Question 18

Compare and contrast the pharmacology of  noradrenaline, vasopressin and phenylephrine when used as vasopressors in the critically ill.

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College Answer

Noradrenaline is the catecholamine released by postganglionic adrenergic nerves. Direct agonist acting on alpha (vasoconstrictor: arterial and venous) and beta-1 (contractility, pro-arrhythmic) adrenergic receptors. Not absorbed enterally. Rapidly metabolised by COMT and MAO, resulting short (minutes) duration of effect (usually administered as intravenous infusion into central vein at rate of 0.5 to 100 mcg/min). Used clinically to increase blood pressure (usually in the setting of vasodilatory shock).

Vasopressin is a hormone/neurotranmitter with a complex series of effects. Direct action on a number of receptors (V1 (vascular: vasoconstriction), V2 (renal: anti-diuresis), V3 (pituitary), OTR (oxytocin receptor subtypes) and P2 (purinergic). Not absorbed enterally. Rapidly inactivated by trypsin and peptidases, resulting in short (minutes) duration of effect (longer on kidneys as very low concentration are required). Used clinically as treatment for diabetes insipidus (IM, IV or

intranasal), and more recently by intravenous infusion (via central vein at rates of 0.01 to 0.1

U/min) to increase blood pressure (usually in the setting of vasodilatory shock) or as a large intravenous bolus providing potent vasoconstriction during cardiac arrest (40 units). Potentiates the action of other vasoconstrictor agents.

Phenylephrine is a synthetic alpha-1 adrenoreceptor agonist, similar in structure to adrenaline. Not administered enterally, biotransformation not well described (not metabolised by COMT) but duration of action longer than naturally occurring catecholamines (still minutes). Used clinically for vasoconstrictor effects, usually administered intravenously either in small bolus doses or occasionally as an intravenous infusion (via a central vein at rates of 40 to 180 mcg/min).

Refractory hypotension may respond to agents with combined alpha-1 & alpha-2 activity (e.g. noradrenaline).

Discussion

Great masses of text in homage to noradrenaline and vasopressin are available elsewhere. Phenylephrine is less common.

A Comparison of Selected Vasopressors

Features

Noradrenaline

Phenylephrine

Vasopressin

Class

Endogenous catecholamine

Synthetic catecholamine

Endocrine nonapeptide

Pharmacokinetics

Half-life 2-3minutes
Metabolised by MAO and COMT

Half-life 5-10 minutes

0.002 units /kg/min;

or, 2-2.4 units/hr

Receptor activity

Predominantly alpha-1 agonist activity;
Some beta-1 and beta-2 effects at high doses

Affinity for receptors decreases in acidosis

Strongly selective for alpha-1 receptors

Affinity for receptors decreases in acidosis

Acts on V1 receptors (for vasopressor activity) and on V2 receptors (for antidiuretic activity).
Some crossover with oxytocin with respect to uterine contraction.
Affinity for receptors is unchanged by acidosis

Mechanism

Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins

Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins

V1 effect is by  Gq-protein coupled receptors, which also increases intracellular IP3.
V2 effect is via Gs-protein coupled receptors, and cAMP.

Clinical effects

Arterial and venous vasoconstriction
Reflex bradycardia 
Increased afterload and preload

Arterial and venous vasoconstriction
Reflex bradycardia 
Increased afterload and preload

Arterial and venous vasoconstriction
Reflex bradycardia 
Increased afterload and preload 
Increased resoprtion of water in the cortical collecting duct

References

For those (like me) who are unfamiliar with phenylephrine, there is an excelent monograph on its properties published by Schering-Plough (it is the Briefing Document for NDAC Meeting in December 14, 2007)