Question | Answer |
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. |