Drugs Used In The Treatment Of Alzheimer's Disease PDF

DRUGS USED IN THE TREATMENT OF ALZHEIMER'S DISEASE 1 DEMANS The word dementia, which is popularly called dementia in our language, is etymologically derived from the Latin word mens, which means mind, and dementia means loss of mind. As it is used in Latin, it means "the subsequent loss of the settl...

DRUGS USED IN THE TREATMENT OF ALZHEIMER'S DISEASE 1 DEMANS The word dementia, which is popularly called dementia in our language, is etymologically derived from the Latin word mens, which means mind, and dementia means loss of mind. As it is used in Latin, it means "the subsequent loss of the settled, existing, acquired mind". 2 MIND Mind includes cognitive-cognitive functions such as Orientation (person, place, time) Memory Detection Attention Intelligence Argumentation Assessing reality. 3 DEMENTIA It is a progressive, primary degenerative syndrome that leads to deterioration in cognitive functions and disrupts professional and social life. It is a physiological condition that does not disrupt social life and goes with the decrease in some functions with old age(senility) in the central nervous system and other organs, which starts with the advancement of age. 4 ETIOLOGY OF DEMENTIA Alzheimer's disease (50-70%) Multiinfarct dementia (7-20%) Alcoholic dementia (5-10%) Normal pressure hydrocephalus (1-4%) Brain tumors (1-4%) Huntington's disease (1-5%) Chronic drug intoxication (3-8%) Liver failure, depression, pernicious anemia, hypo- and hyperparathyroidism, Parkinson's disease, PSP (progressive supranuclear palsy), ALS (amyotrophic lateral sclerosis), cerebellar atrophy, neurosyphilis, AIDS, Cushing's syndrome, prion diseases, multiple sclerosis, and epilepsy (7-10%) 5 CLASSIFICATION OF DEMENTIA 6 CLASSIFICATION OF DEMENTIA Lew Body Dementia It is a special type of dementia that is associated with Parkinson's disease but in which signs of dementia appear earlier. Forgetfulness, stagnation, slowing down, dreaming, and falls are common in these patients. Niemman Pick's Disease This disease is a dementia that occurs with early language impairment and then behavioral disorders develop, in which the frontal and lateral lobes of the brain are predominantly affected. Huntingon's Korea It is a hereditary disease that begins in adulthood. Its main characteristics are chorean-style movements and mental disorders. The disease is inherited as an autosomal dominant. The main pathological findings are macroscopic atrophy in the corpus striatum, neuronal degenerations in the nucleus caudatus and other deep nuclei, as well as in the frontal cerebral cortex. 7 ALZHEIMER’S DISEASE It was described in 1907 by the German physician Alois Alzheimer. 123/100.000 Alzheimer's is a progressive dementia. The characteristic pathological findings of Alzheimer's are extracellular senile plaques in the brain, neurofibrillary tangles within neurons, synapse and neuron loss. Loss of cholinergic neurons in the basal nuclei causes amnesia and loss of cognitive function, while serotonergic and noradrenergic loss causes depression and other behavioral symptoms. 8 ALZHEIMER’S DISEASE It leads to gradual destruction of memory and the ability to learn, speak, reason, judge, communicate and carry out activities of daily living and changes in behavior. Alzheimer's Disease is the most common cause of dementia, which is popularly called "dementia". Dementia is a state of decreased mental ability that affects daily life 9 TYPES OF ALZHEIMER’S DISEASE Familial (genetic) can be 1-5% or sporadic Familial β-amyloid production due to mutations in 3 different genes Sporadically, the most important risk factor is age. It is around 5-10% over the age of 65 and 30-40% over the age of 85. 10 ALZHEIMER’S DISEASE RISK FACTORS Age Family history Depression Female gender Head traumas, previous infections Mother's age at birth Low level of education Presence of apolipoprotein E4 polymorphism (chromosome 19) 11 ALZHEIMER’S PATHOGENESIS Diffuse atrophy of the cerebral cortex, entorhinal cortex and hippocampus Senile plaques; The amount of plaques is linked to the severity of intellectual loss. Neuron Losses Loss of cholinergic neurons (degeneration of Meynert nucleus) Decrease in choline acetylase activity Decrease in the amount of acetylcholine (Acetylcholine is the main transmitter in memory and learning functions.) Decrease in the amounts of noradrenaline, serotonin and somatostatin Neurofibrillary tangle; They are intracellular double-helix filament protein strands. This is the overphosphorylated form of tau protein that stabilizes the structure of microtubules. Noradrenergic, Serotonergic, Glutaminergic neuronal loss Accumulation of aluminum, zinc, calcium Alzheimer's causes neurofibrillary degeneration Genetic factors 12 Viruses and bacteria Key neurochemical changes in Alzheimer's disease. Neurotransmitter Change in Alzheimer's disease Connection with symptoms Acetylcholine Decrease in levels Cognitive decline Glutamate Excessive glutamate neurotransmission Memory loss Dopamine Decrease in levels Deterioration in movements Serotonine Decrease in the number of serotonin receptors Changes in mood and emotions 13 From: www.niapublications.org/pubs/unraveling/01.htm From: www.niapublications.org/pubs/unraveling/01.htm Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though to be important for neuronal growth, survival, and repair. Enzymes cut the APP into fragments, the most important of which for AD is called -amyloid (beta-amyloid) or A. Beta-amyloid is “sticky” so the fragments cling together along 14 with other material outside of the cell, forming the plaques seen in the AD brain. ALZHEIMER’S PATHOGENESIS 15 ALZHEIMER’S PATHOGENESIS 16 ALZHEIMER’S PATHOGENESIS Stimulates glutamate NMDA (N-methyl D-aspartate) receptors, causing excess calcium entry into the nerve cell and cell destruction. 17 DIAGNOSTIC METHODS OF ALZHEIMER’S History, Blood tests, Physical and neurological examination Mental status examination, Neuropsychological tests Mini-mental status review (MMSE): Questionnaire scoring cognitive and behavioral status MRI, tomography, autopsy 18 TREATMENT APPROACH Primary objective: To maximize functional performance by improving cognition, mood, and behavior to improve quality of life Treatment of specific symptoms Regulations on social support, legal and care Nonpharmacological Pharmacological 19 NONPHARMACOLOGICAL Cognitive therapies (Cognitive enhancement) Personal or group treatment Regular appointments Family and carers, contact Landscaping, modifications Ensuring safety, attention 20 NONPHARMACOLOGICAL Be friendly Be witty Tailor your approach Don't talk about complicated concepts Speak slowly Be physically close to the patient Don't seem to care about the patient and the family Create an environment that will provide trust and emotional intimacy. Touch the patient 21 SYMPTOMATIC TREATMENTS Psychoses Delusions; delusion or delusion, thought that does not correspond to reality in a certain society and age, hallucinations; hallucination, perceptual disorder) Sleep disturbance Aggression, agitation 22 PHARMACOLOGICAL TREATMENT APPROACH 1- Cholinergic replacement 2- Inhibition of β amyloid formation 3- Correction of other non-cholinergic mediator deficiencies 4- Neurotrophic factor therapy 5-Reduction of free oxygen radical formation with antioxidants 6-Reducing inflammation 7- Reducing the formation of tau protein 8-Estrogen replacement 9-Apolipoprotein E: Statins 10-Cerebral vasodilators 11-Transplantation 12-Chelators, Calcium channel blockers 23 COLLERGIC AGENTS A) Cholinergic agonists: Xanomelin, Milamelin, Memric B) Cholinesterase inhibitors: Generation I Physostigmine Tacrine Generation II Donepezil Rivastigmin Galantamine Eptastigmin Huperz C) ACh precursors: Lesitin (phosphatide colin), citidine diphosphate colin, LAPC (1alpha glyceric phosphorylcholine) 24 TREATMENT ON OTHER MEDIATORS B) Glutamatergic drugs: NMDA receptor antagonists Memantin: 25 CHOLINOMIMETICS (CHOLINESTERASE INHIBITORS) They are reversible cholinesterase inhibitors that can pass to the CNS, that increase the level of ACh They do not affect peripheral cholinesterase They slow down the progression of the disease, reduce the formation of toxic amyloid They heal delusions, agitations and hallucinations They are also useful in dementia with Lewy bodies Tacrine is not used due to the high number of side effects (hepatotoxic) Donepezil, Rivastigmine, Galantamine 26 CHOLINOMIMETICS (CHOLINESTERASE INHIBITORS) They are used in mild and moderate cases Effects and side effects are similar to each other Starting with a small dose, the dose is increased slowly according to the patient's endurance Improvement in the patient's cognitive function after switching to the maintenance dose should be assessed after 2-4 months (then every 6 months) If there is no improvement within 4 months, if the condition has worsened, the dose is reduced and the treatment is discontinued. 27 COMMON SIDE EFFECTS Nausea, vomiting, decreased appetite Insomnia, confusion, fatigue, dizziness, drowsiness Arrhythmia and bradycardia Rarely, peptic ulcer It should be used with caution in ulcer susceptibility, asthma, COPD, supraventricular conduction disorders (such as sick sinus, A-V block), urinary retention and liver disorder. Contraindications: Pregnancy and lactation 28 DONEPEZIL It provides symptomatic treatment in mild and moderate Alzheimer's. Film tablet, effervescent and orally dispersible tablet forms are available. Ineffective in severe cases and non-Alzheimer's dementia. 29 DONEPEZIL CYP3A4 inhibitors (such as itraconazole and erythromycin) and CYP2D6 inhibitors (such as fluoxetine) may inhibit the metabolism of donepesil. Ketoconazole increases average donepezil concentrations by 30%. Enzyme inducers such as rifampicin, phenytoin, carbamazepine, and alcohol may lower donepezil levels. Since the significance of the inhibitory or inducing effect is unknown, such drug combinations should be used with caution. Donepezil hydrochloride has the potential to interact with drugs that have anticholinergic activity. There is also the potential for synergistic activity with concomitant treatments with drugs such as succinylcholine, other nerve and muscle blocking agents, or cholinergic agonists or beta-blocker agents that have effects on cardiac conduction. 30 RIVASTIGMINE Side effects similar to donepezil are asthenia, loss of appetite, weight loss, dizziness, abdominal pain, GI bleeding (GI symptoms are more common in women), angina pectoris, convulsions. Rivastigmine is metabolized mainly by hydrolysis by esterases. Since the basic cytochrome is metabolized at very low levels by P450 isoenzymes, no pharmacokinetic interactions with other drugs metabolized by these enzymes are expected. In view of pharmacodynamic effects, rivastigmine should not be used concomitantly with other cholinomimetic drugs and may interfere with the activity of anticholinergic drugs. As a cholinesterase inhibitor, rivastigmine may exacerbate the effects of succinylcholine-type muscle relaxants during anaesthesia. Rivastigmine may inhibit the metabolism of butyrylcholinesterasemediated metabolized drugs, although metabolic drug interactions are considered unlikely, given its metabolism. 31 RIVASTIGMINE Because rivastigmine has a plasma half-life of approximately 3.4 hours and a duration of acetylcholinesterase inhibition of approximately 9 hours, it is recommended that in cases of asymptomatic overdose all EXELON PATCH transdermal patches be removed immediately and no further patch inserted for the next 24 hours. In case of overdosage associated with severe nausea and vomiting, the use of antiemetics should be considered. For other adverse events, symptomatic treatment should be instituted as needed. In very severe overdose, atropine can be used. An initial dose of 0.03 mg/kg i.v. atropine sulfate is recommended; Subsequent doses are adjusted according to clinical response. 32 GALANTAMINE There are effervescent tablet, solution, and extended-release capsule forms. It is partially metabolized by various cytochromes, mainly CYP2D6 and CYP3A4. Contraindications: Advanced renal impairment, lactation, impaired galactose metabolism 33 MEMANTINE NMDA (N-methyl D-aspartate) is a noncompetitive receptor antagonist. Glutamate stimulates these receptors, causing excess calcium to enter the nerve cell and cause cell destruction, Memantine prevents this. Does not affect the enzyme cholinesterase Prevents the formation of β amyloid It is used in moderate and severe Alzheimer's. Side effects: Headache, dizziness, lightheadedness, confusion, hallucinations, anxiety, dyspnea It should be used with caution in epilepsy and renal dysfunction (relative contraindications). Contraindicated in severe renal insufficiency. Drug interactions: Amantadine, ketamine, dextromethorphan, dantrolene, baclofen, ranitidine, procainamide, quinine, nicotine, hydrochlorothiazide, anticholinergics, anticonvulsants, barbiturates, dopamine agonists (substances such as L-dopa, bromocriptine), neuroleptics, oral anticoagulants 34 RILUZOLE An antiglutamate agent. It inhibits glutamate release, blocks NMDA and kainate receptors, and blocks voltage-dependent Na channels. It is used in Amyotrophic Lateral Sclerosis (ALS) (a progressive disease characterized by degeneration of the upper and lower motor neurons of the brain and spinal cord. Important finding is spacity (muscle relaxants such as baclofen, tizanidine are used) 35 ADJUNCTIVE DRUGS IN THE TREATMENT OF ALZHEIMER'S For depression: Serotonin and serotonin-noradrenaline reuptake inhibitors For agitation and psychotic symptoms: Atypical antipsychotic drugs with low anticholinergic and extrapyramidal side effects are used in the smallest dose of clozapine, olanzapine, quetiapine, risperidone. 36 DRUGS THAT ARE INCONVENIENT TO USE IN ALZHEIMER’S Tricyclic antidepressants, Antiparkinsonian drugs with anticholinergic effect, Belladona alkaloids that cross the blood-brain barrier, Antispasmodics, Quinidine, Long-acting benzodiazepines It should be noted that dopaminergic antiparkinsonian drugs can easily cause hallucinations and orthostatic hypotension. 37 DIETARY PRINCIPLES TO REDUCE THE RISK OF ALZHEIMER'S 1. Minimize saturated fat and trans fat. 2. Vegetables, legumes (beans, peas, and lentils), fruits, and whole grains should be the primary elements of the diet. 3. One ounce (one small handful) of nuts or other nuts provides a healthy source of daily vitamin E 4. A reliable source of vitamin B12 (supplemental vitamin B12,) 5. Choose multivitamins without iron and copper, (if necessary, take iron if your doctor recommends it) 6. Avoid using aluminum-containing products such as baking soda, cookware, antacids, 7. 40 minutes of brisk walking 40 minutes or equivalent aerobic exercise 3 times a week 38