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Boards: Pharmacology > Injectable Anesthetics > Flashcards

Injectable Anesthetics Flashcards

1
Q

GABA Binding Site on GABA A R

A

btw a1, b2 subunits

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2
Q

Benzodiazepines binding site on GABA A R

A

btw a1, g2

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3
Q

Ethanol, inhalants binding site on GABAA

A

on a subunit

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4
Q

Neurosteroids, propofol binding site on GABA A

A

Beta subunit

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5
Q

Barbiturates binding site on GABA A

A

Beta subunit, separate from neurosteroids or propofol

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6
Q

GABA A R - conservation among species?

A

Where agents work is conserved among species

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7
Q

Ideal Injectable Anesthetic Agent

A

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

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8
Q

Basic Structure of Barbiturates

A

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

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9
Q

Thiopental from Oxybarbiturate

A

o Replace Carbon 2 oxygen with sulfur  thiobarbiturate (thiopental) from oxybarbiturate
 increased lipophilicity = increased potency with faster onset, short DOA

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10
Q

Thiobarbiturate

A

sulfur atom at position 2; thiopental and thiamylal

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11
Q

Oxybarbiturate

A

oxygen at position 2; pentobarb, phenobarb, methohexital

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12
Q

MOA Barbiturates - lower doses

A

enhance GABAA
 decreases rate of GABA dissociation, increases duration Cl channel open
 increases Cl conductance –> hyperpolarization of postsynaptic neuron –> CNS depression, unconsciousness

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13
Q

MOA Barbiturates - higher doses

A

direct activation of channel, mimics GABA
o Inhibits synaptic actions of excitatory glutamate, neuronal (central) nAChR
 Role of effect unknown

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14
Q

Ultra-Short Acting Barbiturates

A

Used for induction: thiopental, thiamylal, methohexital

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15
Q

Methohexital

A

-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

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16
Q

Thiamylal

A

ethyl radical in thiopental replaced by allyl radical, no longer available

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17
Q

Short Acting

A

Pentobarbital

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18
Q

Pentobarbital

A

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

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19
Q

Thiopental

A

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’

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20
Q

Thiopental: redistribution

A

= 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

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21
Q

Formulation of Thiopental

A

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

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22
Q

PK Effects - Thiopental

A

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’)

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23
Q

Thiopental Metabolism

A

hepatic microsomes/ER of hepatocytes, CYP450 inducer

Prolonged effect if problems with CYP450 system

Significant hepatic dysfunction must be present before prolongation of duration

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24
Q

Thiopental Elimination

A

Renal

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25
Q

Thiopental: CNS Effects

A
  • 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
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26
Q

Barbiturate Neuroprotective Effects

A

Methohexital assoc with CNS excitation, epileptiform sz – do not use in sz patients

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27
Q

Ophtho Effects - barbiturates

A

Slightly decrease in IOP

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28
Q

CV effects - barbiturates

A
  • 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
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29
Q

Respiratory effects - barbiturates

A
  • 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
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30
Q

Hepatic, renal, GI - barbiturates

A
  • 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
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31
Q

Placental effects - barbiturates

A

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

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32
Q

Analgesic effects barbiturates

A
  • No analgesia
    o At subanesthetic dose, can actually be hyperalgesic
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33
Q

Perivascular effect following barbiturate injury

A

barbiturate slough,” vascular tissue damage,

Very alkali, pH ~10

Aspirate back as much as possible, inject lidocaine locally - flush

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34
Q

Glucose effect of barbiturates

A

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

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35
Q

Glucose administration to animals recovering from barbiturate ax

A

can result in re-anaesthetization
 Glucose slows hepatic enzymes
 Fructose, lactate, pyruvate, glutamate
 Can also see with epi, adrenergic agents

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36
Q

Species susceptibility to the barbiturate glucose effect

A

o Dogs, cats: intermediate
o Goldfish: refractory
o Specific lab animals, exotics VERY sensitive

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37
Q

Greyhounds and Barbiturates

A

 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

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38
Q

Barbiturates in horses

A

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

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39
Q

Barbiturates and ruminants

A

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’

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40
Q

Barbiturates in Swine

A

Limited by IV access; dose requirement  by 35% when hypovolemic, does not trigger MH

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41
Q

Use of Barbiturates

A

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)

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42
Q

Propofol + Barbiturates

A

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

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43
Q

Propofol

A
  • More rapid awakening than with other agents, 1977
  • Structure
    o Substituted isopropylphenol (2,6-diisopropylphenol)
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44
Q

Propofol MOA

A

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

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45
Q

PK of Propofol

A

–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

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46
Q

Propofol Metabolism in Cats

A

extrahepatic metabolism demonstrated in pulmonary tissue; hepatic lipidosis doesn’t increase morbidity or mortality
* Don’t do hepatic glucuronidation well, rely on pulmonary

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47
Q

Propofol PK - dogs

A

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

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48
Q

Propofol Metabolism

A

Hepatic: glucuronidation, ring hydroxylation to water soluble partially active metabolite that further degraded to inactive metabolites via CYP2B11

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49
Q

Excretion of propofol

A

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

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50
Q

Propofol Effects - CNS

A

 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

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51
Q

CV Effects - Propofol

A

–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

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52
Q

Why see vasodilation with propofol?

A
  • 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
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53
Q

Respiratory effects propofol

A

 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

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54
Q

GI Effects Propofol

A

Humans –> anti emetic properties
 Not demonstrated in vet med

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55
Q

Hepatic/renal effects - propofol

A

no change in HBF, GFR in face of VD
 Also have extra hepatic metabolism

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56
Q

MSK effects - propofol

A

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

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57
Q

Neonatal/Fetal Effects - Propofol

A

crosses placenta, readily cleared - acceptable for c section

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58
Q

Analgesia effects propofol?

A

None

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59
Q

Propofol - extravascular effects?

A

none, not assoc with tissue necrosis

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60
Q

Propofol Infusion Syndrome

A

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

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61
Q

Propofol Infusion Syndrome MOA

A

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

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62
Q

Propofol in Cats

A

–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

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63
Q

What do cats develop with frequent/daily propofol administration and why?

A

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

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64
Q

Propoflow 28 in cats

A

concern of benzyl alcohol, use for normal dosing
 Avoid as CRI
 Unclear how well metabolize preservative

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65
Q

Horses and Propofol

A

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

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66
Q

Ruminants and Propofol

A

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

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67
Q

Propofol in Swine

A

rapid, smooth; does not induce MH
o Apnea effect during induction/intubation

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68
Q

Propofol Formulations

A
  1. Emulsions
  2. Propoflo 28
  3. Lipid-free microemulsion
  4. Fospropofol
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69
Q

Propofol Emulsion

A

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

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70
Q

Propofol Lipid Emulsion and bacterial growth

A

 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

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71
Q

Propofol 28

A

preservative: benzyl alcohol
 Dogs

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72
Q

Propofol Lipid-Free Microemulsion

A

 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

73
Q

Fospropofol

A

prodrug being investigated,
 Water soluble, less painful on injection
 Onset time significantly longer

74
Q

Alfaxalone

A

Structure: neurosteroid

MOA:
o GABAA R (beta subunit)
o Low doses: increases Cl conductance, hyperpolarization
o High doses: GABA agonist

75
Q

Propofol Pro Tips

A

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

76
Q

Alfax Formulations

A
  1. cremophor EL (20% castor oil)
  2. Alfaxan
  3. Alfax Multidose (28d)
77
Q

cremophor EL (20% castor oil)

A

 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

78
Q

Alfaxan

A

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

79
Q

Alfax Multidose (28d)

A

= chlorocresol, benzethonium chloride, ethanol
 2018
 Not advised for CRI in cats bc unclear how well can metabolize preservatives

80
Q

Alfax PK dogs

A

Vd following 2mg/kg = 2.4L/kg, terminal plasma elimination HL (t1/2 ) at same dose 25’, clearance 60+/-13mL/kg

81
Q

Alfax PK Cats

A

VD following 5mg/kg = 1.8L/kg, t1/2 45’, plasma clearance 25+/-8mL/kg/min

82
Q

Alfax PK Horses

A

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

83
Q

Alfaxalone onset, DOA

A
  • Rapid onset, short DOA
    o Terminal half life 25 min in dogs (45 min in cats)
    o Greyhounds similar to beagles
84
Q

Alfaxalone - metabolism

A

Hepatic
o Phase I: cytochrome P450 –> 5 metabolites, conserved across species
o Phase II: conjugation-dependent
 Cats: alfaxalone sulfate, glucuronide
 Dogs: alfaxalone glucuronide

85
Q

Elimination of Alfax

A

renal, biliary, fecal

86
Q

Alfax metabolites - cats

A

axalone sulfate, glucuronide

87
Q

Alfax metabolites - dogs

A

Alfax glucuronide

88
Q

Ophthalmic effects - alfax

A

Increase IOP

89
Q

CNS Effects - alfax

A

 Unconsciousness, ax
 Decrease CBF, ICP, CMRO2
 Shift in dominant frequency band to δ from β

90
Q

Resp Effects - Alfax

A

 Heavily dose-depression apnea, depression
 Decreased RR, MV, PaO2
 Increased PaCO2
 Less present to absent at clinically used doses

91
Q

CV Effects - Alfaxalone

A

 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

92
Q

Hepatic, Renal, GI Effects Alfax

A

No controlled studies, cytochrome p450 metabolism
o Other

93
Q

What molecule is alfax derived from?

A

Progesterone

94
Q

Other Alfax Effects

A

 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

95
Q

Alfax Recovery

A

o Paddling, myoclonus, trembling
o Generally regarded as smooth
o Horses, donkeys: smooth to absolutely horrific recoveries
Alpacas also reported to have rough recoveries

96
Q

Alfax in Dogs

A

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

97
Q

Alfax in Cats

A

o CRI doses increased vs dogs, 0.18mgkgmin
o Safe for cats <12wks
o More likely to have trembling, paddling during recovery vs propofol

98
Q

Alfax in Horses

A

Recovery scores significantly worse with alfaxalone
o Suitable for field ax at 2mg/kg/hr + medetomidine 5mcg/kg/hr

99
Q

Ruminants and Alfax

A

Mitosis in ruminants, no effect on IOP

100
Q

Swine and Alfax

A

recumbency, deep sedation, minimal SE
o Volume of injectate limit use to small pigs

101
Q

Alfax Clinical Practice Tips

A

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

102
Q

Etomidate Structure

A

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

103
Q

Etomidate Formulation

A

 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

104
Q

Etomidate MOA

A

o Agonist at GABAA R, hypnosis
 Low dose: enhances GABA affinity
 High dose: direct activation

105
Q

PK Etomidate

A

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

106
Q

Metabolism of Etomidate

A

Hydrolysis of ethyl ester side chain by hepatic and plasma esterases – nearly complete
o <3% excreted unchanged in urine

107
Q

Etomidate Excretion

A
  • Water soluble inactive metabolite that is excreted in urine, bile, and feces
108
Q

Etomidate CNS Effects

A

 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

109
Q

CV Effects Etomidate

A

 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

110
Q

Resp Effects Etomidate

A

 Postinduction apnea possible – high dose admin quickly
 decreases VT, increases RR (offsets self)

111
Q

Analgesic effects etomidate?

A

None

112
Q

Hepatic, GI effects etomidate

A

no Changes
 Retching, regurgitation, hypersalivation
 Humans: nausea, vomiting

113
Q

Adrenocortical suppression

A

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

114
Q

Other Etomidate Effects

A

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)

115
Q

Cats and Etomidate

A

Decreased spontaneous firing of cortical neurons as well as thalamus and reticular neurons
o Excessive salivation noted, fragility of feline RBC

116
Q

Dogs and Etomidate

A

vomiting, myoclonus, excitement, hemolysis – still choice for CV instability, increased ICP, cirrhosis

117
Q

Horses and etomidate

A

Not used clinically

118
Q

Sheep and Etomidate

A

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

119
Q

Pigs and Etomidate

A

No MH triggering

120
Q

Clinical Use Tips for Etomidate

A

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

121
Q

Ketamine

A

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

122
Q

Ketamine Formulation

A

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

123
Q

Ketamine Structure

A

o Phencyclidine (PCP) derivative
o Racemic mixture: R(-), S(+) isomers
 S isomer = 3-4x more potent, increased analgesia/metabolism
 R isomer = more emergence delirium

124
Q

MOA Ketamine

A

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

125
Q

Lipid solubility, protein binding ketamine

A
  • 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
126
Q

Ketamine Metabolism

A

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

127
Q

CNS Effects - ketamine

A

 Resembles cataleptic state
* Appears away but not responsive to stimuli
 Increases CBF, CMRO2, ICP
* Can attenuate increased ICP with eucapnia, benzos or thiopental

128
Q

Ketamine and Seizures

A
  • Epileptiform EEG but no post ictal period
  • Safer to avoid in sz patients
  • Does not increase threshold
  • Anti-convulsant, neuroprotective
129
Q

Recovery with Ketamine

A

smooth to violent
* Dogs, pigs: recovery can be erratic, twitching, dysphoric

Emergence delirium, potentially caused by misrepresented auditory and visual stimuli

130
Q

CV Effects: ketamine

A

 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

131
Q

Resp Effects Ketamine

A

 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

132
Q

What is the breathing pattern most commonly assoc with ketamine?

A

 Apneustic breathing: prolonged inspiration, inspiratory hold, short expiration

133
Q

Analgesia effects of Ketamine

A

 Occurs at subanesthetic doses DT NMDA R: somatic pain, less clear opioid component
 Helps prevent central sensitization

134
Q

MSK Effects Ketamine

A

 Rigidity +/- spontaneous movement
 Increased IOP, increased tone extraocular m

135
Q

Hepatic, renal, GI effects - etomidate

A

no effects

136
Q

Etomidate Fetal/Neonate Effects

A

 Crosses placenta
 Profound neonatal depression when dam induced with ket+midaz vs other injectables

137
Q

Cats and Ketamine

A

can spray orally, won’t like bc pH 3-3.5 – will salivate
o Can combine ket + xyla + T/Z

138
Q

Cats and Ketamine

A

can spray orally, won’t like bc pH 3-3.5 – will salivate
o Can combine ket + xyla + T/Z

139
Q

Bears and ketamine

A

sudden arousal (with a2), DO NOT USE

140
Q

Ruminants, camelids and ketamine

A

ketamine stun, different doses/cocktails to achieve different levels of out

141
Q

Equine and ketamine

A

extensive use, sedate appropriately beforehand
o Induction, bolus top ups, maintenance, CRI

142
Q

Clinical Use Tips - ketamine

A

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

143
Q

Telazol

A
  • Tiletamine (dissociative) + Zolazepam (benzo)
    o More potent, long duration vs ketamine
    o 2-(ethylamino)-2-(2-thienyl)-cyclohexanone hydrochloride
144
Q

Telazol Metabolism

A

o Cats, ruminants: zolazepam longer = better, slow
o Dogs: tiletamine longer, poor recoveries, rigid
o Swine: smooth

145
Q

Telazol formulations

A

o Reconstitution variability
o pH 2-3.5

146
Q

Telazol and CV Effects

A
  • Does not sensitize to epinephrine-induced arrhythmias
147
Q

Telazol in horses

A

incoordination
o Can be used for induction after appropriate sedation

148
Q

NZWR and Telazol

A

tiletamine = nephrotoxin, other lagomorphs appear okay

149
Q

Tigers (big cats) and Telazol

A

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

150
Q

Metomidate

A

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

151
Q

Magnesium Sulfate

A

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

152
Q

Chloral Hydrate

A

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

153
Q

Effects of chloral hydrate

A

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

154
Q

Chloralose

A

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

155
Q

Urethane

A

Lab animals, concern for carcinogenesis

156
Q

PIVA

A

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

157
Q

TIVA

A
  • Total intravenous anesthesia (TIVA): maintenance of GA through inj only
    o Field ax
    o Total injectable anesthesia slightly difference – IM
    o Ensure people safety
158
Q

PK of TIVA/PIVA

A

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

159
Q

Benefits of TIVA/PIVA

A

 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

160
Q

TIVA/PIVA reptiles

A

don’t have to hyperventilate to maintain ax, only breath 1x Q5min, minimize shunting

161
Q

Context Sensitive half time

A

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)

162
Q

Goals/Advantages of TIVA/PIVA

A

o Less CV depression: increased MAP, increased CO, better perfusion
o Avoid catastrophic complications: AKI, GI hypoperfusion/sloughing, death

163
Q

Drawbacks of TIVA/PIVA

A

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

164
Q

MAC reduction of lidocaine CRI in horses, dogs, rabbits, reptiles

A

~30%

165
Q

Monitoring with TIVA

A

o No spontaneous movement, no nystagmus, will preserve palpebral
 Eye position depends on drugs used

166
Q

If too light with TIVA…

A

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

167
Q

If too deep with TIVA…

A

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

168
Q

When use TIVA/PIVA?

A

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

169
Q

Donkeys

A

: higher dose of a2 for premed, maintenance

170
Q

Cattle

A

much more sensitive, use 1/10th xylazine dose, lower concentration xylazine

171
Q

Sheep

A

pulmonary edema DT activation of PIMS (pulmonary interalveolar macrophages – hypoxemia
 Happens whether clinically hypoxemic or not, do not use

172
Q

GKX

A

 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

173
Q

MKX

A

“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

174
Q

Fent and chickens

A

o Fent MAC sparing 50mcg/kg/h in chickens
o Propofol evaluated in chickens, swans, penguins

175
Q

Reptiles

A

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

176
Q

Drugs to Avoid/Not use for TIVA/PIVA

A
  1. Barbiturates
  2. Etomidate
177
Q

Why avoid barbiturates for TIVA/PIVA

A

prolonged/rough recoveries
 Context sensitive half life: 5x  after short infusions
 Induction only

178
Q

Why avoid etomidate for TIVA/PIVA

A

 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

Boards: Pharmacology (9 decks)

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