Injectable Anesthetics (L&J Chp 15) Flashcards
Why use injectable anesthetics?
- Reliable sedation
- Reliable anesthesia
- Administered IV to induce unconscious state suitable for intubation, transition to inhalant anesthesia
- CRIs, intermittent bolus, IM to maintain ax for short time
Ideal injectable anesthetic agent
- water soluble
- long shelf life
- stable when exposed to heat, light
- large safety margin
- Short duration of action with no cumulative effects and readily metabolized into non-toxic metabolites +/- excreted from the body
- Adequate analgesia for the procedure
- Some degree of muscle relaxation
- No creation of unpredictable life-threatening changes in CV, resp fxn
Barbiturates
Injectable anesthetics, anticonvulsants
Derivatives of barbituric acid –> combo of urea, malonic acid
Barbiturate Chemical Structure
Barbituric acid does not have sedative or hypnotic properties on own
Side-chains added at position 5 in the pyrimidine nucleus impart hypnotic activity
Draw basic chemical structure of a barbiturate
XXX
Barbiturate Chemical Structure: side chain length
-length of the side chain at position 5 influences the potency, duration of action of these drugs –> longer side chains increase potency
Barbiturate Chemical Structure: if a sulfur atom replaces oxygen at position 2…
Faster onset of action, shorter duration of action
***Any modification of the barbiturate that increases the lipophilicity of the molecule will increase potency, shorten onset time/duration of action
Barbiturate Chemical Structure: Stereoisomers
- Many barbiturates (thiopental, thiamylal, methohexital) have asymmetric carbon atoms in one of the side chains attached to the barbiturate ring at position 5 –> creates stereoisomers
- Potency: L isomers > D isomers (2x)
- Supplied as racemic mixtures
How barbiturates classified
- Duration of action - long, intermediate, short, ultrashort
- Chemical structure
Thiobarbiturates
Thiopental
Thiamylal
Sulfur atom at position 2
Oxybarbiturates
Pentobarbital
Phenobarbital
Methohexital
Oxygen atom at position 2
Which barbiturates are commonly used for anesthesia?
Ultra-short acting thiobarbiturates (thiopental)
Thiopental
- Ultra-short acting, most commonly used
- Yellow crystalline powder buffered with water/saline to produce 2.5%, 5% or 10% solutions
- Solution = alkaline (pH 10-11)
- Tissue necrosis if perivascular injection
- Solution stable at room temp for 1 week –> as solution ages, crystals precipitate –> progressive loss of potency –> higher doses may be needed to produce GA
Thiamylal
- Ultrashort acting thiobarbiturate
- Vs thiopental: ethyl radical in thiopental replaced with an allyl radical
- Commonly used in vet med but no longer commercially available
Methohexital
- Ultrashort acting oxybarbiturate
- Methyl group at N-1 position
- 2x potent as thiopental with increased incidence of excitatory SE
- Methohexital sodium: supplied as a powder, reconstituted w sterile water or saline to produce 2.5% solution stable up to 6wks if refrigerated
Pentobarbital
- Short acting oxybarbiturate
- Identical to methohexital except lacks methyl group at N-1 position
- Extensive hepatic metabolism –> totally dependent on liver for biotransformation, elimination
- Duration of action: 4-8x longer than thiopental in most species
- Longer duration of action/lower therapeutic index –> replaced in most domestic species
Pentobarb and sheep/goats
Rapidly metabolize drug
Require supplemental doses if anesthesia maintained beyond 20-30min
Current uses of pentobarb
- Injectable anesthetic in lab rodents, esp for non-recovery procedures
- Primary ingredient in euthanasia solutions
Barbiturates: Analgesic Effects
- Do not produce antinociception
- Analgesia only during unconsciousness
- Additional analgesics should be administered to patients undergoing painful procedures
- At sub anesthetic doses, may be hyperalgesic –> effect controversial, not likely clinically significant
Barbiturates: Canine
- greyhounds relatively deficient in hepatic microsomal enzymes needed to metabolize thiobarbiturates
- deficiency + lean bodies + low fat stores = prolonged recoveries from thiopental anesthesia when larger doses administered
- Barbiturates not recommended for sight hound breeds
- Use of anesthetic-sparing premeds, minimal thiobarbiturate doses has allowed safe induction in these breeds with minimal delay in recovery
Barbiturates: fetal/neonatal effects
- IV barbiturates cross placenta –> establish dynamic equilibrium btw maternal and fetal circulation
- Key: placental circulation passes through the liver before reaching the fetal CNS –> reduces overall drug exposure for most highly metabolized drugs
- K9: thiopental more profoundly depressed neurological reflexes in puppies born by c section vs propofol, epidural anesthesia
- Ewes: uterine blood flow transiently decreased when thiopental used to induce preg ewes
Barbiturates: Resp System Effects
- Dose-dependent depression of ventilatory centers
- Decreased responsiveness to hypoxemia, hypercabia
- Decrease in RR, MV
- Transient periods of apnea commonly reported after large, rapidly administered doses
- K9: thiopental –> bronchoconstriction, reduce mucociliary clearance
- Laryngeal reflexes may be less affected with thiopental vs other induction agents - may be a good choice for evaluation of laryngeal function
Barbiturates: Hepatic effects
- Little change in hepatic fxn
- Only modest decreases in hepatic blood flow appreciated
- Stimulate increase in microsomal enzymes but only after 2-7d sustained drug administration
Barbiturates: renal effects
- Renal blood flow may be decreased slightly by thiopental admin DT decreases in systemic BP, CO
- K9: 15mgkg induction dose TP –> GFR 2.04 +/- 0.36mL/kg/min (does not differ significantly from other induction agents)
Barbiturates: GI effects
- Little change in GI fxn
- No reports of diarrhea, GI stasis
- TP: decreases LES tone in cats
Barbiturates: CV effects
- TP: decrease SV, myocardial contractility
- Mild decrease in arterial BP seen but often offset by compensatory increase in HR
- Venodilation after TP admin –> sequestration of RBCs in spleen, increase in splenic size, decrease in PCV
- VD cutaneous and skeletal BV may also predispose patient to hypothermia
- Ventricular arrhythmias ventricular bigeminy
- Incidence of arrhythmias may be reduced with adequate ventilation, oxygenation prior to TP administration
- TP sensitizes myocardium to epic-induced arrhythmias in most species studied
Barbiturates: CNS Effects
- CNS depression, anesthesia
- Electroencephalogram: depressed in dose-dependent fashion with TP –> alpha awake pattern progressing to gamma and ohm waves until burst suppression and flat EEG
Barbiturates: IOP
Reduced slightly by TP admin
Methohexital: CNS effects
Associated with CNS excitation, epileptiform sz
Poor choice for patients with sz
Barbiturates: Cerebroprotective effects
- cerebral metabolism of oxygen (CMRO2) reduced by up to 55% in a dose-dependent fashion
- Cerebral blood flow, ICP also decreased in parallel with reduction in CMRO2
- CPP not usually adversely affected bc ICP decreases more than the MAP
- k9: pretreated with TP, subjected to isolated brainstem ischemia auditory evoked potentials were increased compared to dogs not treated with TP
- Mitigating effect of immediate post arrest hypothermia in dog with posttischemic encephalopathy might be enhanced by TP
- TP = appropriate choice for patients with sz, intracranial dz
Dissociative anesthetics
- phencycline derivates
- Produce state of ‘dissociative anesthesia’ characterized by dissociation of the thalamocortical and limbic systems, which produces change in awareness
Which are the two dissociative anesthetics most commonly used in veterinary medicine?
- Ketamine
- Tiletamine
Chemical structure of ketamine
2-(o-chlorophenol)-2-methylamino-cyclohexanone hydrochloride
Isomers of ketamine
- 2 optical isomers exist DT asymmetric carbon
- most formulas contain racemic mixture –> purified S-ketamine formulation available in some countries
- Racemic ketamine available as a 10% aqueous solution
- pH 3.5-5.5, preserved by benzethonium chloride
Positive (S) isomer of ketamine vs negative (R) isomer of ketamine
Positive (S) isomer produces more intense analgesia, metabolized more rapidly, and has lower incidence of emergence reactions than negative (R) isomer
Chemical structure of tiletamine
2-(ethylamino)-2-(2-thienyl)-cyclohexanone hydrochloride
Tiletamine formulations
- Only available in combination with benzodiazepine, zolazepam –> Telazol, Zoletil
- Available as white powder, reconstituted with 5mL diluent
- Final concentrations depend on product being used
DA MOA
- Act on NMDA, opioid, monoaminergic, muscarinic R
- Also interact with VG Ca channels
- Do not appear to interact with GABA receptors as other injectable anesthetics do
DA action at NMDA R
- Non-competitive agonists at the NMDA R
- Bind to phenylcycline-binding site –> prevents glutamine, an excitatory NT, from binding
- Prevention of glutamate binding results in depression of thalamacortical, limbic, and reticular activating systems
DA Action at Opioid R
- mu, gamma, kappa
- Activity at opioid R imparts analgesic properties but clinical significance of action at clinically relevant doses debatable
DA Action Monoaminergic R
May also contribute to antinociception
DA Action at Muscarinic R
- Bc DA associated with anticholinergic symptoms (ie emergence delirium, bronchodilator, sympathomimetic actions), thought that these drugs have antagonist activity at muscarinic receptors
- Many of these effects may also be related to SNS-stimulating effects of DAs
Etomidate
- Synthesized in 1964, introduced to human med in 1972
- Appreciated for minimum CV effects, cerebroprotective effects
Chemical Structure of Etomidate
-Imidazole derivative
R-(+)-pentylethyl-1H-imidazole-5-carboxysulfate
-Exists in two isomers –> (+) isomer produces hypnosis
Etomidate Chemical Properties
Unstable in neutral solutions
Insoluble in water
Etomidate Available Formulations
0.2% solution in 35% propylene glycol with pH 6.9
Commercially available preparations have high osmolality –> may result in some of its adverse effects, including potential for erythrocyte damage
Etomidate MOA
- Agonist activity at the GABA R
- Enhances action of NT GABA to increase chloride conductance into the cell, resulting in hyper polarization of the postsynaptic neuron –> CNS depression, hypnosis
Etomidate Analgesic Effects
- Does not produce antinociception
- P requires additional analgesics
Etomidate Metabolism
- Hydrolysis of its ethyl ester side-chain by hepatic enzymes, plasma esterase’s
- Forms water-soluble, pharmacologically inactive metabolite that excreted in bile, urine, feces
How much etomidate is excreted in the urine?
<3%
Hydrolysis of the drug is nearly complete
Etomidate Pharmacokinetics
- Described in cats, people
- Open three compartment model
- Redistributed rapidly in the cat (0.05h)
What is the elimination half-life of etomidate in the cat?
2.89h
What is the volume of distribution of etomidate in the cat at steady state?
LARGE
4.88 +/- 2.25L/kg
What is the total clearance of etomidate in the cat?
2.47 +/- 0.78L/kg/h
Other pharmacokinetic features of etomidate
- Penetrates brain quickly –> rapid induction of anesthesia
- Recovery from single injection also rapid DT redistribution of the drug from brain to inactive tissue sites
Is etomidate protein bound or not?
YES! approx 75% bound to albumin so if hypoalbuminemic, have increases in pharmacologically active drug
Therapeutic index of etomidate
LD50/ED50 = 26.0 (rats)
Etomidate Respiratory System Effects
- Minimal effects on the resp system
- Postinduction apnea reported after rapid IV administration
- In most P, any reduction in VT seen after etomidate administration usually offset by increase in RR
Etomidate Hepatic System
Hepatic function tests not affected by etomidate administration
Etomidate Renal System
- Does not decrease renal blood flow, GFR
- Renal function tests not affected by etomidate administration
Etomidate Muscle Effects
- Myoclonus, dystonia, tremor
- MOA: disinhibition of subcortical structures that normally suppress extrapyramidal motor activity
How decrease myoclonal activity see with etomidate
-Adequate premedication +/- coinduction with a benzo immediately prior to etomidate administration
Etomidate pain on injection
- IV admin frequently results in pain
- DT propylene glycol vehicle or hyperosmolar nature of the commercial product
How reduce incidence of pain on injection of etomidate
- Large vein
- Running IV line
- IV admin of opioid immediately prior to etomidate administration
Etomidate Endocrine System
- Adrenocortical suppression*
- Dose-dependent inhibition of conversion of cholesterol to cortisol
- Suppression occurs for at least 6h in K9, 5h in FL
- Infusions for long durations not recommended
- Proposed mechanism for increased mortality in human patients in some studies following etomidate anesthesia
What patient populations are not the best candidates for etomidate?
- Pre-exisiting adrenocortical disease (Addison’s)
- Highly stressed patients
- Used as a CRI to maintain anesthesia
