Chapter 15 Antiparkinson Drugs
Benztropine Mesylate (Cogentin)
Class: Anticholinergic Benztropine (Cogentin) is an anticholinergic drug used for Parkinson's disease and also for extrapyramidal symptoms from antipsychotic drugs. Mechanism of action: block the effects of the neurotransmitter acetylcholine at cholinergic receptors in the brain as well as in the rest of the body. Indications: used as adjunct drug therapy in Parkinson's disease due to their antitremor properties. The purpose of their use is to reduce excessive cholinergic activity in the brain. Accumulation of acetylcholine in Parkinson's disease causes an overstimulation of the cholinergic excitatory pathways, which results in tremors and muscle rigidity. Cogwheel rigidity is an example. Benztropine is to be used with caution in hot weather or during exercise because it may cause hyperthermia. Other adverse effects include tachycardia, confusion, disorientation, toxic psychosis, urinary retention, dry mouth, constipation, nausea, and vomiting. Anticholinergic syndrome can occur when it is given with other drugs that are associated with a high incidence of anticholinergic effects. Alcohol is to be avoided. Benztropine is available as tablets and in injectable form. Acetylcholine is responsible for causing increased salivation, lacrimation (tearing of the eyes), urination, diarrhea, increased GI motility, and possibly emesis (vomiting). The acronym SLUDGE is often used to describe these cholinergic effects. Anticholinergics have the opposite effects. They can cause dry mouth or decreased salivation, urinary retention, decreased GI motility (constipation), dilated pupils (mydriasis), and smooth muscle relaxation.
Entacapone (Comtan)
Class: Catechol Ortho-Methyltransferase Inhibitor (COMT) Indicated for the adjunctive treatment of Parkinson's disease. Entacapone is taken with levodopa and is effective from the first dose, and benefits are seen within a few days. Entacapone helps minimize the wearing-off effect, and when used with levodopa, it can also reduce on-off effects. The levodopa dosage can often be reduced when taken with entacapone. Mechanism of action: work presynaptically to block COMT. COMT is the enzyme that catalyzes the breakdown of the body's catecholamines Adverse reactions include GI upset, dyskinesias, and urine discoloration, orthostatic hypotension, syncope, dizziness, fatigue, hallucinations, anxiety, somnolence, rash, dyspnea. Entacapone is contraindicated in patients with known drug allergy and used with caution in patients with preexisting liver disease. Entacapone is available only for oral use. It is also available in combination tablets that contain various doses of entacapone, carbidopa, and levodopa (Stalevo). **Do not take with MAOIs
Carbidopa-Levodopa (Sinemet)
Class: Dopamine replacement drug Indications: directly restore dopaminergic activity in Parkinson's disease. Mechanism of action: stimulate presynaptic dopamine receptors to increase brain levels of dopamine. Dopamine must be administered orally as levodopa, because exogenously administered dopamine cannot pass through the blood-brain barrier. Levodopa is the biologic precursor of dopamine and can penetrate into the CNS. Levodopa is broken down outside the CNS. The large doses needed result in high peripheral levels of dopamine and lead to many unwanted adverse effects. These adverse effects include confusion, involuntary movements, GI distress, hypotension, and cardiac dysrhythmias. Therefore, levodopa is given with carbidopa. Carbidopa is a peripheral decarboxylase inhibitor with little or no pharmacologic activity when given alone. When given in combination with levodopa, carbidopa inhibits the breakdown of levodopa in the periphery and thus allows smaller doses of levodopa to be used. Lesser amounts of levodopa result in fewer unwanted adverse effects. Contraindications: Levodopa and carbidopa are both contraindicated in cases of angle-closure glaucoma; however, they may be used cautiously in patients with open-angle glaucoma. Neither drug is to be used in patients with any undiagnosed skin condition, because both drugs can activate malignant melanoma. Adverse effects: palpitations, hypotension, urinary retention, depression, dyskinesia, orthostatic hypotension.
Ropinirole (Requip)
Class: Nondopamine Dopamine Receptor Agonist. This nonergot drug has a better adverse effects profile (e.g., fewer dyskinesias) than bromocriptine. Ropinirole, pramipexole, and rotigotine are more specific than bromocriptine for the D2 subfamily of dopamine receptors (D2, D3, and D4). This, in turn, results in more specific antiparkinson effects with fewer of the adverse effects. These drugs (ropinirole, pramipexole, and rotigotine) can be effective in both early- and late-stage Parkinson's disease and appear to delay the need for levodopa therapy. They can be used as monotherapy and adjunctive therapy with levodopa. Ropinirole and rotigotine are also indicated for treatment of moderate to severe primary restless legs syndrome. All drugs are contraindicated in patients with known drug allergy. Adverse effects include dizziness, GI upset, and somnolence. Drug interactions occur with any drug metabolized by cytochrome P-450 enzyme 1A2 (e.g., warfarin, ciprofloxacin).
Bromocriptine
Class: Nondopamine Dopamine Receptor Agonists (Ergot derivative) Indications: used to treat various stages of Parkinson's disease, either alone or in combination with other drugs. Bromocriptine also inhibits the production of the hormone prolactin, which stimulates normal lactation and can be used to treat women with excessive or undesired breast milk production (galactorrhea) and for treatment of prolactin-secreting tumors. Mechanism of action: Bromocriptine works by activating presynaptic dopamine receptors to stimulate the production of more dopamine. Its chief site of activity is the D2 subclass of dopamine receptors. Adverse effects: Ataxia, dizziness, headache, depression, drowsiness, GI upset, visual changes. Contraindications: These drugs are not to be used concurrently with adrenergic drugs due to the cardiovascular risk for excessive catecholamine activity.
Amantadine (Symmetrel)
Class: dopamine modulator Indications: Amantadine is generally indicated in the early stages of Parkinson's disease while there are still some intact neurons in the basal ganglia. It is usually effective for only 6 to 12 months, after which it often fails to relieve hypokinesia and rigidity. It is often used to treat dyskinesia associated with carbidopa-levodopa. It is also indicated for influenza virus infection. Mechanism of action: release of dopamine and other catecholamines from their storage sites in the presynaptic fibers (the nerve cell must not be destroyed yet by the disease). Adverse effects: dizziness, orthostatic hypotension, peripheral edema, insomnia, agitation, anxiety, headache, hallucinations, nausea, dry mouth. Amantadine (Symmetrel) is an antiviral drug most often for influenza virus infection. It is also indicated for treatment of mild to moderate Parkinson's disease. It helps to control symptoms of tremor, including motor rigidity, by virtue of both its dopaminergic and anticholinergic effects.
Rasagiline (Azilect) and Selegiline (Eldepryl)
Class: selective MAO-B inhibitors Indications: Rasagiline and selegiline are used as monotherapy or in conjunction with levodopa therapy (as adjunctive drugs) in the treatment of Parkinson's disease. Rasagiline is given once a day, whereas selegiline is given twice a day with breakfast and lunch. Studies have shown that selegiline-treated patients required levodopa therapy approximately 1.8 times later than control patients. Mechanism of action: prevent MAO enzymes from breaking down catecholamines (including dopamine). Adverse effects: headache, insomnia, dizziness, nausea, hypotension, confusion, rash, weight loss, diarrhea, stomatitis, dyskinesia, back pain, somnolence, impulse control disorders. Selegiline is available as an oral tablet and an orally disintegrating tablet for buccal use known as Zelapar, which can provide improved drug absorption. In addition, a transdermal form of the drug known as Emsam is available, which is indicated only for major depressive disorder. Rasagiline (Azilect) is available as an oral tablet. Rasagiline is FDA approved for monotherapy, but selegiline is also being used in such a manner. Both are approved as adjunctive therapy with levodopa. Assess: cardiac system for hypotension.
