1) Alzheimer's disease is a progressive brain disorder that destroys memory and thinking skills. The main pathologies are amyloid plaques and neurofibrillary tangles in the brain.
2) Current treatments only temporarily slow the worsening of symptoms but do not stop or reverse the disease process. Cholinesterase inhibitors and memantine are used to manage cognitive and behavioral symptoms.
3) The FDA recently approved aducanumab as the first drug that targets and reduces amyloid plaques in the brain, which may slow clinical decline in Alzheimer's disease.
4. Introduction and Definition:
• Defined as a gradual progressive dementia affecting cognition,
behavior and functional status.
• The underlying pathophysiology is still unknown & there is NO Cure.
• Drugs may reduce the disease symptoms, but the disease is
eventually fatal.
5.
6.
7. Introduction and Definition:
• AD affecting the whole family as will as the patient.
• The patient needs assistance and supervision is increases until late stages
of the disease.
• It is named after the ALOIS ALZHEIMER who characterize the disease in
1907.
8.
9. Epidemiology:
• Approximately 5.3 million Americans suffer from AD.
• Most cases of AD are in people aged > 65 years of age. But 4% of
cases are found in people younger than 65 years.
• Survival following a diagnosis of AD is between 4 – 8 years (but it may
reach 20 years).
• It is the 5th leading cause of death in patient aged more than 65 years.
11. 1. Genetic Factor:
• May contribute to errors in protein synthesis resulting in the
formation of abnormal proteins involved in pathogensis.
• EARLY ONSET AD: mutation in 3 genes (presenilin 1 on chromosome
14, amyloid precursor protein on chromosome 21, presenilin 2 on
chromosome 1) accumulation of amyloid beta in the brain
increase oxidative stress and neuronal destruction.
• LATE ONSET AD: genetic susceptibility is more sporadic, the
apolipoprotein E gene on chromosome 19 has been identified as a
strong risk factor for late onset AD.
12. 2. Other factors:
1. Age.
2. Decreased reserved capacity of the brain.
3. Head injury.
4. Down syndrome.
5. Depression.
6. Risk factor of vascular disease: atheroscelerosis, CHD, obesity, diabetes,
metabolic syndrome.
14. Pathophysioogy (Hypothesis):
• Pathological hallmarks of AD in the brain include NeuroFibrillary
Tangle (NFTs) and amyloid plaques (β-amyloid accumulations).
• In addition to; degeneration of neurons
and synapses and cortical atrophy.
15. • They are primarily located in brain regions involved in learning,
memory and emotional behaviors such as the cerebral cortex,
hippocampus, basal forebrain and amygdala.
16.
17. NeuroFibrillary Tangles (NFTs)
• They are intracellular abnormally phosphorylated tau protein.
• They interfere with neuronal function, result in cell damage, and
there presence has been correlated with the severity of dementia.
• They affect neurons that provide most of the cholinergic innervation
to the cortex.
• Unfortunately, tangles are insoluble after the cell dies, and they
cannot be removed once established.
18. amyloid plaques
• Extracellular protein deposit of beta amyloid protein.
• Beta amyloid protein undergo a conformational changes that render it
insoluble.
• Overtime, the beta amyloid protein deposits become compacted into
plaque which is become neurotoxic.
19. Acetylcholine
• As a result of plaques and tangles, the acetylcholine pathway
damaged; leading to a shortage of acetylcholine.
• This will result in learning and memory impairment.
• The loss of acetylcholine activity correlate with the disease severity.
20. Glutamate
• Glutamate is the main excitatory neurotransmitter in the CNS.
• In AD, glutamate neurotransmitter is over activated from astrocytes
found in the extracellular compartment.
• The activation of glutamate will rise the level of calcium ions, in which
it will induce secondary cascades which lead to neuronal death and
an increased production of Amelyoid Precursor Protein (APP)
22. • Aphasia: Inability to speech
• Circumlocution: the use of many words where fewer would do
• Anomia: A problem with word finding. Impaired recall of words with
no impairment of comprehension or the capacity to repeat the words
• Apraxia is a neurological disorder characterized by the inability to
perform learned (familiar) movements on command
• Agnosia is the loss of the ability to recognize objects, faces, voices, or
places.
• Executive function is a set of mental skills that include working
memory, flexible thinking, and self-control. We use these skills every
day to learn, work, and manage daily life. Trouble with executive
function can make it hard to focus, follow directions, and handle
emotions, among other things
32. Treatment –Goal of Treatment:
• PRIMARY GOAL: Symptomatic treatment of cognitive difficulties and
preserve patient function as long as possible.
• Secondary goals: Managing psychiatric and behavioral sequelae.
• Current AD treatments have not been shown:
• to prolong life
• cure AD
• or halt or reverse the pathophysiologic processes of the disorder.
33. Current therapies are aimed at either:
Current therapies only palliative and provide short-term benefit. At best,
they provide a modest reduction in the rate of loss of cognitive
functioning in Alzheimer's patients.
34. Current therapies are aimed at either:
- Improving cholinergic transmission within the CNS
- cholinesterase inhibitors (Rivastigmine, donepezil, and galantamine)
- Preventing excitotoxic actions resulting from overstimulation of N-
methyl-D-aspartic acid (NMDA)-glutamate receptors in selected brain
areas.
- NMDA-receptor antagonist (Memantine)
36. Pharmacotherapy Principles & Practice 5th Edition 2019
Clinical disease, MRI/CT to confirm, MMSE for staging
Example: Baseline MMSE is 20,,,, after 1 year the MMSE 16-18,,,so change drug
37. GENERAL APPROACH TO TREATMENT:
• Clinical trials have consistently demonstrated modest benefits of early
and continuous treatment with cholinesterase inhibitors.
• Used alone for Mild to moderate AD
• NMDA-receptor antagonist (Memantine) was added in moderate to
severe disease may also provide additional benefit. current evidence
does not support its use in earlier stages of the disease (mild).
38. GENERAL APPROACH TO TREATMENT:
• Current guidelines recommend initiation of cholinesterase inhibitors
for AD with no preference for a specific agent.
- Donepezil, rivastigmine, and galantamine are indicated in mild to moderate
AD.
- Donepezil is also indicated in severe disease.
• There is no evidence supporting combination therapy of more than
one cholinesterase inhibitor. It is reasonable to change to a different
cholinesterase inhibitor if the decline in MMSE score is greater than
two to four points after 1 year with the initial agent.
39. GENERAL APPROACH TO TREATMENT:
• Provision of education to the patient and family at the time of
diagnosis, including:
• (1) discussion of the course of illness,
• (2) realistic expectations of treatment, and
• (3) importance of legal and financial planning, are essential to appropriate
treatment.
• (4) the duration seen in 3 – 24 months
41. Cholinesterase Inhibitors:
• Work by enhancing cholinergic activity in patients with AD by
inhibiting the hydrolysis of acetylcholine through reversible inhibition
of cholinesterase.
- Donepezil.
- Rivastigmine.
- Galantamine.
42. • All have demonstrated efficacy compared with placebo, and a limited
number of direct comparisons do not suggest major differences in efficacy
or tolerability among the three drugs .
• All are used for the treatment of mild to moderate Alzheimer's disease .
Donepezil is also indicated for severe AD
• Selection of an agent is therefore based largely upon ease of use, individual
patient tolerability, cost, and clinician and patient preference.
• They have modest symptomatic benefit for cognitive, functional and global
in patients with mild – to – moderate disease. And the duration seen in 3 –
24 months.
• The benefit is modest, so the indefinite use (long life) of cholinesterase
inhibitors should not be implemented for patients without obvious benefit
or suffer from intolerable side effect.
43. They have short t ½ .
Tab & ODT
Due to GIT S/E Cap/XR cap/ solution
45. Side Effect:
1. GIT: nausea and diarrhea:
• dose related
• resolved with time or dose reduction.
• Donepezil is the least
2. weight loss and anorexia.
3. Bradycardia and hypotension. (D/C)
4. Sleep disturbances: insomnia and vivid dreams more associated with
donepezil.
46. Contraindications & Precautions:
• Contraindicated in patients with bradycardia and known cardiac
conduction system disease.
Galantamine: should not be used in patient with end stage kidney
disease (CrCl < 15 ml/min) and severe hepatic failure.
Rivastigmine: patch dosage form require dose adjustment in patient
with hepatic disease or low body weight (<50 kg).
47. Follow up & Monitoring:
• Patients who are started on a cholinesterase inhibitor should be seen
for follow-up at three and six months to assess drug tolerance (side
effects) and response (MMSE).
• A phone call at two weeks can be useful to troubleshoot early side
effects.
• Patients on a stable dose of drug are then seen every 6 to 12 months
thereafter.
• Routine laboratory monitoring is not required for any of the
cholinesterase inhibitors.
48. Assessment of Response:
• Response to cholinesterase inhibitors can be slight and gradual. We
typically counsel patients and families to anticipate a six-month trial
before making a decision about whether the medication is helping or
not.
Assessment of level of cognition:
Mini-Mental State Examination (MMSE).
Caregiver impression of change, behavioral symptoms, sleep, and
other neuropsychiatric symptoms should also be assessed at each visit.
49. Duration of treatment:
• 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.
50. Patients who do not respond initially:
• Some clinicians, patients, and families choose to stop treatment after
a six-month trial if there has been NO subjective or objective
improvement.
• HOW to D/C CHOLINESTERASE INHIBITORS?
Unless the medication is already at the lowest dose, it should be
tapered by 50 percent for two to three weeks before stopping to
minimize risk of worsening.
51. Other Reasons for Discontinuation:
• Intolerable side effects despite dose reduction.
• Rate of cognitive, functional, or behavioral decline is greater on
treatment compared with pretreatment baseline.
• Comorbidities or nonadherence make continued use of the drug
unacceptably risky or futile.
52. NMDA Receptor Antagonist: MEMANTINE
• A noncompetitive antagonist of the NMDA type of glutamate
receptors, which are located throughout the brain.
• Blocking NMDA receptors may protect neurons from this effect
without disrupting normal neurotransmission.
53. MEMANTINE:
• Clinical uses:
1. In combination with cholinesterase inhibitors when the patient
cognition reach moderate stage (MMSA =< 18).
2. As alternative to cholinesterase inhibitors (cholinesterase inhibitors
CI, allergy, intolerable side effects).
Starting dose Maintenance
dose
54.
55. New treatment for Alzheimer's disease
• According to the FDA, Aducanumab reduces beta-amyloid plaques,
which is reasonably likely to lead to a reduction in clinical decline due
to Alzheimer's disease. This could mean more time for individuals to
actively participate in daily life, have sustained independence and
hold on to memories longer.
