ANTIPSYCHOTIC

DRUGS
Yeoh Peng Nam
Professor

Objectives

To know the typical first generation

antipsychotic agents
To know the second generation
antipsychotic agents
Their mechanisms of action
Side effects

Antipsychotic (AP) Drugs

Treatment of schizophrenia:
overactivity of mesolimbic
dopaminergic pathway,
possible involvement of 5-HT and
glutamate

All useful AP drugs currently block

[B] D2 receptors in the mesolimbic
DA system

Dopamine Receptors (for interest only)

Cloning of DA receptors show 6
Five distinct DA receptors
subtypes
(D1-D5)
1. D1 receptor family (D1,
Distribution of DA receptors in
D5)
CNS
1. (+) cAMP
-D1: striatium , neocortex
2. (+) PIP2 hydrolysis 
-D2: striatium , SNpc,
Ca2+ mobilisation;
pituitary
PKC activation
-D3: olf tubercle, n.
accumbens,
2. D2 receptor family (D2L,
hypothlamus
D2S D3, D4)
(-) cAMP
-D4: frontal cortex,
medulla, midbrain
(+) K+ currents
-D5: hippocampus ,
(-) voltage gated
Ca2+ currents
hypothalamus

Antipsychotic Drugs

Classical / Typical/ First

Generation Antipsychotic
Agents (FGAs)
Phenothiazines:
Chlorpromazine
thioridazine
trifluoperazine
fluphenazine
Thioxanthenes:
flupenthixol
Butyrophenones:
haloperidol

Close relationship bet

binding to D2 receptors and
efficacy to relieve [+]
symptoms of Schizophrenia
D2 receptors linked to Gi;
inhbit adenyl cyclase
activity
Typical AP:
high affinity for D2
receptors & block these
receptors

Antipsychotic Agents: Relationship between Clinical

Potency and Affinity for Dopamine D2 receptors
Prevention of 50%
haloperidol binding

The more potent

the inhibition, the
more potent is the
AP action

TRICYCLIC ANTIPSYCHOTIC AGENTS

First Generation
Antipsychoics (FGAs)

piperidine
side chain

Mechanism of action of AP

DA interacts with postsynaptic D1 & D2 receptors

and presynaptic D2 & D3 receptors
Postsynaptic D1 receptors
[A] Gs [A] AC to [+] cAMP

Postsynaptic D2 receptors

[A] Gi to [I] AC to [-] cAMP

[A] receptor operated K+ channels
Suppress voltage gated Ca++ current
[S] PLC (via [A] of Gi [A] IP3- Ca++ pathway to
modulate a number of Ca++ dependent activities
including protein kinases

[S] D2 & D3 autoreceptors :

D2 autoreceptors suppress synthesis of DA (limit
phosphorylation of tyrosine hydroxylase & limiting DA
release)

Mechanism of action of AP (2)

All AP [B] D2 receptors and
autoreceptors;
some block D1 receptors
Initially: Block pre- & postsynaptic receptors
Presynaptic [B]:
[-] negative feedback >
[+] synthesis & [+] release
of DA
Postsynaptic [B] > [-] DA
transmission

Mechanism of action of AP (3)

Chronic treatment :
[+] DA receptors (upregulation)
[+] depolarsation block
leading to [-] cell firing

Repeated treatment:
neurons enter a state of physiological
depolarisation inactivation with reduced
production and release of DA

In addition to receptor blockade

Onset of all AP Action : slow (days to

weeks)

AP: Pharmacokinetics

AP: Given orally or via i.m. injection, once

or 2X a day
Absorption
can be erratic; wide variation of peak plasma
concentration as a function of dose
Relationship bet plasma level and clinical effect
is widely variable (adjust the dose on a trial
and error basis)

Plasma T : Most AP drugs have of 15-30

hrs
Clearance:
depends on hepatic metabolism via oxidative
and conjugation reactions

Compliance amongst patients is about 40%

AP: Pharmacokinetics

Slow release preparations: active drug

is esterified with heptanoic or
decanoic acid and dissolved in oil
Given im , duration of action is 2-4
week
Initially might produce side effects
Used to improve compliance
Acute toxicity has been slight

Typical AP:
Treatment of Schizophrenia

Effective treats [+] symptoms of up to

70% of S patients
Negative symptoms (emotional flattening,
social isolation) are not controlled

Prevention of recurrence of schizophrenic
attacks (long term treatment)

Depot preparations: preferred as
40% of patients are poorly controlled (poor
compliance)
30% are treatment resistant

Typical AP: Clinical Efficacy

DA mediate salience of environmental events and
internal representations
S: hyper dopaminergic state: distortion of how
patient assigns relevance to a particular experience
Hallucinations: may reflect actual experience of
attributing abnormal salience of internal
representations
Delusions (false idea without any foundation): maybe
a cognitive effort to make sense of abnormal
experiences
For clinical improvement :optimal D2 receptor should
be 70% occupied; > 70% occupancy --> side effects

Antipsychotic drugs: Actions

Onset: takes several weeks; receptor blocking

action is immediate
Neuroleptic effect:

Calming effect, apathetic, (-) initiative

Displays few emotions, slow response to external stimuli
Tends to drowse off, but easily aroused
No change in intellectual function
Inhibition of aggression

Normalize disturbed sleep; improve appetite

Antiematic action
Antihistamine-H1 effect (sedation)
Anticholinergic effect (atropine like)
-adrenoceptor blocking effect (hypotension)

AP: Side Effects

Extrapyramidal effects (EPS) / Parkinsons syndrome /:

block of D2 nigrostriatal pathway (> if D2 block is >75%;
less if drug dissociate rapidly from receptor)
{normally D2 pathway are balance by mACh pathway in
striatum} 
[+] mAChR (striatum) [+]GABA outflow
Also Involves 5HT2 receptors

EPS: motor disturbances:

Acute dystonias (< atypical AP)

Abnormal involuntary movements (spasm,
protruding tongue, torticollis)
Akathisia (restlessness)

AP: Side Effects 2

Pseudoparkinsonism :(5-10% of patients)

Occurs within 3 months of therapy,
Masked face, tremor, rigidity
Treatment: [-] symptoms with anticholinergic drugs
Tardive dyskinesia (< atypical AP, thioridazine);
occurs after several years of therapy (10-20%
patients esp > 50 yrs): no treatment, irreversible
? Supersentitivity of D2 receptors (striatum)
(+) catecholamine &/or glutamate release (striatum)
excitotoxic neurodegeneration
Involuntary repetitive movements

Oral facial, hand and leg movements, rocking

May become chronic, disabling, irreversible

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AP: Side Effects (3)

Hyperprolactineamia:( > if D2 block is >75%)

[B]: Tuberohypophyseal D2 pathway {DA block
release of prolactin (anterior pituitary)
Sedation, hypotension, weight gain
Anticholinergic effects
Obstructive jaundice
Leukopenia (clozapine), agranulocytosis
Neurolept malignant syndrome ([+] Ca++ release]
Muscle rigidity, hyperthermia, mental confusion 
death (renal or cvs failure)
Lower Seizure Threshold
Disrupt temperature regulation (heat stroke / cold
exposure)
May produce catalepsy (frozen response)

ATYPICAL OR SECOND GENERATION

ANTIPSYCHOTIC AGENTS (SGA)

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ATYPICAL
ANTIPSYCHOTIC
AGENTS

clozapine

Respiridone

Second Generation Antipsychotics (SGAs)

Olanzapine

Quetiapine

Atypical AP (SGAs)
Now: 1st Line Treatment

Improve positive and negative symptoms

Low level of motor side effects (EPS)

Has other side effects

Blocks many receptors (including 5HT2)
Clozapine acts to block D1 and D2 non
selectively, has high affinity for D4
receptors

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ATYPICAL ANTIPSYCHOTIC DRUGS

Second Generation Antipsychotics (SGAs)

Clozapine (D1, D2, D4)

Risperidone (5HT2A)
Olanzapine (most R)
Quetiapine (1 )
Aripiprazole
(block 5HT2 ; partial
agonist 5HT2A )
Ziprasidone
Clozapine is effective
in those resistant to
Typical drugs

Multiple affinity receptor

target agents (MARTAs)
block D1, D2, 1,
muscarinic, 5HT2A,
5HT6, 5HT7,
High 5HT2 / D2 ratio :
clozapine, risperidone
Selective for D2 /
D3receptors
Side effects:
[-] EPS
[-]Autonomic effects
has other side effects
(agranulocytosis, Wt
gain)

Antipsychotic Drug:
Mechanism of Action
Exact Mechanism is unknown


Classified into 3 categories
1.Traditional:High(XD2), Low(X5HT2A)
2.Atypical:Moderate to high(XD2 ),
high(X5HT2A)
3.Atypical, clozapine-like: Low (XD2 ),
high(X5HT2A)
X: Block

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Partial Dopamine Agonists

Aripiprazole - D2 partial agonist

[+] D2 activity in low D2 activity areas
(mesocortical area involved in cognition
and [-] symptoms of schizophrenia
[-] D2 activity in high D2 activity areas
(mesolimbic area : schizophrenia)

Weak 5HT2A antagonist

Potent agonist activity on 5HT1A

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Second Generation Antipsychotic Drugs

CHARACTERISTICS OF ANTIPSYCHOTIC DRUGS

CLASSICAL
mACh
Chlorpromazine
++
Thioridazine*
+++
Haloperidol
+
Flupenthixol
-

PS
++
+
+++
++

HPL
+++
+++
+++
+++

SED

[+]Wt

++
++
+

++ +++
+++ ++
+
+
++
+

[-BP]

BD
-

ATYPICAL
+++
Clozapine
+++
++ +++
+
Risperidone
+
+
++
++
+
+
Olanzapine
++
+
++ +++
+
+
Quetiapine
+
+
+
Aripiprazole
+
+
+
+
+
+
+
++
Ziprasidone
+
+
++
+
+
- : no effect; + : very low effect; +: low effect; ++: medium effect;
+++: high effect; PS: Parkinsonism; HPL: Hyperprolactinemia;
BD: Blood Dyscrasias; *: cardiothoxic

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Mechanism of Action

FGAs: primary effect occur in the limbic

system, including the ventral striatum;
EPS related to D block in the dorsal
striatum
5HT2A block in combination with modest
D2 block leads to release of dopamine in
the prefrontal cortex leading to decrease
in negative symptoms and improvement
of cognition seen with SGAs
Polymorphism in the 5HT2A receptor gene
may explain some of the variance seen
with clozapine

Additional Side Effects

Weight gain can aggravate risk of cvs

mortality and increase risk of diabetes
Some SGAs (risperidone, aripiprazole,
ziprasidine) and phenothiazines use are
associated with increase in serum
triglycerides and cholesterol leading to
development of the metabolic syndrome

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Pharmacokinetics

Antipsychotics are
highly lipophilic, highly bound bound to
membranes and plasma proteins
Widely distributed and accumulate in tissues
Largely metabolised by cytochome P450
system, except ziprasidone (adehyde oxidase):
risperidone and its metabolite, 6-OHrisperidone are metabolised through CYP 2D6
and are subjected to polymorphic metabolism
(about 30% of africans and asians are slow
metabolisers: more likely to have side effects)

Pharmacokinetics

Most antipsychotics have long T

(20-40 hr) except quetiapine and
ziprasidone which have short T
Most can be dosed once daily
Only clozapine has established
therapeutic range (plasma conc
>250 350 ng/mL)

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Pharmacogenetics

Customised medicine
Individualised therapy- tailored to
patients genetic makeup
Patients with polymorphisms in gene
encoding the:
5HT2A R : show slightly > improvement
to clozapine

5HT2C R : show slightly > wt gain

Current Practice

Increasing use of atypical AP

Despite cost
Associated with less EPS side effects
Whether better in other respects
remain uncertain

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TIMA : TEXAS IMPLEMENTATION

OF MEDICATION ALGORITHM

TIMA ANTIPSYCHOTIC ALGORITHM

Stage 1: SGA

Partial /no
response

(A/O/Q/R/Z)

Partial /no
response

Stage 2A: FGA

/another SAG

Partial /no
response

Stage 5: FGA /
SGA

Partial /no
response

Stage 2
Another SAG
Partial /no
response

Stage 3:
Clozapine

Stage 4: Clozapine +
FGA/SGA/ECT

Partial /no
response

Stage 6: Combination Therapy:

SGA +FGA / SGA + SGA/
FGA / SGA + ECT
FGA/SGA + others (mood stabilizers

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Thank You
Read Rang, Dale, Ritter & Flower,
Pharmacology, 6th ed., 2007,
ch38. pg545

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