Neurodegenerative Diseases Pharmacology PDF

Pharmacology of Neurodegenerative Diseases Learning Objectives • Classify antiparkinsonian drugs and explain their: – MOA – Uses – Adverse effects – Drug interactions and precautions Classification of drugs I. Drugs that affect brain dopaminergic system: A. Dopaminergic agonists: Bromocriptine,...

Pharmacology of Neurodegenerative Diseases Learning Objectives • Classify antiparkinsonian drugs and explain their: – MOA – Uses – Adverse effects – Drug interactions and precautions Classification of drugs I. Drugs that affect brain dopaminergic system: A. Dopaminergic agonists: Bromocriptine, Pergolide B. Dopamine precursor: Levodopa (l-dopa) C. Peripheral decarboxylase inhibitors: Carbidopa, benserazide D. MAO-B inhibitor: Selegiline, rasagiline E. COMT inhibitors: Entacapone, Tolcapone F. Dopamine facilitator: Amantadine II. Drugs that affect brain cholinergic system: A. Central anticholinergics: Procyclidine B. Antihistaminics: Orphenadrine, Promethazine Pharmacologic strategies for dopaminergic therapy of Parkinson’s disease Levodopa (L-dopa) + Carbidopa • Carbidopa: – Dopa decarboxylase inhibitor • Clinical uses – all types but not in drug induced parkinsonism – rigidity and bradykinesia are resolved Levodopa: Adverse effects • GIT: anorexia, nausea, and vomiting: 80% – Tolerance develops quickly • CVS: – Orthostatic hypotension: 30-40% – Cardiac arrhythmias • Centrally mediated adverse effects – Dyskinesias: 80% – Serious mental disturbances: 10 - 15% Pharmacologic Therapy: Anticholinergics • Decreases acetylcholine: dopamine ratio. • Minimize resting tremor and drooling • But are not as effective as other agents for rigidity, bradykinesia, and gait problems. Side effects: • Cognitive impairment (avoid in older patients), • Worsen urinary retention or constipation. With Levodopa: • Erratic and decreased levodopa absorption. Pharmacologic Therapy: Amantadine • Effective as monotherapy and – adjunct therapy for off time and dyskinesia. • Extended release was approved by FDA for dyskinesias in PD. • Side effects: – Dizziness, orthostatic hypotension, hallucinations, restlessness, anticholinergic effects, and – Insomnia (↓s by ER tablets at bedtime). Pharmacologic Therapy: Selective MAO-B Inhibitors • Selegiline, and Rasagiline • Less D/I with Tyramine-rich foods than nonselective MAOIs. • Selegiline and rasagiline: – Provide a mild symptomatic benefit and helps in delay dopaminergic medications – Combined with levodopa • Delay motor complications. • Reduce off time with motor fluctuations on levodopa . • Serotonin syndrome with: – Opioid analgesics, antidepressants, and – Serotonergic agents, or cold and weight loss products Alzheimer’s disease: Treatment • Cholinesterase inhibitors: – Tacrine – Donepezil – Rivastigmine – Galantamine • NMDA receptor antagonist: – Memantine Pharmacologic Therapy • ChE Inhibitors: Donepezil, Rivastigmine, and Galantamine • Selection: MOA, ADR, titration schedules, potential DIs, and patient and caregiver preference. • Switch to another ChE inhibitor if lack of efficacy, lose clinical benefit, or experience safety/tolerability issues. • Switch should be after maximally tolerated dose for 3 to 6 months. Discontinue ChE inhibitor: • Poor tolerance or adherence, no improvement after 6 months • Fail monotherapy with at least two agents, combination therapy, or deteriorate at the pretreatment rate Donepezil • Reversibly and noncompetitive inhibitor of centrally active acetylcholinesterase. • 5- 10 mg/day- mild, moderate and severe • 23-mg dose-moderate to severe. • Most frequent adverse effects: • Nausea, Vomiting and diarrhea • Headache, dizziness, syncope, bradycardia, and muscle weakness. Drug Interactions • With CYP 2D6 or 3A4 inhibitors: ↑ peripheral side effects • With CYP2D6 and 3A4 inducers: ↑ elimination of donepezil. Rivastigmine (oral and patch) • For mild to moderate, active on both AChE and butyrylcholinesterase - broader efficacy. • Oral: SD – 1.5-3 mg BD, MD - 3-6 mg BD • From oral to patch: first patch after the last oral dose for < 6 mg/day oral - 4.6 mg/24 hour patch for 6-12 mg/day oral – 9.5 mg/24 hour patch. If side effects cause intolerance: • Several doses can be held, and then dosing can be restarted at the same or next lower dose. • No expected effect on rivastigmine metabolism. • With CYP450 inducer or inhibitor. Galantamine • • • • • For mild to moderate: only active on AChE SD: IR - 4mg BD and ER – 8mg OD morning MD: IR – 8 to 12 mg BD and ER – 16 to 24 mg OD morning Elevates Ach in the cerebral cortex and Modulates the nACh receptors to ↑ Ach release from surviving presynaptic nerve terminals. • ↑s glutamate and serotonin levels also • Renal and Liver impairment: Max 16 mg • KFT < 30ml/ minute - Not used Drug interaction: • With CYP3A4 and 2D6 inhibitors - ↑ galantamine and ↑ • Cholinergic side effects. Novel Therapy for Mild Alzheimer • Disease: Aducanumab (Aduhelm) • Accelerated approval for AD in adults for early stages with mild symptoms. • First anti-amyloid-beta antibody • Approval on surrogate endpoint reduction of amyloid beta plaque Side effects: • Brain swelling in 35%. 19% brain bleeding. • Headache, confusion, dizziness