Compare and contrast the pharmacology of ketamine, morphine and dexmetatomidine when used for analgesia in the critically ill.

[Click here to toggle visibility of the answers]

College Answer

Ketamine is a non barbiturate general anaesthetic, produces a state of “dissociative anaesthesia” with profound analgesia. Pharmaceutics: racemic mixture , clear liquid in ampoule with 200mg in 2mL. Pharmacokinetics: initial rapid redistribution (T 1/2 10 to 15 minutes) representing anaesthetic action, followed by beta phase half life of about 2.5 hrs. 2-
50% protein bound. Volume of distribution 1.8 L/kg, 90% excreted by urine (mainly after extensive hepatic metabolism to less active metabolites, only 4% unchanged). Can be administered IV, IM or SC. Pharmacodynamics: onset of action within 30 seconds and duration of analgesia approximately 30 minutes (profound analgesia of shorter duration). Relative preservation of respiratory reflexes (except at higher dosages), can increase BP and ICP, and result in involuntary movements and emergent reactions. Anaesthetic doses 1-2 mg/kg, but analgesia can be obtained with lower doses (eg. 10-20 mg; 0.1-0.3 mg/kg) or by low dose infusion (eg. 0.1 mg/kg/hr). Value if need short periods of profound analgesia.

Morphine is an opioid analgesic which activates predominantly mu opioid receptors. Pharmaceutics: clear liquid in ampoule with 10 (or 15) mg in 1 mL. Pharmacokinetics:
initial rapid redistribution, followed by more prolonged elimination phase half life of about
2 hrs. 35% protein bound. Volume of distribution 3.3 L/kg, 90% excreted by urine (mainly after hepatic metabolism to active metabolite morphine-6-glucuronide which has a longer half life). Can be administered IV, IM or SC. Pharmacodynamics: rapid onset of action when injected intravenously and duration of analgesia dose (up to hours). Effects significantly prolonged with hepatic or renal dysfunction. Adverse effects include hypotension, sedation, and significant depression of respiratory and gastrointestinal
function, and rarely “biliary” spasm. Antagonist exists: naloxone. Dosage: 10 mg IM, or 1-2 mg boluses (eg. with PCA) and infusion of 1-5 mg/hr.

Dexmedetomidine is a relatively selective alpha-2 adrenoreceptor agonist (providing its sedative and analgesic effects). Pharmaceutics: expensive, clear liquid in ampoule with
200mcg in 2 mL. Pharmacokinetics: initial rapid redistribution (six minutes), followed by more prolonged elimination phase half life of about 2 hrs. 94% protein bound. Volume of distribution 1.5 L/kg. Near complete hepatic metabolism to inactive metabolites which are then excreted in the urine. Administration only by IV infusion (load of 1 mcg/kg, followed by 0.2 to 0.7 mcg/kg/hr). Effects may be prolonged with hepatic or renal dysfunction. Predominant adverse effects include hypotension, bradycardia (including sinus arrest) and dry mouth. Predominant use is for profound sedation for short periods (eg. 24 hours).

Discussion

First of all, let me waggle a shaming finger at the misspelling of dexmedetomidine. It is, of course, possible that some underpaid typist was charged with writing up the college paper from dictated notes, if the examiners in 2004 were loath to soil their carefully manicured hands with the crudeness of keyboard work. Nevermind. At least it is correct in the answer.

Features

Ketamine

Morphine

Dexmedetomidine

Class

NMDA receptor antagonist

Opiate

Central Alpha-2 agonist

Pharmacokinetics

Multiple possible routes of administration

Half life 0.5-2hrs

Hepatic metabolism into weakly active metabolites, which are cleared renally

Multiple possible routes of administration

Half-life 4-9 hours, however has a rapid initial redistribution.

Hepatic metabolicm into active metabolites, which are cleared renally

IV administration

Half-life 20 minutes

Hepatic metabolism into inactive metabolites

Receptor activity

NMDA receptor antagonist

opiate receptor agonist

Central alpha-2 receptor agonist

Mechanism

Competitive antagonism of glutamate neurotransmission at the NMDA receptor

Activates opioid receptors, which activatenumerous intracellular signalling pathways including decreasing the intracellular cAMP levels and closing voltage-sentitive calcium channels, overall leading to decreased neuronal excitability

Acts on presynaptic alpha-2 receptors to decrease the release of synaptic noradrenaline in the central nervous system, thereby decreasing sympathetic outflow.

Benefits in analgesia

Reduces opiate requirements

Effective co-analgesic

Effective for procedural analgesia and sedation

Strong analgesic

Decreases sympathetic responses to pain

Decreases sedation requiremens

Improves tolerance of uncomfortable features of ICU stay (eg. ETT, central lines)

Reduces opiate requirements

Effective co-analgesic

Effective for procedural analgesia and sedation

Additional benefit of sedation without respiratory depression

Adverse effects

Confusion
Delirium
Bronchorrhoea
Sialorrhoea
Sympathetic stimulation

Confusion
Delirium
Hypotension
Euphoria/Dysphoria
Respiratory depression
Constipation

Bradycardia
Hypotension