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A detailed description of the pharmacological treatments used in Alzheimer’s disease

Introduction

The nervous system is involved in the transmission of signals for communication and for coordination of body systems.The principle cell of the nervous system is a neuron, the neuron components are a cell body, dendrites, axon, synaptic terminals and myelin sheath (not always).The cell body component of the neuron integrates signals and coordinates metabolic activities.

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Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation. The axon in the neuron conducts the signal and the synaptic terminals transmit the signals. The myelin sheath is the coating on some neurons that that acts as an insulator to speed the conduction of nerve impulses, usually around only the axon of a neuron.

The transmission of a nerve impulse along a neuron from one end to the other occurs as a result of chemical changes across the membrane of the neuron. The membrane of an unstimulated neuron is polarized—that is, there is a difference in electrical charge between the outside and inside of the membrane. The inside is negative with respect to the outside. Such polarization is established by maintaining an excess of sodium ions (Na+) on the outside and an excess of potassium ions (K+) on the inside. Na+/K+ pumps in the membrane actively restore the ions to the appropriate side.

Other ions, such as large, negatively charged proteins and nucleic acids, reside within the cell. It is these large, negatively charged ions that contribute to the overall negative charge on the inside of the cell membrane as compared to the outside. In addition to crossing the membrane through leakage channels, ions may also cross through gated channels. Gated channels open in response to neurotransmitters, changes in membrane potential, or other stimuli. The following events characterize the transmission of a nerve impulse.

Resting potential: The resting potential describes the unstimulated, polarized state of a neuron.

Graded potential: A graded potential is a change in the resting potential. A graded potential occurs when the stimulus causes Na+ or K+ gated channels to open. Na+ channels open, positive sodium ions enter, and the membrane depolarizes (becomes more positive).

If the stimulus opens K+ channels, then positive potassium ions exit across the membrane and the membrane hyperpolarizes (becomes more negative).

Action potential: An action potential is capable of traveling long distances. If a depolarizing graded potential is sufficiently large, Na+ channels in the trigger zone open. In response, Na+ on the outside of the membrane becomes depolarized (as in a graded potential).

Repolarization: In response to the inflow of Na+, K+ channels open, this time allowing K+ on the inside to rush out of the cell. The movement of K+ out of the cell causes repolarization by restoring the original membrane polarization. Soon after the K+ gates open, the Na+ gates close.

Hyperpolarization: This is when K+ channels closes and more K+ has moved out of the cell. As a result, the membrane becomes hyperpolarized.

Refractory period: The membrane is polarized, but the Na+ and K+ are on the wrong sides of the membrane. During this refractory period, the axon will not respond to a new stimulus. To re-establish the original distribution of these ions, the Na+ and K+ are returned to their resting potential location by Na+/K+ pumps in the cell membrane. Once these ions are returned to their resting potential the neuron is ready for another stimulus.

Transmission of Nerve Impulses between Neurons:

The nerve impulse (action potential) travels down the presynaptic axon towards the synapse, where it activates voltage-gated calcium channels leading to calcium influx, which triggers the simultaneous release of neurotransmitter molecules from many synaptic vesicles by fusing the membranes of the vesicles to that of the nerve terminal. The neurotransmitter molecules diffuse across the synaptic cleft, bind briefly to receptors on the postsynaptic neuron to activate them, causing physiological responses that may be excitatory or inhibitory depending on the receptor.

The central nervous system (CNS) is that part of the nervous system that consists of the brain and spinal cord. The central nervous system is one of the two major divisions of the nervous system. The other is the peripheral nervous system (PNS) which is outside the brain and spinal cord.

The peripheral nervous system (PNS) connects the central nervous system (CNS) to sensory organs (such as the eye and ear), other organs of the body, muscles, blood vessels and glands.

The hippocampus is one of the first regions of the brain to suffer damage; memory problems and disorientation appear among the first symptoms. Damage to the hippocampus can also result from oxygen starvation (hypoxia), encephalitis, or medial temporal lobe epilepsy. People with extensive, bilateral hippocampal damage may experience anterograde amnesia—the inability to form or retain new memories.

Cholinesterase is a family of enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.

Cholinesterase inhibitors work by increasing levels of acetylcholine, a chemical messenger involved in memory, judgment and other thought processes. Certain brain cells release acetylcholine, which helps deliver messages to other cells. After a message reaches the receiving cell, various other chemicals, including an enzyme called acetylcholinesterase, break acetylcholine down so it can be recycled.

Alzheimer’s disease (AD) is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception. Alzheimer’s disease is a result from an increase in the production of beta-amyloid protein in the brain that leads to nerve cell death. The only way to know for certain that someone has AD is to examine a sample of their brain tissue after death. The following changes are more common in the brain tissue of people with AD: Neurofibrillary tangles which are twisted fragments of protein within nerve cells that clog up the cell. Another change which is common in brain tissue of a patient with AD is neuritic plaques (containing beta-amyloid protein) mentioned above. This results in abnormal clusters of dead and dying nerve cells, other brain cells, and aberrant protein deposits.

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When nerve cells are destroyed, there is a decrease in the chemicals/electrical signal that helps nerve cells send messages to one another, which are called neurotransmitters. As a result, areas of the brain that normally work together become disconnected.

The probability of having Alzheimer’s disease increases substantially after the age of 70 and may affect around 50% of persons over the age of 85. However Alzheimer’s disease is not a normal part of aging and is not something that certainly happens in later life, many people live to over 100 years of age and never develop Alzheimer’s disease.

Fig 1 (http://www.alz.org/brain/images/09a.jpg)

In fig 1 above is a view of how massive cell loss changes the whole brain in advanced Alzheimer’s disease. This illustration shows a crosswise “slice” through the middle of the brain between the ears. In the Alzheimer’s brain, the cortex shrivels up, damaging areas involved in thinking, planning and remembering. Shrinkage is especially severe in the hippocampus, an area of the cortex that plays a key role in formation of new memories. The ventricles spaces grow larger.

The risks factors implicated in Alzheimer’s disease are age, ApoE4, Down’s syndrome, head injury, low education and also family history i.e. genes. The main risk factor for Alzheimer’s disease is increased age. As a population ages, the frequency of Alzheimer’s disease continues to increase. Studies show that 10% of people over 65 years of age and 50% of those over 85 years of age have Alzheimer’s disease. There are also genetic risk factors for Alzheimer’s disease. Most patients develop Alzheimer’s disease after age 70. However, 2%-5% of patients develop the disease in the fourth or fifth decade of life (40s or 50s). At least half of these early onset patients have inherited gene mutations associated with their Alzheimer’s disease. Also a child of a patient with early onset Alzheimer’s disease who has one of these gene mutations has a 50% risk of developing Alzheimer’s disease. Other risk factors for Alzheimer’s disease include high blood pressure (hypertension), coronary artery disease, diabetes, and possibly elevated blood cholesterol. Individuals who have completed less than eight years of education also have an increased risk for Alzheimer’s disease. These factors increase the risk of Alzheimer’s disease, but this does not mean Alzheimer’s disease is necessarily expected in persons with these factors.

The onset of Alzheimer’s disease is usually gradual, and it is slowly progressive. Problems of memory, particularly for recent events (short-term memory) are common early in the course of Alzheimer’s disease. Mild personality changes, such as less spontaneity, apathy, and a tendency to withdraw from social interactions, may occur early in the illness. As the disease progresses, problems in abstract thinking and in other intellectual functions develop. Further disturbances in behaviour and appearance may also be seen at this point, such as agitation, irritability and a deteriorating ability to dress appropriately. Later in the course of the disorder, affected individuals may become confused or disoriented. Eventually, patients will be unable to engage in conversation, become erratic in mood, uncooperative, and lose bladder and bowel control. In late stages of the disease, persons may become totally incapable of caring for themselves, and a result of this could be death. Those who develop the disorder later in life more often die from other illnesses (i.e. heart disease).

Fig 2 – Deaths from Alzheimer’s disease: (http://www.alz.org/downloads/Facts_Figures_2011.pdf)

From Fig 2 Alzheimer’s disease is the sixth-leading cause of death in the country and the only cause of death among the top 10 in the United States that cannot be prevented, cured or even slowed. From the data in the graph, death rates have declined for most major diseases while deaths from Alzheimer’s disease have risen 66 percent during the same period.

Unfortunately, there is no cure for AD. However there are goals in treating AD, these goals are to slow the progression of the disease (although this is difficult to do), manage behaviour problems, confusion, sleep problems, and agitation, modify the home environment and support family members and other caregivers.

Cholinesterase blockers are one of the main treatments of AD. Cholinesterase inhibitors are prescribed to treat symptoms related to memory, thinking, language, judgment and other thought processes. The different cholinesterase inhibitors are Donepezil, Rivastigmine, Galanthamine, Tacrine and Memantine. The three main drugs currently licensed for the treatment of AD are Donepezil, Rivastigmine and Galanthamine.

Donepezil is the generic name and the brand name is Aricept. Donepezil is approved at all stages of Alzheimer’s disease. However the side effects of this drug are nausea, vomiting, loss of appetite and increased frequency of bowel movements. Galanthamine, brand name Razadyne, is approved for the mild to moderate stages of AD. The side effects of Galanthamine are nausea, vomiting, loss of appetite and increased frequency of bowel movements. Memantine (brand name Namenda), is approved for moderate to severe stages of AD, The side effects of this drug are headache, constipation, confusion and dizziness. Rivastigmine (brand name Exelon), approved for mild to moderate Alzheimer’s, the side effects of Rivastigmine are nausea, vomiting, loss of appetite and increased frequency of bowel movements. Tacrine (also known as Cognex), this was the first cholinesterase inhibitor and was approved in 1993 but is rarely prescribed today; this is because of associated side effects which include possible liver damage.

Cholinesterase inhibitors work by increasing levels of acetylcholine, a chemical messenger involved in memory, judgment and other thought processes. Certain brain cells release acetylcholine, which helps deliver messages to other cells. After a message reaches the receiving cell, various other chemicals, including an enzyme called acetylcholinesterase, break acetylcholine down so it can be recycled.

But Alzheimer’s disease damages or destroys cells that produce and use acetylcholine, thereby reducing the amount available to carry messages. A cholinesterase inhibitor slows the breakdown of acetylcholine by blocking the activity of acetylcholinesterase. By maintaining acetylcholine levels, the drug may help compensate for the loss of functioning brain cells.

The benefits of cholinesterase inhibitors are that people taking the cholinesterase inhibitor medications performed better on memory and thinking tests than those taking a placebo, or inactive substance. In terms of overall effect, most experts believe cholinesterase inhibitors may delay or slow worsening of symptoms for about six months to a year; although some people may benefit more dramatically or for a longer time.

Namenda is approved to treat moderate-to-severe Alzheimer’s disease. Namenda works by a different mechanism than other Alzheimer’s treatments; it is thought to play a protective role in the brain by regulating the activity of a different brain chemical called glutamate. Glutamate also plays a role in learning and memory. Brain cells in people with Alzheimer’s disease release too much glutamate (Alzheimer’s Association 2007). Namenda helps regulate glutamate activity. Namenda works by blocking the receptors for the neurotransmitter glutamate. It is believed that glutamate plays an important role in the neural pathways associated with learning and memory. In brain disorders such as Alzheimer’s disease, overexcitation of neurons produced by abnormal levels of glutamate may be associated with neuronal cell dysfunction (resulting in cognitive and memory deficits) and eventual cell death (leading to deterioration and collapse of intellectual functioning). By selectively blocking a type of glutamate receptor (NMDA receptor) while allowing for normal neurotransmission, Namenda may help reduce the excitotoxic effects associated with abnormal transmission of glutamate. (psychatlanta.com)

Namenda may have increased benefit when used with Aricept, Exelon, Razadyne, or Cognex. Memantine, a voltagegated and uncompetitive NMDA antagonist with moderate affinity, can protect neurons from excitotoxicity. It was approved for treatment of the patients with moderate to severe AD. (Alzheimer’s Association 2007)

A growing body of evidence suggest that drugs indicated for other conditions may also possess preventive efficacy for AD. Among the most promising are antioxidants, nonsteroidal, statins, certain anti hypertensive agents, alcohol, fish oil and possibly estrogen. Antioxidants have been recommended for prevention of dementia. The use of natural antioxidants may inhibit damage to the muscarinic receptors caused by free radicals, possibly by preventing or treating AD. High dietary intake of vitamins C and E lower the risk of AD. Estrogen is a weak antioxidant, it is biologically plausible that hormone replacement therapy (HRT) could protect against AD (Zandi PP et al 2002). AD is more likely to develop in a person with atherosclerotic cerebrovascular disease (Postiglione 1995). Antiatheroscleotic pharmacotherapies are used to treat atherosclerotic cerebrovascular disease, which then prevents AD from occurring (John B et al 2004). Folic acid is a AD preventer and is effective against AD. Folic acid is effective because it reduces homocysteine concentration, increased levels of homocysteine concentration increases the risk of AD. Statins is very effective at reducing the risk of AD. Statins reduce the risk of AD by reducing the cholesterol levels by interfering with the activity of enzyme. Moderate take of alcohol and intake of N-3 fatty acids reduces the risk of AD. Studies have shown that intake of N-3 fatty acids and weekly consumption of fish can decrease the risk of AD by 60 %.

Pharmacological treatments of Alzheimer’s disease are limited. Recent observational studies have shown that use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against the development of the disease, possibly through their anti-inflammatory properties.(Mahyar et al 2007)

The results from research which has been carried out has been varied. Caffeine can be used as a treatment in Alzheimer’s disease (Chuanhai et al 2009). Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs), as does adenosine, exerts effects on neurons and glial cells of all brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Caffeine, through antagonism of ARs, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases i.e. Alzheimer’s disease. (Gary W et al 2009).

Studies shows that people that take regular supplements decrease the risk of AD. Many people take folate (vitamin B9), vitamin B12, and vitamin E. However, there is no strong evidence that taking these vitamins prevents AD or slows the disease once it occurs. Recent studies have shown that people believe that the herb ginkgo biloba prevents or slows the development of dementia. However, high-quality studies have failed to show that this herb lowers the chance of developing dementia. Treatment of ancillary symptoms of Alzheimer disease has improved as well. Techniques have evolved to treat depression, sleeplessness, agitation, paranoia. Also family support is a cure in its own why which gives the patient a feel good feeling to overcome AD.

References

Volume 20, Supplement 1, 2010 – “Therapeutic Opportunities for Caffeine in Alzheimer’s Disease and Other Neurodegenerative Diseases” (Guest Editors: Alexandre de Mendonca and Rodrigo A. Cunha) Pages 3-15

Volume 20, Number 3, June 2010 – Special Issue “Basics of Alzheimer’s Disease Prevention” (Editor: Jack de la Torre) Pages 687-688

Supplement 3, November 2010 – “Anesthetics and Alzheimer’s Disease” (Guest Editors: Pravat K. Mandal and Vincenzo Fodale) – November 2010 Pages 1-3

Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline

Volume 14, Issue 1, pages 1–26, January 2007, From mild cognitive impairment to prodromal Alzheimer disease: A nosological evolution J.L. Molinuevo, C. Valls-Pedret, L. Rami, Volume 1, Issue 3, June 2010, Pages 146-154

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Mahyar Etminan et al 2003,Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies doi: 10.1136/bmj.327.7407.128, BMJ. 2003 July 19; 327(7407): 128.

Gary W Arendash, Takashi Mori, Chuanhai Cao, Malgorzata Mamcarz, Melissa Runfeldt, Alexander Dickson, Kavon Rezai-Zadeh, Jun Tan, Bruce A Citron, Xiaoyang Lin, Valentina Echeverria, and Huntington Potter. Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-%u03B2 Levels in Aged Alzheimer’s Disease Mice. Journal of Alzheimer’s Disease, Volume 17:3 (July 2009)

Chuanhai Cao, John R Cirrito, Xiaoyang Lin, Lilly Wang, Deborah K Verges, Alexander Dickson, Malgorzata Mamcarz, Chi Zhang, Takashi Mori, Gary W Arendash, David M Holzman, and Huntington Potter. Caffeine Suppresses Amyloid-%u03B2 Levels in Plasma and Brain of Alzheimer’s Disease Transgenic Mice. Journal of Alzheimer’s Disease, Volume 17:3 (July 2009)

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