AN INTERLUDE: HYPERTENSION – ALZHEIMER’S Dr. Darbha Aneeta Yizhar Academia of Noesis And Eupheus # +91 8454 075 171 + 91 9730933 851 E : [email protected]
AN INTERLUDE: HYPERTENSION – ALZHEIMER’S
Dr. Darbha AneetaYizhar Academia of Noesis And Eupheus
# +91 8454 075 171 + 91 9730933 851
HYPERTENSION
Blood pressure levels are a function of cardiac output multiplied by peripheral resistance (the resistance in the blood vessels to the flow of blood)
HYPERTENSION The major factors which help maintain blood pressure (BP) include the sympathetic nervous system and the kidneys.
Optimal healthy blood pressure is a systolic blood pressure of <120 mmHg and a diastolic blood pressure of <80
<120/80.
HYPERTENSIONCategory Systolic Blood
PressureDiastolic Blood Pressure
Normal < 120 <80
Pre-hypertension 120-139 80-89
Hypertension – Stage 1
140-159 90-99
Hypertension – Stage 2
>160 >100
PREVALENCE OF HYPERTENSION BY AGE Age
18-2930-3940-4950-5960-6970-7980+
% Hypertensive4112144546465
HYPERTENSION Normal regulatory mechanisms fail, hypertension develops.
Hypertension dangerous It gives off no warning signs or symptoms.
Untreated hypertension can result in: Arteriosclerosis --Kidney damage Heart Attack --Stroke Enlarged heart --Blindness
FACTORS INFLUENCING THE DEVELOPMENT OF HYPERTENSION
High-normal blood pressure
Family history of hypertension
African-American ancestry Overweight
FACTORS INFLUENCING THE DEVELOPMENT OF HYPERTENSION
Excess Consumption of Sodium Chloride
Certain segments of the population are ‘salt sensitive’ because their blood pressure is affected by salt consumption
FACTORS INFLUENCING THE DEVELOPMENT OF HYPERTENSION
Alcohol consumption
FACTORS INFLUENCING THE DEVELOPMENT OF HYPERTENSION Exercise Less active individuals are 30-50% more likely to develop hypertension.
FACTORS INFLUENCING THE DEVELOPMENT OF HYPERTENSION
Other Dietary Factors Potassium: Calcium: Magnesium:
TREATMENT FOR HYPERTENSION
Maintain a healthy weight, lose weight if overweight.
Be more physically active. Drink alcoholic beverages in moderation.
Reduce the intake of salt and sodium in the diet to approximately 2400 mg/day.
THE DASH DIETThe Dietary Approaches to Stop Hypertension clinical trial (DASH)
Diet rich in fruits, vegetables, and low fat dairy foods, can substantially lower blood pressure in individuals with hypertension and high normal blood pressure.
DASH STUDY Control:
Ca, Mg, & K ~ 25% of US dietMacronutrients and fiber ~ US average
Fruits and VegetablesFruits and vegetables increased to 8.5
servingsK and Mg to 75%
Combination:Add 2-3 servings low-fat dairy to fruit &
vegetable diet.Ca, K and Mg increased to 75%
DASH STUDY OUTCOMES
Fruit and Vegetable Diet:Decrease in systolic and diastolic blood
pressure in entire study group and in the hypertensive subgroup.
Combination Diet:Significant decrease in both systolic and
diastolic blood pressure in both groups.Greatest drop was in systolic BP in
hypertensive group (11.4 mmHg)
DASH DIET IMPLICATIONS Combination diet affects comparable to pharmacological trails in mild hypertension.
Population wide reductions in blood pressure similar to DASH results would reduce CHD by ~ 15% and stroke by ~27%
Great potential in susceptible groups: African Americans and elderly.
THE DASH DIET The DASH Diet includes: 7-8 servings of grains and grain
products 4-5 servings of vegetables 4-5 servings of fruits 2-3 servings of low fat dairy products 2 or less servings of meat, poultry and
fish 2-3 servings of fats and oils Nuts, seeds and dry beans 4-5 times
/week Limited ‘sweets’ low in fat.
SODIUM IN FOODS Conversion of milligrams to milliequivalents (mEq):mg/atomic weight x valence = mEq.
Atomic weight sodium = 23, valence = 1
2400 mg/23 x 1 = 104.3 mEq sodium
REDUCING SODIUM IN THE DIET Use fresh poultry, fish and lean
meat, rather than canned or processed.
Buy fresh, plain frozen or canned with “no salt added” vegetables.
Use herbs, spices and salt-free seasoning blends in cooking and at the table; decrease or eliminate use of table salt.
Choose ‘convenience’ foods that are lower in sodium.
REDUCING SODIUM IN THE DIET When available, buy low- or reduced-sodium or ‘no-salt-added’ versions of foods like:Canned soup, canned vegetables, vegetable juices
cheeses, lower in fatcondiments like soy saucecrackers and snack foods like nuts
processed lean meats
ALZHEIMER’S DISEASE AND IT’S
TREATMENT
WHAT IS ALZHEIMER’S ?
Alzheimer's disease (AD), also known as Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer’s is the most common form of dementia. This incurable, degenerative, terminal disease was first described by a German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him.
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.
Many scientists believe that Alzheimer's disease results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) in the brain that leads to nerve cell death.
Generally, it is diagnosed in people over 65 years of age, although the less-prevalent early onset of Alzheimer’s can occur much earlier.
In 2006, there were 26.6 million sufferers worldwide.
Alzheimer’s is predicted to affect 1 in 85 people globally by 2050.
Statistics of Alzheimer’s
disease
Stages of Alzheimer’s
Disease
1) Early Stage This is considered as a mild/early stage and the
duration period is 2-4 years. Frequent recent memory loss, particularly of
recent conversations and events. Repeated questions, some problems expressing
and understanding language. Writing and using objects become difficult and
depression and apathy can occur. Drastic personality changes may accompany
functional decline. Need reminders for daily activities and difficulties
with sequencing impact driving early in this stage.
Symptoms of Developing A.D
2) Second stage This is considered as a middle/moderate stage and the
duration is 2-10 years. Can no longer cover up problems. Pervasive and persistent memory loss impacts life across
settings. Rambling speech, unusual reasoning, confusion about
current events, time, and place. Potential to become lost in familiar settings, sleep
disturbances, and mood or behavioral symptoms accelerate. Nearly 80% of patients exhibit emotional and behavioral
problems which are aggravated by stress and change. Slowness, rigidity, tremors, and gait problems impact
mobility and coordination. Need structure, reminders, and assistance with activities of
daily living.
Continued
3) Moderate stage Increased memory loss and confusion. Problems recognizing family and friends. Inability to learn new things. Difficulty carrying out tasks that involve
multiple steps (such as getting dressed). Problems coping with new situations. Delusions and paranoia. Impulsive behavior. In moderate AD, damage occurs in areas of
the brain that control language, reasoning, sensory processing, and conscious thought
Continued
4) Last stage This is considered as the severe stage and the
duration is 1-3 years. Confused about past and present. Loss of
recognition of familiar people and places Generally incapacitated with severe to total loss of
verbal skills. Unable to care for self. Falls possible and immobility
likely. Problems with swallowing, incontinence, and illness. Extreme problems with mood, behavioral problems,
hallucinations, and delirium. Patients need total support and care, and often die
from infections or pneumonia
Continued
Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.
Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computer tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia.
The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.
Diagnosis of Alzheimer’s
Disease
.
PET scan of the brain of a person with AD showing a loss of function in the temporal lobe.
Neuropsychological tests such as the mini-mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.
Psychological tests for depression are employed, since depression can either be concurrent with AD, an early sign of cognitive impairment, or even the cause.
When available as a diagnostic tool, SPECT and PET neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving mental status examination. In a person already having dementia, SPECT appears to be superior in differentiating Alzheimer's disease from other possible causes, compared with the usual attempts employing mental testing and medical history analysis.
Diagnostic Tools
Scientists don’t yet fully understand what causes AD, but it is clear that it develops because of a complex series of events that take place in the brain over a long period of time. It is likely that the causes include genetic, environmental, and lifestyle factors.
Some drug therapies propose that AD is caused by reduced synthesis of the neurotransmitter acetylcholine.
Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid leading to generalized neuroinflammation.
Alzheimer's disease is characterized by a build-up of proteins in the brain. Though this cannot be measured in a living person, extensive autopsy studies have revealed this phenomenon. The build-up manifests in two ways:
Plaques– deposits of the protein beta-amyloid that accumulate in the spaces between nerve cells
Tangles – deposits of the protein tau that accumulate inside of nerve cells
Causes of Alzheimer’s
Disease
Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau protein.
Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD.
Plaques are dense, mostly insoluble deposits of amyloid – beta peptides and cellular material outside and around neurons.
Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves.
Although many older individuals develop some plaques and tangles as a consequence of ageing, the brains of AD patients have a greater number of them in specific brain regions such as the temporal lobe.
Neuropathology
Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ).
Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane.
APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis.
One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules.
These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein.
In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.
Amyloid Precursor Protein
Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.
Exactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology of AD is not known. The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilization of glucose by neurons.
Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response.
Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain derived neurotrophic factor (BDNF) have been described in AD
Mechanism
Apolipoprotein E (APOE) found on chromosome 19 appears to be a predisposing genetic risk factor for the late on-set of AD – the most typical AD.
APOE helps carry cholesterol in the bloodstream.
APOE comes in several different forms, or alleles.
Three forms—APOE ε2, APOE ε3, and APOE ε4—occur most frequently.
Apolipoprotein E
Aricept Used to delay or slow the symptoms of ADDonepezil • Loses its effect over time • Used for mild, moderate and severe AD • Does not prevent or cure AD
CelexaCitalopram Used to reduce depression and anxiety • May take 4 to 6 weeks to work • Sometimes used to help people get to sleep
Depakote Used to treat severe aggressionSodium Valproate • Also used to treat depression and anxiety
Exelon Used to delay or slow the symptoms of AD Rivastigmine • Loses its effect over time • Used for mild to moderate AD • Can get in pill form or as a skin patch • Does not prevent or cure AD
Used to reduce depression and anxiety• May take 4 to 6 weeks to work• Sometimes used to help people get to sleep
Depakote® (DEP-uh-cote)Sodium valproate (so-DEE-um VAL-pro-ate)
Used to treat severe aggression• Also used to treat depression and anxiety
Exelon® (EKS-uh-lawn)Rivastigmine (riv-uh-STIG-meen)
Used to delay or slow the symptoms of AD• Loses its effect over time• Used for mild to moderate AD• Can get in pill form or as a skin patch• Does not prevent or cure AD
Medicines used to treat A.D and its
Symptoms
Namenda Used to delay or slow the symptoms of ADMemantine • Loses its effect over time • Used for moderate to severe AD • Sometimes given with Aricept®, Exelon® • Does not prevent or cure AD
Razadyne Used to prevent or slow the symptoms of AD Galantamine • Loses its effect over time • Used for mild to moderate AD • Can get in pill form or as a skin patch • Does not prevent or cure AD
Zoloft Used to reduce depression and anxiety Sertraline • May take 4 to 6 weeks to work • Sometimes used to help people get to sleep
Trileptal Used to treat severe aggression Oxcarbazepine • Also used to treat depression and anxiety
Tegretol Used to treat severe aggression Carbamazepine • Also used to treat depression and anxiety
Remeron Used to reduce depression and anxiety Mirtazepine • May take 4 to 6 weeks to work • Sometimes used to help people get to sleep
Continued
Although there is currently no way to cure Alzheimer's disease or stop its progression, researchers are making encouraging advances in Alzheimer's treatment, including medications and non-drug approaches to improve symptom management.
Mild/Moderate AD: Cholinesterase inhibitors increase the levels of
acetylcholine in the brain, which plays a key role in memory and learning. This kind of drug postpones the worsening of symptoms for 6 to 12 months in about half of the people who take it. Cholinesterase inhibitors most commonly prescribed for mild to moderate Alzheimer's disease include Aricept (donezepil HCL), Exelon (rivastigmine), and Razadyne (galantamine).
Treatment
Moderate/Severe AD: Namenda (memantine) regulates
glutamate in the brain, which plays a key role in processing information. This drug is used to treat moderate to severe Alzheimer's disease and may delay the worsening of symptoms in some people. It may allow patients to maintain certain daily functions a little longer than they would without the medication.
Continued
Razadyne Razadyne (galantamine HBr) is FDA-approved for
mild and moderate stages of the disease. Razadyne is a cholinesterase inhibitor that prevents
the breakdown of acetylcholine in the brain. Acetylcholine plays a key role in memory and learning; higher levels in the brain help nerve cells communicate more efficiently. Razadyne also stimulates nicotinic receptors to release more acetylcholine in the brain.
Drugs for Alzheimer’s
Razadyne delays the worsening of Alzheimer's symptoms for 6 to 12 months in about half of the people who take it.
Razadyne is available in tablet and capsule form, and is commonly started at 4 mg twice a day. If it's well tolerated after 4 weeks, the dosage may be increased to 8 mg twice a day.
Razadyne also comes in an extended release, once-a-day tablet.
Razadyne is available in generic form (galantamine HBr).
Continued
Exelon (Rivastigmine) Exelon is FDA approved for mild and moderate
stages of the disease; it is also approved for the treatment of mild to moderate dementia due to Parkinson's disease.
Exelon is available as a capsule, liquid, and patch.
Continued
Exelon is a cholinesterase inhibitor that prevents the breakdown of acetylcholine and butyrylcholine in the brain by blocking the activity of two different enzymes. Acetylcholine and butyrylcholine play a key role in memory and learning.
When given orally, bioavailability is about 40% in the 3 mg dose. The compound can cross the blood-brain barrier.
Continued
Aricept (Donepizel) One of the most widely used drugs to
treat the symptoms of Alzheimer's disease. Aricept is FDA-approved for mild, moderate, and severe stages of the disease.
Continued
Aricept is available in tablet form or an orally disintegrating tablet form, and is commonly started at 5 mg a day.
Can cross the blood-brain barrier.
Continued
Namenda (Memantine) Namenda is an N-methyl D-aspartate
(NMDA) antagonist that regulates the activity of glutamate in the brain. Glutamate plays a key role in memory and learning, but excess glutamate can lead to the disruption of nerve cell communication or nerve cell death.
Continued
Studies involving Namenda have shown that the drug can slow the rate of decline in thinking and the ability to perform daily activities in individuals who have moderate to severe Alzheimer's disease
A dysfunction of glutamatergic neurotransmission is thought to be involved in the etiology of AD.
Namenda is available in generic form (memantine HCL).
Continued
A molecule designed by a Purdue University researcher to stop the debilitating symptoms of Alzheimer's disease has been shown in its first phase of clinical trials to be safe and to reduce biomarkers for the disease.
The molecule, called a beta-secretase inhibitor, prevents the first step in a chain of events that leads to amyloid plaque formation in the brain. This plaque formation creates fibrous clumps of toxic proteins that are believed to cause the devastating symptoms of Alzheimer's.
Researchers at Mount Sinai School of Medicine have found that a compound called NIC5-15, might be a safe and effective treatment to stabilize cognitive performance in patients with mild to moderate Alzheimer's disease. The two investigators, Giulio Maria Pasinetti, M.D., Ph.D. , and Hillel Grossman, M.D., presented Phase IIA preliminary clinical findings at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD) in Vienna on July 12.
New Treatments for A.D
NIC5-15's potential to preserve cognitive performance will be further evaluated in a Phase IIB clinical trial. Early evidence suggests that NIC5-15 is a safe and tolerable natural compound that may reduce the progression of Alzheimer's disease-related dementia by preventing the formation of beta-amyloid plaque, a waxy substance that accumulates between brain cells and impacts cognitive function.
Continued
http://www.sciencedaily.com/releases/2008/01/080123101629.htm
http://www.sciencedaily.com/releases/2009/07/090712145228.htm
http://www.nia.nih.gov/Alzheimers/Publications/CaringAD/other/medicines.htm
http://en.wikipedia.org/wiki/Rivastigmine http://en.wikipedia.org/wiki/Galantamine http://en.wikipedia.org/wiki/Donepezil http://en.wikipedia.org/wiki/Mementine Newsweek; 06/15/98, Vol. 131 Issue 24, p52,
2p,
References
Harvard Mental Health Letter; Apr2010, Vol. 26 Issue 10, p7-7, 1/2p
Asian Journal of Animal & Veterinary Advances; 2010, Vol. 5 Issue 1, p13-23, 11p, 1 Chart, 2 Graphs
Medical Device Daily; 2/16/2010, Vol. 14 Issue 30, p1-6, 2p
Continued
An Introduction to Medicinal Chemistry by Graham L. Patrick, pp. 589-590.
Abbott, Alison. Neuroscience: The plaque plan. Nature (London, United Kingdom) (2008), 456(7219), 161-164.
Bolognesi, Maria L.; Matera, Riccardo; Minarini, Anna; Rosini, Michela; Melchiorre, Carlo. Alzheimer's disease: new approaches to drug discovery. Current Opinion in Chemical Biology (2009), 13(3), 303-308.
Assigned Reading
What are the three stages of Alzheimer’s Disease?
What are some of the diagnostic tools of diagnosing Alzheimer’s Disease?
What drugs are used to treat mild/moderate Alzheimer’s Disease?
Which drug is most commonly used to treat Alzheimer’s Disease?
Have current pharmaceutical agents been successful in slowing the progress of Alzheimer’s Disease?
Why is it important to develop ‘biomarkers’ for Alzheimer’s Disease?
Questions