Week 13 Pharmacology

Anaesthetic agents

Concepts of Anaesthesia (6 A s)

  • Anaesthesia – Loss of consciousness
  • Analgesia – Pain control
  • Amnesia – Unable to lay new memory and unable to recall them
  • Areflexia – Loss of autonomic and sensory reflexes
  • Akinesia- Skeletal muscle relaxation
  • Anxiolysis – Control of anxiety

Inhaled anaesthetic agents:

  • Volatile agents (Learn as a group rather than individual agents).
    • Concentration of an inhaled anaesthetic is proportional to its partial pressure
    • Rate of reaching therapeutic concentration depends on inhaled concentration, solubility, vol of pulm ventilation, pulm blood flow, partial pressure gradient between arterial and mixed venous blood
    • Less soluble agents raise their partial pressure in the blood faster and rapidly equlibrate with the brain –> fast onset of action.
    • Concentration of inhaled gas directly increases tension in arterial blood.
    • The degree of effect of pulm ventilation depends on if gas has high or low solubility
    • Elimination
      • Agents that are relatively insoluble in blood and brain are eliminated faster than more soluble ones.
      • Desflurane and sevoflurane – fast
      • Isoflurane and halothane – slow. Also slower after longer exposure due to build up in tissues.
      • All of them mostly eliminated via lungs, some hepatic metabolism
      • Hepatic metabolism halothane> sevoflurane>isoflurane>N2O
    • PD
      • GABA – a receptor Chloride channel activated at high concentration and facilitate GABA action at low concentration–> inhibitory synaptic transmission
      • Hyperpolarization via activation of K channels
      • Decrease time of nicotinic receptor opening.
    • SE
      • Decrease mean arterial pressure proportionally to alveolar concentration
      • Halothane – bradycardia
      • Desflurane and isoflurane – tachycardia
      • With exception of N2O all of them cause a dose dependent decrease in tidal volume and increase RR–> overall decreased minute ventilation.
      • Increase apnoec throshold and depress vent response to hypoxia
      • Depress mucocilliary function
      • Bronchodilators (halothane, sevoflurane)
      • Decrease metabolic rate of brain
      • Increase cerebral blood flow and ICP
      • Decrease hepatic blood flow
      • Hepatotoxicity – halothane 1:20 000


Nitrous Oxide

(It is a Volatile agent but it is Important to know in detail as we use it commonly in ED).

  • Not very blood soluble so fast onset and offset
  • Increases post op nausea and vomiting
  • PD – NMDA inhibitor?
  • Least likely to increase cerebral blood flow
  • Doesn’t trigger malignant hypertension
  • Inert, non toxic, minimal CVS effects, environmentally friendly, non explosive
  • MAC >100%, high cost


Need to understand concept of MAC.

  • Minimum alveolar anaesthetic concentration – median concentration that results in immobility of 50% of patients when exposed to a noxious stimulus.
  • An indication of potency
  • N2O >100%, desflurane 6-7%, sevoflurane 2%, isoflurane 1.4%, halothane 0.75%
  • MAC is reduced when intravenous adjuvants are used, also with age and hypothermia
  • MAC increased in pregnancy, chronic use of centrally active drugs, etOH abuse
  • MAC of inhaled anaesthetics is additive


IV anaesthetic agents:

  • Most have faster onset than rapid action inhaled agents so used commonly for induction
  • Most don’t have enough analgesic property so need combination
  • Barbiturates
    • Sodium thiopentone (important).
      • Rapid onset and rapid offset if bolus dose, slow offset if infuion
      • Induction
      • Cardiovasc depression
      • Avoid in porphorias
      • IV bolus –> rapidly crosses BBB –> plasma brain equilibrium reached in less than a minute.
      • High lipid solubility
      • Then rapidly redistributed to muscle and fat
      • SE
        • Decrease mean arterial pressure, SV, cardiac out put. (myocardial depressant, inc venous capacitance)
        • Potent resp depressant
        • Transient apnoea
        • Lowers medulla sensation of CO2
        • Reduced cerebral metabolism and blood flow – good for use in suspected cerebral swelling
        • Reduce hepatic blood flow and eGFR – but not toxic to these.



  • Rapid onset and rapid recovery
  • Used in induction and maintence
  • Can cause hypotension
  • Anti emetic
  • 97% protein bound
  • Vd 700-1500L (lipid soluble)
  • Distribution half life 2-8mins
  • Redistribution half life is 30-60mins
  • Rapidly metabolised in liver (10x faster than thiopentone)
  • Excreted in urine as conjugates, less than 1% unchanged drug
  • Extrahepatic metabolism also
  • SE
    • Resp supression, transient apnoea
    • Marker hypotension through peripheral vasodilation
    • Negative ionotrope
    • Pain at site of admin



  • Moderately rapid onset and recovery
  • Dissociate anaesthetic state – catatonia, amnesia, analgesia without LOC.
  • Emergence phenomena – disorientation, illusions, vivid dreams
  • Cardiovasc stimulation, increased cerebral blood flow
  • PD – antagonises the NMDA receptor by competing with glutamic acid (excitatory). Increase central sympathtic output and decrease reuptake of Noradrenaline at nerve terminals.
  • Only IV anaesthetic with analgesic and anaesthetic property
  • CV stimulant (increase HR, CO and BP) – peak 2-4mins post injection, normalise in 10-20mins
  • Increase cerebral blood flow and ICP
  • Decrease RR
  • Airway reflexes preserved
  • PK – Highly lipiphilic
  • Rapidly distributed to well perfused organs then less well perfused ones
  • Hepatic and tissue metabolism
  • Renal and biliary excretion



  • Midazolam (Probably the one needed in details for anaesthetic purpose)
    • Slow onset and recovery
    • Used pre anaesthetic for anxyiolytic, sedation and amnesia. (premed)
    • Flumazenil reversal available
    • Cardiovasc stability
    • Marked amnesia
    • Used in conscious sedation and balanced anaesthesia – by itself it plateaus at a level insufficient for surgical anaesthesia.
    • Use local anaesthetics and opiates for the analgesia
    • T1/2 – 2-4 hrs
    • GABA agonist


Opiates (already covered).

  • Fentanyl
    • Slow onset and recovery
    • Naloxone reversal
    • Conscious sedation, balanced anaesthesia, marked analgesia
    • Opoid agonist
    • Blunting of Autonomic reflex in higher doses


Miscellaneous – etomidate, dexmedetomidine

  • Etomidate
    • Rapid onset and moderately fast recovery
    • Causes decreased involuntary muscle movements. Provides cardiovasc stability
    • Minimal cardiovasc and resp depression
    • No analgesia so need opiods concurrently
    • Initial distribution 3mins then redistribution half life 29mins (short anaesthetic effect)
    • Metabolised in liver and plasma, only 2% unchanged drug excreted renally
    • SE
      • Pain at injection site
      • Nausea vomiting post
      • Myoclonic activity
      • Adrenocortical suppression
  • Dexmedetomidine
    • selective alpha 2 agonist in CNS (8 times more selective than clonidine)
    • binds all 3 subtypes of alpha2 receptor (A, B, C)
    • Sedation
      • reduces sympathetic activity and agitation, causing a state resembling the non-REM phase of sleep without impairing cognitive function
      • sedation is induced by inhibition of noradrenergic activity via activation of alpha-2 receptors at the locus coeruleus
        produces a patient who is sedated but can be easily roused with minimal stimulation
        minimal respiratory depression (RR, PaCO2, SpO2, and higher PF ratios)
    • Analgesia
      • posterior horns of the spinal cord where the modulation of pain impulses is mediated by the noradrenergic bulbar/spinal pathway
      • peripheral nerve mechanisms also implicated
      • reduce need for opioid analgesia
    • Neuroprotective effects
      • decreases circulating and cerebral catecholamines and CNS glutamate
    • Other effects
      • decreases CBF, CNS VO2, and mild decrease in ICP
      • decreases shivering
      • suppression of stres response to surgery and other noxious stimuli


  • PK (particularly metabolism). – Zero Order Kinetics
    • Water soluble, rapidly absorbed from GIT
      (when fasting, peak etOh levels in plasma within 30mins)
    • Stomach food delays absorption
    • Rapid distribution
    • Vd 0.5L/kg
    • 90% oxidised in liver, rest excreted via lungs and renally
    • Zero order kinetics – elimination independent of concentration and time
    • etOH –>acetaldehyde via alcohol dehydrogenase pathway(main one – in liver and gastric mucosa) and microsomal ethanol oxidising system(only significant when blood concentration is above 100mg/dL – also induced in chronic consumption).
    • acetaldehyde–> acetate in liver by aldehyde dehydrogenase
  • PD
    • Increases GABA action on GABA -a receptors
    • Inhibit glumate ability to open NMDA receptor.
    • Organ system effects.
    • CNS – sedation, anxiolytic, slurred speech, ataxia, impaired judgement, disinhibition
    • Coma, resp depression , death
    • Myocardial suppression
    • Peripheral vasodilator (by acetaldehyde)
  • Withdrawal.
    • Hyperexcitability
    • Seizures
    • Tremor
    • Psycosis/agitation/anxiety
    • Insomnia
    • Abates after 1-2 d



(basic; what’s in Katzung should be enough).

  • Causes extreme discomfort in people who take alcoholic beverages
  • Flushing, headache, nausea, vomiting, sweating, hypotension, confusion
  • Acts by inhibiting aldehyde dehydrogenase –> acetaldehyde accumulation
    slow elimination, onset of full action in 12 hrs
  • Poor compliance so not commonly used
  • Inhibits metabolism of phenytoin, isoniazid and oral anticoagulants.


Methanol / Ethylene glycol:

  • Common causes of intoxication
  • Methanol poisoning – visual disturbance like being in a snow storm. Upto 30hrs delay in symtoms. Bradycardia, prolonged coma and seizures and resistant acidosis all other effects. Sudden cessation of resp.
    • Check blood levels urgently
    • >50mg/dL needs haemodialysis
    • Treat with fomepizole or ethanol
  • Ethyl glycol/antifreeze – transient excitation followed by CNS suppression. 4-12hrs later severe acidosis develops
    • Dx with anion gap acidosis, osmolar gap, oxylate crystals in urine.
    • Rx – ethanol, fomepizole, dialysis


Balanced anaethesia – the use of both IV and inhaled anaesthetic to achieve maximum effect with minimal toxicity/side effects.

IV usually used to induce and inhaled are used to maintain anaesthetic.

Muscle relaxants used to assist in intubations and assist surgical conditions



  • Tell me about Propofol
  • Tell me about Thiopentone
  • Tell me about Ketamine
  • Tell me about Halothane
  • Tell me about Benzodiazapines
  • Tell me about Midazolam
  • Tell me about Diazapam
  • Tell me about Flumazanil
  • Tell me about Ethanol
  • Tell me about Methanol