tract 7!ample cholestyramine

V Most common e!ample is chelation of agents with ditri$alentmetals 7!amples Ca4 A"4 ?n4 ;g4 mu"tiitamins4 anta!ids4 et!:!he"ate 9rodu!ts su!h as anti$ioti!s in the @uino"one ortetra!%!"ine fami"%

V @esult N decreased effecti$eness of both agentsV ManagementN separate doses (1 hour before or " hoursafter)

II) DistributionV Ieast common type of pharmacokinetic interactionV 3rug#3rug interactions of this type are 'uite rare

V 3rug#3isease state interactions more commonV 2f a drug is particularly hydro or lipophillic+ then patients withcertain disease states (8F+ @F+ obesity) may react differently

III) MetabolismV Most common type of pharmacokinetic drug interactionV 8epatic en>ymes V C%to!hrome ) *,3 s%stemmetaboli>esnumerous drugs Many different isoen>ymes

V %A+ "3;+ 1A"+ "R+ and "1R most commonV %A most clinically significant

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V Many drugs indu!e or inhi$it certain hepatic en>ymesV Many drugs are su$stratesof the , :C systemV 3rugs that indu!e this system de!reasethe concentrationsof other drugs metaboli>ed by , :C (results in decreased

therapeutic effects)V 3rugs that inhi$it ,:C en>ymes cause in!reasesin theconcentrations of other drugs metaboli>ed by ,:C (mayincrease risk of ad$erse effects)

V 6ote that other substances (foods like grapefruit+ herbs liket. WohnXs 0ort+ and smoking) can also affect , :C

V , :C %A isoen>yme most common ommon %A inducersV arbama>epineV

,henobarbitalV ,henytoinV @ifampin

ommon %A inhibitorsV AmiodaroneV annabinoidsV 7rythromycin and clarithromcyinV A>ole antifungalsV Flu$o!amine+ fluo!etine+ nefa>odone+ sertraline+ otherspossibleV ,rotease inhibitorsV 5rapefruit

IV) E&cretionV Iess common than metabolism or absorptionV ubstance A may alter the renal (or other types of)elimination of substance B

V 7!ample

,robenecid competiti$ely inhibits renal tubular e!cretion ofmany agents+ resulting in reduced clearance of penicillins+cephalosporins+ ben>odia>epines+ sulfonylureas+ others

)harma!od%nami! Drug Intera!tions

I) %ynergistic! additi-e! or agonist effectsV -wo (or more) products may ha$e similar mechanisms ofaction (MAs)+ desired treatment outcomes+ or ad$erse effect

profilesV 7!amples

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Io$astatin O clofibrate N decreased lipid and triglycerideprofiles and increased risk of myopathy or rhabdomyolysis Acetyl salicylic acid (AA) O ginkgo biloba N increased risk ofbleeding (both agents ha$e antiplatelet effects)

II) AntagonismV pposing MAs+ desired treatment outcomes+ or ad$erseeffect profiles

V ne foot on the brake+ one on the gasV 7!amples Bethanechol (cholinergic agent) and ipratropium(anticholinergic agent) 8eparin and protamine

Albuterol and atenololCommon4 C"ini!a""% Signifi!ant Drug Intera!tions

Antidepressants Anticon$ulsants isapride (re$erted to Tin$estigationalU drug) 3igo!in 7strogens and oral contracepti$es tatins

0arfarin 6on#prescription medications

Antidepressants Antidepressants are used by a huge portion of the population

3rug 2nteraction potential $aries greatly

Although many antidepressants affect , :C (inhibition)+different isoen>ymes are affected to a different degree

,redict A63 )REENTdrug interactions

Many , :C interactions possible

@elati$e ranking of newer antidepressants based on , :Cdrug interaction potential&

V Most likely to interact& Flu$o!amine+ fluo!etine+ paro!etine+ nefa>odone

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V erapamil S diltia>emV imetidine (not other 8"s)

II) henytoin ,henytoin may decrease the effecti$eness of&V s+ itracona>ole+ mebenda>ole+ mida>olam+ A+cyclosprine+ theophylline+ do!ycycline+ 'uinidine+ disopyramide+carbama>epine ,henytoinXs effecti$eness may be decreased by&

V @ifampin+ folic acid+ theophylline+ antacids+ sulcralfate+ andsome chemo

V ontinuous enteral feedings as feeds bind to phenytoin+

drastically decreasing absorption

Agents which may increase phenytoin concto!icity&V 268+ flucona>ole+ ticlopidine+ amiodarone+ cimetidine+disulfiram+ fluo!etine+ sulfonamides

,henytoin may increase the to!icity of these agents&V 0arfarin+ dopamine+ barbiturates+ alproic acid may either increase or decrease phenytoin

concentrations

III) Valproic acid 4VA)

Agents that may decrease A concentrations&V arbama>epine+ cholestyramine+ lamotrigine

A may decrease concentrationseffects of&V ,henytoin

Agents that may increase A concentrations&V imetidine+ erythromycin+ salicylates (AA)

A may increase concentrationseffects of&V -ricyclic antidepressants (-As)

Digo&in 3igo!in (dig)

V Many clinically significant drug interactionsV ariety of mechanisms

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(,rocoagulants)V 7strogens sV itamin (M2s)

(3ecreased absorption)V Aluminum hydro!ideV holestyramine et al

(7n>yme induction)V BarbituratesV arbama>epineV 5riseoful$inV

,henytoinV 6afcillinV @ifampin

Drugs that in!rease $"eeding tenden!%

(Inhi$it 9ro!oagu"ant fa!tors)V AntimetabolitesV ?uinidineV ?uinineV alicylates

(U"!erogeni! drugs)V orticosteroidsV 6A23 and E "s to a lesser e!tent

7nhanced anticoagulant effectsV ther anticoagulants+ antiplatelets+ thrombolyticsV Altered metabolism+ etc. Alcohol Antimicrobials including 'uinolones+ MH#-M,+erythromycin+ #a>ole antifungals+ metronida>ole ,henytoin 3isulfiram imetidine thers

Many herbal products and dietary supplements can also

interact with warfarin @emember the Tour GsU

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V Fe$erfewV 5inkgo bilobaV 5insengV 5arlic

V 5inger

Many others possible+ including t. WohnXs 0ort

$on.prescription drug interactions imetidine has many drug interactions

V 6ote other 8" antagonists are safer options

oughold medications V watch blood pressure

AA S other 6A23

Antacids# watch chelation drug interactions

8erbal products V so little is known about their safety whencombined with prescription drugs

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Age as a Consideration in Drug Thera9%

Many factors can alter a patientXs responses to drugs+ andsometimes you can do something about them to help normali>ethe drug response. ne that you canXt do anything about is theirage.

-his handout highlights some of the ma*or age#relatedfactors you should consider during your clinical e!periences. -heemphasis is on pharmacokinetics+ since changes in the way anindi$idual absorbs+ distributes+ metaboli>es+ and e!cretes drugsare among the key factors that affects drug responses.

-here are some data presented in this handout& some key

facts and concepts that you need to know. 8owe$er+ a ma*orpurpose of these notes is simply to get you thinking about the agesof your patients ahead of time.

-hatXs so that when you get more detailed information aboutspecific drugs you might ha$e a better idea of how to prescribethem and monitor their effects / hopefully to optimi>e therapy andminimi>e problems as best as possible. DouXll be better able toanticipate how things might change or need to be changed.

- *, -

"he 01ive (ights2 of %rug Administrationirtually e$ery pharmacology book includes a section on whatXs

called the TFi$e @ights of 3rug Administration.U Briefly+ they statethat before you gi$e any drug you should make sure that youha$e or know the right& patient drug dose route of administration time of administration2nterestingly+ and although this fundamental concept seems to be

the epitome of common sense+ superficially simple or ob$ious+and applicable to all health care pro$iders who administer drugs+they are almost ne$er mentioned to medical students. 2n thesections that follow+ weXll address some of these issues.


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of the ma*or determinants of pharmacokinetics reach adultle$els by one year of age.

Ta$"e 1: A99ro8imate Ages at hi!h Se"e!ted Determinants of)harma!o+ineti!s Rea!h FAdu"t


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2n addition+ immature glial de$elopment+ especially e$identamong premature infants+ permits greater permeability of theblood#brain barrier+ allowing both drugs and bilirubin rapid andmore complete access to the central ner$ous system+ leading to a

heightened risk of ad$erse effects.

-he $olume of distribution within neonatal bodycompartments differs greatly from the adult. -otal body watercontent amounts to


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Ta$"e 2: Summar%' Some )h%sio"ogi! Chara!teristi!s of Infants4 andTheir )harma!o+ineti! Conse@uen!es

Chara!teristi! Conse@uen!e

8igh total body water content 7!panded $olume of distribution+ diminished blood

le$els+ of water#soluble drugs

Iow body fat 2ncreased blood le$els of highly lipid#soluble drugs

2ncreased membranepermeability+ especially ofskin+ blood#brain barrier

7nhanced topical absorption of drugs+ to!ins4enhanced 6 effects of lipid#soluble drugs

@elati$ely lower gastric acid#secreting capacity

More complete andor faster absorption of drugs thatare completely or partially inacti$ated by gastric acid+or drugs that are mainly ioni>ed at low p8

2mmature body temperatureregulation

May dehydrate 'uickly+ thereby ele$ating concentrationof drug in blood+ other a'ueous fluid compartments

2mmature renal or hepaticfunction

3elayed e!cretion or metabolism of certain drugs(longer half#life)

####################A$sor9tion 5astric acidity does not begin to approach adult $alues untilabout two to three months of age. -his early relati$e lack of gastricacid contributes to e!aggerated absorption of some drugs so that+for e!ample+ oral ben>yl penicillin (which at older ages isinacti$ated by gastric acid) is well absorbed in infants.

5astric emptying rates reach adult le$els at about ; to =months.

Barriers such as the skin and the blood#brain barrier become

more effecti$e as the infant grows+ making the child somewhat less$ulnerable to to!ic effects of some drugs.

Distri$ution ,rotein binding of drugs generally reaches adult le$els byone year of age. Before then+ the relati$ely diminished le$els ofplasma proteins+ coupled with a lower binding capacity of thoseproteins for many drugs+ has clinical implications for drugs thatnormally tend to be normally e!tensi$ely bound.

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@ecall that drug molecules+ while they are bound to plasmaproteins+ are pharmacologically inacti$e (and are also unable to bee!creted or metaboli>ed). -hus+ for a gi$en total le$el (orconcentration) of drug in the blood+ a greater fraction will be

unbound+ and so there e!ists the potential for greater (if note!cessi$e or to!ic) effects.

hildren also ha$e a relati$ely higher total body watercontent until about two years of age. -hus+ to account for a greater$olume of distribution of water#soluble drugs+ children youngerthan that age may re'uire larger doses than older children.

5i$en the presence of both diminished plasma protein le$els

and protein binding capacity (which could warrant reduced dosesof highly bound drugs)+ and a higher body water content (whichcould necessitate reduced dosages)+ e!tra care in dosing andmonitoring are important.

;eta$o"ism Metabolic rates in infants and children up to about two tothree years of age are+ in general+ higher than adult $alues. -heydecline to adult rates by puberty. -herapeutic drug dosagesrelati$e to body weight may be greater for children than for adults.

An important e!ample is theophylline. 2ts dose should beindi$iduali>ed for each child based on body weight+ with furtherdosage ad*ustments to account for indi$idual metabolic $ariations.-his is done+ in part+ bynmonitoring the childXs plasmaconcentrations of the drug. As the child matures+ hepatic en>ymesmay change such that the clearance of theophylline will bereduced+ and further dosage ad*ustments probably will be needed.

E8!retion Mature renal and hepatic function is not reached until aboutsi! to 1" months of age.

Kntil then+ repeat doses of drugs should be gi$en cautiously.

3osages of drugs e!creted largely unchanged(unmetaboli>ed) by the kidneys+ such as digo!in (for congesti$eheart failure) and gentamicin (an aminoglycoside antibiotic).

Dosage AdHustments

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-he package inserts and other Tprescriber informationUsources for many drugs / particularly drugs that are usede!tensi$ely in pediatrics / will list pediatric dosage guidelines. Doushould a"&a%s check written guidelines before deciding on a dose4

indeed+ you should always check an authoritati$e source to seewhether a drug should be prescribed for a child at all+ since somemedications are not appro$ed for use in patients younger than acertain age.

ometimes you may ha$e to estimate pediatric dosages&1. ome recommended ad*ustments are 'uite general (e.g.+ they

will list recommended dosages for a rather wide range of ages).". -he ad*ustments may be based solely on age+ or on body

weight in addition to age. But in e$ery case they are nothingmore than recommended starting points.%. 2f there are impairments in drug distribution or (more likely) in

disposition (metabolism andor e!cretion) or due to drug#druginteractions+ further ad*ustments will be needed+ depending onthe drug.

-here are se$eral formulas that can be used to e!trapolate apediatric dose from the usual adult dose.

1. ne formula is based on body surface area&hildXs dose N body surface area (m ") ! (adult dose) 1.en or more drugs (or e$en a fewer number)+ itbecomes $irtually impossible to keep control of e$erything+ a$oidsignificant drug interactions+ and pre$ent drug#induced side effectsfrom becoming almost as problematic as the disorders for whichthey are being gi$en.

2n too many cases+ e$en when the only drugs taken areprescribed drugs and the number is relati$ely small+ therapy fallsfar short of the goal of causing no harm.

)harma!o+ineti! Changes in O"der Adu"ts

As we grow older+ drug absorption+ distribution+ metabolismand e!cretion can be altered through the combined influences ofage#related physiologic changes+ disease+ nutrition+ and drugtherapy.

-he ma*or pharmacokinetic changes are e!plained in thefollowing discussion and summari>ed in -able :+ on the ne!t page.

All of them help e!plain why+ in most cases+ drug doses should bereduced in elderly persons+ and why especially careful monitoring

of therapy (and communication and coordination between multiple prescribers) is so important.

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A common but incorrect assumption that relates to olderindi$iduals o$erall+ and perhaps to drug therapy in particular+ is thatTe$erything deterioratesU with age. Although many of the factors

that affect pharmacokinetics do decline as one reaches the age of;: and beyond (and some actually start to decline after the age of:C+ and for some people e$en before then)+ many do not declineintrinsically. -hat is+ many of the physiologic changes that occur aswe age+ and that we ascribe to agingper se+ really donXt change atall.

2nstead+ the changes of such factors as cardiac output+ orhepatic or renal function+ occur secondary to diseases that aremore common in elderly indi$iduals. -hey do not reflect

senescence in the truest sense. 0hen thinking about how pharmacokinetic changes in theelderly might necessitate changes in drug therapy+ you need tothink beyond the ob$ious. 2t may be ob$ious+ for e!ample+ that apatient will (and sometimes must) recei$e a drug that dependsgreatly on hepatic metabolism (or renal e!cretion) as a prime wayto terminate its effects in the body+ e$en if or when that patient hasli$er disease (or renal disease).

0hat is not so ob$ious+ but is so critically important toremember+ is that most drugs depend on the interrelated functionof se$eral organs for their entry into+ and elimination from+ thebody. 2tXs na[$e to belie$e that for the patient with a Tbad li$er+U allone needs to do is choose an alternati$e but otherwise similar drugthat isnXt metaboli>ed (or is metaboli>ed much less) and administerit carelessly.

Moreo$er / and this appears to be especially true for theelderly / although a particular disease may appear to alter thefunction of mainly one organ (e.g.+ the li$er)+ other organs andorgan systems+ and their essential functions+ can be affected too. Agood e!ample of this is heart failure+ which is much more commonin the elderly.

-he heart does not absorb+ metaboli>e+ or e!crete drugs.8owe$er+ because one of its prime functions is to deli$er blood tothe key absorpti$e+ metaboli>ing+ and e!creting organs+ heartdysfunction can cause a host of pharmacokinetic changes that

complicate therapy. Iikewise+ drugs that e!ert a ma*or effect on a

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particular organ or organ system can also ha$e an impact onpharmacokinetic processes carried out by other organs.

ther common age#associated conditions that can ha$e a

widespread impact on pharmacokinetics include dehydration+malnutrition+ hyper#or hypotension+ diabetes+ and pulmonarydisease.

Ta$"e ,: Summar%' Some )h%sio"ogi! Chara!teristi!s of O"der Adu"ts4and their )harma!o+ineti! Conse@uen!es

Chara!teristi! Conse@uen!e

3ecreased body watercontent 6arrower distribution+ increased blood le$els+ of watersoluble drugs

2ncreased body fat 3ecreased blood le$els of highly lipid#soluble drugs

3ecreased serum albuminle$els

2ncreased free le$els (and effect+ metabolisme!cretion)of drugs that are normally highly protein#bound

@elati$ely lower gastric

acid#secreting capacity

More complete andor faster absorption of drugs thatare completely or partially inacti$ated by gastric acid+ or

drugs that are mainly ioni>ed at low p8

3ecreased cardiac outputand local blood flow

ardiac output falls about %C between the ages of :Cand ;: years4 splanchnic and hepatic blood flow declineby about the same amount4 renal blood flow (and 5F@)fall to about half their $alues measured at age :C.Iocally reduced blood flow can reduce entericabsorption of drugs+ andor reduce drug metabolismand e!cretion. E&cretory changes are the mostimportant:

3ecreased li$er mass andhepatocyte function

3ecreased metabolism (and longer half#life) of drugsdepending on hepatic metabolism4 e!cessi$e initialeffects of some drugs that normally depend on first#pass metabolism4 li$er mass declines about %Cbetween age :C and ;:.

##################### Finally+ donXt underestimate the capacity of one determinant

of pharmacokinetics in the older indi$idual to compensate forchanges in another. For e!ample+ circulating le$els of many

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hormones stay remarkably constant in the later years of life.Although hormone synthesis and release may truly be reduced+ fore!ample+ changes of other factors may be sufficient to compensatefor the reduced synthesis+ thereby maintaining circulating hormone

le$els at le$els similar to those found in younger adults.

A$sor9tion f the four main pharmacokinetic factors that go$ern thefates and actions of drugs+ absorption seems to be the leastaffected. (Although it might be affected least+ the changes can beimportant nonetheless+ and we will focus on absorption of drugsadministered orally).

2f there are changes+ they usually in$ol$e the rate at whichdrugs are absorbed from the 52 tract. -he bioa$ailability (e!tent ofabsorption) of oral doses is affected much less and much lessoften.

5astric p8+ which affects the ioni>ation and diffusibility ofdrugs+ tends to increase because of decreased gastric acidsecretion. -here are also decreases in gut motility+ surface area (atleast in terms of surface area that can functionally absorb drugswell)+ and blood flow.

-hese changes are more likely caused by disease+ nutritionalstatus+ and drug therapy+ than by simple age#related physiologicchanges. $erall+ neither the rate of drug absorption from the gut+nor the amount of a dose that is absorbed (bioa$ailability) ischanged much.

8owe$er+ as noted below+ significant age#associateddecreases in hepatic metabolism (and hepatic blood flow) can

make it appear as if greater amounts of some drugs ha$e beenabsorbed.

Distri$ution -he lean body mass of an older adult decreases by ": to%C. Actually+ this change starts much earlier in life. 7stimatesindicate that women lose+ on a$erage+ about : kg of lean bodyweight between the ages of ": and


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Body water content decreases+ and body fat increases+ withand generally in proportion to the fall of total body weight. -hefraction of total body water comprised of e!tracellular water seemsto shrink the most in parallel with declines of lean body mass.

,lasma concentrations of water#soluble drugs are increasedbecause the drugs are distributed throughout a smaller relati$e$olume of body water. ,lasma concentrations of lipid#soluble drugsare decreased because of distribution into a relati$ely greateramount of fat.

Iean muscle mass decreases concomitant with aging andthe fall of lean body mass. -his contributes to an age#related fall ofthe basal (or resting) metabolic rate+ which also affects drug

metabolism and e!cretion. ,art of the fall of basal metabolic ratethat occurs with age depends on the indi$idualXs life#style& it fallsmuch less in indi$iduals who remain acti$e+ through e!ercise+ andfalls much more in those who ha$e a sedentary life style.

erum albumin le$els usually decrease in the later years+although the changes may not be as significant or conse'uentialas was pre$iously thought. -he declines+ no matter how great'uantitati$ely+ usually reflect decreases in albumin synthesis moreso than albumin loss $ia renal tubular changes (e!cretion).

6onetheless+ since many drugs tend to bind to albumin+ thedecreased number of binding sites will lead to a proportionatelyhigher number of unbound and therefore pharmacologically acti$emolecules in the circulation. As a result+ greater and potentiallymore ad$erse effects may occur unless the dose is reducedproperly.

Multiple drug therapies+ common in the older adult+ may

result in competiti$e displacement of some drugs from a limitednumber of protein binding sites+ thereby increasing free bloodconcentrations e$en more.

;eta$o"ism -hree main factors seem to contribute to age#associateddecreases in drug metabolism+ mainly in the li$er&

1. decreased acti$ity of the li$erXs drug metaboli>ing en>ymes.". decreased hepatic blood flow+ which is responsible for

deli$ering drugs to their site of metabolism.%. decreased functional li$er mass.

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3isease+ altered nutritional status+ and drug therapy seem toaffect hepatic en>yme acti$ity and blood flow the most. 3ecreased li$er function+ which can be monitored fairly well

with simple blood tests (e.g. by measuring A- and AI-) has aparticularly great impact on orally administered drugs thatordinarily undergo e&tensi-e hepatic first.pass metabolism:

$erall+ reduced metabolism can increase the amount ofsome drugs that enter the bloodstream. 2n the case of drugssub*ected to first#pass metabolism+ the e!cessi$e rise of bloodle$els is especially important when drug therapy is initiated+ i.e.+before the en>yme systems become saturated after repeated

dosing. @educed metabolism+ whether first#pass or otherwise+simultaneously decreases the rate at which drugs appear to becleared from the bloodstream as the result of metabolism. 2n $iewof this+ diminishing li$er function is one more reason for ad$isingthat drug doses be reduced+ and monitored much more carefully+ inthe older patient.

-hereXs not much clinical data to make 'uantitati$eassessments of age#related changes in drug metabolism ingeneral+ or with respect to specific aspects of hepatic drugmetabolism. -hatXs because most of the data ha$e been collected fromanimal studies. 6onetheless+ and clearly+ TchangesU in themetabolic clearance of certain drugs that depend on certaincofactors+ en>ymes+ or en>yme families for their biotransformationoccur.

8owe$er+ it isnXt known for sure whether (for e!ample)...o there is an To$erall lossU of hepatic en>ymes4o otherwise functional en>ymes are damaged (e.g.+ byfree radical#mediated attack)4o there may be increased synthesis of replacementen>ymes with functional (drug#metaboli>ing) capacitieslower than younger forms of the en>yme4o there is a loss of en>yme cofactors4 oro other alterations in the hepatocytesX intracellular milieu

occur.

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E8!retioneduced renal drug e&cretion accounts for more ad-erse

drug effects in the elderly than any other singlepharmaco3inetic factor:About two out of e$ery three older adults ha$e some clinicallysignificant age#related renal function decline or dysfunction. -hema*or changes seem to in$ol$e reduced glomerular filtration and+to a lesser e!tent+ tubular secretion.

@enal status is usually assessed as the creatinine clearance+which can be appro!imated from measurements of plasma

creatinine le$els. uch measurements are a common part of bloodtests gi$en to most patients+ and they should be checked routinelyin the elderly.

,ackage inserts for many drugs gi$e guidelines (note the wordguidelines) about how to modify the dose or dose inter$aldepending on the creatinine le$el or clearance $alue. Dou need tocheck these recommendations too before prescribing+ and beaware that the guidelines donXt replace the need for careful andoften fre'uent assessment of the actual drug responses and of thepatient o$erall.

)harma!od%nami! Changes in O"der Adu"ts

-he sections abo$e discussed altered drug responses in theelderly because of pharmacokinetic changes. For e!ample+ andunusually heightened or prolonged response to a particular drugmight be e!plained in terms of increased or prolonged blood le$els

due to decreased metabolism or e!cretion.

8owe$er+ there is also e$idence that+ compared with youngerpersons+ the elderly e!perience greater (or lesser) response to aparticular dose of some drugs e$en when the plasmaconcentration of free (acti$e) drug is the same+ and in theTtherapeutic range.U -hat is+ the changed response intensity is notcaused by too much (or too little) drug at acti$e sites+ but byincreased or decreased responses of the target cells to the drug

molecules that are there. -his is apharmacodynamic alteration ofdrug response.

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Much less is known about pharmacodynamic changes thanabout pharmacokinetic alterations+ in part because thepharmacodynamic changes are harder to measure.

6onetheless+ some of what is known can be helpful whenad*usting drug dosages for elderly patients+ when anticipatingaltered and sometimes unwanted effects+ and when trying tounderstand why these changes make the patient more or lessTsensiti$eU to the effects of a drug. 0hat follows is a brief o$er$iewof how some of these changes are thought to come about+ withe!amples of each.

Re!e9tor or Other Ce""u"ar Changes3ecreased responses to some drugs may be caused by an age#related decrease in the number of receptors with which the drugmust interact. -his has been used to e!plain+ for e!ample+ arelati$ely weaker ability of drugs like epinephrine to stimulate theheart+ and a relati$ely weaker ability of the adrenergic blockers thatcan block those receptors.

2n addition+ age can bring about changes in the cellsX secondmessenger systems that are needed to translate the interactionbetween an agonist and its receptors into the e$entualpharmacologic response.

Changes in Ref"e8es and Other 7omeostati! ;e!hanisms 3rugs acting on one organ or system sometimes triggerrefle!es aimed at maintaining+ more or less+ the status 'uo.8owe$er+ in the elderly some of these compensatory processescan be impaired.

-his sort of control is particularly important+ and common+ inthe cardio$ascular system. For e!ample+ some antihypertensi$edrugs can cause an abrupt fall in blood pressure / a phenomenoncalled orthostatic hypotension / when the patient stands upsuddenly. 6ormally the autonomic ner$ous system respondsalmost instantaneously to constrict blood $essels in the legs.0ithout this refle!+ blood would tend to pool in the legs and thebrain could be depri$ed of sufficient blood flow+ e$en if for amoment+ such that di>>iness+ fainting+ a fall+ and serious in*ury

could occur. 2n the elderly+ howe$er+ the protecti$e refle!es seemto be diminished+ and so the risks are increased.

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Nutritiona" Changes 6utritional deficiencies can account for some altered drug

responses in the elderly. For e!ample warfarin e!erts its effects inthe li$er by inhibiting the synthesis of itamin #dependent clottingfactors. An inade'uate intake of itamin #containing foods+therefore+ can intensify the drugXs main effect+ leading to abnormalor e!cessi$e bleeding.

2tXs important to reali>e that a patient need not be in a state ofgeneral+ symptomatic malnutrition or malnourishment for somead$erse drug effects to occur. A deficiency of *ust one nutrient can

ha$e significant effects on the responses to specific drugs. 2t isalso important to assess for factors+ age#related and otherwise+that could affect nutritional status.

-hings to look for include&1. chronic diarrhea or $omiting.". diminished appetite or taste%. difficulties with chewing or swallowing.

ome problems can be caused by age+ disease+ psychologicfactors (e.g.+ depression)+ and e$en by therapy with certain otherdrugs. 2t is e$en important to consider economic factors that couldaffect a patientXs ability to buy and eat a proper+ healthy diet.

Side Effe!ts in the E"der"% -he conse'uences of diseases encountered by the elderly+or the administration of drugs used to treat them+ are too numerousto discuss separately. 8owe$er+ we can make somegenerali>ations about some common drug#induced side effects

that are most likely to occur and be bothersome+ since some ofthem can be caused by se$eral of the drug groups often gi$en to(or self#prescribed by) the elderly.

2t is important to note that without proper recognition andmanagement+ drug side effects can become so intense andbothersome (let alone dangerous) that they outweigh some of thedesired therapeutic benefits. -his may cause the patient to nottake their drugs are recommended+ or to stop therapy with one or

more drugs altogether.

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Antimus!arini! Effe!ts Many drugs and groups of drugs cause antimuscarinic

(anticholinergic+ or atropinelike) effects. -hese are effects thatoccur because drugs block the muscarinic subtype of receptors foracetylcholine and parasympathomimetic drugs.

3rugs ha$ing antimuscarinic properties that are commonlyused by the elderly include mydriatics (pupil#dilating drugs)+ drugsused to manage symptoms of colds and hay fe$er (antihistamines)+and drugs used for certain types of mental illnesses (e.g.+antidepressants and antipsychotics).

Antimuscarinic effects can worsen glaucoma4 prostate+ boweland bladder problems4 and hypotension.

7%9otension As noted abo$e+ se$eral age#associated pharmacokineticand pharmacodynamic changes occur in the cardio$ascularsystem. -hese can contribute to a prolonged and or e!cessi$elowering of blood pressure+ or acute but significant (anddangerous) posture related hypotension.

-his problem is caused not only by drugs gi$en specifically tolower blood pressure (antihypertensi$e drugs)+ but also by otherdrugs that may lower blood pressure as a usual side effect.

7!amples of drugs used to treat insomnia and other sleepdisorders+ an!iety+ depression+ psychosis+ parkinsonism+ sei>uredisorders+ pain+ and e$en some manifestations of commonallergies or the cold and flu. And most+ if not all+ of these drugs can

cause other relati$ely common and problematic side effects for theelderly+ as noted ne!t.

Sedation4 Confusion4 Ata8ia -he most common side effects caused by drugs with 6depressant acti$ity are sedation and drowsiness+ confusion anddisorientation+ and ata!ia. ome drugs+ notably some of theben>odia>epines (e.g.+ dia>epam / AI2KM) that are consideredTpreferredU drugs for an!iety and insomnia+ can also produce short#

term memory loss (amnesia) or Thango$er+U depending on theirindi$idual pharmacologic profiles.

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(for e!ample) drug absorption. -he more comple! the treatmentplan+ the greater the chance for noncompliance+ whether thecompliance is intentional+ unintentional+ or simply una$oidablebecause the regimen is so complicated.

ne way to minimi>e the problems of polypharmacy is to keep themedication regimen as simple as possible& the fewest number ofdrugs+ and the smallest number of daily doses and administrationtimes.

". Financial considerations may make it difficult for the elderlyperson to decide whether purchasing medications (e$en paying for

a modest co#pay) takes priority o$er other necessities of life(buying food+ paying the rent). 2t can also influence a decision toself#medicate with cheaper (although not necessarily less effecti$e)drugs instead of those that are prescribed by the physician.

Kse of self#medicating drugs can cause additional problems in itsown right. 2f you+ the prescriber+ are aware of (or can actuallyrecommend and super$ise their use)+ then you might be able tomodify other aspects of drug therapy to minimi>e the number orse$erity of side effects (e.g.+ from drug interactions).

f course+ if you are unaware of drug use by your patient you willbe clueless in many ways. ne of the greatest dangers of thisignorance is a more difficult task of determining why themedication regimen youX$e prescribed isnXt working or is causingso many problems (e.g.+ ad$erse effects). Dou can spend andwaste much time and money *uggling drugs and ordering tests ifyou arenXt fully aware of your patientXs drug taking.

-he only way to find out+ of course+ is to ask and ask aboute!plicitly Twhat drug(s) are you taking.U

%. 0hether because of financial reasons+ a period of symptomrelief+ or an episode of unpleasant side effects+ medications maygo unused and be sa$ed until the patient feels a need to take themagain. ome medications may become outdated during this time+losing some or all of their acti$ity by the time they are taken again.

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Many patients simply feel they do not need some (or e$en any) ofthe drugs prescribed for them+ or at least they donXt need such highdoses.

. ,hysiologic changes from aging and illness can cause suchproblems as forgetfulness+ confusion+ or anore!ia+ which can leadto unintentional noncompliance despite the best intent to takemedications as directed.

:. pecial senses+ physical strength+ and de!terity may beimpaired. Auditory problems may make it difficult to hear ad$ice

about therapy+ e$en though the best of $erbal instructions mightha$e been gi$en.

isual impairments can make it difficult to read written directions orlabels of medication containers+ or to identify the shape+ si>e+ orcolor of a medication.

Altered taste (and smell) may make it difficult to distinguish oneli'uid medication from another that is packaged in a similarcontainer and looks alike in other ways.

onditions such as arthritis can make it difficult to open medicationcontainers+ most of which ha$e child#resistant caps.

;. 8abits+ practices+ and social or cultural beliefs held for manyyears+ which pre$iously kept the patient 'uite well+ may limitwillingness to comply with therapy. ome of these factors mayinclude the use of nonprescription drugs or other remedies

(TtraditionalU or not)+ or certain diets+ that can ha$e an influence ondrug taking or drug responses. uch knowledge of Tmyself+ theway 2 was for years+&U can make taking medications+ or toleratingthe side effects or essential monito

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