Use of Sedative/Premedication Drugs

Question 1

TRANQUILLIZERS

Answer 1

Classically, ‘sedative’ drugs are defined as TRANQUILLIZERS (reduce apprehension and fear)

Question 2

Sedatives

Answer 2

• make the animal sleepy, but it is easily aroused
• Sedatives are NOT ANAESTHETICS – there is a limit to their action

Question 3

Hypnotics

Answer 3

induce sleep and at high doses some may produce general anaesthesia

Question 4

Alpha-2 agonists Structure

Answer 4

Structure: many (but not xylazine) are based on imidazole

Alpha 2 receptors are associated with sympatholytic properties.

Question 5

Alpha-2 Agonists in Veterinary Use

(5)

Answer 5

1. Xylazine (Rompun, various generics), Routes of administration (ROA): IV, IM, epidural. Used in all species (except pigs). Very low doses needed in ruminants.
2. Detomidine (Domosedan or Dormosedan in USA). Generics include Equimidine, Domidine, Medesan. ROA IV, IM, trans- mucous membranes (TMM), epidural.
3. Romifidine (Sedivet - horses). ROA IV, IM. Main use in horses – less ataxia than others (also less sedation and less analgesia). Longest duration of effect.
4. Medetomidine (Domitor; Sedator), ROA IV, IM, TMM. Epidural. Licensed in dogs and cats. Wide use in rodents etc. Also has been used in all domestic species. Very powerful sedative/hypnotic/analgesic.
5. Dexmedetomidine (Dexdomitor) – launched in 2008. Watch this space.

Question 6

Alpha-2 Antagonists in Use

Answer 6

• Atipamezole (Antisedan. Generics include Atipam) Veterinary Licence in UK and most countries world-wide.
• Yohimbine (veterinary authorisation in many countries but not UK), idazoxan and analogues (no licence - some ‘wild-life’ use).
• Antagonists are used to reverse sedative and other actions of alpha2-agonists.

NB. Antagonists have actions of their own: anti-depressant, anti-obesity, aphrodisiac!

Question 7

List the main cardiovascular side effects of alpha 2 adrenoceptor agonist drugs

Answer 7

• Bradycardia and fall in cardiac output (CO).
• Initially vasoconstriction (peripheral action of drug on the blood vessels) and increase in peripheral resistance.
• Initial hypertension, then slight fall as CO drops.
• Much later (? after sedation has waned) long lasting centrally mediated vasodilation and some hypotension.

Question 8

Alpha-2 Agonists and Colic

Answer 8

• Alpha 2 agonists are excellent analgesics in colic, possibly partly because they inhibit gut motility.
• They cause marked bradycardia.
• Vasoconstriction (and hence colour of mucous membranes) may be seen in early colic (due to pain) but can also be caused by alpha-2 adrenergic agonists.
• Splenic contraction means that they cause a small rise in PCV.
• All these changes must be taken into account if a horse with colic has been given an alpha 2 agonist.

Question 9

Alpha 2 adrenoceptor agonists inhibit ADH (arginine vasopressin) release. What practical effect does this have?

Name one clinical condition where, as a result of this effect, there is an absolute contraindication to the use of alpha 2 agonists.

Answer 9

• Reduced ADH (arginine vasopressin) release will increase urine production.
• Main CI is blocked urinary outflow (most commonly a blocked urethra).

Question 10

Benzodiazepines

(Mech of Action)

Answer 10

• Agonists act at several sites in CNS, especially cerebral cortex, limbic system and midbrain.
• Benzodiazepines are agonists for the BZ1/BZ2 sites on the GABAa receptor, producing enhanced chloride conductance; they alter receptor structure to increase the number of chloride channels opened by the binding of GABA.
• No effect on peripheral GABAa receptors (because of the absence of a benzodiazepine binding site), central GABA receptors (calcium and potassium channels) and glycine receptor sites.

Question 11

List five major actions of benzodiazepines.

Answer 11

1. Anti-anxiety
2. Hypnosis (sleep)
3. Muscle relaxation
4. Anti-convulsant,amnesia
5. Also used IV to stimulate appetite in cats.

Question 12

Which benzodiazepine is water soluble and non-irritant to the vein?

Answer 12

Midazolam

Question 13

Name an antagonist to diazepam

Answer 13

• Flumazenil (trade name Anexate) available in UK.
• Sarmazenil available in some other European countries.

Question 14

Phenothiazines and Butyrophenones

Mech of Action

Answer 14

• Antagonists for dopamine-2 (DA2) receptors in the CNS.
• Principal sites of action believed to be the reticular activating system (RAS) and hypothalamus.
• Side effect is alpha-1 receptor blockade – causes hypotension and is probably contributes to sedative effects.

Question 15

At what receptors does acepromazine exert its effect? Is it an agonist or an antagonist?

Answer 15

• Major effects as an antagonist at dopamine and alpha-1 adrenoceptors.
• Minor effects at a number of other receptors.

Question 16

Which other group of sedative drugs exerts its effect at the same receptors as acepromazine?

Answer 16

• Butyrophenones
• Butyrophenones include azaperone (licensed for use in pigs) and fluanisone (a component of Hypnorm, licensed for use in rabbits).

Question 17

By what routes can acepromazine be administered? For each route, indicate the time from administration until maximal effect is achieved.

Answer 17

• IV 20+ mins
• IM/SC 40+ mins
• Oral 40+ mins (horses are very sensitive to oral doses!)

Question 18

List FOUR contraindications or partial contraindications to the use of acepromazine.

Answer 18

Only ABSOLUTE CI would be severe liver failure.

Routinely not used if there is:

1. Hypovolaemia (blood loss, toxaemia, shock etc) as vasodilation will make animal faint – however, once fluid deficits have been replaced may use with care to counteract vasconstriction of shock, although better agents exist to do this.
2. Use with care (low doses and be ready to counteract side effects) in Boxer dogs (vasovagal bradycardia and fainting), giant breed dogs (deep long lasting sedation), stallions (priapism a very rare complication, treatable if noticed as it happens).
3. Product information CI epilepsy, but neurologists argue this one

Question 19

What is the antagonist to acepromazine?

Answer 19

• None are available
• If serious hypotension does occur after giving acepromazine, treat with IV fluids.
• Do not give adrenaline!
• Acepromazine causes alpha-1 adrenergic blockade, so that adrenaline may stimulate an unopposed beta-2 adrenergic receptor action. This effect will increase vasodilation and so hypotension may become even worse

Question 20

Which agent has marketing authorisation as a sedative agent in the pig?

Answer 20

• Azaperone

Question 21

antagonist for Medetomidine

Answer 21

• antagonise with Atipamezole
• Atipamezole is a specific alpha 2 adrenoceptor ANTAGONIST

Question 22

What are good Sedative Drugs indicated for Horses?

Answer 22

• detomidine and butorphanol
• Xylazine
• Romifidine

Question 23

In a Detomidine and Butorphanol combo, what is the purpose of the opioid?

Answer 23

• Butoprhenol is the the opioid
• to reduce the reaction to touch

Question 24

List THREE methods that you could use to reduce the dose of induction agent required in a patient with cardiovascular disease, with the aim of minimising the adverse cardiovascular effects on the patient

Answer 24

1. Use premedication: drugs such as opioids provide analgesia, but they also produce good sedation with minimal cardiovascular side effects.

*However, you should be cautious about using medetomidine: although it provides profound sedation and reduces the dose of induction agent required, it also has profound adverse cardiovascular effects.

*ACP is fine to use in some types of cardiovascular disease but should be avoided in others.

2. Use a co-induction technique, combining your induction agent with a benzodiazepine (diazepam or midazolam).

*Benzodiazepines can cause excitement if administered alone as a pre-med in healthy patients but this problem is minimised if they are used at the time of induction. Benzodiazepines reduce the dose of induction agent required and have minimal cardiovascular side effects.

3. Administering the induction agent slowly to effect (rather than giving a rapid bolus) will also often reduce the dose which is required for induction.

Question 25

What are the theoretical advantages of using sevoflurane instead of isoflurane for a box induction in a cat?

Answer 25

• Sevoflurane has a lower blood:gas solubility than isoflurane, therefore its speed of onset is quicker, resulting in a faster induction.
• It is also less irritant to the respiratory tract than isoflurane, so may cause less breath holding during induction.
• However, sevoflurane is not licensed for use in cats

Question 26

How would you carry out a box induction in a cat?

Answer 26

• Quiet environment
• Put the patient inside the box
• De-nitrogenate the box by filling it with 100% oxygen for 5-10 minutes
• Start inhalant agent
• Observe the cat in the box
• Watch for the excitement phase
• Watch for the relaxed phase
• If cat in abnormal position you must intervene and adjust position (e.g. flexed neck)
• Watch breathing, initially rapid rate and later slower rate of breathing
• Flush box with 100% oxygen to remove isoflurane
• Open box and take cat out
• Intubate the trachea
• Maintain the cat on inhalant agent and oxygen

Question 27

If you decided to induce anaesthesia using a triple combination of ketamine/medetomidine/methadone, how would you carry this out?

Answer 27

Draw up all drugs into one syringe. Inject i/m.

May need to use a crush cage depending on how aggressive the cat is.

Leave cat in cage, cover with a towel, dim lights and keep quiet so the drugs can take effect in a calm environment.

Drugs should take effect within about 5 mins. If they haven’t worked after 10mins, it is likely your injection didn’t go fully i/m!

Remove cat from cage and assess depth of anaesthesia.

Supplement oxygen, place i/v catheter.

Depending on procedure to be performed you may need a tiny dose of propofol to allow endotracheal intubation and maintenance with an inhalational agent (for a long procedure).

Question 28

Monitoring of anaesthesia may be different in a cat induced using ketamine/medetomidine/methadone (compared to propofol for example).

What signs would you expect to see?

Answer 28

Ketamine preserves CNS reflexes to a greater extent. The cat may swallow, salivate and may have an active palpebral reflex. Jaw tone is likely to be greater than after propofol or isoflurane.

Ketamine also stimulates the sympathetic nervous system so the heart rate and blood pressure may be higher than you might expect in an animal anaesthetised with propofol or isoflurane.

Question 29

You take the bandage off the catheter and see a swelling around the catheter site in the leg. You are worried that the thiopentone has gone extravascularly. What is the most important consequence of this?

Answer 29

• The thiopentone is highly irritant extravascularly and will cause skin and subcutaneous necrosis
• Flush the area with sterile saline with lidocaine added
• The saline will dilute the thiopentone and the lidocaine may cause local vasodilation to increase uptake of the drug out of the subcutaneous tissues

Question 30

You realise that you will probably have to anaesthetise the cat daily for several days to flush the wound and keep it clean.

Which anaesthetic agent is not suitable for induction of anaesthesia in a cat several days in a row? Why not?

Answer 30

• Cats have difficulty metabolising both the phenol and the lipids in propofol.
• Repeated doses in a short period of time can lead to drug accumulation.
• Some studies have reported slow recoveries and toxic effects such as anorexia, diarrhoea and anaemia with repeated use of propofol in cats