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DRUGS USED IN DISORDERS OF THE

CENTRAL NERVOUS SYSTEM AND


TREATMENT OF PAIN
Lecture 5:
Psychoses and Antipsychotic Agents
Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 5
Learning Objectives:
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.

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

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CNS Pharmacology
Lecture 5

Antipsychotic classification (2)


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

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CNS Pharmacology
Lecture 5
Overview of antipsychotic drugs:
 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

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CNS Pharmacology
Lecture 5
Schizophrenia
 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

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CNS Pharmacology
Lecture 5
Symptoms and signs of schizophrenia:
 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
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CNS Pharmacology
Lecture 5
Symptoms and signs of (2)
 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.
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CNS Pharmacology
Lecture 5
Schizophrenia (2)
 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

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CNS Pharmacology
Neural Pathways Involved in Schizophrenia Lecture 5

 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

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CNS Pharmacology
Lecture 5
Classes of dopamine receptor:
Type 2nd messenger + Location in CNS and postulated function
cellular effects
D1 cAMP increase Mainly postsynaptic inhibition
Functions unclear
D2 cAMP decrease Mainly presynaptic inhibition of dopamine synthesis/release in
K conductance up nigrostriatal, mesolimbic and tuberoinfundibular systems
Ca conductance down 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

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CNS Pharmacology
Lecture 5

Psychosis and Dopamine Pathways


 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
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CNS Pharmacology
Lecture 5

Antipsychotic Drugs (Neuroleptics)


 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

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CNS Pharmacology
Lecture 5

Antipsychotic Drugs (2)


 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

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?)
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CNS Pharmacology
Lecture 5

Antipsychotic Drugs (3)


 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)

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Relative affinity of clozapine,
CNS Pharmacology
Dopamine-blocking actions of Lecture 5
antipsychotic drugs. chlorpromazine, and haloperidol at
D1 and D2 dopaminergic receptors.

Marc Imhotep Cray, M.D. Modified from: Lippincott Illustrated Reviews-Pharmacology Sixth Edition. 2015 16
CNS Pharmacology
Lecture 5
Antipsychotic Drugs (5)
Antipsychotic drugs block at dopaminergic and serotonergic receptors as
well as at adrenergic, cholinergic, and histamine binding receptors

Modified from: Lippincott Illustrated Reviews-Pharmacology Sixth Edition. 2015

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CNS Pharmacology
Effect of D2 dopamine receptor Lecture 5
blockade on dopaminergic
pathways in brain
Modified from: Battista E. Crash Course
Pharmacology 4e. 2012

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CNS Pharmacology
Lecture 5

Typical drugs:
 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

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CNS Pharmacology
Lecture 5

Side effects of typical antipsychotics:


 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
Evolution of EPS side effects:
 TI is very large • 4 hr acute dystonia (muscle
 At high doses, convulsions can rarely occur spasm, stiffness, oculogyric crisis)
 Weight gain • 4 day akathisia (restlessness)
• 4 wk bradykinesia (parkinsonism)
• 4 mo tardive dyskinesia

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CNS Pharmacology
Lecture 5

Side effects of typical antipsychotics (2)


 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)

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CNS Pharmacology
Lecture 5
Atypical drugs:
 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)
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CNS Pharmacology
Idiosyncratic reaction & pharmacokinetics: Lecture 5

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 For NMS, think FEVER:
Fever
rigidity, diaphoresis, profound hyperthermia, and Encephalopathy
myoglobinuria Vitals unstable
 Tx-antipsychotic should be discontinued and supportive Enzymes increase
care given along with bromocriptine to overcome DA Rigidity of muscles
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
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CNS Pharmacology
Lecture 5
Other Uses of Antipsychotic Drugs:
 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)

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CNS Pharmacology
Lecture 5

THE END

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CNS Pharmacology
Further study (SDL): Lecture 5
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

Lectures/discussions to follow:
6. Drugs Affecting Movement Disorders and
Other Neurodegenerative Disorders
7. Analgesics
8. Anesthetics

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