Phaeochromocytomas

Phaeochromocytoma (a tumor in the adrenal medulla) is not uncommon in rats, but rare in humans. Pheochromocytomas are induced in rats by a variety of non-genotoxic substances that may act indirectly by stimulating chromaffin cell proliferation. They are not known to be similarly inducible in other species. In the rat, a mechanism for the development may be hypercalcaemia (Tischler et al. 1999 Capen et ah, in Haschek et al. 2001). 

Phentolamine and phenoxybenzamine are older O -adrenoceptor antagonists, which may be used occasionally in course of the surgical removal of phaeochromocytoma, with the aim to suppress the vasoconstrictor effects of noradrenaline/adrenaline released from the tumor as a result of surgical manipulation. 

Deficiency of adrenal medullary catecholamines appears to give no ill effects, and replacement therapy is therefore not used, but adrenal medullary tumours, phaeochromocytomas, secrete excess catecholamines often causing hypertension with dramatic episodes of headache, palpitations, pallor, sweating and anxiety. This condition is normally treated surgically, but preoperative preparation is mandatory to avoid catastrophic effects of surges of catecholamine release. A combination of alpha- and beta-adrenergic receptor blockade is normally used, with drugs such as phenoxybenzamine or doxazosin as alpha-blockers, and propranolol as a non-selective beta-blocker. 

Alpha-adrenoceptor antagonists are used as antihypertensives and to reduce afterload in the treatment of heart failure. Urapidil and, to a lesser extent, ketanserin are used in the treatment of essential hypertension and acute perioperative hypertension. In contrast to other vasodilators urapidil does not increase intracranial pressure when given intravenously, making it preferable for use in neurosurgical interventions. The effects of the excessive catecholamine concentrations in patients with phaeochromocytoma can be treated by the non-selective ol- and o2-adrenoceptor antagonists phentolamine or phenoxybenzamine. 

Prazosin and doxazosin are selective al blockers with similar properties. They are competitive antagonists that can be displaced from the al receptor by increases in catecholamine concentrations. This makes them unsuitable for use in the peri-operative management of phaeochromocytoma. Urapidil is an agonist at both central a2 and serotoninergic 5-HTlA receptors, and also has antagonist actions at cardiac pi adrenoceptors. 

Labetalol is a non-selective 31-, 32- and a 1-adrenoceptor antagonist. The ol-blocking properties (which are substantially weaker than the 3-blocking activity) are largely responsible for its vasodilatory effect. Labetalol is used orally in patients with phaeochromocytoma. During... 

Noradrenaline is used to treat shock-like conditions associated with peripheral vasodilatation, e.g. sepsis, systemic inflammatory response syndrome (SIRS), neurogenic shock. The rationale of its use in sepsis and SIRS is to counteract the vasodilatory effects of nitric oxide. Following the surgical removal of phaeochromocytoma and similar tumours, noradrenaline is often given to maintain blood pressure in the initial period. During and after cardiac surgery, it may be used to optimise haemodynamic parameters in combination with other drugs, such as phosphodi-esterase inhibitors. Dose... 

Carbon tetrachloride was tested for carcinogenicity by various routes of administration. It produced liver neoplasms in mice and rats and mammary neoplasms in rats following subcutaneous injection. In one study in mice by inhalation, an increased incidence of phaeochromocytomas was reported. In experiments involving administration of carbon tetrachloride after known carcinogens, the occurrence of tumours and/or pre-neoplastic lesions of the liver in mice, rats and hamsters was enhanced. 

Two different pentachlorophenol formulations were tested for carcinogenicity by oral administration in two separate experiments in mice. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas was observed in males exposed to either formulation and of hepatocellular adenomas in females exposed to one of the formulations. A dose-related increase in the incidence of adrenal phaeochromocytomas was observed in male mice exposed to either formulation, and an increase was also seen in females exposed to one of the formulations at the highest dose. A dose-related increase in the incidence of malignant vascular tumours of the liver and spleen was seen in female mice exposed to either formulation (lARC, 1991). 

Trichloroethane was tested for carcinogenicity in a two-year study in male and female B6C3F] mice and Osborne-Mendel rats by oral administration and in Sprague-Dawley rats by subcutaneous injection. In the study by oral administration, 1,1,2-trichloroethane produced hepatocellular neoplasms and adrenal phaeochromocytomas in mice of each sex but did not significantly increase the proportion of rats with neoplasms at any site relative to untreated controls. In the study in rats by subcutaneous injection,... 

MEN, multiple endocrine neoplasias, including thyroid carcinomas and tumours of the adrenal medulla, (phaeochromocytoma). 

If patient has phaeochromocytoma, circulatory collapse, or blood dyscrasias... 

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 (J-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. 

To block all the effects of adrenaline and noradrenaline, antagonists for both a- and P-receptors must be used. This can be a matter of practical importance, e.g. in phaeochromocytoma (see p. 495). 

Accidental overdose with adrenaline occurs occasionally. It is rationally treated by propranolol to block the cardiac p effects (cardiac arrhythmia) and phentolamine or chlorpromazine to control the a effects on the peripheral circulation that will be prominent when the P effects are abolished. Labetalol (a + p block) would be an alternative. P-adrenoceptor block alone is hazardous as the then unopposed a-receptor vasoconstriction causes (severe) hypertension (see Phaeochromocytoma, p. 494). Use of antihypertensives of most other kinds is irrational and some may also potentiate the adrenaline. 

Phentolamine is a nonselective a-adrenoceptor blocker. It is given i.v. for brief effect in adrenergic hypertensive crises, e.g. phaeochromocytoma or the MAOI-S5nnpathomimetic interaction. In addition to a-neceptor block it has direct vasodilator and cardiac inotropic actions. The dose for hypertensive crisis is 2-5 mg i.v. repeated as necessary (in minutes to hours). The use of phentolamine as a diagnostic test for phaeochromocytoma is appropriate only when biochemical measurements are impracticable, since it is less reliable. 

Phenoxybenzamine is an irreversible nonselective a-adrenoceptor blocking drug whose effects may last 2 days or longer. The daily dose must therefore be increased slowly. It is impossible to reverse the circulatory effects by secreting noradrenaline (norepinephrine) or other sympathomimetic drugs because its effects are insurmountable. This makes it the preferred a-blocker for treating phaeochromocytoma (see p. 495). 

Phaeochromocytoma blockade of P-agonist effects of circulating catecholamines always in combination with adequate a-adrenoceptor block. Only small doses of a P-blocker are required. 

Hypertension may occur whenever blockade of P-receptors allows pre-existing a-effects to be unopposed, e.g. phaeochromocytoma. 

Clonidine reduces blood pressure with little postural or exercise related drop. Its most serious handicap is that abrupt or even gradual withdrawal causes rebound hypertension. This is characterised by plasma catecholamine concentrations as high as those seen in hypertensive attacks of phaeochro-mocytoma. The onset may be rapid (a few hours) or delayed for as long as 2 days it subsides over 2-3 days. The treatment is either to reinstitute clonidine, i.m. if necessary, or to treat as for a phaeochro-mocytoma. Clonidine should never be used with a p-adrenoceptor blocker which exacerbates withdrawal hypertension (see phaeochromocytoma). Common... 

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