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Alzheimer’s disease

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Brief Information about Alzhiemer's Disease

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Alzheimer’s disease

  1. 1. ALZHEIMER’S DISEASE Mahek Mistry 4th Pharm.D Department of Pharmacy.
  2. 2.  Alzheimer’s disease (AD) is a non- reversible, progressive dementia manifested by gradual deterioration in cognition and behavioral disturbances.  AD is primarily diagnosed by exclusion of other dementias.  There is currently no cure for AD; however, drug treatment can slow symptom progression over time.  The Alzheimer’s Association has developed a checklist of common symptoms.
  3. 3. Epidemiology and Etiology  AD is the most common type of dementia.Table-2  The prevalance of AD increases with age and it is the most prevalent in persons age 65 years and older.  The severity of AD also correlates with increasing age and is classified as mild, moderate or severe.  The mean survival time of persons with AD is reported to b approximately 6 years from the onset of the symptoms until death.
  4. 4. Epidemiology and Etiology  Although AD does not directly cause death, it is associated with an increase in various risk factors which often contribute to death such as senility, sepsis, stroke, pneumonia, dehydration, and decubitus ulcers.  Exact etiology is unknown; however, it has been suggested that genetic factors may contribute to errors in protein synthesis resulting in formation of abnormal proteins involved in the pathogenesis of AD.
  5. 5. Epidemiology and Etiology  Mutations in three genes, presenilin 1 on chromosome 21, amyloid precursor protein (APP) on chromosome 21, and presenilin 2 on chromosome 1, lead to an increase in β- A4 peptide fragments of APP which forms neuritic plaques that are the pathologic hallmark of AD.  Genetic susceptibility is more sporadic and it may be more dependent on environmental factors.
  6. 6. Epidemiology and Etiology  The apolipoprotein E (apo E) gene on chromosome19 has been identified as a strong risk factor for late-onset AD.  There are three variants of apo E; however, carriers of two or more of the apo E4 allele have an earlier onset of AD (approximately 6 years earlier) compared with non- carriers.9 Only  50% of AD patients have the apo E4 allele, thus indicating it is only a susceptibility marker.
  7. 7. Pathophysiology  The pathologic hallmarks of the disease in the brain include neurofibrillary tangles and neuritic plaques made up of various proteins, which result in a shortage of the neurotransmitter acetylcholine.  These are primarily located in brain regions involved in learning, memory, and emotional behaviours such as the cerebral cortex, hippocampus, basal forebrain, and amygdala.
  8. 8. Tangles  Neurofibrillary tangles are intracellular and consist of abnormally phosphorylated tau protein which is involved in microtubule assembly.  It interferes with neuronal function resulting in cell damage, and their presence has been correlated with severity of dementia.  These tangles are insoluble even after the cell dies, and they cannot be removed once established.  The neurons that provide most of the cholinergic innervation to the cortex are most prominently affected.  Therefore, prevention is the key to targeted therapy of these tangles.
  9. 9. Plaques  Neuritic or senile plaques are extracellular protein deposits of fibrils and amorphous aggregates of β-amyloid protein.  This formed protein is central to the pathogenesis of AD.  The β-amyloid protein is present in a non-toxic, soluble form in human brains.  In AD, conformational changes occur that render it insoluble and cause it to deposit into amorphous diffuse plaques associated with dystrophic neuritis.  Over time, these deposits become compacted into plaques and the β-amyloid protein becomes fibrillar and neurotoxic.  Inflammation occurs secondary to clusters of astrocytes and microglia surrounding these plaques.
  10. 10. Acetylcholine (Ach)  It is responsible for transmitting message b/w certain nerve cells in the brain.  In AD, plaques and tangles damage these pathways, leading to a shortage of Ach, resulting in learning and memory impairment.  The loss of Ach activity correlates with the severity of AD.  The basis of pharmacologic treatment of AD has been to improve cholinergic neurotransmission in the brain.  Acetylcholinesterase is the enzyme that degrades Ach in the synaptic cleft. Blocking this enzyme leads to an increased level of Ach with a goal of stabilizing neurotransmission.  In the United States, the four cholinesterase inhibitors approved for the treatment of AD are tacrine, donepezil, rivastigmine, and galantamine.
  11. 11. Glutamate  Primary excitatory neurotransmitter in the central nervous system (CNS) involved in memory, learning, and neuronal plasticity.  In AD, one type of glutamate receptor, N-methyl-D- aspartate (NMDA), is less prevalent than normal. There also appears to be over activation of unregulated glutamate signalling.  This results in a rise in calcium ions that induces secondary cascades which lead to neuronal death and an increased production of APP.  The increased production of APP is associated with higher rates of plaque development and hyperphosphorylation of tau protein.  The drug memantine is a non-competitive NMDA antagonist which targets this pathophysiologic mechanism.  Memantine is presently the only agent in this class that is approved for the treatment of AD.
  12. 12. Cholesterol  Increased cholesterol concentrations have been associated with AD.  The cholesterol increases β-amyloid protein synthesis which can lead to plaque formation.  Also, the apo E4 allele is thought to be involved in cholesterol metabolism and is associated with higher cholesterol levels.
  13. 13. Estrogen  Estrogen appears to have properties that protect against memory loss associated with normal aging. It has been suggested that estrogen may block β-amyloid protein production and even trigger nerve growth in cholinergic nerve terminals.  Estrogen is also an antioxidant and helps prevent oxidative cell damage.  It is important to note, however, that the Women’s Health Initiative Memory Study reported that hormone replacement with either estrogen alone or estrogen plus medroxyprogesterone resulted in negative effects on memory.
  14. 14. Clinical Presentation and Diagnosis  Diagnosing AD relies on a thorough medical and psychological history, mental status testing, and laboratory data to exclude other possible causes.  There are no biological markers other than those pathophysiologic changes found at autopsy that can confirm AD.  The diagnostic criteria are based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) or the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA).  These diagnostic criteria are 85% to 90% accurate in diagnosing AD.
  15. 15. Clinical Presentation and Diagnosis  AD is a progressive disease, which overtime affects multiple area of cognition.  The symptoms of AD can be divided in to cognitive, non-cognitive and functional symptoms.
  16. 16. Treatment  The current gold standard of treatment for cognitive symptoms includes pharmacologic management with a cholinesterase (ChE) inhibitor and/or an NMDA antagonist.  There are currently four ChE inhibitors available on the United States market: tacrine, rivastigmine, galantamine, and donepezil.  The use of tacrine is limited due to its propensity for hepatotoxicity and difficult titration schedule.  Essential elements in the treatment of AD include education, communication, and planning with the family/caregiver of the patient.
  17. 17. Nonpharmacological Treatment  Mainly this disease can be devastating to both the patient and family.  Upon the initial diagnosis, the patient and family should be counselled on the course of the illness, prognosis, available treatments, legal decisions, and quality-of- life issues.  The life of a patient with Alzheimer’s disease must become progressively more simple and structured as the disease progresses.
  18. 18. Pharmacological Treatment  Different classes of drug which is given in treatment of AD : ◦ Cholinesterase Inhibitors (Donezepil, Rivastigmine, Galatamine, Tacrine). ◦ NMDA Receptor Antagonist (Memantine).
  19. 19. Cholinesterase Inhibitors  All have the indication for the treatment of mild to moderate dementia of the Alzheimer’s type.  Tx should begin as early as possible.  ChE inhibitor therapy should be discontinued in patients who experience poor tolerance or compliance, who show a lack of clinical improvement after 3 to 6 months at optimal dosing.
  20. 20. Donezepil  It is a piperidine cholinesterase inhibitor, which reversibly and non- competitively inhibits centrally acting Acetylcholinesterase.  Approved for tc of mild to moderate dementia of the AD.  ADR with donezepil includes nausea, vomiting and diarrhea.
  21. 21. Rivastigmine  Has central activity for both the acetylcholinesterase and butyrylcholinesterase enzyme.  Approved for the treatment for mild to moderate dementia of AD.  Cholinergic side effects are common.
  22. 22. Galantamine  It is a ChE inhibitor, which elevates acrtylcholine in the cerebral cortex by slowing the degradation of acetylcholine.  It also modulates the nicotinic acetylcholine receptors to increase acetylcholine from surviving presynaptic nerve terminals.  In addition, it may increase glutamate and serotonin levels.
  23. 23. Galantamine  It is approved for the treatment of mild to moderate demtia of AD.  ADR is nausea, vomiting, diarrhea.
  24. 24. NMDA Receptor Antagonist - Memantine  It is a non-competitive anatagonist oo the N- methyl-D-aspartate type of glutamate receptor.  It regulates activity throughout the brain by controlling the amount of calcium that enters the nerve cell, a process essential for establishing an environment required for information storage.  Overstimulation of the NMDA receptor by excessive glutamate allows too much calcium into the cell, disrupting information processing.  Blocking NMDA receptors with memantine may protect neurons from the effects of excessive glutamate without disrupting
  25. 25. NMDA Receptor Antagonist  Memantine is indicated for the treatment of moderateto-severe dementia of the Alzheimer’s type.  The initial dose is 5 mg/day with increases to 20 mg/day if needed, with a minimum of 1 week between dosage increases.  Doses greater than 5 mg/day should be given in two divided doses. A suggested titration is: 5 mg/day for at least 1 week; 5 mg twice daily for at least 1 week; 15 mg/day (5 mg in the morning and 10 mg in the evening) for at least 1 week; then 10 mg twice daily.  If the patient has a creatinine clearance of 5 to 29 mL/minute, then the target dose should be 5 mg twice daily. It is likely to be given as monotherapy, but can be given in combination with ChE inhibitors.
  26. 26. NMDA Receptor Antagonist  ADR includes constipation, confusion, dizziness, headache, coughing and hypertension.  These adverse effects are similar to those experienced with ChE inhibitors. Extra monitoring should be done if memantine is given concurrently with a ChE inhibitor.
  27. 27. Thank You