Lecture 8 - Synthesis Of Nor Adrenaline - 24 Sep 2006

AUTONOMIC NERVOUS SYSTEM ADRENERGIC MECHANISMS

LEARNING OBJECTIVES The Students should be able to: - describe the synthesis, release and metabolism of noradrenaline -

describe the characteristics of neuronal and extraneuronal uptake of catecholamines

- differentiate between directly and indirectly acting sympathomimetic amines

Learning Objectives (contd) -

describe the pharmacological actions of sympathomimetic amines

- identify the receptors upon which sympathomimetic amines act - describe the uses of α- and β-

Neurotransmitters Used in the Peripheral Nervous System

Synthesis of Noradrenaline

Synthesis of Noradrenaline Tyrosine, a dietary amino acid is the substrate for the synthesis of noradrenaline. It is taken up into adrenergic nerves by an active transport system.

Catecholamine Synthesis, Storage, Release, and Reuptake Pathways

Inhibitors of Noradrenaline Synthesis These include: α-methyl-p-tyrosine: inhibits the conversion of tyrosine to L-DOPA. Carbidopa, benserazide: these agents inhibit dopa-decarboxylase activity. They are used as adjuncts in the treatment of Parkinsonism. α-methyldopa: is converted into a false transmitter. It is used in the treatment of hypertension.

Storage of Noradrenaline  Noradenaline is stored in storage vesicles in association with ATP (ratio 1 to 4).  Other contents of the vesicles include dopamine-β-hydroxylase and chromogranins.  These are released along with noradrenaline when the nerve is stimulated.  Storage of noradrenaline and other monoamines in the vesicles is inhibited by reserpine and related rauwolfia alkaloids.

Release of Noradrenaline  Release of noradrenaline from the nerve terminals, when stimulated, is by the process of exocytosis.

Steps in Synaptic Transmission

Noradrenaline can also be released from adrenergic nerve terminals by c) Displacement from the storage site: this is the mechanism of action of indirectly acting sympathomimetic amines eg tyramine. b) Impairment of storage mechanisms leading to release and subsequent depletion of the vesicles. Reserpine acts in this manner.

Inhibitors of Noradrenaline Release Negative feedback mechanism Noradrenaline can act on specific receptors on adrenergic nerve terminals producing a negative feedback effect that limits the amount of transmitter released. Inhibition of this negative feedback mechanism would result in increased release of the neurotransmitter.

Adrenergic Neurone Blockers Examples: guanethidine, bethanidine and bretylium These drugs • have local anaesthetic properties • are substrates for the uptake1 process • prevent the uptake of noradrenaline by competing for the same transport system d) deplete neuronal stores of noradrenaline by preventing the uptake of noradrenaline.

Uses 2) Treatment of hypertension 3) Treatment of cardiac arrhythmias (especially bretylium).

Side effects 7) Diarrhoea 8) Postural hypotension 9) Failure of ejaculation 10) Nasal congestion

Noradrenergic Depleting Agents Eg. Reserpine Reserpine: It is an alkaloid from the Rauwolfia sp. It depletes catecholamine (and other monoamines) stores peripherally and centrally. Reserpine enters the nerve terminal by passive diffusion. Inside the cytoplasm, it prevents the uptake of noradrenaline into the storage vesicles.

Uses  Reserpine can be used (though not much nowadays) in the treatment of hypertension.  It can also be used in psychiatric disorders such as schizophrenia.

Inactivation of Noradrenaline  Noradrenaline released from the nerve terminal is inactivated by enzymatic or non-enzymatic pathways.

Enzymatic Pathway  This involves two enzymes, monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) acting in concert.

 MAO is present in almost all tissues.  Very high levels are found in the intestine where they inactivate biologically active monoamines in the diet.  MAO in the lungs and kidneys inactivate circulating monoamines while in neuronal tissues, MAO inactivate noradrenaline that is present in the cytoplasm.  MAO is inhibited by selegiline, pargylline and iproniazid.

 COMT is widely distributed in tissues.  High activity in liver, kidney, smooth and cardiac muscle cells and other tissues innervated by adrenergic nerves.  COMT is inhibited by pyrogallol and tropolones.

Norepinephrine Metabolism

Non-Enzymatic pathway This involves the uptake of noradrenaline and related amines into neuronal and extraneuronal tissues. Two uptake processes • Uptake1 (neuronal uptake) • Uptake2 (extraneuronal uptake)

Uptake1: This is uptake followed by storage. It b) Is an active transport process c) is sodium dependent d) is proportional to the density of adrenergic innervations f) is saturable g) conserves transmitter

This process is inhibited by cocaine, tricyclic antidepressants and adrenergic neuron blockers. Other substrates for the process include dopamine and tyramine.

Mechanisms of Action of Cocaine and reserpine

Uptake2: This is uptake followed by destruction. It • occurs at high substrate concentrations • becomes important when uptake1 is blocked or saturated c) is inhibited by steroids