Antipsychotic drugs

Monrudee Sukma; Ph.D.

 Psychoses
group of disorders which include
breakdown of the personality
thought disturbances
impaired perception of reality
inappropriate behavior
severe depression, schizophrenia
 Schizophrenia
a mental disorder caused by some inherent
dysfunction of brain
disordered thinking, social withdrawal, paranoia,
hallucinations
chronic, progressive disease which usually begins
during adolescence or young adulthood
Positive
genetic Negative
predisposition Cognitive
Suspicious Affective flattening Impaired attention
() Alogia ( Impaired working
Unusual thought ) memory
content (delusions) Anhedonia ( Impaired
Hallucination ) executive
 Antipsychotic agents
are able to reduce psychotic
symptoms in a wide variety of
conditions
schizophrenia, bipolar disorder,
psychotic depression, senile psychoses,
various organic psychoses, drug-induced
psychoses
are able to improve mood and reduce
anxiety and sleep disturbances
5
 Neuroleptics
subtype of antipsychotic drug that
produces a high incidence of
extrapyramidal side effects (EPS) at
clinically effective doses or catalepsy
in laboratory animals

6
Antipsychotic drugs
Chemical Class Drug
Typical antipsychotic drugs
Phenothiazines Aliphatic Chlorpromazine
Piperidine Thioridazine
Piperazine Fluphenazine
Thioxanthene Thiothixene
Butyrophenone Haloperidol
Dibenzoxazepine Loxapine
Atypical antipsychotic drugs
Dibenzodiazepine Clozapine
Benzisoxazole Risperidone
Thienobenzodiazepine Olanzapine
Dibenzothiazepine Quetiapine
Dihydroindolone Ziprasidone
Dihydrocarbostyril Aripiprazole

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 Antipsychotic Drugs: Relation of
Chemical Structure to Potency and
Toxicities

8
Structural formulas of some older
antipsychotic drugs

Piperidine side chain

9
Structural formulas of some newer
antipsychotic drugs

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 Mechanism of action
Dopamine receptor blocking activity
in the brain
Serotonin receptor blocking activity
in the brain

11
 Mechanism of action
Dopamine receptor blocking activity
All of older and most of newer drugs
block dopamine receptors in brain
clinical efficacy of typical antipsychotic
drugs correlates closely with their
relative ability to block D2 receptors in
mesolimbic system of brain

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 Distribution and characteristics of
dopamine receptors in CNS

D1 D5 D2 D3 D4
Putamen Hippocamp Caudate Frontal corte
Nucleus us putamen cortex x
accumbens Hypothalam Nucleus Medulla
Olfactory us accumbens Midbrain
tubercle Olfactory
Cortex tubercle
Correlations between therapeutic potency of
antipsychotic drugs and their affinity for
binding to dopamine D1 or D2 receptors

14
 Dopaminergic pathway in
CNS
Pathway Effects of inhibition
Nigrostriatal or SNC striatum Movement disorders
extrapyramidal
pathway
Mesolimbic pathway ventral tegmental Psychological effects
area (VTA) (esp positive
mesolimbic structure symptoms)
Mesocortical pathway VTAcortex Decrease motivation,
initiation, thought
process and executive
planning
Tuberoinfundibular arcuate nucleus in Endocrine effects
(neurohypophyseal) hypothalamus
pathway pituitary gland
dopamine
Dopaminergic pathway

17
Mechanism of action of antipsychotic drugs

Tyrosine Presynaptic
Dopaminergic pathways
dopaminergic
L-DOPA neuron
Mesolimbic pathway
Mesocortical pathway
DA
Nigrostriatal pathway
Tuberofundibular pathway MAO
DA
D2R

D2R Antipsychotics

Signal transduction

Therapeutic Effects
Therapeutic effects
Adverse Effects Postsynaptic
neuron
 Effect of antipsychotic drugs

Antipsychotic Drugs

Dopamine D2 receptor blockade

Movement disorders
Psychological effects Dystonia ()
Antipsychotic Dyskinesia ( )
Impaired performance Akathisia (
)
Sedation Parkinsonism
Neuroleptic malignant syndrome (NMS)
Endocrine effects Tardive dyskinesia
Gynecomastia
Galactorrhea Gynecomastia
Menstrual irregulation
Impotence ()
Weight gain
20
 Movement disorders from antipsychotics

Akathisia
Acute Dystonia Tardive Dyskinesia
1.
& Dyskinesia
2. 1.

1. 2.
3.
2. 3.
3.
Parkinsonism
1. 4.
4. 2. 5.
3.
4. cogwheel rigidity
& shuffling
5.
6.
7.

0 1 2 3 4 5 6 7 90 100 110 365 730

()
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 Atypical antipsychotics
5-HT/DA receptor antagonist (SDA)

negative symptoms

extrapyramidal side effect
 Clozaril
(Clozapine)

Zyprexa Zeldox
(Olanzapine) (Ziprasidone)

Abilify
(Aripiprazole)
Risperdal Seroquel
(Risperidone)(Quetiapine)

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25
Differences among antipsychotic drugs

Mechanism Type of agent

D2 and 5HT2A Second generation
antagonism (olanzapine (Zyprexa(R)),
risperidone (Risperdal (R)
),
quetiapine (Seroquel(R)),
Multiple actions Clozapine (Clozaril)
ziprasidone (Geodon (R)))
(D1, D2 and 5HT2-3
antagonism)
Mixed dopaminergic Aripiprazole (Abilify )
agonism and
 SDA dopamine
neurotransmission
Nigrostriatal tract
EPS
Mesocortical tract
negative symptoms
Mesolimbic tract
positive symptoms
 Serotonergic control of dopamine
release at nigrostriatal tract

striatum

stimulation of 5HT2A
receptor decreased DA
DA release

DA
substantia nigra

Rostral raphe nuclei

 Serotonergic control of dopamine
release at nigrostriatal tract

SDA blockade of 5HT2A

receptor increased DA
striatum release and partially offset
D2 blockade by SDA

DA
Less Extrapyramidal
syndrome (EPS)

DA
substantia nigra

Rostral raphe nuclei

Adverse Pharmacologic Effects
of Antipsychotic Drugs

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34
 Antipsychotic Drugs: Relation of
Chemical Structure to Potency and
Toxicities

35
 Cardiovascular ADR
Orthostatic hypotension
Syncope ( ) , falls and injuries
Prolongs QT intervals
Thioridazine, pimozide, haloperidol,
ziprazedone
DI: TCAs, antiarrythmics, cisapride,
metoclopramide
Clozapine: myocarditis, cardiomyopathy
Risperidone: increase risk of stroke in
elderly
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 Other ADRs
Wt gain:
Max:clozapine, olanzapine
Min: aripiprazole, ziprazedone
Metabolic diseases
Blood dyscrasia (
)
BM suppression: agranulocytosis (
)
Clozapine: 1%
Fever, malaise, resp. infection
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 Therapeutic uses
Treatment of schizophrenia
Typical antipsychotics are most effective in tx positive
symptoms of schizophrenia (delusions, hallucinations,
thought processing, agitation)
The newer agents with 5-HT2A receptor blocking
activity may be effective in many pts who are resistant
to traditional agents, especially in tx negative
symptoms of schizophrenia (social withdrawal, blunted
emotions, ambivalence, reduced ability to relate to
people)
Prevention of severe nausea and vomiting
Typical antipsychotics (most commonly
prochlorperazine) are useful in tx of drug-induced
nausea

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 Therapeutic uses
Other uses:
tranquilizers to manage agitated and disruptive behavior
from other disorders
combination with narcotic analgesics: chronic pain with
severe anxiety

Chlorpromazine: intractable hiccups

Promethazine: pruritus
Pimozide: motor and phonic tics of Tourette's disorder
Risperidone, haloperidol: tic disorder
Risperidone: management of disruptive behavior and
irritability from autism

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 Pharmacokinetics
After PO: variable absorption that is
unaffected by food (except for ziprasidone
and paliperidone, absorption is increased
with food)
pass into brain
large volume of distribution
bind well to plasma proteins
Metabolize: cytochrome P450 system in the
liver, particularly CYP2D6, CYP1A2, and
CYP3A
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 Pharmacokinetics
Fluphenazine decanoate, haloperidol
decanoate, and risperidone
microspheres are slow-release (up to
2 to 4 weeks) injectable formulations:
deep gluteal IM injection
long acting formulation that can be
administered q 3-4 wk
useful for poorly compliant pt
little physical dependence
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 Drug interactions
Potentiate effect of sedatives and
analgesics, alcohol, hypnotics,
antihistamine, cold remedies
Inhibit action of dopaminergic
agonists and levodapa worsen
symptoms of Parkinsons disease
CYP2D6, CYP1A2, CYP3A inhibitors &
inducers
 Cautions and
contraindications
acute agitation accompanying
withdrawal from alcohol or other drugs
seizure threshold
chlorpromazine and clozapine are
contraindicated in pts with seizure disorders
All of atypical antipsychotics carry
warning of increased risk for mortality
when used in elderly pts with dementia-
related behavioral disturbances and
psychosis

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 Clozapine
resistant schizophrenia
first line agranulocytosis
positive & negative symptoms, EPS
ADR: bone marrow suppression, seizures, cardiovascular side
effects

Paliperidone = 9-hydroxyrisperidone, active metabolite of risperidone

Risperidone is rapidly converted to 9-hydroxyrisperidone in vivo in
most patients, except for about 10% of patients who are poor
metabolizers
Paliperidone exhibits neuroleptic activity similar to that of parent
drug
 Risperidone
positive & negative symptoms
muscarinic receptor
anticholinergic side effect

receptor
Dose related extrapyramidal side effects
 Olanzapine
Benefits
Effective against negative and positive symptoms
Little or no extrapyramidal system dysfunction
Problems
Associated with significant weight gain
Dose-related lowering of seizure threshold
Can be associated with extrapyramidal and
anticholinergic side effects at higher dosages
 Ziprasidone
Benefits
Have antidepressant-like effect (inh 5HT&NE
reuptake, 5HT1AR agonist, 5HT1DR antagonist)
antidepressant or anti-anxiety in pt with psychotic
disorders
Less weight gain than clozapine
Parenteral form available

Problems
OT prolongation
should not be combined with other drugs that
prolong QT interval: thioridazine, pimozide, and
group IA or III antiarrhythmic drugs
 Quetiapine
Benefits
Very well tolerated good sedating and anxiolytic
effects
Neutral for extrapyramidal and prolactin side
effects
Generally only mild moderate effects on weight

Problems
May be less useful for severe psychosis
Less potent D2 antagonist
Dose related effects on blood pressure and pulse
Short t1/2 and twice-daily dosing
 Aripiprazole
Benefits
Relatively well tolerated
No intrinsic effects on lipids or glucose and no weight gain
Unique mechanism of action as only partial D2 agonist

Problems
May be less useful for severe psychosis
May be too activating in some patients causing agitation
and Extrapyramidal Side-Effects especially akathisia
Novel toxicities possible

(mg) (mg)

Chlorprom 25,50,100 Pimozide 1,4
azine 2,4 Thioridazin 10,25,50,1
Flupentixol 0.5, 2.5, 5 e 00
Fluphenazi 0.5,1,2,5,1 Trifluopera 5,10
ne 0 zine 10,25
Haloperido 2,4,8 Zuclopenth 53


Preparations Tradename Equivalent IM

dose (mg) dos
e
(q 2-
Fluphenazine Prolixin 25 25 4
12.5-
decanoate decanoate mg wk)
50

Haloperidol injection
Haldol 50 /ml 100 50-
decanoate decanoate mg 200

Flupentixol injection
Fluanxol depot 20 /ml 40 20-
decanoate injection mg 100 54
 Equivalent poten Daily dose
dose (mg) cy (mg/day)
Aliphatic 100 200-600
phenothiazine
chlorpromazine
Piperidine 100 200-600
phenothiazine
thioridazine
Piperazine 8 8-64
phenothiazine 5 5-30
Perphenazine 2 2-20
Trifluoperazine
Thioxanthenes 25
fluphenazine
Zuclopenthixol 2
Flupentixol
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Treatment of Mania

(unipolar disorder)
(depression) (mania)

(bipolar disorder)

58


(mania)
(depression)















 mood stabilizing agents
treatment of bipolar disorder
reduces hyperactivity
improves organization of thoughts
mood-stabilizing drugs
lithium
anticonvulsants (valproic acid, carbamazepine,
lamotrigine)
antipsychotics (aripiprazole, chlorpromazine,
olanzapine, quetiapine, risperidone, and
ziprasidone, olanzapine plus fluoxetine in
combination and quetiapine)

60
 Lithium
Treatment of mania and recurrences
of mania and depression in bipolar
disorder
decreases manic behavior
modulates frequency and magnitude of
mood swings

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 Lithium (2)
enter neuronal cells via Na+ channels
alters membrane conductance
decreases neuronal excitation
decrease release and increases
reuptake of NE
interfere with IP3 metabolism

62
Pharmacological properties
Precise mechanism remains unknown
Inhibit inositol monophosphatase and
thus interfere with the
phosphatidylinositol pathway
Decrease in functioning of protein kinase
(glycogen synthase kinase-3 (GSK-3))
interaction with transcription factors
modulate energy metabolism, provide
neuroprotection, and increase
neuroplasticity
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 Pharmacokinetics
Absorbed readily and almost completely from GI
Peak plasma conc. Occurring in 2-4 hr.
95% is eliminated in urine
Elimination t1/2 = 20-24 hr
80% is reabsorbed by proximal renal tubules

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 Pharmacokinetics
Li+ can be increased by any diuretics,
NSAIDs
Serum level
0.6-1.25 mEq per liter
900-1500 mg of lithium carbonate/day
in outpatient and 1200-2400 mg/day in
hospitalized manic pt.

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 Toxic reactions and side
effects
Acute intoxication
Vomiting, profuse diarrhea, tremor, ataxia, coma,
convulsion
More serious;
Neuro: Mental confusion, heperreflexia, tremor, seizures,
coma and death
Cardio: arrhythmias, hypotension, albuminuria
Treatment
No specific antidote, supportive

Decreases thyroid function (reversible or

nonprogressive)
Lithium-induced diabetes insipidus
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 Drug interaction
Diuretics, NSAIDs
Renal clearance of lithium is reduced about
25% by diuretics (eg, thiazides) doses by
similar amount
Antipsychotic, sedatives, antidepressant,
anticonvulsant drugs risk of increased
CNS toxicity
Anticholinergics alter GI motility Li+
level

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 Clinical Pharmacology of
Lithium
Bipolar Affective Disorder
especially in the manic phase
Other Applications
Recurrent endogenous depression
(lithium + imipramine)
Schizoaffective disorder (a mixture of
schizophrenic symptoms and depression
or excitement)

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