Pharmacology of Parkinson’s Disease Flashcards Preview

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Flashcards in Pharmacology of Parkinson’s Disease Deck (22):
1

Know the pathways of excitation/inhibition in the basal ganglia, and how it related to the neurochemistry of Parkinson's Disease

In Parkinson’s disease, dopamine is not produced due to death of cells in the substantia nigra.

The result on the D1 side of the path is that the GPi is not inhibited the way it should be causing unopposed inhibition from the GPi to the VL thalamus (Too much inhibition)

The result on the D2 side of the path is that the medium spiny neurons of the striatum are NOT inhibited so they fire GABA signs like crazy causing unopposed inhibition of the GPe. This unopposed inhibition means the GPe can’t fire its own GABA neurons, so the STN is highly active. The result of a highly active glutaminergic STN is excitation of the GPi. And as above, the GPi inhibits the VL thalamus, once again causing too much inhibition of the system.

Thus, loss of dopamine causes too much inhibition on both the D1 and D2 arm of the pathway, inhibiting the thalamus’s signaling ability to the cortex. Clinically, this presents as freezing; the inability to start moving even when thinking about moving.

2

Rational of using Dopamine receptor agonists

Don't replace dopamine, but do BIND to D2 receptors and agonize dopamine effects. Have large half-lives and are able to give sustained dopaminergic activity. Less risk of dyskinesia than with L-DOPA

3

Rational of using L-DOPA and carbidopa

L-DOPA is an intermediate produce in the synthesis of dopamine endogenously. Since Parkinson’s is a disease of too little dopamine synthesis, giving L-DOPA can help replenish some of the missing dopamine in the brain. Carbidopa cannot cross the BBB but can inhibit degradation of L-DOPA in the guy and liver by blocking dopamine decarboxylase. Thus, by giving L-DOPA with carbidopa, you can deliver a high dose of L-DOPA to the brain where it can be converted to dopamine in the basal ganglia.

4

Rational of using Anticholinergic Drugs

When there is loss of dopamine, there is over-activity of cholinergic interneurons in the putamen and caudate (DA inhibits ACh). The anticholingerics used in Parkinson’s block muscarinic receptors. These drugs are less effective than L-DOPA, but are sometimes used as initial therapy for tremor. However, side effects make these drugs difficult to tolerate.

5

Rational of using Monoamine Oxidase Inhibitors

MAO is responsible for breaking down dopamine into DOPAC. By inhibiting this action, the effects of dopamine (and L-DOPA) can be potentiated. There are two types of MAO A and B. MAO-A has dangerous side effects because it affects the breakdown of many different monoamines (EPI, NE, 5HT, DA), limiting therapeutic use to MAO-B inhibitors, which are dopamine specific

6

Rational of using Catechol-o-methyl Transferase Inhibitors

COMT is also part of the metabolism pathway of L-DOPA and dopamine. Giving COMT inhibitors can potentiate the effects of these molecules, making L-DOPA dosing less frequent.

7

Rational of using Amantadine

It is unclear what the major mechanism of action for Parkinson’s efficacy is in this drug. It increases the availability of endogenous dopamine in the caudate and putamen. It is also a glutamate receptor (NMDA) antagonist.

8

Drug info:
L-DOPA (with carbidopa)

Endogenous precursor to DA. Very short acting; peak action 30-60min, cleared in 2 hours

ADRs: Acute nausea, hypotension, depression, and psychosis
Chronic dyskinesia and psychosis

9

Drug info: Bromocriptine

D2 receptor agonist

ADRs: Nausea, Changes in mentation, Sudden onset of sleep

10

Drug info: Pergolide

D2 receptor agonist (also D1 and 5HT)

ADRs: Nausea, Changes in mentation, Sudden onset of sleep

11

Drug info: Pramipexole

D2 receptor agonist (also D3 and D4)

ADRs: Nausea, Changes in mentation, Sudden onset of sleep

12

Drug info: Ropinirole

D2 receptor agonist (also D3 and D4)

ADRs: Nausea, Changes in mentation, Sudden onset of sleep

13

Drug info: Cabergoline

D2 receptor agonist (also D3, D4 and 5HT)

Very long half-life (65 hours)

ADRs: Nausea, Changes in mentation, Sudden onset of sleep

14

Drug info: Amantidine

Glutamate Receptor Antagonist

Increases availability of endogenous DA

15

Drug info: Trihexyphenidyl

Anticholinergic

ADRs: Swallowing difficulties, Decreased Bowel motility, Urinary retention

16

Drug info: Benztropine

Anticholinergic

ADRs: Swallowing difficulties, Decreased Bowel motility, Urinary retention

17

Drug info: Diphenhydramine

Anticholinergic
1st generation antihistamine: Antagonizes H1 and M receptors

ADRs: Swallowing difficulties, Decreased bowel motility, Urinary retention, Sedation

18

Drug info: Rasagiline

MAO Inhibitor
Allow reduction in L-DOPA doses by 20-30%

ADRs: Worsening of postural hypotension

Numerous DDIs and Drug-Food interactions associated with MAO Is

19

Drug info: Selegiline

MAO Inhibitor
Allow reduction in L-DOPA doses by 20-30%

ADRs: Worsening of postural hypotension

Numerous DDIs and Drug-Food interactions associated with MAO Is

20

Drug info: Tolcapone

COMT Inhibitor

ADR: Inhibits liver enzymes and has caused liver toxicity

21

Drug info: Entacapone

COMT inhibitor

22

D1 vs D2 receptors, and the role they play in movement

D1: Excited by dopamine. Stimulation results in production of cAMP. They are GABAerngic, so when stimulated by DA, they result in increased inhibition of globus pallidus interal (GPi) segment. The GPi inhibits the ventro-lateral thalamus (VL). The VL activated the cortex to create desired movement

D2: Inhibited by binding dopamine. These neurons project to the globus pallidus external (GPe) segment and are GABAergic, meaning they inhibit the GPe neurons from firing. The GPe neurons (aka inhibitory) project to the subthalamic nucleus (STN). The STN has glutaminergic neurons that are excitatory and stimulate GPi. Stimulation of GPi results in inhibition of VL.