Pharmacology Case 6 Dementia PDF

PHARMACOLOGY: DEMENTIA Dr. Adam Gratton NMT200 MSc ND December 4, 2023 LECTURE COMPETENCIES 1. Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used to manage dementia A. Cholinesterase inhibitors - Donepezil B. NMDA receptor antagonists...

PHARMACOLOGY: DEMENTIA Dr. Adam Gratton NMT200 MSc ND December 4, 2023 LECTURE COMPETENCIES 1. Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used to manage dementia A. Cholinesterase inhibitors - Donepezil B. NMDA receptor antagonists - Memantine 2. Compare and contrast the indications, and adverse effects of drugs to manage responsive behaviours in patients with dementia A. Antidepressants B. Antipsychotics C. Cholinesterase inhibitors D. NMDA receptor antagonists E. Benzodiazepines LECTURE COMPETENCIES 3. Recall medications that may contribute to dementia or cognitive impairment 4. Prescribe appropriate medications for people with dementia based on patient history INTRODUCTION Cognitive screening can help determine when impairment is beyond that associated with normal aging Areas of cognition that can be affected include memory, language, orientation, visuospatial, and executive function Mood and behaviour changes may stem from cognitive decline May be associated with the presence of another disease (Parkinson’s, Alzheimer’s, etc.) INTRODUCTION As dementia progresses, patients often exhibit behaviours and psychological manifestations like delusions, hallucinations, anxiety, depression, agitation, and apathy We will discuss drug options to treat dementia and options to treat specific responsive behaviours separately COGNITIVE IMPAIRMENT AS AN ADVERSE EFFECT OF MEDICATION Anticholinergic adverse effects of medications can lead to cognitive impairment Various anticholinergic burden calculators are available online DRUG OPTIONS FOR DEMENTIA GOALS OF THERAPY Alter the natural disease progression to optimize function and meet patient and caregiver goals Manage cognitive, behavioural, and psychological symptoms Mitigate the risk of harm to self and others Minimize medication side effects Alleviate caregiver burden CHOLINESTERASE INHIBITORS Block the metabolism of acetylcholine within the synaptic cleft resulting in increased acetylcholine and increased cholinergic transmission They are the mainstays of treatment for cognitive and functional symptoms of most causes of dementia They may also help with managing responsive behaviours CHOLINESTERASE INHIBITORS While clinically detectable, the benefits of cholinesterase inhibitors for Alzheimer’s disease are typically small to moderate The benefit may consist mainly of disease stabilization and small improvements in activities of daily living and clinician-rated global clinical state Up to 68% of people with Alzheimer’s disease respond to cholinesterase inhibitors with an initial period of cognitive stabilization (2–5 months) before continuing to decline at the pretreatment rate DONEPEZIL The only cholinesterase inhibitor indicated for all disease severities of Alzheimer’s disease and is also used in other neurological diseases that cause dementia ADVERSE EFFECTS Common adverse effects include diarrhea, nausea, vomiting, anorexia and/or weight loss, vivid dreams, tremor, vertigo, and other cholinergic effects (e.g., rhinorrhea, increased urinary frequency) Headache, nausea, and diarrhea occur in more than 10% of those who take donepezil ADVERSE EFFECTS Conflicting evidence regarding cardiac safety profile Health Canada suggests that all cholinesterase inhibitors pose a small risk of QT interval prolongation N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ANTAGONISTS The proposed mechanism of action of the NMDA receptor antagonist memantine is to block glutamate- induced neuronal excitotoxicity, a process that is implicated as a final common pathway in neuronal death Memantine may have a small clinical benefit on cognition, activities of daily living (ADL), and behaviour and mood in moderate to severe Alzheimer’s disease MEMANTINE Not typically used as monotherapy unless cholinesterase inhibitor therapy is contraindicated or has failed/adverse effects are intolerable. It is more often used in combination with cholinesterase inhibitors to augment the response in severe disease ADVERSE EFFECTS Generally well tolerated; dizziness (7%), headache (6%), confusion (6%), constipation (5%), nausea/vomiting (3%) DRUG OPTIONS FOR THE TREATMENT OF RESPONSIVE BEHAVIOURS RESPONSIVE BEHAVIOURS Typically falls within three contexts Those related to the underlying neurocognitive disorder which often occur predictably according to the stage of dementia - In Alzheimer disease, depression and apathy often occur early together when disease is mild while psychosis and agitation occur with moderate to severe disease RESPONSIVE BEHAVIOURS Those related to psychiatric illness that predates the diagnosis of dementia (anxiety, depression, etc.) Psychiatric history is important as symptoms of psychiatric illness that occurred earlier in the patient’s life may recur in a slightly different form RESPONSIVE BEHAVIOURS Those related to a delirium-like presentation which are typically associated with a medical or environmental precipitant - New medication, new roommate, death in the family, etc. ANTIDEPRESSANTS Many patients in the early stages of dementia experience depression Depression can manifest with prominent cognitive impairment in patients without dementia and a significant proportion of these patients will progress to dementia ANTIDEPRESSANTS Guidelines do not recommend the routine use of antidepressants to manage mild to moderate depression in people living with mild to moderate dementia, unless they have a pre-existing mental health problem ANTIDEPRESSANTS SSRIs (except for paroxetine) are less likely than tricyclic antidepressants to cause anticholinergic side effects or to worsen orthostatic hypotension, which are common and problematic in this population TCAs should generally be avoided Limited evidence suggests that antidepressants improve nondepression- related responsive behaviours Antidepressants are commonly used for anxiety (including compulsive behaviour), agitation, and sexually inappropriate behaviour. ANTIPSYCHOTICS Use is challenging due to the significant risk of adverse effects Antipsychotic medication is generally reserved for the treatment of agitation or psychosis in patients with dementia when symptoms are severe, dangerous, or cause clinically significant distress Risperidone and olanzapine have the most evidence in this population CHOLINESTERASE INHIBITORS AND MEMANTINE Responsive behaviours typically improve with the use of these medications to treat dementia However, the overall effect may not be enough to prevent the use of other medications when disease severity is moderate to severe BENZODIAZEPINES Evidence is conflicting on their efficacy Their use can result in oversedation, falls, and worsening cognition However, they are sometimes indicated for severe agitation, especially when other options are contraindicated or fail CASE #1 76-year-old patient with a recent diagnosis of Alzheimer-related dementia Mini-mental state examination (MMSE) score of 20 suggesting mild- moderate severity Current medications include donepezil 5 mg/day PO, diphenhydramine 25 mg PRN, doxepin 3 mg QHS PO, pravastatin 40 mg PO daily, hydrochlorothiazide 25 mg PO daily, candesartan 16 mg PO daily, CASE #1 CONSIDERATIONS Class discussion SAMPLE QUESTION Which of the following adverse effects occurs most commonly with donepezil therapy? A. Muscle cramps B. Fatigue C. Headache D. Vomiting