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.
- Sodium thiopentone (important).
Propofol
- 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
Ketamine
- 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
Benzodiazepines
- 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
Ethanol:
- 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
- Water soluble, rapidly absorbed from GIT
- 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
Disulfiram
(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
Vivas
- 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