Lect. 5 Psychoses and Antipsychotic Agents

1. DRUGS USED IN DISORDERS OF THE
CENTRAL NERVOUS SYSTEM AND
TREATMENT OF PAIN
Lecture 5:
Psychoses and Antipsychotic Agents
Marc Imhotep Cray, M.D.

2. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Learning Objectives:
2
1. The four well-defined dopamine systems in the brain as they
relate to antipsychotic drug action and side effects.
2. The distinction between “typical” and “atypical” antipsychotics.
3. The difference in the mechanism(s) of action between a typical
antipsychotic, an atypical anti-psychotic and the partial agonist
aripiprazole.
4. The common and rare side effects associated with the use of both
low potency and high potency typical antipsychotics
5. The common and rare side effects associated with the use of the
second-generation atypical anti-psychotics.

3. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Classification Schema: Antipsychotic Agents
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FIRST-GENERATION ANTIPSYCHOTIC
(low potency)
Chlorpromazine THORAZINE
Prochlorperazine COMPAZINE
Triflupromazine
Thioridazine
FIRST-GENERATION ANTIPSYCHOTIC
(high potency)
Fluphenazine PROLIXIN
Haloperidol HALDOL
Pimozide ORAP
Thiothixene NAVANE
SECOND-GENERATION ANTIPSYCHOTIC
Aripiprazole ABILIFY
Asenapine SAPHRIS
Clozapine CLOZARIL
Lurasidone LATUDA
Olanzapine ZYPREXA
Quetiapine SEROQUEL
Paliperidone INVEGA
Risperidone RISPERDAL
(also called “typical” antipsychotics)
(also called “atypical” antipsychotics)

4. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Antipsychotic classification (2)
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Typical antipsychotic drugs are often sub-classified according to their
oral milligram potency (high potency or low potency)
 High-potency drugs (piperazine phenothiazines, e.g., fluphenazine,
and haloperidol) are more likely to produce extrapyramidal reactions
 Low-potency drugs (aliphatic phenothiazines, e.g., triflupromazine;
piperidine phenothiazines, e.g., thioridazine) are less likely to produce
acute extrapyramidal reactions and more likely to produce sedation
and postural hypotension
Atypical antipsychotic agents (e.g., risperidone, olanzapine) have
generally replaced typical drugs for initial treatment of first-episode
patients
 Clozapine is reserved for treatment-resistant patients

5. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Overview of antipsychotic drugs:
5
 Antipsychotic drugs (also called neuroleptics or major tranquilizers)
are used primarily to treat schizophrenia, but are also effective in other
psychotic and manic states
 Use involves a difficult trade-off between benefit of alleviating
psychotic symptoms and risk of a wide variety of troubling adverse
effects
 Antipsychotic drugs are not curative and do not eliminate chronic
thought disorders, but they often decrease intensity of hallucinations
and delusions and permit person with schizophrenia to function in a
supportive environment

6. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Schizophrenia
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 Schizophrenia is a type of chronic psychosis characterized by delusions,
hallucinations (often in form of voices), and thinking or speech
disturbances
 Onset of illness is often during late adolescence or early adulthood
 It occurs in about 1% of population and is a chronic and disabling
disorder
 aged 15–45 years, with a greater proportion being male
 Has a strong genetic component and probably reflects some
fundamental biochemical abnormality, possibly a dysfunction of
mesolimbic or mesocortical dopaminergic neuronal pathways

7. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Symptoms and signs of schizophrenia:
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 Symptoms fall into two groups (positive and negative) that may have
different underlying causes
 Positive symptoms include:
 Delusions – false personal beliefs held with absolute conviction
 Hallucinations – false perceptions in the absence of a real external
stimulus; most commonly, these are auditory (hearing voices) and
occur in 60–70% of schizophrenics, but they can be visual, tactile or
olfactory
 Thought alienation and disordered thought – belief that one’s
thoughts are under the control of an outside agency (e.g. aliens,
government etc.)
o This type of belief is common, and thought processes are often
incomprehensible

8. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Symptoms and signs of (2)
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 Negative symptoms include:
 Poverty of speech – restriction in the amount of spontaneous speech
 Flattening of affect – loss of normal experience and expression of
emotion
 Social withdrawal
 Anhedonia – inability to experience pleasure
 Apathy – reduced drive, energy, and interest
 Attention deficit – inattentiveness at work or on interview
N.B-The distinction between the positive and negative symptoms is of
importance as “first generation” neuroleptic drugs tend to have most effect on
positive symptoms, whereas negative symptoms are fairly refractory to
treatment and carry a worse prognosis. “Second generation” drugs have been
shown to improve negative symptoms.

9. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Schizophrenia (2)
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 This patient exhibits the flat affect that is
common to schizophrenia
 She appears to be responding to internal
stimuli-perhaps attending to auditory
hallucinations
 Alternatively, she may have significant negative
symptoms including anhedonia, amotivation,
and poverty of speech
 Finally, she may have parkinsonism secondary
to anti-psychotic medication

10. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5Neural Pathways Involved in Schizophrenia
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 The therapeutic action of typical antipsychotic drugs not certain, but is correlated best
with antagonist activity at postjunctional dopamine (DA) D2-receptors in mesolimbic
and mesocortical areas of the CNS where DA normally inhibits adenylyl cyclase activity

11. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Classes of dopamine receptor:
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Type 2nd messenger +
cellular effects
Location in CNS and postulated function
D1 cAMP increase Mainly postsynaptic inhibition
Functions unclear
D2 cAMP decrease
K conductance up
Ca conductance down
Mainly presynaptic inhibition of dopamine synthesis/release in
nigrostriatal, mesolimbic and tuberoinfundibular systems
Affinity of neuroleptics for D2 receptors correlates with
antipsychotic potency
D3 Unknown Localized mainly in limbic and cortical structures concerned with
cognitive functions and emotional behavior
Not clear whether antipsychotic effects of neuroleptics are
mediated by the D3 type
D4 Similar to D3 type; clozapine has particular affinity for D4
receptors

12. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Psychosis and Dopamine Pathways
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 Research in dopamine, 5-HT, and Glu neurotransmitters led to most
early drugs’ targeting the dopamine system, primarily as dopamine
D2 receptor antagonists
 Typical antipsychotics (e.g., chlorpromazine, haloperidol) are better
for treating positive signs than negative signs
 For treating negative signs, the newer (atypical) antipsychotic drugs
(e.g., clozapine, risperidone) target other receptors, particularly 5-HT
 Neurologic (e.g., dystonia, parkinsonism), anticholinergic (e.g.,
blurred vision), and antiadrenergic (e.g., hypotension) adverse
effects can occur

13. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Antipsychotic Drugs (Neuroleptics)
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 Antipsychotics are divided into first-generation (typical) and second-
generation (atypical) agents
 First-generation drugs are further classified as “low potency” or
“high potency”
 Classification does not indicate clinical effectiveness of drugs,
but rather specifies affinity for dopamine D2 receptor, which,
in turn, may influence the adverse effect profile of the drug

14. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Antipsychotic Drugs (2)
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BLOCKADE AT OTHER SITES LEADS TO SIDE EFFECTS:
 Blockade of D2 receptors in extrapyramidal system (basal ganglia)
induces iatrogenic parkinsonism
 This complication can be reduced by anticholinergic drugs, such as
benztropine (Cogentin)
o This restores dopamine–acetylcholine balance
 L-Dopa should not be used to treat antipsychotic-induced
extrapyramidal symptoms (Why?)
 Typical antipsychotics block D2-dopamine receptors in limbic system,
which probably accounts for therapeutic effects of these drugs in
reducing the symptoms of psychoses, hallucinations, and delusions

15. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Antipsychotic Drugs (3)
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 Blockade of D2 receptors in the pituitary enhances the release of
prolactin, which induces galactorrhea and gynecomastia
 Blockade of histamine receptors often leads to sedation, but these
drugs have little abuse potential and display no tolerance
 Blockade of M-cholinoceptors leads to anticholinergic symptoms
 Blockade of α-adrenoceptors induces hypotension and
tachycardia>>arrhythmias
 Serotonin (5-HT) receptors are also blocked by newer atypical drugs
 Effect on hypothalamus shifts body temperature toward ambient
temperature (poikilothermia)

16. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
16Modified from: Lippincott Illustrated Reviews-Pharmacology Sixth Edition. 2015
Dopamine-blocking actions of
antipsychotic drugs.
Relative affinity of clozapine,
chlorpromazine, and haloperidol at
D1 and D2 dopaminergic receptors.

17. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Antipsychotic drugs block at dopaminergic and serotonergic receptors as
well as at adrenergic, cholinergic, and histamine binding receptors
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Modified from: Lippincott Illustrated Reviews-Pharmacology Sixth Edition. 2015
Antipsychotic Drugs (5)

18. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5Effect of D2 dopamine receptor
blockade on dopaminergic
pathways in brain
Modified from: Battista E. Crash Course
Pharmacology 4e. 2012
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19. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Typical drugs:
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 Phenothiazines include:
 Chlorpromazine (Thorazine) and thioridazine (Mellaril), which are
low potency phenothiazines
 Fluphenazine (Prolixin) which is a high-potency phenothiazine
 Thiothixene (Navane), pimozide (Orap), and haloperidol are also
high potency antipsychotics

20. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Side effects of typical antipsychotics:
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 Side effects of typical antipsychotics are related to their potency
 High-potency typical antipsychotics induce most extrapyramidal
symptoms
 Low-potency typical antipsychotics induce fewer extrapyramidal
symptoms, but they induce more anticholinergic effects, more
hypotension, and more sedation than high-potency typical
antipsychotics
 TI is very large
 At high doses, convulsions can rarely occur
 Weight gain
Evolution of EPS side effects:
• 4 hr acute dystonia (muscle
spasm, stiffness, oculogyric crisis)
• 4 day akathisia (restlessness)
• 4 wk bradykinesia (parkinsonism)
• 4 mo tardive dyskinesia

21. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Side effects of typical antipsychotics (2)
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 Tardive dyskinesia is a major complication that can develop after
long-term administration of typical antipsychotics
 Following months or years treatment
 Orofacial symptoms predominate in adults
 D2 blocker should be stopped, but structural changes occur and
may be irreversible
 An atypical antipsychotic (e.g. aripiprazole) may help alleviate
symptoms and should help maintain control of the schizophrenia
 Anticholinergics do not reduce tardive dyskinesia
 They aggravate symptoms
 One proposed theory is that tardive dyskinesia is due to an up-
regulation of D2-receptors in basal ganglia
 possible increased sensitivity of presynaptic dopamine receptors)

22. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Atypical drugs:
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 Risperidone (Risperdal) is a newer antipsychotic with 5HT2 receptor-blocking
activity and fewer extrapyramidal symptoms than the typical antipsychotics
 increase prolactin (causing lactation and gynecomastia)
 Dibenzodiazepines such as clozapine and olanzapine have a low affinity for D2
receptor and a higher affinity for D1 and D4 receptors
 Clozapine (Clozaril) also blocks 5HT2-receptors as well as D-receptors
 It induces the fewest extrapyramidal symptoms
 Is effective in some patients that are refractory to other antipsychotics
 Can cause agranulocytosis; WBC counts must be monitored
 Olanzapine (Zyprexa) is similar to clozapine but does not cause agranulocytosis
 However, it leads to metabolic syndrome, type 2 diabetes, and
hyperlipidemia
 Weight gain is more significant with atypicals (Olanzapine/clozapine)

23. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Idiosyncratic reaction & pharmacokinetics:
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Toxicity:
 Neuroleptic malignant syndrome (NMS) is a rare but severe
idiosyncratic reaction to antipsychotic medication
 (20% mortality rate)
 Syndrome is characterized by autonomic instability, muscle
rigidity, diaphoresis, profound hyperthermia, and
myoglobinuria
 Tx-antipsychotic should be discontinued and supportive
care given along with bromocriptine to overcome DA
receptor blockade, muscle relaxants such as diazepam or
dantrolene to reduce muscle rigidity
Pharmacokinetics:
 These drugs are very long acting
 Binding to many tissues results in a large Vd
 Many drug metabolites due to extensive metabolism in liver
For NMS, think FEVER:
Fever
Encephalopathy
Vitals unstable
Enzymes increase
Rigidity of muscles

24. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Other Uses of Antipsychotic Drugs:
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 Manic phase in bipolar disorder
 Schizoaffective disorders
 Atypical psychotic disorders
 Depression with psychotic manifestations
 Tourette syndrome (haloperidol, pimozide [Orap] or risperidone)
 Severe nausea or vomiting associated with, e.g., radiation
treatment and cancer chemotherapy, as well as postoperative
nausea and vomiting
 With the exception of thioridazine, typical antipsychotic
agents have strong antiemetic activity due to DA D2-receptor
blockade in chemoreceptor trigger zone (CTZ) of medulla
o most commonly used are phenothiazines prochlorperazine
and promethazine (both are void of antipsychotic activity)

25. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
THE END
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26. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
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Lectures/discussions to follow:
6. Drugs Affecting Movement Disorders and
Other Neurodegenerative Disorders
7. Analgesics
8. Anesthetics
Further study (SDL):
MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders
Companion eNotes: CNS- Central Nervous System Pharmacology
Textbook Reading: Meltzer H. Ch. 29 Antipsychotic Agents & Lithium
In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 501-13
Online resource center: Medical Pharmacology Cloud Folder