Ch 21 (182-191) CNS Drugs for Parkinsons

Question 1

Parkinsons disease and symptoms

Answer 1

-slowly progresive neurodegenerative disorder
-sympoms:
tremor, rigidity, posutral instability, slowed movement
nonmotor symptoms: autonomic disturbances, sleep disturbances, depression, psychosis, dementia

Question 2

Parkinsons: underlying cause of motor symptoms

Answer 2

loss of dopaminergic neurons in the substantia nigra

-damage to the extrapyramidal system –> dyskinesias (disorders of movement) result
-neurotransmission is disrupted primarily in the brain’s striatum (proper fxn of the striatum requires a balance between two neurotransmitter : ACh and dopamine (ACh is an inhibitory transmitter; ACh is excitatory)
-the neurons that release dopamine INHIBIT neurons that release GABA (inhibitory neurotransmitter). Neurons that release ACh excite the neurons that release GABA
IMBALANCE results from degeneration of the neurons in the substantia nigra that supply dopamine to the striatum
-Therefore, if dopamine is absent, then GABA is releases (not inhibited)
-overactivity of GABAergic neurons contributes to the motor symptoms
neuronal degeneration begins long (5-20) years before motor symptoms appear

Question 3

Drugs Employed for parkinsons

Answer 3

neurochemical basis of parkinsons: too litle striatal dopamine and too much acetylcholine
-give drugs that can restore the functional balance between dopamine and acetylcholine

2 type of drugs used:
1. dopaminergic agents (drugs that directly or indirectly activate dopamine receptors)
2. anticholinergic agents (drugs that blcok receptors for acetylcholine

Question 4

How do dopaminergic drugs act (MOA)

Answer 4

-Levodopa is converted to dopamine which activates dopamine receptors directly
-inhibitors of monoamine oxidase-B (MAO-B) prevent dopamine breakdown
-amantadine promotes dopamine release (and may also block dopamine reuptake)
-inhibitors of catechol-O-methyltransferase (COMT) enhance the effects of levodopa by blocking its degradation

Question 5

how do anticholinergic agents work (MOA)

Answer 5

blockade of muscarinic receptors in the striatum

Question 6

Levodopa/Carbidopa

Dopamine Replacement

Answer 6

First line drug for PD
MOA: undergoes conversion to DA in the brain and then activates DA Receptors (carbidopa blocks destruction of levodopa in the periphery)

Question 7

PD
inital treatment - drug selection

Answer 7

mild symptoms–> treatment can begin with selegiline (a MAO-B inhibitor that confers mild, symptomatic benefit)
severe symptoms–> treatment can eithr begin with levodopa (combined with carbidopa) or a dopamine agonist
if improving motor fxn is primary objective –> levodopa is preferred
if drug induced dyskinesias are a primary concern –> dopamine agonsit is preferred

Question 8

management of motor fluctuations

Answer 8

long term treatment with levodopa or dopamine agonists is associated with two types of motor fluctuations: “off” time (drug isnt relieving symptoms) and drug-induced dyskinesias (involuntary movements)
-off times can be reduced with: dopamine agonsits, COMT inhibitors, MAO-B inhibitors
-only drug recommended for dyskinesias is amantadine

Question 9

Levodopa effects & loss of effect

dopamine cannot cross BBB, therefore it cannot be used to treat PD

Answer 9

Beneficial effects: may take several months to develop & long term therapy doesn’t maintain positive drug effects
Acute loss of effect: gradual loss -“wearing off” and abrupt loss-“on-off”

Question 10

Levodopa MOA

Answer 10

MOA: levo enters brain via active transport system that carries it across the BBB. once in brain, the drug undergoes uptake into the remaining dopaminergic nervve terminals that remain in the striatum. Following uptake, levo is converted to dopamine, its active form

Question 11

Levodopa Pharmacokinetics

Answer 11

administee orally, undergoes rapid absorption from SI
-high protein foods will reduce therapeutic effects (bc neutral amino acids compete with levodopa for intestinal absorption)

Question 12

Levodopa Adverse Effects

Answer 12

most are dose dependent
-Nausea and vomiting: early in treatment d/t activation of dopamine receptors in the chemoreceptor trigger zone of the medulla
-Dyskinesias: about 80% of people develop involuntary movements within the first year. managed by reducing dose, administrating amantadine
-Cardiovascular Effects: postural hypotension
-psychosis: 20% of patients. visual hallucinations, vivid dreams or nightmares, paranoid ideation (2nd generation antipsychotics can help; clozapine & quetiapine)
-CNS effects: range from anxiety and agitation to memory and cognitive impairment
-other: may darken sweat and urine, could activate malignant melanoma