The tricyclic antidepressants have potent and complex effects on the cardiovascular system, both directly and through interactions with other drugs. Through a combination of anticholinergic activity, direct myocardial depressant activity and an effect on the adrenergic neuron, they can cause a combination of arrhythmias, blood pressure abnormalities and congestive heart failure. These changes, although most common with overdose, can occur at therapeutic levels. In addition a number of drug-drug interactions can occur between the tricyclics and agents used in the treatment of cardiovascular disease, as exemplified by tricyclic antagonism of the antihypertensive effect of guanethidine. Awareness of these factors is necessary to insure proper therapeutic utilization of the tricyclics as well as to treat effectively their toxicity.

A review of the cardiovascular effects and toxicity of tricyclic antidepressants.

Reduced effect of morphine in midbrain raphe lesioned rats.

The pharmacological effect of a drug is partly dependent upon its concentration at its site of action, which in turn is partly dependent upon its rate of elimination. The rate of elimination of many lipophilic drugs is governed by the activity of the hepatic microsomal mixed-function oxidases. Consequently any alteration in the activity of these enzymes may result in a modification of drug action. A wide range of chemically unrelated substances may stimulate the activity of the mixedfunction oxidases by enzyme induction. The drugs most frequently encountered as enzymeinducing agents in man are barbiturates, rifampicin and Phenytoin. Enhancement of drug metabolism by ethanol, tobacco smoking and diet may also involve enzyme induction. Enzyme induction is normally associated with a reduction in drug efficacy but may also alter the toxicity of certain substances. Enzyme induction has been assessed in man by measuring changes in the pharmacokinetics of a marker drug, or changes in the disposition of endogenous compounds such as γ-glutamyltranspeptidase, D-glucaric acid and 6β-hydroxycortisol. The therapeutic problems associated with enzyme inhibition have received much less attention than those associated with enzyme induction. The effect on the rate of elimination of a particular drug will depend upon the fraction of the dose that is normally metabolised by the inhibited enzyme and on the affinity of the enzyme for the drug and the inhibitor. An alteration in the dosage schedule is usually only necessary for drugs with a small therapeutic ratio.

Clinical Implications of Enzyme Induction and Enzyme Inhibition

Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta-blockers, calcium channel blockers, female hormones, nonsteroidal anti-inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.

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Comprehensive review of cardiovascular toxicity of drugs and related agents.

This review focuses on the history of investigations into the behavioural reaction resulting from excess stimulation of post-synaptic 5-hydroxytryptamine receptors and the relative risk of this occurring with different combinations of drugs. Other aspects, particularly treatment with 5-hydroxytryptamine receptor antagonists, are reviewed in a recent separate paper [44]. The first human case was in 1955 and animal work had defined the characteristic features by 1958, and established they were lessened by chlorpromazine. Substantial evidence of a 'dose-effect' relationship existed by 1984. The relative risk with different drug combinations is assessed from available evidence and argued to be strongly associated with the degree of elevation of 5-hydroxytryptamine, which is greatest following combinations of irreversible inhibitors of monoamine oxidase A and B with potent serotonin reuptake inhibitors. The various serotonergic drugs that may be implicated in serotonin syndrome are tabulated and discussed in relation to the relative risk. It is suggested that the proposed 'diagnostic criteria' for serotonin syndrome are inappropriate since there is a continuous spectrum from side effects to toxicity. The term 'serotonin syndrome' may encourage the presumption that it is an idiosyncratic response, as neuroleptic malignant syndrome is usually considered to be. The terms 'toxic serotomimetic reaction' or 'toxic serotonin syndrome' may be preferable alternatives. The differences between serotonin syndrome and neuroleptic malignant syndrome are highlighted with examples from difficult or questionable cases in the recent literature. It is proposed that more systematic national collection of toxicity data is essential in order to quantify the relative risk of serotonin syndrome with various combinations of serotonergic drugs.

Serotonin syndrome: history and risk.

Monoamine oxidase inhibitors (MAOI) in clinical use have an irreversible action on MAO, and this persists until the enzyme has been resynthesized. The effects of small daily doses of MAOI are therefore cumulative. The biochemical effects of these drugs will involve several substrates of MAO, e.g. dopamine, tyramine, serotonin and, to a lesser extent, noradrenaline and adrenaline.MAO probably regulates the metabolism of catecholamines and serotonin in tissues, while catechol-O-methyltransferase is responsible for the metabolism of circulating noradrenaline and adrenaline.Certain pharmacological effects of MAOI are related to the accumulation of monoamines in various tissues that follows the decrease of intraneuronal deamination. Among these effects are reversal of the reserpine syndrome in animals and augmentation of the pharmacological action of monoamines. Other effects are unrelated to the inhibition of MAO, e.g. immediate desynchronization of EEG and initial pressor effects.MAOI may potentiate or change the action of several other drugs and even certain foods. The mechanisms involved are usually reasonably predictable from animal experiments. Substrates of MAO, e.g. dopamine and tyramine, evoke augmented and prolonged effects in patients treated with MAOI. This is partly due to an impaired metabolism of the circulating amines. In addition, inhibition of intestinal and hepatic MAO largely increases the absorption of tryamine from cheeses and other foods. Usually innocuous amounts of tyramine may therefore cause hypertensive reactions in patients treated with MAOI. Indirectly acting sympathomimetic amines, such as amphetamines, ephedrine and MAOI with amphetamine-like properties, can be potentiated, because they may release increased amounts of nor-adrenaline from sympathetic nerve endings after MAO inhibition. The effects of any amine, whether a substrate of MAO or not, may be enhanced by MAO inhibitors producing postganglionic block. This is due to ;denervation' supersensitivity of adrenergic receptors.Harmful pharmacological interaction is also possible between MAO inhibitors and agents which release (reserpine) or replete (amine precursors, e.g. L-DOPA in broad beans) monoamines centrally and peripherally. Drugs that sensitize adrenergic and tryptaminergic receptors to the action of monoamines, e.g. imipramine-like compounds, may be greatly potentiated by MAO inhibitors. The anti-hypertensive effects of thiazides and ganglion-blocking agents may be enhanced by MAOI. A few drugs are known to exert prolonged effects in occasional patients treated with MAOI, e.g. pethidine, phenothiazines and pentobarbital. MAOI may possibly decelerate the metabolism of these compounds by a nonspecific inhibition of liver microsomal enzymes. Finally, a great number of agents have been found empirically to evoke augmented effects after inhibition of MAO, e.g. insulin and anti-Parkinson drugs.

Folke Sjöqvist

Papers

Psychotropic drugs (2). Interaction between monoamine oxidase (MAO) inhibitors and other substances.