Sedatives

Question 1

3 categories of sedatives

Answer 1

1. phenothiazines
2. alpha-2 agonists
3. benzodiazepines

Question 2

Caution regarding many IV CNS depressants - what must we avoid upon injection? what will this look like?

Answer 2

Accidental injection into carotid artery may be fatal
-immediate violent seizures followed by collapse
-convulsive seizures and death

Question 3

Common properties of most sedatives

Answer 3

Reduction of induction dose & MAC reduction
-~half dose of unmedicated patient

Improved quality of recovery from general anesthesia
-smoother

Question 4

what type of drug is acepromazine? acepromazine main effects? main use?

Answer 4

Phenothiazine
-major tranquillizer & sedative
-anti-emetic
-anti-arrhythmic
-main use is restraint

Question 5

onset of phenothiazines is fastest in a _____ environment?

Answer 5

quiet

Question 6

mechanism of action of phenothiazines?

Answer 6

• Blocks dopamine D2 receptors in brain
  > Dopamine is needed for wakefulness & motor activity

Question 7

most adverse effects of phenothiazines are due to

Answer 7

especially peripheral α1 blocking (in addition to dopamine receptor targets)

Question 8

what do α1 receptors do? what does stimulation cause? what about blockade? what do phenothiazines cause?

Answer 8

α1 stim > blood vessel constriction in most tissues
α1 stimulation by NE also causes constriction of G.I. & urinary tract sphincters

α1 blockade by phenothiazines causes vasodilation and sphincter relaxation > side effects

Question 9

potential adverse effects of phenothiazines? Some particular adverse effects for ruminants and horses?

Answer 9

• Peripheral α1 blockade > vasodilation > hypotension
• Ruminants: regurgitation due to relaxed cardiac sphincter

Male horse: penile prolapse
* Dose-dependent duration, can last 1-2 hours > edema > constriction of blood supply > ischemic necrosis > amputation required in worst cases

Question 10

acepromazine effect on blood pressure?

Answer 10

large decrease

Question 11

how are phenothiazines related to seizures? Literature vs common conceptions.

Answer 11

-literature shows phenothiazines do not promote seizures, and possibly inhibit them
-widespread (false) belief that acepromazine causes seizures

Question 12

what type of drug is azaperone? what is it used for and why?

Answer 12

-butyrophenone, sedative
* Used in swine practice in place of acepromazine because it has a 1-day meat WDT in swine, vs 7 days for acepromazine

Question 13

4 important alpha-2 agonists

Answer 13

Xylazine
Detomidine
Dexmedetomidine
Romifidine

Question 14

xylazine effects and timeline

Answer 14

• Sedation lasts ~2 h (dose-dependent)
• Analgesia is excellent but lasts only ~30 min (dose-dependent)

Question 15

Alpha-2 Agonists mechanism of action

Answer 15

α2 stim. opens K+ channels > inhibits APs in pathways in brain related to:
* Wakefulness (> sedation)
* Pain (> analgesia)
* BP control (> hypotension)
* Motor activity (> muscle relaxation)
* Respiration: may be dramatic drop in O2 exchange

Pre-synaptic alpha-2a stimulation opens K+ channels
> inhibits NT release in various brain pathways

CNS effects

Question 15

Alpha-2 Agonists mechanism of action

Answer 15

α2 stim. opens K+ channels > inhibits APs in pathways in brain related to:
* Wakefulness (> sedation)
* Pain (> analgesia)
* BP control (> hypotension)
* Motor activity (> muscle relaxation)
* Respiration: may be dramatic drop in O2 exchange

Pre-synaptic alpha-2a stimulation opens K+ channels
> inhibits NT release in various brain pathways

CNS effects

Question 16

potential adverse effects of alpha2 agonists

Answer 16

Large animals:
– vasoconstriction (stim. of α1 and α2b R on blood vessels) > initial rise in BP, then see bradycardia due to slower central α2 stim. which inhibits SNS outflow > potential for hypotension
– These effects are highly variable; depend on dose and other factors
- significant muscle relaxation

Decreased GI motility > bloat (large dogs)

• May kill small ruminants, calves, sick cows via pulmonary edema

Question 17

alpha2 agonist special effect for cats

Answer 17

cats will vomit

Question 18

what happens if an alpha2 agonist is injected into the carotid?

Answer 18

“As with many tranquilizers, immediate violent seizures followed by collapse may result from inadvertent administration into the carotid artery”

Question 19

how can we reverse the effects of alpha2 agonists?

Answer 19

alpha2 antagonist

Question 20

Main uses of xylazine:

Answer 20

Few uses in small animals (e.g., to induce vomiting in cats) Large animals:
* Alone > restraint
* With ketamine > general anesthesia
* With opioid > short surgical procedure
* Epidural analgesia (horses)
* Has been used with acepromazine for heavy sedation

Question 21

what animals are particularly sensitive to alpha2 agonists and why? Consequence?

Answer 21

• Many domestic ruminants are highly sensitive Possess an alpha-2D receptor that other species lack > require only 1/10th the dose of other species

Question 22

detomidine uses? What should we watch out for? why would we use this vs xylazine?

Answer 22

-approved for horses only
-analgesia is thought to last as long as sedation
-Animals may kick even when fully sedated
-Used when pain greater, or longer effect desired
(main difference vs xylazine is duration of action)

Question 23

dexmedetomidine uses? what species? advantages over xylazine?

Answer 23

Approved for use in dogs & cats
The most popular alpha-2 agonist in small animal practice
* Safer than xylazine

Question 24

what is romifidine used for? what species? comparison to xylazine?

Answer 24

• For horses, alpha2 agonist
• 50% longer sedation than xylazine (0.5 – 3 h, depending on dose) & less head droop and ataxia than equipotent doses of xylazine or detomidine > helpful for dentistry

Question 25

Alpha-2 Agonist Reversal Agents

Answer 25

Atipamezole, yohimbine
* α2 antagonists
* Atipamezole is more specific for α2 vs. α1
* Reverse sedation & most CV effects
> Titrate to effect – don’t be overzealous or may cause increased SNS effects and pain

Question 26

benzodiazepines: main one used, and effects

Answer 26

Mainly diazepam
* Sedative, muscle relaxant, & anticonvulsant

Question 27

mechanism of action of benzodiazepines

Answer 27

Inhibits APs in post-synaptic cells by facilitating GABA (the main inhibitory NT in brain)

Question 28

why are benzodiazepines considered safe? what is a possible adverse effect?

Answer 28

• Safe because little effect on CV system
• Overdose effects can be reversed by flumazenil,
  a competitive inhibitor of the BZD binding site
• Dose-dependent respiratory depression
  *hepatic necrosis in cats
• Excitement & paradoxical aggression problems in healthy small animals & horses > administered in combination with other drugs

Question 29

how are benzodiazepines metabolized? what is an issue that can arise in cats?

Answer 29

• Hepatic metabolism
  – Cats: fulminant hepatic necrosis (lethargy, jaundice +/- death); idiosyncratic; may follow >2 days admin.

Question 30

unique use of benzodiapzepines in cats

Answer 30

Effective appetite stimulant in cats – eat within seconds of injection

Question 31

possible adverse behavioural outcome from benzodiazepines and how we can alleviate this

Answer 31

• Excitement & paradoxical aggression problems in healthy small animals & horses > administered in combination with other drugs
  A 1:1 mixture of diazepam:ketamine is a very common
  induction mixture in small animal medicine

Question 32

similar drug to benzodiazepine - when would we use this instead?

Answer 32

Midazolam is similar but water soluble, so better for IM use when rapid effect is desired (also shorter T1/2)