Catecholamines COMT inhibitors

MAO is a more fascinating enzyme. It is also widely distributed throughout the body tissues. However, unlike COMT, it is also associated with neuronal mitochondria. This is significant, because catecholamines in the cytosol of the neuronal cell are not immune from its oxidative ravages unless protected within the synaptosomal vesicles. In addition, unlike COMT, inhibitors of MAO have significant effects on amine levels with physiological consequences. Several such MAO inhibitors have pharmacological applications in the treatment of depression and hypertension, as will be seen. 

Administration of a catechol-O-methyltransferase (COMT) inhibitor in conjunction with a drug that increases catecholamine levels would dramatically increase levels of catecholamines, leading to a hypertensive crisis, cardiac insufficiency, and possibly death. 

COMT inhibitors may inhibit the normal metabolism of ephedrine (and the catecholamines it releases at adrenergic nerve endings), which could result in a marked exaggeration of its normal effects. See also COMT inhibitors -I- Sympathomimetics Directly-acting , above. 

Both COMT inhibitors and drugs with noradrenaline re-uptake inhibitory activity can impair the inactivation of catecholamines, so in theory the effects of catecholamines may be increased by concurrent use. However, this did not appear to occur in the above studies. 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

It is generally aeeepted that COMT is an extraeellular enzyme in the CNS that catalyses the transfer of methyl groups from S-adenylmethionine to the meta-hydroxy group of the eateehol nueleus. Until recently the only inhibitors of this enzyme were pyragallol and eateehol whieh were too toxic for clinical use. Now other inhibitors have been developed, e.g. entaeapone and tolcapone, but these are used mainly to protect dopa (also a catecholamine) from O-methylation, in the treatment of Parkinson s disease (Chapter 15). 

Monoamine oxidase (MAO) inhibitors MAO and COMT are the 2 major enzyme systems involved in the metabolism of catecholamines. Do not treat patients concomitantly with entacapone and a nonselective MAO inhibitor. 

Inhibitor of catecholamine O- methyltrans-ferase (COMT). The CNS-impermeant enta-capone inhibits peripheral degradation of L-dopa and thus enhances availability of L-dopa for the brain. Accordingly, it is suitably only for combination therapy with L-dopa. 

Substrates of COMT include xenobiotics catechols, catecholamines, and catechol estrogens. Three functional classes of chemicals are known to inhibit COMT. S-Adenosyl-I-homocysteine (SAH) is a potent inhibitor of COMT as well as the other SAM-dependent methyltransferases. Inhibition results from SAH binding to the SAM binding site on the enzyme. Certain divalent ions such as Ca+2 and trivalent metal ions such as the salts of lanthanides, neodymium, and europium are excellent inhibitors of COMT. A number of catechol-type substrates such as pyrogallol, fla-vonoids, pyrones, pyridenes, hydroxyquiolines, 3-mercaptotyramine, and tropolones are irreversible inhibitors of COMT. 

Catechol estrogens are potent inhibitors of tyrosine kinase activity in vitro. High concentrations of catechol estrogens are necessary to cause measurable inhibition, but the physiologic role of this interaction remains uncertain. Catechol estrogens have also been shown to be potent inhibitors of the COMT-medi-ated inactivation of catecholamines. 

TERMINATION OF THE ACTIONS OF CATECHOLAMINES The actions of NE and Epi are terminated by (1) reuptake into nerve terminals by NET (2) dilution by diffusion out of the junctional cleft and uptake at end organs and extraneuronal sites by ENT, OCTl, and OCT2. Subsequent to uptake, the catecholamines are subject to metabolic transformation by MAO and catechol-0-methyltransferase (COMT). In addition, catecholamines are metabolized by sulfotransferases (see Chapter 3). Termination of action by a powerful degradative enzymatic pathway, such as that provided by AChE in cholinergic transmission, is absent from the adrenergic system. Inhibitors of neuronal reuptake of catecholamines (e.g., cocaine, imipramine) potentiate the effects of the... 

Since both MAO and COMT are intracellular enzymes, extracellular catecholamines must enter cells before catabolism can occur. This may involve a mediated transport of the catecholamines across the cell-membrane (Para. S.2.8). Certain drugs which block the formation of catecholamine metabolites, without themselves being inhibitors of either MAO or COMT, may act by blocking the uptake of catecholamines into such sites of catabolism (e.g. phenoxybenzamine). 

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