Etomidate, Metomidate,Chloral Hydrate, Magnesium Sulfate , Chloralose

1. Etomidate
 used as an induction and maintenance agent due to its minimal
cardiopulmonary and cerebral protective effects

2. Chemical Structure
• An imidazole derivative(R‐(+)‐pentylethyl‐1H‐imidazole‐5 carboxylate
sulfate)
• Exists in two isomers, only the (+) isomer producing hypnosis.
• Unstable in neutral solutions and is insoluble in water
• Supplied as a 0.2% solution in 35% propylene glycol with a pH of 6.9
Commercially available etomidate preparations have adverse effects
including the potential for erythrocyte damage

3. Mechanism of action
• Has agonist activity at the GABA receptor
• Enhances the action of the inhibitory neurotransmitter GABA, which
increases chloride conduction into the cell
• resulting in hyperpolarization of the postsynaptic neuron results in CNS
depression and hypnosis

4. Pharmacokinetics
• Penetrates the brain quickly, resulting in a rapid induction of anesthesia
• Recovery from etomidate is also rapid due to redistribution to inactive
tissue sites
• 75% of etomidate is bound to albumin, conditions where albumin
concentrations are decreased result in increased in pharmacologically
active drug
• undergoes hydrolysis of its ethyl ester side‐chain that forms a
water‐soluble, pharmacologically inactive metabolite that is excreted in
the urine, bile, and feces
• Hepatic enzymes and plasma esterases carry out the hydrolysis
• less than 3% of etomidate is excreted unchanged in the urine(nearly
complete)

5. Central Nervous System
• Primary CNS effect of etomidate is hypnosis
• It decreases the spontaneous firing of (cortical neurons) and the firing
rate of neurons (thalamus and reticular formation)
• causes vasoconstriction of the cerebral vasculature and reduces cerebral
blood flow and CMRO2
• Mean arterial blood pressure is unchanged, cerebral perfusion pressure is
maintained
• Elevated intracranial pressure is reduced much like it is after thiopental
administration
• Reducing the cerebral metabolic rate of oxygen consumption while
lowering the rate of rise of intracranial pressure and producing
immobilization may reduce the effects of a hypoxic insult to the brain of
animals
• produces changes in the EEG similar to the barbiturates (also been
associated with grand mal seizures)

6. Cardiovascular System
• Characterized by cardiovascular stability
• Baroreceptor function and sympathetic nervous system responses appear to
remain intact
• In patients with dilated cardiomyopathy, however, arterial blood pressure
remains stable during etomidate anesthesia due to increases in arterial resistance
and aortic impedance along with decreases in aortic compliance
• Arterial pressure is maintained due to an increase in left ventricular afterload,
which adversely affects left ventricular systolic and diastolic performance in
patients with impaired left ventricular function
• should be emphasized that etomidate is usually only suitable for induction of
anesthesia and that the greatest cardiovascular effects the patient is likely to
experience will be due to the drugs used to maintain anesthesia (usually inhalant
anesthetics) which may negate or alter any potential benefits from using
etomidate.

7. Respiratory system
• Minimal effects on the respiratory system.
 Postinduction apnea has been reported after rapid intravenous
administration

8. Hepatic, Renal and Gastrointestinal Systems
• Does not decrease renal blood flow or glomerular filtration rate.
• Hepatic and renal function tests are not affected

9. Endocrine system
• Adrenocortical suppression has been documented
• causes a dose‐dependent inhibition of the conversion of cholesterol to
cortisol
 Care should be exercised when anesthetizing patients with existing
adrenocortical disease (e.g., Addison’s disease), highly stressed patients
or when etomidate is being used as a constant rate infusion to maintain
anesthesia.
 Infusion of etomidate for long durations is not recommended.

10. Analgesic effects
• Does not produce antinociception
Patients undergoing painful procedures should have appropriate
analgesics administered

11. Muscle
Myoclonus, dystonia, and tremor can occur with etomidate
administration
• The result of disinhibition of subcortical structures that normally suppress
extrapyramidal motor activity
Myoclonic activity can be decreased with adequate premedication and/or
the intravenous administration of a benzodiazepine immediately prior
to etomidate administration

12. Pain on injection
 IV administration of etomidate frequently results in Pain
• Due to the propylene glycol vehicle or the hyperosmolar nature of the
commercial product
Pain can be lessened by administration of etomidate into a large vein,
through a running intravenous line, or intravenous administration of an
opioid immediately prior to etomidate administration

13. Other considerations
• current formulation of etomidate is hyperosmotic when compared to
plasma in propylene glycol (4640 mOsm/L)
• associated with intravascular hemolysis (in dogs)

14. Species‐Specific Effects

15. Ruminant
• IV bolus of 1 mg/kg of etomidate did not depress cardiovascular function
in the ewe or fetus.
• Acid–base alterations led to transient but slight respiratory depression of
the mother and fetus
• Etomidate crosses the placenta, rapidly and reaches the fetus in high
amounts, fetal elimination occurred just as quickly as it did in the dam
• during anesthesia, etomidate blocks cortisol output

16. Swine
• Provides cardiovascular
stability, decreases cerebral
blood flow, and renal blood
flow remains essentially
unchanged
• Does not trigger malignant
hyperthermia in susceptible
pigs
Equine
 Etomidate is not used
clinically in horses

17. Clinical Use
• Reasonable induction agent for those
patients with some types of myocardial
disease, cardiovascular instability,
and/or intracranial lesions.
• Pain on intravenous injection has been
reduced by IV administration of an
opioid analgesic prior to etomidate
injection
• Myoclonus following intravenous
etomidate administration has also been
described, premedication with
sedatives such as benzodiazepines
may reduce the incidence
• Duration of anaesthesia is dose
dependent, but awaking from a single
dose of etomidate is more rapid than
after barbiturate
 Maintenance of anesthesia with
etomidate is not recommended due to
the previously discussed
adrenocortical suppression and
erythrocyte damage

18. Alfaxalone
• Althesin® was formulated for human use while Saffan® was marketed for
veterinary use.
• alfaxalone is poorly water soluble, it was originally combined with a weak
anesthetic, alphadolone, and formulated in a 20% polyoxyethylated castor oil
vehicle.
• However, the castor oil formulation, Cremophor EL®, was associated with
hyperemia in cats and histamine release with resultant anaphylactic reactions in
dogs
• recently, a solution containing alfaxalone in a non‐cremophor (cyclodextran)
vehicle (Alfaxan‐CD®) has been approved for dogs and cats in several countries.
This formulation is not associated with histamine release .

19. Chemical Structure
• 3‐α‐hydroxy‐5‐α‐pregnane‐11,20‐dione is a neuroactive steroid
molecule capable of inducing anesthesia.
• It is supplied as a 1% solution in
2‐hydroxypropyl‐β‐cyclodextrin.
• The solution does not contain an antimicrobial preservative so
any solution remaining in the vial following withdrawal of the
required dose should be discarded.

20. Mechanism of action
• Alfaxalone produces CNS depression by activity at GABA receptors
• Increases chloride conduction into the cell, resulting in hyperpolarization
of the postsynaptic membrane.

21. Pharmacokinetics
• It appears alfaxalone undergoes both cytochrome P450‐dependent (Phase
I) and conjugation‐dependent (Phase II) hepatic metabolism. Cats and
dogs seem to form the same five Phase I metabolites of alfaxalone. While
cats produce alfaxalone sulfate and alfaxalone glucuronide in Phase II,
dogs are observed to produce alfaxalone glucuronide. These metabolites
are then eliminated by the hepatic/ fecal and renal routes (Jurox summary
of product characteristics).

22. Pharmacodynamics

23. Central Nervous System
Cerebral blood flow, intracranial pressure, and cerebral metabolic
oxygen demands are all decreased
• In dogs anesthetized with halothane, alfaxalone administration resulted in
changes in the electroencephalogram

24. Cardiovascular system
• Studies utilizing clinical doses of alfaxalone in horses, sheep, and swine
have also demonstrated stable cardiovascular parameters.
• Intravenous administration of alfaxalone produces dose‐dependent
cardiovascular depression in dogs and cats (Arterial blood pressure,
cardiac output, and heart rate decreased in cats that were given 15 mg/kg
and 50 mg/kg of intravenous alfaxalone)

25. Respiratory system
• In dogs and cats, the administration of alfaxalone produces
dosedependent respiratory depression, with apnea being the most
common side‐effect
• In dogs, the duration of apnea was related to the dose of alfaxalone
administered

26. Hepatic, Renal and Gastrointestinal Systems
• no controlled studies examining the effect of alfaxalone alone on hepatic or
renal blood flow have been published.
• alfaxalone undergoes cytochrome P450 hepatic metabolism. Induction of
the cytochrome P450 enzyme leads to an increase in the rate of
alfaxalone degradation, which may decrease the duration of anesthesia
• Administration of alfaxalone‐alphadolone in Greyhounds decreased
hepatic blood flow and hepatic oxygen supply

27. Other effects
• Alfaxalone is a steroid compound derived from progesterone; therefore it
is possible that sex‐specific metabolism could produce pharmacokinetic
differences between male and female animals

28. Species‐specific effects

29. Equine
• used to induce and maintain anesthesia in horses
• When administered intravenously to horses following xylazine and
guaifenesin, 1 mg/kg of alfaxalone satisfactorily induced anesthesia,
although tremors/shaking were reported
• compared with ketamine, 1 mg/kg of alfaxalone with 0.02 mg/kg
diazepam IV produced shorter induction times (18 ± 4 s) with similar
anesthesia times
• Recovery scores, however, were significantly worse in horses receiving
alfaxalone
• Alfaxalone has also been administered as a constant rate infusion to
maintain general anesthesia in horses undergoing field castration. In this
study, alfaxalone at a dose of 2 mg/kg/h and medetomidine at a dose of 5
μg/kg/h were determined to be suitable for short‐term field anesthesia in
the horse

30. Ruminant
• produce acceptable anesthesia while maintaining cardiovascular and
respiratory function in sheep
• It has been demonstrated that a constant rate infusion of alfaxalone in
desflurane‐anesthetized sheep reduced inhalant requirements while
cardiorespiratory parameters remained similar to sheep anesthetized with
desflurane alone
• a 2 mg/kg intravenous dose of alfaxalone produced minimal changes in
cardiopulmonary and acid–base variables

31. Small Ruminant
• Anaesthesia may be induced in healthy sheep and goats by the
intravenous injection of 3mg/kg Saffan and this is sufficient for intubation
and a smooth transition to inhalation anaesthesia. When Saffan is to be
used as sole agent in lambs and kids for disbudding, recommended
intravenous dose rates are 4–6mg/kg.
• The effects of Saffan on the heart rate, arterial blood pressure (ABP) and
respiratory rate are dose-dependent. Saffan at 2.2 mg/kg i.v. Produces a
short-lived decrease in heart rate and ABP with some slowing of
respiration. This dose may produce about 10 minutes of surgical
anaesthesia with recovery to the standing position about 20 minutes after
injection. A dose of 4.4 mg/kg Saffan may produce a longer duration of
decreased heart rate and ABP, and about 15 minutes of anaesthesia with
complete recovery after a further 30 minutes.

32. Swine
• induce sedation and anesthesia in pigs.
• Alfaxalone alone or in combination with diazepam has been injected
intramuscularly in pigs. This rapidly produced recumbency, deep
sedation, and minimal side‐effects
• In pigs premedicated with intramuscular azaperone, intravenous
alfaxalone resulted in satisfactory conditions for intubation with minimal
side‐effects

34. Clinical use
• the dose should be tailored according to concurrent drug administration
and physical status
• alfaxalone can be effective when administered intravenously or
intramuscularly. However, due to volume of injection, the intramuscular
route of administration should be limited to small patients.
• recovering from alfaxalone anesthesia, it is recommendedthat animals
be left in a quiet, dark area where they are not handled or disturbed
except for necessary monitoring. Paddling of the limbs, muscle twitching,
hyper‐reactivity, and ataxia have been reported in animals(obtunded by
the use of sedative agents.)

35. Other Injectable Anaesthetics

36. Metomidate
• First compound of the imidazole class of anaesthetics designed as a
non‐barbiturate intravenous hypnotic drug
• Freely soluble in water but aqueous solutions are unstable and should be
used within 24 h.
• Has a short duration of action of less than 25 min; however animals will
sleep for several hours
• Recovery in horses may be extremely violent
• Characterized by cardiovascular stability
• Produces profound muscle relaxation but little analgesia

37. Chloral Hydrate
• 1,1,1‐trichloro‐2,2‐dihydroxyethane, is a hypnotic that was first introduced in 1869
• Crystalline substance that has a distinct odor and volatizes slowly at room temperature
• Readily soluble in water and aqueous solutions remain generally stable
• Metabolized to trichloroethanol which is responsible for most of the observed effects.
• MOA is unknown, it is likely that trichloroethanol interacts with the GABA receptor
in a similar fashion as the other injectable anesthetics.
• Dose‐dependent sedation, margin of safety is quite narrow
• Myocardial contractility is reduced, resulting in hypotension
• Ventricular fibrillation and sudden death in the recovery period have been reported
• Perivascular injection results in necrosis and sloughing of the vessel wall and the
surrounding tissues

38. • Horse : 10% solution is infused until the horse becomes ataxic (after 40–
60mg/kg have been administered) when thiopental (5 mg/kg) or
methohexital (2.5 mg/kg) is injected i.v. as a bolus. Surgical anaesthesia is
maintained by injection of increments of barbiturates (thiopental 1 mg/kg
or methohexital 0.5 mg/kg). If anaesthesia is to extend for more than 45
minutes, it may prove necessary to give more chloral hydrate
(approximately 10 mg/kg but to effect)

39. Magnesium sulfate
• Better thought of as a muscle relaxant
• combined with chloral hydrate, it hastens the onset of anesthesia, increases
its depth, and reduces the toxicity associated with chloral hydrate and
CNS depressant rather than an injectable anesthetic
• recommended mixture is : 2 parts chloral hydrate to 1 part magnesium
sulfate.
• Dilute solutions induce anesthesia in small animal patients.
• Been used for euthanasia, but it should only be administered after the
animal is rendered unconscious with another anesthetic agent

40. Chloralose
• Prepared by heating glucose and chloralhydrate
• Limited to laboratory animals being used in non‐survival surgical
experiments
• Anaesthesia produced similar to chloral hydrate but the effects last 8–10 h
• Chloralose is transformed to chloraldehyde and glucose and the safety
margin is relatively large.
• Recovery is slow and marked by paddling and muscle fasciculations
 Little indication for its use in veterinary medicine.

41. Canine
• Should be considered as an intravenous induction agent in patients with
cardiovascular instability, increased intracranial pressure, and/or
cirrhosis (Despite side‐effects)

42. Feline
• When used as an induction agent in normal cats, etomidate has been
demonstrated to be an acceptable induction agent producing minimal
cardiopulmonary effects
• When investigated as an intravenous induction agent for cats with
decreased cardiovascular reserve, etomidate administered at a dose of 1–2
mg/kg titrated to effect was determined to be effective
• Excessive salivation was noted in all cats
• Due to the fragility of feline red blood cells, cats may be more likely to
have intravascular hemolysis

43. Canine
• alfaxalone in the dog show that intravenous administration for induction of
anesthesia will increase intraocular pressure. And unlike some formulations of
propofol and etomidate, intravenous injection of alfaxalone does not cause pain on
injection
• Recovery from alfaxalone anesthesia is longer compared to propofol and has been
associated with adverse events such as paddling, rigidity, myoclonus, and
vocalization
• Alfaxalone has been delivered as a constant rate infusion to maintain anesthesia in
dogs, and has been shown to be an effective anesthetic producing clinically acceptable
hemodynamic values
• significant respiratory depression was observed, therefore ventilatory monitoring is
recommended cardiovascular and respiratory parameters remain quite stable in dogs
that are administered alfaxalone at clinically relevant doses, with postinduction apnea
being the most commonly reported side‐effect
• average induction dose for alfaxalone was 2.2 mg/kg in non‐premedicated dogs and
1.6 mg/ kg in dogs that received premedications

44. Feline
• used for sedation as well as induction and maintenance of anesthesia in
the cat.
• cardiopulmonary parameters remain relatively stable with
hypoventilation and hypoxia being the most frequent side‐effects of the
administration of high doses of alfaxalone
• When compared to propofol, cats receiving alfaxalone were more likely to
have episodes of paddling and trembling during recovery