Psychopharmacological Agents, which are employed to treat mental or behavioural diseases (psychiatric illnesses), are called psychotropic drugs, psychotherapeutic agents or psychoactive agents. They can be divided into the following groups:
1. Antipsychotics (neuroleptics; major tranquilizers): They are used to treat patients of psychosis or schizophrenia.
2. Antianxiety drugs (anxiolytics; minor tranquilizer): These drugs treat anxiety states. They are also used as sedative or hypnotics.
3. Antidepressant drugs: They are used in the treatment of depression.
4. Hallucinogens: These substances cause hallucinations. They are not used therapeutically.
ANTIPSYCHOTICS of the Psychopharmacological Agents
In schizophrenia (psychosis), the mental function is sufficiently impaired. So the patient is unable to meet the demands of day to day life. There occurs distortion in thought and perception, hallucination and delusion. Following circumstantial evidences suggest that dopamine (DA) overactivity is responsible for most manifestations of schizophrenia:
• The typical antipsychotic drugs like haloperidol and pimozide act by blocking post-synaptic DA receptors (D2) strongly in mesolimbic frontal system.
• Drugs that increase the central DA activity, e.g. levodopa (DA precursor) or ampheta min
(DA releaser) or apomorphine (DA receptor agonist) either aggravate schizophrenia or precipitate the symptoms of schizophrenia in normal individual. Apart from this, abnormal 5-HT metabolism, endogenous opioides, prostaglandins, and noradrenaline have also been implicated in psychosis because typical antipsychotic drugs do not provide absolute cure of schizophrenia. Further, atypical neuroleptics llke clozapine and olanzepine have little effect on D1 or D2 receptors but bind more avidly to 5-HT2, D4, ct1 and H1 receptors. 5-HT has a modulatory role on DA pathways. Another neurotransmitter implicated in pathophysiology of schizophrenia is glutamate because glutamate NMDA receptor antagonists such as phencyclidine and ketamine produce psychotic symptoms on administration to normal subjects, e.g. hallucinations and thought disorders.
Antipsychotics of the Psychopharmacological Agents are classified on their chemical groupings as:
I. Typical or classical neuroleptics which block both D1 and D2 receptors:
1. Phenothiazines: Chlorpromazine, triflupromazine, thioridazine, trifluoperazine.
2. Butyrophenones: Haloperidol, droperidol, trifluperidol, penfluridol.
3. Thiozanthines: Flupenthixol, chlorprothizene, thiothixene.
• Diphenylpiperidines: Pimozide
• Benzamides : Suipride
• Dihydroindoles: Molindone
IL Atypical neuroleptics which have selectivity towards dopairtine D2 receptors.
1. Dinenzodiaze pines: Clozapine, olanzapine, loxapine
2. Miscellaneous: Risperidone, quetiapine, ziaprasidone, aripiprazole
III. Rauwolfia alkaloids (act by depleting DA, NA and 5-HT): reserpine.
Pharmacokinetics of Psychopharmacological Agents
On oral administration, most of the neuroleptics including chlorpromazine are erratically and incompletely absorbed. These drugs are highly lipophilic. They are extensively protein bound. They cross the blood—brain and placental barriers freely. They are metabolized in liver by oxidation followed by glucuronide conjugation. The half-life of most of the neuroleptics ranges between 20—40 hours. Metabolites are usually inactive and are eliminated by kidney.
Mechanism of Action of Psychopharmacological Agents
The antipsychotic action of typical neuroleptics is due to their ability to competitively block postsynaptic D2 receptors in mesolimbic system. These drugs also have a variety of other therapeutically useful and unwanted effects as a result of blockade of DA receptors as under:
- Competitive blockade of D1 and D2 receptors in nigrostriatal pathway leads to unwanted extrapyramidal effects.
- Blockade of D2 receptors in the turberoinfundibular pathway (connects arcuate nuclei and periventricular neurons to hypothalamus and posterior pituitary) leads to endocrine effects.
- Blockade of D2 receptor in CTZ leads to antiemetic effect.
- Many of their autonomic side effects are due to a—adrenergic blocking and anticholinergic properties.
The antipsychotic effects of atypical neuroleptics are due to a combination of 5-HT2, D4 and D2 receptor blockade. Lower affinity for D1 and D2 receptors appears to be responsible for the absence of extrapyramidal side effects. They also antagonize a1, M1 and H1 receptors.
Aripiprazole is a new atypical neuroleptic drug. It is a partial agonist at D2 and 5-HT1A while antagonist at 5-HT2A receptors (vaguely referred to as DA: 5-HT stabilizer in CNS). Extrapyramidal symptoms are very low but it may cause neurolept-malignant syndrome (NMS).
Atypical neuroleptics differ from typical neuroleptics as under:
- Unique receptor affinity profile
- Effectiveness against the negative as well as positive symptoms of schizophrenia
- Effectiveness in patients refractory to typical neuroleptics
- Lesser liability for inducing extrapyramidal side effects
Pharmacological Actions of Neuroleptics (Psychopharmacological Agents)
Qualitatively, the pharmacological actions of the various neuroleptics are similar with only minor differences.
Chlorpromazine (CPZ) is the first effective phenothiazine neuroleptic. It is a three ring structure where two benzene rings are linked by sulphur and nitrogen atoms. It can be taken as the prototype and its pharmacological actions will be discussed.
1. Although it causes sedation, tolerance develops to this effect much faster than tolerance to its antipsychotic effect. So it is not a serious drawback in the long-term therapy. Even in very high doses, it does not cause real hypnosis or anaesthesia.
2. In psychotic patients, it causes emotional quietening, psychomotor slowing and affective indifference (neuroleptic syndrome).
3. In normal individuals, it brings about quietening and psychomotor slowing.
4. Acting on the chemoreceptor trigger zone, it has antiemetic effect.
5. It causes hypothermia by acting on hypothalamus.
6. In women, it inhibits ovulation and release of prolactin release inhibiting hormone. So it promotes lactation due to its later effect. In fact all phenothiazines promote lactation and weight gain.
7. Chlorpromazine lowers seizure threshold. So it may exacerbate epileptic fits. Atypical neuroleptics have minimal effect on seizure threshold.
8. Chlorpromazine induces muscle relaxation and attenuate schizophrenic catatonia.
9. Neuroleptics potentiate narcotic and non- narcotic analgesia. Haloperidol has significant analgesic action.
10. It has weak anti-histaminic and antiserotonin action.
11. Phenothiazines have anticholinergic activity.
12. Phenothiazines block alpha-adrenergic receptors and cause hypotension and failure of ejaculatiom
13. Chlorpromazine exhibits a quinidine like effect on cardiac potential. So it can cause bradyarrhythmias.
14. Chlorpromazine inhibits the secretion of ACTH, growth hormone, gonadotropins, ADH and insulin (neuroendocrine blocking effect).
Neuroleptics have a very high therapeutic index. So acute toxicity is not a problem. However, drugs of this group are used for long
period, i.e. for months or some times for years. So these can produce adverse effects which are attributed to the extension of pharmacological effects and receptor activity.
Important side effects of the Psychopharmacological Agents are:
1. Parkinson like syndrome causing akinesia, rigidity and tremors.
2. Tardive dyskinesia develops in 10 to 20% of patients on classical neuroleptics after interval of a few months to several years of therapy. It is due to nigrostriated DAreceptor up regulation and supersensitivity following prolonged use of DA receptor blocking neuroleptics. Such patients may approach to dentist. So dentist must be able to recognize it and explain the patient that it is not a dental problem.
3. AntichoLinergic effects: Dryness of mouth, blurring of the vision, diminished sweating, decreased gastric secretion. Dryness of mouth may lead to dental caries and candidiasis.
4. Adrenergic blocking effect: Postural hypotension and inhibition of ejaculation in males.
5. Pseudo pregnancy in women due to inhibition of prolactin-releasing inhibitory hormone as a result of its blocking effect on dopamine receptors in the anterior pituitary.
6. Weight gain in both men and women.
7. Rare side effects: Skin rashes, jaundice, blood dyscrasias, photosensitivity and coloration.
1. Chlorpromazine and other neuroleptics potentiate the actions of central nervous system depressants like alcohol, barbiturates, opioids, antihistaminics and analgesics.
2. Chlorpromazine antagonizes the action of guanethidine, methyldopa and clonidine.
3. Antacids decrease absorption of neuroleptics from gut and anticholinergics increase intestinal metabolism.
4. Barbiturates and phenytoin increase metabolism of neuroleptics by causing induction of hepatic microsomal enzymes.
Therapeutic Uses of the Psychopharmacological Agents
1. Schizophrenia and allied psychiatric disorders.
2. Acute mania in bipolar depression along with lithium.
3. Preanaesthetic medication: Mainly promethazine is used due to its sedative, antihistaminic, anticholinergic and antiemetic effects.
4. Droperidol in combination with fentanyl, a narcotic analgesic, is employed to induce neuroleptanalgesia.
5. Aggressive behaviour: Haloperidol is effective in violent aggressives arid in self- mutilated syndrome.
6. Chlorpromazine and selected phenothiazines are used to treat intractable hiccough.
7. Almost all neuroleptics, except thioridazine, molindone and atypical agents, are used to control a wide range of drug and disease induced vomiting at doses much lower than those required for psychosis due to D2 receptor blockade in CTZ as well as gastrointestinal tract.
8. Phenothiazines, like promethazine, can be used for relief of pruritus due to their antihistaminic effects.
Important Features of other Neuroleptics Butyrophenones
• Haloperidol: It is most widely used butyrophenon. Its pharmacological properties are similar to phenothiazines. It has less anticholinergic and alpha-receptor blocking actions in comparison to chlorpromazine. It has very potent dopamine antagonistic effect and is a potent
antipsychotic drug. Its oral dose is 2—6 mg daily and intramuscular dose is 3—5 mg.
• Trifluperidol: It is similar to but slightly more potent than haloperidol. Oral dose is 0.5—8 mg daily.
• Droperidol: It is a short acting potent neuroleptic which is mostly used in combination with fantanil to induce leptanalgesia.
• Penfluridol: It is a long acting neuroleptic which is useful for chronic schizophrenia, affective withdrawal and social maladjustment.
• Chiorprothixene: It is a thioxanthine analogue of CPZ. It has similar properties to CPZ.
• Flupenthixole: It causes less sedation than CPZ. It is useful in schizophrenia and other psychoses particularly in withdrawn and apathetic patients. However, it should not be given to patients having psychomotor agitation or mania. It is also used in depression at lower doses for a short period.
• Clopenthixol: It is a thiozanthine derivative. Like chiorpromazine it also has
anxiolytic and antidepressant effect. It is devoid of antiemetic effect. It causes mild sedation and hypotension. It produces moderate extrapyramidal effects.
• Clozapine: It is a dinenzodiazepine. It produces moderate sedation, mild postural hypotension and has no antiemetic effect. Extrapyramidal effects are minimal. It may produce tremors, convulsions, salivation and hypertension. The major limiting factor is higher incidence of agranulocytosis.
• Olanzapine: It has similar properties as that of clozapine but is devoid of agranulocytosis. Main disadvantage is that it causes weight gain.
• Ziprasidone: It is like olanzapine but causes less weight gain. Depot injection is available. It causes QT prolongation.
• Pimozide: It is a diphenylpiperidine. It is an antiemetic drug. It produces mild sedation. Extrapyramidal effects are also minimal. It can produce hypothermia and hyperprolactinaemia.
• Loxapine: It is a dibenzoxazepine which is similar in action as that of CPZ. Its onset of action is quick and duration of action is up to 12 hours. It has no advantage over other antipsychotics.
• Sulpiride: It is a benzamide. It has mild extrapyramidal effects and produces mild sedation, hypothermia and hyperprolactinaemia. It is an antiemetic drug also.
• Risperidone: Its antipsychotic activity is due to D, + 5-HT2 receptor blockade. It also blocks a1, a2 and H1 receptors. It has few extrapyramidal side effects.
• Quetiapine: It has similar properties as that of risperidone but less potent. So it is given twice a day. Important adverse effects are postural hypotension and dry mouth.
• Reserpine: It is a principal alkaloid of Rauwolfia serpentine. Its central nervous system effects are similar to chlorpromazine so it produces tranquilization, sedation and extrapyramidal effects. Now it is hardly used in psychiatry because of its serious toxicity.
• Aripiprazole: It is a recent atypical neuroleptic with a noval mechanism of action. It does not block central dopaminergic receptors. It is a partial agonist at and 5-HT2A receptors while antagonist at 5- HT2A receptor. It is vaguely considered as DA: 5-Hlstabiliser in CNS. Extrapyramidal symptoms are low but it may cause genetically mediated neurolept-malignant syndrome (NMS) in some individuals.
Points for Dental Students
1. Concurrent use of following drugs should be avoided by dentist in a patient receiving classical aritipsychotic drugs:
• Erythromycin + pimozide—to avoid prolongation of QT interval and cardiac arrhythmias
• Tramadol (an opioid analgesic) + phenothiazines /butyrophenones—to avoid lowering of seizure threshold
• Hydroxazine (an antihistamine) + thioridazine—to avoid prolongation of QT interval and cardiac arrhythmias
2. Clozapine (atypical antipsychotic drug) induces paradoxical hypersalivation particular in night. So inorder to provide dry field in such patients during dental procedures scopolamine (300 mg) should be chewed arid swallowed.
3. A patient on classical neuroleptics may develop bruxism which leads to dental attrition due to grinding of teeth. This can be reduced by a dentist using a suitable antianxiety drug.
1. Schizophrenia (psychosis) may be due to limbic dopaminergic hyperactivity together with increased density and supersensitivity of mesolimbic dopamine U2 receptors. Apart from this, abnormal 5-HT metabolism, endogenous opioids, prostaglandins, and noradrenaline have also been implicated in psychosis.
2. Dopamine D2 receptor block is responsible for antipsychotic, antiemetic and neuroendocrine effects of neuroleptics while blockade of D1 receptors of the extrapyramidal system is responsible for motor disturbances. 5-HT block may contribute to anti- psychotic action. Noradrenaline block is responsible for hypotension and muscarinic M1 receptor block affords protection against extrapyramidal effects.
3, Important indications of antipsychotics
4. Important side effects are:
a. Parkinsonism-like syndrome
b. Tardive dyskinesia
c. Weight gain
e. Anticholinergic and adrenergic blocking effects.
5. Important drug interactions are:
a. Antacids decrease the absorption of neuroleptics
b. Anticholinergics increase intestinal metabolism of neuroleptics
c. Barbiturates and phenytoin increase metabolism of neuroleptics
d. Chiorpromazine potentiates the effects of alcohol, barbiturates and other central nervous system depressants while antagonize the actions of guanethidine, methyldopa and clonidine.
6. Antipsychotic effects of clozapine and risperidone are due to U2 and 5-HT2 receptor blocked.