General Anaesthesia Flashcards
Definitions
Anaesthesia- loss of feeling
General anaesthesia: whole body
Local anaesthetic: affects part to which applied
GA: state of reversible unconsciousness with reduced sensitivity (i.e. muscle relaxation and analgesia) and response to stimuli
Three components: unconsciousness, analgesia, muscle relaxation
Balanced anaesthesia combines drugs to optimize these three components, allowing for a more unified state of anaesthesia and lower doses of individual drugs
Stages of anaesthesia
with increasing depression of CNS function:
Stage 1: voluntary movement- still aware, conscious; likely to see paddling
Stage 2: involuntary movement or excitement- lost consciousness, but limbs may still be working
Stage 3: surgical anaesthesia- not responsive and fully unconcious
Stage 4: medullary paralysis- depress brain function that controls CV/resp function–> detrimental effects
Why do we anaesthetize animals?
to perform painful surgical or diagnostic procedures
Aims: to minimize patient suffering, reduce risk to vet, facilitate the proceudre by immoblizing the patient (i.e. CT/MRI)
Combo of drugs to achieve anaesthesia
Premedicants: drugs given prior to a GA; typically a sedative-opioid combo
Induction drugs: typically IV- drugs used to achieve tranisition from consciousness to unconsciousness
Maintenance drugs: drugs used to maintain anaesthetic state (can be same drug used for induction or two different drugs)
Lipid theory of anaesthesia
drugs partition into the lipid bilayer of cell and by dissolving drugs, change fluidity–> change dimensions/permeability of the membrane
Pros: 1) correlation: lipid solubility and potency have direct correlation 2) pressure reversal: by increasing hydrostatic pressure, anaesthesia was reversed. Also increase excitability–>restore normal function
Cons: 1) temperature: temp change can cause similar fluidity changes in membrane, but doesn’t cause anaesthesia 2) stereoselectivity: both isomers exactly the same lipid solubility but one elicits anaesthesia and the other doesn’t 3) cut-off phenomenon: GA molecules are hydrocarbon chains. up to a point, if you increase chain legnth, you increase the potentcy, but at some point, you lose potency, even as lipid solubility continues to increase with increasing chain length. 4) correlation with enzyme inhibition
bottom line: lipid solubility likely has moreto do with GETTING to the target
Protein theory of anaesthesia
GAs work by interacting with a protein
Receptor interaction: i.e. thiopentone with GABA receptors
Small hyperpolarisaion with 3mmol of GABA. 3mmol in the presence of propofol results in MUCH larger hyperopolarization. see similar effects with Etomidate. Genetically modified cell with change in GABA receptor–> takes away effect of propofol and etomidate.
Two pore domain K channels: relatively new target–> regulators of membrane excitability of CNS. if you have modified channels, does response curve shifted to the right and get less sensititivy to halothane.
Likely, GAs work by interacting/target with more than one receptor, i.e. glycine receptors, NMDA receptors, Na+ channels
Effects of GA on CVS and Respiration
decrease contractility of isolated heart preparations
effects on CO and BP vary
cardiac dysrrhytmia- halothane particularly sensitizes heart to catecholamines
decreased respiration (bear in mind when using with opiates)
increase arterial pCO2
Effects of GA on nervous system
@ cellular level: inhibit conduction of APs
inhibit transmission at synapses- 1) decrease NT release 2) decrease action of NT 3) decrease excitability of post-synaptic cell
Reticular formation (responsible for cortical arousal) and hippocampus (responsible for short term memory) are particularly susceptible
IV anaesthetic agents
typically used to induce anaesthesia- occasionally used to maintain anaesthesia (see TIVA)
Advantages: 1) rapid smooth induction 2) rapid protection of the airway- for maintainence of patent, protected airway (also for inhalational agents)- important in dyspneic patients and those at risk of regurg/aspiration 3) no environmental pollution
Disadvantages: IV access required- small patients or patients with thrombosed veins
Ideal properties of IV anaesthetic
stable on storage
non-irritant to veins or perivascular tissues
rapid/smooth induction
rapid metabolism- no accumulation
rapid/smooth emergency and recovery
non-toxic to liver/kidneys
minimal adverse CVS or resp. fx (most agents don’t meet this ideal)
good analgesic
good muscle relaxant.
IV anaesthetic agents- specific drugs
Propofol
Steroid anaesthetics i.e. alfaxalone
Barbiturates i.e. thiopentone and pentobarbitone
Imidazole derivatives i.e. etomidate
Dissociative agents i.e. ketamine, tiletamine
Mechanism of action of induction agents- Propofol
Chemically unrelated to others (hindered phenol- phenol is a cyclic saturated 6-C molecule and is very caustic. hindered phenol has side chains and is less caustic).
Oil at room temp (formulated as an emulsion)
enhanced GABA transmission (increased flux of Cl-), similar to BZP but at a different site
As rapid as thiopentone
short acting, smooth and rapid recovery
suitable for TIVA
Propofol pharmokinetics and metabolism
highly protein bound (98% plasma-protein bound), but very lipid soluble
large volume of distribution (>3L/kg–beyond total body water)
redistribution and metabolism- you administr dose, rapidly circulates and crosses BBB–>CNS. As it continues circulating, it accumulates in lipid tissues. Not a huge problem because it’s metabolised very rapidly–can top up dose as needed.
Metabolised at liver and another site (suggestion that it’s the lungs)- metabolism happens in the liver but not enough happens there to metabolism ALL the propofol
Conjugated (sulphate and glucuronide) prior to excretion in the urine
rapidly cleared (>40 ml/kg/min)
Alfaxalone
steroid anaesthetic agent- insoluble in water, presented in cyclodextrin vehicle
Enhances inhibitory action of GABA- also, it possibly inhibits nicotinic ACh receptors and noradrenaline uptake
Advantages: high therapeutic index- as a group, GAs have narrow index
rapid induction
rapid metabolism
suitable for TIVA- short acting, good recovery
Thiopentone- mechanism of action
thiopentone=barbiturate
reversibly depress activity of all excitable tissue
reticular activating system is particularly susceptible
enhance inhibitory action of GABA- allosteric site (not same site as GABA, but another binding site on the receptor); promote binding of GABA to GABA-a receptor, enlarge GABA-induced chloride currents.
Barbiturates- pharmokinetics
Characteristics: weak acids (sodium salts, pH>10) need allosteric solution for administration
>60% unionized in blood
>80% plasma protein bound- good distribution though d/t lipid solubility
repeat administration results in accumulation in fat stores
Metabolism: heptic oxidation, conjugation, renal excretion
half life= 8 hours- long time to clear drug
NOT good for TIVA
Redistribution
surgical anaesthesia- rapidly, drug gets sequestered into fat sores, draws out of brain. later, almost all drug is still in the body, just not at the brain. if you want to top up, you can saturate the fat stores–>very long state of anaesthetic hangover.
Etomidate
imidizaole derivative
potent, short acting non-barbiturate
similar to thiopentone
enhance inhibitory action of GABA
rapid induction/recovery
poor quality of anaesthesia– muscle hypertonicity, hyperexcitability on recovery.
Ketamine
dissociative agents
sensation of dissociation- 15 seconds; unconsciousness- 30 seconds; lasts 10-15 minutes
Mechanism of action: interrupts the association between limbic and cortical regions by acting on NMDA receptor (excitatotory) ion channge which receptor is intergral part of. inhibits NMDA receptors
Ketamine can physically block the open ion channel but it also decreases frequency of opening by binding modulatory sites.
Clinical aspects of propofol pharmokinetics
pharmocological effect may be enhanced in hypoproteinemia
propofol is highly protein bound. may get enhanced anaesthetic effect if patient is hypoproteinemic because FREE drug is responsible for effect.
Pharmacological effect is NOT prolonged if 1) repeated IV doses are administered (i.e. it’s suitable for maintenance in dogs because it’s rapidly metabolsed) 2) in dogs with hepatic dysunfction because it’s capable of metabolism elsewhere besides liver. don’t see prolonged elimination even with dogs with hepatic dysfunction
nb: a prolonged effect may be seen in cats. cats don’t metabolise phenol very well–> not used for maintenance in cats or in cats with hepatic dysfunction
Propofol effects on CNS
rapid loss of consciousness without specific analgesia( not blocking nociceptive pathway)- ~5 minutes duration– long enough for induction
Reduced cerebral blood metabolic rate and blood flow- benefical effects under anaesthesia, decreased metabolic products, less need for oxygen and nutrients
decreased intracranial pressure–this is good because too much Q to brain leads to increased intracranial pressure
Anti-covulsant action- can be used in some circumstances to prevent seizures.
Propofol effects on CV system
transient fall in BP due to vasodilation and mild myocardial depression (not a huge amount clinically)
heart rate usually unchanged
take care in shocked/hypovolemic patients–see much more dramatic CV effects. normally, BRR tries to compensate BP. propofol interferes with BRR.
not inherently arrhythmogenic- doesn’t sensitize heart to catecholamines
Propofol effects on respiratory system and other organs
Respt: post induction apnoea is quite common- this is OK as long as you can support ventilation- more likely to see it if you give v. high doses v. quickly
Other organs: non-irritant if injected perivascularly
pain (cold) on injection reported in people (cats?)
occasional muscle twitching/rigidity of extensors
repeated use (i.e. on consecutive days) can cause oxidative damage to RBCs in cats (heinz body anemia)
Clinical summary of propofol
used as an IV induction agent
occasionally used as a maintenance agent in dogs
used to treat status epilepticus in dogs
Licensed in dogs and cats
Caution in: shocked/hypovolemic patients, cats with hepatic dysfunction, cats requiring repeat anaesthetics
Formulations of propofol
- lipid emulsion: preservative free- problem= bacterial growth- grow well in lipid
discard within 6 hours of opening (data sheet says throw out immediately)
- lipid emulsion with preservative:
“propoflo plus” with benzyl alcohol
use within 28 days of opening
Contraindications: prolonged infusion (>30 minutes); do not give more than 24mg/kg per anaesthetic (=around 30 minutes)
Be cautious if <5 months of age, pregnant or lactating- not shown to be safe
concern of build-up of benzyl alcohol causing toxicity.
Alfaxalone effects on CNS
not v. many differences between propofol and alfaxalone
rapid loss of consciousness without specific analgesia
reduced cerebral metabolic rate, Q and IC pressure
Anecdotal reports of muscle twitching and rigidity on induction or during recovery (uncommon)a
Alfaxalone effects on CVS, respiratory system
CV: dose-dependent CV depression
Clinical doses: mild hypotension primarily due to vasodilation (alfaxalone doesn’t impair BRR cf. propofol)
Cyclodextrin formulation is NOT associated with hisamine release (cf. Saffan=historical version of alfaxalone)
Resp system: post-induction apnea does occur but not often- even less common than in propofol
Recovery: occasionally poor quality, stormy recovery- particularly if you’ve had a short period of anaesthesia cf. propofol
Clinical use of Alfaxalone
used as IV induction agent
also used as maintenance agent for short anaesthetics in dogs (cats?)
Licensed in dogs and cats (alfaxan)- used in rabbits off-license and sometimes used in horses, but it’s not a greta idea
previous formulation in cremophor (Saffan) caused life-threatening histamine release in dogs- only used in cats
Little tissue toxicity if injected perivascularly- can be given IM, but less reliable (unlike propofol, which is NOT given IM).
Thiopentone clinical use
Previously used as an IV induction agent- vet prep no longer available
v. few indications: e.g. top-up anaesthesia in horses- deepens plane of anaesthesia
Effects: accumulate if repeated doses given
unconsciousness, decreased IC pressure and anticonvulsant
mild decrease in BP and increase HR
post induction apnea
tissue necrosis if injected peri-vascularly due to strongly alkaline solution
Pentobarbitone
very similar structure to thiopentone
less plasma protein bound (40%)
slow onset of action (cf thiopentone)- lower lipid solubility
longer duration (30-45 minutes) in dog
profound respiratory depression
not recommended for anaesthetic use
licensed only for euthanasia d/t narrow therapeutic index.
Etomidate
probably not used often, altohugh sometimes used in cardiac disease
occasionally used as an induction agent but no vet license.
minimal CVS or resp. depression
Can cause involuntary movement/muscle twitching (induction quality isn’t great)
pain on injection reported
inhibits steroidogenesis–inhibits conversion of cholesterol to cortisol– not a problem in a lot of patients but certain critical pateitns need stress hormone to deal with hemorrhage/sepsis.
Dissociative anaesthesia
dissociative agents produce a different quality of anaesthesia. unlike blanket depression, get dissociation between cortex and limbic system.
features include: sensory loss with specific analgesia
increased muscle tone
eyes open and slow nystagmus (esp. in horses)
active reflexes incl. laryngeal/pharyngeal reflexes (palpebral reflex may still be patent)
less profound CVS and resp. depression
Ketamine effects on CNS
loss of consciousness with analgesia
increased cerebral oxygen consumption and cerebral blood flow– increased IC pressure- troublesome if head trauma or brain tumor
convulsions in dogs/horses if used as sole agent
hallucinations/emergence delirium– agitated recovery– dysphoria.
Ketamine effects on other systems
Musculoskeletal: muscle tone may be increased
CV: mild increases in BP, HR and CO
Respiration: minimal effect- especially if in combo with other drugs
Clinical use of Ketamine
never use as sole agent for anaesthesia
typical uses: 1) to induce anaesthesia in dogs, cats and horses- combined with benzodiazepine and injected IV
2) to induce and maintain anaesthesia (~30 minutes) in dogs and cats: combined with alpha 2 agonist (+/- butorphanol) and injected IM
3) to provide analgesia in dogs and cats: much lower doses given IM or by IV infusion- can use ketamine alone in this context
Licensed in dogs, cats, horses and primates
Caution in patients with: elevated IC pressure, a history of seizures (can promote seizure activity), pre-existing tachycardia or animal in which tachycardia would be detrimental
Total intravenous anaesthesia (TIVA)
anaesthesia maintained by intermittent boluses or continuous infusion
-avoids risk to people administering drugs i.e. no enviro pollution
easy to administer- implies without intubating but modern techniques in small animals use intubation
known pharmacokinetics
inhalational anaesthetics may be unsuitable in some individuals i.e. airway surgery or malignant hyperthermia.
Ideal TIVA agents
ideal properites of iV agent, but also short-acting, rapidly metabolised and cleared (no accumulation), inactive and nontoxic metabolites
Which agents are used?
*Propofol (preservative free form): caution in cats; no analgesia, CVS and respr. depression
Propofol plus specfic analgesic (ketamine or fentanyl or alpha 2 agonist)
Alfaxalone (in small animals)- likely need to combine with analgesic.
Triple drip: alpha 2 agonist + GGE + ketamine- popular for field anaesthesia in horses
Inhalational anaesthetics
typically used for maintenance of anaesthesia
advantages: 1) delivery/elimination depends on ventilation- no hepatic metabolism/renal excretion requirements. easy to adjust anaesthetic depth- very rapdi adjustment
Disadvantages: equipment required i.e. ET tube, carrier gas (O2), vaporiser, breathing system, etc; environmental pollution- leakage into immediate environment; volatile agents generates CFCs; NO can behave as greenhouse gases.
Inhalational anaesthetic agents as induction agents
less commonly used to induce- usually when you can’t get IV access
Advantages: IV access can be secured after induction
Disadvantages: environmental pollution; takes longer and delay in securing airway may be a problem in some cases (dyspnea/regurg.)
Pharmacokinetics of inhalational anaesthetics
structure: small, lipid-soluble–cross alveolar membranes easily
halogenated hydrocarbon: i.e. halothane
halogenated ether: i.e. isoflurane (most of newer compounds)
HC or ether have implications for metabolism
Speed of induction/recovery of inhalational anaesthetic agents
Blood:gas partition coefficient: numerical value which describes where the substance would rather be.
LOW blood:gas gives rapid induction/recovery i.e. in order to achieve equilibrium, not much of drug needs to move into blood. can achieve equilibrium rapidly. i.e. would prefer to stay in alveolar air. LOW blood:gas allows for rapid control
Oil:gas partition coefficient: relates to lipid solubility. the more lipid soluble, the more rapid it reaches site of action
HIGH oil:gas gives high potentcy
Physiological factors:
alveolar ventilation rate: speed at which patient is breathing
cardiac output: speed at which blood is moving
Metabolism and elimination of inhalational anaesthetics
elimination primarily by exhalation- helps control duration and reovery from anaesthesia.
metabolism in liver- extent depends on the agent
potential production of toxin metabolites- risks to patient and staff
metabolism of drugs important not in duration of action but formation of metabolites.
Minimum alveolar concentration (MAC)
MAC describes the minimum alveolar concentration at which 50% of patients will not respond to a particular stimulus, i.e how much of a drug needs to be in the alveolus which would render patient anaesthetized
MAC compares the potency of different inhalational anaesthetics
the lower the MAC, the more potent the drug is.
lots of different factors that can influence MAC value
Factors which can alter MAC
species
age: mac lower in geriatrics and neonates (i.e. need less of an agent)
pregnancy: mac decreased
hypothermia: mac decreased d/t peripheral vasoconstriction
drugs: premedicants can greatly reduce MAC
Ideal properties of inhalation anaesthetic
stable on storage- halothanes don’t meet this
easily vaporized: volatile- want it to be easily vaporized
nonflammable- ether=flammable
non-irritant to airways and NOT pungent- might dissuade animal from breathing in
undergoes minimal metabolism (non-toxic)
compatibile with equipment incl. soda lime (CO2 absorbant- soda lime can interact/interfere with some agents)
low blood: gas partition coefficient
minimal adverse CVS or resp. effects
good analgesic and muscle relaxant
Individual inhalational anaesthetic agents
Volatile agents: Halothane, isoflurane, desflurane, sevoflurane
Gas: Nitrous oxide
Halothane physical properties
chemical structure: halogenated hydrocarbon (impact on CV effect)
Liquid: preparations contain preservative thymol- nb thymol can build-up in vaporizers- need to have halothane vaproziers clean.
Vapor pressure (mmHg): 244 —the higher the vapor pressure, the more volatile (i.e easily vaporized)
MAC (%): 0.9 —MAC value is pretty low (i.e potent)
Oil: gas partition coefficient: 224 (pretty high, i.e. potent)
Blood: gas partition: 2.5 (moderately low, moderately rapid rate of change of depth)
% metabolised: ~20– pretty high, potential to generate toxic metabolites.
Halothane effects on CNS
dose dependent depression without specific analgesic action
reduces metabolic O2 consumption
potent cerebral vasodilator: increased blood flow, increase IC pressure, impaired perfusion–> undesireable– critical factor in head trauma or brain tumor.
Halothane effects on CVS and resp. system
CV: hypotension(all agents cause hypotension- different mechanisms)
depression of myocardial contractility (decreased stroke volume)–> decreased CO–>decreased BP
minimal change in TPR
sensitizes myocardium to catecholamines- dysrrhythmias more common in presence of halothanes- ethers don’t tend to do this.
Resp system: dose-dependent depression- apnea at ~2 x MAC —usually clinically manageable
Halothane effects on other organs
Liver: mild, transient dysfunction due to hypoxia- reflects effect on CO, decreased liver perfusion
rarely, immune-mediated hepatic necrosis (consequence of metabolite binding to cells and trigger immune-mediated hepatic necrosis)
Kidney: reduced blood flow
Muscle: moderate relaxation (potentiates NMBDs (muscle relaxants)
trigger for malignant hyperthermia- rare, life-threatening excessive release of Ca2+ from SR–>muscle rigidity–>heat–>acidosis–> pigs most likely.
Clinical summary of halothane
licensed in NON-food producing animals
potent
moderate speed of induction/recovery
relatively high rate of metabolism
significant myocardial depression
potentially arrhythmogenic
use has declined rapidly in recent years.
Isoflurance physical properties
Halogenated ehter (not as dysrrhythmic)
Volatile liquid
Vapor pressure: 240 (high- easily vaporized)
MAC: 1.3 (slightly higher than halothane)
Oil: gas partition: 91 (lower lipid solubility, therefore less potent than halothane)
Blood: gas partition: 1.5 (lower than halothane- more rapid rate of change of depth)
% metabolised: 0.2 (very low)
Isoflurane CNS effects
Dose dependent depression without specific analgesic action
reduces metabolic O2 consumption
less cerebral vasodilation than halothane; still potential for increase in IC pressure. Responsiveness to CO2 retained. Ventilation drives CO2 level down, increases vasoconstriction to off-set increase in IC pressure. This doesn’t happen with halothane.
Isoflurance CV and resp system effects
Hypotension: related to peripheral vasodilation. CO maintained (except for deep plane anaesthesia); peripheral vascular resistance falls
Less sensitisation to catecholamines
Resp system: dose dependent depression, see a little more with isoflurane than with halothane
Isoflurane effects on other organs
Liver: hepatic dysfunction less likely (cf halothane)- hepatic Q better maintained- better CO, better liver perfusion
Minimal metabolism- decreased risk of getting toxic metabolites
Kidney: reduced blood flow
muscle: good relaxation (potentiates NMBs)
trigger for malignant hyperthermia
Clinical summary of Isoflurane
cf. halothane
Licensed in non-food producing animals
faster speed of induction/recovery/change of depth
pungent odor (not ideal for induction)
minimal metabolism
CO better maintained
less arrhythmogenic
most widely used inhalational agent
Sevoflurane- physical properties
Halogenated ether; voltaile liquid
Vapor presure: 170
MAC: 2.3
Oil: gas partition: 47 (not very potent, less lipid soluble)
Blood: gas partition coefficient: 0.68 —very low, even faster rate of change of depth
% metabolised: 3 -pretty low
Sevoflurane organ system effects
Similar to iso in most respects
CV: increases in heart rate less likely (c.f iso and deslurane)
resp system: minimal airway irriation- less aversive smell
Kidney: concern of fx on kidney when it first came out.
product of metabolism F- potentially nephrotoxic
reacts with soda lime (CO2 absorbant) to yield COmpound A which is nephrotoxic in rats, but not shown to be nephrotoxic in any other animal. If existing kidney disease, consider not using sevoflurane.
Clinical summary of Sevoflurane
licensed in dogs
rapid induction/recovery/change of depth
pleasant odor and minimal airway irritation- suitable for induction
low rate of metabolism
care in patients with existing renal insufficiency
Desflurane- physical properties
least important, no veterinary license
halogenated ether
Boiling point= 23 degrees C (need specialized vaporiser)
Vapor pressure- 669 (very vey volatile)
MAC %: 7.2
Oil: gas- 19 (reduced lipid solubility- much less potent)
Blood: gas- 0.42 (rapid change of plane, onsent and recovery)
% metabolised: 0.02
Desflurane CV and resp effects
Similar to iso in most respects
CV: rapid increases in inspired concentration can increase HR and arterial BP (catecholamines)
Resp system: high inspired concentrations can cause airway irritation
Clinical summary of desflurane
no veterinary license
low potency
fastest speed of induction/recovery/change of depth
airway irritation (not ideal for induction)
minimal metabolism
used in people for “day-case” surgery
not yet widely used in vet med, but could be useful where you need rapid recovery i.e. in brachycephalic patients.
Methoxyflurane physical properites
Older agent
vapor pressure: 23- difficult to vaporize
MAC: 0.29 (very very potent)
Oil: gas 970
blood: gas 15 –slow onset/recovery/rate of change of depth
% metabolised: very high
halogenated ether
potentially nephrotoxic metabolite.
Nitrous oxide- physical properties
N2O
Colorless gas, without taste or odor
stored under pressure in cylinders
Mac% >100 —over 100%, can’t anaesthetize with NO alone
Oil: gas 1.4 —not potent, very low lipid solubility
Blood: gas 0.47 – rapid onset/recovery/rate of change
% metabolised: <0.01
Nitrous effects
Organ systems: generally minimal
CNS: provides specific analgesia- NMDA receptor antagonist- blocks central sensitization
Side effects: prolonged low-level exposure inactivates vitamin B12 dependent enzymes–> bone marrow suppression, defective myleination causing polyneuropathy
teratogenic- can cause birth defects.
Clinical use of NO
used as an adjunct, not as sole agent: use of 50-75% of N2O has sparing effect on volatile agent–> need less isoflurane
Must have minimum of 30% oxygen + isoflurane or sevoflurane, otherwise patient becomes hypoxemic
Used to speed induction
2nd gas effect: high volume of uptake of nitrous oxide has “concentrating” effect on volatile agent in alveoli–>speeds on set
Also, N2O has low blood: gas partition coefficient.
Diffusion hypoxia at end of anaesthesia: N2O diffisues back into alveoli lowering arterial partial pressure of oxygen. Provie 100% oxygen for 10 minutes after N2O turned off.
Caution: expands gas filled cavities
Contraindicated in ruminants, GDV, pneumothorax etc.
