Injectable Anesthetics Flashcards
GABA Binding Site on GABA A R
btw a1, b2 subunits
Benzodiazepines binding site on GABA A R
btw a1, g2
Ethanol, inhalants binding site on GABAA
on a subunit
Neurosteroids, propofol binding site on GABA A
Beta subunit
Barbiturates binding site on GABA A
Beta subunit, separate from neurosteroids or propofol
GABA A R - conservation among species?
Where agents work is conserved among species
Ideal Injectable Anesthetic Agent
water soluble, long shelf-life, stable when exposed to heat and light, potent, large safety margin, short duration, no cumulative effects, readily metabolized or excreted, adequate analgesia and muscle relaxation, minimal CV/R side effects
Basic Structure of Barbiturates
Derivatives of barbituric acid with urea + malonic acid
Barbiturate acid alone has no sedative, hypnotic properties
o Modification of carbon 5 in pyrimidine nucleus gives hypnotic properties
R1, R2 side chains create properties of barbiturates
Longer side chain: increasess potency, affects DOA
Due to R1/R2 side chain asymmetry at carbon 5, become racemic mixture in solution
L-isomers 2x potent D-isomers
All drugs made by modifications of these R1/R2 side chains
Thiopental from Oxybarbiturate
o Replace Carbon 2 oxygen with sulfur thiobarbiturate (thiopental) from oxybarbiturate
increased lipophilicity = increased potency with faster onset, short DOA
Thiobarbiturate
sulfur atom at position 2; thiopental and thiamylal
Oxybarbiturate
oxygen at position 2; pentobarb, phenobarb, methohexital
MOA Barbiturates - lower doses
enhance GABAA
decreases rate of GABA dissociation, increases duration Cl channel open
increases Cl conductance –> hyperpolarization of postsynaptic neuron –> CNS depression, unconsciousness
MOA Barbiturates - higher doses
direct activation of channel, mimics GABA
o Inhibits synaptic actions of excitatory glutamate, neuronal (central) nAChR
Role of effect unknown
Ultra-Short Acting Barbiturates
Used for induction: thiopental, thiamylal, methohexital
Methohexital
-Shown to cause sz DT substitution at R group
-methyl group at N-1 position, 2x potency vs thiopental
Powder, 2.5% solution stable in fridge for 6 weeks
Thiamylal
ethyl radical in thiopental replaced by allyl radical, no longer available
Short Acting
Pentobarbital
Pentobarbital
o Pentobarbital (oxybarbiturate) – identical to methohexital but lacks methyl group at N1
Extensive hepatic metabolism = totally dependent on the liver
Duration 4-8x longer than thiopental (except in sheep, goats – only lasts 20-30min)
Low therapeutic index
Most common euthanasia solution
Thiopental
o Highly lipid soluble, high protein binding <65% - binds to albumin
–Highly protein bound – decreased protein binding (other drugs – aspirin, bute) or hypoproteinemia – leads to increased drug effects
o 20-30s induction time, DOA 10-15’
Thiopental: redistribution
= principle limiting factor for ax duration following single dose
Bc so lipophilic, rapid cerebral equilibration –> induction of ax –> rapid re-distribution less perfused areas (skeletal m), ultimately fat
In general: lipid solubility increases with substitution of sulfur at C2 in barbiturate ring
Formulation of Thiopental
powder, reconstitute prior to admin
Not stable in solution
pH 10-11: painful on inj
pKa 7.4: 50% ionized at physiologic pH
* Patient becomes more acidemic, greater non-ionized fraction –> non-ionized form crosses cell membrane –> more potent, increased effectiveness as can better cross lipid cell layer
* Not best induction agent for sick patient
* Alkalemia: ionized form favored, ax effect decreased
PK Effects - Thiopental
Vol of distribution ~40mL/kg in sheep (45), dogs, and rabbits (38-90)
Elimination HL REALLY short in rabbits 43’) vs dogs (3h, 182’), sheep (>4hrs, 252’)
Thiopental Metabolism
hepatic microsomes/ER of hepatocytes, CYP450 inducer
Prolonged effect if problems with CYP450 system
Significant hepatic dysfunction must be present before prolongation of duration
Thiopental Elimination
Renal
Thiopental: CNS Effects
- EEG pattern – depressed - α pattern progresses to δ and θ waves – then burst suppression and flat EEG
-Sdation, hypnosis, ax - dose dependent - Decreased CBF, ICP - decrease in parallel - CPP not adversely affected bc ICP decrease is greater than MAP
-55% decrease in CMRO2, dose dependent
Barbiturate Neuroprotective Effects
Methohexital assoc with CNS excitation, epileptiform sz – do not use in sz patients
Ophtho Effects - barbiturates
Slightly decrease in IOP
CV effects - barbiturates
- decreases SV, contractility, BP (vasodilation), PCV (splenic sequestration)
- increase HR, splenic size
- Predisposition to hypothermia from venodilation
-
Bigeminy (one regular complex, one abN)
o Sensitizes heart to catecholamine-induced arrhythmias
o Arrhythmogenic – classically = bigeminy
o Can decrease incidence with preoxygenation, ventilation - Transient: rapid redistribution
Respiratory effects - barbiturates
- Depression, +/- apnea – usually larger dose as a bolus
- decreases RR, MV, response to arterial hypoxemia/central response to hypercapnia
- Dogs: bronchoconstriction, decreased mucociliary clearance
- Maintains laryngeal motion
Hepatic, renal, GI - barbiturates
- Little to no change in healthy patients, only modest decreases HBF
- increased microsomal enzymes only after 2-7d sustained drug admin
- TP: decreased LES tone in cats
- Slightly decreased RBF, likely DT systemic decrease BP/CO
Placental effects - barbiturates
severe depression of puppies, don’t have great fat supplies for redistribution or metabolism
o decreased uterine blood flow
o Placental circulation passes through liver before reaching CNS, decreased overall exposure for most metabolized drugs
Analgesic effects barbiturates
- No analgesia
o At subanesthetic dose, can actually be hyperalgesic
Perivascular effect following barbiturate injury
barbiturate slough,” vascular tissue damage,
Very alkali, pH ~10
Aspirate back as much as possible, inject lidocaine locally - flush
Glucose effect of barbiturates
Return to anesthetized state after recovery given glucose effect of hepatic microsomal function
o Go back to sleep after bolus of dextrose, plasma concentration of barbiturates s
o Barbiturates selectively inhibit glucose transport by some facilitative glucose transporter isoforms in mammalian cells and across BBB
Glucose administration to animals recovering from barbiturate ax
can result in re-anaesthetization
Glucose slows hepatic enzymes
Fructose, lactate, pyruvate, glutamate
Can also see with epi, adrenergic agents
Species susceptibility to the barbiturate glucose effect
o Dogs, cats: intermediate
o Goldfish: refractory
o Specific lab animals, exotics VERY sensitive
Greyhounds and Barbiturates
decreased hepatic microsomal enzymes: prolonged recovery, cytochrome P450 2B11
* Also affects metabolism of propofol, alfaxalone
* Unknown whether missing or mutant allele – both have been found
decreased body fat: decreased redistribution, prolonged recovery
In general, barbiturates not recommended for sight hounds
Barbiturates in horses
3 compartment open model
HL 1-2min, clearance in horses and ponies ~3.5mL/kg/min
EL HL in horses 147+/-20 vs ponies 222+/-44min
Requires significant sedation first
Do not give guaifenesin/thiopental to horse that has just maximally exercised
Barbiturates and ruminants
three compartment open model, short duration DT elimination by hepatic metabolism and uptake into fat
HL sheep 196+/-64min, VD 1000+/-200mL/kg, clearance 3.5mL/kg/min, time of awakening ~30-40’
Barbiturates in Swine
Limited by IV access; dose requirement by 35% when hypovolemic, does not trigger MH
Use of Barbiturates
o Reduce doses with other CNS depressants, hypovolemia, hypoproteinemia, acidemia, uremia
o Rapid induction of ax, 20-30s , DOA 15’ in dogs
o Coadmin with lidocaine can reduce incidence of ventricular arrhythmias (may cause toxicity)
Propofol + Barbiturates
o No improvement 1:1 with propofol for induction, recovery times/quality superior than TP alone
Mixtures <1:1 do not maintain bactericidal properties against Pseudomonas, Staph aureus, E coli, Candida albicans
Propofol
- More rapid awakening than with other agents, 1977
- Structure
o Substituted isopropylphenol (2,6-diisopropylphenol)
Propofol MOA
o Enhances GABAA R
Binds to beta subunit
decreased GABA dissociation, prolonged channel opening –> hyperpolarization of postsynaptic cell
o Inhibition of NMDA R: decreased excitation from NMDA, not main effect
Potential role in myoclonus SE
PK of Propofol
–Rapid CNS uptake
—97-98% bound to albumin, also erythrocyte membrane
–Redistribution to other tissues – terminates effect
–Hepatic metabolism: glucuronidation, ring hydroxylation to water soluble partially active metabolite that further degraded to inactive metabolites via CYP2B11
Extrahepatic metabolism or extrarenal excretion may occur
Plasma clearance exceeds hepatic BF, supports extrahepatic metabolism +/- extrarenal clearance
Propofol Metabolism in Cats
extrahepatic metabolism demonstrated in pulmonary tissue; hepatic lipidosis doesn’t increase morbidity or mortality
* Don’t do hepatic glucuronidation well, rely on pulmonary
Propofol PK - dogs
o Dogs: Vd 17.9L/kg, Vdss 9.7mL/kg
o Greyhounds – smaller volume of distribution – suggesting recovery will be slower
o Dogs >8.5yo = slower clearance rate vs younger dogs
o No accumulation in most species
Propofol Metabolism
Hepatic: glucuronidation, ring hydroxylation to water soluble partially active metabolite that further degraded to inactive metabolites via CYP2B11
Excretion of propofol
renal, inactive metabolisms +/- exhaled
o Humans: metabolized in lungs, breathed off
Same recovery time in hepatic cirrhosis patients or liver transplant patients vs normal patients
o Vet med: unknown if similar to humans, or metabolites stored and slowly exhaled
Propofol Effects - CNS
Sedation, hypnosis, ax
decreased ICP, CMRO2
Maintains central responses to CO2, CBF autoregulation
* Better in patients that have pathology with intracranial pressure, s to BF
Anti-convulsant
CV Effects - Propofol
–Markedly dose-dependent
–Vasodilation/ decreased ABP, SVR and CO
–decreased Inotropy – Ca mobilization/usage, favoring PNS
–No compensatory HR increase/impaired baroreceptor response
–Sensitizes myocardium to epi-induced arrhythmias
* Not arrhythmogenic on own
–Worse in hypovolemic, elderly, LV dysfunction (DCM) – not able to tolerate decreased CO
Why see vasodilation with propofol?
- Decreased SNS activity (decreased PNS as well, but more decrease in sympathetic)
- Increased Ca influx – cardiac, vascular
- Altered Ca mobilization intracellularly – reduces usage
- Inhibition of prostacyclin synthesis
o Potent VC - NO stimulation, may be carrier
- Activates K-ATP channels
Respiratory effects propofol
Depression, apnea: dose, administration rate dependent
Transient cyanosis regularly, esp with rapid injection
decreased VT/RR (CRI), effects likely to worsen over time
Blunted ventilatory response to hypercarbia, hypoxemia
GI Effects Propofol
Humans –> anti emetic properties
Not demonstrated in vet med
Hepatic/renal effects - propofol
no change in HBF, GFR in face of VD
Also have extra hepatic metabolism
MSK effects - propofol
relaxation, myoclonus, dystonia
Can give ketamine 0.5-1mg/kg IV
Give enough time to go away, 1-2min after induction – front limbs > hind limbs
Neonatal/Fetal Effects - Propofol
crosses placenta, readily cleared - acceptable for c section
Analgesia effects propofol?
None
Propofol - extravascular effects?
none, not assoc with tissue necrosis
Propofol Infusion Syndrome
o Described in people, rare in animals (1 case report)
Unknown if propofol itself or propofol metabolism
Assoc with high dose, long duration of propofol CRI
Propofol Infusion Syndrome MOA
o Mitochondrial electron transport chain
Failure of ATP production, metabolic acidosis, cell death
Can’t produce anything including normal Krebs cycle ATP
Hyperkalemia
o Myocardial failure, bradycardia, asystole, other arrhythmias, death
Propofol in Cats
–Heinz body anemia
Repeat daily dosing: Bandage changes, radiation therapy
–MOA: Oxidative injury to RBCs
–CS: Facial edema, malaise, anorexia, diarrhea potentially by third day, Recovery times increased after second day
What do cats develop with frequent/daily propofol administration and why?
Heinz body anemia
o More oxidizable sulfhydryl groups on RBC membrane Heinz body formation
Other species clear normally in spleen, liver
Cats don’t utilize glucuronidation pathway well
o Often depends on cat, how affected by it
Propoflow 28 in cats
concern of benzyl alcohol, use for normal dosing
Avoid as CRI
Unclear how well metabolize preservative
Horses and Propofol
Rapid, smooth induction but potential for unpredictable excitement
o Excitement can be prevented if admin GG 3min prior
o Short duration
o Smooth recovery, esp if xyla+prop
Good sedative following desflurane for recovery
o Will see myoclonic activity
o CRI: unpredictable, poor analgesia but works as sole agent or with other ax
Ruminants and Propofol
rapid, smooth
o Apnea effect during induction/intubation
o Goats: short elimination half life 15mi, large volume of distribution (2.56L/kg), rapid clearance rate (275mL/kg/min)
o Sheep: longer elim HL 26min, decreased VD 1+/-0.5L/kg, decreased clearance 85+/-28mL/kg/min
Propofol in Swine
rapid, smooth; does not induce MH
o Apnea effect during induction/intubation
Propofol Formulations
- Emulsions
- Propoflo 28
- Lipid-free microemulsion
- Fospropofol
Propofol Emulsion
1% propofol, 10% soybean oil, 2.25% glycerol, 1.2% egg lecithin
Discard vials in 6hr, CRI tubing/syringes in 12hr
Slightly viscous, white substance
pH 6.5-8.5
Stable at room temp, not light sensitive
Highly lipid soluble
Will support bacterial growth – strict aseptic technique needs to be used with multidose vials
Not controlled, inexpensive
Propofol Lipid Emulsion and bacterial growth
Will support bacterial growth – strict aseptic technique needs to be used with multidose vials
* Cats, dogs receiving propofol 3.8x more likely to receive wound infections vs animals that did not receive propofol
Propofol 28
preservative: benzyl alcohol
Dogs
Propofol Lipid-Free Microemulsion
Increases shelf life, decreases pain on injection
Antimicrobial agents, decreased emulsion instability
PK, PD similar to lipid formulation in dogs, cats
Reportedly caused severe pain, complications in dogs
Horses: 3h CRI = similar CP, biochemical results
Fospropofol
prodrug being investigated,
Water soluble, less painful on injection
Onset time significantly longer
Alfaxalone
Structure: neurosteroid
MOA:
o GABAA R (beta subunit)
o Low doses: increases Cl conductance, hyperpolarization
o High doses: GABA agonist
Propofol Pro Tips
o Admin over 60-90s to decrease apnea
o 20-30s to see ax effect once administered
o Duration of unconsciousness 2-8’
o To minimize pain on injection, large vein/catheter, lidocaine prior, dilute in line
Alfax Formulations
- cremophor EL (20% castor oil)
- Alfaxan
- Alfax Multidose (28d)
cremophor EL (20% castor oil)
Poorly water soluble
Combined with alphadolone, formulated in 20%polyexyethylated castor oil vehicle
Saffan in vet med
Hyperemia in cats
Histamine release, anaphylaxis in dogs
Alfaxan
cyclodextrin carrier, 2-hydroxypropyl-beta-cyclodextrin
3-α-hydroxy-5-α-pregnane-11,20-dione) – neuroactive steroid capable of inducing anesthesia; 1% solution in 2-hydroxypropyl-β-cyclodextrin
Makes steroid water-soluble so can admin variety of routes
2012 - expensive, controlled
6hr once opened
Alfax Multidose (28d)
= chlorocresol, benzethonium chloride, ethanol
2018
Not advised for CRI in cats bc unclear how well can metabolize preservatives
Alfax PK dogs
Vd following 2mg/kg = 2.4L/kg, terminal plasma elimination HL (t1/2 ) at same dose 25’, clearance 60+/-13mL/kg
Alfax PK Cats
VD following 5mg/kg = 1.8L/kg, t1/2 45’, plasma clearance 25+/-8mL/kg/min
Alfax PK Horses
following 1mgkg Vd 1.6+/-0.4L/kg, t1/2 33.4min, plasma clearance 37+/-11mL/kg/min
Foals: t1/2 23+/-5’, clearance 20+/-6mLkgmin, Vd 0.6+/-0.2L/kg
Alfaxalone onset, DOA
- Rapid onset, short DOA
o Terminal half life 25 min in dogs (45 min in cats)
o Greyhounds similar to beagles
Alfaxalone - metabolism
Hepatic
o Phase I: cytochrome P450 –> 5 metabolites, conserved across species
o Phase II: conjugation-dependent
Cats: alfaxalone sulfate, glucuronide
Dogs: alfaxalone glucuronide
Elimination of Alfax
renal, biliary, fecal
Alfax metabolites - cats
axalone sulfate, glucuronide
Alfax metabolites - dogs
Alfax glucuronide
Ophthalmic effects - alfax
Increase IOP
CNS Effects - alfax
Unconsciousness, ax
Decrease CBF, ICP, CMRO2
Shift in dominant frequency band to δ from β
Resp Effects - Alfax
Heavily dose-depression apnea, depression
Decreased RR, MV, PaO2
Increased PaCO2
Less present to absent at clinically used doses
CV Effects - Alfaxalone
Very heavily dose dependent decreased BP, CO, HR (Increased HR in cats)
* Studied up to 50mg/kg in cats, transient
decreased BP, increased HR in dogs
* Transient
Parameters stable at clinical doses +/- increase HR
* <6mg/kg dogs
Hepatic, Renal, GI Effects Alfax
No controlled studies, cytochrome p450 metabolism
o Other
What molecule is alfax derived from?
Progesterone
Other Alfax Effects
No demonstrated sex-specific metabolism even though derived from progesterone, unlike many other steroid compounds
No Heinz body anemia assoc
C sections: improved Apgar scores, overall survivability better at 24hr, 30d
Alfax Recovery
o Paddling, myoclonus, trembling
o Generally regarded as smooth
o Horses, donkeys: smooth to absolutely horrific recoveries
Alpacas also reported to have rough recoveries
Alfax in Dogs
Can be dosed as CRI, OK to use in young dogs (under 12 weeks were tested)
o No pain on injection, recovery longer than propofol with more adverse events (dysphoria)
o Greyhounds: deficient in hepatic microsomal enzymes (cytochrome P450 2B11) needed to metabolize
Alfax in Cats
o CRI doses increased vs dogs, 0.18mgkgmin
o Safe for cats <12wks
o More likely to have trembling, paddling during recovery vs propofol
Alfax in Horses
Recovery scores significantly worse with alfaxalone
o Suitable for field ax at 2mg/kg/hr + medetomidine 5mcg/kg/hr
Ruminants and Alfax
Mitosis in ruminants, no effect on IOP
Swine and Alfax
recumbency, deep sedation, minimal SE
o Volume of injectate limit use to small pigs
Alfax Clinical Practice Tips
o Volume limits its use to small patients
o When recovering – leave animal in dark area without handling except for monitoring
o Paddling, twitching, hyperreactivity, and ataxia have been reported
o Can use in exotics and other species
Responses of sedation, ax tend to be conserved across species
o Repeat dosing not assoc with accumulation in cats
o IM sedation useful, but challenging with volumes
Etomidate Structure
o Imidazole derivative: R-(+)-pentylethyl-1H-imidazole-5 carboxylate sulfate
o R(+) isomer = 5x potency of S(-), R(+) produces hypnosis
o Unstable in neutral solution, insoluble in water
Etomidate Formulation
0.2% solution in 35% propylene glycol, pH 6.9, hyperosmolar
Pain on injection DT propylene glycol
* Use large vein, run into line
Damage to RBCs, intravascular hemolysis DT high osmolality
* 4640mOsm/L vs plasma 300mOsm/L
Etomidate MOA
o Agonist at GABAA R, hypnosis
Low dose: enhances GABA affinity
High dose: direct activation
PK Etomidate
open three compartment model in cats, people
o Fast onset, short DOA DT redistribution (cats = 30min)
EL HL 2.9h
VDss 4.9+/-2.25L/kg
Clearance 2.5 +/-0.8L/kg/hr
o 75% protein bound to albumin, greater active fraction with hypoproteinemia
o Therapeutic index in rats very large vs thiopental, 26
Metabolism of Etomidate
Hydrolysis of ethyl ester side chain by hepatic and plasma esterases – nearly complete
o <3% excreted unchanged in urine
Etomidate Excretion
- Water soluble inactive metabolite that is excreted in urine, bile, and feces
Etomidate CNS Effects
decreased CMRO2, ICP, CBF (vasoconstriction)
Maintains CPP
* CPP maintained because no loss in MAP (previously elevated ICP is reduced ) – may preserve cerebral metabolic state
* No change in cerebral oxygen extraction fraction in dogs with cerebral hypoperfusion
Caution with seizure history – human study, EEG changes, associated with grand mal seizures
CV Effects Etomidate
Cardiac stability: no changes in HR, SV, CO, or MAP , CVP or CI; baroreceptor function and SNS responses appear intact
May increase LV afterload (DCM patients)
* Other agents/inhalant may negate effect
Resp Effects Etomidate
Postinduction apnea possible – high dose admin quickly
decreases VT, increases RR (offsets self)
Analgesic effects etomidate?
None
Hepatic, GI effects etomidate
no Changes
Retching, regurgitation, hypersalivation
Humans: nausea, vomiting
Adrenocortical suppression
Etomidate
Dose dependent inhibition of the conversion of cholesterol to cortisol
Cortisol synthesis inhibited up to 6h in dogs by blockage of 11-beta-hydroxylase
Mechanism for increased mortality in humans following anesthesia
Could be problematic in Addisonian or sick/septic patient
Not for CRI use
Other Etomidate Effects
Myoclonus, trembling: extrapyramidal signs
–Disinhibition of subcortical structures that normally suppress extrapyramidal motor activity
–Can be offset by benzo
Maintains laryngeal reflex
Crosses placenta rapidly: metabolized as fast or faster as dam (sheep)
Cats and Etomidate
Decreased spontaneous firing of cortical neurons as well as thalamus and reticular neurons
o Excessive salivation noted, fragility of feline RBC
Dogs and Etomidate
vomiting, myoclonus, excitement, hemolysis – still choice for CV instability, increased ICP, cirrhosis
Horses and etomidate
Not used clinically
Sheep and Etomidate
crosses placenta but doesn’t cause fetal depression (metabolized quickly by the dam), 1mg/kg bolus did not depress CV fxn of ewe or fetus
Pigs and Etomidate
No MH triggering
Clinical Use Tips for Etomidate
o Dose is affected by ASA status
o Induction within ~30s IV admin
o CV or neuro cases (not seizures)
o Pain injection can be mitigated by an opioid
o Awakening from single dose of etomidate more rapid than after barbiturate admin
o Myoclonus can be mitigated by a benzo
o Maintenance of anesthesia not recommended – adrenocortical suppression, RBC damage
No accumulation
Ketamine
Dissociative anesthesia: dissociation of limbic and thalamocortical systems
Two optical isomers exist, positive S+ isomer produces more intense analgesia, metabolized more rapidly, and has lower incidence of emergence reactions than R- isomer
Ketamine Formulation
o Preserved with benzethonium chloride, racemic mixture
o 10% aqueous solution
o pH 3.5-5.5
o Purified S-ketamine available in some countries
Ketamine Structure
o Phencyclidine (PCP) derivative
o Racemic mixture: R(-), S(+) isomers
S isomer = 3-4x more potent, increased analgesia/metabolism
R isomer = more emergence delirium
MOA Ketamine
NMDA antagonist, non-competitive
o PCP binding sites
o Normally excitatory; antagonism = inhibitory
o Other receptor targets = opioid, monoaminergic, VG Ca channels, muscarinic, VG Na channels (H site)
o Some action at μ, δ, κ - clinical relevance to analgesia at relevant doses debatable
o Serotonergic receptors may contribute to analgesia
o Anticholinergic receptors may contribute to dissociative effects (emergency delirium, bronchodilation, sympathomimetic), may also be stimulation of SNS
Lipid solubility, protein binding ketamine
- Highly lipid soluble, 50-60% protein bound
o Fast onset, short DOA
o Easily crosses BBB - Peak plasma concentrations occur within 1min IV, 10min following IM
Ketamine Metabolism
o Demethylation by microsomal enzymes to norketamine (active metabolite)
All species
o Norketamine hydroxylated, conjugated to water-solub inactive metabolites for renal excretion
Exception: cats, directly excrete norketamine – why problematic in UO cats, stay asleep
o Care in animals with significant hepatic and renal dysfunction
CNS Effects - ketamine
Resembles cataleptic state
* Appears away but not responsive to stimuli
Increases CBF, CMRO2, ICP
* Can attenuate increased ICP with eucapnia, benzos or thiopental
Ketamine and Seizures
- Epileptiform EEG but no post ictal period
- Safer to avoid in sz patients
- Does not increase threshold
- Anti-convulsant, neuroprotective
Recovery with Ketamine
smooth to violent
* Dogs, pigs: recovery can be erratic, twitching, dysphoric
Emergence delirium, potentially caused by misrepresented auditory and visual stimuli
CV Effects: ketamine
Direct negative inotrope, usually overcome by SNS stim
SNS outflow increased: increased HR, NE uptake postsynaptically inhibited
increased SVR, Pulmonary VR, HR, CO, myocardial O2 consumption
Resp Effects Ketamine
No significant depression when solo
Bronchodilation, decreased airway resistance – attractive for asthma, obstructive airway dz
Normal ventilatory response to decreased PaO2, increased PaCO2
Apneustic breathing: prolonged inspiration, inspiratory hold, short expiration (MCQ)
increased airway secretions, salivation
Maintain laryngeal, pharyngeal reflexes –> uncoordinated, not protective of airway
What is the breathing pattern most commonly assoc with ketamine?
Apneustic breathing: prolonged inspiration, inspiratory hold, short expiration
Analgesia effects of Ketamine
Occurs at subanesthetic doses DT NMDA R: somatic pain, less clear opioid component
Helps prevent central sensitization
MSK Effects Ketamine
Rigidity +/- spontaneous movement
Increased IOP, increased tone extraocular m
Hepatic, renal, GI effects - etomidate
no effects
Etomidate Fetal/Neonate Effects
Crosses placenta
Profound neonatal depression when dam induced with ket+midaz vs other injectables
Cats and Ketamine
can spray orally, won’t like bc pH 3-3.5 – will salivate
o Can combine ket + xyla + T/Z
Cats and Ketamine
can spray orally, won’t like bc pH 3-3.5 – will salivate
o Can combine ket + xyla + T/Z
Bears and ketamine
sudden arousal (with a2), DO NOT USE
Ruminants, camelids and ketamine
ketamine stun, different doses/cocktails to achieve different levels of out
Equine and ketamine
extensive use, sedate appropriately beforehand
o Induction, bolus top ups, maintenance, CRI
Clinical Use Tips - ketamine
o Onset within 10 min of IM
o Duration longer with IM due to higher dose usually given
o Don’t reverse the sedative/tranq before the ketamine has worn off – emergence delirium
o IV admin = ax induction within 45-90s
o Duration of single induction dose ket-diaz, tiletamine-zolaz = 20’
o Ocular, laryngeal, and pharyngeal reflexes may remain intact even if patient is anesthetized
Telazol
- Tiletamine (dissociative) + Zolazepam (benzo)
o More potent, long duration vs ketamine
o 2-(ethylamino)-2-(2-thienyl)-cyclohexanone hydrochloride
Telazol Metabolism
o Cats, ruminants: zolazepam longer = better, slow
o Dogs: tiletamine longer, poor recoveries, rigid
o Swine: smooth
Telazol formulations
o Reconstitution variability
o pH 2-3.5
Telazol and CV Effects
- Does not sensitize to epinephrine-induced arrhythmias
Telazol in horses
incoordination
o Can be used for induction after appropriate sedation
NZWR and Telazol
tiletamine = nephrotoxin, other lagomorphs appear okay
Tigers (big cats) and Telazol
o Past neurological events, opinion vs evidence
o Delayed recovery, hind limb paresis, hyper-reflexia, seizures, death
o New studies say its ok; old cats it’s the same morbidity as other cocktails
Metomidate
o First compound of imidazole class designed as non-barbiturate hypnotic
o Freely soluble in water, aqueous solutions unstable and need to be used within 24hr
o Short duration of action <25min, but prolonged recovery
o CV stability - decreased HR, slight decreased CO
o Stable minute ventilation
o Profound m relaxation, no analgesia
o Violent recovery in horses
Magnesium Sulfate
muscle relaxant
o Combined with chloral hydrate – reduces toxicity
o Global CNS depression, resp arrest occurs frequently
o Can be used as euthanasia solution if unconscious
o + chloral hydrate = hastens onset of ax, increases depth, decreases toxicity assoc with CH
2 parts CH: 1 part MS
Chloral Hydrate
o 1,1,1 – trichloro-2,2-dihydroxyethane
o Unknown MOA
o Narrow safety margin
Dose required to produce ax ~ minimal lethal dose
o Slow onset, requires metabolism to active metabolite = trichloroethanol
o 1869 – distinct odor, volatizes slowly at room temperature
o Likely trichloroethanol interacts with GABAA receptor
Effects of chloral hydrate
o Dose-dependent sedation, CV depression
Lag time in sedation DT formulation of active metabolite
Difficult to assess degree sedation, depression
o Irritating to stomach, mucous membranes – perivascular injection results in sloughing
o Can have severe resp depression
o Vfib, sudden death reported in recovery
Chloralose
o Laboratory animals, non-survival
o Heating glucose and chloral hydrate
o Effects 8-10hr
o Elevated BP, HR, RR
o Slow and marked paddling during recovery – little indication for its use in vet med
Urethane
Lab animals, concern for carcinogenesis
PIVA
maintenance of GA via combination of inhal, inj agents
o Adequate ax conditions with minimal CV depression as long as required
o decreases neg SE of inhal
o Balanced ax – multimodal to decrease dose of each
TIVA
- Total intravenous anesthesia (TIVA): maintenance of GA through inj only
o Field ax
o Total injectable anesthesia slightly difference – IM
o Ensure people safety
PK of TIVA/PIVA
o Single IV bolus: higher incidence of AE
o CRI: if don’t do initial IV bolus, will take 4-5 HL to reach steady state
o Why usually combine loading dose + CRI
o Intermittent bolus: rapid up/down, can go into sub-therapeutic range
Benefits of TIVA/PIVA
Limit inhalant to minimize use of VPs, anticholinergics ( risk of arrhythmias)
Better maintenance of cerebral perfusion pressure/cerebral autoregulation
Lar par
Debilitated patients: septic abdomen, hemoabdomen, CV compromise
TIVA/PIVA reptiles
don’t have to hyperventilate to maintain ax, only breath 1x Q5min, minimize shunting
Context Sensitive half time
time taken for blood plasma concentrations of a drug to decrease by one half after infusion that was maintaining a steady state is stopped
Prolonged infusion of drug, how does that alter the half life of the drug?
* Thiopental: do not use as CRI, HL = 50’ after bolus, doubles after 1hr
* Fentanyl: dramatically increased context-sensitive HL ~2-3hr mark
Avoid: Diazepam, thiopental, prolonged fentanyl (>2-3hr)
Goals/Advantages of TIVA/PIVA
o Less CV depression: increased MAP, increased CO, better perfusion
o Avoid catastrophic complications: AKI, GI hypoperfusion/sloughing, death
Drawbacks of TIVA/PIVA
o CRIs require IV, IO access
Pinnapeds (seals, sea lion): very deep jugular v bc dive deep into cold water, do not want significant heat loss
Can be challenging to get IV in reptiles, likely need IO
May need multiple IV access points
o Syringe pumps, multiple bags – equipment heavy
Can calculate drip rate with bags!
o Watch volume of IV fluid admin, compatibility of drugs
Metoclopramide, blood products do not play well with others
MAC reduction of lidocaine CRI in horses, dogs, rabbits, reptiles
~30%
Monitoring with TIVA
o No spontaneous movement, no nystagmus, will preserve palpebral
Eye position depends on drugs used
If too light with TIVA…
o Too light: quickened palpebral, increased rapid eye movement (nystagmus), increasedd lacrimation,
increased RR/VT, increased muscle tension (necks of horses), movement
Quick eyes = quick feet
If too deep with TIVA…
absent palpebral, central globe, increased RR/decreased VT (shallow breaths), Cheyne-Stokes breathing
Specific form of periodic breathing
Waxing, waning amplitude of flow/VT – deeper breathing, shallower breathing, apnea, reverse
Characterized by crescendo-decrescendo pattern of resp btw central apnea
When use TIVA/PIVA?
o Airway wash +/- need to repeatedly extubate patient during procedure
o Thoracotomies: minimize/ exposure of WAG
o Persistent hypotension despite appropriate fluid therapy, inotropic support
o Persistent hypoxemia
Pyothorax, severe pulmonary dz
Hypoxic pulmonary VC: well oxygenated alveolus, capillary bed open but if not getting oxygen, alteration in VG-K channels in alveolar smooth muscle + ca channels vasoconstriction to shift blood AWAY from poorly oxygenated alveoli
Humans: HPV blunted by volatile anesthetics
Not evaluated in veterinary patients
o Maintain CPP
Inhalants: CPP graph is linear, lose area of autoregulation btw 60-150mmHg
o Avoid hyperventilation
Reptiles
Donkeys
: higher dose of a2 for premed, maintenance
Cattle
much more sensitive, use 1/10th xylazine dose, lower concentration xylazine
Sheep
pulmonary edema DT activation of PIMS (pulmonary interalveolar macrophages – hypoxemia
Happens whether clinically hypoxemic or not, do not use
GKX
GG = 5% solution, >5% solun GG: RBC lysis
Ketamine = 1000mg
Xylazine = 650mg/L horse, 65mg/L cow
Titrate to effect, 1L mixture ~60min procedure time
* Not safe for recovery beyond 60min mark
MKX
“Triple drip” if can’t get GG
Midaz 50mg/L
Ket 1000mg/L
Xyla 650mg/L
Titrate to effect, 1L mixture, ~60min procedure time, sedate for recovery period
Fent and chickens
o Fent MAC sparing 50mcg/kg/h in chickens
o Propofol evaluated in chickens, swans, penguins
Reptiles
o Short procedures done with single IM inj of combo of anesthetics
Alfax, midaz, +/- hydro, +/- ket
o Wildlife, exotic species – avoid giving one agent
o Inhalants for prolonged periods/sx px has historically required hyperventilation
Vasodilation/hypotension, d shunting, d ventilatory drive, requires NE/epi
Does not improve with hyperventilation/hypocapnia!
o TIVA or PIVA with alfax to maintain normocapnia, predictable recovery
Drugs to Avoid/Not use for TIVA/PIVA
- Barbiturates
- Etomidate
Why avoid barbiturates for TIVA/PIVA
prolonged/rough recoveries
Context sensitive half life: 5x after short infusions
Induction only
Why avoid etomidate for TIVA/PIVA
No drug accumulation so seems like it would be great
Inhibition of 11-betahydroxylase –> adrenocortical suppression (up to 6hr in dogs)
* 11-betahydroxylase converts cortisone to cortisol
Also avoid propylene glycol
