Comparative Pharmacology of Sedating and Analgesic Agents

Many questions from past papers have asked the canddiates to compare and contrast various sedative and analgesic agents. Specifically, the candidates have been expected to have indepth familiarity with propofol, dexmedetomidine, ketamine, morphine, tramadol, and celecoxib.

Examples of such questions have included the following:

  • Question 17 from the first paper of 2008 (propofol vs. dexmedetomidine)
  • Question 11 from the second paper of 2004 (ketamine vs. morphine vs. dexmedetomidine)
  • Question 7 from the first paper of 2003 (anaesthetics used to control raised intracranial pressure)
  • Question 3 from the second paper of 2001 (tramadol, celecoxib and ketamine)

The discussion section of each question offers a tabulated answer. In order to simplify revision, these tables are reproduced below with minimal alteration.

Propofol
Feature Properties
Class
  • Phenol alcohol
  • General anaesthetic
Chemical properties
  • Aqueous 1% emulsion containing soya oil and egg lecithin
  • Supports the growth of bacteria
  • Nutritionally rich: 1kcal/ml
Pharmacokinetics
  • Half-life 2-3minutes
  • Metabolised by the liver; inactive metabolites.
  • Extensive distribution into fat and protein (98% protein bound)
  • Half life of redistribution = 2 to 8 minutes
  • Terminal elimination = 3 to 20 hours
Receptor activity
  • GABA agonist
Mechanism of action
  • Thought to be a GABA agonist;
  • Increases inhibitory neurotransmission
Indications
  • Sedation (rapid onset)
  • Anaesthesia
  • Rapid induction of anaesthesia (eg. for intubation)
  • Decrease of cerebral metabolic demand
Advantages in head injury
  • Short half life
  • Decreases cerebral metabolic demand, thus decreasing ICP
  • Decreases seziure activity
Disadvantages in head injury
  • Hypotension may exacerbate secondary brain injury
Adverse effects
  • Loss of airway reflexes
  • Hypotension
  • Hyperlipidemia
  • Propofol infusion syndrome
Midazolam
Feature Properties
Class
  • Benzodiazepine
Pharmacokinetics
  • Half-life 90 minutes;
  • Metabolised by the liver;
  • Active metabolites are renally excreted
  • Extensive distribution into fat and protein (97% protein bound)
Receptor activity
  • GABA agonist
Mechanism of action
  • Allosteric modulator of GABA neurotransmission; increases the rate of opening of GABA channels
Indications
  • Sedation (slower onset)
  • Anaesthesia
  • Anxiolytic
  • Decrease of cerebral metabolic demand
Advantages in head injury
  • Decreases cerebral metabolic demand, thus decreasing ICP
  • Decreases seziure activity
Disadvantages in head injury
  • Slow waking; context-sensitive half-life becomes prolonged
  • Sudden withdrawal may precipitate seizures
  • Prolonged effect in renal or hepatic impairment
Adverse effects
  • Loss of airway reflexes
  • Prolonged sedation may be undesirable
  • Slow onset of maximal effect (up to 30min) results in unnecessarily large doses being given by impatient staff
  • Tolerance and dependence develops
  • Benzodiazepines in general (not just midazolam) are associated with an increased risk of delirium, particularly among the elderly
Dexmedetomidine
Feature Properties
Class
  • Sedative dissociative
Pharmacokinetics
  • IV administration
  • Initial rapid redistribution (6 minutes)
  • Prolonged elimination phase half life =  2 hrs.
  • 94% protein bound.
  • Volume of distribution 1.5 L/kg
  • Hepatic metabolism into inactive metabolites
     
Receptor activity
  • Centrally acting alpha-2 receptor agonist
Mechanism of action
  • Acts on presynaptic alpha-2 receptors to decrease the release of synaptic noradrenaline in the central nervous system, thereby decreasing sympathetic outflow.
Indications
  • Sedation (slower in onset compared to propofol)
  • Analgesia: synergy with opiates
  • Management of agitation in both intubated and non-intubated patients
Advantages in head injury
Disadvantages in head injury
  • No effect on cerebral metabolic demand
Benefits in analgesia
  • Reduces opiate requirements
  • Effective co-analgesic
  • Effective for procedural analgesia and sedation
  • Additional benefit of sedation without respiratory depression
Adverse effects
  • Bradycardia
  • Hypotension
Ketamine
Feature Properties
Class
  • Dissociative anaesthetic
Pharmacokinetics
  • Multiple possible routes of administration
  • Half life 0.5-2hrs
  • 50% protein bound
  • Volume of distribution 1.8 L/kg
  • Hepatic metabolism into weakly active metabolites, which are cleared renally
Receptor activity
  • NMDA receptor antagonist
Mechanism of action
  • Competitive antagonism of glutamate neurotransmission at the NMDA receptor
Indications
  • Sedation for procedures
  • Co-analgesia with opiates
  • Induction of anaesthesia of patients whose haemodynamic stability is only assured by their sympathetic excitation
Advantages in head injury
  • Can be used in trauma patients who are haemodynamically stable
Disadvantages in head injury
  • Will probably increase ntracraial pressure
Benefits in analgesia
  • Reduces opiate requirements
  • Effective co-analgesic
  • Effective for procedural analgesia and sedation
Adverse effects
  • Confusion
  • Delirium
  • Bronchorrhoea
  • Sialorrhoea
  • Sympathetic stimulation
Morphine
Feature Properties
Class
  • Opiate
Pharmacokinetics
  • 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
Receptor activity
  • opiate mu- receptor agonist
Mechanism of action
  • Activates opioid receptors, which activate numerous intracellular signalling pathways including decreasing the intracellular cAMP levels and closing voltage-sentitive calcium channels, overall leading to decreased neuronal excitability
Benefits in analgesia
  • Strong analgesic
  • Decreases sympathetic responses to pain
  • Decreases sedation requiremens
  • Improves tolerance of uncomfortable features of ICU stay (eg. ETT, central lines)
Adverse effects
  • Confusion
  • Delirium
  • Hypotension
  • Euphoria/Dysphoria
  • Respiratory depression
  • Constipation
Thiopentone
Feature Properties
Class
  • Barbiturate
Pharmacokinetics
  • Half life ~ 9 hours; rapid redistribution decreases the duration of effect.
  • Extensive distribution into fat
Receptor activity
  • GABA receptors
Mechanism of action
  • Allosteric modulator of GABA neurotransmission; increases the duration of opening of GABA channels
Indications
  • Rapid sequence induction
  • Decrease of cerebral metabolic demand
Advantages in head injury
  • Decreases cerebral metabolic demand, thus decreasing ICP
  • Decreases seziure activity (very potent antiepileptic)
  • Well tolerated in hemodynamic instability
Disadvantages in head injury
  • Very slow waking; as drug redistributes from tissue compartment
Adverse effects
  • May precipitate acute porphyria
  • May have a immunosuppressant effect by enhancing porphyrin synthesis.

A comparison of analgesics

Question 3 from the second paper of 2001 put these drugs specifically in the context of  procedural sedation, "to aid the dressing of severe burns".

Features

Tramadol

Celecoxib

Ketamine

Class/mechanism

Partial opioid receptor agonist;
Serotonin receptor agonist

NSAID (selctive for COX-2)

Anaesthetic;
NMDA receptor antagonist

Advantages

Synergistic with other analgesics

Less respiratory depression than with other opiates

Low toxicity
Synergy with opioids

Dissociative sedation
Opioid-sparing effect

Disadvantages

Weak opioid effect
Lowers seziure threshold
Slow onset
Interacts with SSRIs

May cause renal impairment
May cause platelet dysfunction
Slow onset
Weak analgesic

Confusion, delirium
Emergeance phenomena
Requires speialist staff to be present

 

References

Arain, Shahbaz R., and Thomas J. Ebert. "The efficacy, side effects, and recovery characteristics of dexmedetomidine versus propofol when used for intraoperative sedation." Anesthesia & Analgesia 95.2 (2002): 461-466.

Venn, R. M., and R. M. Grounds. "Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions†."British journal of anaesthesia 87.5 (2001): 684-690.

Jakob, Stephan M., et al. "Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials." JAMA307.11 (2012): 1151-1160.

Zor, Fatih, et al. "Pain relief during dressing changes of major adult burns: ideal analgesic combination with ketamine." Burns 36.4 (2010): 501-505.

Norman, Aidan T., and Keith C. Judkins. "Pain in the patient with burns." Continuing Education in Anaesthesia, Critical Care & Pain 4.2 (2004): 57-61.

Power, Camillus Kevin. "Burns Injury Pain Management-the evidence or not!."Official publication of the National Academy of Burns-India (2009).