Tiêu đề 15. DRUGS USED IN PARKINSONISM.pdf ✅

PHARMD GURU Page 1 Currently available drugs off er temporary relief from the symptoms of the disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease. A) LEVODOPA AND CARBIDOPA:  Levodopa is a metabolic precursor of dopamine (Figure 8.6). 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. DRUGS USED IN PARKINSONISM
PHARMD GURU Page 2  Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body. The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa, a dopa decarboxylase inhibitor that does not cross the blood-brain barrier. 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 deficiency. Dopamine itself does not cross the blood-brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and is converted to dopamine in the brain (see Figure 8.6). 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. THERAPEUTIC USES: Levodopa in combination with carbidopa is a potent and efficacious drug regimen currently available to treat Parkinson disease. In approximately two-thirds of patients with Parkinson disease, levodopa–carbidopa treatment substantially reduces the severity of the disease for the first few years of treatment. Patients then typically experience a decline in response during the third to fifth year of therapy. 4. 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
PHARMD GURU Page 3 generally correlate with the plasma concentrations of levodopa, or perhaps give rise to the more troublesome “on-off” phenomenon, in which the motor fluctuations are not related to plasma levels in a simple way. Motor fluctuations may cause the patient to suddenly lose normal mobility and experience tremors, cramps, and immobility. 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. 5. ADVERSE EFFECTS: a) Peripheral effects: Anorexia, nausea, and vomiting occur because of stimulation of the chemoreceptor trigger zone of the medulla (Figure 8.7). Tachycardia and ventricular extrasystoles result from dopaminergic action on the heart. Hypotension may also develop. Adrenergic action on the iris causes mydriasis, and, in some individuals, blood dyscrasias and a positive reaction to the Coombs test are seen. Saliva and urine are a brownish color because of the melanin pigment produced from catecholamine oxidation. b) CNS effects: Visual and auditory hallucinations and abnormal involuntary movements (dyskinesias) may occur. These CNS effects are the opposite of parkinsonian symptoms and reflect the overactivity of dopamine at receptors in the basal ganglia. 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 (Figure 8.8). Concomitant administration of levodopa and monoamine oxidase inhibitors (MAOIs), such as phenelzine, can produce a hypertensive crisis caused by enhanced catecholamine production. Therefore,
PHARMD GURU Page 4 caution is required when they are used simultaneously. In many psychotic patients, levodopa exacerbates symptoms, possibly through the buildup of central catecholamines. In patients with glaucoma, the drug can cause an increase in intraocular pressure. Cardiac patients should be carefully monitored because of the possible development of cardiac arrhythmias. Antipsychotic drugs are generally contraindicated in parkinsonian patients, because these potently block dopamine receptors and produce a parkinsonian syndrome themselves. However low doses of certain “atypical” antipsychotic agents are sometimes used to treat levodopa-induced psychiatric symptoms. B. SELEGILINE AND RASAGILINE: Selegiline, also called deprenyl, 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 (Figure 8.9). 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 mid- afternoon. 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.