Background

• Substantia nigra (neuron) die in the brain leads to low levels of dopamine. (They produce DA that facilitates the communication of substantia nigra with corpus striatum). There is a genetic disposition.
• Dopamine (DA) controls smooth voluntary muscle movement, lack of DA is associated with Parkinson’s: bradykinesia, rigidity, shaking/tremor, postural instability.
• Initially tremor on one side, eventually bilaterally.
• "Off" period: muscle rigidity, slow movement, difficulty starting movement.
• Patients with PD has high incidence of depression: treatment with SSRI/SNRI.
• Psychosis can occur in advanced PD (body gets too much DA treatment), use quetiapine (less motor SE) or clozapine (low risk of movement SE, but ↑ agranulocytosis, seizure)

 

Drug induced PD

• Due to their dopamine receptor antagonist.
• 1^st & 2^nd generation antipsychotics (especially haloperidol, Risperdal), dopamine blocking agent (metoclopramide), Phenothiazines (prochlorperazine).

 

Dopamine replacement agents

• Drugs Levodopa/carbidopa (Sinemet, Parcopa RapiTab)
• Levodopa is a precursor of dopamine; carbidopa prevents peripheral breakdown of levodopa before it crosses BBB to provide efficacy.
• Common SE: N/V (GI effect is common), dyskinesia, confusion/hallucination/psychosis (due to increase in dopamine, occur more commonly in elderly), hypoTN, drowsiness
• Frequent dosing (can go up to 6-8X/day), slow titration to avoid orthostasis, dizziness, sleepiness

 

Dopamine agonist

• Drugs: Pramipexole (Mirapex, caution vision change), Ropinirole (Requip)
• Stimulates dopamine receptor. More common use for restless leg syndrome (dosed QHS) than for Parkinson.
• Avoid use with antipsychotics (block dopamine receptor), dopamine blocker (phenothiazine, metoclopramide), non-selective MAOI (2 wk separation, isocarboxazi-Marplan, phenelzine-Nardil, tranylcypromine-Parnate); Do not drink alcohol, increase drowsy

 

More advanced disease state

COMT inhibitor

• Drugs: Entacapone (Comtan) + levo/carbidopa (Stalevo), Tolcapone (Tasmar)
• MOA: prevent breakdown of levodopa and enhances its action; Used only with Sinemet, cannot be used alone.
• SE: hallucination & GI, dyskinesia, orthostasis; side effects are linked with higher level of levodopa therefore increased level of dopamine, producing psychotic like symptoms.
• Tolcapone (Tasmar): rarely used due to hepatotoxicity

 

 

Apomorphine (Apokyn)

• MOA: dopaminergic agonist, a morphine derivative affects the hypothalamic region of the brain.
• SE: severe N/V (treat with trimethobenzamide (Tigan) or similar antiemetics, refer to oncology chapter: some DA blockers are being used as antiemetics, and DA agonists can causes N/V), hypotension, somnolence, QT prolongation.
• Indication: Parkinson's disease or erectile dysfunction. In higher doses it is a highly effective emetic (induce vomiting).
• Glass ampule SC inj.

 

Other drugs

Selective MAO-B inhibitors

• Drugs: Selegiline (Eldepryl, Zelapar-ODT, Emsam patch), Rasagiline (Azilect).
• MOA: prevent breakdown of dopamine.
• SE: 5HT syndrome, hypertension (due to NE). Although this class might be more selective for DA, it may still target neurotransmitters like: 5HT, NE.
• DI: Avoid combination with other serotonergic agents (refer to depression chapter for the list of agents); HTN crisis if taken with tyramine rich food.
• Above max dose will become non-selective.

 

Centrally-acting anticholinergics

• Drugs: Benztropine (Cogentin), trihexyphenidyl (Artane)
• Primarily used for tremor in younger patients (on beers list for elderlies). These drugs are under the big umbrella term of anticholinergics (refer to overactive bladder chapter for list of anticholinergics).
• SE: dry mouth, large pupils, urinary retention, constipation, and a fast heart rate.
• Avoid use in with angle closure glaucoma, and in elderly.

 

Amantadine (Symmetrel)

• Dopamine reuptake inhibitor; use for mild dyskinesia in addition to tremor.
• SE: toxic delirium (in renal impairment).  

 

Quiz

Which of the following is a dopamine agonist?

1. Trihexyphenidyl
2. Carbidopa/levodopa
3. Pramipexole
4. Entacapone
5. Answer:C. Pramipexole is a dopamine agonist used for the treatment of Parkinson’ s disease. Trihexyphenidyl is an anticholinergic agent. Entacapone is a COMT inhibitor. Carbidopa/levodopa is a decarboxylase inhibitor (carbidopa) combined with a dopamine precursor (levodopa). All of these agents can be used for the treatment of Parkinson’ s disease.

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