Levodopa and dopa-decarboxylase inhibitors
Levodopa ('dopa' stands for dihydroxyphenyl-alanine) is a natural amino acid precursor of dopamine. The latter cannot be used because it is rapidly metabolised in the gut, blood and liver by monoamine oxidase and catechol-O-methyltrans-
ferase; even intravenously administered dopamine, or dopamine formed in peripheral tissues, is insufficiently lipid-soluble to penetrate the CNS. But levodopa is readily absorbed from the upper small intestine by active amino acid transport and has a t1/ 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.
But a major disadvantage is that levodopa is also extensively decarboxylated to dopamine in peripheral tissues so that only 1-5% of an oral dose of levodopa reaches the brain. Thus large quantities of levodopa would 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 arrhythmia and postural hypotension. This problem has been largely circumvented by the development of decarboxylase inhibitors, which do not enter the central nervous system, so that they prevent only the extracerebral metabolism of levodopa. The inhibitors are given in combination with levodopa and there is a range of formulations comprising a decarboxylase inhibitor with levodopa:
• co-careldopa (carbidopa + levodopa in proportions 12.5/50 mg, 10/100,25/100, 25/250) (Sinemet)
• co-beneldopa (benserazide + levodopa in proportions 12.5 mg/50 mg, 25/100,50/200) (Madopar).
The combinations produce the same brain concentrations as with levodopa alone, but only 25% of the dose of levodopa is required, which smooths the action of levodopa and reduces the incidence of adverse effects, especially nausea, from about 80% to less than 15%.
Levodopa alone and in combination (see above) is introduced gradually and titrated according to response, the dose being altered every 2 weeks. The dose is increased to provide sufficient benefit for each individual patient, not to a standard dose since this is very variable.
Compliance is important. Abrupt discontinuation of therapy leads to dramatic relapse.
Adverse effects. Postural hypotension occurs. Nausea may be a limiting factor if the dose is increased too rapidly; it may be helped by cyclizine 50 mg taken 30 min before food or by domperidone (little of which enters the brain). Levodopa-induced dyskinesias take the form of involuntary limb jerking or head, lip or tongue movements and constitute a major constraint on how the drug is used (see later). Mental changes may be seen: these include depression, which is common (best controlled with a tricyclic antidepressant), dreams, and hallucinations and delusions (clozapine may help). Agitation and confusion occur but it may be difficult to decide whether these are due to drug or to disease. In these circumstances, the drugs most likely to be the cause of a toxic confusional state (antimuscarinics and direct dopamine agonists) are withdrawn.
Interactions. With nonselective monoamine oxidase inhibitors (MAOI), the monoamine dopamine formed from levodopa is protected from destruction; it accumulates and also follows the normal path of conversion to noradrenaline (norepinephrine), by dopamine p-hydroxylase; severe hypertension results. The interaction with the selective MAO-B inhibitor, selegiline, is possibly therapeutic (see below). Tricyclic antidepressants are safe. Levodopa antagonises the effects of antipsychotics (dopamine receptor blockers). Some antihypertensives enhance hypotensive effects of levodopa. Metabolites of dopamine in the urine interfere with some tests for phaeochromocytoma, and in such patients it is best to measure the plasma catecholamines directly.
Dopa-decarboxylase is a pyridoxine-dependent enzyme and concomitant use of pyridoxine, e.g. in self-medication with a multivitamin preparation, can enhance peripheral conversion of levodopa to dopamine so that less is available to enter the CNS, and benefit is lost. This effect does not occur, of course, with the now usual levodopa-decarboxylase inhibitor combinations.
These mimic the effects of dopamine, the endogenous agonist, which stimulates both the main two types of dopamine receptor, D( and D2 (coupled respectively to adenylyl cyclase stimulation and inhibition). The D2-receptor is the principal target in Parkinson's disease; chronic Dj stimulation appears to potentiate the response to D2 stimulation despite acutely having an inhibitory action on adenylyl cyclase. The main problems with dopamine (i.e. the prodrug, levodopa) are its short t1/, and, possibly, the consequences of delivering large amounts of substrate to an oxidative pathway, MAO (see below). On the other hand, the problems of developing synthetic alternatives are:
• reproducing the right balance of D2 and D2 stimulation (dopamine itself is slightly Dj selective, in test systems, but its net effect in vivo is determined also by the relative amounts and locations of receptors — which differ in Parkinsonian patients from normal)
• avoiding the undesired effects of peripheral, mainly gastric, D2-receptors
• synthesising a full, not partial, agonist.
Bromocriptine (a derivative of ergot) is a D2-receptor agonist, but also a weak a-adrenoreceptor antagonist. It is commonly used with levodopa. The drug is rapidly absorbed after administration by mouth; the t1/ is 5 h, so that its action is smoother than that of levodopa, which can be an advantage in patients who develop end-of-dose deterioration with levodopa. Dosing should start very low (1-1.25 mg p.o. at night), increasing at approximately weekly intervals and according to clinical response.
Nausea and vomiting are the commonest adverse effects; these may respond to domperidone but tend to become less marked as treatment continues. Postural hypotension may cause dizziness or syncope. In high dose confusion, delusions or hallucinations may occur and, after prolonged use, pleural effusion and retroperitoneal fibrosis.
Lisuride (t'/2 2 h) and pergolide (t1^ 6 h) are similar to bromocriptine, though the latter also stimulates Dj-receptors. Cabergoline, also an ergot derivative, has a t|/2 of more than 80 h. This long duration of action allows it to be used in a single daily (or even twice weekly) dose, which is appreciated by patients who are often taking other drugs every
2-3 hours; it is also valuable for night-time problems due to lack of levodopa. Pramipexole is a non-ergot dopamine D2-receptor agonist that is more effective against tremor than the others. Ropinirole is a direct D2-receptor agonist, which is also a non-ergot derívate. There are insufficient data to allow an informed choice between these drugs.
Apomorphine is a derivative of morphine having structural similarities to dopamine; it is a full agonist at Dj- and D2-receptors. Its main use is in young patients with severe motor fluctuations and dyskinesias (the 'on-off' phenomenon, see above) when it is given by s.c. injection or infusion for patients with levodopa resistant 'off'. The rapid onset of action by the s.c. route (self-administration can be taught) enables the 'off' component to be aborted without the patient waiting 45-60 minutes to absorb another oral dose of levodopa. Apomorphine may need to be accompanied by an antiemetic, e.g. domperidone (which does not cross the blood-brain barrier as does metoclopramide), to prevent its characteristic emetic action. Overdose causes respiratory depression; it is antagonised by naloxone. Apomorphine can induce penile erection (without causing sexual excitement) and it enhances the penile response to visual erotic stimulation.
Monoamine oxidase (MAO) enzymes have an important function in modulating the intraneuronal content of neurotransmitter. The enzymes exist in two principal forms, A and B, defined by specific substrates some of which cannot be metabolised by the other form (Table 20.3). The therapeutic importance of recognising these two forms arises because they are to some extent present in different tissues, and the enzyme at these different locations can be selectively inhibited by the individual inhibitors: moclobemide for MAO-A (used for depression, p. 379) and selegiline for MAO-B (Table 20.3).
Selegiline is a selective, irreversible inhibitor of MAO type B. The problem with nonselective MAO inhibitors is that they prevent degradation of dietary amines, especially tyramine, which is then able to act systemically as a sympathomimetic: the
Explanation: the specific substrate for MAO-A is serotonin, whilst for MAO-B it is the nonendogenous amine, phenylethylamine (present in many brands of chocolate). Noradrenaline, tyramine and dopamine can be metabolised by both isoforms of MAO. MAO-A is the major form in liver and in neurons (both CNS and peripheral sympathetic); MAO-B is the major form in gut, but is also present in the liver, lungs and glial cells of the CNS.
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