Question 15

Compare and contrast the pharmacology of noradrenaline and dobutamine.

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College Answer

The best answers used tables and key pharmacological headings for comparisons, and 
avoided long sentences/ paragraphs.

An answer that correctly considered the following sections would be awarded a very good 
pass: Presentation, pharmacodynamics, mechanism of action, organ effects, side effects and 
pharmacokinetics.
Many candidates failed to identify agents as natural / synthetic catecholamines. 
Few answers correctly mentioned the available preparations of these drugs or considered the 
structure activity relationships. Only 3 candidates commented that dobutamine is a racemic 
mixture. 
Intracellular second messenger pathways were often incorrectly recounted or not mentioned at 
all. Pharmacodynamic effects on all organ systems, and all CVS parameters (HR, inotropy, 
PVR, SVR, SBP/DBP/MAP, regional circulations) should be considered. Metabolic fate and 
clinical dosage ranges were frequently incorrectly quoted.

Discussion

For all their complaining, the examiners passed almost everybody (84% of the candidates scored more than 5.0). 

Name Noradrenaline Dobutamine
Class Vasopressor Inotrope
Chemistry Endogenous catecholamine Synthetic catecholamine
Routes of administration IV IV
Absorption Basically zero oral availability due to destruction by brush border enzymes in the gut (COMT and MAO) Basically zero oral availability due to destruction by brush border enzymes in the gut (COMT and MAO)
Solubility pKa = 8.85; water-soluble pKa = 10.14; sparingly soluble in water
Distribution VOD = 0.12 L/kg, i.e. essentially confined to the circulating volume; 25% protein-bound VOD = 0.2 L/kg, i.e. essentially confined to the circulating volume. Protein binding is unknown- presumably, minimal
Target receptor Noradrenaline is highly selective for the alpha-1 receptor Dobutamine is a racemic mixture of stereoisomers; net effect is a partial alpha-1 agonist effect, a full beta-1 agonist effect, and a weak beta-2 agonist effect
Metabolism Metabolised rapidly and completely by COMT and MAO Metabolised rapidly and completely by COMT and MAO
Elimination Metabolites are renally excreted. Half-life is ~2 minutes Metabolites are renally excreted. Half-life is ~2 minutes
Time course of action Very short acting, very rapid onset of effect Very short acting, very rapid onset of effect
Mechanism of action By binding to the alpha-1 receptor, noradrenaline increases the release of a secondary messenger (inositol triphosphate, IP3) which results in the release of calcium into the cytosol, and thus enhanced smooth muscle contractility. By binding to the beta-1 receptor, dobutamine causes an increase in intracellular cAMp, which leads to increased calcium availability inside the cardiac myocytes, and therefore increased contractility and pacemaker automaticity
Clinical effects Increased peripheral resistance, increased afterload, increased blood pressure; redistribution of blood flow from splanchnic circulation and skeletal muscle. Increased heart rate, increased contractility, increased lusitopy; decreased peripheral vascular resistance due to beta-2 effect
Single best reference for further information TGA PI document TGA PI document

References

von Euler, Ulf Svante. "Noradrenaline." (1956): 349.

RUFFOLO Jr, ROBERT R. "The pharmacology of dobutamine." The American journal of the medical sciences 294.4 (1987): 244-248.

Smith, K. Shirley, and A. Guz. "L-Noradrenaline in treatment of shock in cardiac infarction." British medical journal 2.4850 (1953): 1341.

Rokyta Jr, Richard, et al. "The effects of short-term norepinephrine up-titration on hemodynamics in cardiogenic shock." Physiol Res 59.3 (2010): 373-8.

Ruffolo Jr, Robert R., and Karen Messick. "Systemic hemodynamic effects of dopamine,(±)-dobutamine and the (+)-and (−)-enantiomers of dobutamine in anesthetized normotensive rats." European journal of pharmacology 109.2 (1985): 173-181.