K4i / 23B07: Describe the mechanism of action, dose, pharmacokinetics and pharmacodynamics of clonidine

23B07: Exam Report

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

38% of candidates passed this question.

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.

K4i / 23B07: Describe the mechanism of action, dose, pharmacokinetics and pharmacodynamics of clonidine

Clonidine

Chemical

An aniline derivative

Use

  1. Hypertension
  2. Sedation
  3. Analgesia
  4. Chronic pain
  5. Withdrawal

Presentation

Tablets, syrup

Clear, colourless solution 150mcg/mL

Dose

Up to 100mg/day

(IV) 15 – 300mcg → acts in 10 mins, lasts 3 – 7hrs

(EPIDURAL) 150mcg

(PO) 50 – 600mcg TDS

Route

PO/IV/Epidural

Onset

Acts within 10 mins

DoA

Lasts 3 – 7 hours (IV)

MoA

Partial α agonist →α2 : α1 affinity 200 : 1

  1. α2 agonism at PRE-SYNAPTIC SYMP PERIPHERAL NERVES → ↓NA production
  2. α2 agonism at CNS/SC

→ Decreased symp outflow

→ Augments endogenous opiate release

→ Sedation/anxiolysis

3. α1 agonism of vessels → some VC

PD

CVS

  • ↑BP initially due to α2 agonism in peripheral vasculature
  • Then sustained ↓BP due to centrally mediated ↓ symp tone & ↑ Vagal tone
  • longer lasting ↓HR & ↓VR
  • ↓SVR with chronic use → ↓response vessels to vasoactive substances & symp stimulation
  • No effect on inotropy
  • Reduction in coronary and systemic vascular resistance

CNS

  • Dose reated sedation, analgesia & anxiolysis
  • Depresses sympathetic outflow and afferent A elta & C fibre mediated somatosympathetic reflexes
  • ↓ICP & ↓IOP by ↓CBF & ↓CMRO2

GI

  • ↓gastric & SB motility
  • Antisialagogue
  • ↑BGL due to α-adrenoreceptor stimulation

Renal – ↓ renal vascular resistance = diuresis

PK

A

OBA 85%

D

V. lipid soluble

Penetrates CNS

20% PPB

VD 2.5L/kg

M

<half dose metabolized in liver to inactive metabolite

E

65% excreted unchanged

t ½ B 6 – 24hrs

Adverse Effects

  • Drowsy
  • Dry mouth
  • Fluid retention
  • Impotence
  • Constipation
  • Rebound hypertension & ↑HR