ALZHEIMER’S DISEASE

SUBJECT: SYSTEMIC PHARMACOLGY

20-10-2014

MERIN BABU

M.Pharm 1st Semester

Department of Pharmacology

ALZHEIMER’S DISEASE

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 brain.

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

Absent mindness

Forgetting appointments

Confusions in some situations

Middle stage Alzheimer’s

Deeper difficulty remembering learned

information

Speech impairment

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

(PSEN1).

Mutation on chromosome 1 --- produces a protein PRESENILIN 2

(PSEN2).

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

Age

Ethnicity

Presence of apoE4 allele increases risk of developing late onset AD.

CAUSES OF ALZHEIMER’S

ENVIRONMENTAL & OTHER FACTORS:

Factors like:

- Age

- Decreased reserve capacity of brain ( decreased brain size,

decreased mental activity)

- Head injury

- Risk of vascular diseases ( Hypercholestremia, Hypertension, CHD, Obesity, Diabetes)

PATHOPHYSIOLOGY

• 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

PATHOPHYSIOLOGY

AMYLOID CASCADE HYPOTHESIS:

• Neuritic plaques ( amyloid/ senile

plaques) are extracellular lesions

found in brain & cerebral

vasculature.

• βAP plaques are formed from the

protein APP.

• Altered APP processing --- leads

to overproduction of βAP

production --- plaque formation ---

induces neurodegeneration ---

neuronal loss --- dementia.

PATHOPHYSIOLOGY

NEUROFIBRILLARY HYPOTHESIS:

• 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

collapses.

PATHOPHYSIOLOGY

INFLAMMATORY MEDIATORS:

• Brain amyloid deposition is associated with local inflammatory and

immunologic alleviations.

• It is associated with release of Nitric oxide, cytokines, other radical

species & complement factors that injure neurons and promote

inflammation.

CHOLINERGIC HYPOTHESIS:

• 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.

PATHOPHYSIOLOGY

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

nerve cells.

• 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.

SYMPTOMS

COGNITIVE NON-COGNITIVE FUNCTIONAL

Memory loss

Aphasia

Apraxia

Agnosia

Disorientation

Impaired execution function

Depression, psychotic

symptoms

( Hallucination,

delusions)

Behavioural

disturbances

( Physical & verbal

aggression,

motor hyperactivity,uncooperativeness)

Inability to care for self

SYMPTOMS

DIAGNOSIS

- 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

LAB TESTS TO BE PERFORMED :

DIAGNOSIS:

CT or MRI scan.

TREATMENT FOR CONGNITIVE SYMPTOMS IN AD

MILD-MODERATE DISEASE:

Cholinesterase Inhibitor:

DONEPEZIL

RIVASTIGMINE

GALANTAMINE

MODERATE-SEVERE DISEASE:

Anti-glutamatergic drug:

MEMANTINE

CHOLINESTERASE INHIBITORS

1st line therapy for the symptomatic treatment of cognitive symptoms in mild-

moderate AD.

TACRINE:

• 1St cholinesterase inhibitor approved for the treatment of Alzheimer’s

disease.

• 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

ENZYME INHIBITED

AChE AChE, BuChE AChE

MECHANISM Non-competitive Non-competitive Competitive

INDICATION Mild- Severe AD Mild-moderate AD Mild- moderate AD

METABOLISM CYP 2D6CYP 3A4

Esterase CYP 2D6CYP3A4

ADVERSE EFFECTS

Nausea

VomitingDiarrhoea

Nausea, Vomiting,

Diarrhoea, Loss of

appetite, muscle

weakness, Weight loss

Nausea, Vomiting,

Diarrhoea, Loss of appetite, Weight loss

CHOLINESTERASE INHIBITORS

NMDA RECEPTOR ANTAGONIST

MEMANTINE:

- New NMDA receptor antagonist

- Slow the functional decline in

moderate- severe AD.

- Better tolerated than other anti-ChE

- Side effects:

constipation

tiredness

headachedrowsiness

DRUG MOA STUDIES TRIAL SPONSOR

SEMAGACESTAT Drug blocks the

enzyme γ-secretase (

along with β-

secretase) is

responsible for APP proteolysis

A study of

Semagacestat

for Alzheimer’s patient

Phase 3 Eli lily & company

EVP-6124 Study of the

safety and

effectiveness

of two doses

of

investigational

study drug

EVP-6124 in

subjects with

Alzheimer’s disease

Phase 3 FORUM

pharmaceuticals

NEWER ADVANCES

NEWER ADVANCES

DRUG STUDIES TRIAL SPONSOR

R (+) PRAMIPEXOLE Safety study of R (+)

Pramipexole to treat early AD

Phase 2 Virginia

Commonwealth University

REFERENCE

i. Laurence L.B, Bruce A C, Bjorn C K. Goodman and Gilman’s The

Pharmacological Basis of Therapeutics.2011. 12th edition. China: Mc Graw Hill

books; pp: 619- 623.

ii. Dipiro J T, Talbert R L, Yee G C et al. Pharmacotherapy- A Pathophysiological

Approach. 7th edition. China : Mc Graw Hill books; pp: 1085.

iii. Roger Walker, Cate Whittlesea. Clinical pharmacy and therapeutics. 5th edition.

Sydney: Churchill Livingstone; 2012.

iv. KD Tripathi, Essentials of medical pharmacology. 6th edition. New Delhi : Jaypee

Brothers Medial Publishers; 2009.

v. http://wikipedia.com

vi. www.clinicaltrials.org