Chapter 28: Drugs Used in Parkinsonism & Other Movement Disorders

A. Pathophysiology

Parkinsonism (paralysis agitans) is a common movement disorder that involves dysfunction in the basal ganglia and associated brain structures. Signs include rigidity of skeletal muscles, akinesia (or bradykinesia), flat facies, and tremor at rest (mnemonic RAFT).

1. Naturally occurring parkinsonism

The naturally occurring disease is of uncertain origin and occurs with increasing frequency during aging from the fifth or sixth decade of life onward. Pathologic characteristics include a decrease in the levels of striatal dopamine and the degeneration of dopaminergic neurons in the nigrostriatal tract that normally inhibit the activity of striatal GABAergic neurons (Figure 28–1). Most of the postsynaptic dopamine receptors on GABAergic neurons are of the D₂ subclass (negatively coupled to adenylyl cyclase). The reduction of normal dopaminergic neurotransmission leads to excessive excitatory actions of cholinergic neurons on striatal GABAergic neurons; thus, dopamine and acetylcholine activities are out of balance in parkinsonism (Figure 28–1).

2. Drug-induced parkinsonism

Many drugs can cause parkinsonian symptoms; these effects are usually reversible. The most important drugs are the butyrophenone and phenothiazine antipsychotic drugs, which block brain dopamine receptors. At high doses, reserpine causes similar symptoms, presumably by depleting brain dopamine. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a by-product of the attempted synthesis of an illicit meperidine analog, causes irreversible parkinsonism through destruction of dopaminergic neurons in the nigrostriatal tract. Treatment with type B monoamine oxidase inhibitors (MAOIs) protects against MPTP neurotoxicity in animals.

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.

A. Levodopa

1. Mechanisms

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.

2. Pharmacologic effects

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).

3. Toxicity

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.

B. Dopamine Agonists

1. Bromocriptine

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.

2. Pramipexole

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.

3. Ropinirole

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.

4. Apomorphine

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

1. Mechanism

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.

2. Clinical use

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

1. Mechanism of action

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.

2. Clinical uses

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.

3. Toxicity

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.

E. Amantadine

1. Mechanism of action

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.

2. Pharmacologic effects

Amantadine may improve bradykinesia, rigidity, and tremor but is usually effective for only a few weeks. Amantadine also has antiviral effects.

3. Toxicity

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

1. Mechanism of action

The drugs (eg, benztropine, biperiden, orphenadrine) decrease the excitatory actions of cholinergic neurons on cells in the striatum by blocking muscarinic receptors.

2. Pharmacologic effects

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.

3. Toxicity

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.

Based on your understanding of the receptors affected by drugs used in Parkinson’s disease, what types of autonomic side effects can you anticipate? (See Chapters 8 and 9) The Skill Keeper Answers appear at the end of the chapter.

A. Physiologic and Essential Tremor

Physiologic and essential tremor are clinically similar conditions characterized by postural tremor. The conditions may be accentuated by anxiety, fatigue, and certain drugs, including bronchodilators, tricyclic antidepressants, and lithium. They may be alleviated by β-blocking drugs including propranolol. Beta blockers should be used with caution in patients with heart failure, asthma, diabetes, or hypoglycemia. Metoprolol, a β₁-selective antagonist, is also effective, and its use is preferred in patients with concomitant pulmonary disease. Antiepileptic drugs including gabapentin, primidone, and topiramate, as well as intramuscular injection of botulinum toxin, have also been used to treat essential tremor.

B. Huntington’s Disease and Tourette’s Syndrome

Huntington’s disease, an inherited disorder, results from a brain neurotransmitter imbalance such that GABA functions are diminished and dopaminergic functions are enhanced (Figure 28–1). There may also be a cholinergic deficit because choline acetyltransferase is decreased in the basal ganglia of patients with this disease. However, pharmacologic attempts to enhance brain GABA and acetylcholine activities have not been successful in patients with this disease. Drug therapy usually involves the use of amine-depleting drugs (eg, reserpine, tetrabenazine), the latter having less troublesome adverse effects. Dopamine receptor antagonists (eg, haloperidol, perphenazine) are also sometimes effective and olanzapine is also used.

Tourette’s syndrome is a disorder of unknown cause that frequently responds to haloperidol and other dopamine D₂ receptor blockers, including pimozide. Though less effective overall, carbamazepine, clonazepam, and clonidine have also been used.

C. Drug-Induced Dyskinesias

Parkinsonism symptoms caused by antipsychotic agents (see Chapter 29) are usually reversible by lowering drug dosage, changing the therapy to a drug that is less toxic to extrapyramidal function, or treating with a muscarinic blocker. In acute dystonias, parenteral administration of benztropine or diphenhydramine is helpful. Levodopa and bromocriptine are not useful because dopamine receptors are blocked by the antipsychotic drugs. Tardive dyskinesias that develop from therapy with older antipsychotic drugs are possibly a form of denervation supersensitivity. They are not readily reversed; no specific drug therapy is available.

D. Wilson’s Disease

This recessively inherited disorder of copper metabolism results in deposition of copper salts in the liver and other tissues. Hepatic and neurologic damage may be severe or fatal. Treatment involves use of the chelating agent penicillamine (dimethylcysteine), which removes excess copper. Toxic effects of penicillamine include gastrointestinal distress, myasthenia, optic neuropathy, and blood dyscrasias. Trientine and tetrathiomolybdate have also been used.

E. Restless Legs Syndrome

This syndrome, of unknown cause, is characterized by an unpleasant creeping discomfort in the limbs that occurs particularly when the patient is at rest. The disorder is more common in pregnant women and in uremic and diabetic patients. Dopaminergic therapy is the preferred treatment, and both pramipexole and ropinirole are approved for this condition. Opioid analgesics, benzodiazepines, and certain anticonvulsants (eg, gabapentin) are also used.

Questions 1 and 2. Bradykinesia has made drug treatment necessary in a 60-year-old male patient with Parkinson’s disease, and therapy is to be initiated with levodopa.

1. Regarding the anticipated actions of levodopa, the patient would not be informed that

   • (A) Dizziness may occur, especially when standing

   • (B) He should take the drug in divided doses to avoid nausea

   • (C) Livedo reticularis is a possible side effect

   • (D) The drug will probably improve his symptoms for a period of time but not indefinitely

   • (E) Uncontrollable muscle jerks may occur

2. The prescribing physician will (or should) know that levodopa

   • (A) Causes fewer CNS side effects if given together with a drug that inhibits hepatic dopa decarboxylase

   • (B) Fluctuates in its effectiveness with increasing frequency as treatment continues

   • (C) Prevents extrapyramidal adverse effects of antipsychotic drugs

   • (D) Protects against cancer in patients with melanoma

   • (E) Has toxic effects, which include pulmonary infiltrates

3. Which statement about pramipexole is accurate?

   • (A) Effectiveness in Parkinson’s disease requires its metabolic conversion to an active metabolite

   • (B) It should not be administered to patients taking antimuscarinic drugs

   • (C) Pramipexole causes less mental disturbances than levodopa

   • (D) The drug selectively activates the dopamine D₃ receptor subtype

   • (E) Warfarin may enhance the actions of pramipexole

4. A patient with parkinsonism is being treated with levodopa. He suffers from irregular, involuntary muscle jerks that affect the proximal muscles of the limbs. Which of the following statements about these symptoms is accurate?

   • (A) Coadministration of muscarinic blockers prevents the occurrence of dyskinesias during treatment with levodopa

   • (B) Drugs that activate dopamine receptors can exacerbate dyskinesias in a patient taking levodopa

   • (C) Dyskinesias are less likely to occur if levodopa is administered with carbidopa

   • (D) Symptoms are likely to be alleviated by continued treatment with levodopa

   • (E) The symptoms are usually reduced if the dose of levodopa is increased

5. A 51-year-old patient with parkinsonism is being maintained on levodopa-carbidopa with adjunctive use of low doses of tolcapone but continues to have off-periods of alkinesia. The most appropriate drug to “rescue” the patient but that will only provide temporary relief is

   • (A) Apomorphine

   • (B) Benztropine

   • (C) Carbidopa

   • (D) Pramipexole

   • (E) Selegiline

6. Concerning the drugs used in parkinsonism, which statement is accurate?

   • (A) Dopamine receptor agonists should never be used in Parkinson’s disease before a trial of levodopa

   • (B) Levodopa causes mydriasis and may precipitate an acute attack of glaucoma

   • (C) Selegiline is a selective inhibitor of COMT

   • (D) The primary benefit of antimuscarinic drugs in parkinsonism is their ability to relieve bradykinesia

   • (E) Therapeutic effects of amantadine continue for several years

7. A previously healthy 40-year-old woman begins to suffer from slowed mentation, lack of coordination, and brief writhing movements of her hands that are not rhythmic. In addition, she has delusions of being persecuted. The woman has no history of psychiatric or neurologic disorders. Although further diagnostic assessment should be made, it is very likely that the most appropriate drug for treatment will be

   • (A) Amantadine

   • (B) Bromocriptine

   • (C) Diazepam

   • (D) Haloperidol

   • (E) Levodopa

8. With respect to pramipexole, which of the following is accurate?

   • (A) Activates brain dopamine D₃ receptors

   • (B) Effective as monotherapy in mild parkinsonism

   • (C) May cause postural hypotension

   • (D) Not an ergot derivative

   • (E) All of the above

9. Tolcapone may be of value in patients being treated with levodopa-carbidopa because it

   • (A) Activates COMT

   • (B) Decreases the formation of 3-O-methyldopa

   • (C) Inhibits monoamine oxidase type A

   • (D) Inhibits neuronal reuptake of dopamine

   • (E) Releases dopamine from nerve endings

10. Which of the following drugs is most suitable for management of essential tremor in a patient who has pulmonary disease?

    • (A) Diazepam

    • (B) Levodopa

    • (C) Metoprolol

    • (D) Propranolol

    • (E) Terbutaline

1. In prescribing levodopa, the patient should be informed about adverse effects, including gastrointestinal distress, postural hypotension, and dyskinesias. It is reasonable to advise the patient that therapeutic benefits cannot be expected to continue indefinitely. Livedo reticularis (a netlike rash) is an adverse effect of treatment with amantadine. The answer is C.

2. Levodopa causes less peripheral toxicity but more CNS or behavioral side effects when its conversion to dopamine is inhibited outside the CNS. The drug is not effective in antagonizing the akinesia, rigidity, and tremor caused by treatment with antipsychotic agents. Levodopa is a precursor of melanin and may activate malignant melanoma. Use of levodopa is not associated with pulmonary dysfunction. The answer is B.

3. Pramipexole is a dopamine D₃ receptor activator and does not require bioactivation. It is excreted in unchanged form. Confusion, delusions, and hallucinations occur more frequently with dopamine receptor activators than with levodopa. The use of dopaminergic agents in combination with antimuscarinic drugs is common in the treatment of parkinsonism. Warfarin may enhance the action of ropinirole, another dopamine receptor agonist. The answer is D.

4. The form and severity of dyskinesias resulting from levodopa may vary widely in individual patients. Dyskinesias occur in up to 80% of patients receiving levodopa for long periods. With continued treatment, dyskinesias may develop at a dose of levodopa that was previously well tolerated. Muscarinic receptor blockers do not prevent their occurrence. They occur more commonly in patients treated with levodopa in combination with carbidopa or with other dopamine receptor agonists. The answer is B.

5. Apomorphine, via subcutaneous injection, is used for temporary relief of off-periods of akinesia (rescue) in parkinsonian patients on dopaminergic drug therapy. Pretreatment with the antiemetic trimethobenzamide for 3 days is essential to prevent severe nausea. The answer is A.

6. The non-ergot dopamine agonists (pramipexole, ropinirole) are commonly used prior to levodopa in mild parkinsonism. The mydriatic action of levodopa may increase intraocular pressure; the drug should be used cautiously in patients with open-angle glaucoma and is contraindicated in those with angle-closure glaucoma. Antimuscarinic drugs may improve the tremor and rigidity of parkinsonism but have little effect on bradykinesia. Selegiline is a selective inhibitor of MAO type B. Amantadine is effective for only a few weeks. The answer is B.

7. Although further diagnosis is desirable, choreoathetosis with decreased mental abilities and psychosis (paranoia) suggests that this patient has the symptoms of Huntington’s disease. Drugs that are partly ameliorative include agents that deplete dopamine (eg, tetrabenazine) or that block dopaminergic receptors (eg, haloperidol). The answer is D.

8. Pramipexole is a non-ergot agonist at dopamine receptors and has greater selectivity for D₃ receptors in the striatum. Pramipexole (or the D₂ receptor antagonist ropinirole) is often chosen for monotherapy of mild parkinsonism, and these drugs sometimes have value in patients who have become refractory to levodopa. Adverse effects of these drugs include dyskinesias, postural hypotension, and somnolence. The answer is E.

9. Tolcapone and entacapone are inhibitors of COMT used adjunctively in patients treated with levodopa-carbidopa. The drugs decrease the formation of 3-O-methyldopa (3-OMD) from levodopa. This improves patient response by increasing levodopa levels and by decreasing competition between 3-OMD and levodopa for active transport into the brain by l-amino acid carrier mechanism. The answer is B.

10. Increased activation of β adrenoceptors has been implicated in essential tremor, and management commonly involves administration of propranolol. However, the more selective β₁ blocker metoprolol is equally effective and is more suitable in a patient with pulmonary disease. The answer is C.

Pharmacologic strategy in Parkinson’s disease involves attempts to enhance dopamine functions or antagonize acetylcholine at muscarinic receptors (See Chapters 8 and 9). Thus, peripheral adverse effects must be anticipated.

1. Adverse effects referable to activation of peripheral dopamine (or adrenoceptors in the case of levodopa) include postural hypotension, tachycardia (possible arrhythmias), mydriasis, and emetic responses.

2. Adverse effects referable to antagonism of peripheral muscarinic receptors include dry mouth, mydriasis, urinary retention, and cardiac arrhythmias.

When you complete this chapter, you should be able to:

• ❑ Describe the neurochemical imbalance underlying the symptoms of Parkinson’s disease.

• ❑ Identify the mechanisms by which levodopa, dopamine receptor agonists, selegiline, tolcapone, and muscarinic blocking drugs alleviate parkinsonism.

• ❑ Describe the therapeutic and toxic effects of the major antiparkinsonism agents.

• ❑ Identify the compounds that inhibit dopa decarboxylase and COMT and describe their use in parkinsonism.

• ❑ Identify the chemical agents and drugs that cause parkinsonism symptoms.

• ❑ Identify the most important drugs used in the management of essential tremor, Huntington’s disease, drug-induced dyskinesias, restless legs syndrome, and Wilson’s disease.