Alzheimer Disease (AD)

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2 Alzheimer Disease (AD) 2 Alzheimer's disease is a progressive degenerative disease that attacks the brain and results in impaired memory, thinking and behavior. It was first described by Dr. Alois Alzheimer in The disease begins gradually, with forgetfulness of recent events or of familiar tasks. Its progress is different for each individual, but eventually there is confusion, impaired judgment and changes in behavior. Progressive means that persons with the disease get worse over time. The average life expectancy following diagnosis is three to nine years

3 Alzheimer Disease (AD) As a person's condition declines, she or he often withdraws from family and society. Eventually most Alzheimer's patients are unable to care for themselves. Alzheimer's disease is only one form of dementia, which means a loss of cognitive and intellectual functioning. It may also be caused by strokes, and Parkinson's disease. 3

4 Alzheimer's disease The disease process is associated with plaques and tangles in the brain. 4

5 Causes of Alzheimer's disease 1. Genetics 2. Cholinergic hypothesis AD is caused by reduced synthesis of the neurotransmitter acetylcholine. 3. Amyloid hypothesis Extracellular amyloid beta (A β ) deposits are the fundamental cause of the disease 4. Tau hypothesis Tau protein abnormalities lead to the disintegration of microtubules in brain cells. 5. Other hypotheses Such as Herpes simplex viral infection or Oxidative stress 5

6 Alzheimer D Unfortunately, no curative treatment is currently available. Some medications, however, can temporarily improve symptoms and functioning for some people, although they do not prevent progression of the basic disease process. Exercise programs are beneficial with respect to activities of daily living. Treatment of behavioral problems or psychosis due to dementia with antipsychotics is common In 2010, there were between 21 and 35 million people worldwide with AD. It most often begins in people over 65 years of age. It affects about 6% of people 65 years and older. 6

7 Approach for Anti-AD Treatment Strategy With the advancing destruction of the cholinergic network, the overall quantity of ACh released decreases below the level necessary for transmission. Inhibition of acetylcholine esterase (AChE) may prolong the life of Ach in the synapse, modulating the strength and the duration of the signal 7

8 Anti-Alzheimer Drugs 8 Acetylcholine esterase inhibitors are the first group of drugs approved for AD indication. Inhibition of acetylcholine esterase (AChE) may prolong the life of Ach in the synapse, modulating the strength and the duration of the signal. The U.S. FDA has so far approved four AChE inhibitors. Tacrine, donepezil, rivastigmine & galantamine

9 Drugs 9 A. Cholinesterase inhibitors: to enhance acetylcholine Tacrine (Cognex) 1993 Donepezil (Aricept) 1997 Rivastigmine (Exelon) 1998 Galantamine (Reminyl) 2000 B. NMDA (glutamate) receptor antagonists: NMDA (N-Methyl-D-aspartate) receptor is an ionotropic type of glutamate receptors Memantine (Ebixa) 2002 Dr M Bakr 9

10 Tacrine HCl (Cognex) 1,2,3,4-Tetrahydro-9-aminoacridine, 10 NH 2 N HCl The first on the market, approved in It is an aminoacridine, It is non-classical, reversible inhibitor of acetylcholinesterase Its use has been limited because of hepatotoxicity On the basis of X-ray crystal studies it was reported that a tryptophan residue (Trp-84) at the catalytic surface of acetylcholinesterase is the binding site for the aromatic ring.

11 Donepezil (Aricept) H 3 CO H 3 CO O N Donepezil hydrochloride, approved in 1997, It is another non-classic centrally acting reversible AChEI. It exhibits greater CNS AChE selectivity, Has a longer half-life time that permits once-a-day dosing and lower hepatoxicity than Tacrine.

12 Rivastigmine (Exelon) 12 N O O N Rivastigmine Used as tartarate salt (Exelon), approved in 2000, It is a centrally selective arylcarbamate AChEI, S- isomer is active because of the slow dissociation of the carbamylated enzyme, it has been referred to as pseudo-irreversible AChEI. has a similar profile to Donepezil.

13 Galantamine HBr (Reminyl) 13 Used a HBr salt (Reminyl), approved in It is an alkaloid. Initially extracted from daffodils Specific, competitive & reversible ACHEI. It acts also as an allosteric modulator at nicotinic cholinergic receptors potentiating nicotinic cholinergic neurotransmission.

14 Mode of action 14 NH 2 O O O N O O N N N Rivastigmine AChE inhibitors. Only one is carbamate AChE inhibitor. Others bind differently They work by delaying the breakdown of acetylcholine, a brain chemical needed for nerve cells to communicate. Currently, donepezil, rivastigmine & galantamine are used significantly more than tacrine because of a lower incidence of side effects.

15 Memantine (Namenda, Axura) 1-Amino-3,5-dimethyl-adamantane 15 H 3 C NH 2 CH 3 It has been approved by the FDA in 2003 Memantine Memantine is first used as an anti-influenza agent. Memantine has been shown to be moderately efficacious in the treatment of moderate to severe AD. Its cage-like structure precludes its catabolism by oxidative enzymes, as it is excreted in the urine unchanged.

16 Memantine Memantine does not appear to be a miracle drug, but it does seem to help slow the worsening of Alzheimer symptoms, allowing patients to continue normal daily living activities for a few months longer. Some patients have reported improved memory and thinking skills, but for most, memantine just slows the progression of the disease. 16

17 Memantine: Mode of action 17 A non-competitive NMDA receptor antagonist A new class of anti-alzheimer drugs (N-methyl-D-aspartate blockers). [NMDA blockers] It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. It acts as neuroprotective as it prevents excessive influx of calcium into neuronal cells that may lead to excitotoxicity. Memantine blocks surplus amounts of a brain chemical glutamate Combination of memantine & donepezil is better than donepezil alone

18 NMDA receptor antagonist Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis. 18

19 The Anti-Alzheimer's Prescription. 1. Eat more fruits and veggies 2. Reach for berries Contains Anthocyanosides, which fight memory impairment associated with free radicals and beta-amyloid plaques in the brain 3. Increase omega-3 fatty acids Found in fatty fish like salmon, mackerel, and tuna 4. Take folic acid supplements Folic acid reduces homocysteine increasing cognitive function 5. Go Mediterranean 6. Control your blood pressure 7. Have strong social support 19

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