AD Therapy Lecture PDF

PHAR323 MODULE II ALZHEIMER’S DISEASE Dr. Noor Alsalemi, PhD, PharmD, BSc, RPEBC Assistant Professor, College of Pharmacy - Qatar University  Learning Objectives The aim of this module is to enable students to integrate all relevant aspe...

PHAR323 MODULE II ALZHEIMER’S DISEASE Dr. Noor Alsalemi, PhD, PharmD, BSc, RPEBC Assistant Professor, College of Pharmacy - Qatar University  Learning Objectives The aim of this module is to enable students to integrate all relevant aspects of pharmacy in order to optimize medicine use and pharmaceutical care in patients with Alzheimer’s Disease (AD). By the end of this module, and after reviewing the required reading material and completing the preparatory work, students should be able to: 1. Demonstrate knowledge of the epidemiology, etiology and pathophysiology of AD. 2. Describe the roles of amyloid beta, cholinergic deficiency and glutamate excess in inducing neuronal injury in Alzheimer’s disease 3. Recognize and differentiate signs, symptoms and risk factors associated with AD and identify and interpret the criteria and tools used for screening, diagnosing and assess the severity of AD. 4. Explain the different modes of action of mediations used to treat AD. 5. Describe the key pharmacokinetic and pharmacodynamics properties of medications used for treating AD, their side effect profile and their potential drug interactions. 6. Formulate patient specific goals of therapy and desired treatment outcomes for people with AD. 7. Critically evaluate the safety and effectiveness of treatment options through the stages of AD. 8. Formulate evidence-based treatment recommendations and monitoring plans for people with AD. 9. Discuss the pharmacological and non-pharmacological strategies to manage the behavioral and psychological symptoms of dementia (BPSD) associated with AD. AY22-MZ Case Study: Mrs. Fatima Mrs. Fatima is a 73-year-old lady who went to her doctor following the recommendation of her daughter. At the doctor’s office, her cognitive function was assessed. Chief complain (CC): Increasing memory problems over the past 2 years (forgets to pay bills, leaves the stove on, can’t spell her name, etc.). Fatima’s daughter convinced her to visit the doctor, during the visit her MMSE score was 25/30 with errors in orientation, attention, calculation and difficulty in finding words. History of present illness (HPI): Fatima’s memory problems have got worse over the past two months, to the point that last week she became confused and disoriented when shopping for her groceries, became agitated, and refused to pay the bill, stating that she had already paid. Fatima reports that her mother also had memory problems. Case Study: Mrs. Fatima Past psychiatric history (PPH): At the doctor’s Fatima also indicated that she had problems sleeping, and that she felt depressed because she recognizes that she is having memory problems. But denied changes in her appetite or suicidal ideation. There is no past history of mental illness. Past medical history (PMH): Her medical comorbidities include diabetes (controlled with diet and metformin), history of gastric ulcers (she takes an antacid occasionally for heartburn), and constipation (uses a regular stool softener). Social history (SH): Widow for the past 3 years, has 2 daughters: one lives in Jordan and the other one is a housewife with 3 children. Fatima lives alone, but lives close to her daughter and has a housekeeper that stays with her except for the weekends. She has never smoked or consumed alcohol. Reflect on the disease 2 minutes Write you know, feel and think about – A patient’s life with AD – Therapy options – Your thoughts and aspirations regarding the learning the topic. AD Mind map Patches weekly Goals of Therapy ü Primary goal: treat the symptoms associated with cognitive decline and preserve patient function for as long as possible. ü Secondary goals: manage psychiatric and behavioral sequelae. ü Modify and reduce risk factors. AD –Management Principles Early Stages Intermediate Stages Late Use of AD Refer to specific If non-pharm Discuss early-stage medications unsuccessful, use medications with groups or to treat targeted to patient adult day cognitive specific and family services for decline behaviors. Watch for SEs and D/C Provide appropriate ASAP appropriate end- structured Treat of-life care as activities needed Define behavioral Provide patient symptoms appropriate treatment for specific Seek support and mood comorbid treatment organizations disorders medical goals using non- conditions pharm approaches AY22-MZ  Identify the possible causative factors for cognitive and noncognitive symptoms, and adapt the caregiving environment to remedy the situation. Sleep disturbances, wandering, urinary incontinence, agitation, and aggression should be managed with behavioral and environmental interventions if possible Nonpharmacologic Therapy On initial diagnosis, the patient and caregiver to be educated on the course of illness, available treatments, legal decisions, lifestyle changes that will become necessary, and other quality-of-life issues. Primary prevention includes smoking cessation, increasing physical activity, and reducing midlife obesity, hypertension, and diabetes. Adherence to the Mediterranean Diet or Dietary Approaches to Stop Hypertension (DASH) Diet may reduce the risk of cognitive impairment or decline. Pharmacologic Therapy of Cognitive Symptoms Mild to moderate – AchIs Select based on ADRs and dosage forms No difference between agents – Consider aducanumab Moderate – severe – Memantine monotherapy – Add memantine to existing AchIs – Memantine + Donepezil TIPS – Pharmacologic Therapy of Cognitive Symptoms A reasonable response may be a slowed decline in abilities and delayed long-term care placement. Simplify dosing regimens, taking patient and caregiver preferences into consideration to improve medication adherence and persistence. Treatment gaps may be associated with a loss of benefits when medication is stopped but this is controversial. Behavioral symptoms may require additional pharmacologic approaches. CHOLINESTERASE INHIBITORS 6 months on target dose, then re-evaluate. If no benefit: taper down Donepezil, rivastigmine, and galantamine by 50% for 2-3 wks or First line therapy for mild-moderate AD add memantine Donepezil is is also indicated for severe AD Newly diagnosed AD should be offered a trial of a cholinesterase inhibitor for symptomatic treatment of cognition and global functioning Duration: efficacy should be assessed, and if not effective, the med should be stopped, or memantine is added if indicated. Switching to another ChI is not advisable. There is no consensus on how long to continue cholinesterase inhibitors in patients who are tolerating therapy, and even patients who respond initially will ultimately progress. Lanctôt KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, Einarson TR. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta- analysis. Cmaj. 2003 Sep 16;169(6):557-64. Copyrights apply OPTIONS FOR PATIENTS ON ENTERAL FEEDING CHOLINESTERASE INHIBITORS Benefit: Modest: small improvement in cognition, neuropsychiatric symptoms, and activities of daily living – NNT: over minimum of 12 weeks 7 patient (stabilization to some improvement) 42 patient (marked improvement) – NNH: 12 patient over minimum of 12 weeks (side effects) No trials have assessed the effectiveness of one agent over another. Successful treatment shows a MMSE score decline of less than 2 points per year with benefit lasting 3–24 months. Lanctôt KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, Einarson TR. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta- analysis. Cmaj. 2003 Sep 16;169(6):557-64. Monitoring Treatment with AChIs Baseline Ø Urea, electrolytes, liver function tests, blood pressure, heart rate and weight. Ø To prevent side effects dose titration is required on starting therapy During treatment Ø Heart rate: monthly while the dose is titrated up. Ø Blood pressure and weight: every six months. Ø Side effects (affecting about 10% to 20% of patients): nausea and vomiting (usually diminish within 2 to 4 days). Other SEs: Muscle cramps, bradycardia, increased gastrointestinal acid, reduced appetite, and decreased weight. Donepezil and galantamine are metabolized by CYP450 and could potentially interact with CYP450 inhibitors, such as fluoxetine and paroxetine, exacerbating cholinergic side effects. Memantine is not metabolized by CYP450 = safe in combination with ACHIs. AY22-MZ N-methyl-D-aspartate (NMDA) receptor antagonists Memantine Indicated for moderate – severe AD – Monotherapy – Combination with donepezil (Namzaric) Memantine may help mitigate some of the GI effects seen with cholinesterase inhibitors Not used for mild AD (no significant benefit according to trials) – Mild – Moderate AD and intolerant of AChIs, or have a contraindication to AChIs N-methyl-D-aspartate (NMDA) receptor antagonists Other indications for memantine: – Vascular or mixed dementia – Older adults with Down syndrome (no benefit) Memantine Dosing Memantine: initiated 5 mg once daily; the dose can be increased by 5 mg weekly to a maximum tolerated dose of 20 mg per day, usually in two divided doses. – An extended-release form for once-daily is available. – When medication is discontinued, a tapering schedule with a similar timeline should be followed. Namzaric: – Was on donepezil 10 mg: initiate Namzaric 7mg /10mg OD evening, then increase every 1 week or more to max of 28mg/10mg, if tolerated – Was on memantine daily dose of >20mg and donepezil 10 mg: Initial: 28 mg/10 mg once daily in the evening.  Monitoring Treatment – ChI and Memantine Patients symptoms should be reassessed 2-4 months after reaching maintenance dose, and every 6 months thereafter. Ø Cognition (MMSE score) Ø ADL activities Ø Overall clinical response, including SEs Medications can be used even if the MMSE score < 10 only if evidence that the drug is having a suitable effect. Monitor for: ChI: Skin rashes, GI side effects, weight loss, Afib, bradycardia, dizziness, insomnia and syncope Memantine: Headache, confusion, dizziness, hallucinations http://sydney.edu.au/medicine/cdpc/resources/deprescribing-guidelines.php When to stop ChI and Memantine?  Disease-modifying therapies (DMTs) Disease-modifying therapies (DMTs) aimed at changing the course of AD rather than managing symptoms. Monoclonal antibodies Controversial Approval Ø Aducanumab recently approved for mild AD - reduces amyloid β plaques Ø Confirm the presence of amyloid beta pathology prior to treatment initiation. Ø IV: Administered in monthly 1-hour infusions starting at 1mg/kg, over 24 weeks the dose is increased to 10 mg/kg. Ø Lecanemab approved in 2023 for mild AD - reduces amyloid β plaques Ø Confirm the presence of amyloid beta pathology prior to treatment initiation. Testing for apolipoprotein E ε4 (ApoE ε4) status prior to treatment initiation is recommended. Ø IV: 10 mg/kg once every 2 weeks. Aducanumab Aducanumab should be initiated in patients with mild cognitive impairment or mild dementia stage of the disease, who also have evidence of a buildup of amyloid plaques in the brain. This was the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease that were studied. Aducanumab may be co-administered with other drugs used in the treatment of AD including cholinesterase inhibitors (donepezil, rivastigmine, galantamine), memantine, and psychotropic agents (antidepressants, antipsychotics, hypnotics). Aducanumab – Safety Monitoring ARIA (Amyloid-related imaging abnormalities) ARIA can take the form of edema (ARIA-E) and/or microhemorrhage (ARIA-H). – Most patients (70 %) with ARIA-E are asymptomatic, but others have fatigue, headache, confusion, dizziness, falls, vision change, or nausea. – Resolves over time without long-term side effects Monitoring: – Clinical: During the titration phase, monitor for clinical symptoms: headache, confusion, focal neurologic signs including vision disturbance Serial monitoring with cognitive tests should be administered by the clinical team with each dose administration – Include family reporting – MRI: A brain MRI is required prior to initiating therapy and prior to the 5th, 7th, and 12th doses.  Dosing protocol of Aducanumab https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Aducanumab%20Flow %20chart&p=BOOKS&id=573062_Screen__Shot__2021-08-03__at__11.52.00__PM.jpg Management of behavioral and Category Medications psychological symptoms of dementia (BPSD) Depression Escitalopram and Mirtazapine Sleep-Wake Cycle Modulator Melatonin Apathy Depression Aripiprazole, Risperidone, Atypical Antipsychotics Olanzapine, and Quetiapine Anxiety Delusions Psychotic Episodes Pimavanserin Hallucinations Carbamazepine and Sexual or social disinhibition Aggressiveness Levetiracetam Sleep–wake cycle disturbances Mood Stabilizer Lithium Aggression Agitation Stimulant Methylphenidate Agitation Brexpiprazole  AD – Alternative Treatments There are studies supporting the use of: Selegiline (MAOB inhibitor) Amyloid Therapy Estrogen Therapy Anti Inflammatory agents (NSAIDs) Cholesterol Lowering medications* Herbal and dietary supplements: Ginkgo biloba Coenzyme Q Omega-3 fatty acids Vitamin E No scientific studies have proven the effectiveness of these agents in AD. TIP: What is good for the heart is good for the brain! AY22-MZ  References 1. Dr. Monica Zollezzi’s Lecture, AY22-23 PHAR380 2. Peron EP, Zimmerman KM, Crouse EL, Slattum PW, Hobgood SE. Alzheimer Disease. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e New York, NY: McGraw-Hill. 3. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet 2021; published online March 2. http://dx.doi.org/10.1016/S0140-6736(20)32205-4. 4. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer's Disease: Causes and Treatment. Molecules. 2020 Dec 8;25(24):5789. 5. Press D, Buss S. Treatment of Alzheimer disease. UpToDate, Oct 2023. AY22-MZ