| 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. |
| 1. Naturally occurring parkinsonism Pathologic characteristics | 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. 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. |
| 2. Drug-induced parkinsonism— | 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. |
| 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. |
| 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. 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 | 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 |
| levadopa Toxicity— | 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. |
| 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 function. 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. |
| 1. Bromocriptine—Common adverse effects | 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. |
| 2. Pramipexole adverse effects | 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. |
| ropinirole adverse effects | Adverse effects and contraindications are similar to those of pramipexole. |
| 4. Apomorphine— | 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. |
| 4. Apomorphine adverse effects | 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 Mechanism— | Selegiline and rasagiline are selective inhibitors of monoamine oxidase type B, the form of the enzyme that metabolizes dopamine. Hepatic metabolism of selegiline results in the formation of desmethylselegiline (possibly neuroprotective) and amphetamine. |
| Monoamine Oxidase Inhibitors Clinical use | Selegiline has minimal efficacy in parkinsonism if given alone but can be used adjunctively with levodopa. |
| Monoamine Oxidase Inhibitors potency | 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 monoamine oxidase inhibitors | 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 (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 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. |
| COMT Clinical uses— | The drugs are used as adjuncts to levodopacarbidopa, 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. |
| COMT 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 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 | 2. Pharmacologic effects—Amantadine may improve bradykinesia, rigidity, and tremor but is usually effective for only a few weeks. Amantadine also has antiviral effects |
| amantadine Toxicity— | 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. |
| Acetylcholine-Blocking (Antimuscarinic) Drugs Mechanism of action— | 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. |
| Acetylcholine-Blocking (Antimuscarinic) Drugs Pharmacologic effects— | 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. |
| Acetylcholine-Blocking (Antimuscarinic) Drugs Toxicity— | 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. |
| 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. |
| Physiologic and Essential Tremor alleviating | 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. |
| 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.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 Huntington’s Disease and Tourette’s Syndrome | 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 | 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 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.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. |
| D. Wilson’s Disease toxic effects | 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. |
