2008A03 Describe the ideal pharmacokinetic and pharmacodynamic properties of agents used for sedation.
Outline the pharmacology of midazolam and propofol with reference to these ideal properties.

Ideal

Propofol

Midazolam

Long shelf life

Y

Y

Stable in solution

Y

Y

No reconstitution required

Y

Y

Low risk bacterial contamination

N

Y

Painless injection

N

Y

No histamine release

Y

Y

No anaphylaxis

Rare

Rare

Water soluble

N

Hydrophilic in the ampoule

Lipophilic in blood

Cheap

Y

Y

No precipitation with drug or crystalloid

Y

Y

Safe following inadvertent arterial injection

Y

Y

Safe following extravasation

Y

Y

Ideal

Propofol

Midazolam

Admin:

Parenteral

IV, IM, PO, SL, IN, PR

IV only

IV bolus e.g. 0.3mg/kg q2min

IV infusion e.g. 1-3mg/kg/h

All routes listed are possible

PO 0.5mg/kg

IV bolus e.g. 0.025mg/kg q 5min

IV infusion

Time course:

Rapid onset

Rapid peak effect

Rapid offset after bolus (distrib)

Rapid offset after infusion (metab)

Y (30 sec)

Y (1-2 mins)

Y (5-10mins)

Y (e.g. CSHT 20 mins at 2 hours)

Y (2 min)

N (10 mins)

N (60 mins)

Y/N (CSHT 40 mins at 2 hours)

Absorption: high oral bioav

Very low

30%

Distribution

Rapid effect site equilibration

  -High lipid solubility

  -High unionized fraction at pH 7.4

Rapid distribution

Extensive distribution (delays saturation)

Y (t_1/2ke0 2.6 mins)

Y

Y (>99%)

Y (t_1/2α fast 2 mins)

Y (V_DSS 4L/kg)

Y/N (t_1/2ke0 4 mins)

Y

Y (90%

Y (t1/2α ?)

Y (V_DSS 1.5L/kg)

Metabolism

Rapid clearance

Short t_1/2β

No active metabolites (prolongs effect)

Y: 30-60mL/kg/min

No: 5-12 hours (unimportant)

None

Y/N: 10mL/kg/min

Y: 4 hours

a-OH-midazolam, oxazepam

(these undergo glucuronidation)

Excretion

No accumulation of inactive products in renal failure

Y

Y

Ideal

Propofol

Midazolam

Rousable unconsciousness

Y

Y

Anxiolysis

N

Y

Antegrade amnesia

Y (less effective)

Y (more effective)

Analgesic

N

N

Anti-emetic

Y

Y

Anti-convulsant

Y (but 10% myoclonus)

Y

No emergence delirium

Less common

More common

High therapeutic index

Low

Sedation 1-2mcg/mL

Hypnosis 2-4mcg/mL

High

0.025mg/kg sedation

0.2mg/kg hypnosis

Antidote

No

Flumazenil 0.1mg (1mL NEAT) for

Midazolam 1mg (1mL NEAT)

Ideal

Propofol

Midazolam

No cardiovascular depression

Significant, dose-dependent

↓SNS output, ↓L-Ca²⁺ activity

↓HR, ↓contractility at high dose

↓SVR ~20% (major effect)

↓CO

↓mAP ~15%

Mild, dose-dependent

↓SNS output

↓HR, ↓contractility, ↓SVR

↓CO

↓mAP

No respiratory depression

Significant, dose-dependent

↓RR, ↓TV

↓Response to ↓PaO₂, ↑PaCO₂

Mild, dose-dependent

↓RR, ↓TV

↓Response to ↓PaO₂, ↑PaCO₂

Preserved airway reflexes

Less

More

Bronchodilation

Y

N

No stimulation of airway secretion

Y

Y