Chapter 21 Drugs for Parkinson's Disease

Levodopa/Carbidopa/Entacapone

More convenient than taking separate doses costs a little less disadvantage: only available in immediate-release tablets - only available in three strengths

Acute Loss of effect and on-off phenomenon

Off times may occur at any time even if dosage is high enough

Levadopa Adverse Effects: Cardiovascular Effects

Orthostatic Hypotension Dysrhythmias

Anticholinergic agents

Prevent activation of cholinergic receptors; dykinesias caused by PD are partially caused by excessive stimulation of cholinergic receptors Bentropine (Cogentin)

Dopaminergic Agents MOA Amantadine

Promotes dopamine release

Dopaminergic Agents MOA Levodopa

Promotes dopamine synthesis

Ways to prevent on-off phenomenon

Shorten the dosing interval Give with a drug that prolongs levodopa's 1/2 life - entacapone (slows metabolism of levodopa) Give a direct acting dopamine agonist - Pramipexole Avoid meals with high protein

Dopaminergic Agents MOA Dopamine Agonists

Stimulate dopamine receptors directly

Levadopa Drug Interactions

- First-generation antipsychotics - decrease therapeutic effects of levodopa because they work by blocking receptors for dopamine - Anticholinergics - enhance response to levodopa

Levadopa Adverse Effects: Psychosis

- Hallucinations, vivid dreams, and nightmares, paranoia Can treat paranoia with a SGA

Levodopa Adverse Effects

- Nausea and vomiting - Dyskinesias - Cardiovascular Effects - Psychosis - May darken sweat and urine - can activate malignant melanoma

Carbidopa Advantages

- No therapeutic effects of its own - Increases the available levodopa in the CNS and allows for 75% decrease of levodopa dosage; therefore reduces cardiovascular and GI adverse effects - Effects come mainly from levodopa when given in combination

Levodopa Administration

- Orally administered, rapid absorption from small intestine - Food delays absorption (empty stomach) - High-protein foods will reduce therapeutic effects (on/off effect)

Dopamine Agonist - Pramipexole (Mirapex)

- Relieves motor symptoms by causing direct activation of dopamine receptors * first line drug for motor symptoms (caused by parkinson's)

Levadopa

- Relieves motor symptoms by undergoing conversion to dopamine in surviving nerve terminals in the striatum - Drug holiday is around 10 days and may need to be hospitalized due to paralysis or immobility - Drug holiday helps to decrease tolerance to levodopa and able to start back at a lower dose (decrease tolerance and go back to smaller dose)

Entacapone (Comatan)

- Selective, reversible inhibitor of COMT - Only for use with levodopa (does nothing for PD alone) - Inhibits metabolism of levodopa in the intestines and peripheral tissues - prolongs time that levodopa is available to the brain - increases levodopa availability by inhibiting COMT, which decreases production of levodopa metabolites that compete with levodopa for transport

Mirapex Adverse Effects

- Sleep attacks (Narcolepsy) - Hypotension (decrease BP, or increase BP by increasing or decreasing HTN drugs)

COMT Inhibitors

Inhibit metabolism of levodopa in the periphery No direct therapeutic effects of their own - make more levodopa available to the brain Two COMT inhibitors available - entacapone (safer and more effective) don't use by itself

Dopaminergic Agents MOA Selegiline

Inhibits dopamine breakdown

How long can off times last?

A few minutes to a few hours

Entacapone (Comatan) Adverse Effects

Can cause vomiting and diarrhea, other adverse effects are from the increasing levodopa levels

Dopaminergic Agents

By far the most commonly used drugs for PD Promote activation of dopamine receptors Levadopa (Dopar)

Drug Therapy for Parkinson's: Two Major Categories

Dopaminergic agents Anticholinergic Agents

Dopaminergic Agents MOA COMT Inhibitors

Enhance effects of levodopa by blocking its degradation

Levodopa Effectiveness

Highly effective, but benefits diminish over time - Most effective in first 2 years - by end of 5 years symptoms may return to pretreatment level

Therapeutic Goals for Parkinson's Disease

Ideal treatment (reverse neuronal degeneration or prevent further degeneration does not exist - characterized by dyskinesias and akinesia - Proper function of striatum requires a balance between the neurotransmitters dopamine and acetylcholine (ACh) - Imbalance between dopamine and ACh results from degeneration of the neurons that supply dopamine to the striatum Goal is to improve patient's ability to carry out activities of daily life - treats sx. Drug selection and dosages are determined by extent to which PD interferes with work, dressing, eating, bathing, etc.