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Q.1- Alpha Methyl dopa is a drug used in the treatment of hypertension. Explain its possible mode of action.

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Describe the steps of catecholamines synthesis  and degradation and highlight the clinical significance of these reactions.

Answer- Catecholamines are synthesized from Tyrosine.

Cells in the adrenal medulla synthesize and secrete epinephrine and nor epinephrine. In humans  80% of the catecholamine output is epinephrine.

Synthesis and Secretion of Catecholamines

Synthesis of catecholamines begins with the amino acid tyrosine, which is taken up by chromaffin  cells in the medulla and converted to norepinephrine and epinephrine through the following steps :

1) Tyrosine is hydroxylated to DOPA (Dihydroxy Phenyl Alanine) by Tyrosinase (Figure-1), that requires BH4 (Tetra hydro biopterine) and NADPH. The reaction is similar to hydroxylation of phenyl alanine to form Tyrosine. Tyrosinase  meant for catecholamine synthesis is different for the one required for Melanin synthesis.

2) Dopa decarboxylase, a Pyridoxal phosphate (B6-P)-dependent enzyme, forms dopamine by decarboxylation of DOPA (Figure-1).

3) Subsequent hydroxylation of Dopamine  by dopamine -β-oxidase then forms norepinephrine (Figure-1). The enzyme requires molecular oxygen, vitamin C and  Copper ion for its activity.

4) In the adrenal medulla, phenyl ethanolamine-N-methyltransferase utilizes S-adenosylmethionine to methylate the primary amine of norepinephrine, forming epinephrine (Figure-1).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure-1- showing the steps of synthesis of Catecholamines

Norepinephrine and epinephrine are stored in electron-dense granules which also contain ATP and several neuropeptides. Secretion of these hormones is stimulated by acetylcholine release from preganglionic sympathetic fibers innervating the medulla. Many types of “stresses” stimulate such secretion, including exercise, hypoglycemia and trauma. Following secretion into blood, the catecholamines bind loosely to and are carried in the circulation by albumin and perhaps other serum proteins.

Adrenergic Receptors and Mechanism of Action

These hormones bind adrenergic receptors on target cells, where they induce essentially the same effects as direct sympathetic nervous stimulation.  There are multiple receptor types which are differentially expressed in different tissues and cells. The alpha and beta adrenergic receptors and their subtypes were originally defined by differential binding of various agonists and antagonists and, more recently, by analysis of molecular clones.

Receptor

Effectively Binds

Effect of Ligand Binding

Alpha1 Epinephrine, Norepinphrine Increased free calcium
Alpha2 Epinephrine, Norepinphrine Decreased cyclic AMP
Beta1 Epinephrine, Norepinphrine Increased cyclic AMP
Beta2 Epinephrine Increased cyclic AMP

 

Physiologic Effects of Medullary Hormones

In general, circulating epinephrine and norepinephrine released from the adrenal medulla have the same effects on target organs as direct stimulation by sympathetic nerves, although their effect is longer lasting. Additionally, of course, circulating hormones can cause effects in cells and tissues that are not directly innervated. The physiologic consequences of medullary catecholamine release are justifiably framed as responses which aid in dealing with stress. A listing of some major effects mediated by epinephrine and norepinephrine are:

  • Increased rate and force of contraction of the heart muscle: this is predominantly an effect of epinephrine acting through beta receptors.
  • Constriction of blood vessels: norepinephrine, in particular, causes widespread vasoconstriction, resulting in increased resistance and hence arterial blood pressure.
  • Dilation of bronchioles: assists in pulmonary ventilation.
  • Stimulation of lipolysis in fat cells: this provides fatty acids for energy production in many tissues and aids in conservation of dwindling reserves of blood glucose.
  • Increased metabolic rate: oxygen consumption and heat production increase throughout the body in response to epinephrine. Medullary hormones also promote breakdown of glycogen in skeletal muscle to provide glucose for energy production.
  • Dilation of the pupils: particularly important under conditions of low ambient light.
  • Inhibition of certain “non-essential” processes: an example is inhibition of gastrointestinal secretion and motor activity.

Common stimuli for secretion of adrenomedullary hormones include exercise, hypoglycemia, hemorrhage and emotional distress. The alpha and Beta blockers are used as drugs to inhibit the action of catecholamines.

Catecholamine degradation

Catecholamines are degraded in the liver by two enzymes, COMT( Catechol-O-Methyl-Transferase) and MAO(Mono amine Oxidase). By the action of COMT, epinephrine and Nor epinephrine are converted to metanephrine and nor metanephrine respectively. Both these products are further acted upon by MAO to form VMA (Vanillyl Mandelic acid) and MOPG (3-Methoxy 4- hydroxyphenylglycol). These products are further excreted in urine. Epinephrine and nor epinephrine can be acted upon directly also by MAO to form DOPG and DOMA (Figure-2).The Excretory products are increased in Pheochromocytoma and that forms the basis for the diagnostic test.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure-2- showing the steps of degradation of Catecholamines

Clinical Significance-

Methyldopa (L-α-Methyl-3,4-dihydroxyphenylalanine; AldometAldorilDopametDopegyt, etc.) is a drug used as a sympatholytic or antihypertensive agent . It is less commonly used now following  the introduction of alternative safer classes of agents. However, it continues to have a role in otherwise difficult to treat hypertension and gestational hypertension (also known as pregnancy-induced hypertension (PIH)) and pre eclampsia.

Mechanism of action- Methyldopa has a dual mechanism of action:

  • It is a competitive inhibitor of the enzyme DOPA decarboxylase, also known as aromatic L-amino acid decarboxylase, which converts L-DOPA into dopamine. This inhibition results in reduced dopaminergic and adrenergic neurotransmission in the peripheral nervous system. This effect may lower blood pressure and cause central nervous system effects such as depression, anxiety, apathy, and parkinsonism.
  • It is converted to α-methylnorepinephrine by dopamine beta-hydroxylase (DBH). α-methylnorepinephrine is an agonist of presynaptic central nervous system α2-adrenergic receptors. Activation of these receptors in the brainstem appears to inhibit sympathetic nervous system output and lower blood pressure.

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure-3  showing the  mechanism of action of alpha methyl DOPA. 

2) L-DOPA-L-DOPA crosses the protective blood–brain barrier, whereas dopamine itself cannot. Thus, L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson’s disease and dopamine-responsive dystonia.

Once L-DOPA has entered the central nervous system, it is converted into dopamine by the enzyme  DOPA decarboxylase (DDC). Pyridoxal phosphate (vitamin B6) is a required cofactor in this reaction, and may occasionally be administered along with L-DOPA, usually in the form of pyridoxine.

3) Dopamine drips are intravenous deliveries of dopamine, that can be necessary for a hemodynamically unstable patient, at risk of shock caused by low blood pressure. These can include patients with a recent history of open heart surgery, heart attacks, or renal failure.

4) Pheochromocytoma- Pheochromocytomas and paragangliomas are catecholamine-producing tumors derived from the sympathetic or parasympathetic nervous system. Elevated plasma and urinary levels of catecholamines and the methylated metabolites, metanephrines, are the cornerstone for the diagnosis.

 

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