1. Antipsychotic agents By
S.Bohlooli PhD

2. Typical neuroleptic: older agents fitting this description
Neuroleptic: synonym for antipsychotic drug; originally indicated drug with antipsychotic efficacy but also neurologic (extrapyramidal motor) side effects
Typical neuroleptic: older agents fitting this description
Atypical neuroleptic: newer agents: antipsychotic efficacy with reduced or no neurologic side effects

3. NEUROLEPTIC Drug PHENOTHIAZINES: Chlorpromazine Thioridazine
TYPICAL NEUROLEPTICS:
PHENOTHIAZINES:
Chlorpromazine
Thioridazine
Fluphenazine
THIOXANTHENE
Thiothixene
BUTYROPHENONES
Haloperidol

4. NEUROLEPTIC Drugs Risperidone Clozapine Olanzapine Quetiapine
ATYPICAL NEUROLEPTICS:
Risperidone
Clozapine
Olanzapine
Quetiapine

5. Figure Structural formulas of some older antipsychotic drugs: phenothiazines, thioxanthenes, and butyrophenones. Only representative members of each type are shown

7. KEY CONCEPTS:
All neuroleptics are equally effective in treating psychoses, including schizophrenia, but differ in their tolerability.
All neuroleptics
block one or more types of DOPAMINE receptor, but differ in their other neurochemical effects.
show a significant delay before they become effective.
produce significant adverse effects.

8. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS
The older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system.
Typical neuroleptics block the dopamine-2 receptor.

9. Figure 18-1. Sites of action of neuroleptics and lithium
Figure Sites of action of neuroleptics and lithium. In varicosities ("terminals") along terminal arborizations of dopamine (DA) neurons projecting from midbrain to forebrain, tyrosine is oxidized to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, then decarboxylated to DA by aromatic L-amino acid decarboxylase (AAD) and stored in vesicles. Following exocytotic release (inhibited by Li+) by depolarization in the presence of Ca2+, DA interacts with postsynaptic receptors (R) of D1 and D2 types (and structurally similar but less prevalent D1-like and D2-like receptors), as well as with presynaptic D2 and D3 autoreceptors. Inactivation of transsynaptic communication occurs primarily by active transport ("reuptake") of DA into presynaptic terminals (inhibited by many stimulants), with secondary deamination by mitochondrial monoamine oxidase (MAO). Postsynaptic D1 receptors, through Gs, activate adenylyl cyclase (AC) to increase cyclic AMP (cAMP), whereas D2 receptors inhibit AC through Gi. D2 receptors also activate receptor-operated K+ channels, suppress voltage-gated Ca2+ currents, and stimulate phospholipase C (PLC), perhaps via the bg subunits liberated from activated Gi (see Chapter 1), activating the IP3-Ca2+ pathway, thereby modulating a variety of Ca2+-dependent activities including protein kinases. Lithium inhibits the phosphatase that liberates inositol (I) from inositol phosphate (IP). Both Li+ and valproate can modify the abundance or function of G proteins and effectors, as well as protein kinases and several cell and nuclear regulatory factors. D2-like autoreceptors suppress synthesis of DA by diminishing phosphorylation of rate-limiting TH, and by limiting DA release (possibly through modulation of Ca2+ or K+ currents). In contrast, presynaptic A2  adenosine receptors (A2R) activate AC and, via cyclic AMP production, TH activity. Nearly all antipsychotic agents block D2 receptors and autoreceptors; some also block D1 receptors (Table 18-2). Initially in antipsychotic treatment, DA neurons activate and release more DA, but following repeated treatment, they enter a state of physiological depolarization inactivation, with diminished production and release of DA, in addition to continued receptor blockade. ER, endoplasmic reticulum.

10. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS
Typical neuroleptics do not produce a general depression of the CNS, e.g. respiratory depression
Abuse, addiction, physical dependence do not develop to typical neuroleptics.

11. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS
Typical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms.

12. Positive/active symptoms include thought disturbances, delusions, hallucinations
Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene

13. THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS
All appear equally effective; choice usually based on tolerability of side effects
Most common are haloperidol ,chlorpromazine and thioridazine
Latency to beneficial effects; 4-6 week delay until full response is common
70-80% of patients respond, but 30-40% show only partial response

14. THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS (Continued)
Relapse, recurrence of symptoms is common ( approx. 50% within two years).
Noncompliance is common.
Adverse effects are common.

15. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
Anticholinergic (antimuscarinic) side effects:
Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence
Antiadrenergic (Alpha-1) side effects:
Orthostatic hypotension , reflex tachycardia
Sedation
Antihistamine effect: sedation, weight gain

16. KEY CONCEPT: DYSTONIA NEUROLEPTIC MALIGNANT SYNDROME PARKINSONISM
DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).
DYSTONIA
NEUROLEPTIC MALIGNANT SYNDROME
PARKINSONISM
TARDIVE DYSKINESIA
AKATHISIA

17. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)
Increased prolactin secretion (common with all; from dopamine blockade)
Weight gain (common, antihistamine effect?)
Photosensitivity (v. common w/ phenothiazines)
Lowered seizure threshold (common with all)
Leukopenia , agranulocytosis (rare; w/ phenothiazines)
Retinal pigmentopathy (rare; w/ phenothiazines)

18. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)
Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine).
Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked.

20. MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS and Some Side Effects
DOPAMINE-2 receptor blockade in meso- limbic and meso-cortical systems for antipsychotic effect.
DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS
DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia

21. LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE:
Dopamine neurons reduce activity.
Postsynaptic D-2 receptor numbers increase (compensatory response).
When D2 blockade is reduced, DA neurons resume firing and stimulate increased # of receptors >> hyper- dopamine state >> tardive dyskinesia

22. MANAGEMENT OF EPS
Dystonia and parkinsonism: anticholinergic antiparkinson drugs
Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive
Akathisia: benzodiazepines, propranolol
Tardive dyskinesia: increase neuroleptic dose; switch to clozapine

23. ADDITIONAL CLINICAL USES OF TYPICAL NEUROLEPTICS
Adjunctive in acute manic episode
Tourette’s syndrome (Haloperidole )
Control of psychosis in depressed patient
Phenothiazines are effective anti-emetics,
Esp. prochlorperazine
Also, anti-migraine effect

24. GENERAL CHARACTERISTICS OF ATYPICAL NEUROLEPTICS
Effective antipsychotic agents with greatly reduced or absent EPS, esp. reduced Parkinsonism and tardive dyskinesia
All atypical neuroleptics block dopamine and serotonin receptors; other neurochemical effects differ
Are effective against positive and negative symptoms of schizophrenia; and in patients refractory to typical neuroleptics

25. HYPOTHESIZED MECHANISMS OF ACTION OF ATYPICAL NEUROLEPTICS
Combination of Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the “pines” like clozapine
Combination of Dopamine-2 and Serotonin-2 receptor blockade (esp. risperidone)

26. PHARMACOLOGY OF CLOZAPINE
FDA-approved for patients not responding to other agents or with severe tardive dyskinesia
Effective against negative symptoms
Also effective in bipolar disorder
Little or no parkinsonism, tardive dyskinesia, PRL elevation, neuro-malignant syndrome; some akathisia

27. Blockade of alpha-1 adrenergic receptors
Blockade of muscarinic cholinergic receptors
Blockade of histamine-1 receptor

28. PHARMACOLOGY OF CLOZAPINE (Continued )
Other adverse effects;
Weight gain
Increased salivation
Increased risk of seizures
Risk of agranulocytosis requires continual monitoring

29. PHARMACOLOGY OF OLANZAPINE
Olanzapine is clozapine without the agranulocytosis.
Same therapeutic effectiveness
Same side effect profile

30. PHARMACOLOGY OF QUETIAPINE
Quetiapine is olanzapine without the anticholinergic effects.
Same therapeutic effectiveness
Same side effect profile

31. EPS incidence is dose-related Alpha-1 receptor blockade
Resperidone
Highly effective against positive and negative symptoms
Adverse effects:
EPS incidence is dose-related
Alpha-1 receptor blockade
Little or no anticholinergic or antihistamine effects
Weight gain, PRL elevation

32. 1st acute episode w/ + or +/- symptoms
General Therapeutic Principles for Use of Neuroleptics in Schizophrenia (NIH Consensus Statement, 1999)
Use typical for:
1st acute episode w/ + or +/- symptoms
Switch to atypical if:
Breakthrough after Rx w/ typical
Use typical (depot prep) when:
Patient is noncompliant

33. Typical; switch to Atypical
General Therapeutic Principles for Use of Neuroleptics in Schizophrenia
If response is inadequate to:
Typical; switch to Atypical
Atypical; raise dose or switch to another Atypical
Typical and Atypical; switch to clozapine ®
For maintenance, lifetime Rx is required.