Neuroleptics

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Alternative names and definitions

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Psychotropics, major tranquilizers, antipsychotics, ataractic

neuro=nerve lepsis=a taking hold, a seizure

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Neuroleptics:
1.Mode of Action
2. Major Sites of Action
3. Peripheral receptors blocked

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1.-block dopamine excitatory receptors (D2) in the CNS (Parkinsonian side effects seen at high doses)
OR
-inhibition of reuptake of adenosine in the CNS (anti-anxiety and sedative actions)
2. striatal and cortical brain regions; limbic system also blocked (emotional response reduced).
3. alpha adrenoceptors, 5-HT, histamine, acetylcholine

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Drug groups within the neuroleptics (4):

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1.Phenothiazine group
2.Butyrphenones (e.g azaperone)
3.Misc (behaviour modifying compounds such as buspirone-prevention of urine spraying)

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Phenothiazines (and Butyrophenones)
1.Major Effects

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1. suppression of spontaneous locomotor activity and reduction in complex behaviours **NO APPRECIABLE ANALGESIA**:
-decreased spontaneous motor activity sedation, reduced aggression
-catalepsy at higher doses
-antiemetic (block of dopamine receptors in the medulla CTZ)
-supression of conditioned avoidance behaviour
-seizure threshold may be lowered
-excitement may be suppressed (e.g. morphine mania in the cat and amphetamine or apomorphine induced excitement [D2])
-hypothalamic and/or medullary vasomotor reflexes reduced

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2.Other CNS Effects

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(i) Hypothalamus/pituitary axis:
-hypothermia (depletion of central catecholamine stores)
-loss of temperature control (hyperthermia may result if ambient temperature is high)

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Adverse effects due to doses higher than those which produce a depressant effect

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1. Interference with pituitary function:
-block FSH and LH release (ovulation and oestrus inhibited)
-ADH and MSH release is inhibited, possibly also oxytocin
-Prolactin secretion is enhanced (dopamine normally has an inhibitory influence on this via tubero-infundibular neurons)

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Other CNS effects in Brainstem and Chemoreceptor Trigger Zone

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1.Brainstem-respiratory control is little affected but vasomotor reflexes are impaired; respiration is depressed at higher doses
2. Chemoreceptor Trigger Zone-CTZ medulla blocked, thus nausea and vomiting are inhibited (dog)

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Other Phenothiazine Actions:
Cardiovascular

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1. CARDIOVASCULAR-lowered TPR and CO=reduced BP
-reduction of arrhythmias through antagonism of adrenaline and noradrenaline
-PCV is decreased (as is Hb)-due to haemodilution because of preferential venular dilation and increased splenic storage because of trabecular and capsular muscle relaxation (alpha block)

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Other Phenothiazine Actions:
Convulsions and Autonomic

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1. CONVULSIONS:-block stimulants such as nicotine and nikethimide therefore may induce convulsions
2.AUTONOMIC-Anticholinergic action causing blurred vision
-antiadrenergic action: release of adrenaline from the adrenal medulla, decrease salivation and decreased sweating
-adrenaline may provoke a hypotensive crisis
-potentiation of local anaesthetic action combined with alpha block prohibits use with epidural anaesthetics

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Other Phenothiazine Actions:
Hyperglycaemia and Penile Prolapse

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1.HYPERGLYCAEMIA-adrenaline released from adrenal medulla and inhibit insulin action
2. PENILE PROLAPSE-horses treated with acetylpromazine and CAN BE PERMANENT-block of alpha adrenoceptors in retractor penis muscle

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Pharmacokinetics/Pharmacodynamics/Disposition/Elimination

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1.Good Absorption by in all routes of admin (usually give IV for rapid premed followed by PO)
2.Metabolism extensive and almost entirely hepatic microsomal (care in patients with liver failure)-hydroxylation and glucaronide formation & sulphoxidation
3.Active metabolites of acetylpromazine have tranquilizer activity
4. Excretion of inactive metabolites fairly slow in urine; also excreted in milk
5.Should not be given to food producing animals near slaughter

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Adverse Reactions/Contraindications/Precautions

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-may decrease liver function and produce jaundice
-enhance toxicity of organophosphates and local anaesthetics (block cholinesterase)
-potentiate other CNS depressants (therefore reduce doses)
-caution if old/debilitated animals due to CV effects

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Uses:

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-sedation/tranquilization as anaesthetic premedicants
-signs of action: ptosis, head drop, protrusion of nictitating membrane and hindlimb ataxia

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Phenothiazine formulations and adv/disadv.:

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1.Promazine: better absorbed orally than others, granules in feed (shoeing, etc), DOA=4-6 hours
2.Acetylpromazine: more potent, exhibits less side effects, weak antiemetic, hypotensice, spasmolytic, NOT ANTICONVULSANT (lowers threshold for seizures); causes lowering of BP and bradycardia-often followed by sinoatrial arrest (Atropine always used as premedicant).
3. Prochlorperazine (not so sedative as phenothiazines alone)
4.Trimeprazine: good sedative antihistamine, antitussive, spasmolytic; less hypotensive than some and said to be more predictable in the horse; may have a degree of analgesic action

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Butyrophenone formulations and adv/disadv

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1.Droperidol: 400x potency of chlorpromazine (restricted to neuroleptanalgesia=deep tranquilization and analgesis through mutual potentiation of a major tranquilizer and a narcotic analgesic[fentanyl])
2.Azaperone: safe, short acting, best in ungulates (restricted in pig)
3.Buspirone-urine spraying in cats (anti anxiety) long lasting, less side effects than with diazepam