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Pharmacology 4-8

What are neurodegenerative diseases characterized by? Premature, primary death of specific nerve cell populations
What does neurodegeneration of functionally-linked areas produce? -movement disorders and/or -personality changes
How is each disorder characterized? Each disorder is distinct, progressive, and irreversible.
Do drugs cure neurodegenerative diseases? No, and they don't prevent degeneration either. Neither do they stimulate recovery but some drugs may retard degradation.
What are the two main classes of neurodegenerative diseases that involve malfunction of the extrapyramidal system (particularly substantia nigra and striatum)? Hypokinetic (ex: Parkinson's) and Hyperkinetic (Huntington's)
What kind of condition is Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease an example of? A neurodegenerative disease that involves muscle weakness and atrophy due to the degeneration of motor neurons in the spinal cord and cerebral cortex.
What is an example of a disease that is characterized by dementia due to degeneration of neurons in the hippocampus and cerebral cortex? Alzheimer's disease
What are the factors for selective neurodegeneration? -genetic and environmental interactions -excitotoxicity -energy metabolism -free radicals
What enzyme removes superoxide ions from the body and what do free radicals damage? Superoxide dismutase. Free radicals may produce damage of DNA, proteins, lipid peroxidation of membranes.
What is excitotoxicity? Excessive glutamate release which produces excessive influx of Ca 2+, that is excitation induced, into neurons
How does the environment and the genetics influence neurodegenerative diseases? -there's a genetic link-ex: Huntington's disease -no widespread environmental link yet established to any neurodegenerative diseases -genetic predisposition and environmental toxins, or viral infections may contribute to Parkinson's disease
Explain what role does energy metabolism play in selective neurodegeneration drug-induced or age associated decline in energy metabolism results in changes in membrane metabolism, removal of voltage dependent Mg 2+ , block of NMDA-receptor activationn and an increase in Ca 2+ influx
What is Parkinson's disease and what are some symptoms of that? A progressive neurologic disorder of muscle movement, disorder of basal ganglia. Characterized by: bradykinesia, tremors, muscular rigidity, abnormal posture, shuffling gait, mask-like face, impaired speech, inability to perform skilled tasks
What does the pathology Parkinson's disease involve? -presence of Lewy bodies (pathological oligomers of alpha-synuclein) in surviving neurons -degeneration of nigrostriatal dopamine neurons that project to the striatum
What is the etiology of Parkinson's disease -cause not established -aging, environmental and genetic factors can contribute to development of the disease
Is Parkinsonism the same as Parkinson's disease? No. Parkinsonism refers to disorders that resemble Parkinson's disease but have a known cause and variable rates of progression and responses to drug therapy -encephalitis lethargica -multiple small storkes -traumatic brain therapy -antipsychotic dru
What two pathways are involved in the normal physiology of basal ganglia? What receptors control them? Direct and indirect pathways. D1 receptors control the direct pathway and D2 receptors control the indirect one.
What normally happens during the direct and indirect pathways of the basal ganglia? Direct pathway: -DA activates the direct output pathway (GABA) -inhibits GABA neurons Indirect pathway: -DA inhibits the direct output pathway (GABA) -activates GABA neurons -inhibits Glut neurons decreases activity of GABA neurons
What happens in the basal ganglia in Parkinson's disease? -reduced amount of DA acting on D1 and D2 -direct pathway inhibited and indirect pathway activated -GABA neurons activated, Glutamate neurons inhibited -net decrease in the excitatory input to the cortex -disruption of muscle control
Give examples of the major classes of drugs and the drugs that are used in the improvement of Parkinson's disease symptoms? Increase DA synthesis: -L-Dopa -carbidpoa/L-dopa -entacapone -entacapone/L-Dopa/carbidopa Decrease DA catabolism: -selegiline -rasagiline DA receptor agonists: -bromocriptine -ropinirole -pramipexole -apomorphine Others: -amantadine
What are some antagonists of muscarinic and cholinergic receptors used with Parkison's disease? benztropine and trihexyphenidyl
What are some characteristics of L-dopa? -precursor of DA that passes BBB -decreases Parkinsonism symptoms (rigidity, tremor) -patients experience decline in response after 3-5 years -half life of 1-2 hours =orally available, rapidly absorbed from sm. intestine -only 1-3% reaches brain
What are side effects of L-dopa in the PNS? caused by the peripheral conversion of DA to NE: -nausea -vomiting -anorexia -cardiac arrhythmias -orthostatic hypotension
What are side effects of L-dopa in the CNS? -visual and auditory hallucinations -abnormal involuntary movements (dyskenesia) -may cause mood changes (depression, psychosis, anxiety)
Which medication is the medication of choice for symptomatic treatment of Parkinson's disease? Levedopa/Carbidopa-blocks peripheral metabolism of L-Dopa and increases L-Dopa availability in brain -allows to reduce dose and allows for less side effects of peripheral DA
What is Entacarpone/Levodopa/Carbidopa? A medication used to treat symptoms of Parkinson's disease. Inhibits cathechol-O-methyltransferase, decreases peripheral metabolism of L-Dopa at periphery and increases L-Dopa availability in the brain
What is Selegiline (deprenyl)? An anti-parkinson's symtpoms drug used as adjunct treatment,inhibits MAO-B, decreases production of H2O2 (and free radicals), little benefit when taken alone, may cause insomnia (caused by amphethamine/methamphetamine which is a metabolite)
What is Rosagiline? A drug used to treat symptoms of Parkinson's, selectively inhibits MAO-B in brain, not metabolized to amphetamine like Selegiline (amphetamine is what causes insomnia)
What are Bromocriptine, Ropinirole, Parmipexole? All treat Parkinson's symptoms. Bromocriptine- D2 agonis, D1 partial agonist Ropinirole-D2 and D3 agonist Pramipexole-D2 and D3 agonist
How are DA receptor agonists used clinically? -effective in monotherapy in early stage of disease or as adjunct therapy to L-Dopa in later stages of the disease -orally active -begin with low doses then increase gradually, usual maintenance dose is 10-30 mg/day.
What are some side effects presented with DA receptor agonists? -cardiovascular effects-cardiac arrhythmias, postural hypotension -neurological effects: depression, confusion, sleepiness, hallucinations, impulsivity -GI problems- nausea, vomiting -contraindicated in patients with heart or mental problems
What is Apomorphine? A DA receptor agonist drug.Acute treatment for patients with advanced disease for "off" periods. Administered subQ. Side effects; nausea, vomiting, arrhythmias, postural hypotension, hallucinations, pronounced sleepiness
What are Benztropine and or Trihehyphenidyl? Muscarinic antagonists. Alleviate tremor and rigidity (not very helpful for bradykinesia) as monotherapy or along with other drugs -block overstimulation of muscarinic receptors -side effects: blurred vision, dry mouth, urinary retention, constipation
What is Amantadine? -used to alleviate bradykinesia and rigidity in Parkinson's in patients with mild to moderate disease prior to initiation of L-Dopa. Moderately increase DA release, blocks cholinergic muscarinic receptors and glutamatergic NMDA receptors.
What are some side effects of Amantadine (used for Parkinson's)? Hallucinations and confusion, nausea, dizziness, rash of the low extremities, special caution taken when prescribing to patients with CHF and glaucoma -was originally developed as antiviral to treat influenza
What is Alzheimer's disease? -progressive dementing disorder, results from widespread degeneration of synapses and neural in cerebral cortex and hippocampus, impaired short-term memory and cognition.
What are signs and symptoms of Alzheimer's? memory loss, language deterioration,impaired ability to mentally manipulate visual information, poor judgement, confusion, restlessness and mood swings -degeneration of basal forebrain cholinergic neurons, presence of amyloid senile plaques
What are some risk factors for Alzheimer's? Age, incidence increases with age, eight leading cause of death for people over 65. Genes-mutation of the amyloid precursor protein (APP gene), 10% of cases are inherited, mutation in presenilin 1(PS1)a more agressive form of FAD,mutation in presenilin 2
What are ways to treat Alzheimer's? No cure and no way to slow progression of disease. Symptoms improved with drugs. AChE inhibitors (donezepil, galantamine, rivastigmine, tacrine) or NMDA receptor inhibitors (memantine)
What are Donezepil and or Rivastigmine? AChE inhibitors. Block ACh degradation, increase ACh, benefits may be reatined for several years, good oral bioavailability, variable half-life. Donezepil and galantamine metabolized by P450s, rivastigmine metabolized by ChE
What are some side effects of AChE inhibitors? -tremors -bradychardia -nausea, vomiting -diarrhea -anorexia
What is Memantine? Used to treat symptoms of Alzheimer's. MNDA receptor antagonist (low affinity) derivative of amantadine.Protects neurons from Ca2+ overload (excitotoxicity. Improved daily activites and cognitive function, benefits additive when given with donezepil.
What are some side effects of Memantine (Alzheimer's)? Dizziness, headache, confusion, agitation, constipation.
Created by: rcernetchi