ANTIPSYCHOTIC DRUGS (NEUROLEPTICS) The introduction in the mid-1950s of chlorpromazinecan truly be said to have revolutionized the practice of psychiatry. Prior to that time no regularly efficacious treatment was available for the most common psychotic disorders. Discovery of the neuroleptics made possible the release to their homes and to their communities of many thousands of patients who previously faced the prospect of lifetime institutionalization. There is a tendency among students of medicine to regard psychotherapeutic drugs in general and neuroleptics in particular, as the province of psychiatry. In fact, surveys have indicated that two thirds of all prescriptions for antidepressants and neuroleptics are written by physicians other than psychiatrics. It is therefore essential that all physicians have a working general knowledge of the indications, adverse effects, and drug interactions of the neuroleptics. P s y c h o s i s is the condition most often treated with neuroleptics. The most common forms of psychosis for which neuroleptics are indicated are the schizophrenic disorders. These are characterized by chronicity, impaired function and disturbances of thinking and affect. The American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders third edition provides the following criteria for the use of neuroleptics: One or more psychotic symptoms such as delusions, hallucinations, illogical thinking, or disorganized behaviour Deterioration from a previous level of functioning Continuous signs of the illness for at least 6 months tendency toward onset before age 45 smptoms not due to affective disorders symptoms not due to organic mental disorders or mental retardation. The dopamine hypothesis of schizophrenia states that hyperactivity in dopaminergic systems causes the signs and symptoms characteristic of the disease. Primary support for the hypothesis comes from the observation that all clinically effective antipsychotic drugs block one or another aspect of dopamine function. Further evidence is provided by the fact that chronic treatment with amphetamine, a drug believed to interact with dopaminergic systems, causes a syndrome that closely resembles paranoid schizophrenia . The majority of antipsychotics block dopamine receptors (D1 and D2) in the forebrain. This blockade is though to participate mainly in antipsychotic effects. Blockade of D2 receptors, however, appears also in the striatum and induces unwanted extrapyramidal effects (Fig. 1). Moreover, repeated administration causes an increase in D2 receptors sensitivity due to an increase in abundance of these receptors. This appears to underlie both tolerance to antipsychotic effects and the tardive dyskinesias that are caused by prolonged use of most antipsychotics. Although psychosis is the primary indication for use of neuroleptics, they are widely prescribed as well for a variety of abberant behaviors of nonspecific origin including a g g r e s s i o n, h o s t i l i t y, and s e l f - d e s t r u c t i v e behavior. Neuroleptics have also antiemetic properties. Nausea and vomiting are profoundly influenced by dopamine-sensitive receptors of a medullary center called the chemoreceptor trigger zone (CRT). The antiemetic properties of neuroleptics are believed to arise from dopaminergic blockagde of CRT. Thus, neuroleptics, especially chlorpromazine and prochlorperazine, often are used to control nausea and emesis in a variety of disease states as well as that associated with cancer chemotherapy. Adverse effects Extrapyramidal motor systém (EPMS) Neuroleptics are believed to act as antagonists of dopaminergic components of the EPMS. The functional consequences of neuroleptic-induced disturbance of the EPMS may be divided into four distinct syndromes: parkinsonian syndrome, acute dystonia, akathisia, and tardive dyskinesia. The first three occur soon after initiation of neuroleptic therapy and usually are amenable to treatment. These early-onset extrapyramidal disturbances are thought to be due to the direct effects of dopaminergic blockade in the striatum as mentioned above. Parkinsonian syndrome (PS) that is characterized by tremors and rigidity of skeletal muscles, especially of the upper limbs. Akinesia, a state of decreased motor activity, is often a major sign of the PS. Anticholinergic antiparkinsonian drugs are of value in treating the neuroleptic-induced condition. Acute dystonia may appear shortly after initiation of neuroleptic therapy. Hypertonicity of the muscles of the neck and back may progress to opisthotonos. Difficulty in swallowing and spasms of the muscles of tongue, and eyes may occur. At the first appearance of dystonia, administration of the neuroleptic should be stopped and the patient reassured as to the essentially benign nature of the condition. Especially severe cases may require the parenteral administration of an anticholinergic antiparkinsonian agent. Akathisia . The literal meaning of this term is „without sitting“. It refers particularly to motor restlessness and a desire on the part of patient to be in constant motion. It is resonable to conclude that this syndrome may contribute to noncompliance by some patients. Reduction of dosage may be of value. Tardive dyskinesia. As is implied by its name, tardive dyskinesia has a delayed onset, sometimes becoming apparent only after years of treatment. Among the most prominent signs are athetoid or, choreiform movements of voluntary muscles. Usually the face and mouth are involved causing repetitive sucking, chewing and lip smacking, the togue may be injured. Most important is the apparent irreversibility of the condition. It responed poorly if at all to antiparkinsonian agents and may worsen rather than improve with discontinuation of neuroleptic treatment. Tardive dyskinesia has many of the features of a supersensitivity phenomenon (compensatory increase in dopamine release and/or increased sensitivity of selective receptors). Neuroleptic malignant syndrome An unusual and sometimes fatal reaction to antipsychotic drugs that combines features of disordered temperature regulation and extrapyramidal reactions is called the neuroleptic malignant syndrome (NMS). About 10% of patients with NMS die. The hallmarks of NMS are hyperthermia and rigidity, presumably of extrapyramidal origin. In addition, delirium and increased blood pressure ofter occur. Treatment is uncertain but should include termination of all neuroleptics and use of general supportive measures including body cooling and rehydration as needed. NMS is believed to be caused by inhibition of dopaminergic receptors in the hypothalamus (disorder of temperature regulation), in EPMS (rigidity), and increased intracellular calcium. Among those claimed to have some beneficial effects are bromocriptine (stimulates dopaminergic receptor), and dantrolene (an intracelullar Ca2+ antagonist). Sedation in general, neuroleptics depress activity in the central nervous system. The resulting drowsiness and sedation are sometimes useful in agited patients but more often are regarded as undesired properties. This is especially true during maintenance therapy. There appears to be no relationship between the degree of sedation produced and the actual antipsychotic effects. Although multiple mechanisms are probably involved, activity of neuroleptics at histaminergic and cholinergic receptors in the CNS seems a likely factor. The depressant effects of antipsychotic drugs are at least additive with those of ethanol, barbiturates, opiates, and other depressants of CNS activity. Appropriate adjustement in dosage should be made when neuroleptics are combined with such drugs. Seizures. Neuroleptics decrease the convulsive threshold and may precipitate seizures in persons with pre-existing CNS pathology. Potentiation of the depressant effects of barbiturates does not extend their anticonvulsant properties. For this reason, doses of barbiturates and other antiepileptic agents should not be reduced routinely on initiation of antipsychotic drug therapy. Furthermore, neuroleptics are contraindicated in the treatment of conditions such as ethanol and barbiturates withdrawal. Cardiovacular system: Antimuscarinic effects may results in tachycardia while direct action on myocardium can cause prolongation of the QT interval and a widening of the QRS complex. In the periphery, neuroleptics appear to be selectively active at α-adrenergic receptors, and epinephrine reversal may occur. This is a phenomenon in which doses of epinephrine that usually produce pressor effects result in hypotension owing to unopposed stimulation of β- adrenergic receptors. The pressor agent of choice in neuroleptic-induced hypotenion is norepinephrine. Those physicians who prescribe neuroleptics must také into account possible untoward effects on the myocardium particularly in those patients with pre-existing coronary atherosclerosis or disturbances in cardiac rhythm. Temperature regulation Neuroleptics serve to loosen in general the homeostatic mechanisms that normally maintain body temperature. Disordered temperature regulation is thought to be mediated by neuroleptic blockade of muscarinic receptors. Thus, patients maintained on neuroleptics may become hyperthermic when exposed to high environmental temperature, and several deaths have been reported. On the other hand, an early use of chlorpromazine was to facilitate the lowering of body temperature prior to cardiac surgery because of decrease in body temperature due to cold setting. Endocrine systems. Dopamine released by the hypothalamus passes through the hypothalamicoadenohypophyseal portal system to the pituitary where it functions to inhibit the release of prolactiv. The antidopaminergic effects of neuroleptics trhus account for the increasse in serum prolactin that is consistently seen in patients treated with these drugs.Neurolpetic-induced hyperprolactinemia is sometimes associated with galactorrhea, menstrual changes, and gynecomastia. A number of other adverse effects of antipsychotic drugs may have an endocrine component. These include sexual dysfunction and undesired weight gain. MISCELLANEOUS ADVERSE EFFECTS Peripheral antimuscarinic action is ofter associated with one or more signs of an atropin- like syndrome. Thus, blurred vision, exacerbation of narrow angle glaucoma, dry mouth, sinus tachycardia, constipation, urinary retention. and decreased sweating may occur. Jaundice Liver dysfunction, usually in the form of cholestatic jaundice, was associated with chlorpromazine use. The condition is usually reversible on discontinuation of neuroleptic use. If treatment is to continue, the agent from another chemical class should be chosen. Periodic liver function tests are indicated in patients chronically treated with phenothiazines. Hematological disorders Blood dyscrasias, including agranulocytosis, leukopenia, thrombocytopenic purpura are rare. However, because of the possibly fatal outcome of these disorders .patients and their families should be warned to report sore throat or other signs of infection. Dermatological effects With long-term treatment , ususual sensitivity to the sun and discoloration of the skin may occur. A possibly related condition is deposition of fine particulate matter in the lens and cornea of the eye. Ocular changes have most often been associated with long term, high-dose therapy with thioridazine. Under these circumstances, regular examinations of the eye are indicated. It is generally assumed that some measures of tolerance develops to the sedative and hypotensive effects of neuroleptics. Physical dependence on antipsychotic drugs is seldom reported. However, a withdrawal syndrome including vomiting and movement disorders has been described. For this reason, gradual reduction in dosage following long-term treatment is prudent. PHARMACOKINETICS. A prototyp of neuroleptics is chlorpromazine. It has multiple metabolites. Its large apparent volume of distribution (Vd = 22 L/kg) results in low plasma concentrations. When given orally it is incompletely absorbed with a bioavailability of about 30%. T1/2 varies between 2 and 24 hours. Plasma steady state concentrations are reached in around 1 week. Neuroleptics can be divided according to the structure: Phenothiazines with aliphatic side chain (group )1: chlorpromazine, levomepromazine are profoundly sedating, moderatery antimuscarinic, with moderate extrapyramidal effect, piperazine side chain (group 2): fluphenazine, perphenazine, trifluoroperazine, prochlorperazine: little sedation, little antimuscarinic action, high extrapyramidal effect piperidine side chain (group 3): thioridazine moderately sedation, much antimuscarinic action, little extrapyramidal effect, Butyrophenones: haloperidol, droperidol are similar to group 3 phenothiazines Diphenylbutylpiperidines : fluspirilen and pimozide are long-acting Dihydroindolones: molidone Thioxanthines: chlorprothixene, flupenthixol Oxypertine and loxapine similar to phenothiazines in toxicity Clozapine has higher affinity for D3-D4 receptors, the risk of agranulocytosis Sulpirid and remoxipride : little sedation and extrapyramidal effects Contraindication: Pregnancy and lactation, cautions: elderly, coma due to cerebral depressants, epilepsy, hepatic impairment (phenothiazines). Avoid in children, cardiac disturbance, hypokalemia (fluspirilen, pimozid). Avoid in basal ganglia disease, other as with phenothiazines (haloperidol) Motor cortex Striatum ACh DA GABA Substantia nigra Fig 1: Representation of relationships between cholinergic (ACh), dopaminergic (DA) and GABA-producing neurons in the basal ganglia. GABA and dopaminergic neurons are regulating the stimulating action of the cholinergic neuron on the striated muscle. Administration of a neuroleptic agent results in the inhibition of dopaminergic receptors at the postsynaptic membrane of the cholinergic neuron. The extrapyramidal syndrom due to desinhibition of the cholinergic neuron occurs.