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Med/Psych Update

Prevent -drug interactions with inhibitors

Andreea L. Seritan, MD Avoid adverse events when prescribing Assistant clinical professor Department of psychiatry and behavioral sciences for patients with University of California, Davis

r. B, age 78, has a long history of To help you minimize adverse DDIs in well-controlled and AD patients, this article describes: Mwas diagnosed with Alzheimer’s® Dowden• pharmacokinetic Health and pharmacody Media- dementia 6 months ago. He is living at home namic effects of cognitive enhancers and has been taking , 10 mg/d, and used in AD management , 100 mg bid. CopyrightFor personal• DDIs with use medications only commonly This morning Mr. B’s wife calls and reports prescribed to AD patients that he is experiencing sudden difficulty • how to avoid adverse events related walking, , and “feeling drunk.” to , , and When you ask about Mr. B’s medications, . his wife says that her husband’s internist had prescribed , 200 mg/d, for onychomycosis, and Mr. B has taken 1 dose. Pharmacologic changes with aging You promptly discontinue the itraconazole, is the study of the and Mr. B’s symptoms resolve. time course of and their metabolites through the body. Pharmacokinetic interac- Drug-drug interactions (DDIs) in Alzheim- tions involve alterations in the plasma con- er’s disease (AD) patients such as Mr. B centration of a drug by a second agent.3 can be serious and even life-threatening. Absorption of medications is decreased On average, persons age ≥65 use 4.5 pre- in the elderly because of reduced intesti- scription agents and 2 over-the-counter nal blood flow and motility. Absorption preparations per day,1 and the number of further decreases if patients concomitantly concurrently used medications is a signifi- take antacids, high-fiber supplements, or cant predictor of adverse drug reactions.2 medications. Cognitive enhancers, including ace- Distribution. With aging, body tylcholinesterase inhibitors (AChEIs) mass typically decreases and adipose tis- and , are the most widely pre- sue increases. Because most psychotropics scribed agents for AD patients. The FDA are lipid-soluble, their volume of distri- has approved and rivastig- bution increases with age. This leads to mine for mild to moderate dementia, me- drug accumulation and longer half-lives. mantine for moderate to severe dementia, On the other hand, water-soluble medica- and donepezil for mild to severe dementia tions such as distribute in a smaller Current Psychiatry (Table 1, page 58).3-5 volume and pose a higher risk of . Vol. 7, No. 2 57 continued

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Table 1 Pharmacokinetic features of cognitive enhancers Agent Protein binding CYP-450 activity Other features AChEIs

 Donepezil 96% CYP 2D6, 3A4 substrate Once-daily dosing

Rivastigmine 40% None Metabolized by

Galantamine 18% CYP 2D6, 3A4 substrate Nicotinic modulation

NMDA

Memantine 45% None No hepatic

CYP-450: cytochrome P-450; AChEIs: inhibitors; NMDA: N-methyl-D-aspartate Source: References 3-5

In plasma, drugs circulate freely or bound drug effect. Mr. B experienced symptoms Clinical Point to proteins—mainly albumin and α1-acid consistent with lamotrigine toxicity. Age-associated glycoprotein. Aging can cause decreased . The age-associated decline decline in renal plasma albumin and increased α1-acid in renal related to a diminished glycoprotein.6 Additionally, malnutrition, glomerular filtration rate leads to de- clearance leads to mellitus, and hepatic and renal creased excretion of active metabolites decreased excretion disease—all more common with advancing and lithium, making older patients more of active metabolites age—may cause hypoalbuminemia, which susceptible to lithium toxicity. The magni- and lithium increases the free fraction of drugs bound tude of the decline in renal clearance varies to albumin.6 Table 1 includes information among patients and is exacerbated by con- about cognitive enhancers’ protein binding. comitant conditions—such as diabetes and When 2 or more highly protein-bound hypertension—and medications—such drugs are coadministered, mutual dis- as anti-inflammatory drugs placement occurs and the free fraction of (NSAIDs).4 diuretics, angioten- each drug increases. A recent sin-converting inhibitors, and cy- described toxicity with dizzi- clooxygenase-2 (COX-2) inhibitors such as ness, , and falling in a 76-year-old celecoxib may elevate lithium levels.3 man after was added to his regi- Pharmacokinetics of AChEIs. AChEIs men.7 The mechanism appeared to be mu- have relatively few pharmacokinetic in- tual displacement from albumin combined teractions, although donepezil and galan- with metabolism of valproate inhibited by tamine are metabolized through the ’s aspirin.7 CYP 2D6 and 3A4 pathways. Metabolism. Liver size and hepatic Because does not undergo blood flow decrease with aging.6 Cyto- hepatic metabolism, it is least likely of the chrome P-450 3A4 pathway activity slows, cognitive enhancers to have pharmacokinet- but the 2D6 pathway is not affected.4 Oxi- ic interactions with other medications. Riv- dative metabolism through CYP pathways astigmine did not lead to increased adverse is slower, but conjugation reactions are events when administered concomitantly not.6 Table 2 3,5,7,8 lists major substrates and with 22 different classes of medications—in- inhibitors of CYP . cluding antidiabetics, cardiovascular drugs, Azole are potent inhibitors of gastrointestinal agents, and NSAIDs.9 CYP 3A4,4 of which both donepezil and la- motrigine are substrates (Table 2). In Mr. B’s is the study of the time case, lamotrigine and donepezil levels in- course and intensity of drugs’ pharmacolog- creased because of this pharmacokinetic in- ic effects. Pharmacodynamic interactions in- teraction. Because donepezil also is metabo- volve changes in a drug’s action at a receptor or lized by the CYP 2D6 pathway, the increase biologically active site.3 Pharmacodynamic Current Psychiatry 58 February 2008 in concentration is unlikely to modify the interactions may result from an antagonistic Med/Psych Update

Table 2 DDIs in AD patients: CYP-450 substrates and inhibitors* CYP 2D6 CYP 3A4 Substrates Second-generation antipsychotics Second-generation (substances metabolized antipsychotics by enzyme) Donepezil Benzodiazepines Galantamine Donepezil antidepressants Galantamine Haloperidol Lamotrigine  Tricyclic antidepressants Trazodone Clinical Point Inhibitors Combining memantine with Duloxetine Grapefruit juice other NMDA Itraconazole antagonists could Sertraline Nefazodone cause , * All cytochrome P (CYP) 450 enzymes are induced by , , carbamazepine, and . Smoking also induces CYP 1A2. dizziness, , DDIs: drug-drug interactions; AD: Alzheimer’s disease Source: References 3,5,7,8 and

Table 3 Potential drug-drug interactions in AD patients taking cognitive enhancers Interaction Mechanism Potential sequela(e) AChEIs + i in CNS Cognitive worsening,

AChEIs + beta blockers Vagal stimulation and , sympathetic blockade

AChEIs + h Acetylcholine in PNS : hypersalivation, abdominal pain,

AChEIs + antipsychotics (rare) h Acetylcholine/ Parkinsonian syndrome, rigidity i in striatum

Ginkgo biloba + warfarin Antiplatelet aggregation Gastrointestinal bleeding, and anticoagulation hematuria, subcutaneous ecchymosis

AChEIs: acetylcholinesterase inhibitors; PNS: peripheral nervous system Source: References 3,5,10 or synergistic mechanism (Table 3).3,5,10 Do- medications with anticholinergic effects.4 pamine neurons degenerate with aging, par- Memantine, an derivative ticularly after age 70, and the number of cho- and N-methyl-D-aspartate (NMDA) re- linergic receptors decreases in AD patients. ceptor antagonist, is a weak As a result, these patients may become more with atropinic effects.11 Because sensitive to antipsychotics, selective sero- memantine is not metabolized by the CYP- tonin inhibitors (SSRIs)—which 450 pathway, it lacks pharmacokinetic Current Psychiatry indirectly reduce dopamine outflow—and DDIs.12 However, combining memantine Vol. 7, No. 2 59 continued on page 64 Med/Psych Update

continued from page 59 Table 4 antagonism. In a retrospective study of 836 community-living older adults (age Medications with moderate to 13 strong anticholinergic activity ≥65) with probable dementia, Roe et al compared anticholinergic use in 418 who Class Examples were taking donepezil with 418 matched Antiarrhythmics controls who were not taking donepezil. They found: • 33% of those taking donepezil also Antiparkinsonians Benztropine, , were receiving anticholinergics, com- pared with 23% of controls Antipsychotics , • 26% of all patients in the study used , , , multiple anticholinergic medications. Similarly, a study of pharmacy claims Chlorpheniramine, for AChEIs among 557 Medicaid benefi- , , ciaries aged ≥50 found that 35% of patients , taking AChEIs also received at least 1 anti- Clinical Point cholinergic drug.14 Gastrointestinal/ , belladonna Concurrent use of urinary , dicyclomine, Antiparkinsonian agents. Interaction anticholinergics , , , of antiparkinsonian medications with and AChEIs is fairly H2 Cimetidine, AChEIs could limit the of either common but is rarely blockers drug when treating comorbid AD and 5 appropriate because Muscle relaxants Parkinson’s disease (PD), although in practice, clinical deterioration of parkin- of pharmacologic Tricyclic , , sonism has not been reported.15 In one antagonism antidepressants , , , study, 25 PD patients stabilized on le- vodopa/ were given donepe- Source: References 5,13,14 zil, 5 mg/d, or placebo for two 2-week courses separated by a washout of at least with other NMDA antagonists—such as 2 weeks. At steady state, pharmacokinetic amantadine or —could parameters were unchanged and no clini- cause hallucinations, dizziness, headache, cally significant DDIs were observed.16 fatigue, and confusion.11 Concurrent use with drugs that lower threshold, Cardiovascular agents. Concurrent use of such as tricyclic antidepressants, may in- AChEIs and beta blockers, chan- crease the risk of . nel inhibitors, or digoxin could worsen bradycardia and cause syncope. The risk is higher in patients: DDIs with cognitive enhancers • with sick sinus syndrome or other Anticholinergics. Because anticholinergic bradyarrhythmias drugs can worsen cognitive impairment • taking antipsychotics that could induce and cause delirium they are contraindi- ,11 such as ziprasi- cated in older patients—especially those done or haloperidol. with AD. Antihistamines, histamine H2 In patients taking these cardiovascu- blockers, low- first-generation anti­ lar drugs, make sure that heart rate is >60 psychotics (FGAs), and tricyclic antide- bpm before AChEI treatment, and monitor pressants are common medications with regularly. anticholinergic effects (Table 4).5,13,14 Anticholinergics can counteract Other agents. AChEIs inhibit the me- AChEIs’ beneficial effect. Concurrent use tabolism of succinylcholine and therefore of anticholinergics and AChEIs is fairly augment and prolong this drug’s neuro- common in clinical practice but is rarely muscular blockade. Discontinue AChEIs Current Psychiatry 64 February 2008 appropriate because of pharmacologic before administering succinylcholine for , such as for electroconvulsive treatment. AChEIs may lead to toxicity when add- ed to cholinergic agents such as bethan- echol.11 Similarly, AChEIs may precipitate a cholinergic crisis—with increasing weak- ness, hypersalivation, abdominal pains, and diarrhea—when used in conjunction with peripheral acetylcholinesterase in- hibitors such as the agents and . The mechanism is increased acetylcholine available at the neuromuscular junction.

DDIs with other psychotropics Antipsychotics. Nearly one-half of AD patients experience delusions, often in the middle stage of the disease, and many are prescribed second-generation antipsychot- ics (SGAs) to control delusions, hallucina- tions, sundowning, agitation, or aggression. Concomitant use of AChEIs and antipsy- chotics may increase the risk of extrapyra- midal symptoms by disrupting the acetyl- /dopamine balance in the striatum.5 In AD patients taking donepezil and ris- peridone, case reports describe parkinso- nian syndrome and rigidity with immobil- ity, which resolved after the was discontinued.5,11 When rivastigmine and were coadministered, however, no clinically relevant adverse in- teractions were noted in a 20-week, open- label trial of 65 patients with AD, 10 with , and 10 with both.17 The FDA has warned of increased risk of death when SGAs are used to treat behavioral disturbances in dementia pa- tients. In a recent meta-analysis of 15 placebo-controlled trials, cognitive tests scores worsened when AD patients took , olanzapine, , or risperidone. A significant risk for cerebro- vascular events was seen, especially with risperidone, although no clear causal re- lationship was established.18 Falls, injury, and syncope were not increased, and pa- tients with less severe dementia, outpa- tients, and those selected for were less affected. Thus, provide careful follow-up and avoid long-term unwar- ranted antipsychotic use in AD patients. continued Med/Psych Update

Highly anticholinergic FGAs such as Related Resources chlorpromazine are not recommended for • Jacobson SA, Pies RW, Greenblatt DJ. Handbook of geriatric AD patients (Table 4, page 64). psychopharmacology. Washington, DC: American Psychiatric Publishing; 2002. • Sandson, NB. Drug- primer. Washington, Antidepressants. Up to 30% of AD pa- DC: American Psychiatric Publishing; 2007. tients experience major .19 SS- Drug Brand Names RIs are the antidepressants most often Amantadine • Symmetrel Hyoscyamine • Anaspaz, used to treat depression and in Amitriptyline • Elavil Levbid, Levsin Amoxapine • Asendin Imipramine • Tofranil AD patients. Aripiprazole • Abilify Itraconazole • Sporanox Citalopram, , or venla- Atropine • Sal- Lamotrigine • Lamictal faxine are good choices for patients with Benztropine • Cogentin Levodopa/carbidopa • • Urecholine Sinemet AD because of minimal CYP inhibitory Biperiden • Akineton Lithium • Eskalith, Lithobid activity.4 Fluvoxamine, fluoxetine, and Bupropion • Wellbutrin • Ativan Buspirone • BuSpar Meclizine • Antivert paroxetine inhibit CYP 2C9, through Carbamazepine • Tegretol Memantine • Namenda which warfarin and some other drugs Celecoxib • Celebrex Mirtazapine • Remeron Chlorpheniramine • Nefazodone • Serzone with a narrow therapeutic index are me- Clinical Point Chlor-Trimeton Neostigmine • Prostigmin tabolized.6 Chlorpromazine • Thorazine Olanzapine • Zyprexa The herbal Cimetidine • Tagamet • Serax Citalopram • Celexa Oxybutynin • Ditropan Benzodiazepines are contraindicated in supplement Clomipramine • Anafranil Paroxetine • Paxil elderly patients (especially those with Clozapine • Clozaril Pimozide • Orap Cyclobenzaprine • Flexeril Promethazine • Phenergan AD) because of the high risk of delirium, inhibits platelet Cyproheptadine • Periactin Protriptyline • Vivactil worsened cognitive function, paradoxical Dextromethorphan • Benylin, Pyridostigmine • Mestinon 20 aggregation and Delsym, others Quetiapine • Seroquel disinhibition, and falls. If benzodiaze- Dicyclomine • Bentyl Ranitidine • Zantac pines are necessary to control anxiety, use can cause bleeding Digoxin • Lanoxin Risperidone • Risperdal Diphenhydramine • Rivastigmine • Exelon intermediate-duration agents that do not complications Disopyramide • Norpace Scopolamine • Scopace undergo oxidative metabolism and have Donepezil • Aricept Sertraline • Zoloft Doxepin • Adapin, Sinequan Succinylcholine • Anectine no active metabolites, such as lorazepam, Duloxetine • Cymbalta • Restoril oxazepam, or temazepam.19 See Table 2 Escitalopram • Lexapro Thioridazine • Mellaril for more information on Erythromycin • E-Mycin Tolterodine • Detrol Fluconazole • Diflucan Trazodone • Desyrel DDIs. Fluvoxamine • Luvox Trihexyphenidyl • Artane Fluoxetine • Prozac Valproate • Depakote Galantamine • Reminyl, Venlafaxine • Effexor Herbal supplements. Ginkgo biloba Razadyne Warfarin • Coumadin and (Chinese club moss) are Haloperidol • Haldol • Geodon Hydroxyzine • Vistaril Zolpidem • Ambien the herbal supplements used most com- monly by dementia patients. Ginkgo in- Disclosure The author reports no financial relationship with any hibits platelet aggregation and can cause company whose products are mentioned in this article or bleeding complications, with or without with manufacturers of competing products. concomitant antiplatelet or anticoagulant

Bottom Line Alzheimer’s disease patients are at risk for pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs). When using potent cytochrome P-450 inhibitors, be aware of medications the patient is taking that are substrates of these enzymes. Avoid concomitant use of acetylcholinesterase inhibitors (AChEIs) and anticholinergics. Other DDIs, such as AChEIs with antipsychotics or antiparkinsonian drugs, are rarely clinically significant. Periodic follow-up and close monitoring of side effects may help prevent Current Psychiatry 66 February 2008 iatrogenic adverse events. therapy such as aspirin, warfarin, and NSAIDs. Enzyme induction of CYP 2C19 by ginkgo, leading to subtherapeutic levels of , has been implicated in a report of fatal seizures. Huperzine A is a natural and should not be combined with AChEIs because of the risk of additive adverse effects.10

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