Alzheimer’s Disease The Cholinesterase Inhibitor Medications Alzheimer’s Disease The Cholinesterase Inhibitor Medications

Diagnosed Dementia Patients PCPsNeurologistsPsychiatristsAll others Source: National Disease and Therapuetic Index (Diagnosis codes: 3310, 2900, 2901, 2902, 2903, 2904) /99 to 10/2000 Diagnosis visits (millions)

Mayeux R et al. N Engl J Med. 1999;341: Cholinergic Hypothesis  Role — Acetylcholine (ACh) is an important neurotransmitter in brain regions involved in memory  Impact — Loss of ACh in AD correlates with impairment of memory  Treatment approach — Enhancement of cholinergic function may stabilize or improve cognitive function and may affect behavior and daily functioning

Cholinergic Hypothesis Cholinergic deficiency contributes to cognitive decline in AD It may contribute to behavioral symptoms of AD – –Psychosis-agitation – –Apathy-indifference – –Disinhibition – –Aberrant motor behavior

Cholinergic Hypothesis (cont’d)  Atrophy of the nucleus basalis of Meynert, the source of choline acetyltransferase, causes deficit  Other neurochemical and neurohistologic abnormalities contribute to the psychopathology of AD  Cholinergic therapy may partially improve behavioral symptoms of AD  Cholinergic therapy does not interrupt the disease process

Current Medications Used to Treat AD Other 25% Aricept 44% *Risperdal 9% *Paxil 3% *Zyprexa 3% *Zoloft 3% Vitamin E 3% *Ativan 4% *Haldol 6% *These uses are investigational. Source: National Disease and Therapeutic Index, 1998.

Cholinesterase Inhibitors FDA-approved agents: tacrine, donepezil, rivastigmine Doses – –Tacrine: 80 to 160 mg/d – –Donepezil: 5 and 10 mg/d – –Rivastigmine: 6 to 12 mg/d – –Galantamine: 20 to 50 mg/d Efficacy in mild/moderate AD Limited information on long-term treatment and in late-stage disease May be helpful in Lewy body disease Krall WJ, Sramek JJ, Cutler NR. Ann Pharmacother

Cholinesterase Inhibitors (cont’d)   Side-effect profiles are similar — — Tacrine: liver toxicity, nausea, vomiting, diarrhea — — Donepezil: nausea, vomiting, diarrhea, muscle cramps — — Rivastigmine: nausea, vomiting, diarrhea, headache, dizziness — — Galantamine: nausea, vomiting, agitation, sleep disturbances

6 – 4 – 2 – 0 – -2 – -4 – -6 – -8 – -10 – -12 – -14 – -16 – Cognitive Function (  ADAS –Cog) Untreated Cholinesterase Inhibitor (CI) 1 year2 years Hypothesized Treatment Effect in Alzheimer’s Disease

Acetylcholinesterase Inhibitor Development rivastigmine (Exelon ® ) tacrine (Cognex ® ) 1999 donepezil (Aricept ® ) 2001 galantamine (Reminyl ® )

Characteristics of Cholinesterase Inhibitors Dose Drug Bindingescalation Dosing tacrine Noncompetitive,6-week stepsqid (Cognex ® ) reversible donepezil Noncompetitive,4-6-week stepqd (Aricept ® ) reversible rivastigmine Noncompetitive2-week stepsbid (Exelon ® ) reversible Davis KL, Powchik P. Lancet. 1995;345: Aricept ® package insert. Exelon ® package insert.

Tacrine (Cognex ® )  Half-life of 3–5 hours (variable, affected by food intake)  4-times-daily dosing of 10 to 40 mg (40 to 160 mg/day)  Metabolized by the cytochrome P450 isoenzyme CYP1A2  Associated with hepatotoxicity (monthly liver testing suggested) Davis KL, Powchik P. Lancet. 1995;345: Crimson ML. Pharmacotherapy 1998;18(2 pt 2):47S-54S.

Bryson HM, Benfield P. Drugs Aging. 1997;10: Aricept ® package insert. Donepezil (Aricept ® )  The first second-generation cholinesterase inhibitor  Half-life of 70 hours  Once-a-day dosing of 5 to 10 mg  Metabolized by cytochrome P450 isoenzymes CYP3A and CYP2D6  Higher doses associated with cholinergic side effects, but generally well tolerated

Rivastigmine (Exelon ® )  Newer second-generation cholinesterase inhibitor  Half-life of 1.5 hours  Dosing (bid) of 3 to 12 mg/day  Metabolism is almost totally independent of the hepatic cytochrome P450 system  Gastrointestinal adverse events are common, including weight loss Exelon ® package insert.

Outcome Scales Used in Phase III Trials of AD Drugs Cognition Alzheimer’s Disease Assessment Scale- Cognitive Subscale (ADAS-cog) Global change Clinician Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) Activities of daily living Interview for Deterioration in Daily Living Activities in Dementia (IDDD) Progressive Deterioration Scale (PDS) Progressive Deterioration Scale (PDS) Clinical Dementia Rating-Sum of Boxes (CDR-SB) Clinical Dementia Rating-Sum of Boxes (CDR-SB) Behavioral disturbances Neuropsychiatric Inventory (NPI) (ADL)

Rosen WG et al. Am J Psychiatry. 1984;141: Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog)  Primary outcome measure — A validated, sensitive, and psychometric measure — Contains 11 items that measure cognitive change — Scoring range is 0–70; higher scores = greater cognitive impairment — Efficacy is measured as mean change from baseline

Schneider LS et al. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S Clinician Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus)  Evaluates 4 areas: cognition, behavior, daily functioning, general psychiatric symptoms  Scores range from 1 (markedly improved) to 7 (markedly worse)

Tacrine Safety  Adverse gastrointestinal effects (somewhat alleviated by concomitant food intake)  Elevated liver transaminase levels (ALT) — 25%–30% of patients with ALT > 3 times the upper limit of normal  Monitoring of liver function required Farlow M et al. JAMA. 1992;268: Knapp MJ et al. JAMA. 1994;271:

Donepezil: Percentage of Patients With Improvement in ADAS-cog (Rogers) Rogers SL et al. Neurology. 1998;50: Change in ADAS-cog (LOCF*) Treatment group  7  4  0 † Placebo7.8%26.8%57.7% Donepezil 5 mg/day15.4%37.8%78.7% Donepezil 10 mg/day25.2%53.5%81.1% * Last observation carried forward. † Includes patients who did not improve or decline.

Donepezil Safety  Individual adverse events that occurred significantly more frequently with donepezil 10 mg than with placebo: — Nausea (17%) — Diarrhea (17%) — Vomiting (10%) — Fatigue (8%) — Muscle cramps (8%) Rogers SL et al. Neurology. 1998;50:

Donepezil Safety (cont)  In the largest trial (N = 818), digestive system and nervous system adverse events occurred more frequently with donepezil 5 mg and 10 mg than with placebo — Digestive system = 36% vs 24% — Nervous system = 38% vs 29% Burns A et al. Dement Geriatr Cogn Disord. 1999;10:

* In the largest trial, donepezil 5 mg was significantly better than placebo using the ADAS-cog scale, but scores worsened from baseline. Donepezil Summary  Donepezil (5* and 10 mg) improves cognition and global function in patients with mild-to-moderate AD  Long-term efficacy is maintained for up to 50 weeks  ADL may be partially maintained by donepezil  Donepezil is generally safe and well tolerated

Rivastigmine Safety  During the maintenance phase, adverse events with rivastigmine 6–12 mg (1–4 mg)* compared with placebo were: — Dizziness, 14% (8%) vs 4% — Nausea, 20% (8%) vs 3% — Vomiting, 16% (5%) vs 2% — Dyspepsia, 5% (6%) vs 1% — Sinusitis, 4% (1%) vs 1% Corey-Bloom J et al. Int J Geriatr Psychopharmacol. 1998;1: * p < 0.05 vs placebo for all events except rivastigmine 1–4 mg for dizziness and sinusitis (not different from placebo).

Rivastigmine Safety (cont)  Rivastigmine was generally safe and well tolerated  There was no evidence of hepatotoxicity  Fewer adverse events were observed with concomitant food administration versus administration without food  In addition to nausea and vomiting, rivastigmine was associated with significant weight loss Exelon  [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2000.

Rivastigmine Summary  Rivastigmine (6–12 mg) improves cognition and global function in patients with mild-to-moderate AD  Positive effects on ADL have been observed in some studies  Rivastigmine is generally safe and well tolerated, although cholinergic side effects occur at high doses

1. Tariot PN et al. Neurology. 2000;54: Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393: Galantamine (Reminyl ® ) Galantamine (Reminyl ® )  Galantamine has a dual mechanism of action — Competitive inhibition of acetylcholinesterase 1 — Allosteric modulation of presynaptic and postsynaptic nicotinic receptors 2  Galantamine improves major aspects of AD (eg, cognition, behavior, function) 1  Galantamine is generally safe and well tolerated 1

Dual Mechanism of Action Dual Mechanism of Action Postsynaptic nerve terminal M receptor N receptor Presynaptic nerve terminal Galantamine  ACh and other neurotransmitters M receptor N receptor ACh Choline Acetic acid Galantamine N = nicotinic M = muscarinic ACh = acetylcholine Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393: Tariot PN et al. Neurology. 2000;54:

Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393: Galantamine: Potential Advantages of Nicotinic Receptor Modulation  May increase release of ACh — Release of other neurotransmitters also increases  May have a neuroprotective effect

Galantamine Safety (cont) GalantamineGalantamine Placebo16 mg/day24 mg/day (n = 286) (n = 279) (n = 273) Adverse events* (%)(%)(%) Nausea Vomiting Anorexia Agitation Diarrhea Tariot PN et al. Neurology. 2000;54: *  5% of patients receiving galantamine and more often than in patients receiving placebo.

GI Adverse Events  Nausea: incidence related to treatment initiation and dose escalation — Typically transient, resolving within 1 week — Rarely severe  Weight loss: reported as an adverse event in  5% of patients, with none discontinuing treatment Reminyl ® package insert.

Comedication  Minimal potential for clinically relevant drug interactions — No effect on kinetics of digoxin or warfarin  As with other cholinergics, galantamine should be used with caution in patients with heart block or sick sinus syndrome

Agents in Development  Memantine–NMDA receptor antagonist — Improvement in patients with severe AD and VaD 1 — Recent phase III trials indicate significant improvement compared with placebo in CIBIC-plus scores 2 — Patients with moderately severe and severe AD benefited the most 1. Winblad B, Portis N. Int J Geriat Psychiatry. 1999;14: Reisberg B. World Alzheimer Congress, 2000.

4. Lahiri DK et al. Ann NY Acad Sci. 2000;903: O’Banion K. World Alzheimer Congress, Dovey HF et al. J Neurochem. 2001;76: Agents in Development (cont)  Immunization against  -amyloid 1  Huprine X—acetylcholinesterase inhibitor 2  Xanomeline patch—m1/m4 muscarinic receptor agonist 3  AIT-082 (purine hypoxanthine derivative)— increases neurotransmission 4  COX 2 inhibitors—neuroinflammation therapy 5  Protease inhibitors—target  -secretases to prevent amyloid formation 6 1. Schenk DB et al. Nature. 1999;400: Camps P et al. Mol Pharmacol. 2000;57: Shannon HE et al. Schizophr Res. 2000;42:

Current Treatment Summary  Cholinergic agents initially improve and transiently maintain cognitive abilities in patients with mild-to-moderate AD  Cognitive abilities worsen over time, indicating treatment does not stop (but may delay) the progression of AD  New treatments that maintain cognitive ability and stop the progression of AD are needed

Referrals SHANDS at UF Geriatric Psychiatry Inpatient Unit Intake and Referral Line UF Psychiatry Clinical Trials Program STUDY94