HUF 2-67 General anesthetics Flashcards
4 stages of general anaesthesia
- Analgesia and amnesia
- Excitement
- Disinhibition of inhibitory neurons
- Delirium, combative behaviour
- Increased and irregular HR, BP, respiration - Surgical anaesthesia
- Lower but regular HR, BP, respiration
- Loss of consciousness
- Immobility
- Muscle relaxation
- Inhibition o many autonomic reflexes
- Should be achieved rapidly and maintained throughout surgery - Medullary depression
- Severe CNS depression, vasomotor and respiratory centres at medulla
- Coma and possibly death
Molecular targets of general anaesthetics (GA)
Propofol, Thiopental: GABA-A receptor (β2 and β3 subunits)
NO, Ketamine: NMDA, AMPA, nAChR, 2-pore K+ channels
Halogenated ethers and alkanes: GABA-A R, Glycine R, NMDA, AMPA, nAChR, 2-pore K+ channels
- ↑ Neuronal inhibition as a result of
1. Stimulation of GABA-A and glycine receptors and K+ channels
2. Inhibition of nAChR, AMPA and NMDA - Anaesthetised state is favoured when more neurons are inhibited
Which brain areas are affected most by GAs?
- ↓ Thalamic activity (↓ cortical neuronal activity)
- ↓ Cortical areas (mesial parietal cortex, posterior cingulate cortex)
- Disconnected neuronal communication network between temporal, parietal and occipital lobes
Other regions: frontal cortex, hippocampus, RF, brainstem
Delivering GA to brain
Thiopental, Propofol, Ketamine (IV)
- Reach brain rapidly for induction of anaesthesia
NO, Halothane, Isoflurane, Desflurane, Sevoflurane (inhaled as gas or vaporised liquid)
- Inhaled GA diffuse from alveoli to bloodstream (takes time)
- Lipophilic GA reach target site on brain neurons
* Easier to control amount of inhaled GA reaching brain and stage 3 anaesthesia
Rapid onset and short duration of IV GA
- More CO is directed towards “vessel-rich” organs e.g. brain, liver, kidneys
- High perfusion, small capacity to store GA (low % of BW) - GA quickly redistributed to less perfused ms, and subsequently to least perfused fat tissues
- High capacity to store GA
- Slowly release to circulation continuously after drug administration terminates
e. g. Thiopental: approx. onset <0.5 min
- Thiopental level in fat is gradually increasing, up to >4h after single dose
Multiple doses or continuous infusion of Thiopental
- Continuous redistribution and accumulation in fat tissues over time
- More Thiopental slowly released by fat tissues into circulation - Hepatic clearance important in Thiopental elimination
- Saturated at high [Thiopental]
- Elimination follows 0th-order kinetics
- t1/2 dose-dependent - Result: high levels of Thiopental in brain even if no new drug is added
∴ “Hang-over” effect: drowsiness, respiratory depression
Conclusion: Thiopental good for induction, but NOT to be used for maintenance of anaesthesia
Thiopental vs. Propofol
Thiopental: slow hepatic clearance (dose-dependent)
Propofol: fast hepatic clearance
Propofol is metabolised by liver at faster rate
=> Cont. infusion can induce and maintain stage 3 anaesthesia
BUT
- Lacks analgesic effect => Co-administered with opioid analgesic in total IV anaesthesia
- Severe pain at injection site (minimised by fospropofol - prodrug)
- Propofol infusion syndrome (PRIS): heart failure, rhabdomyolysis, metabolic acidosis, renal failure; potentially fatal
Conclusion: associated risks and problems with repeated or continuous Propofol and Thiopental administration
Ketamine vs. other IV GA
- Slightly slower onset (~1m) and longer duration of action (10-20m)
- Dissociative anaesthesia: analgesia, amnesia, eyes open, preserved consciousness with muscle tone but immobile
Pros:
- Intermediate rate of hepatic clearance - no hang-over effect (significant when given repeatedly or infusion)
- Strong analgesic effect
- No respiratory depression
Cons:
- Sympatho-mimetic property by stimulating sympathetic outputs and inhibition of catecholamine reuptake
=> ↑ HR, BP, CBP
- Psychotomimetic effects: delirium, delusions, hallucination during recovery from anaesthesia (less pronounced in children)
Conclusion: ketamine is good at induction of anaesthesia, BUT the CNS side effects limit its use as maintenance GA in adults
Inhaled GAs: partial pressure
- Inspired and reach alveoli as gas
- Gas dissolves incompletely in aq environment (GAaq vs. GA)
- Closed “container” of BV: GA exerts pressure on top of blood solution (blood constituents and other gases)
=> Partial pressure in blood - Blood solubility: how many GAaq can be dissolved in blood
- Pi: PP of GA in inspired air
- Palv: PP of GA in alveoli
- Pa: PP of GA in aterties
- Pb: PP of GA in brain
- Eqm: Pi = Palv = Pa = Pb (GA administered over time)
- Sufficient Pb => Anaethesia
- GA must first “leave” blood solution and diffuse across membranes to reach receptors in brain
=> Favoured by high lipophilicity
Pa and solubility in blood
- GA diffuses down conc. gradient to alveoli
=> Palv ↑ from zero as GA inspired
=> GA diffuses to blood vessel
=> Pa ↑ from zero - Diff. of BA aq solubility => Number of GAaq in blood differs
- GA high blood solubility => Palv = Pa achieved slow
- GA low blood solubility => Palv = Pa achieved fast
∵ Fewer molecules required o exhaust capacity of blood to accept GA into solution
=> Palv = Pa at faster rate
Significance of faster Pa = Palv
- GA low blood solubility => Palv = Pa achieved fast => High Pa achieved quickly => Fast GA diffusion to raise Pb => Pb = Pa = Palv - GA high blood solubility => Palv = Pa achieved slow => High Pa achieved slowly => Slow GA diffusion to raise Pb => Pb = Pa = Palv achieved slowly
Blood:gas (B:G) partition coefficient (λ)
- Conc. ratio of GA that is distributed between aq form and gas form
- Small λ (B:G) means less GA is dissolved in blood (lower blood solubility) and more GA in gas form
=> GA reaches brain sooner
=> Achieve anaesthetic state faster (fast onset) - One way to alter onset time of inhaled GA
- ↑ Ventilation rate
=> ↓ Time needed for Pi = Palv
=> ↓ Time needed for Pb = Pa = Palv
=> Faster onset time
Oil:gas (O:G) partition coefficient (λ)
- Conc. ratio of GA that is distributed between lipophilic species in aq environment of brain and gas form
- Commonly used GA: small λ(B:G) => small λ(O:G)
- GA small λ(O:G)
=> Greater proportion of GA in gas form (less soluble in lipid)
=> *** Very few GA present in total - Brain: aq interstitium and lipophilic cell membranes
- GA in brain dissolved and dissociates into hydrophilic and lipophilic (GA-L) species
=> Less GA-L formed - GA-L binds target site (Meyer-Overton rule)
=> More molecules of GA (higher conc.) needed to bind target site
λ(O:G), minimal alveolar conc. (MAC) and potency
- MAC: Palv (in % or atm) required to abolish movement in 50% of patients to a standard surgical incision
- Large MAC: more GA needed; low potency
- Same argument for GA with small λ(O:G) (smaller proportion of GA-L for a given dose)
- MAC of NO is so high that 100% of inspired gas is required to cause anaesthesia
=> Potency too low for practical use - Large λ(B:G)
=> Pa = Palv acheived slow
=> More lipophilic species in brain due to high λ(O:G)
Slower onset GA:
- Pb is raised to equal Palv; greater aq solubility
=> More GA-L present (large λ(O:G))
=> More target binding
=> Smaller GA dose required to achieve given level of response
=> Small MAC; high potency
Comparison of inhaled GAs
Increasing order of potency (decreasing order of onset time):
NO, Halothane, Isoflurane, Desflurane, Sevoflurane
Major toxicity
- NO: bone marrow depression; peripheral neuropathy
- Halothane: dysrhythmia due to sensitivity to catecholamines; halothane hepatitis; malignant hyperthermia
- Sevoflurane: potential nephrotoxicity
* High potency = Low MAC = High λ(O:G) = High λ(B:G) = Low onset time (appearance of signs of general anaesthesia)
