Anti-Parkinsons/ Neurodegenerative Diseases Flashcards
As of now, what is the major role of drugs used to treat neurodegenerative diseases?
Retard neuronal degeneration
Neurodegenerative diseases mainly affect extrapyramidal systems. What is an example of 2 areas usually affected? What is usually spared?
Substancia Nigra, Striatum
Cortex
What is an example of a hypokinetic neurodegenerative disorder? A hyperkinetic one?
Hypo - Parkinson
Hyper - Huntingtons
What is a neurodegenerative disease involving muscle
weakness and atrophy due to degeneration of motor neurons in the spinal cord and cerebral cortex?
Amyotrophic lateral sclerosis (ALS)
What is a neurodegenerative disease characterized by
dementia due to degeneration of neurons in the hippocampus and cerebral cortex?
Alzheimers
What are three elements that may contribute to Parkinson’s disease?
Genetic predisposition
Environmental toxins
Viral Infections
What is a progressive neurological disease characterized by impaired voluntary movement and tremors at rest, bradykinesia, muscular rigidity, mask like facce and impaired speech?
Parkinson’s disease
What dopaminergic neuronal population is lost in Parkinson’s disease? How much of the population in lost before symptoms are seen? What is another hallmark of these neurons?
Nigrostriatal Dopamine Pathway
80% neuronal loss before symptoms
Lewy bodies in the surviving neurons
What is the protein that aggregates to form Lewy bodies?
alpha-Synuclein
Parkinson’s disease is considered an idiopathic disease. Why?
Because the exact cause of the disease is not known
What is the difference between Parkinsonism and Parkinson’s disease? What are 2 known drug causes of Parkinsonism?
Parkinsonism, known cause for the symptoms
Parkinson’s, no known cause for disease
Haloperidol and Chlorpromazine
Regarding the normal physiology of the basal ganglia, what is the major dopamine receptor of the direct pathway? What is the effect of dopamine on the direct pathway? What is the net effect of direct pathway activation and how?
D1 receptor
Dopamine activates the direct pathway
Facilitation of movement, inhibit GABA to thalamus
Regarding the normal physiology of the basal ganglia, what is the major dopamine receptor of the indirect pathway? What is the effect of dopamine on the indirect pathway? What is the net effect of indirect pathway activation?
D2
Dopamine inhibits the indirect pathway
Inhibition of movement
What is the effect of degeneration of basal ganglia neurons of dopamine levels? What is the effect of loss of DA on the direct pathway? Indirect pathway? On overall movement and why?
Reduction of dopamine release
Direct pathway now inhibited
Indirect pathway now activated
Movement in inhibited because of less excitatory input to cortex
There are 4 examples of drugs used to treat Parkinsons that increase dopamine synthesis. They are _
L-DOPA
L-DOPA/Carbidopa
Entacapone
Entacapone/L-DOPA/Carbidopa
There are 2 examples of drugs used to treat Parkinsons that decrease the catabolism of dopamine. They are _
Selegiline
Rasagiline
There are 4 examples of drugs used to treat Parkinsons that act as DA receptor agonists. They are _
Bromocriptine
Ropinirole
Pramipexole
Apomorphine
There are 2 examples of drugs used to treat Parkinsons that act as muscarinic antagonists. They are _
Benzotropine
Trihexyphenidyl
What is L-DOPA? What Parkinson symptoms does it treat? What is the L-DOPA wearing off effect?
Dopamine precursor that crosses BBB
Decreases rigidity and tremor
After 3-5 years, decreased effects of the medication in patients
What is the enzyme that metabolizes L-DOPA in the periphery such that only 1-3% of the drug reaches the brain?
aromatic l-amino acid decarboxylase
What is the basis of peripheral side effects of L-DOPA? What are some examples (5)?
Peripheral conversion of DA to NE
nausea, vomiting, anorexia, cardiac arrhythmias, orthostatic hypotension
What are 3 general CNS side effects of L-DOPA?
Hallucinations
Dyskinesia (invol. movements)
Mood changes
What is the medication of choice for the treatment of Parkinson’s disease? What is the mechanism? How does this drug improve the side effect profile of L-DOPA
- L-DOPA/Carbidopa
- Carbidopa blocks aromatic l-amino acid decarboxylase in the periphery, more L-DOPA reaches brain.
- Use less L-DOPA, less side effects
What is the mechanism if action of entacapone/Levodopa/Carbidopa ?
Entacapone blocks catechol-O-methyltransferase, which further decreases metabolism of L-DOPA. More L-DOPA reaches brain
What is the mechanism of action of selegiline? How is it used to treat Parkinson’s disease?
Selegiline blocks monoamine oxidase B, reduces DA catabolism.
Also reduces formation of neurotoxic free radical
Used as adjunct in combination with L-DOPA
What is the reason behind the selegiline side effect of insomnia?
It is metabolized to methamphetamine and amphetamine
In addition to selegiline, what is another MAO-B inhibitor used to treat Parkinson’s? How is it advantageous over selegiline?
Rasagiline
It is not metabolized to methamphetamine and amphetamine, so no insomnia
Bromocriptine, ropinirole and pramipexole are all agonists at dopamine receptors. What subtypes do they bind to?
Bromocriptine - D1 and D2
Ropinirole and Pramipexole - D2 and D3
Bromocriptine, ropinirole and pramipexole are all agonists at dopamine receptors. What is the timeline for their use in treating Parkinson’s disease?
Early in disease, can use alone
Late in disease, use in combination with L-DOPA
What types of side effects can be expected when using Bromocriptine, ropinirole and pramipexole? (3)
Cardiovascular
GI
Neurological
What patient population should not use Bromocriptine, ropinirole and pramipexole? (2)
Mental Problem patients
Heart problem patients
What is apomorphine? How is it administered? How should it NOT be administered?
Dopamine receptor agonist
Should be administered IM
Should not be administered IV, causes thrombus or pulmonary embolism
What are 2 muscarinic antagonists used in the treatment of Parkinson’s disease? What symptoms do they alleviate (2)? Why do these drugs function in Parkinson’s disease?
Benztropine and Trihexyphenidyl
Tremor and rigidity
Usually, nigrostriatal DA neurons inhibit Ach release, lost in Parkinson’s disease
Of the drugs that are used to treat Parkinson’s disease, which are likely to produce blurred vision, dry mouth, urinary retention, constipation, aggravation of glaucoma?
Benztropine and Trihexyphenidyl
Are muscarinic antagonists, list is of typical antimuscarinic effects
What are the symptoms alleviated by amantadine? What are the mechanisms (3)?
Reduces bradykinesia and rigidity
- increase DA release
- Blocks cholinergic receptors
- Blocks NMDARs
What drug used to treat Parkinson’s is associated with the following side effects: hallucinations and confusion, nausea, dizziness, rash of the low extremeties? What patients should not use this drug?
Amantadine
Patients with congestive heart disease, patients with glaucoma
What disease is associated with degeneration of basal forebrain cholinergic neurons, amyloid plaque, neurofibrilary tangles and loss of Neurons in the cortex and hippocampus?
Alzheimers
What are the 2 major pathways affected in Alzheimer’s disease?
Nucleus Basalis cholinergic pathway
Septohippocampal cholinergic pathway
What are the 3 risk factors for Alzheimer’s disease?
Age
Gender
Genes
What are the 4 genes associated with Alzheimers? Which are associated with early onset AD and late onset AD?
Amyloid precursor protein - APP - Early
Presenilin 1 - Early
Presenilin 2 - Early
Apolipoprotein E4 - Late
What are 4 drugs used to treat Alzheimer’s disease that work by inhibiting acetylcholinesterase?
Donepezil
Galantamine
Rivastigmine
Tacrine
Arrange donepezil, galantamine, rivastigmine and tacrine in order of decreasing half life
Donepezil - 70 hrs
Galantamine - 7hrs
Tacrine - 3 hrs
Rivastigmine - 1.5 hrs
What are the CYP enzymes responsible for the metabolism of donepezil, galantamine, rivastigmine and tacrine? Which is metabolized by plasmacholinesterase as well?
CYP3A4 and CYP2D6
Rivastigmine
While donepezil, galantamine, rivastigmine and tacrine are all relatively safe, which is likely to be associated with hepatotoxicity? What are other side effects associated with these drugs?
Tacrine
Tremors, diarrhea, anorexia, bradycardia, nausea and vomiting
What is memantine? What other drug for AD is it related to? What is its mechanism (i,e. how is it protective)? Benefits are observed when administered with what other drug?
NMDA receptor antagonist
Derivative of amantadine
Blocks NMDA receptors and assoc. calcium influx that can be neurotoxic
Beneficial if admin. with donepezil
Dizziness, headache, confusion, agitation, constipation. These are all side effects associated with _
Memantine
