Anti-Dementia Medications Erman C. Fandialan MD, FPNA Department of Clinical Neurosciences University of the East Ramon Magsaysay Memorial Medical Center

DEMENTIA Clinical syndrome marked by the insidious onset and slow progression of a cognitive impairment which impairs at least two areas of cognitive function

Primary Dementias Alzheimer's disease (>60%). Diffuse Lewy body disease (DLBD) Frontotemporal dementia (Pick’s disease). Primary Progressive Aphasia (speech) Posterior Cortical Atrophy (vision) Parkinson's disease. Hunington’s disease. Progressive Supranuclear Palsy

Secondary Dementias Infection: CJD,HIV,Crypto Metabolic: Hypothyroid Deficiency States: B12 def Toxins: Alcohol, Drugs, Heavy Metals Cancer: Brain Tumors, Carcinomatous Meningitis, Paraneoplastic Syndrome Trauma: SDH, Boxers Dementia Others: NPH, MS, Dialysis Dementia, Depressio Vascular dementias

DIFFERENTIAL DIAGNOSIS OF DEMENTIA Other Primary dementias: Frontal lobe dementia Parkinson’s disease Progressive supranuclear palsy,others: Vascular Dementias: Multi-infarct dementia SID,SVCVD (Binswanger’s disease) Diffuse Lewy Body Disease* Vascular dementias and AD AD and Lewy body dementias AD 5% 10% 65% 5% 7% 8% Small GW, et al. JAMA. 1997;278:1363-1371. American Psychiatric Association. Am J Psychiatry. 1997;154(suppl):1-39. Morris JC. Clin Geriatr Med. 1994;10:257-276.

Preventive Treatments in Alzheimer's Disease Anti-oxidative agents: Vit.E, Folate, Fish oil Anti-inflammatory agents: NSAIDs?,etc. Statins: Cholesterol Lowering Agents Exercise: Physical and Mental

Drug Treatment of Alzheimer's disease Treatment of specific behavioral symptoms (i.e.: hallucinations/delusion, agitation and aggression, depression, sleep disorders). Treatment of Cognitive Loss- Cholinesterase Inhibitors Additional treatments In AD: Memantine Beta Secretates Inhibitors Immunization

BEHAVIORAL PROBLEMS IN DEMENTIA Present in 80% of cases Major source of caregiver stress, institutionalization Common at all stages of the disease Much more treatable than the underlying dementia Poorly described in the literature

THREE BASIC PRINCIPLES Simplicity Limited goals The “no-fail” environment

DEPRESSION 20-30% incidence in Alzheimer’s disease, often early in the course of the illness Most important treatable cause of excess disability Responds very well to treatment

ACUTE BEHAVIOR CHANGE I atrogenic I nfection I llness I njury I mpaction I nconsistency I s the patient depressed?

AGITATION Present in up to 80% of patients Up to 34% of patients are combative Few predictors Probably a very heterogeneous problem Cornerstone of treatment is nonpharmacologic

EMPIRICALLY EFFECTIVE MEDS FOR AGITATION Atypical neuroleptics (best when agitation is clearly related to delusions or hallucinations) Anticonvulsants Trazodone Beta-blockers Buspirone Benzodiazepines Others

THE BEST NUMBER OF MEDICATIONS TO USE IS ZERO (or sometimes one) WHEN IN DOUBT, GET RID OF MEDICATIONS!

Treatment Goals Slow the progressive deterioration Maintain current capabilities Delay nursing home placement

Therapies for AD Acetylcholinesterase Inhibitors: 1993: Tacrine (Cognex) approved by FDA 1996: Donepezil (Aricept) 2000: Rivastigmine (Exelon) 2001: Galantamine (Reminyl/Razadyne) NMDA Receptor Antagonist 2003: Memantine (Abixa/Ebixa/Namenda/Axura)

Cholinergic Changes in AD The most prominent neurotransmitter abnormalities are cholinergic Reduced activity of choline acetyltransferase (synthesis of acetylcholine) Reduced number of cholinergic neurons in late AD (particularly in basal forebrain) Selective loss of nicotinic receptor subtypes in hippocampus and cortex The associated decline of cognitive function in AD with decreased cholinergic neurotransmission in the cortex, hippocampus, and amygdala is the basis for what is known as the cholinergic hypothesis of AD

Cholinergic Theory

CHOLINESTERASE INHIBITORS Name (Trade Name) Class Selectivity Time to Max Serum Conc. Food Delay Absorption Serum Half-life Protein Bindings (%) Meta-bolism Dose (mg/day) Daily Dosings Hepato-toxicity Tacrine (Cognex) Acridine Butyrylcholine-esterase > acetylcholin-esterase 1-2 hours Yes 1.3-2.0 hours 75 CYP*1A2, CYP2D6 80-160 4 Donepezil (Aricept) Piperidine acetylcholin-esterase 3-5 hours No* 70-80 hour 96* CYP2D6,* CYP3A4 5-10 1 Rivastigmine (Exelon) Carbamate acetylcholin-esterase = Butyrylcholine-esterase 0.5-2 hour 2 hour 40 Nonhepatic 6-12 2 No Galantamin (Reminyl) Phenanthrene Alkaloid acetylcholin-esterase; allosteric nicotinic modulator 0.5-1. hour 5-7 hour 10-20 CYP2D6, CYP3A4 16-24 From: Cummings, J.L. (2001). Treatment of alzheimer’s disease. Clinical Cornerstone, 3(4), 27-36.

CHOLINESTERASE INHIBITORS Presumably increases acetylcholine at synapses Improvement in cognition (? 6-12 months better) Improvement in function (ADLs, variable) Improvement in behavior (? basal ganglia) Slowing of disease course Treatment delays nursing home placement There is loss of benefit with delay of treatment Need to consider early intervention

Galantamine HBr Mechanisms of Action Increases amount of acetylcholine available in synaptic cleft by inhibiting breakdown of acetylcholine By modulating activity at nicotinic receptors, it may increase release of acetylcholine from surviving presynaptic nerve terminals Combination action may diminish cholinesterase supersensitivity from developing, prolonging the benefit. May provide greatest delay of illness progression May require increase of dose after patient declines below initial baseline, to maintain benefit for longer term. The clinical significance of these mechanisms is unknown These 2 mechanisms of action are synergistic

Galantamine HBr Mechanisms of Action Increases amount of acetylcholine available in synaptic cleft by inhibiting breakdown of acetylcholine By modulating activity at nicotinic receptors, it may increase release of acetylcholine from surviving presynaptic nerve terminals Combination action may diminish cholinesterase supersensitivity from developing, prolonging the benefit. May provide greatest delay of illness progression May require increase of dose after patient declines below initial baseline, to maintain benefit for longer term. The clinical significance of these mechanisms is unknown These 2 mechanisms of action are synergistic

Galantamine HBr GI Tolerability Nausea and vomiting: typically transient and related to treatment initiation and dose escalation Among patients experiencing nausea, median duration was 5 to 7 days Weight loss: reported as an adverse event in  5% of patients, with none discontinuing treatment due to weight loss Nausea and vomiting were typically of mild-to-moderate severity; rates of discontinuation were < 4% for this adverse event Patients who vomited usually had only 1 occurrence, and it tended to coincide with an increase in Reminyl (galantamine HBr) dose The rates of nausea and vomiting were reduced to baseline levels soon after each dose increase Nausea and vomiting were readily managed by dietary modification, dosing with meals, and use of antiemetics In the open-label extension phase, patients usually regained the weight they lost during the initial phase of the study

Galantamine HBr Pharmacokinetics Linear pharmacokinetics Bioavailability: 90% Half-life: 7 hours - can provide decrease inhibition at night!! Low (18%) plasma protein binding Hepatic metabolism via multiple pathways, primarily CYP2D6 and CYP3A4 Renal excretion The pharmacokinetics of Reminyl® (galantamine HBr) are well suited to its purpose Predictable levels Readily absorbed Active when needed Few drug-drug interactions Low potential for drug-drug interactions Renally excreted

Galantamine HBr Simple, one-step dose escalation 8 mg/day starting dose for 4 weeks (4 mg bid) 16 mg/day maintenance dose for at least 4 weeks (8 mg bid) The flexibility to increase to 24 mg/day (12 mg bid) – should try after 12 weeks if further benefit sought Taken preferably with morning and evening meals Later, better with morning meal, mid-afternoon snack. (Avoid nocturnal cholinergic activation!!) This slide summarizes the dosing of Reminyl® (galantamine HBr) Clear dosing range established Escalation step is 4 weeks 16 mg/day is the target maintenance dose In appropriate patients, 24 mg/day can be used

New Treatments in Alzheimer's Disease For cognitive loss Memantine Beta Secretase Immunization in AD

Memantine Drug Treatment of Alzheimer's disease low to moderate affinity, noncompetitive NMDA-receptor antagonist and protects the neuronal system from pathological activation of glutamate (reduces Ca influx) Memantine is indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. Can be used with Cholinesterase Inhibitors!

Beta Secretase inhibitors Drug Treatment of Alzheimer's disease Beta Secretase inhibitors also called BACE1 (β-site of APP cleaving enzyme) or memapsin-2 — is an aspartic-acid protease important in the pathogenesis of Alzheimer’s disease Drugs to block this enzyme (BACE inhibitors) in theory would prevent the build up of beta-amyloid and may help slow or stop the disease. Several companies are in the early stages of development and testing of this new potential class of treatment.

Metabolism of Amyloid Precursor Protein (APP) Extracellular sAPP sAPP Beta secretase Alpha secretase A Neuronal Membrane Gamma secretase Intracellular A From: DeKosky, S.T. (2001). Epidemiology and pathophysiology of alzheimer’s disease. Clinical Cornerstone, 3(4), 15-24.

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