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Perspectives on Premeds - Phenothiazines: from Mental Health to Premedication

Introduction

Phenothiazines were originally investigated in the 1870s, although it wasn’t until the 1950s that acepromazine was introduced in human medicine for the treatment of schizophrenia.1 However, the use of acepromazine  in humans was quickly abandoned due to it's side effects, but it remains popular in veterinary medicine, and is the only licensed phenothiazine in small animal practice. Acepromazine will be the focus of this article.

Acepromazine is commonly used for premedication prior to general anaesthesia and as a tranquilliser/sedative.

Pharmacology of Acepromazine

Acepromazine  acts mainly as dopamine receptor (D1 & D2) antagonist,2 but it also blocks α1 adreno-receptors, and has anticholinergic & antihistamine activity (muscarinic receptor & H1 receptor blockades). There is also evidence that acepromazine has membrane stabilising effects by blocking ion channels.3 Most clinical activity is via depression of the central nervous system.

Acepromazine is more than 90% protein bound and is highly lipophilic, readily crossing the blood-brain barrier and placenta.

Hepatic metabolism is via phase 1 and 2, and some metabolites may be active. Excretion is via the bile and urine.3

Acepromazine is not recommended in patients with compromised liver function, porto-systemic shunts, animals with immature liver function (less than 12 weeks of age) or patients with hepatobiliary disease.2

Acepromazine is not analgesic.

Clinical Effects

Acepromazine delivers its clinical effects via the antagonistic activity at the dopamine receptors in the basal ganglia, medulla and hypothalamus of the central nervous system. This results in an increased threshold to external stimuli and a reduction in motor activity. Peripherally acepromazine has antagonistic activity at α1 receptors resulting in vasodilation.3

1. Time to onset & duration of clinical effects

Time to onset of action is dependent on the route of administration: 

  • 10-15 minutes following intravenous administration.2,4
  • 30-40 minutes following intramuscular administration.2,4

In healthy animals the duration of action of acepromazine  is approximately 6 hours, with the effects starting to wane after 3-4 hours.3 In debilitated or hypothermic patients the duration of action may be extended.

2. Sedation

The main clinical effects of acepromazine are:

  • Mood altering and calming
  • At low doses: Tranquillisation (indifference) and anxiolysis (with minimal hypnosis, narcosis or marked sedation). 2,3,4
  • Sedation at higher doses. Initially dose dependent, plateauing at higher doses with no further intensification of sedative activity but with an increase in side-effects and duration of action.2,3,4 Murrell (2007) suggests doses greater than 0.05mg/kg have no additional sedative activity.4

Animals administered acepromazine  should be handled quietly and left undisturbed. Sedation may be temporarily overcome by stimulation and animals may rouse or become excitable if handled. For this reason, acepromazine is commonly combined with an opioid (neuroleptanalgasia) to improve the quality and reliability of sedation, and to provide analgesia.2,3

3. Dose sparing

Acepromazine may potentiate the central nervous system depression caused by other sedatives/anaesthetics resulting in a dose sparing effect.3

4. Cardiovascular system

a. Peripheral vasodilation & hypotension

Antagonism of the α1 adrenoceptors and depression of the central & peripheral sympathetic nervous systems results in peripheral vasodilation and hypotension. This is normally well tolerated in healthy animals.2,3 An increase in heart rate is occasionally seen in response to the hypotension, although bradycardia may also occur.3

The use of acepromazine in animals with cardiovascular disease or hypovolaemia should be carefully considered as the vasodilation may result in cardiovascular collapse.2

The management of acepromazine-induced hypotension is problematic. Adrenaline is contraindicated: Following acepromazine  administration (α1 receptor antagonism) adrenaline will preferentially activate β2 adrenoceptors and cause additional vasodilation and hypotension. Dugdale (2010) suggests the use of an α1 agonist e.g. phenylephrine and fluid therapy to manage acepromazine induced hypotension, although Sinclair & Dyson (2012) suggest crystalloids may result in further vasodilation.5

Phenothiazines may potentiate the cardiovascular depressive effects of other agents.

b. Syncope, giant breeds and Boxer dogs

The hypotension and possible bradycardia following the administration of acepromazine can lead to cardiovascular collapse and fainting, particularly in brachycephalics and some Boxer dogs.2,3

Giant breeds are often considered to be more sensitive to the cardiovascular effects of acepromazine, possibly due to allometric scaling, and therefore metabolic body size may be a more suitable determinant for dose selection.3

Acepromazine has long-lasting effects which are not antagonisable, and its administration should therefore be avoided if hypotension or cardiovascular compromise are present or anticipated.2

c. Anti-arrhythmic effects

Acepromazine is considered to impart an anti-arrhythmic action via three suggested mechanisms: Antagonism of the α1 adrenoceptors in the heart; a reduction in overall sympathetic activity; reduced conduction velocity in cardiac muscle cells via membrane stabilisation.2,3 The antiarrhythmic effects of ACP are of unknown relevance in small animal practice.2

5. Body temperature

Following Acepromazine administration animals should be vigilantly monitored for the changes in body temperature that may occur as a consequence of peripheral vasodilation and depression of the thermoregulatory centre. Hypothermia may reduce drug metabolism, increase anaesthetic recovery time and affect immune and cardiovascular function. Therefore, careful measures to prevent or reduce heat loss should be taken.2,3,4

6. Respiratory effects

Popovic et al (1972) reported that clinical doses of acepromazine administered to dogs and cats had little or no influence on respiratory function and had a calming influence on patients with airway disease or dysfunction.6 However, the effects of acepromazine are long-lasting, may cause relaxation of the pharyngeal muscles compromising airway function and, in laterally recumbent patients experiencing excessive sedation, may result in an inability to maintain a patent airway.2

Phenothiazines reduce the sensitivity of the respiratory centre to the stimulatory effects of carbon dioxide resulting in a slight reduction in respiratory rate. However, in healthy animals, the tidal volume remains relatively stable (or slightly reduced) and there is little change to blood gases and minute volume.3

At clinical doses in healthy animals ACP has little overall effect on the pulmonary system. Nevertheless, at higher doses respiratory depression can occur.2

Acepromazine may potentiate the respiratory depressive effects of some opioids2,3 and other sedative/anaesthetic agents.

7. Anti-emetic effects

Dopamine activity in the chemoreceptor trigger zone of the medulla oblongata is inhibited by phenothiazines resulting in depression of the vomiting centre.7 This produces a mild anti-emetic effect which is particularly useful for reducing the nausea and vomiting associated with some opioids (and possible α2-agonists).3 In a study reported by Valverde et al (2004), when ACP was administered at least 15 minutes prior to an opioid known to induce emesis (morphine) there was a reduction in the incidence of vomiting from 75% to 25%.8

Although Acepromazine has anti-emetic properties, it is not effective for directly treating motion sickness (caused by stimulation of the vestibular system), although the anxiolytic action may reduce the incidence of nausea/vomiting.3

8. Acepromazine and anti-histamine effects

The H1 receptor depressive action of acepromazine causes a mild anti-histamine effect.3 Acepromazine administration is therefore not recommended prior to intradermal skin allergy testing.2,3

9. Seizure threshold

There is no current clinical data to suggest acepromazine has a detrimental effect on animals with a history of seizures, or that it is contraindicated in animals undergoing myelography.2,3 Indeed, acepromazine was historically used as an anticonvulsant for the treatment of metaldehyde poisoning. In a series of canine myelograms reported by Drynan et al (2012) there was no difference in the incidence of seizures in animals that received acepromazine + methadone premedication when compared to a group that received methadone alone.9

10. Spleen, PCV and haemoglobin

Splenic enlargement, via relaxation of the capsule, results in sequestration of erythrocytes and platelets. Consequently, a decreased packed cell volume (PCV) and haemoglobin concentration are commonly observed following the administration of acepromazine.10 In a study performed by Sutil et al (2017) PCV, red blood cell count and haemoglobin concentrations started to decrease 15 minutes after acepromazine administration and had not returned to baseline levels by the conclusion of the study period (12 hours). An 18% reduction in PCV was reported in this study. 11

11. MDR1 mutants

In a 2016 paper by Deshpande et al, intravenously administered acepromazine resulted in more profound sedation with a longer duration of action in MDR1 mutant animals when compared to normal controls.12 In such animals the dose of acepromazine should be reduced or an alternative product considered.



Summary of Acepromazine

Depression of the CNS via antagonism of D1, D2, α1, muscarinic & H1 receptors.
Readily crosses the blood-brain barrier & placenta.
Liver metabolism. Excretion via bile & urine.
Tranquillisation & anxiolysis at low doses.
Sedation at higher doses. Sedation plateaus/increased side effects/increased duration of action at higher doses.
Following administration handle patients quietly and minimise stimulation to reduce the possibility of arousal/excitement.
Onset: 10-15 minutes (intravenous); 30-40 minutes (intramuscular)
Long duration of action. Approximately 6 hours in healthy patients. Clinical effects begin to wane after 3-4 hours.
Not analgesic.
Combine with opioid to improve quality & reliability of sedation & provide analgesia.
Dose sparing effects on other CNS depressants.
Minimal respiratory effects in healthy animals although higher doses may cause respiratory depression.
Hypotension via peripheral vasodilation and depression of SNS. Usually well tolerated in healthy animals.
Syncope in some Boxer dogs and brachycephalics.
Hypothermia via peripheral vasodilation and depression of thermoregulatory centre. Monitor regularly and manage accordingly.
Potentiation of cardiovascular and respiratory effects of the other CNS depressants
Anti-arrhythmic.
Mild anti-emetic.
Mild anti-histamine. Avoid administration prior to intradermal skin testing.
Splenomegally & reduced PCV & Hb.
Giant breeds “more sensitive”. Select dose based on metabolic body size. Reduce dose.
MDR1 mutants. Reduce the dose or administer an alternative product.
Not antagonisable.

Article by
Dr. Karen Heskin
BVSc CertSAO MRCVS

Veterinary Technical Manager, Jurox UK

Originally published: Thursday, 11th October 2018

References

1. Collard JF & Maggs R (1958). Clinical trial of acepromazine maleate in chronic schizophrenia. BMJ, 1452-1454
2. BSAVA Manual of Canine & Feline Anaesthesia & Analgesia. 3rd Edition. (2016)
3. Dugdale A (2010). Veterinary Anaesthesia: Principles to Practice.
4. Murrell J (2007).  Choice of premedicants in cats and dogs. In Practice 29, 100-106
5. Sinclair MD & Dyson DH (2012). The impact of acepromazine on the efficacy of crystalloid, dextran and ephedrine treatment in hypotensive dogs under isoflurane anesthesia. Veterinary Anaesthesia and Analgesia 39, 563-573
6. Popovic NA, Mullane JF & Yhap EO (1972). Effects of acetylpromazine maleate on certain cardiorespiratory responses in dogs. American Journal of Veterinary Research 33, 1819-1824
7. Lorenzutti AM, Martin-Flores M, Litterio NJ, Himelfarb MA & Zarazaga MP (2015).  Evaluation of the antiemetic efficacy of maropitant in dogs medicated with morphine and acepromazine. Veterinary Anaesthesia and Analgesia 43, 195-198
8. Valverde A, Cantwell S, Hernandez J, Brotherson C (2004). Effects of acepromazine on the incidence of vomiting associated with opioid administration in dogs. Veterinary Anaesthesia and Analgesia 31, 40-45
9. Drynan EA, Gray P & Raisis (2012). Incidence of seizures associated with the use of acepromazine in dogs undergoing myelography. Journal of Veterinary Emergency and Critical Care 22, 262-266
10. Dyson DH, Maxie MG & Schnurr D (1998). Morbidity and mortality associated with anesthetic management in small animal veterinary practice in Ontario. J Am Anim Hosp Assoc 34, 325-335
11. Sutil DV, Mattoso CRS, Volpato J et al (2017). Hematological and splenic Doppler ultrasonographic changes in dogs sedated with acepromazine or xylazine. Veterinary Anaesthesia & Analgesia 44, 746-754
12. Deshpande D, Hill KE, Mealey KL, Chambers JP & Gieseg MA (2016). The effect of the canine ABCB1-1 mutation on sedation after intravenous administration of acepromazine. Journal of Veterinary Internal Medicine 30, 636-641

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