Medications for Dementia Chapter 41 Medications for Dementia

Drug Overview Cognitive Function Cholinesterase inhibitors donepezil (Aricept) rivastigmine (Excelon) galantamine (Razadyne) NMDA receptor antagonist memantine hydrochloride (Namenda)

Drug Overview Cholinesterase Inhibitors NMDA Receptor Antagonists Management of mild to moderate Alzheimer’s-type dementia Often initiated by PCPs or after consultation NMDA Receptor Antagonists Moderate to severe dementia of Alzheimer’s type May be given in addition to cholinesterase inhibitors May be initiated by PCP or after consultation

Mechanism of Action Cholinesterase Inhibitors Block enzyme that degrades acetylcholine in the brain resulting in more acetylcholine at the synaptic cleft and enhances cholinergic transmission Diminishes signs and symptoms of dementia and improves function and slows progression

Mechanism of Action NMDA Receptor Antagonist NMDA receptor is linked to learning and memory Stimulated by glutamic acid Excessive stimulation leads to excitotoxicity Blockade of this receptor blocks excitotoxic effects associated with abnormal transmission of glutamate

Treatment Principles Standardized Guidelines Practice Parameter Screening for dementia: Recommendation and rationale Practice Parameter Diagnosis of dementia (an evidence-based review): Report on the Quality Standards Subcommittee of the American Academy of Neurology

Treatment Principles Cardinal Points of Treatment Evidence suggests that cholinesterase inhibitors stabilize cognitive and functional ability for approximately 1 year Tacrine is not widely prescribed because of the need for frequent liver monitoring and qid dosing Consider donepezil as first line Potential drug interactions All metabolized through the CYP 450 enzyme system

Treatment Principles Cardinal Points of Treatment Patients with moderate to severe dementia may be started on memantine, which may be given concurrently with donepezil Identify and treat presence of depression and/or delirium Avoid medications with sedating or anticholinergic effects Treat any metabolic disorders, infections, and comorbid illnesses

How to Monitor Monitoring of Functional Ability and Staging Folstein Mini-Mental State Exam (MMSE) Global Deterioration Scale (GDS) Katz Assessment of ADLs and IADLs Clinical Evaluation and Family Observation Laboratory Tests Liver function tests CBC Routine serum chemistry

How to Monitor Assessment HR, BP Signs and symptoms of toxicity

Patient Variables Geriatrics Age does not influence metabolism or clearance of cholinesterase inhibitors Use galantamine with caution in patients with severe renal impairment Reduce dose of memantine and use with caution in patients with severe renal impairment (CrCl, 5 to 29 ml/min)

Patient Variables Pediatrics Pregnancy and Lactation Efficacy not established Pregnancy and Lactation Category C: donepezil Category B: rivastigmine, galantamine, memantine No controlled studies in pregnancy Unknown secretion of drugs into breast milk

Patient Variables Race and Gender Plasma concentrations are up to 50% higher in women

Patient Education Do Not Change Dose Without Consulting Provider Advise of Initial and Long-term/Delayed Side Effects Advise of Purpose, Expectations from Treatment, and Time Frame to Note Improvement, Not Cure Counsel Regarding Behavioral and Environmental Management of Disease

Patient Education Advise Patient Regarding Long-Term Care, Including In-Home Services, Adult Day Care, Assisted Living Facilities, and Nursing Homes

donepezil (Aricept) Precautions May exaggerate succinylcholine-type muscle relaxation in anesthesia Vagotonic effects on HR may be provoked; use with caution in patients with conduction abnormalities May increase gastric acid secretion May cause bladder outflow obstruction Use with caution in patients with asthma

donepezil (Aricept) Pharmacokinetics Absorption: 100% Peak level: 3 to 4 hours Half-life: 70 hours Steady state: 15 days Metabolization: P450 2D6 and 3A4 Excretion: Urine (17%)

donepezil (Aricept) Adverse Effects Drug Interactions Nausea (5% to 19%) Diarrhea (8% to 15%) Insomnia (5% to 14%) Vomiting, fatigue, muscle cramping, anorexia (3% to 8%) Drug Interactions CYP 3A4 and 2D6 substrates No effect on pharmacokinetics of theophylline, cimetidine, warfarin, and digoxin

memantine (Namenda) Precautions Adverse Effects (8%) Seizures, severe renal impairment, genitourinary conditions, concomitant use of other NMDA antagonists Adverse Effects (8%) Hypertension, tachycardia, dizziness, headache, back pain, gait abnormalities, arthralgia, confusion, somnolence, hallucinations, others

memantine (Namenda) Drug Interactions acetazolamide cimetidine dichlorphenamide hydrochlorothiazide methazolamide nicotine ranitidine sodium bicarbonate