Alzheimer’s disease

Contents

•       Pathophysiology of Alzheimer’s
disease

•       Pharmacology of drugs used in AD

Objectives

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

a)      Explain the pathophysiology of
Alzheimer’s Disease

b)      Explain the pharmacology of drugs
used in Alzheimer’s Disease

c)       Discuss the treatment of Alzheimer’s
Disease

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

Alzheimer’s disease

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

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

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

·        
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 of Alzheimer’s disease:

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

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

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

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

Etiology of 

Alzheimer’s disease

·        
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

·        
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

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

·        
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

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

Pathogenesis of 

Alzheimer’s disease

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-

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

·        
Important
in maintaining normal cholinergic neurotransmission

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

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

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

·        
Thus
estrogen is important in maintaining normal cholinergic neurotransmission

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

·        
Prevents
cell damage by acting as an antioxidant

Role of Apo lipo protein E and cholesterol

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

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

·        
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

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

Stages
of Alzheimer’s disease:

Symptoms
of developing Alzheimer’s disease

Early stage:

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

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

·        
Repeated questions, some problems expressing and
understanding language

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

·        
Drastic personality changes may accompany
functional decline

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

Second
stage:

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

·        
Decreased
performance in the demanding employment or social situations

·        
Blunting
of emotions and apathy common

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

·        
Patients
have difficulty in finding words and names

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

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

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

Final
stage:

·        
There
is disturbance of practically all intellectual functions

·        
Patients
are disoriented and incapacitated

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

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

·        
Loss
of former personality traits

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

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

·        
Death
is usually the result of pneumonia or other infections

Diagnosis
of Alzheimer’s disease

·        
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

·        
CT or MRI

·        
Positron Emission Tomography (PET)

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

·        
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 Alzheimer’s disease

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

Nonpharmacologic Therapy/ Basic Principles of
Care for the Alzheimer’s Patient

Symptomatic Treatment of 

Alzheimer’s disease

1.
Antidepressants:

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

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

·        
All
patients with dementia should be carefully evaluated for depression

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

·        
Tricyclic antidepressants

·        
Newer
Serotonin Specific Reuptake Inhibitors

·        
Atypical antidepressants

·        
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:

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

·        
Chronic therapy of MAOI causes changes in
receptor sensitivity.

Drug interaction:

·        
Cheese

·        
Cold cough remedies

·        
Reserpine and levodopa.

These are metabolized in liver and excreted through urine.

Adverse effect:

·        
Fatigue

·        
Irritability

·        
tremor

·        
Insomnia

·        
Headache

·        
Dizziness

·        
Weight gain

·        
Blurred vision

·        
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

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

       e.g.
Nortyptyline, protryptiline, Amoxapine

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

4. Atypical
   anti-depressants: Trazadone, Bupropion, Mianserin, Nefazodone

Adverse effects

·        
Dry mouth

·        
Bad taste

·        
Constipation

·        
Epigastric distress

·        
Palpitation

·        
Blurred vision

·        
Sedation

·        
weakness

2. Hypnotics

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

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

·        
At
such times hypnotics are given

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

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

·        
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

·        
Chloral
hydrate has been used in low doses

·        
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

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

·        
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

·        
Anxiety
frequently affects patients with memory loss

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

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

4.
Neuroleptics

·        
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

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

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

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

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

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

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

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

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

·        
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   

·        
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 in Alzheimer’s disease:

Antidepressants:

Anxiolytics:

Antipsychotics:

Hypnotics:

Therapeutic treatment of Alzheimer’s disease

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

Ø  Piperidine cholinesterase inhibitor
with specificity for inhibition of acetylcholinesterase

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

Ø  Beneficial in patients with moderate
to severe AD

Ø  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

Ø  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

•      
Provide a calm,quiet environment  

•      
Provide a consistent routine

•      
Perform adls at same time each day

•      
Avoid changes in routine or environment

•      
Reassure and explain frequently

•      
Do not argue with the patient

•      
Protect safety

•      
Patient at increased risk of accidents

•      
Eliminate caffeine from the diet

GUIDELINES FOR CARE OF THE CONFUSED
PATIENT

•      
Provide activities to distract the patient from
inappropriate behavior

•      
Maintain a regular routine

•      
Use patience and understanding

•      
Maintain a calm, quiet environment

•      
Use simple, clear words and sentences

•      
Give frequent praise and reassurance

•      
Use touch and other forms of nonverbal
communication

•      
Use reality orientation

REALITY ORIENTATION

Helps the confused patient with reality by frequent
reminders of:

•      
who he is

•      
where he is

•      
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

•      
Do not respond in anger

•      
Leave and come back later if possible

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

•      
Offer distractions

•      
Communicate and reassure

•      
Be aware of your nonverbal communication

•      
Sit down, you will appear less threatening

•      
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.