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.

 

List:

·      PC

·      PK

·      PD

 

Physicochemical:

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

 

Pharmacokinetic:

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 (t1/2ke0 2.6 mins)

Y

Y (>99%)

Y (t1/2α fast 2 mins)

Y (VDSS 4L/kg)

 

Y/N (t1/2ke0 4 mins)

Y

Y (90%

Y (t1/2α ?)

Y (VDSS 1.5L/kg)

Metabolism

Rapid clearance

Short t1/2β

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

 

Pharmacodynamic:

 

CNS:

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)

 

Other:

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

 

 

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