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Pharmacology > Injectable Anesthetics (L&J Chp 15) > Flashcards

Injectable Anesthetics (L&J Chp 15) Flashcards

1
Q

Why use injectable anesthetics?

A
  • 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
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2
Q

Ideal injectable anesthetic agent

A
  • 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
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3
Q

Barbiturates

A

Injectable anesthetics, anticonvulsants

Derivatives of barbituric acid –> combo of urea, malonic acid

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4
Q

Barbiturate Chemical Structure

A

Barbituric acid does not have sedative or hypnotic properties on own
Side-chains added at position 5 in the pyrimidine nucleus impart hypnotic activity

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5
Q

Draw basic chemical structure of a barbiturate

A

XXX

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6
Q

Barbiturate Chemical Structure: side chain length

A

-length of the side chain at position 5 influences the potency, duration of action of these drugs –> longer side chains increase potency

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7
Q

Barbiturate Chemical Structure: if a sulfur atom replaces oxygen at position 2…

A

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

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8
Q

Barbiturate Chemical Structure: Stereoisomers

A
  • 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
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9
Q

How barbiturates classified

A
  1. Duration of action - long, intermediate, short, ultrashort
  2. Chemical structure
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10
Q

Thiobarbiturates

A

Thiopental
Thiamylal
Sulfur atom at position 2

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11
Q

Oxybarbiturates

A

Pentobarbital
Phenobarbital
Methohexital
Oxygen atom at position 2

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12
Q

Which barbiturates are commonly used for anesthesia?

A

Ultra-short acting thiobarbiturates (thiopental)

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13
Q

Thiopental

A
  • 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
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14
Q

Thiamylal

A
  • Ultrashort acting thiobarbiturate
  • Vs thiopental: ethyl radical in thiopental replaced with an allyl radical
  • Commonly used in vet med but no longer commercially available
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15
Q

Methohexital

A
  • 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
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16
Q

Pentobarbital

A
  • 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
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17
Q

Pentobarb and sheep/goats

A

Rapidly metabolize drug

Require supplemental doses if anesthesia maintained beyond 20-30min

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18
Q

Current uses of pentobarb

A
  1. Injectable anesthetic in lab rodents, esp for non-recovery procedures
  2. Primary ingredient in euthanasia solutions
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19
Q

Barbiturates: Analgesic Effects

A
  • 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
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20
Q

Barbiturates: Canine

A
  • 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
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21
Q

Barbiturates: fetal/neonatal effects

A
  • 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
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22
Q

Barbiturates: Resp System Effects

A
  • 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
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23
Q

Barbiturates: Hepatic effects

A
  • 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
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24
Q

Barbiturates: renal effects

A
  • 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)
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25
Q

Barbiturates: GI effects

A
  • Little change in GI fxn
  • No reports of diarrhea, GI stasis
  • TP: decreases LES tone in cats
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26
Q

Barbiturates: CV effects

A
  • 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
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27
Q

Barbiturates: CNS Effects

A
  • 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
28
Q

Barbiturates: IOP

A

Reduced slightly by TP admin

29
Q

Methohexital: CNS effects

A

Associated with CNS excitation, epileptiform sz

Poor choice for patients with sz

30
Q

Barbiturates: Cerebroprotective effects

A
  • 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
31
Q

Dissociative anesthetics

A
  • phencycline derivates
  • Produce state of ‘dissociative anesthesia’ characterized by dissociation of the thalamocortical and limbic systems, which produces change in awareness
32
Q

Which are the two dissociative anesthetics most commonly used in veterinary medicine?

A
  • Ketamine

- Tiletamine

33
Q

Chemical structure of ketamine

A

2-(o-chlorophenol)-2-methylamino-cyclohexanone hydrochloride

34
Q

Isomers of ketamine

A
  • 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
35
Q

Positive (S) isomer of ketamine vs negative (R) isomer of ketamine

A

Positive (S) isomer produces more intense analgesia, metabolized more rapidly, and has lower incidence of emergence reactions than negative (R) isomer

36
Q

Chemical structure of tiletamine

A

2-(ethylamino)-2-(2-thienyl)-cyclohexanone hydrochloride

37
Q

Tiletamine formulations

A
  • Only available in combination with benzodiazepine, zolazepam –> Telazol, Zoletil
  • Available as white powder, reconstituted with 5mL diluent
  • Final concentrations depend on product being used
38
Q

DA MOA

A
  • 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
39
Q

DA action at NMDA R

A
  • 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
40
Q

DA Action at Opioid R

A
  • mu, gamma, kappa
  • Activity at opioid R imparts analgesic properties but clinical significance of action at clinically relevant doses debatable
41
Q

DA Action Monoaminergic R

A

May also contribute to antinociception

42
Q

DA Action at Muscarinic R

A
  • 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
43
Q

Etomidate

A
  • Synthesized in 1964, introduced to human med in 1972

- Appreciated for minimum CV effects, cerebroprotective effects

44
Q

Chemical Structure of Etomidate

A

-Imidazole derivative
R-(+)-pentylethyl-1H-imidazole-5-carboxysulfate
-Exists in two isomers –> (+) isomer produces hypnosis

45
Q

Etomidate Chemical Properties

A

Unstable in neutral solutions

Insoluble in water

46
Q

Etomidate Available Formulations

A

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

47
Q

Etomidate MOA

A
  • 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
48
Q

Etomidate Analgesic Effects

A
  • Does not produce antinociception

- P requires additional analgesics

49
Q

Etomidate Metabolism

A
  • 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
50
Q

How much etomidate is excreted in the urine?

A

<3%

Hydrolysis of the drug is nearly complete

51
Q

Etomidate Pharmacokinetics

A
  • Described in cats, people
  • Open three compartment model
  • Redistributed rapidly in the cat (0.05h)
52
Q

What is the elimination half-life of etomidate in the cat?

A

2.89h

53
Q

What is the volume of distribution of etomidate in the cat at steady state?

A

LARGE

4.88 +/- 2.25L/kg

54
Q

What is the total clearance of etomidate in the cat?

A

2.47 +/- 0.78L/kg/h

55
Q

Other pharmacokinetic features of etomidate

A
  • Penetrates brain quickly –> rapid induction of anesthesia
  • Recovery from single injection also rapid DT redistribution of the drug from brain to inactive tissue sites
56
Q

Is etomidate protein bound or not?

A

YES! approx 75% bound to albumin so if hypoalbuminemic, have increases in pharmacologically active drug

57
Q

Therapeutic index of etomidate

A

LD50/ED50 = 26.0 (rats)

58
Q

Etomidate Respiratory System Effects

A
  • 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
59
Q

Etomidate Hepatic System

A

Hepatic function tests not affected by etomidate administration

60
Q

Etomidate Renal System

A
  • Does not decrease renal blood flow, GFR

- Renal function tests not affected by etomidate administration

61
Q

Etomidate Muscle Effects

A
  • Myoclonus, dystonia, tremor

- MOA: disinhibition of subcortical structures that normally suppress extrapyramidal motor activity

62
Q

How decrease myoclonal activity see with etomidate

A

-Adequate premedication +/- coinduction with a benzo immediately prior to etomidate administration

63
Q

Etomidate pain on injection

A
  • IV admin frequently results in pain

- DT propylene glycol vehicle or hyperosmolar nature of the commercial product

64
Q

How reduce incidence of pain on injection of etomidate

A
  • Large vein
  • Running IV line
  • IV admin of opioid immediately prior to etomidate administration
65
Q

Etomidate Endocrine System

A
  • 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
66
Q

What patient populations are not the best candidates for etomidate?

A
  • Pre-exisiting adrenocortical disease (Addison’s)
  • Highly stressed patients
  • Used as a CRI to maintain anesthesia

Pharmacology (7 decks)

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