Drugs for Parkinsons

Question 1

Parkinsons

Answer 1

Tremor, rigidity, bradykinesia, mask like expression
-Can be idiopathic (elderly) or as a complication of influenza of 1918, meds, MPTP toxicity, neurological disorders

-Loss of nigrostriatal dopamine neurons, loss of dopaminergic innervation of basal ganglia

Question 2

Strategies Parkinsons Therapy

Answer 2

1) Replace or mimic dopamine
- D2 (D2, D3, D4) like receptors most important therapeutically in PD and associated with indirect nigrostriatal pathway
- D3 receptors are lower in abundance, but mediate some neuroprotective effects
- synergistic interactions between D1-like and D2-like receptors (balance between them are important for greatest efficacy)
2) anticholinergics, amantadine

Question 3

Replacing dopamine

Answer 3

• dopamine doesn’t cross BBB, so exploit synthesis of dopamine (from tyrosine with L-DOPA as intermediate)
• L-DOPA is transported in the brain by Tyr transporter
• L-DOPA then decarboxylated into dopamine

Question 4

Rate limiting step of dopamine synthesis

Answer 4

Tyrosine Hydroxylase

Question 5

L-DOPA

Answer 5

Levodopa

• reversal of rigidity, tremor, bradykinesia, reduced facial expression
• Improved mental function and sense of well-being
• 1/3 of patients respond well, 1/3 not well at all

Question 6

L-DOPA side effects

Answer 6

• GI: nausea and vomiting because of stimulating of D2 receptors in chemoreceptor trigger zone (CTZ)
• CV: orthostatic hypotension because of stimulation of dopamine receptors in kidney and vasculature but tolerance develops in a few weeks
• Other: dec prolactin secretion (stimulation of D2 receptors in pituitary), mydriasis (can lead to glaucoma because high levels of dopamine act on b receptors), sweating, sleep disturbances), brownish discoloration of body fluids

Question 7

L-DOPA long term side effects

Answer 7

Motor: fluctuations in efficacy

• on-off effect or bradykinetic episodes
• wearing off- effects don’t last until next dose

Neurological: abnormal involuntary movements (dystonia, dyskinesias, chorea, oral movements) - 80% of patients taking L-DOPA for 3 years

Psychic- hallucinations, paranoia, mania, anxiety, depression due to stimulation of dopamine receptors in targets of mesolimbic and mesocortical pathways

Neuroendocrine effects- renewed sexual interest and behavior, hypersexuality

Question 8

L-DOPA pharmacokinetics

Answer 8

-oral administration
-absorption depends on GI transit time (longer transit- more degradation in gut- less absorption (unlike other drugs), decreased by anticholinergics)
-peak levels 1/2-2 hrs
-1/2 life 1-3 hrs
more than 95% decarboxylated in periphery so cannot cross the brain and excreted in urine

Question 9

Carbidopa

Answer 9

• Structurally like L-DOPA
• Inhibitor of aromatic amino acid decarboxylase in periphery to block metabolization leading increased L-DOPA in brain
• decrease dose of L-DOPA and decrease side effects especially GI effects in periphery

-LDOPA only available in US in formulation with carbidopa

Question 10

Monoamine Oxidase B Inhibitors

Answer 10

Selegiline, Rasagiline

• MAO-B preferentially metabolizes DA
• blocks catabolism of dopamine, and can inhibit MAO-A at higher doses (requires additional precautions)
• Use in adjunct to L-DOPA (inc efficacy, dec L-DOPA dose, dec on-off effect)

Question 11

MAO-A metabolizes

Answer 11

5-HT and NE

Question 12

MAO-B metabolizes

Answer 12

DA

-Inhibited by Selegiline and Rasagiline

Question 13

Catechol-O-methyl transferase (COMT) inhibitors

Answer 13

Tolcapone
Entacapone

blocks catabolism of dopamine and L-DOPA
Use in adjunct to L-DOPA

Question 14

Tolcapone

Answer 14

COMT inhibitor
more potent and longer acting
central and peripheral actions
hepatotoxic

Question 15

Entacapone

Answer 15

peripheral COMT inhibitor

Question 16

Contraindications of L-DOPA

Answer 16

Abrupt discontinuation
-result in symptoms resembling neuroleptic malignant syndrome because of dopamine receptors being stimulated constantly
Closed angle glaucoma because of stimulation of B receptors
Melanoma- L-DOPA precursor of melanin
Breast feeding mother because inhibits prolactin secretion

Question 17

Use with Caution for L-DOPA

Answer 17

psychosis, cardiac disease (can cause arrythmias), peptic ulcer (cause bleeding), open angle glaucoma (if intraocular pressure is well controlled)

Question 18

Monotherapy or add on dopamine agonists

Answer 18

Pramipexole
Ropinerole
Rotigotine

All are D2/D3 agonists, rotigotine is also D1 agonist and is transdermal

Question 19

Dopamine agonists that are Add on with L-DOPA

Answer 19

Bromocriptine-D2 agonist

Apomorphine- non ergot D1/D2 agonist

Question 20

Dopamine agonists

Answer 20

Agonist at D2 and other dopamine receptors, activity at D3 may confer greater efficacy and may mediate neuroprotective effects
-Use monotherapy or add on with L-DOPA to improve response especially with fluctuations in efficacy

Question 21

Dopamine agonist side effects

Answer 21

nausea, vomiting, postural hypotension, hallucinations

-lower incidence of dyskinesias than with L-DOPA

Question 22

Anticholinergics

Answer 22

Trihexyphenidyl
Benztropine
Procyclidine

Block actions of striatal cholinergic interneurons which lowers GABA activity
Generally less effective than L-DOPA
Used alone early in course of disease

Question 23

Side effects of anticholinergics

Answer 23

constipation, urinary hesitance, retention, mental confusion, hallucinations

Question 24

Normal activity of dopamine and ach with GABA

Answer 24

Dopamine from substantia nigra and Ach from striatal cholinergic interneurons in corpus striatum activates GABA

-in parkinsonism, dopamine is not present, so Ach is acting unopposed, leading to inc activation of GABA

Question 25

Amantadine

Answer 25

Antiviral
Unknown mechanism- may release dopamine and/or have anticholinergic properties and some NMDA activity
-less efficacious than L-DOPA
-also used for tx or prophylaxis of influenza A virus

• monotherapy or adjunct to L-DOPA
• Sometimes used early in treatment and often effective only for few weeks
• approved for parkinson’s dyskinesia in 2017

Question 26

SE of amantadine

Answer 26

similar to dopamine agonists, may produce livedo reticularis, peripheral edema, headache
-use with caution in pts with seizure disorders

Question 27

Pimavenserin

Answer 27

Indicated for PD psychosis

-inverse agonist and antagonist activity at 5-HT2a and 5-HT2c receptors