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PARKINSONISM Parkinsonism is characterized by a combination of rigidity, bradykinesia, tremor, and postural instability that can occur for a variety of reasons but is usually idiopathic. Cognitive decline occurs in many patients as the disease advances. DRUGS USED IN PARKINSON DISEASE Currently available drugs offer temporary relief from the symptoms of the disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease. One . Levodopa and carbidopa Levodopa is a metabolic precursor of dopamine. It restores dopaminergic neurotransmission in the corpus striatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra. In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra (typically about 20 percent of normal) is adequate for conversion of levodopa to dopamine. Thus, in new patients, the therapeutic response to levodopa is consistent, and the patient rarely complains that the drug effects“wear off .” Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of taking up exogenously administered levodopa and converting it to dopamine for subsequent storage and release. Consequently, motor control fluctuation develops. 1. Mechanism of action: a. Levodopa: Because parkinsonism results from insufficient dopamine in specific regions of the brain, attempts have been made to replenish the dopamine defi ciency. Large doses of levodopa are required, because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension. b. Carbidopa: Carbidopa, a dopa decarboxylase inhibitor, diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues, thereby increasing the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by four- to fivefold and, consequently, decreases the severity of the side effects arising from peripherally formed dopamine. 2. Actions: Levodopa decreases the rigidity, tremors, and other symptoms of parkinsonism. 3. Absorption and metabolism: The drug is absorbed rapidly from the small intestine (when empty of food). Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This may produce fluctuations in motor response, which generally correlate with the plasma concentrations of levodopa, or perhaps give rise to the more troublesome “on-off ” phenomenon. Ingestion of meals, particularly if high in protein, interferes with the transport of levodopa into the CNS. Large, neutral amino acids (for example, leucine and isoleucine) compete with levodopa for absorption from the gut and for transport across the blood-brain barrier. Thus, levodopa should be taken on an empty stomach, typically 45 minutes before a meal. Withdrawal from the drug must be gradual. Adverse effects: a. Peripheral eff ects: Anorexia, nausea, and vomiting occur because of stimulation of the chemoreceptor trigger zone of the medulla. Tachycardia and ventricular extrasystoles result from dopaminergic action on the heart. Hypotension may also develop. b. CNS eff ects: Visual and auditory hallucinations and abnormal involuntary movements (dyskinesias) may occur. Levodopa can also cause mood changes, depression, psychosis, and anxiety. 6. Interactions: The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness. Concomitant administration of levodopa and monoamine oxidase inhibitors (MAOIs), such as phenelzine, can produce a hypertensive crisis. In many psychotic patients, levodopa exacerbates symptoms. In patients with glaucoma, the drug can cause an increase in intraocular pressure. Antipsychotic drugs are generally contraindicated in parkinsonian patients. However low doses of certain “atypical” antipsychotic agents are sometimes used to treat levodopa-induced psychiatric symptoms. Two. DOPAMINE RECEPTOR AGONISTS Drugs acting directly on postsynaptic dopamine receptors may have a beneficial effect in addition to that of levodopa. Unlike levodopa, they do not require enzymatic conversion to an active metabolite, act directly on the postsynaptic dopamine receptors, have no potentially toxic metabolites, and do not compete with other substances for active transport into the blood and across the blood-brain barrier. Moreover, drugs selectively affecting certain (but not all) dopamine receptors may have more limited adverse effects than levodopa. Dopamine agonists have an important role as first-line therapy for Parkinson’s disease, and their use is associated with a lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy. In consequence, dopaminergic therapy is often initiated with a dopamine agonist. Alternatively, a low dose of carbidopa plus levodopa (eg, Sinemet-25/100 three times daily) is introduced, and a dopamine agonist is then added. The response to a dopamine agonist is generally disappointing in patients who have never responded to levodopa. Bromocriptine Bromocriptine is a D2 agonist. This drug has been widely used to treat Parkinson ’sndisease in the past but is now rarely used for this purpose, having been superseded by the newer dopamine agonists. Pergolide Pergolide, another ergot derivative, directly stimulates both D1 and D2 receptors. It too has been widely used for parkinsonism but is no longer available in the United States because its use has been associated with the development of valvular heart disease. It is nevertheless still used in certain countries. Pramipexole Pramipexole is not an ergot derivative, but it has preferential affinity for the D3 family of receptors. It is effective as monotherapy for mild parkinsonism and is also helpful in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations. Pramipexole may ameliorate affective symptoms. Pramipexole is rapidly absorbed after oral administration, reaching peak plasma concentrations in approximately 2 hours, and is excreted largely unchanged in the urine. Ropinirole Another nonergoline derivative, ropinirole (now available in a generic preparation) is a relatively pure D2 receptor agonist that is effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations Rotigotine The dopamine agonist rotigotine, delivered daily through a skin patch, is approved for treatment of early Parkinson’s disease. It supposedly provides more continuous dopaminergic stimulation than oral medication in early disease Adverse Effects of Dopamine Agonists A. Gastrointestinal Effects Anorexia and nausea and vomiting may occur when a dopamine agonist is introduced and can be minimized by taking the medication with meals. Constipation, dyspepsia, and symptoms of reflux esophagitis may also occur. Bleeding from peptic ulceration has been reported. B. Cardiovascular Effects Postural hypotension may occur, particularly at the initiation of therapy. Painless digital vasospasm is a dose-related complication of long-term treatment with the ergot derivatives (bromocriptine or pergolide). C. Dyskinesias Abnormal movements similar to those introduced by levodopa may occur and are reversed by reducing the total dose of dopaminergic drugs being taken. D. Mental Disturbances Confusion, hallucinations, delusions, and other psychiatric reactions are potential complications of dopaminergic treatment and are more common and severe with dopamine receptor agonists than with levodopa. Three. MONOAMINE OXIDASE INHIBITORS – TYPE B Selegiline and rasagiline Selegiline selectively inhibits MAO Type B (which metabolizes dopamine) at low to moderate doses but does not inhibit MAO Type A (which metabolizes norepinephrine and serotonin) unless given at above recommended doses, where it loses its selectivity. By, thus, decreasing the metabolism of dopamine, selegiline has been found to increase dopamine levels in the brain. Therefore, it enhances the actions of levodopa when these drugs are administered together. Selegiline substantially reduces the required dose of levodopa. Unlike nonselective MAOIs, selegiline at recommended doses has little potential for causing hypertensive crises. However, if selegiline is administered at high doses, the selectivity of the drug is lost, and the patient is at risk for severe hypertension. Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than midafternoon. Rasagiline an irreversible and selective inhibitor of brain monoamine oxidase Type B, has five times the potency of selegiline. Unlike selegiline, rasagiline is not metabolized to an amphetamine like substance Four. CATECHOL-O-METHYL TRANSFERASE INHIBITORS Mechanism of action: Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism, especially catechol-O-methyl transferase (COMT), and this increases plasma levels of 3-Omethyldopa (3-OMD). Elevated levels of 3-OMD have been associated with a poor therapeutic response to levodopa. Selective COMT inhibitors such as tolcapone and entacapone also prolong the action of levodopa by diminishing its peripheral metabolism. Levodopa clearance is decreased and relative bioavailability of levodopa is thus increased. Uses: Tolcapone and entacapone are used for adjunctive therapy in patients who are already taking L-dopa/dopa decarboxylaseinhibitor combinations with unsatisfactory control (e.g. end-ofdose deterioration). These agents improve symptoms with less on–off fluctuations, as well as reducing the levodopa dose requirement by 20–30%. Adverse effects These include the following: • Nausea, vomiting, diarrhoea and constipation; • increased levodopa-related side effects; • Dizziness • Hepatitis – rare with entacapone, but potentially lifethreatening with tolcapone (liver function testing is mandatory before and during treatment) • Urine discoloration. Five. APOMORPHINE Subcutaneous injection of apomorphine hydrochloride (Apokyn), a potent nonergoline dopamine agonist that interacts with postsynaptic D2 receptors is effective for the temporary relief (“rescue”) of off-periods of akinesia in patients on optimized dopaminergic therapy. It is rapidly taken up in the blood and then the brain, leading to clinical benefit that begins within about 10 minutes of injection and persists for up to 2 hours. Nausea is often troublesome, especially at the initiation of apomorphine treatment; accordingly, pretreatment with the antiemetic trimethobenzamide or domperidone for 3 days is recommended before apomorphine is introduced and is then continued for at least 1 month. Other adverse effects include dyskinesias, drowsiness, insomnia, chest pain, sweating, hypotension, syncope, constipation, diarrhea, and mental or behavioral disturbances Six: AMANTADINE Use: Amantadine has limited efficacy, but approximately 60% of patients experience some benefit. Severe toxicity is rare. Mechanism of action: Endogenous dopamine release is stimulated by amantadine, which also inhibits reuptake of dopamine into nerve terminals. Seven: MUSCARINIC RECEPTOR ANTAGONISTS Muscarinic antagonists (e.g. trihexyphenidyl, benzatropine, orphenadrine, procyclidine) are effective in the treatment of parkinsonian tremor and to a lesser extent rigidity, but produce only a slight improvement in bradykinesia. They are usually given in divided doses, which are increased every two to five days until optimum benefit is achieved or until adverse effects occur. Their main use is in patients with Parkinsonism caused by antipsychotic agents. Adverse effects These include the following: • Dry mouth, blurred vision, constipation; • Precipitation of glaucoma or urinary retention • Cognitive impairment, confusion, excitement or psychosis, especially in the elderly.