Anti-Parkinson Drugs
Posted in Anti-Parkinsonism, Pharmacology
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Wednesday, 22 February 2012 By Unknown
*Anti-Parkinson Drugs:-
-Amantadine
-Apomorphine
-Benztropine
-Cabidopa
-levodopa
-pramipexol
-selegiline
-rasagiline
-entacapone
*Parkinson's Disease:-Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities. Most cases involve people over the age of 65, among whom the incidence is about 1 in 100 individuals.
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*Levodopa And Carbidopa:
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 8.7). 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:The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa [kar-bi-DOE-pa], a dopa decarboxylase inhibitor that does not cross the blood-brain barrier. Carbidopa diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues; thus, it increases the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by four- to five-fold 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's disease. In approximately two-thirds of patients with Parkinson's 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.
Thus, levodopa should be taken on an empty stomach, typically 45 minutes before a meal.
5.Adverse effects:
*Peripheral effects: Anorexia, nausea, and vomiting occur because of stimulation of the chemoreceptor trigger zone of the medulla.Tachycardia and ventricular extra systoles result from dopaminergic action on the heart. Hypotension may also develop.
*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.
-Concomitant administration of levodopa and monoamine oxidase (MAO) inhibitors, such as phenelzine, can produce a hypertensive crisis caused by enhanced catecholamine production.
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*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. Therefore, it enhances the actions of levodopa when these drugs are administered together.
-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 (MAO) Type B, has five times the potency of selegiline. Unlike selegiline, it is not metabolized to an amphetamine-like substance.
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*Amantadine:
-It was accidentally discovered that the antiviral drug amantadine, which is effective in the treatment of influenza, has an antiparkinsonism action.
-Amantadine has several effects on a number of neurotransmitters implicated in causing parkinsonism, including increasing the release of dopamine, blockading cholinergic receptors, and inhibiting the N-methyl-D-aspartate (NMDA) type of glutamate receptors. Current evidence supports an action at NMDA receptors as the primary action at therapeutic concentrations.
-The drug may cause restlessness, agitation, confusion, and hallucinations, and at high doses, it may induce acute toxic psychosis.
-Amantadine is less efficacious than levodopa, and tolerance develops more readily. However, amantadine has fewer side effects. The drug has little effect on tremor, but it is more effective than the anticholinergics against rigidity and bradykinesia.
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*Dopamine-receptor agonists:
-Bromocriptine
-Apomorphine
- pramipexole
- ropinirole
- rotigotine
-This group of anti-Parkinson compounds includes bromocriptine, an ergot derivative, and two newer, nonergot drugs, ropinirole, pramipexole and rotigotine.
-These agents have durations of action longer than that of levodopa and, thus, have been effective in patients exhibiting fluctuations in their response to levodopa.
-Initial therapy with the newer drugs is associated particularly with less risk of developing dyskinesias and motor fluctuations when compared to patients started with levodopa therapy.
-Bromocriptine, pramipexole, and ropinirole are all effective in patients with advanced Parkinson's disease complicated by motor fluctuations and dyskinesias. However, these drugs are ineffective in patients who have shown no therapeutic response to levodopa.
-Apomorphine is also used in severe and advanced stages of the disease as an injectable dopamine agonist to supplement the oral medications commonly prescribed.
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