Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 28. Drugs Used in Parkinsonism & Other Movement Disorders

Drugs Used in Parkinsonism & Other Movement Disorders: Introduction

Movement disorders constitute a number of heterogeneous neurologic conditions with very different therapies. They include parkinsonism, Huntington's disease, Wilson's disease, and Gilles de la Tourette's syndrome. Movement disorders, including athetosis, chorea, dyskinesia, dystonia, tics, and tremor, can be caused by a variety of general medical conditions, neurologic dysfunction, and drugs.

High-Yield Terms to Learn

Athetosis Involuntary slow writhing movements, especially severe in the hands; "mobile spasm" Chorea Irregular, unpredictable, involuntary muscle jerks that impair voluntary activity Dystonia Prolonged muscle contractions with twisting and repetitive movements or abnormal posture; may occur in the form of rhythmic jerks Huntingdon's disease An inherited adult-onset neurologic disease characterized by dementia and bizarre involuntary movements Parkinsonism A progressive neurologic disease characterized by shufflinq gait, stooped posture, resting tremor, speech impediments, movement difficulties, and an eventual slowing of mental processes and dementia Tics Sudden coordinated abnormal movements, usually repetitive, especially about the face and head Tourette's syndrome A neurologic disease of unknown cause that presents with multiple tics associated with snorting, sniffing, and involuntary vocalizations (often obscene) Wilson's disease An inherited (autosomal recessive) disorder of copper accumulation in liver, brain, kidneys, and eyes; symptoms include jaundice, vomiting, tremors, muscle weakness, stiff movements, liver failure, and dementia

Parkinsonism

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).

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).

FIGURE 28-1

Schematic representation of the sequence of neurons involved in parkinsonism and Huntington's chorea. Top: Neurons in the normal brain. Middle: Neurons in parkinsonism. The dopaminergic neuron is lost. Bottom: Neurons in Huntington's disease. The GABAergic neuron is lost.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 9th ed. McGraw-Hill, 2004: Fig. 28-1.)

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.

Drug Therapy of Parkinsonism

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.

Levodopa

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.

FIGURE 28-2

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, 11th ed. McGraw-Hill, 2009: Fig. 28-5.)

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).

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.

Dopamine Agonists

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).

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.

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. 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.

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.

A related dopamine agonist, rotigotine, which is delivered via skin patch, was recently withdrawn because of crystal formation affecting its availability and efficacy.

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.

Monoamine Oxidase Inhibitors

Mechanism

Selegine and rasagilene 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.

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.

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).

Catechol-O-Methyltransferase (COMT) Inhibitors

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.

Clinical Uses

The drugs are used individually 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.

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.

Amantadine

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.

Pharmacologic Effects

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

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.

Acetylcholine-Blocking (Antimuscarinic) Drugs

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.

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.

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.

Skill Keeper: Autonomic Drug Side Effects

(See Chapters 8 and 9)

Based on your understanding of the receptors affected by drugs used in Parkinson's disease, what types of autonomic side effects can you anticipate? The Skill Keeper Answers appear at the end of the chapter.

Drug Therapy of Other Movement Disorders

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 -blocking drugs including propranolol.  blockers should be used with caution in patients with congestive heart failure, asthma, diabetes, or hypoglycemia. Metoprolol, a 1-selective antagonist, is also effective, and its use is preferred in patients with concomitant pulmonary disease. Antiepileptic drugs including gabapentin and topiramate, as well as intramuscular injection of botulim toxin, have also been used to treat essential tremor.

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.

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.

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.

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.

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 ropinirole , a long-acting drug, is approved for this condition. Opioid analgesics and benzodiazepines are also used.

Skill Keeper Answers: Autonomic Drug Side Effects

(See Chapters 8 and 9)

Pharmacologic strategy in Parkinson's disease involves attempts to enhance dopamine functions or antagonize acetylcholine at muscarinic receptors. 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.

Checklist

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, 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 tremor, Huntington's disease, drug-induced dyskinesias, restless legs syndrome, and Wilson's disease.

Drug Summary Table: Drugs Used for Movement Disorders

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities Levodopa (+/- carbidopa) Precursor of dopamine Carbidopa inhibits peripheral metabolism via dopa decarboxylase Primary drug used in Parkinson's disease Oral, COMT and MAO type B inhibitors diminish doses and prolong actions Duration of effects: 6-8 h; GI upsets, dyskinesias, behavioral effects; on-off phenomena Dopamine agonists Pramipexole Ropinirole Apomorphine Bromocriptine (rarely used) D2 agonists (apomorphine bromocriptine, and ropinirole); D3 agonist (pramipexole)

Pramipexole and ropinirole used as sole agents in early Parkinson's disease and adjunct to L-dopa; apomorphine "rescue" therapy Oral; pramipexole: short half-life (tid dosing), renal elimination Ropinirole, CYP1A2 metabolism; drug interactions possible Anorexia, nausea, constipation postural hypotension, dyskinesias, mental disturbances MAO inhibitors Rasagiline Selegiline Inhibit MAO type B Rasagiline for early PD Both drugs adjunctive with L-dopa Oral; half-lives permit bid dosing Serotonin syndrome with meperidine and possibly SSRIs and TCAs. COMT inhibitors Entacapone Tolcapone Block L-dopa metabolism in periphery (both) and CNS (tolcapone) Prolong L-dopa actions Oral Toxicity: relates to increased levels of L-dopa Antimuscarinic agents Benztropine, and others Block M receptors Improve tremor and rigidity not bradykinesia Oral: once daily Typical atropine-like side effects Drugs for Huntington's disease Tetrabenazine, reserpine Haloperidol Tetrabenazine and reserpine: deplete amines Haloperidol: D2 antagonist Reduce symptom (eg, chorea) severity Oral (see Chapter 11 Oral (see Chapter 29) Tetrabenazine: depression, hypotension, sedation Haloperidol: extrapyramidal dysfunction Drugs for Tourette's syndrome Haloperidol Haloperidol: D2 receptor blocker

Reduce vocal and motor tic frequency and severity Oral Haloperidol: extrapyramidal dysfunction Clonidine Clonidine: 2 blocker

Oral

COMT, catechol-O-methyltransferase; MAO, monoamine oxidase; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.



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