Discuss the pharmacology of levo-dopa.

Outline:

·        Mechanism of action.

·        Pharmacokinetics.

·        Clinical use.

·        Adverse effects.

·        Drug interactions.

Suggested Answer:

Levodopa is a natural amino acid precursor of dopamine and is used in the treatment of Parkinson’s disease. Dopamine cannot be used because it is rapidly metabolized in the gut, blood and liver by MAO and COMT. Levodopa is readily absorbed from the upper small intestine by active amino acid transport and has a half-life of 1.5 h. It can traverse the blood-brain barrier by a similar active transport, and within the brain it is decarboxylated by dopa decarboxylase to the neurotransmitter dopamine. Levodopa penetrates the CNS and is enzymatically converted to dopamine in the basal ganglia. There is considerable evidence that symptoms of parkinsonian syndrome, regardless of the causeof the syndrome, are related to depletion of dopamine in the corpus striatum, and levodopa is believed to act principally by increasing dopamine concentration in the brain.

Substantial amounts of levodopa are metabolized in the lumen of the stomach and intestines and on first pass through the liver. Most absorbed levodopa is decarboxylated to dopamine; more than 95% of the drug is decarboxylated peripherally by aromatic l-amino acid decarboxylase, a widely distributed enzyme. Small amounts of levodopa are metabolized to norepinephrine,epinephrine, and 3-methoxytyramine. A small quantity of levodopa is methylated to 3-O-methyldopa; this metabolite is present in plasma and accumulates in the CNS because of its long half-life. Dopamine is further metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA) and excreted in urine.

As levodopa is extensively decarboxylated to dopamine in the peripheral tissues, only 1- 5% of an oral dose of levodopa reaches the brain. Thus large quantities of levodopa have to be given. These inhibit gastric emptying, delivery to the absorption site is erratic and fluctuations in plasma concentration occur. The drug and its metabolites cause significant adverse effects by peripheral actions, notably nausea, but also cardiac dysrhythmia and postural hypotension. This problem has been largely circumvented by the development of decarboxylase inhibitors, which do not enter the CNS, so that they prevent only the extracerebral metabolism of levodopa. The inhibitors, e.g. carbidopa, benserazide, are given in combination with levodopa and there is a range of formulations comprising a decarboxylase inhibitor with levodopa in various proportions: carbidopa + levodopa in Sinemet and benserazide + levodopa in Madopar. The combinations produce the same brain concentrations as with levodopa alone, but only 25% of the dose of levodopa is required, which smoothes the action of levodopa and reduces the incidence of adverse effects, especially nausea, from about 80% to less than 15%.

Levodopa-induced involuntary movements may take the form of general restlessness or head, lip or tongue movements or choreoathetosis. Involuntary movements occur in about 50% of patients on long-term therapy and may consist of grimacing, bruxism, gnawing, chewing, twisting and protrusion of the tongue, rhythmic opening and closing of the mouth. Intermittent myoclonic body jerks during sleep, ataxia, increased hand tremor, and muscle twitching and blepharospasm (which may be an early sign of excessive dosage) may also occur.

Mental changes may be seen: these include depression, which is common, dreams and hallucinations. Numerous mild to severe CNS and psychiatric disturbances may be produced by levodopa and may include decreased attention span, memory loss, insouciance, nervousness, anxiety, agitation, restlessness, confusion, insomnia, vivid dreams, nightmares, daytime somnolence, euphoria, malaise, and fatigue. Serious psychiatric disturbances requiring reduction of dosage or complete withdrawal of the drug have included severe mental depression with or without suicidal tendencies, dementia, toxic delirium, paranoid delusions, hallucinations, and hypomania with inappropriate or excessive sexual behavior.

Nausea, vomiting, and anorexia (which may be accompanied by weight loss) occur frequently in patients receiving levodopa. Adverse GI effects of levodopa generally occur early in therapy while dosage is being increased and may be relieved by temporaryreduction of dosage or administration of the drug with food. Other adverse GI effects which have been reported less frequently include duodenal ulcer, GI bleeding, constipation, diarrhea, epigastric and abdominal distress and pain, flatulence, hiccups, sialorrhea, dry mouth, dysphagia, change in taste sensation (including bitter taste), burning of the tongue.

Orthostatic hypotension occurs frequently following therapeutic doses of levodopa; however, it is usually asymptomatic and tolerance usually develops within a few months. If orthostatic hypotension causes dizziness or syncope, levodopa dosage should be reduced and the patient should be advised to wear elastic stockings until previous dosage of levodopa is tolerated. Cardiac irregularities occur infrequently with levodopa and may include palpitation, sinus tachycardia, ventricular tachycardia or extrasystole, atrial flutter or fibrillation, or block of atrioventricular conduction. Cardiac arrhythmias caused by levodopa can be prevented by concomitant administration of a beta-adrenergic antagonist such as propranolol. Other reported adverse cardiovascular effects of levodopa include flushing and hypertension.

With non-selective MAOI, the dopamine formed from levodopa is protected from destruction; it accumulates and also follows the normal path of conversion to noradrenaline, by dopamine b-decarboxylase; severe hypertension results. Pyridoxine may be present in ordinary vitamin preparations in sufficient quantity to produce an increase in activity of peripheral decarboxylases for which it is a cofactor. It has been found to reduce plasma L-dopa concentration and to increase HVA synthesis. Pyridoxine may thus be a contributory factor to reduced effectiveness of L-dopa unless the patient is also given a peripheral decarboxylase inhibitor at the same time. Reserpine depletes the basal ganglia of dopamine and thus should not be given with L-dopa. The phenothiazines may produce a parkinsonism-like state in toxic dosage. If any antimuscarinic drug is to be used with L-dopa, it should be given 2 hours before or after the latter so as to allow for maximal absorption of L-dopa. An antimuscarinic drug delays gastrointestinal motility and allows more time for intestinal decarboxylases to act on L-dopa, thus reducing its bioavailability and increasing the amount of dopamine formed peripherally.

L-dopa is contraindicated in patients with severe psychoneurosis, closed angle glaucoma and cardiac disease. It should not be given within 2 weeks of administering MAOIs so as to avoid precipitating a hypertensive crisis. Patients with active peptic ulcer disease must be carefully managed since gastrointestinal bleeding may occasionally occur with L-dopa. As L-dopa is a precursor of skin melanin, it should be avoided in patients with a history of melanoma.