Catecholamines transport metabolism

NE is synthesized by tyrosine hydroxylation (meta ring position) followed by decarboxylation and side chain p carbon hydroxylation. The synthesis of this catecholamine is regulated by tyrosine hydroxylase. Tyrosine hydroxylation is also a key step in the synthesis of two other important catecholamines, dopamine and epinephrine. NE is packaged via active transport into synaptic (or chromaffin) vesicles prior to release by neuronal depolarization. The effects of NE are mediated by adrenergic receptors (a or P) which are G protein coupled resulting in either increases or decreases in smooth muscle tone as well as increases in cardiac rate and contractility. These effects arise out of receptor mediated increases in intracellular Ca and activation or inhibition of various protein kinases. The effects of NE are terminated essentially as a result of its active transport into the presynaptic nerve ending via an energy and Na" dependent process which utilizes the norepinephrine transporter (NET). Ultimately, NE and other catecholamines are metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). 

Mechanism of Action Lithium s pharmacologic mechanism of action is not well understood and probably involves multiple effects. Possibilities include altered ion transport, increased intraneuronal catecholamine metabolism, neuroprotection or increased brain-derived neurotrophic factor, inhibition of second messenger systems, and reprogramming of gene expression.29... 

Ordinarily, low concentrations of catecholamines are free in the cytosol, where they may be metabolized by enzymes including monoamine oxidase (MAO). Thus, conversion of tyrosine to l-DOPA and l-DOPA to dopamine occurs in the cytosol dopamine then is taken up into the storage vesicles. In norepinephrine-containing neurons, the final P-hydroxylation occurs within the vesicles. In the adrenal gland, norepinephrine is N-methylated by PNMT in the cytoplasm. Epinephrine is then transported back into chromaffin granules for storage. 

Pharmacology Lithium alters sodium transport in nerve and muscle cells, and effects a shift toward intraneuronal catecholamine metabolism. The specific mechanism in mania is unknown, but it affects neurotransmitters associated with affective disorders. Its antimanic effects may be the result of increases in norepinephrine reuptake and increased serotonin receptor sensitivity. Pharmacokinetics ... 

The principal mechanism for the deactivation of released catecholamines is, however, not enzymatic destmction but reuptake into the nerve ending. The presynaptic membrane contains an amine pump—a saturable, high-affinity, Na" -dependent active-transport system that requires energy for its function. The recycled neurotransmitter is capable of being released again, as experiments with radiolabelled [ H]NE have shown, and can be incorporated into chromaffin granules as well. Many drugs interfere with neurotransmitter reuptake and metabolism, as discussed in subsequent sections. 

The action of NE at adrenergic receptors is terminated by a combination of processes, including uptake into Ihe neuron and into cxtraneuronal lis.sucs. diffusion away from the synapse. and metabolism. Usually. Ihe primary mechanism for termination of Ihe action of NE is rcuplakc of the catecholamine into tlie nerve terminal. This procc.ss is termed upuike-l and involves a Na /Cl -dcpendenl transmembrane transporter that has a high affinity for NE. This uptake system also transparts certain amines other than NE into the... 

Familial dysautonomia, dopamine [i-liydroxylase deficiency, norepinephrine transporter deficiency, and congenital adrenal hyperplasia include dysautonomias or conditions associated with adrenal medullary dysfunction in which the specific genetic abnormalities have been identified. There are also other disorders involving mutations of genes coding for proteins involved in catecholamine synthesis and metabolism in which the clinical manifestations do not clearly involve the sympathoadrenal systems or may be so globally severe that abnormalities of autonomic or adrenal medullary function are obscured (Table 29-5). 

Guanethidine (initial dose 10 mg daily) is indicated in the management of moderate to severe hypertension. It is transported to presynaptic terminals by the catecholamine uptake mechanism, and then slowly displaces norepinephrine from its storage sites to be metabolized presynaptically. 

In addition to synthesis of new transmitter, NE stores are also replenished by transport ofNE previously released to the extracellular fluid by the combined actions of a NE transporter (NET, or uptake 1) that terminates the synaptic actions of released NE and returns NE to the neuronal cytosol, and VMAT-2, the vesicular monoamine transporter, that refills the storage vesicles from the cytosolic pool ofNE ("see below). In the removal ofNE from the synaptic cleft, uptake by the NET is more important than extraneuronal uptake (ENT, uptake 2). The sympathetic nerves as a whole remove -87% of released NE via NET compared with 5% by extraneuronal ENT and 8% via diffusion to the circulation. By contrast, clearance of circulating catecholamines is primarily by nonneuronal mechanisms, with liver and kidney accounting for >60% of the clearance. Because VMAT-2 has a much higher affinity for NE than does the metabolic enzyme, monoamine oxidase, over 70% of recaptured NE is sequestered into storage vesicles. 

ABSORPTION, METABOLISM, AND EXCRETION When administered oraUy, methyldopa is absorbed by an active amino acid transporter. Peak plasma concentrations occur after 2-3 hours. The drug is eliminated with a of 2 hours (prolonged to 4-6 hours in patients with renal failure). Methyldopa transport into the CNS apparently is an active process. Methyldopa is excreted in the urine primarily as the sulfate conjugate (50-70%) and as the parent drug (25%). The remainder is excreted as other metabolites, including methyldopamine, methylnorepinephrine, and O-methylated products of these catecholamines. 

Endocrine hormones are defined as compounds, secreted from specific endocrine cells in endocrine glands, that reach their target cells by transport through the blood. Insulin, for example, is an endocrine hormone secreted from the p cells of the pancreas. Classic hormones are generally divided into the structural categories of polypeptide hormones (e.g., insulin -see Chapter 6, Fig. 6.15 for the structnre of insnlin ), catecholamines such as epinephrine (which is also a nen-rotransmitter), steroid hormones (which are derived from cholesterol), and thyroid hormone (which is derived from tyrosine). Many of these endocrine hormones also exert paracrine or autocrine actions. The hormones that regnlate metabolism are discussed throughout this chapter and in snbseqnent chapters of this text. 

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