1. CLASSIFICATION OF ANTIPSYCHOTIC DRUGS
More than 20 different antipsychotic drugs are available for clinical use, but with certain exceptions the differences between them are minor.
An important distinction is drawn between the main group, often referred to as classical or typical antipsychotic drugs atypical antipsychotic drugs
“Atypical” commonly refers to the diminished tendency of some newer compounds to cause unwanted motor side-effects. Their pharmacological profile somewhat different from that of “classical” pre-1980 drugs (phenothiazines, thioxanthines and butyrophenones).
Distinction between “typical” and “atypical” groups is not clearly defined, but rests on:
Incidence of extrapyramidal side-effects (less in “atypical” group)
Efficacy in treatment – resistant group of patients
Efficacy against negative symptoms
Classical antipsychotic drugs
Phenothiazines: Chlorpromazine, Triflupromazine, Thioridazine,Trifluoperazine and others.
Butyrophenones: Haloperidol, Trifluperidol, Droperidol, Penfluridol.
Thioxanthenes: Chlorpothixene, Thiothixene, Flupenthixol.
Others: Pimozide, Molindone, Loxapine, Reserpine.
Atypical antipsychotic drugs:Clozapine, Risperidone, Sulpiride, Sertindole, Seroquel

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Pharmacological investigation showed that phenothiazines blocked the action of many different mediators, including histamine, catecholamines, acetylcholine and 5-HT. It is now clear that antagonism at DA receptors is the main determinant of antipsychotic action.

3. There are many type of DA-receptors (see upper).
MECHANISM OF ACTION
There are many type of DA-receptors (see upper).
The antipsychotic drugs probably owe their therapeutic effects mainly to blockade of D2 receptors. The main groups, phenothiazines, thioxanthines and butyrophenones, show preference for D2 over D1 receptors; some newer agents (e.g. remoxipride) are highly selective for D2 receptors, whereas clozapine is relatively non-selective between D1 and D2, but has high affinity for D4.
DA, the naturally occurring agonist, interacts with D1 and D2 receptors, and both receptors are found in high density in the corpus striatum and nucleus accumbens. Most striatal neurons have D1 responses and most accumbens neurons have D2 responses.
DA postsynaptic resposens can be mediated by either D1 and D2 receptors, whereas presynaptic receptors appear to be exclusively the D2 subtype.
Mechanisms of action different DA- receptors see below.
Recent cloning experiments expanded the family of DA receptors subtypes - D3, D4, D5.. There are found primarily in limbic areas (D3), medulla and frontal cortex (D4) or hippocampus (D5).
All antipsychotics (exempt clozapine like) have potent D2 receptor blocking action; antipsychotic potency has shown good correlation with their capacity to bind to D2 receptor. Phenothiazines and thioxanthines also block D1, D3 and D4 receptors.
Blockade of DA-ergic projections to the mesolimbic system and mesocortical areas is probably responsible for the antipsychotic action (because DA overactivity in limbic area is responsible for exacerbate schizophrenia).

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DA-ergic blockade in basal ganglia (nigrostristal pathway) appears to cause the extrapyramidal symptoms, while that in tubero-hypophyseal pathway induces endocrine disorders, and in central trigger zone - is responsible for antiemetic action (fig.8).
Fig.8
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As an adaptive change to blockade of presynaptic D2 receptors (“autoreceptors”) the firing of DA neurons and DA turnover increases initially. However, over a period of time this subsides and gives way to diminished activity, especially in the basal ganglia – corresponds to emergence of parkinsonian effect. Whereas catalepsy arises primarily from acute blockade of postsynaptic D2 receptors. Tolerance to DA turnover enhancing effect of antipsychotics is not prominent in the limbic area – may account for the continued antipsychotic effect (fig. 9,10).
Fig. 9. Sites of action of many antipsychotic drugs on DA neurotransmission.
Blockade of presinaptic receptors increases DA synthesis (1) and release (2) and can reduce passage of K+ though an anion channel. Classic antipsychotic drugs also block postsynaptic DA receptors (3). D2 -DA receptor; G – guanine nucleotide binding protein (G-protein). G-GDP and G-GTP represent G protein bound to either guanosine diphosphate of guanosine triphosphate, respectively.

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Daily treatment with neuroleptics for several weeks produces a reversible cessation of firing of midbrain DA neurons. These inactivated neurons are said to be in a state of “depolarization block” and can be induced to fire again by local application of inhibitory transmitters such as GABA. The molecular mechanism underlying production of depolarization block of midbrain DA neurons is unknown, but the block is presently the most cohesive explanation of antipsychotic action.
Another delayed effect seen with chronic administration of antipsychotic drugs is proliferation of DA receptors, detectable as an increase in haloperidol binding (Seeman 1987), and also a pharmacological supersensitivity to DA, somewhat akin to the phenomenon of denervation supersensitivity.
Fig. 10. Sites of action of many antypsychotic drugs.

7. Although D-receptor blockade occurs rapidly after initial antipsychotic drug treatment, a therapeutic response is not usually observed for several weeks. The time it takes for the clinical response to be manifested is thought to correlate with the delayed induction of depolarization blockade of mesolimbic DA neurons. Induction of depolarization blockade also correlates with a reversal of initial increase in the concentration of DA metabolites in cerebrospinal fluid.
The second view is that neuroleptic drugs primary interact with “ sigma opiate” receptors.
The third is that interaction with one or more the newer D-receptor subtypes ex­plain the action of these drugs. Whatever the underlying mechanism, acute blockade of any known receptor population is not, in isolation, a sufficient explanation for antipsychotic action.
This model fails to explain the antipsychotic activity of clozapine which has weak D2 bloc­king action. However, it has significant 5-HT and α1-adrenoceptor blocking action and is relatively selective for D4 receptors. Thus, antipsychotic action may depend on a specific profile of action of the drugs on several neurotransmitter receptors.(Fig 11)

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Fig.11. Neuroleptic drugs block at DA-ergic, 5-HT-ergic as well as at adrenergic, cholinergic and histamin-binding receptors.
So, antipsychotic action of antipsychotics also depend on a specific profile of action of the drugs on several neurotransmitter receptors, such as 5-HT, α1-adrenoceptor, M-cholinoceptor, H1-receptor blocking action.
Antipsychotic drugs show varying patterns of selectivity in their receptor-blocking effects (tab.), some having affinity for 5-HT and/or D4 receptors.

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Table. Characteristics of antipsychotic drugs.

10. EFFECTS OF ANTIPSYCHOPTIC DRUGS 1.Central Nervous System
Effects of antipsychotic drugs differ in normal and psychotic individuals.
In normal individuals they produce indifference to surrounding, paucity of thought, psychomotor slowing, emotional quiet, reduction in initiative and tendency to go off to sleep. Spontaneous movements are minimized, but slurring of speech, ataxia or motor uncoordination does not occur. This has been referred to as the “neuroleptic syndrome” and is quite different from the sedative action of barbiturates and other similar drugs. The effects are appreciated as “neutral” and “unpleasant” by most normal individuals.
In a psychotic patients they reduce irrational behaviour, agitation and aggressiveness and controls psychotic symptoms. Disturbed thought and behaviour are gradually normalised, anxiety is relieved. Hyperactivity, hallucinations and delusions are suppressed.
All phenothiazines, thioxanthenes and butyrophenones have the same antipsychotic efficacy, but potency differs in terms of equieffective doses. The aliphatic and piperidine side chain phenothizines (chlorpromazine, triflupromazine, thioridazine) have low potency, produce more sedation and cause greater potentiation of hypnotics, opioids etc. The sedative effect is produced immediately while antipsychotic effect takes weeks to develop. Moreover, tolerance develops to the sedative but not to the antipsychotic effect. Thus, the two appear to be independent action. Performance and intelligence are relatively unaffected but vigilance is impaired.
Extrapyramidal motor disturbances initialy linked to the antipsychotic effect but are more prominent in the high potency compounds and least in thioridazine. The effects comprise acute dystonias and tardive dyskinesia. A predominance of lower frequency waves occurs in EEG and arousal response is dampened. However, no consistent effect on sleep architecture has been noted. The disturbed sleep pattern in a psychotic is normalised.

11. Catalepsy arises primarily from acute blockade of postsynaptic D2 receptors in basal ganglia.
Chlorpromazine lowers seizure threshold and can precipitate fits in untreated epileptics. The piperazine side chain compounds have a lower property for this action. The temperature control is knocked off at relatively higher doses rendering the individual poikilothermic – body temperature falls if surrounding are cold. The medullary respiratory and other vital centers are not affected, except at high doses. It is very difficult to produce coma with these drugs. Neuroleptics, except thioridazine, have potent antiemetic action exerted through the central trigger zone. However, they are ineffective in motion sickness.
2. Autonomic Nervous System
Neuroleptics have varying degrees of
α--adrenergic blocking activity clorpromazine=triflupromazine>thioridazine> fluphenazine>haloperidol>trifluoperazine>clozapine>pimozide, i.e. more potent compounds have lower propensity.)
anticholinergic property of neurolrptics is weak and may be graded as thiridazine>chlorpromazine>triflupromazine>trifluoperazine=haloperidol
The phenothiazines have weak H1- antihistamibic and anti-5-HT action as well.

12. 3.Local anaesthetic
Chlorpromazine is as potent a local anaesthetic as procaine. However, it is not used for this purpose because of its irritant action. Others have weaker membrane stabilizing action.
4.Cerebrovascular system
Neuroleptics produce hypotension (primarily postural) by a central as well as peripheral action on sympathetic tone, which is more marked after parenteral administration and roughly parallels the α-adrenergic blocking potency. This is not prominent in psychotic patients and is accentuated by hypovolemia. Partial tolerance develops after chro­nic use. Reflex tachicardia accompanies hypotension.
High doses of chlorpromazine directly depress the heart and produce ECG changes – QT prolongation and suppression of T wave. It exerts some antiarrhythmic action, probably due to membrane stabilization. Arrhythmia may occur in overdose, especially with thioridazine.

13. 5.Skeletal muscle
Neuroleptics have no effects on muscle fibers or neuromuscular transmission. They reduce certain types of spasticity: the site of action being in the basal ganglia or medulla oblongata. Spinal reflexes are not affected.
6. Endocrine system
Neuroleptics consistently increase prolactin release by blocking the inhibitory action of DA on pituitary lactotropes. This may result in galactorrhea and gynecomastia. They reduce gonadotropin secretion but amenorrhea and infertility occur only occasionally. ACTH release in response to stress is diminish corticosteroids levels fail to increase under such circumstances. Release of GH is also reduced but this is not sufficient to cause growth retardation in children or to be beneficial in acromegaly. Decreased release of ADH may result in an increase in urine volume. A direct action on kidney tubules may add to it, but Na+ excretion is not affected.
7.Tolerance and dependence
Tolerance to the sedative and hypotensive actions develops within days or weeks, but maintenance doses in most psychotics remain fairly unchanged over years, despite increased DA turnover in the brain. The antipsychotic, extrapyramidal and other actions based on DA antagonism do not display tolerance.
Neuroleptics are hedonically bland drugs. Physical dependence is probably absent, though some manifestation on discontinuation have been considered to be withdrawal phenomena.

14. PHARMACOKINETICS
Most neuroleptic drugs are highly lipophilic, bind avidly to proteins, and tend to accumulate in highly perfused tissues. Oral absorption is often incomplete and erratic, whereas IM injection is more reliable. With repeated administration, variable accumulation occurs in body fat and possibly in brain myelin. Half-lives are generally long, and so a single daily dose is effective. An esterified derivate of fluphenazine requires dosing only once every few weeks. After long-term treatment and drug administration is stopped, therapeutic effects may outlast significant blood concentrations by days or weeks. This may result from tight binding of parent drug of active metabolites in the brain.
Metabolism of antipsychotic drugs usually starts with oxidation by hepatic microsomal enzymes (P450 system), followed by glucuronidation and excretion in urine. After long-term use, the rate of conversion of parent drug increases slightly, causing a mild metabolic tolerance; however, monitoring the blood concentration of drug is generally not useful in preventing this problem. In individual patients, very wide variations in blood concentration of antipsychotic agent can still achieve control of symptoms. Thioridazine because of its prominent anticholinergic activity in the gastrointestinal tract, may display erratic absorption after oral administration. Even with regular dosing, especially in older patients, periods of inadequate or excessive blood concentrations of drug may result.

15. 1.”Extrapyramidal” reactions include
ANWANTED EFFECTS
Neuroleptic drugs are replete with side effects. Many side effects occur early during treatment and result from neuroleptic blockade of receptors in the central and peripheral nervous systems; others appear later in the course of treatment (fig.12).
1.”Extrapyramidal” reactions include
Parkinsonism, which can mimic idiopathic Parkinson’s disease but is usually of mild degree. It responds to anticholinergic drugs or amantadine;
Akatisia is a subjective sense of restlessness usually accompanied by wild to moderate motor hyperactivity. It is among the most common of side effects and usually responds to α-adrener gic receptor antagonists, anticholinergics, antihistamines or amantadine. Akathisia is sometimes misinterpreted as increased agitation, leading to increased neuroleptic dosing, resulting in greater akathisia.
Acute dystonic reactions are involuntary movements (muscle spasms, protruding tongue, torticollis, etc.), usually appear within a few days of starting neuroleptic treatment and can appear as oculogyric crisis (dystonic posturing of neck, face, and eyes) or combination of focal dystonias. They are frightening but also very responsive to injected anticholinergic or antihistamine drugs. They do not tend to recur during neuroleptic treatment.
These tree reactions occur commonly in the first few weeks, often declining with time, and they are reversible on stopping drug treatment. The occurrence of acute dystonias is consistent with block of DA-nergic nigrostriatal pathway.
Tardive dyskinesia develops after months or years in 20-40% of patients treated with classical antipsychotic drugs, and is one of the main problems of antipsychotic therapy. It characterized by involuntary and excessive oral-facial movements. Sever tardive dyskinesia can cause feeding and breathing to be impaired as well as be disfiguring. There are several the­ories about the mechanism of tardive dyskinesia. One is that it is associated with a gradual increase in the number or hypersensitivity of D2 receptor sites in striatum (up-regulation), which is less marked with the atypical antipsychotic drugs. Another possibility is that chronic block of inhibitory D2-receptors enchances catecholamones and/or glutamate release in the striatum, leading to excitotoxic neurodegeneration.

16. 2.Endocrine effects
DA, released in the median eminence by neurons of the tuberohypophyseal pathway acts physiologically via D2 receptors as an inhibitor of prolactin secretion. The result of blocking D2 receptors by antipsychotic drugs is therefore to increase the plasma prolactin concentration, resulting breast swelling, pain and lactation, which can occur in men as well as women. Other less pronounced endocrine changes including a decrease of growth hormone secretion, but these, unlike the prolactin response, are unimportant clinically.
3. Neuroleptic malignant syndrom.
Neuroleptic malignant syndrom is a rare but serious complication, similar to the malignant hypertermia syndrom seen with certain anesthetics. It occurs in 1% to 2% of patients and is fatal in almost 10% of those affected. This is observed early in treatment and is characterized by a near complete collapse of the autonomic nervous system, causing, for example, fever, muscle rigidity, diaphoresis, mental confusion and cardiovascular instability. Immediate medical intervention with bromcriptine (DA agonist) and dantrolene is nessesary.

17. 4. Sedation, which tends to decrease with continued use, occurs with many antypsychotic drugs. Antihistamine (H1) activity is a property of phenothiazines and contributes to their sedative and antiemetic properties, but not to their antipsychotic action.
5.A variety of peripheral effects.
Blocking muscarinic receptors produce blurring of vision and increased intraocular pressure, dry mouth and eyes, constipation and urinary retention. Acetylcholine acts in opposition to DA in basal ganglia and it is possible that the relative lack of extrapyramidal side-effects with clozapine and thioridazine results from their high antimuscarinic potency.
Blocking α-adrenoreceptors results in the important side-effect in humans of orthostatic hypotension.
Weight gain is a common and troublesome side-effect, probably related to 5-HT antagonism.

18. 6.Various idiosyncratic and hypersensitivity reaction can occur, the most important being.
Jaundice, which occurs with older phenothizines, such as chlorpromazine. The jaundice is usually mild, and of obstructive origin; it disappears quickly when the drug is stopped of substituded by an antipsychotic of different class.
Leukopenia and agranulocytosis are rare, but potentially fatal, and occur in the first few weeks of treatment. The incidence of leukopenia (usually reversible) is less than 1 in for most antipsychotics, but much higher (1-2%) with clozapine, use of which, therefore, requires regular monitoring of blood cell counts. Provided the drug is stopped at the first sign of leukopenia or anemia, the effect is reversible. Olanzapine appears to be free of this disadvantage.
Urticarial skin reactions are common but usually mild. Excessive sensitivity to ultraviolet light may also occur.

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Fig. 12. Side-effects of neuroleptics.

20. CLINICAL USE AND EFFICACY
Although the underlying cause of psychosis is unknown, treatment with neuroleptic drugs usually results in a specific improvement in psychotic sings and symptoms and does not simply cause sedation or reduce agitation. Modern antipsychotic drugs allow many schizophrenics to lead productive lives outside hospitals or less restrictive lives within hospitals. Unfortunately, for about half of patients with schizophrenia, classical neuroleptics are not completely effective in controlling positive symptoms. The progression of negative symptoms can lead to progressive deterioration. In schizophrenia, negative signs and symptoms are generally more resistant to antipsychotic drug therapy and are commonly the cause of chronic disability. It is likely that negative sings and symptoms have a pathophysiological description different from that of positive sings and symptoms and are associated more with decreased frontal lobe metabolic rate. In some patients, negative sings and symptoms way worsen with neutoleptoic treatment. The increased efficacy of clozapine compared to traditional neuroleptics derives primary from its greater efficacy in improving negative sings and symptoms.
All antipsychotic drugs are equally efficacious but differ dramatically in potency and side effects. Treatment choices are empiric, and there is no scientific rationale for having a patient take more than one neuroleptic at a time.
The schedule for antipsychotic administration is dependent on the clinical situation. A severely agitated, violent patient poses an immediate challenge different from that of a quiet and withdrawn catatonic.
Agitation may be rapidly controlled by neuroleptic or neuroleptic combinated with sedative-hypnotic drugs, but true antipsychotic effect will require weeks of treatment.
Neuroleptic choice is dictated by desirability or undesirability of side effects, prior history of side effects and responses, and other individual circumstances.

21. The major use of antipsychotic drugs is in the treatment of schizophrenia and other psychotic disorders . The neuroleptics are the only efficacious treatment for schizophrenia. Not all patients respond, and complete normalisation of behavior is seldom achieved. The traditional neuroleptics are most effective in treating positive symptoms of schizophrenia (delusions, hallucination and thought disorders). The newer agents with 5-HT blocking activity (e.g.sulpirid ) are effective in many patients resistant to the traditional agent, especially in treating negative symptoms of schizophrenia and depression.
Preventation of severe nausea and vomiting. The neuroleptics (most commonly prochlor-perazine), are useful in treatment of drug induced nausea. Nausea arising from emotion should be treated with sedatives and antihistamines, rather than with these powerful drugs.
Other uses. The neuroleptic drugs may be used as tranquilizers to manage agitated and disruptive behavior. Neuroleptics are used in combination with narcotic analgetics for treatment of chronic pain with severe anxiety. Chlorpromazine is used to treat intractable hiccups. Droperidol is a component of neuroleptanesthesia. Prometathazine is not a good antipsychotic drug, but the agent is used in treating pruritus because of its antihistaminic properties.

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