Alzheimer’s disease

Alzheimer’s disease

Contents

       Pathophysiology
of Alzheimer’s disease

       Pharmacology
of drugs used in AD

Intended Learning Outcomes

By the end of this session, students will be able to:

       Explain
the pathophysiology of Alzheimer’s Disease

       Explain
the pharmacology of drugs used in Alzheimer’s Disease

       Discuss
the treatment of Alzheimer’s Disease

       Enumerate
the adverse effects of drugs used in the treatment of Alzheimer’s Disease

Alzheimer’s disease

Ø  Alzheimer’s disease (AD), first
characterized by Alois Alzheimer
a, a German psychiatrist and neuropathologist in 1907 and is a gradually progressive dementia
affecting both cognition and behavior

Ø  ‘Also
known as Senile Dementia of the Alzheimer Type (SDAT)

Ø  A
slowly progressive disease of the brain that is characterized by impairment of
memory and eventually by disturbances in reasoning, planning, language, and
perception

Ø  Many
scientists believe AD results from an increase in the production or
accumulation of a specific protein (beta-amyloid protein) in the brain leading
to nerve cell death

Epidemiology:

Ø  Disease responsible for 55% of the
total causes of dementia

Ø  Survival following AD onset
estimated to be 3 to 20 years, with an average of 8 years

Ø  Known to have affected 35.8 million
people in the world and this number is expected to increase by 1/4th
by 2050

Ø  The most prevalent cause of deaths
in adults after heart disease, cancer and stroke

Etiology

Ø  Although dementia syndrome may be
caused by 60 other disorders, most cases are due to Alzheimer’s followed by
multi infarct dementia or combination of both

Ø  The putative risk factors for the
Alzheimer’s dementia include advancing age, a history of serious head trauma,
hypothyroidism, dementia in a first circle relative and down’s syndrome in a
first circle relative

Ø   Alzheimer’s disease is correlated with
diminished neuron function and decreased neurotransmitters

Ø  The major abnormality observed in
the Alzheimer’s is a 40-90% decrease in the enzyme choline acetyl esterase in
the cerebral cortex and the hippocampus

Ø  Although acetylcholine is the major
neurotransmitter deficit associated, other neurotransmitters like somatostatin
and corticotrophin-releasing factors are also found to be decreased

Pathogenesis

Ø  Brain autopsy studies revealed that
Alzheimer’s patients have cortical atrophy, a significant loss of neurons, an
increase in the neuritic plaques and a high density of neurofibrillary
tangles
.

Neuropathologically AD destroys neurons in the cortex
and limbic areas of the brain such as:

       The basal forebrain, amygdala,
hippocampus, and cerebral cortex

       These areas are responsible for
higher learning, memory, reasoning, behaviour, and emotional control

Anatomically, four major alterations in brain structure are
seen:

       Cortical atrophy, degeneration of
cholinergic and other neurons, presence of neurofibrillary tangles (NFTs), and
the accumulation of neuritic plaques

       The signature lesions of AD are NFTs
and neuritic plaques

Neuro fibrillary
Tangles

       Aggregates of hyper phosphorylated
tau protein

       Tau protein provides structural support to
microtubules

       Aggregations of hyper phosphorylated
tau protein are also referred to as PHF, or “paired helical filaments

       When tau filaments undergo abnormal
phosphorylation at a specific site, they cannot bind effectively to
microtubules, and the microtubules collapse

       Without an intact system of
microtubules, the cell cannot function properly and eventually dies

Neuritic plaques

       Extracellular deposits of beta
amyloid (a 39- to 43-amino acid protein segment) in the gray matter of the
brain

       Primarily composed of beta amyloid
peptides and an entwined mass of broken neurites (axon and dendrite projections
of neurons)

       These polypeptides tend to aggregate
and are neurotoxic

       Plaques are variable in shape and
size, but are on average 50 µm in size

       Accumulation of aggregated amyloid
fibrils disrupts the cell’s calcium ion homeostasis and utilization of glucose
by neurons inducing apoptosis

       The βAP also accumulate in the brain
and cerebral blood vessels

       Two types of glial cells, astrocytes
and microglia, also found in plaques

       Glial cells also secrete
inflammatory mediators and serve as scavenger cells, which may be important in
causing the inflammatory processes that occur in the development of AD

       Enzymes
act on the APP (amyloid precursor protein) and cut it into fragments

       The
beta-amyloid fragment is crucial in the formation of senile plaques in AD

Inflammatory
Mediators-

       increased presence of APP (Amyloid
Precursor Protein), α1-antichromotrypsin and α2-macroglobulin, in
the serum and within amyloid plaques of patients with AD has been proved

       α1-antichromotrypsin and
α2-macroglobulin act as protease inhibitors 
affecting proteolytic breakdown of βAP

       Inflammatory mediators increase βAP
toxicity and aggregation

       The complement-derived Membrane
Attack Complex, is found associated with broken neurites and areas containing
NFTs

The cholinergic system-

       Damage occurs in any nerve cell
population located in or traveling through plaque laden areas

       Cholinergic neurons located at the
base of the forebrain in the nucleus basalis of Meynert, a brain area involved
in thought integration is profoundly damaged

       Axons of these cholinergic neurons
project to the frontal cortex and hippocampus, areas strongly associated with
memory and cognition

Other neurotransmitter abnormalities-

       Serotonergic neurons of the raphe
nuclei and noradrenergic cells of the locus ceruleus are lost

       Mao B activity is increased

       Abnormalities appear in glutamate
pathways of the cortex and limbic structures (If glutamate is allowed to remain
in the synapse for extended periods of time, it can destroy nerve cells)

Estrogen-

Ø  Promotes neuronal growth, prevents
oxidative damage, benefiting cells exposed to βAP

Ø  Important in maintaining normal
cholinergic neurotransmission

Ø  Estrogen receptors are present in
the hippocampus, cerebral cortex, and basal forebrain

Ø  Estrogen receptors colocalize with
receptors for nerve growth factor on cholinergic nerve terminals

Ø  Estrogen supplementation also
prevents decrements in choline uptake and choline acetyltransferase
concentrations

Ø  Thus estrogen is important in
maintaining normal cholinergic neurotransmission

Ø  May also increase NMDA receptor
numbers in brain areas involved in recording new memories

Ø  Prevents cell damage by acting as an
antioxidant

Role of Apo lipo protein E and cholesterol

Ø  Current research reveals the role
for Apo lipo protein E(Apo E) in the pathogenesis of Alzheimer’s disease

Ø  Apo E binds to the β-amyloid in the neurotic plaques and tangles

Ø  Identification of this ApoE4 allele
may eventually be used as a diagnostic aid or may be used for pre-symptomatic
testing for the Alzheimer’s disease

Ø  Cholesterol depletion can inhibit
the amyloidogenic pathway and prevent or slow down the plaque formation process

Stages of Alzheimer’s disease:

Symptoms of developing AD

Early stage:

Ø  A
mild/early stage with duration period 2-4 years

Ø  Frequent
recent memory loss, particularly of recent conversations and events

Ø  Repeated
questions, some problems expressing and understanding language

Ø  Writing
and using objects become difficult and depression and apathy occur

Ø  Drastic
personality changes may accompany functional decline

Ø  Need
reminders for daily activities and difficulties with sequencing impact driving
early in this stage

Second
stage:

Ø  Memory impairment progresses and
early deficits of the early stage becomes more pronounced

Ø  Decreased performance in the
demanding employment or social situations

Ø  Blunting of emotions and apathy
common

Ø  Judgement, the capacity for abstract
thinking and calculations begin to wane or are lost

Ø  Patients have difficulty in finding
words and names

Ø  Prevalence of agitation which can be
aggressive/non-aggressive, physical or verbal, can increase with disease
progression

Ø  Psychotic symptoms like
hallucinations, delusions and paranoia more become more prevalent towards the
end of this stage

Ø  Patients often become disoriented,
lost, or wander and independent living becomes hazardous

Final
stage:

Ø  There is disturbance of practically
all intellectual functions

Ø  Patients are disoriented and
incapacitated

Ø  Activities of daily living is so
impaired that independent living becomes hazardous

Ø  Marked neurologic deficits and often
increased muscle tone, akinesia, resulting in a slow and unsteady gait

Ø  Loss of former personality traits

Ø  Patients often fail to recognize
relatives or even forget their own names

Ø  Eventually become bedfast, become
incontinent of the bowel and bladder

Ø  Death is usually the result of
pneumonia or other infections

Diagnosis of AD

Ø  Usually
diagnosed clinically from the patient history, collateral history from
relatives, and clinical observations, based on the presence of characteristic
neurological and neuropsychological features and the absence of alternative
conditions

Ø  CT
or MRI

Ø  Positron
Emission Tomography (PET)

Ø  Neuropsychological tests such as the
mini-mental state examination (MMSE) are widely used to evaluate the cognitive
impairments needed for diagnosis.

Ø  Psychological tests for depression
are employed, since depression can either be concurrent with AD, an early sign
of cognitive impairment, or even the cause

Treatment of AD

Ø  Two basic divisions of the
Alzheimer’s drug treatment

  1. First division and most often
    used is symptomatic drugs that are palliative and help to control
    unwanted behaviours and maintain patient’s normal functioning. These drugs
    primarily consist of psychotropic agents.

  2. The other division is therapeutic
    drugs.
    These agents are used to stop or reverse the disease process
    and are largely experimental.

Primary
goal

       To symptomatically treat cognitive
difficulties and preserve patient
function as long as possible

Secondary
goal

       Treating the psychiatric and
behavioral sequelae that occur as a result of the disease

Symptomatic Treatment

1. Antidepressants:

Ø  Early stages of Alzheimer’s often
accompanied by depressive symptoms which may respond to drug therapy

Ø  Resolution of the depression results
in improvement of mood, functional abilities, and possibly cognitive functions

Ø  All patients with dementia should be
carefully evaluated for depression

Ø  Depressive symptoms such as
agitation, memory loss and insomnia can be easily confused with dementia

Ø  Tricyclic
antidepressants

Ø  Newer Serotonin Specific Reuptake
Inhibitors

Ø  Atypical
antidepressants

Ø  For depressed Alzheimer’s patients
who do not respond to tricyclics, SSRIs and other standard antidepressants or
those who suffer from troublesome side effects the use of MAOIs should be
considered

Classification of anti-depressants:

A) Monoamine oxidase inhibitors:

       e.g. Hydrazines,
Phenelzine, Clorgiline, selegiline, meclobemide

MOA:

Ø  MAOI
increase the concentration of NE, 5HT, DA within the normal synapse through
inhibition of the MAO enzyme.

Ø  Chronic
therapy of MAOI causes changes in receptor sensitivity.

Drug interaction:

Ø  Cheese

Ø  Cold
cough remedies

Ø  Reserpine
and levodopa.

These are metabolized in liver and excreted through urine.

Adverse effect:

Ø  Fatigue

Ø  Irritability

Ø  tremor

Ø  Insomnia

Ø  Headache

Ø  Dizziness

Ø  Weight
gain

Ø  Blurred
vision

Ø  constipation

B) Tricyclic’s:

  1. Noradrenaline
    and serotonin reuptake inhibitors
    :  these inhibit the re uptake of NA, and
    5HT- e.g. Imipramine, Amitrptyline, Doxepine, clomipramine

  1. Noradrenaline
    re uptake inhibitor:
    Inhibits the reuptake of NA.

       e.g.
Nortyptyline, protryptiline, Amoxapine

  1. Selective
    serotonin re uptake inhibitors: Fluoxetine, paroxetine, Fluvoxamine

  2. Atypical
    anti-depressants:

        Trazadone,
Bupropion, Mianserin, Nefazodone

Adverse effects

Ø  Dry
mouth

Ø  Bad
taste

Ø  Constipation

Ø  Epigastric
distress

Ø  Palpitation

Ø  Blurred
vision

Ø  Sedation

Ø  weakness

2. Hypnotics

Ø  Insomnia is a common complaint among
the elderly and it is even more prevalent in demented patients

Ø  Sleep disturbances can be manifested
by patients being awake at night, trying to go outside, or searching for lost
items

Ø  At such times hypnotics are given

Ø  Sedating antidepressants trazadone
25 to 50mg at bedtime may be beneficial

Ø  The short acting benzodiazepines triazolam,
temazepam and zolpidem are often helpful

Ø  Should be judiciously used because
they can increase confusion and memory impairment, worsen depressive symptoms
and aggrevate most other cognitive functions related to Alzheimer’s

Ø  Chloral hydrate has been used in low
doses

Ø  Has many side effects too and more
drug interactions than benzodiazepines, caution has to be taken because this
drug can exacerbate symptoms of Alzheimer’s

Ø  Diphenhydramine, used for its moderate sedating properties but has anticholinergic
effects that may increase confusion and psychotic symptoms

Ø  Alcohol intake has to be stopped or
kept at very minimum level because of its effects on cognition, disruption of
sleep pattern and other side effects

3. Anxiolytics

Ø  Anxiety frequently affects patients
with memory loss

Ø  Judicious use of benzodiazeoines and
buspirone in treating these symptoms has been successful

Ø  Buspirone effective for the anxiety
and mild agitation of the Alzheimer’s disease and has minimal side effects

4.
Neuroleptics

Ø  Indicated for specific psychotic
symptoms such as auditory and visual hallucination, paranoia, and delusions
with suspiciousness and severe agitation, which are stressful for the patients

Ø  Do not affect higher cortical
functions such as memory, judgement, and problem solving

Ø   High potency anti-psychotics (haloperidol,
fluphenazine) leave the patient prone to extrapyramidal side effects such as
parkinsonism and tardive dyskinesia

Ø  Low potency (chlorpromazine,
thioridazine) are anti cholinergic and have cardiovascular side effects

Ø  Low doses(haloperidol 0.5-1mg) given
once or twice a day are usually sufficient

Ø  The newer atypical antipsychotics(risperidone
and clozaril) with effects on dopamine and serotonin have also been beneficial
but may have extrapyramidal side effect profile

Ø  A late afternoon or early evening dose
may lessen the day time sedation and decrease “sundowning”

Ø  The benefits of these psychotropic
medications are variable and individualised effects are seen and also are
limited by the side effects

Ø  These drugs are useful and can
improve behaviour functioning, easing the patient’s distress

Ø  Antipsychotics have severe and
permanent side effects and their use must be minimised. It is indicated only
for those  symptoms that are harmful and
distressing to the patients that cannot be controlled through other means   

Ø  Because the disease is progressive,
therapy should be evaluated at least every 6 months to ensure that the fewest
drugs are being used in the lowest effective doses

Representative doses of
psychotropic medications
:

Antidepressants:

DRUG

DOSE

Fluoxetin

10mg

Nortriptyline

10mg

Paroxetin

10mg

Phenelzine

15mg

Sertaline

25mg

Anxiolytics:

DRUG

DOSE

Alprazolam

0.25mg

Buspirone

5mg

Lorazepam

0.5mg

Oxazepam

10mg

Antipsychotics:

DRUG

DOSE

Clozapine

25mg

Haloperidol

0.5mg

Risperidone

1mg

Thioridazine

10mg

Thiothixene

1mg

Hypnotics:

DRUG

DOSE

Chloral
hydrate

250-500mg

Temazepam

7.5mg

Triazolam

0.125mg

Zolpidem

5mg

Therapeutic treatment

These drugs
are being developed to slow progression of brain failure or reverse or
alleviate disease symptoms in Alzheimer’s disease patients

1.
Metabolic Enhancers

Ø  Ergoloid mesylates FDA approved for
use in the cognitive decline of the elderly

Ø  A mixture of the methane sulfonate
salts of three dihydrogenated ergot alkaloids (dihydroergocristine,
dihydroergocornine, and alpha- and beta-dihydroergocryptine)

Ø  Originally thought to act as a
cerebral vasodilator, ergoloid mesylates are now classified as metabolic
enhancers

Ø  Modulate synaptic neurotransmission

Ø  Alters glucose and oxygen
utilization

Ø  Act as α-adreno-receptor blockers and as serotonin and dopamine agonists

Ø  Should be given early in the course
of dementia

Ø  Contraindicated in individuals who
have previously shown hypersensitivity to the drug and history of psychosis

2.
Cholinergic agents

Ø  The cholinergic deficit hypothesis
provides the most viable and consistent explanation for the memory impairment
that occurs during Alzheimer’s but it does not account for all the clinical
deficits that occur

Ø  Comparisons between Alzheimer’s
disease patients and age matched controls have demonstrated neuron losses in the
nucleus basalis of Meynert, an area that is thought to provide cholinergic
input and a major cholinergic pathway leading from the septum to hippocampus, a
structure that is critical to normal memory function

Several
pharmacological efforts to augment cholinergic activity have focused on:

  1. Increasing the acetyl choline
    synthesis and release

  2. Limiting the acetyl choline
    breakdown by inhibiting acetylcholine esterase and

  3. Directly stimulating the
    acetylcholine receptors

Agents such
as choline and lecithin serve as precursors to acetylcholine

Lecithin (phosphatidyl
choline) raises the plasma choline level

Examples of Cholinergic agents

       Donepezil

       Rivastigmine

       Physostigmine

       Tacrine

       Galantamine

       Cholinesterase inhibitors block the
acetylcholinesterase(AChE) and increase the availability of the Ach in the
synaptic cleft by limiting its breakdown

       AChE inhibitors have been used most
extensively

       Administered both intravenously and
orally

       Use of physostigmine is limited
because of its short duration of action and adverse effects such as nausea,
vomiting, diarrhoea, dizziness and headache

Tacrine

Ø  Has a longer duration of action than
physostigmine

Ø  Elevates Ach levels in the cerebral
cortex and has shown encouraging results

Ø  Dose related benefits in cognitive
function such as performance of recognition and attentional tasks and improved
measures of quality life

Ø  Nausea, vomiting, diarrhoea and
anorexia are common dose related side effects

Ø  High prevalance of abnormal liver
function tests

Ø  Should be used with caution in
patients with GIT diseases, as it may increase gastric acid secretion and cardiovascular
conditions

Ø  Has a vagotonic effect  on the pulse rate and can cause bradycardia
with sick sinus syndrome (sinus node dysfunction)

Ø  Metabolised by cytochrome P450
system

Ø  Given 4 times a day in an empty
stomach

Ø  Therapy initiated at 10mg, four
times a day for 6 weeks with transaminase levels measures every other week

Donepezil

       Piperidine cholinesterase inhibitor
with specificity for inhibition of acetylcholinesterase

       Fewer peripheral side effects (such
as nausea, vomiting, and diarrhoea) than with nonspecific cholinesterase
inhibitors

       Beneficial in patients with moderate
to severe AD

       Initiated at a 5-mg/day dose in the
morning and titrated to 10 mg/day after 4 to 6 weeks if it is well tolerated

       Side effects nausea, vomiting and
diarrhoea

Rivastigmine

       Has central activity at
acetylcholinesterase and butyrylcholinesterase, but low activity at these sites
in the periphery

       Should be initiated at a dose of 1.5
mg twice daily and titrated upward at a minimum of 2-week intervals to a
maximum daily dose of 12 mg

       Not metabolized through the CYP450
enzyme system

       Cholinergic side effects are the
most common adverse effects

Galantamine

       Allosteric potentiating ligand of
human nicotinic acetylcholine receptors

       Weak competitive and reversible
cholinesterase inhibitor in all areas of the body

       Increases the concentration and thereby
action of acetylcholine in certain parts of the brain

        Modulate the nicotinic cholinergic receptors
on cholinergic neurons to increase acetylcholine release

       It is recommended that a patient be
continued on the maximum tolerated dosage, as accelerated cognitive
deterioration has been seen with dosage reductions

       Should be initiated at 8 mg/day with
dosage titration of 8 mg/day occurring at 4-week intervals

       Metabolized through the CYP450 2D6
and CYP450 3A4 pathways

3. Other
Agents

Memantine

       NMDA-antagonist

        First in a novel class of Alzheimer’s disease
medications acting on the glutamatergic system by blocking NMDA receptors

       Currently indicated for use in AD
patients with moderate to severe illness

       Has 100% bioavailability regardless
of administration with or without food. Protein binding is low

       Metabolism is minimal and is
excreted through urine unchanged

       The half-life ranges from 60 to 100
h

       Should be initiated at 5 mg once a
day and increased weekly by 5 mg a day to the effective dose of 10 mg twice
daily

       Vitamin E and Selegiline

       Lipid
lowering agents

       Gingo
biloba

       Antiinflammatory
agents- NSAIDS

GUIDELINES
FOR CARE OF PATIENT WITH ALZHEIMER’S DISEASE

Ø    Provide a calm,quiet environment        

Ø   provide a consistent routine

Ø   perform adls at same time each day

Ø   avoid changes in routine or environment

Ø   reassure and explain frequently

Ø   do not argue with the patient

Ø   protect safety

Ø   patient at increased risk of accidents

Ø   eliminate caffeine from the diet

GUIDELINES
FOR CARE OF THE CONFUSED PATIENT

Ø  Provide
activities to distract the patient from inappropriate behavior

Ø   maintain a regular routine

Ø   use patience and understanding

Ø   maintain a calm, quiet environment

Ø   use simple, clear words and sentences

Ø   give frequent praise and reassurance

Ø   use touch and other forms of nonverbal
communication

Ø   use reality orientation

REALITY
ORIENTATION

Helps the confused patient with reality by frequent
reminders of:

Ø                  who he is

Ø                  where he is

Ø                  what time it is

Always call the patient by name and identify yourself

Repeat the date, time, and place to the patient throughout
the day

GUIDELINES FOR
CARE OF THE AGGRESSIVE/COMBATIVE PATIENT

Ø  do
not respond in anger

Ø   leave and come back later if possible

Ø   be aware of warning signs of anger, such as
muscle tension, restlessness, pacing, crying, and loud speech

Ø   offer distractions

Ø   communicate and reassure

Ø   be aware of your nonverbal communication

Ø   sit down, you will appear less threatening

Ø   do not touch the patient without his
permission

Summary

       The prevalence of Alzheimer’s
disease (AD) increases with each decade of life and is more common in females.

       Neuritic plaques and neurofibrillary
tangles are the pathologic hallmarks of AD.

       AD affects multiple areas of
cognition and is characterized by a gradual onset with a slow progressive
decline.

       Early initiation and continued,
uninterrupted treatment provide the optimal cognitive benefit.

       Pharmacotherapy for AD focuses on
impacting three domains: cognition, psychiatric symptoms, and activities of
daily living.

       Cholinesterase inhibitors and
memantine are used to treat cognitive symptoms of AD.

       Slow medication dosage titration
with careful monitoring should be done to minimize the incidence of troubling
adverse drug reactions.

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