SUBJECT: SYSTEMIC PHARMACOLGY
M.Pharm 1st Semester
Department of Pharmacology
AD is a progressive neurodegenerative
disorder which affects older individual's
and is common cause of dementia.
Dementia- is the long term loss of ability
to think, memorise clearly.
Atrophy of cortical and subcortical areas
is associated with the deposition of β-
amyloid protein in form of plaques and
formation of neurofibrillary tangles.
There is marked cholinergic deficiency in
STAGES OF ALZHEIMER’S DISEASE
Effects of aging on memory but not AD
Forgetting things occasionally
Misplacing items sometimes
Minor short term memory loss
Early stages of Alzheimer’s
Confusions in some situations
Middle stage Alzheimer’s
Deeper difficulty remembering learned
Late stage Alzheimer;s
Loss of self- awareness
CAUSES OF ALZHEIMER’S- EARLY ONSET
Due to alterations on chromosome 1,14 and 21.
Mutation on chromosome 14 --- produces a protein PRESENILIN 1
Mutation on chromosome 1 --- produces a protein PRESENILIN 2
PRESENILIN 1 & 2 encode for membrane protein involved for AMYLOID
PRECURSOR PROTEIN (APP).
Mutations lead to activity of γ-secretase , an enzyme important in β-
amyloid peptide (βAP) formation.
APP is encoded on chromosome 21.
Mutation on APP gene – overproduction of βAP.
CAUSES OF ALZHEIMER’S- LATE ONSET
Due to apo-lipoprotein E ( apoE) gene.
Gene responsible for production of apoE gene – chromosome 19.
Inheritance of apoE4 allele posses genetic risk in sporadic AD.
Degree of risk depends on:
Number of copies of apoE4 genes
Presence of apoE4 allele increases risk of developing late onset AD.
CAUSES OF ALZHEIMER’S
ENVIRONMENTAL & OTHER FACTORS:
- Decreased reserve capacity of brain ( decreased brain size,
decreased mental activity)
- Head injury
- Risk of vascular diseases ( Hypercholestremia, Hypertension,
CHD, Obesity, Diabetes)
• Lesions in Alzheimer’ disease are:
neuritic plaques and neurofibrillary tangles ( NFTs)
located in cortical areas and medial temporal lobe structures of brain.
• Several mechanisms involved in pathogenesis of AD:
-- βAP aggregation & deposition --- leads to plaque formation.
-- Hyperphosphorylation of Tau protein --- leads to NFT development
-- Inflammatory processes
-- Dysfunction of neurovasculature
-- Oxidative stress
-- Mitochondrial dysfunction
AMYLOID CASCADE HYPOTHESIS:
• Neuritic plaques ( amyloid/ senile
plaques) are extracellular lesions
found in brain & cerebral
• βAP plaques are formed from the
• Altered APP processing --- leads
to overproduction of βAP
production --- plaque formation ---
induces neurodegeneration ---
neuronal loss --- dementia.
• NFTs are found in cells of hippocampus
& cerebral cortex in AD patients.
• NFTs are composed of abnormally
hyper-phosphorylated Tau protein.
• Tau protein provides structural support
to microtubules, cell’s transportation and
skeletal system support.
• When Tau filaments undergo abnormal
phosphorylation at specific site, they
can’t bind to microtubules, thereby
• Brain amyloid deposition is associated with local inflammatory and
• It is associated with release of Nitric oxide, cytokines, other radical
species & complement factors that injure neurons and promote
• Loss of cholinergic activity correlates with AD severity.
• In late AD, number of cholinergic neurons are decreased, loss of
nicotinic receptors in hippocampus and cortex.
OTHER NEUROTRANSMITTER ABNORMALITIES:
• Glutamate & other excitatory amino acid NTs act as potential
neurotoxins for AD.
• If glutamate remains in synapse for a long period of time : destroys
• Blocking of NMDA receptors decreases the glutamate activity in
synapse – decreases cellular injury in AD.
BRAIN VASCULAR DISEASE & HIGH CHOLESTROL:
• ApoE lipoprotein (synthesised in liver, CNS and CSF) carries cholesterol
in blood through brain.
• ApoE4 is associated with increased deposition of βAP.
• Increased cholesterol in brain neurons --- alter membrane functioning ---
leads to plaque formation --- Alzheimer’s disease.
COGNITIVE NON-COGNITIVE FUNCTIONAL
( Physical & verbal
Inability to care for self
LAB TESTS TO BE PERFORMED :
- Rule out Vitamin B12 & folate deficiency.
- Rule out hypothyroidism with Thyroid
functioning tests (TFTs)
- Conduct Blood cell counts, kidney function
test and Liver function test
CT or MRI scan.
TREATMENT FOR CONGNITIVE SYMPTOMS IN AD
1st line therapy for the symptomatic treatment of cognitive symptoms in mild-moderate
• 1St cholinesterase inhibitor approved for the treatment of Alzheimer’s
• It was the 1st centrally acting anti-ChE.
• It inhibits both AChE and BuChE.
• Used to treat mild-moderate AD.
• Now, used rarely because of hepatotoxicity.
DONEPEZIL RIVASTIGMINE GALANTAMINE
AChE AChE, BuChE AChE
MECHANISM Non-competitive Non-competitive Competitive
INDICATION Mild- Severe AD Mild-moderate AD Mild- moderate AD
METABOLISM CYP 2D6
Esterase CYP 2D6
Diarrhoea, Loss of
Diarrhoea, Loss of
appetite, Weight loss
NMDA RECEPTOR ANTAGONIST
- New NMDA receptor antagonist
- Slow the functional decline in
moderate- severe AD.
- Better tolerated than other anti-ChE
- Side effects:
DRUG MOA STUDIES TRIAL SPONSOR
SEMAGACESTAT Drug blocks the
enzyme γ-secretase (
along with β-
responsible for APP
A study of
Phase 3 Eli lily &
EVP-6124 Study of the
of two doses
Phase 3 FORUM
DRUG STUDIES TRIAL SPONSOR
R (+) PRAMIPEXOLE Safety study of R (+)
Pramipexole to treat early
Phase 2 Virginia
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