anesthetic drugs (injectible) Flashcards
what are the elements of the anesthetic state
- unconsciousness (hypnosis)
- amnesia
- analgesia (not same as antinociception) (inhibition but may not be sippression or reflex responses to noxious stimulation)
- immobility (skeletal muscle relaxation)
what are the 4 stages of anethesia
- analgesia
- excitement
- surgical anesthesia
- medullary paralysis
CNS sites of action
- cerebral cortex
- reticular activating system
- others (thalamus, substantia nigra, vestibular system, cerebellum, spinal cord)
cellular sites of action
interference with synaptic mechanisms
- NT synthesis
- NT release
- NT clearance
- NT receptor binding
- postsynaptic membrane potential
- inhibition of axonal nerve impulse conduction
molecular sites of action: membrane protein channels
interaction of anesthetics with specific NT receptor proteins (GABAa receptor)
injectable anesthetics in clinical use
- barbituates (thiopental)
- phenols (propofol)
- steroids (alfaxalone)
- imidazoles (etomidate)
- cyclohezanones (ketamine, tiletamine)
what is the main molecular mechanism of action of “classical” injectable anethetics
- allosteric modulation of the GABAa receptor (increase affinity)
- synergism with benzodiazepines
what are the main mechanims of action of dissociative anethetics
- blockade of the NMDA receptor at subanesthetic dose (use-dependent block and closed channel block)
- decrease in central glutamatergic activity -> analgesia and anesthesia
what is the common pharmacokinetic feature of all highly lipophilic injectable anesthetics
redistribution of drug from CNS to peripheral tissues causes the animal to wake up (needs to go below threshold)
what are phenols
- sedative-hypnotic drug unrelated to barbituates
- risk of microbial growth in the vehicle (intralipid)
gradual depression of CNS activity with phenols
titration of effect possible by increasing the dose: sedation -> hypnosis -> anesthesia
general anesthesia pharmacologic effects of phenol
- rapid onset after IV bolus injection
- rapid recovery without residual CNS depression
- maintenance with repeated IV boluses or CRI
IV, long-term sedation pharmacologic effects of phenols
low risk for drug accumulation
non-hypnotic CNS effects of phenols
- decrease in CBF, ICP, CMRO2
- antiemetic effects
- none or no clinically relevant analgesic effect per se
what systems effects are most severe upon administration at > 1 mg/kg/min
phenol
- respiratory
- cardiovascular
respiratory system adverse effects
phenol
- central respiratory depression (Vt decreases, RR decreases)
- bronchodilation
- inhibition of laryngeal reflexes
cardiovascular system adverse effects
phenol
- hypotension
- centrally (sympathetic vasomotor tone decreases)
- peripherally (neg. inotropic effect & direct vasodilation)
excitatory effects (transient)
phenol
- 10% of dogs and cats
- limb paddling, nystagmus, muscle twitching, myoclonus, and opisthotonus
why is there reduced elimination in cats
reduced conjugation capacity -> oxidative injury to feline RBCs -> Heinz body formation
using propofol with caution
- patients with cardiovascular dysfunction
- patients that cannot be ventilated b/c not intubated
- patients with sepsis/systemic infections
- cats with anemia
combining propofol with other preanethetic drugs
increases induction dose and makes it safer
what is neurosteroid: Alfaxalone
- water soluble compound suitable for IM injection
- CNS depressant and hypnotic effects as origionally described for progesterone and its congeners in rats
biotransformation and elimination of phenols
- extensive hepatic matabolism
- hydroxylation via CYP450 system
- glucuronide conjugation
main effects of alfaxalone - progressive suppression of brain activity
- increasing doses of alfaxalon causes: sedation -> hyposis -> general anesthesia
- none or no clinically relevant analgesic effect per se
main effects of alfaxalone as a general anethetic
- rapid onset of effect after IV bolus injection
- relatively short anesthetic effect
- prolongation of anesthesia with repeated bolus administration or with CRI
- however, not rarely central excitation during recovery, particuarly in cats
main effects of alfazalone - IM sedation
- effective to sedate non-cooperating animals or animal patients at higher risk of anesthetic complications such as trauma patients, cat with FUS, anxious animals
- effective muscle relaxation when combined with benzodiazepines
adverse effects of alfaxalone
respiration
- centrally mediated depression (Vt decreased, RR decreased)
- less than with propofol, if injected slowly IV to effect
- suppression of swallow reflexes (-> intubate animal)
- excitatory signs in recovery period if: (NOT combined with sedatives and/or analgesics/opioids)
cardiovascular system
- unlike, propofol, somewhat lesser side effects
pharmacokinetics of alfaxalone
- fast hepatic metbolism
- no risk for accumulation in cats or sighthounds
principle pharmacologic effect of imidazoles (etomidate)
- ultra-rapid onset of CNS depression with hypnosis in < 20sec
- no antionociception/no analgesic effect per se
- non-hypnotic CNS effects (decrease in EEG activity, decrease in CBF - direct cerebral vasoconstriction, decrease in ICP and CMRO2)
adverse effects of etomidate
- none or minimal respiratory and cardiovascular effects
- occasionally CNS excitatory effects
- inhibition of adrenal steroid genesis (11B-hydrozylase) - responsible for cortisol production
- hemolysis due to high osmolality of solution
- pain upon IV injection
pharmacokinetics of etomidate
- 76% plasma albumin binding
- ~25% total plasma protein binding
- incomplete placental transfer
- fast decline in fetal plasma levels
biotransformation and elimination of etomidate
- extensive hepatic metabolism
- extrahepatic metabolism (plasma ester hydrolysis)
- renal elimination of metabolites
use of etomidate in clinical practice
cautious use in patients with:
- adrenal insufficiency (addison’s disease)
- severe stress syndrome
cyclohezanones produce anethesia-like state called:
“dissociative anesthesia”
- intense analgesia, light sleep, amnesia and catalepsy
ketamine is a racemic mixture of two optical isomers:
- S(+) isoform 3-4 times more potent than R(-)
- S(+) isoform twice as long active as R(-)
- dysphoria: S(+) < R(-)
what are the principle pharmacologic effects of ketamine
dissociative anesthesia
- selective suppression of thalamoneocortical projection system -> disconnection of thalamoneocortical from limbic and other subcortical areas
analgesia
- at subanesthetic doses
what are the typical features of dissociative anethesia
- loss of consciousness despite neuronal activity outside neocortex
- catalepsy
- maintenance of protective reflexes
- skeletal muscle movements
what are the CNS adverse effects of ketamine
- increased EEG activity associated with myoclonus and seizure-like activity
- increase in CBF (cerebral vasodilation)
- emergence delirium (dysohoria)
respiratory adverse effects of ketamine
- mild, transient decrease in RR and Vt
- apneustic, shallow, and irregular breathing pattern
- breath-holding at peak of inspiration
- bronchodilation
cardiovascular adverse effects of ketamine
- indirect stimulation -> increase HR, CO, MAP
- direct negative inotropic and vasodilatory action -> relevant in cases of compromised CVS
- pro-arrhythmogenic effects
digestive system adverse effects of ketamine
increased salivation
neuromuscular system adverse effects of ketamine
- increased muscle rigidity (catatonia)
- decreased nerve conduction
biotransformation and elimination of ketamine
- extensive hepatic (CYP450) metabolism
- N-demethylation to norketamine (20-30% rest activity)
- exception cat: no metabolism to inactivate compounds
