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).

2

Click for larger picture

3

MECHANISM OF ACTIONThere 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.

4

Fig.8Click for larger picture

5

Click for larger picture

6

Click for larger picture

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.

8

Click for larger picture

9

Click for larger picture

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.

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.

12

3.Local anaestheticChlorpromazine 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.

13

5.Skeletal muscleNeuroleptics 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.

14

PHARMACOKINETICSMost 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.

15

ANWANTED EFFECTSNeuroleptic 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.

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.

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.

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.

19

Click for larger picture

20

CLINICAL USE AND EFFICACYAlthough 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.

21

1. 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.

22

REFERENCES1.Pharmacology, Fourth Edition, H.P.Rang,

M.M.Dale, J.M.Ritter, CHURCHILL LIVINGSTONE, 2001.

2.Human Pharmacology, Molecular to Clinical, Third Edition, T.Brody, J.Larner, K.Minneman, Mosby, 1998 by Mosby-Year Book,Inc.

3.Basic & Clinical Pharmacology. A LANGE medical book. 8 EDITION, B.G.Katzung, 2001, McGraw-Hill Comp.

4.Lippincott’s Illustrated Reviews: Pharmacology, 2nd Edition, M.J.Mycek, R.A.Harvey & P.C.Champe, LIPPINCOTT WILLIAMS & WILKINS, 2000.