Question 7

Describe the mechanism of action, dose, pharmacokinetics and pharmacodynamics of clonidine.

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College Answer

This question was broken down into mechanism of action, dose, PK and PD. The mechanism of action required a detailed description of its alpha agonism 200:1 affinity for alpha 2 over alpha 1 including the classification of these receptors and the downstream effects. Correct dose and/or dose ranges for oral and intravenous formulation particularly for different indications for the prescription of clonidine. Pharmacokinetic details expected the absorption, distribution, metabolism and elimination characteristics, with enough detail to demonstrate an understanding. Pharmacodynamic marking was weighted towards the significant cardiovascular, neurological and the relative absence of respiratory effects that make it desirable for use as a sedative/co-analgesic in ICU practice. A description of the these pharmacodynamic effects and why they occur was required to achieve marks in this section.

Discussion

Class Alpha-2 agonist
Chemistry Imidazoline derivative
Routes of administration IV and oral; dose is 50-300mcg up to a maximum dose of 2400 mcg daily, in divided doses. 
Absorption Well absorbed orally, and has minimal first-pass metabolism. Bioavailability is 70-80%
Solubility Reasonably amphoteric: dissolves quite well in both water and fat. pKa is 8.0
Distribution 30-40% protein-bound; VOD is 2.1 L/kg
Target receptor Presynaptic alpha-2 receptors, as well as imidazoline receptors., where it acts as an agonist (which account for a lot of its non-antihypertensive effects)
Metabolism About 30% is metabolised in the liver into numerous metabolites, and the rest is excreted unchanged in the kidney.
Elimination Mainly renally eliminated; half-life is biphasic: by distribution is about 20min, and by elimination 5-7 hrs
Time course of action Duration of the effect is ~ 6 hrs
Mechanism of action Central alpha-2 agonist effect decreases sympathetic outflow by presynaptic downregulation of noradrenaline release. In overdose, peripheral alpha agonist effects dominate, making hypertension a dominant feature.
Clinical effects Class effects (bradycardia, decreased blood pressure, due to central sympatholytic effect), as well as sensitisation of opiate receptors, sedation, analgesia, and an initial hypertensive phase following IV administration. No respiratory depression with sedation, nor any airway reflex loss.
Single best reference for further information TGA PI for IV version of Catapres

References

Stähle, Helmut. "A historical perspective: development of clonidine." Best Practice & Research Clinical Anaesthesiology 14.2 (2000): 237-246.

Lowenthal, D. T., K. M. Matzek, and T. R. MacGregor. "Clinical pharmacokinetics of clonidine." Clinical pharmacokinetics 14 (1988): 287-310.

Dollery, C. T., et al. "Clinical pharmacology and pharmacokinetics of clonidine.Clinical Pharmacology & Therapeutics 19.1 (1976): 11-17.