Question 7

Created on Tue, 06/02/2015 - 15:50
Last updated on Wed, 12/23/2015 - 04:16
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Compare and  contrast the pharmacology  of propofol, midazolam  and  thiopentone when used by infusion for the treatment of raised intra-cranial pressure.

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College Answer

Pharmacology includes pharmaceutics (including preparation), pharmacokinetics (including distribution, elimination and  biotransformation) and  pharmacodynamics (including dose, mechanism of action, effect of various disease states, adverse effects and interactions).  Effects of all drugs are augmented by other CNS depressant drugs.

Propofol is formulated as a white isotonic aqueous emulsion (containing soya oil and egg lecithin) at a concentration of 10 mg/mL.  It supports the growth of bacteria if accidentally introduced so syringes/bottles should be changed every 12 hours.   It is widely and rapidly distributed (98% protein bound), with an initial half life of redistribution of 2 to 8 minutes, but a terminal elimination of 3 to 20 hours (which may influence waking time after prolonged infusion [many days]: context sensitive half-time).  Inactive metabolites are renally excreted.  Usual ICU sedation dose is infusion of 1 to 3 mg/kg/hr (higher infusion rates in Intensive Care have been associated with rhabdomyosysis). Mechanism of action is not clear. Lipid formulation of approx. 1 kcal/mL should be taken into account, and high triglyceride levels may be seen in susceptible patients. Hypotension and depression of cardiac output may occur (more so when bolus doses are used).  Compatible with
5% dextrose but not with many other solutions or drugs. Time to wake after cessation of infusion is short (minutes to hours) depending on duration of infusion (context sensitive half time).   Rapid awakening may increase likelihood of convulsions in those susceptible. Relatively expensive.

Midazolam is formulated as a colourless isotonic but acidic solution (pH 3.3) as 1 or 5 mg/mL. Onset usually seen within minutes (97% protein bound), and usual elimination half-life quoted at 1 to 3 hours, but often seen 6 times longer in critically ill especially elderly or renal failure Metabolised by P450-3A to active metabolite 1-OH-methyl midazolam, and then renally excreted. Usual ICU dosage 0.03 to 0.2 mg/kg/hr.  Mechanism of action is via activation of benzodiazepine receptor, which augments the inhibitory effect of the GABA receptor.  Cardiorespiratory depression is expected.  Rapid cessation may lead to withdrawal.  Compatible with many solutions and drugs (except hartmanns), infusions should be discarded after 24 hours.  Time to wake after cessation of infusion is intermediate (hours to days) depending on duration of infusion and presence of renal or hepatic dysfunction.

Thiopentone is prepared from a powder and dissolved in water giving an alkaline solution with a final concentration of 25 mg/mL.  Onset of action within minutes (80% protein bound, with very large volume of distribution), usual elimination half life quoted at 3 to 8 hours (but presumably longer after prolonged infusion).  Metabolised predominantly in the liver to (?) inactive metabolites which are renally excreted.  Usual ICU dosage is 25 to 100 mg/hour (0.5 to 1.5 mg/kg/hr), with boluses of 25 to 100 mg as required.  Very effective CNS depressant (including resultant isoelectric EEG and fixed dilated pupils).   Incompatible with many solutions (especially if acidic), and infusions should be discarded after 24 hours.  Time to awakening after cessation of infusion is delayed (up to many days), depending on duration of infusion and the presence of hepatic dysfunction.  Barbiturates may precipitate acute porphyria in susceptible patients by enhancing porphyrin synthesis.

Discussion

Features

Propofol

Midazolam

Thiopentone

Class

General anaesthetic phenol

Benzodiazepine

barbiturate

Pharmacokinetics

Half-life 2-3minutes
Metabolised by the liver; inactive metabolites.

Extensive distribution into fat

Half-life 90 minutes;
Metabolised by the liver;
Active metabolites are renally excreted
Extensive distribution into fat

Half life ~ 9 hours; rapid redistribution decreases the duration of effect.

Extensive distribution into fat

Receptor activity

Thought to be a GABA agonist;
Increases inhibitory neurotransmission

Allosteric modulator of GABA neurotransmission; increases the rate of opening of GABA channels

Allosteric modulator of GABA neurotransmission; increases the duration of opening of GABA channels

Advantages in head injury

Short half life

Decreases cerebral metabolic demand, thus decreasing ICP

Decreases seziure activity

Decreases cerebral metabolic demand, thus decreasing ICP

Decreases seziure activity

Decreases cerebral metabolic demand, thus decreasing ICP

Decreases seziure activity (very potent antiepileptic)

Well tolerated in hemodynamic instability

Disadvantages in head injury

Hypotension
Hyperlipidaemia 
Propofol infusion syndrome

Slow waking; context-sensitive half-life becomes prolonged

Sudden withdrawal may precipitate seziures

Prolonged effect in renal or hepatic impairment

Very slow waking; as drug redistributes from tissue compartment

May precipitate acute porphyria