Strategies of drug treatment of parkinsonism involve increasing dopamine activity in the brain, decreasing muscarinic cholinergic activity in the brain, or both.
Although several dopamine receptor subtypes are present in the substantia nigra, the benefits of most antiparkinson drugs appear to depend on activation of the D2 receptor subtype.
Because dopamine has low bioavailability and does not readily cross the blood-brain barrier, its precursor, l-dopa (levodopa), is used. This amino acid enters the brain via an l-amino acid transporter (LAT) and is converted to dopamine by the enzyme aromatic l-amino acid decarboxylase (dopa decarboxylase), which is present in many body tissues, including the brain. Levodopa is usually given with carbidopa, a drug that does not cross the blood-brain barrier but inhibits dopa decarboxylase in peripheral tissues (Figure 28–2). With this combination, the plasma half-life is prolonged, lower doses of levodopa are effective, and there are fewer peripheral side effects.
Pharmacologic strategies for dopaminergic therapy of Parkinson’s disease. The actions of the drugs are described in the text. MAO, monoamine oxidase; COMT, catechol-O-methyltransferase; DOPAC, dihydroxyphenylacetic acid; l-DOPA, levodopa; 3-OMD, 3-O-methyldopa. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 28–5.)
Levodopa ameliorates the signs of parkinsonism, particularly bradykinesia; moreover, the mortality rate is decreased. However, the drug does not cure parkinsonism, and responsiveness fluctuates and gradually decreases with time, which may reflect progression of the disease. Clinical response fluctuations may, in some cases, be related to the timing of levodopa dosing. In other cases, unrelated to dosing, off-periods of akinesia may alternate over a few hours with on-periods of improved mobility but often with dyskinesias (on-off phenomena). In some case, off-periods may respond to apomorphine. Although drug holidays sometimes reduce toxic effects, they rarely affect response fluctuations. However, catechol-O-methyltransferase (COMT) inhibitors used adjunctively may improve fluctuations in levodopa responses in some patients (see below).
Most adverse effects are dose dependent. Gastrointestinal effects include anorexia, nausea, and emesis and can be reduced by taking the drug in divided doses. Tolerance to the emetic action of levodopa usually occurs after several months.
Postural hypotension is common, especially in the early stage of treatment. Other cardiac effects include tachycardia, asystole, and cardiac arrhythmias (rare).
Dyskinesias occur in up to 80% of patients, with choreoathetosis of the face and distal extremities occurring most often. Some patients may exhibit chorea, ballismus, myoclonus, tics, and tremor.
Behavioral effects may include anxiety, agitation, confusion, delusions, hallucinations, and depression. Levodopa is contraindicated in patients with a history of psychosis.
An ergot alkaloid, bromocriptine acts as a partial agonist at dopamine D2 receptors in the brain. The drug increases the functional activity of dopamine neurotransmitter pathways, including those involved in extrapyramidal functions (Figure 28–2). Pergolide is similar.
Bromocriptine has been used as an individual drug, in combinations with levodopa (and with anticholinergic drugs), and in patients who are refractory to or cannot tolerate levodopa. Common adverse effects include anorexia, nausea and vomiting, dyskinesias, and postural hypotension. Behavioral effects, which occur more commonly with bromocriptine than with newer dopamine agonists, include confusion, hallucinations, and delusions. Ergot-related effects include erythromelalgia and pulmonary infiltrates. Use of bromocriptine in patients with Parkinson’s disease has declined with the introduction of non-ergot dopamine receptor agonists.
This non-ergot has high affinity for the dopamine D3 receptor. It is effective as monotherapy in mild parkinsonism and can be used together with levodopa in more advanced disease. Pramipexole is administered orally 3 times daily and is excreted largely unchanged in the urine. The dose of pramipexole may need to be reduced in renal dysfunction. Adverse effects include anorexia, nausea and vomiting, postural hypotension, and dyskinesias. Mental disturbances (confusion, delusions, hallucinations, impulsivity) are more common with pramipexole than with levodopa. In rare cases, an uncontrollable tendency to fall asleep may occur. The drug is contraindicated in patients with active peptic ulcer disease, psychotic illness, or recent myocardial infarction. Pramipexole may be neuroprotective because it is reported to act as a scavenger for hydrogen peroxide.
Another non-ergot, this drug has high affinity for the dopamine D2 receptor. It is effective as monotherapy and can be used with levodopa to smooth out response fluctuations. The standard form is given 3 times daily, but a prolonged release form can be taken once daily. Ropinirole is metabolized by hepatic CYP1A2, and other drugs metabolized by this isoform (eg, caffeine, warfarin) may reduce its clearance. Adverse effects and contraindications are similar to those of pramipexole.
A potent dopamine receptor agonist, apomorphine injected subcutaneously may provide rapid (within 10 min) but temporary relief (1–2 h) of “off-periods” of akinesia in patients on optimized dopaminergic therapy. Because of severe nausea, pretreatment for 3 days with antiemetics (eg, trimethobenzamide) is necessary. Other side effects of apomorphine include dyskinesias, hypotension, drowsiness, and sweating.
C. Monoamine Oxidase Inhibitors
Selegiline and rasagiline are selective inhibitors of monoamine oxidase type B, the form of the enzyme that metabolizes dopamine (Figure 28–2). Hepatic metabolism of selegiline results in the formation of desmethylselegiline (possibly neuroprotective) and amphetamine.
Selegiline has minimal efficacy in parkinsonism if given alone but can be used adjunctively with levodopa. Rasagiline is more potent and has been used as monotherapy in early symptomatic parkinsonism as well as in combinations with levodopa.
3. Toxicity and drug interactions
Adverse effects and interactions of monoamine oxidase inhibitors include insomnia, mood changes, dyskinesias, gastrointestinal distress, and hypotension. Combinations of these drugs with meperidine have resulted in agitation, delirium, and mortality. Selegiline has been implicated in the serotonin syndrome when used with serotonin selective reuptake inhibitors (SSRIs).
D. Catechol-O-methyltransferase (COMT) Inhibitors
Entacapone and tolcapone are inhibitors of COMT, the enzyme in both the CNS and peripheral tissues (Figure 28–2) that converts levodopa to 3-O-methyldopa (3OMD). Increased plasma levels of 3OMD are associated with poor response to levodopa partly because the compound competes with levodopa for active transport into the CNS. Entacapone acts only in the periphery.
The drugs are used as adjuncts to levodopa-carbidopa, decreasing fluctuations, improving response, and prolonging “on-time.” Tolcapone is taken 3 times daily, entacapone 5 times daily. A formulation combining levodopa, carbidopa, and entacapone is available, simplifying the drug regimen.
Adverse effects related partly to increased levels of levodopa include dyskinesias, gastrointestinal distress, and postural hypotension. Levodopa dose reductions may be needed for the first few days of COMT inhibitor use. Other side effects include sleep disturbances and orange discoloration of the urine. Tolcapone increases liver enzymes and has caused acute hepatic failure, necessitating routine monitoring of liver function tests and signed patient consent for use in the United States.
Amantadine enhances dopaminergic neurotransmission by unknown mechanisms that may involve increasing synthesis or release of dopamine or inhibition of dopamine reuptake. The drug also has muscarinic blocking actions.
Amantadine may improve bradykinesia, rigidity, and tremor but is usually effective for only a few weeks. Amantadine also has antiviral effects.
Behavioral effects include restlessness, agitation, insomnia, confusion, hallucinations, and acute toxic psychosis. Dermatologic reactions include livedo reticularis. Miscellaneous effects may include gastrointestinal disturbances, urinary retention, and postural hypotension. Amantadine also causes peripheral edema, which responds to diuretics.
F. Acetylcholine-Blocking (Antimuscarinic) Drugs
The drugs (eg, benztropine, biperiden, orphenadrine) decrease the excitatory actions of cholinergic neurons on cells in the striatum by blocking muscarinic receptors.
These drugs may improve the tremor and rigidity of parkinsonism but have little effect on bradykinesia. They are used adjunctively in parkinsonism and also alleviate the reversible extrapyramidal symptoms caused by antipsychotic drugs.
CNS toxicity includes drowsiness, inattention, confusion, delusions, and hallucinations. Peripheral adverse effects are typical of atropine-like drugs. These agents exacerbate tardive dyskinesias that result from prolonged use of antipsychotic drugs.