In this article we will discuss about the antipsychotic drugs or major tranquilizers and anxiolytics or the minor tranquilizers.
Antipsychotic Drugs or Major Tranquilizers:
These were previously referred as the major tranquilizers and are primarily used for the treatment of schizophrenia and mania though many of them have anxiolytic action too.
Depending on the chemistry, these have been divided into the following groups:
A. Phenothiazine derivatives,
B. Thioxanthene derivatives,
C. Dibenzepine derivatives,
D. Butyrophenone derivatives,
E. Rauwolfia derivatives,
(A) Phenothiazine Derivatives:
These have a three ring structure in which two benzene rings are linked by a sulfur and a nitrogen atom (Fig. 10.1). Substitution on the ring structures are made at positions C2 and N10 as is shown in the figure.
Depending on the substitution at N10, there are three classes of phenothiazines:
(i) Aliphatic side chain of the di-alkyl amine group: e.g. Chlorpromazine, trifluopromazine, acepromazine, promazine etc.
(ii) Piperidine side chain: e.g. Mepazine, thioridazine, mesoridazine, pipracetrazine etc.
(iii) Piperazine side chain: e.g. Prochlorperazine, trifluperazine, fluphenazine, thioproperazine, thioethylperazine, butaperazine etc.
Structure Activity Relationship:
i. Substitution at C2 position produces more active compounds than elsewhere in the ring.
ii. Compounds with substitution by CF3 at C2 are more active than Cl substitution at C2. Any substitution other than F or Cl at C2 does not change potency over the non-substituent group.
iii. Substitution at N10 by aliphatic side chain yields compounds which are least potent; piperidine ring yields little more active and potent while the piperazine ring substitutes are the most potent of all the derivatives of phenothiazines.
iv. Piperidine side chain produces lower extrapyramidal symptoms or syndrome like rigidity, akinesia and tremors etc.
v. Piperazine side chain produces more intense ketatonia or flaccid type of paralysis, more potent antiemetic effect, less tendency to produce sedation and autonomic effects such as hypotension etc.
Mechanism of Action:
Phenothiazine derivatives produce their behavioural effects by blockade of D2 – dopaminergic receptors. In addition, dopaminergic receptors blockade in the basal ganglia appears to cause the extrapyramidal symptoms and that of CTZ is responsible for the antiemetic action.
Chlorpromazine Hydrochloride (CPZ):
Although compared to acepromazine, CPZ is less widely used in veterinary medicine, but CPZ is the most extensively studied drug of the group.
Pharmacological Actions:
All compounds of this group, including CPZ, have a wide range of central and peripheral effects. It has central sedative, antiadrenergic, weakly antihistaminic, weakly anticholinergic, potent local anaesthetic and some skeletal muscle relaxant actions.
In addition, it inhibits the RAS which is responsible for wakefulness. It effectively blocks the conditioned avoidance responses and spontaneous motor activity. It also acts as antiemetic by depressing the CTZ.
CPZ and related compounds possess distinct alpha adrenoceptor blocking effects and can thus prevent or reverse a number of actions of noradrenaline and adrenaline i.e. epinephrine reversal. Therefore, administration of adrenaline is contraindicated whenever phenothiazine derivatives are used.
However, these prevent the epinephrine- induced ventricular fibrillation or arrythmias during halogenated anesthetics (e.g. halothane, meth-oxy-fluorane, etc.) similar to that by alpha adrenoceptor antagonists.
All phenothiazine derivatives cause a fall in body temperature partly due to increased heat loss through dilated cutaneous blood vessels and partly through resetting of the thermoregulatory mechanisms. It also blocks the ovulation and suppresses estrous cycle and decreases libido in man.
Therapeutic Uses:
(i) General restraint of large and small animals;
(ii) Preanesthetic medication; reduces the dose of the anesthetic agents and analgesics by about 50 per cent.
Dose:
Therapeutic use of CPZ is contraindicated in horses because of violent incoordination, muscle weakness and excitement following CPZ administration.
Acepromazine Maleate:
Formerly called acetyl-promazine. It is probably the most extensively used phenothiazine derivative in veterinary medicine. It is more potent than CPZ and promazine and the excitement reactions are rare.
In all species of animals, it causes a fall in blood pressure particularly in horses by vasodilation through the peripheral alpha adrenoceptors. Thus the use of acepromazine is dangerous where acute circulatory failure or shock is a possibility. It is primarily used as a preanesthetic agent in dogs, cats, horses and other species of animals and potentiates the action of barbiturates.
Dose:
Promazine Hydrochloride:
Its potency is less than that of CPZ. It is used as preanesthetic for smooth induction of anesthesia and reduces the dose of anesthesia by 30 to 50 per cent. It is thought to have certain advantages over CPZ at-least in horses as the latter produces excitation in horses while the former does not. Thus, it is often preferred over CPZ in horses as it seldom produces excitement or recumbency.
Dose:
Prochlorperazine Edisylate:
The sedative effect of this compound is moderate compared to that of CPZ or triflupromazine. The hypotensive and respiratory effects are also low compared to promazine.
Dose:
Dog: 1 mg/kg, IM or SC.
Perphenazine:
Pharmacologically, its all actions are similar to that of prochlorperazine. It produces marked extrapyramidal and antiemetic effects and the latter effect is more pronounced as compared to that of CPZ or promazine and is useful in the prevention of motion sickness. Sedative action lasts for 6-8 hrs.
Dose:
Dog and Cat: 0.88 mg/kg ; by oral route; 0.55 mg/kg by IM;
Cattle and Pig: 0.22 mg/kg, IV.
Propiopromazine:
It should not be used in horses as it causes irreversible paralysis of penis. Only used in dogs and cats.
Dose:
Dog and Cat: 0.11-1.1 mg/kg, IV or IM; 1.1-4.4 mg/kg, oral
Triflupromazine:
Its therapeutic use as neuroleptic has been approved in dogs, cats and horses. However, it enhances the rate of erythrocyte cholinesterase inhibition in sheep poisoned with organophosphate compounds.
Dose:
Ethylisobutrazine:
The duration of neuroleptic action ranges between 6-72 hrs. depending on the dose used.
Dose:
Methotrimeprazine:
It is also a phenothiazine derivative and also an analgesic with the analgesic potency equivalent to 0.7 times of that of morphine.
Other Phenothiazine Derivatives:
Effect of Phenothiazine Derivatives on Cardiovascular System:
These drugs produce hypotensive effects by central and peripheral actions, reflex tachycardia and antiarrythmic action due to membrane stabilization similar to that of quinidine.
Effect of Phenothiazine Derivatives on Endocrine Glands:
These drugs being anti-dopaminergic in nature, increase prolactin release by inhibiting effect of dopamine on lactotrophs and result in galactorrhoea and gynecomastia.
(B) Thioxanthene Derivatives:
These derivatives also have aliphatic or piperazine substituents. In thioxanthenes, the analog of CPZ is chlorprothioxene while piperazine substituents are: clopenthixol, flupenthixol, pifutixol and thiothexene. All these are potent and effective antipsychotic agents.
Chlorprothixene:
It is chemically related to phenothiazine derivatives. It has greater depressant and anticholinergic activity than CPZ. It also possesses antiemetic and antihistaminic activity. It is considered as an ideal drug for caesarean section since sedation allows the operation in conjunction with local anaesthetics in dogs.
Dose:
Dog: 2.2-4.4 mg/kg, IV or IM;
Sheep and Goat: 0.5 mg/kg, IV;
Swine: 0.3-1.0 mg/kg, IV
Thiothixene:
Its potency is equivalent to that of trifluopromazine and is used in refractory cases. It is a piperazine substituted thioxanthene. It is highly potent and less sedating.
(C) Dibenzepine Derivatives:
These are another group of tricyclic antipsychotic agents containing a seven member central ring.
There are two families of these drugs:
Loxapine Like Family: e.g. clothiapine, metiapine, loxapine, zotapine etc. These have prominent anti-dopaminergic activity.
Clozapine Like Family: e.g. clozapine, fluperlapine, olanzapine etc. These have low affinity for dopaminergic receptors and interact with other classes of receptors- muscarinic, 5HT2, alpha adrenergic, histaminergic etc.
(D) Butyrophenone or Phenyl-butyl-piperidine Derivatives:
These act as dopaminergic antagonists. Central actions of dopamine and catecholamines are blocked, act by mimicking the action of GAB A or by preventing the effect of glutamate or aspartate on synaptic junctions.
Cardiovascular and respiratory effects of butyrophenone derivatives are minimal, although these produce slight hypotension due to alpha adrenoceptor blockade, and thus, administration of catecholamines is contraindicated as it may worsen the hypotensive crisis. These are potent antiemetics and block the CTZ. Due to their antiemetic efficacy against drug-induced (morphine) emesis, these are preferred for neuroleptanalgesia.
Azaperone:
It is relatively nontoxic and a short acting drug. It is chiefly used in swine where it is administered by IM route. It provides good and dose-related sedative effect in horses, however, IV administration should be avoided as it causes violent excitement in horses. Thus, its use in horses be avoided as the excitement may occur which may be an extremely dangerous situation.
However, the excitement and hypotensive effects in pigs are insignificant. Thus, it is used as a sedative for premedication/or caesarean section in pigs as the cardiopulmonary depressant effect on the newly delivered piglets are minimal. It is used to prevent aggressiveness and fighting on mixing of litters.
Dose:
Pigs: 0.3-0.5 mg/kg, IM
Horses: 0.4-0.8 mg/kg, IM.
Droperidol:
It is about 400 times more active than CPZ or chlorprothixene and about 10 times more potent than haloperidol. It has the shortest action of all the butyrophenones. It is the most potent antiemetic known, being up to 1000 times more potent than CPZ and chlorprothixene.
It has got wide margin of safety due to brief duration of action of about 2 hrs. It produces slowing of respiration and heart rate, hypotension, drop in cardiac output and decrease in myocardial contraction.
Dose:
Pigs: 0.1-0.4 mg/kg
Dog: 0.5 mg/kg, IV.
Haloperidol:
It is less potent than droperidol and is less commonly used in veterinary medicine. It is a potent antiemetic and the antiemetic effect lasts for 4 days in dogs.
Dose:
Dog: 0.02-0.1. mg/kg, IV or IM.
Lenperone:
It is used as anxiolytic, antiemetic and preanaesthetic in dogs. Compared to acepromazine, it has low potency in blocking the alpha adrenergic receptors, produces less arterial hypotension and recovery time is also short.
Dose:
Dogs: 0.22-0.88 mg/kg, IV;
: 0.44-1.76 mg/kg, IM;
: 0.55-2.2 mg/kg,oral
Di-phenyl-piperidine Derivatives:
This is comparatively a new class of drugs and are analogous to butyrophenones and the examples of this group are penfluridol, fluspirilene, pimozide etc.
(E) Rauwolfia derivatives:
Reserpine:
It is not as good as the chlorpromazine and is only used in refractory cases. It depletes catecholamines and 5HT from the nerves. It acts as antiadrenergic, however, does not have anticholinergic effect. It is not a hypnotic.
It was used for the transportation of small and large animals. It produces hypothermia, bradycardia and decreases the respiratory rate. However, it is not being used these days and has become a obsolete drug. Phenothiazine derivatives are preferred because their onset of action is more rapid and recovery is quicker.
In human beings it produces mental depression and suicidal tendency.
Metoserpate:
It was used as tranquilizer for flock treatment of birds prior to handling. However, now it is only of academic interest.
Anxiolytics or the Minor Tranquilizers:
Benzodiazepines are the most commonly used anxiolytics. However, pharmacologically most of the drugs used to treat anxiety are sedatives in nature. And, benzodiazepines, when given in high doses, produce sedative effects.
In human beings drugs of this group are utilised for their antianxiety, sedative, hypnotic, muscle relaxant and retrograde amnesia action. Some of the important ones used in human medicine are: diazepam, chlordiazepoxide, oxazepam, lorazepam, prazepam, alprazolam, midazolam and clonazepam etc. However, in veterinary medicine, mainly diazepam and chlordiazepoxide are used.
These compounds exert their sedative effects through depression of the limbic system and the muscular relaxation through the inhibition of internuncial neurons at the spinal level. When used in combination with other drugs, the cardiopulmonary depressant effects are reduced and also the dose of the anaesthetics is reduced.
Mechanism of Action:
Benzodiazepines produce their action through stimulation of specific benzodiazepine receptors which potentiate the effect of GABA through GABA receptors and Cl– chloride channels which increase the flow of Cl– into the cell, cause hyperpolarization and, therefore, cells become refractory to other stimuli or by an enhancement or facilitation of GABAergic synaptic transmission.
Clinical Uses:
(i) Anxiolytic;
(ii) Premedication;
(iii) Anticonvulsant.
Diazepam:
It is probably the most commonly and widely used among the benzodiazepines. It produces taming effect in animals. It is used as anticonvulsant, muscle relaxant, anxiolytic and hypnotic. It is 20 times more potent than chlordiazepoxide in blocking the decerebrate rigidity in animals. Its principal site of action is in the brain stem reticular formation.
It is the drug of choice for tranquilizing the swines. However, in dogs its use for sedative, ataractic or neuroleptic effect is questionable. But, in horses, diazepam in combination with ketamine and xylazine gives smooth induction and recovery.
Dose:
Dog and Cat: 1 mg/kg, IV or IM;
Swine: 8.5 mg/kg, IM;
Cattle: 0.4 mg/kg, IM
Horse: 0.22 mg/kg ; IM.
Chlordiazepoxide:
Its activity is similar to that of diazepam but less potent. It is not being used very frequently as it has been reported to cause teratogenic effects in human beings if consumed during the 6th week of pregnancy. Its dose in swine is 5-10 mg/kg, IM.
Midazolam:
It has got a short biological half life compared to diazepam: Ten mg of midazolam is equivalent to 200 mg of thiopentone in inducing sleep and duration of sleep. It appears to be a satisfactory substitute for the ultra-short acting barbiturates in inducing anaesthesia. However, further studies are required to be taken up before it is used in veterinary medicine
Other Antianxiety Drugs:
Meprobamate:
It is propanediol carbamate and has the tranquilizing and central muscle relaxant property. But it is rarely used even in human medicine.
Hydroxyzine:
It is an antihistaminic, anticholinergic, antispasmodic, antiemetic local anaesthetic and basically has the H1 receptors antagonistic property. It is sometimes used as a preanesthetic, however, mostly has been replaced by benzodiazepines.
Azapirones:
Buspirone, gepirone, ipsapirone, tiaspirone etc are the examples of this group. The anti-dopaminergic action of these drugs is limited to in vivo. These do not induce extrapyramidal side effects, do not bind with benzodiazipine binding sites or do not facilitate the action of GABA. Also these drugs do not have anticonvulsant activity. These compounds have a selective affinity for the 5HTIA type receptors.
Durg Interactions of Tranquilizers:
Both the antipsychotic and antianxiety drugs potentiate the effect of all other CNS depressant drugs-alcohol, hypnotics, sedatives, narcotic analgesics, anaesthetics etc. Hence, these interactions become therapeutically important.
Preanaesthetics:
If these compounds are used as praeanaesthetics, these not only decrease the dose of anaesthetics but also potentiate the duration of sleep and also the margin of safety as the depression of cardiopulmonary functions becomes minimal.
Neuroleptanalgesia:
This state is quite important and useful for endoscopy and for a variety of minor surgical procedures in severely ill or otherwise poor risk patients. Administration of anxiolytics (diazepam) has been reported to prolong the period of analgesia and increase the muscle relaxation.