Anti alzheimer agent

MEDICINAL CHEMISTRY NOTES

1. Anti-Alzheimer Agent By Mrs. Dhanashri R Mali Assistant Professor, GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik

2. Alzheimer Disease is the most common cause of dementia in people 65 years and older. Affects 10% of people over the age of 65 and Affects 50% of people over the age of 85. contributes to 60-70% of cases of dementia.

3. Defination Dementia is a syndrome characterized by disturbance of multiple brain functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgement . Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily manifesting as a loss of memory, senile dementia, causes problems with memory, thinking and behavior. It is not a normal part of aging.

4. Origin of Alzheimer's Disease The disease was first described by Dr. Alois Alzheimer, a German physician, in 1906. Alzheimer had a patient named Auguste D, in her fifties who suffered from what seemed to be a mental illness. But when she died in 1906, an autopsy revealed dense deposits, now called neuritic plaques, outside and around the nerve cells in her brain. Since Dr. Alois Alzheimer's was the first person who discovered the disease, AD was named after him.

5. Symptoms and sign of AD Gradually worsening difficulty in remembering new information Confusion, disorganized thinking, impaired judgment, trouble expressing themselves Disorientation to time, space & location SIGNS Ten warning signs of Alzheimer's disease 1) Memory loss 2) Difficulty to performing familiar tasks 3) Problems with language 4) Disorientation to time and place 5) Poor or decreased judgment 6) Problems with abstract thinking 7) Misplacing things 8) Changes in mood or behavior 9) Changes in personality 10) Loss of initiative

6. Diagnostic criteria Multiple cognitive deficits manifested by memory impairment and one or more of aphasia, apraxia , agnosia or disturbance in executive functioning. Significant impairment in social or occupational functioning. Gradual onset and continuing cognitive decline Symptoms not due to neurologic, systemic or substance abuse conditions known to cause dementia.

7. Etiology Advancing Age Female sex Family history Trauma Education Environmental factors: Aluminum, Mercury, Viruses Vascular diseases: Stroke Genetic factors

8. Pathogenesis The brains of individuals with Alzheimer’s have an abundance of plaques and tangles. Plaques are deposits of a protein fragment called beta- amyloid that build up in the spaces between nerve cells. Amyloid precursor protein (APP) is a type-I transmembrane glycoprotein. It has referred that 11 amino acid sequence of ß- amyloid protein is neurotoxic for primary neurons.

9. Function of APP is still unclear & believed to be important during development of CNS & in response to s Amyloid beta, also written A β, is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP). They undergo a dramatic conformational change to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils. These fibrils deposit outside neurons in dense formations known as senile plaques or neuritic plaques.

10. ß- amyloid protein accumulation and diffuse plaque formation is associated with local microglial activation, cytokine release, reactive astrocytosis , and a multiprotein inflammatory response. The effects of ß- amyloid initiated inflammatory and neurotoxic processes, including excessive generation of free radicals and peroxidative injury to proteins and other macromolecules in neurons.

11. Tangles are twisted fibers of another protein called tau that build up inside cells. In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells. Tau protein acts to stabilize microtubules in the cell cytoskeleton .

12. In AD, tau is changed chemically and undergoes hyperphosphorylation . Neurofibrillary tangles consist partly of hyperphosphorylated tau, which then links together to form filaments, the density of which is thought to be directly related to the severity of dementia. The resulting effect is to compromise microtubular function, with the eventual destruction of the neurone . These lead to a decline in levels of acetylcholine ( ACh ) within synapses

13. They disable or block communication among nerve cells and disrupt processes the cells need to survive. The destruction and death of nerve cells causes memory failure, personality changes, problems in carrying out daily activities and other symptoms of Alzheimer’s disease.

14. Pathological features Brain shrinkage & localised loss of neurons, mainly in the hippocampus & basal forebrain Loss of cholinergic neurons in the hippocampus & frontal cortex Diffuse atrophy of cerebral cortex & enlargement of ventricular system

15. Treatment There is currently no cure for AD. Currently available medications offer relatively small symptomatic benefit for some patients, but do not slow down disease progression. Goal for treatment: Primary prevention of disease by intervention in key pathogenic mechanisms at a pre-symptomatic stage. Symptomatic improvement consist of enhanced cognition

16. Treatment Acetylcholinesterase inhibitors ( AChEIs ): Tacrine , Donepezil , Galantamine , Rivastigmine Non-competitive N-methyl-D- aspartate (NMDA) receptor antagonist: Memantine Other adjuvant: Antidepressents . Anxiolytics . Antipsychotics. Anticonvulsants

17. Acetylcholinesterase inhibitors ( AChEI ) Acetylcholinesterase ( AChE ) inhibition is important because there is a reduction in the activity of the cholinergic neurons in AD. Mechanism of action: The AChEIs act by preventing the enzymatic degradation of the neurotransmitter acetylcholine ( ACh ) resulting in increased ACh concentrations in the synaptic cleft & enhanced cholinergic transmission

18. Tacrine 1st AChEI approved by FDA for treatment of AD parasympathomimetic and a centrally acting reversible cholinesterase inhibitor no longer used now due to hepatotoxicity Major side effects: GI symptoms (Nausea, Diarrhea, Cramps), altered sleep, bradycardia & muscle cramps Caution when using in people with cardiac conduction conditions such as symptomatic bradycardia or with a history of falls

19. Donepezil A reversible inhibitor of AChE . More hydrophobic & has longer duration of action Readily cross blood–brain barrier to inhibit AChE in the CNS Approx. 96% bound to plasma proteins, An elimination half-life of 70 hours. Indicated for the treatment of symptoms of mild-to-moderate Alzheimer disease.

20. Rivastigmine It is a pseudoirreversible noncompetitive carbamate inhibitor of AChE . Half-life is approximately 2 hours, The inhibitory properties last for 10 hours because of the slow dissociation of the drug from the enzyme. FDA approved its use in mild-to-moderate Alzheimer disease in April 2000. In 2007, for use in managing mild-to-moderate dementia associated with Parkinson disease.

21. Galantamine an alkaloid extracted from the tuberous plant Leucojum aestivum (L.) belonging to the Amaryllidaceae family. A reversible inhibitor with no effect on butyrylcholinesterase . Intranasal galantamine achieved therapeutically relevent drug levels exceeding that of oral dosing & avoided GI side effects

22. NMDA ANTAGONISTS Recent evidence of the involvement of glutaminergic neuronal excito -toxicity in the aetiology of AD. Acts by blocking overexcited NMDA receptors which blocks entry of Ca++ thereby decreasing glutamate release & inhibiting processes which led to neurotoxicity

23. Memantine a novel NMDA receptor antagonist. Mechanism of action: Voltage dependent, low moderate affinity, uncompetitive NMDA receptor antagonism with fast blocking/unblocking kinetics Blocks effect of excessive glutamate, preserving physiologic activation of NMDA receptors required for learning & memory. Adverse effects are mild & reversible and may include headache or dizziness

24. Characteristic Donepezil Rivastigmine Galantamine Memantine Primary mechanism AChE-I AChE-I AChE-I NMDA receptor antagonist Starting dose 5 mg daily 1.5 mg bd (oral) 4 mg bd 5 mg daily Usual treatment (max dose) 10 mg daily 6 mg bd (oral) 12 mg bd 20mg daily Plasma levels increased by Ketoconazole Erythromycin Itraconazole Quinidine Fluoxetine cocaine Ketoconazole Erythromycin Ritonavir Quinidine Paroxetine Fluoxetine Cimetidine Ranitidine Procainamide Quinidine Nicotine

25. Thank you