Methyldopa Monoamine oxidase inhibitors

Patients taking monoamine oxidase inhibitors, anticholinergic drugs (such as tricyclic antidepressants), propranolol, reserpine, guanethidine, and methyldopa should be monitored closely if phenylephrine is used (SEDA-16, 542) (16). 

Monoamine oxidase inhibitors and many pharmacological agents are synergistic, sometimes resulting in a hypertensive crisis. The agents with which the MAOIs may be synergistic include amphetamine, dextroamphetamine, methyl amphetamine, ephedrine, procaine preparations (which usually contain norepinephrine), epinephrine, methyldopa, and phenylpropanolamine (over-the-counter cold preparations). 

In the past few years, the chemistry and pharmacology of the catecholamines and their metabolic inhibitors have been the subject of intensive investigation in many parts of the world but especially by Sjoerdsma and Axelrod at the National Heart Institute. Monoamine oxidase inhibitors have been tried in the treatment of hypertension with both uncertain results and uncertain rationale. Recently, the decarboxylase inhibitor, methyldopa, has been widely recommended in the treatment of hypertension, though, again, the evidence gives no clear idea as to how it works. 

Dopamine is formed within the brain from both L-dopa and l-3-O-methyldopa, but the latter is probably demethylated first. Administration of either amino acid to man or to animals [487, 494,499] enhances brain levels of dopamine and noradrenaline, and of their O-methylated metabolites, the former effect being further enhanced by monoamine oxidase inhibitors and inhibitors of catechol 0-methyl transferase. Cerebral 3-O-methyldopamine arises by methylation of dopamine rather than by decarboxylation of L-3-O-methyldopa, while the increases in cerebral and urinary homovanillic acid levels after L-dopa arise by oxidative deamination and 3-O-methylation of dopamine formed at the periphery and the neuron. The accumulation of the long-lived amino acid, L-3-O-methyldopa, in the brain, and its slow conversion to dopamine, may well explain why the therapeutic effects of L-dopa in Parkinsonism disappear only slowly upon discontinuation of treatment. Indeed, preliminary studies in man [494] indicate that l-3-O-methyldopa exerts a therapeutic action in Parkinsonism without the com-comitant side effects normally associated with L-dopa therapy. The relevant information regarding the fate and mode of action of L-dopa in the central nervous system is summarised in Figure 5.8. 

The COMT inhibitors should not be administered with the monoamine oxidase (MAO) inhibitors (see Chap. 31) because there is an increased risk of toxicity. If the COMT inhibitors are administered with norepinephrine, dopamine, dobutamine, methyldopa, or epinephrine, there is a risk of increased heart rate, arrhythmias, and excessive blood pressure changes. 

Patients taking certain systemic medications are also more sensitive to the pressor effects of phenylephrine. In individuals taking atropine, the pressor effect of phenylephrine is augmented, and tachycardia can occur. Tricyclic antidepressants and monoamine oxidase (MAO) inhibitors also potentiate the cardiovascular effects of topical phenylephrine. The concomitant use of phenylephrine is contraindicated with these agents, even up to 21 days after cessation of MAO inhibitor therapy. Similarly, patients taking reserpine, guanethidine, or methyldopa are at increased risk for adverse pressor effects from topical phenylephrine because of denervation hypersensitivity accompanying the chemical sympathectomy. 

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