ALZHEIMERS-DISEASE

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Alzheimer disease , treatment of alzheimer, pharmacology of alzheimer , all reserved by indra kumar chaudhary college of medicine

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By Dr. Indra kumar chaudhary H.A, MD PHARMACOLOGY OF ALZHEIMER'S DISEASE

Introduction:

An irreversible, progressive neurodegenerative disease that slowly destroys memory and thinking skill. M ost common form of dementia. DEMENTIA refers to progressive, irreversible decline in mental function, impairment of memory, intellectual and personality Introduction

NEUROPATHOLOGY:

Beta-amyloid plaque( neuritic plaques) -Dense deposition of proteins and some cellular materials around the nerve cells Neurofibrillary tangle - Abnormal neurons containing of paired helical filamentous structure would around each other inside the nerve cell 40-90% reduction of choline acetyltransferase NEUROPATHOLOGY

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As the disease progresses, people experience greater memory loss and other cognitive difficulties. Problems can include: ▪ wandering and getting lost ▪ trouble handling money and paying bills ▪ repeating questions ▪ taking longer to complete normal daily tasks ▪ losing things or misplacing them in odd places ▪ personality and behaviour changes Mild Alzheimer's disease

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In this stage, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought. Symptoms may include: ▪ increased memory loss and confusion ▪ problems recognizing family and friends ▪ inability to learn new things ▪ difficulty carrying out multistep tasks such as getting dressed ▪ problems coping with new situations ▪ hallucinations, delusions, and paranoia ▪ impulsive behavior Moderate Alzheimer's disease

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People with severe Alzheimer's cannot communicate and are completely dependent on others for their care. Near the end, the person may be in bed most or all of the time as the body shuts down. Their symptoms often include: ▪ inability to communicate ▪ weight loss ▪ seizures ▪ skin infections ▪ difficulty swallowing ▪ groaning, moaning, or grunting ▪ increased sleeping ▪ lack of control of bowel and bladder Severe Alzheimer's disease

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Cross sections of the brain show atrophy, or shrinking, of brain tissue caused by Alzheimer's disease.

GLUTAMATERGIC HYPOTHESIS:

Glutamate is major excitatory neurotransmitter in cortex and hippocampus. Essential for learning and memory process. NMDA type of glutamatergic receptors going to over activited in AD (Glutamatergic excitotoxicity) GLUTAMATERGIC HYPOTHESIS

N-methyl-D-aspartate receptor(NMDA) Antagonist :

N-methyl-D-aspartate receptor(NMDA) Antagonist Memantine Low to moderate affinity noncompetitive NMDA receptor antagonist for treatment of moderate to severe AD. restores the function of damaged nerve cell and reduce abnormal excitatory signals by the modulation of NMDA receptor activity Improvement in cognitive, functional and global outcome

N-methyl-D-aspartate receptor(NMDA) Antagonist:

N-methyl-D-aspartate receptor(NMDA) Antagonist PHARMACOKINETIC O ral administration as capsule-shaped, film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride well absorbed after oral administration U ndergoes partial hepatic metabolism E xcreted predominantly by kidney 70-90% and also by feces 10-25%

NMDAi cont.:

NMDAi cont. Mechanism of action It block the the activity of Glutamate by binding NMDA receptor Glutamate in normal level have significant role in memory, but if it's low then cognitive problem develop and if it's too high then cause overstimulation of nerve cell leading to cell death. Blocking the activity of glutamate, the Mg2+ binding site will intrupted. so accumulation of Ca2+ ions prevented which prevent nerve cells from apoptosis.

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K NMDA Recognition Site

NMDAi cont.:

NMDAi cont. Memantine when combined with Rivastigmine it will be more fruitful in moderate to severe Alzheimer's disease in case of failure from cholenesterase inhibitor threapy.

NMDAi cont.:

NMDAi cont. Side effects Vomiting constipation hypertension hypertonia headache insomnia Dizziness Agitation Hallucination Anxiety confusion Drowsiness Increased libido

CHOLINERGIC HYPOTHESIS:

Ach is very important neurotransmitter in brain in regions involved in memory. Loss of Ach in CNS during AD correlates with impairement of memory. In AD , NUCLEUS BASALIS OF MEYNERT (NBM) is mainly effected. CHOLINERGIC HYPOTHESIS

ACETYLCHOLINESTERASE Inhibitors:

TACRINE DONEPEZIL RIVASTIGMINE GALANTAMINE - Indicated for treatment of mild to moderate Alzheimer's disease. ACETYLCHOLINESTERASE Inhibitors

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ACETYLCHOLINESTERASE

DONEPEZIL:

DONEPEZIL An aromatic heterocyclic compound that belongs to the class of organic compounds known as n-benzylpiperidines Common names: Aricept, E2020 A noncompetitive, centrally acting reversible acetyl cholinesterase inhibitor Palliative treatment of mild to moderate dementia of the Alzheimer’s type

Pharmacokinetic:

Pharmacokinetic Absorption: Well absorbed with a relative oral bioavailability of 100% Reaches peak plasma concentration in 3-4 hrs. Volume of Distribution: 12 L/kg Metabolism: Metabolized in the liver by CYP2D6 and CYP3A4 Elimination: Half life: 70 hours Excreted in the urine both intact and extensively metabolized form and also by cytochrome P450 system

Mechanism of Action:

Mechanism of Action Involves the reversible inhibition of cholinesterases Prevents the hydrolysis of acetylcholine Leads to increased concentration of acetylcholine at cholinergic synapses

Therapeutic uses:

Therapeutic uses Main therapeutic use: Treatment of Alzheimer’s disease Have also shown to be effective in: Early-stage AD Vascular dementia Parkinson’s diseasedementia/Lewy body diseases Cognitive symptoms associayed with multiple sclerosis

Adverse effect:

Adverse effect Most common side effects: Nausea Diarrhea Vomiting Insomnia Fatigue Anorexia Muscle cramping Abnormal dreams Generally mild to moderate; occur most often during dose intiation or escalation Effects increases with increasing dose and age; occur more commonly in patients who are 85 years old, female, or of low body weight

Galantamine :

Galantamine allosterically modulates nicotinic acetylcholine receptors (nAChRs) in addition to Selective acetylcholinesterase inhibitors treatment of mild to moderate dementia Adequate penetration into the CNS Increase acetylcholine in the brain Dual mode of action

MOA:

MOA

Pharmacokinetics:

Pharmacokinetics Linear Pharmacokinetics Bioavailability: 90% Half life: 7 hours *can provide decrease inhibition at night Low (18%) plasma protein binding Hepatic metabolism via multiple pathways, primarily CYP2D6 and CYP3A4 Renal excretion

Metabolism:

Metabolism Cytochrome P450 Main metabolites *Norgalantamine *O-desmethyl-galantamine *O-desmethyl-norgalantamine *Epigalantamine *Galantaminone

SIDE EFFECTS:

SIDE EFFECTS Stomach pain nausea vomiting diarrhea Anorexia/weight loss fatigue slow heart rate depression sleepiness fainting

Drug Interactions:

Drug Interactions Produce opposite effects (counteract) Anticholinergic properties which cross into the brain atropine  benztropine (Cogentin) trihexyphenidyl (Artane) Increase blood level and SE Reduce activity of liver enzymes reduce breakdown of Galantamine  ketoconazole (Nizoral, Extina, Xolegel, Kuric)  paroxetine (Paxil)

EXCRETION:

EXCRETION Renal clearance: 20–25% of total plasma clearance 20% lower in women than in men No clinically relevant differences in clearance have been observed in populations of different age, race or CYP2D6 metabolizer phenotypes

Rivastigmine (Exelon):

used to treat dementia related to Alzheimer's disease and to Parkinson's disease does not cure either of these diseases, but it may improve memory, awareness, and the ability to perform daily functions restores the balance of neurotransmitters in the brain Rivastigmine (Exelon)

Rivastigmine (Exelon):

Mechanism of Action Reversible acetylcholinesterase inhibitor that causes an increase in concentrations of acetylcholine, which in turn enhances cholinergic neurotransmission Rivastigmine (Exelon)

Rivastigmine (Exelon):

Absorption Bioavailability: 36% (PO) Duration: 10 hr (PO); 24 hr (patch) Peak plasma time: 1 hr (PO); 8 hr (patch) Rivastigmine (Exelon)

Rivastigmine (Exelon):

Distribution Protein bound: 40% Vd: 1.8-2.7 L/kg Metabolism Metabolized by cholinesterase Elimination Half-life: 1.5 hr (PO), 3 hr (patch) Total body clearance: 1.2-2.4 L/min Excretion: Urine (97%) Rivastigmine (Exelon)

Rivastigmine (Exelon):

Adverse Effects >10% Nausea Vomiting Dizziness Diarrhea Headache Anorexia Abdominal pain 1-10% Decreased weight Insomnia Anxiety Asthenia Vertigo Fatigue Rivastigmine (Exelon)

Tacrine:

Tacrine IUPAC name: 1,2,3,4-tetrahydroacridin-9-amine Reversible cholinesterase inhibitor Able to cross blood-brain barrier Treatment of mild to moderate dementia of the Alzheimer's type

Tacrine: Pharmacokinetic:

Tacrine: Pharmacokinetic Absorption: rapidly absorb, bioavailability = 17%. Volume of distribution: 349 ± 193 L Metabolism: Hepatic Cytochrome P450 1A2 Elimination: Half-life = 2-4 hrs Excrete via urine

Tacrine: Therapeutic usage:

Tacrine: Therapeutic usage First centrally acting ChEI to be induced in clinical practice Hepatotoxicity side effects Newly developed tacrine derivatives (eg. 7-methoxytacrine) was developed to provide treatment ability with less side effects.

Tacrine: Adverse effect:

Tacrine: Adverse effect Nausea Vomiting Salivation S weating Bradycardia Hypotension Collapse Convulsions muscle weakness

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