Pharmacology of

Antipsychotic drugs

March 2015

Dr.Datten Bangun,MSc,SpFK
Dr.Sake J Martina SpFK

Dept.Farmakologi &
Therapeutik
Fak.Kedokteran USU

Psychosis
Definition: DSM IV
= A severe mental disorder, with
or without organic damage,
characterized by :
derangement of personality and
loss of contact with reality and
causing deterioration of normal
social functioning.

The hallmark of
schizophrenia
Description:
-Positive symptom: (known by their
presence)
delusions, hallucinations, abnormal
movements, or thought disorders.
-Negative symptom: (characterized by
absence)
social withdrawal, lack of affect, and
reduced motivation.
- Cognitive symptoms (Disorganization of
thought and speech)

Negative Symptoms As
Affect Flattening
Found in about 2/3 of schizophrenic patients
Often suggests a poor prognosis
Alogia
The failure to respond to questions or
comments
Can also take the form of slow or delayed
responses
Avolition
Inactivity or early loss of interest in ongoing
activity
Anhedonia
-inability to derive pleasure

Antipsychotics
(Neuroleptics)
The Dopamine Hypothesis
1. Antipsychotic drugs block D2
dopamine receptors
2. Drugs that increase dopaminergic
activity produce or exacerbate
schizophrenia
3. Dopamine receptor density is
increased in schizophrenia patients
4. PET shows increased D2 receptor
density
5. Successful treatment of schizophrenia
changes HVA in CSF of patients

Douglas L. Geenens, D.O. 2000

DA theory of schizophrenia
DA is a transmitter in the mesocortical and
mesolimbic pathways
Involved in cognition and emotion
Increased activity of these pathways
implicated in psychosis
Amphetamine releases DA and induces
psychosis
Blockade of the D2 dopamine receptor by all
clinically effective antipsychotics
Correlates with antipsychotic potency
7

Dopamine Pathways

Dopamine functions
Motor control - nigrostriatal system
Deficiency results in rigidity, tremor and
difficulty initiating movement
Behavioural effects - mesolimbic system
Overactivity in rats leads to abnormal
behavior
Endocrine control - tubero-infundibular
system
Dopamine and dopamine agonists
suppress prolactin release, dopamine
antagonists may stimulate it

Dopamine Pathways
Nigrostriatal
Projects from the substania nigra to the basal
ganglia
-A part of the extrapyramidal system
-Thus side effects are called extrapyramidal
Controls movements
The term neuroleptics refers to:
Antipsychotics ability to quiet the
neurological system
To their neurological side effects
Douglas L. Geenens, D.O. 2000

Dopamine Pathways
Nigrostriatal
Types of movement disorders caused by
this pathway include:
Akathisia
- Dystonia
- Tremor, rigidity, bradykinesia
Drug-induced Parkinsonism
Chronic blockade can cause
Potentially irreversible movement
disorder
Tardive Dyskinesia
Role is undetermined
Douglas L. Geenens, D.O. 2000

Dopamine Pathways
Tuberoinfundibular

Blockade produces
galactorrhea
cause prolactin elevation

Douglas L. Geenens, D.O. 2000

Other transmitter systems

involved..
+Why this notion? Because not every
psychosis patients were succesfully
treated by CPZ.
Glutamatergic system dysfunction
e.g. effect of phencyclidine blocker
of NMDA type of glutamate receptors
G-protein signaling abnormalities
Serotoninergic system abnormalities
most antipsychotics also affect
serotonin receptors
Dopamine

and serotonin theory of

NMDA indicates N-methyl-d-aspartate.)
schizophrenia

Classification of antipsychotic
drugs:
Typical Antipsychotic Drugs:

Phenothiazines:
Chlorpromazine,
Thioridazine ,
Trifluperazine,
Fluphenazine.
Butyrophenones:
Haloperidol
Benperidol.
Thioxanthenes:
Thiothixene
Others:
Pimozide
Loxapine

Atypical Antipsychotic Drugs:

Clozapine,
Olanzapine,
Risperidone,
Ziprasidone

Prof. Mohamed Adel

Classification of
Antipsychotic drugs

Distinction between typical and

atypical groups is not clearly
defined, but rests on:
1) Atypicals have less tendency to
produce motor side effects
2)Atypicals produce effects on
negative symptoms of
schizophrenia
3)May have effects in therapyresistant patients

Mechanism of Action
Most neuroleptics block central
D2 receptors in the mesolimbic
and mesocortical pathways.
Newer drugs block both
serotonergic and dopaminergic
receptors.

Phenothiazines
Typical antipsychotic
Pharmacologic effects:
(1) Anti psychotic
(2) autonomic nervous system: block
-adrenergic and M-Cholinergic
receptors and result in
hypotension, dry mouth,
constipation and blurred vision.
(3) Endocrine system: increase the
release of prolactin and decrease

Chlorpromazine
Pharmacologic effects and mechanism:
(1)CNS: a. neuroleptic effect

D1, D5---D1-like
receptors
Antipsychotic
drugs probably owe their therapeutic
effects mainly to blockade of D2-receptors (lies in
D2-4------D2-like
midbrain-cortex and midbrain-limbic system ).
receptors

Chlorpromazine
b. antiemetic effect--- inhibit
chemoreceptor trigger zone or
directly depress the medullary
vomiting center.

c. temperature-regulating
effect--- produce hypothermia

Adverse Effects - EPS

Details on two main extrapyramidal
disturbances (EPS):
Parkinson-like symptoms
tremor, rigidity
direct consequence of block of nigrostriatal
DA2 R
reversible upon cessation of antipsychotics

Tardive dyskinesia

involuntary movement of face and limbs

less likely with atypical antipsychotics (AP)
appears months or years after start of AP
? result of proliferation of DA R in striatum
presynaptic?
treatment is generally unsuccessful

Phenothiazines - Side effects

Weight gain 40% - weight gain now attributed
to ratio of binding to D2 and 5-HT2 receptors;
possibly also histamine (for newer
antipsychotics anyway)
Sexual dysfunction
result from NE and SE blockade
erectile dysfunction in 23-54% of men
retrograde ejaculation
loss of libido and anorgasmia in men and
women
Seizures - <1% for generalized grand mal

Phenothiazines - Side effects

Neuroleptic malignant syndrome (NMS):
(1-2% early in trt)
combination of motor rigidity, hyperthermia,
and autonomic dysregulation of blood pressure
and heart rate (both go up)
can be fatal in 5-20% of cases if untreated
treatment discontinue meds; give trts for
fever and cardiac problems

Treatment of NMS
Discontinuation of dopamine
antagonist
Monitoring vital signs, electrolytes,
renal output
Symptomatic treatment of fever
IV
dantrolene/bromocriptine/amantadine
After symptoms subside switch to
atypical anti-psychotic

Sensitivity to sun
some phenothiazines collect in skin (chlorpromazine)
sunlight causes pigmentation changes grayish-purple
splotching (look bruised)
can also occur in eye and cause brown in cornea
this produces a brownish cloud to vision and possibly
permanent impairment
Agranulocytosis - <1%
reduced white blood cell count
lowered resistance to infection
can be fatal
Jaundice elevated bilirubin in liver - < %

Phenothiazines - Drug Interactions

enzyme interactions with barbiturates
(phenobarbital); phenytoin (Dilantin);
carbamazepine (Tegretol) reduce phenothiazine
levels
co-administration must be carefully monitored
to prevent toxicity
enzyme competition with SSRIs increases
levels and may increase side effects

Autonomic side effects of

antipsychotic drugs
1 AdrR blockade-orthostatic hypotension
mAChR blockade dry mouth, blurred vision,
constipation, urinary retention
common with low potency drugs e.g. thioridazine,
clozapine
Cardiac effects: QT, PR elongation, T wave changes,
arrhythmias

26

Other side-effects
Ophtalmological effects: retinal
pigmentation (thioridazine
irreversible, chlorpromazine
benign)
Hepatological effects:
obstructive jaundice
Neurologic : seizures

Haloperidole
entered US market in 1967
more potent than phenothiazines, so doses are lower
also have long half-life
like phenothiazines, they block dopamine and
norepinephrine receptors and show the related side
effects
extrapyramidal effects are worse (due to low blockade
of ACh and thus worse ratio)
but blood pressure effects are less
reduced sedation

no blood abnormalities or jaundice

Neurological Side Effects of antipsychotics

REACTION

Acute dystonia

FEATURES

TIME OF
MAXIMAL RISK

Spasm of muscles of
tongue, face, neck, back;
may mimic seizures; not
hysteria

1to5days

Motor restlessness; not

anxiety or "agitation"

5to60days

Parkinsonism

Bradykinesia, rigidity,
variable tremor, mask
facies, shuffling gait

5to30days

Neuroleptic
malignant
syndrome

Catatonia, stupor, fever,

unstable blood pressure,
myoglobinemia; can be
fatal

Perioral tremor
("rabbit"
syndrome)
Tardive dyskinesia

Akathisia

PROPOSED
MECHANISM
Unknown

Unknown

TREATMENT
Antiparkinsonianagentsare
diagnosticandcurative

Reducedoseorchangedrug:
antiparkinsonianagents,b
benzodiazepinesor
propranololcmayhelp

Antagonismof
dopamine

Antiparkinsonianagents
helpful

Weeks;canpersistfor
daysafterstopping
neuroleptic

Antagonismof
dopaminemay
contribute

Stopneuroleptic
immediately:dantroleneor
bromocriptinedmayhelp:
antiparkinsonianagentsnot
effective

Perioral tremor (may be a

late variant of
parkinsonism)

Aftermonthsoryears
oftreatment

Unknown

Antiparkinsonianagents
oftenhelp

Oral-facial dyskinesia;
widespread choreoathetosis
or dystonia

Aftermonthsoryears
oftreatment(worseon
withdrawal)

Excessfunctionof
dopamine
hypothesized

Preventioncrucial;treatment
unsatisfactory

a.Manydrugshavebeenclaimedtobehelpfulforacutedystonia.Amongthemostcommonlyemployedtreatmentsarediphenhydraminehydrochloride,25or50mgintramuscularly,or
benztropinemesylate,1or2mgintramuscularlyorslowlyintravenously,followedbyoralmedicationwiththesameagentforaperiodofdaystoperhapsseveralweeksthereafter. b.Fordetails
regardingtheuseoforalantiparkinsonianagents,seetherestofslidesc.Propranololofteniseffectiveinrelativelylowdoses(20-80mgperday).Selectivebeta1-adrenergicreceptorantagonists
arelesseffective.d.Despitetheresponsetodantrolene,thereisnoevidenceofanabnormalityofCa2+transportinskeletalmuscle;withlingeringneurolepticeffects,bromocriptinemaybe
toleratedinlargedoses(10-40mgperday).

Extrapyramidal Symptoms
Dopamine Vs Acetylcholine
Dopamine blockade:
A relative increase in cholinergic
activity
causing EPS

Those antipsychotics that have

significant anti-ACH activity are
therefore less likely to cause EPS
When high potency antipsychotics
are chosen, we often prescribe
anti-ACH medication like
Cogentin, diphenhydramine, or Artane
Douglas L. Geenens, D.O. 2000

H1 histamine receptor
blockade effects
Chlorpromazine was first found as an
antihistamin
Sedation
Increased appetite and weight gain
Metabolic syndrome
Common with many atypical antipsychotics
esp clozapine, olanzapine

Schizophrenia - Serotonin
Hypothesis
correlation between DA affinity and antipsychotic
efficacy has become weaker as a result of recently
developed atypical antipsychotic medications that also
show substantial affinity for 5HT2 receptors
Alteration of 5-HT transmission in the brains of
schizophrenics patients have been reported in postmortem studies and serotonin-agonists challenge
studies
There are widespread and complex changes in the 5-HT
system in schizophrenics patients
These changes suggest that 5-HT dysfunction is
involved in the pathophysiology of the disease

Schizophrenia - Glutamate
Hypothesis

Preclinical as well as clinical studies provide

evidence of hypofunction of NMDA receptors as
a primary, or at least, a contributory process in the
pathophysiology of schizophrenia
Several clinical trials with agents that act at the
glycine modulatory site on the NMDA receptor have
revealed consistent reductions in negative
symptoms and variable effects of cognitive and
positive symptoms
These studies also provide evidence that suggests
the effects of clozapine on negative symptoms and
cognition may be through activation of the
glycine modulatory site on the NMDA receptor.

Antipsychotic Drugs New Generations

atypical
About 40-60% do not respond to phenothiazines or
cannot handle side effects
Questions remain about the efficacy of
phenothiazines and haloperidole for negative
symptoms
Drugs needed that are low in extrapyramidal side
effects and at least equal in efficacy for positive
symptoms, perhaps better for negative

Antipsychotic Drugs New

Generations atypical

clozapine
risperidone
olanzapine
sertindole
quetiapine etc.

Atypical antipsychotics
MARTA (multi acting receptor targeted
agents)
clozapine, olanzapine, quetiapine
SDA (serotonin-dopamine antagonists)
risperidone, ziprasidone, sertindole
Selective D2/D3 antagonists
sulpiride, amisulpiride

Clozapine (1989)
Selectively blocks dopamine D2 receptors,
avoiding nigrostriatal pathway
Also blocks NE
More strongly blocks 5-HT2 receptors in cortex
which then acts to modulate some dopamine
activity
Among non-responders to first generation
meds or those who cannot tolerate side effects,
about 30% do respond to Clozapine

Clozapine
Extrapyramidal side effects are minimal
May help treat tarditive dyskinesia
Still shows orthostatic hypotension effects,
sedation, weight gain, increased heart rate
Increased risk for seizures (2-3%)
Agranulocytosis in 1%
Agranulocytosis risks increase when coadministered with carbamazepine
Interactions with SSRIs and valproic acid
increase Clozapine levels and risks

Risperidone (Risperdal; 1994)

Fewer side effects than Clozapine
Marketed as first line approach to treatment
Blocks selective D2, norepinephrine, and 5-HT2
Argued as effective for positive and negative
symptoms (controversial)
Extrapyramidal side effects low (but are shown
at high doses) - controversial
Shares sedation, weight gain, rapid heart beat,
orthostatic hypotension, and elevated prolactin
No agranulocytosis risks
May cause anxiety/agitation (possible OCD)

Risperidone (Risperdal)
Research designs clearly stacked in favor of
Risperidone re showing better profile for
extrapyramidal side effects and for symptom
reduction
Advantages unclear other than agranulocytosis
issue

Olanzipine - Zyprexa 1996

Same poorly supported arguments about
improved negative symptom reduction
Argued to be better than risperidone in
extrapyramidal issues
Does not cause prolactin elevation
Same claim to fame reduced agranulocytosis
risks

Table 2. Comparison of Atypical Antipsychotic D

Drug

EPS

Weight
Gain

Metabolic
Changesb

Prolactin
Secretion

QT
Interval

Sedation

Comments

+++

+++

+++

Cancause
agranulocytosis,
seizures,salivation

Risperidone

++

++

+++

++

+/-

Olanzapine

+++

+++

++

Quetiapine

++

++

++

Ziprasidone

+++

Mayimprove
cognitivefunction

Aripiprazole

+/-

PartialagonistatD2
receptorsand5-HT1A
receptors

Clozapine

Important distinguishing features are highlighted.

b
Risk for diabetes; worsening lipid profile.
a

42

Properties of conventional and

atypical antipsychotic drugs
All have equivalent clinical efficacy in
treating positive symptoms
None cause significant improvement in
cognitive symptoms
All take weeks to months to show effect
Any single conventional will fail in
about 30% of patients; these patients
may respond to atypical drugs.
43

Atypical antipsychotics
advantages
Maybe more effective against
negative symptoms
Less likely to cause EPS and TDs
More favorable side effect profile
improves compliance
44

Metabolic syndrome and

atypical antipsychotic drugs
Increased risk of diabetes
Worsening lipid profile
No clear association with weight gain;
mechanism unknown
Caution and frequent monitoring in patients
with family history of diabetes or cardiovascular
disease

45

Treatment of medicationinduced movement disorders

Parkinsonism
anticholinergics, amantadine

Acute dystonia
anticholinergics (IM)

Akathisia
beta-blockers, BZ

Tardive dyskinesia
clozapine

Long acting antipsychotics

Indicated mainly for patients with low
compliance to treatment
IM:
Haloperidol - Halidol decanoas
Fluphenazine Modiket
Zuclopenthixol Clopixol depot
Flupenthixol Fluanxol depot
Risperidone Risperidal consta
PO:
Penfluridol Semap

Clinical Uses
Treatment of schizophrenia.

The typical neuroleptics ameliorate

positive symptoms of
schizophrenia.

The atypical neuroleptics (Clozapine

& Risperidone) ameliorate mainly
the negative symptoms.

Clinical Uses (contd)

Antipruritic: promethazine used as
antipruritic due to H1- receptor blockade.
Chronic pain with severe anxiety
(neuroleptic + opioid drug).
Tranquilizer in management of agitated
and disruptive behavior.
Preanesthetic medication
(promethazine) to produce sedation.
Intractable hiccups (chlorpromazine)

Clinical Uses (contd)

Antiemetic (prochlorperazine) is used
to stop all types of vomiting: Except
in cases of:
-Motion sickness (treated by blocking
M-receptors in vomiting center by
hyoscine)
-Vomiting associated with Parkinsonism
(neuroleptics block D-receptors
aggravate Parkinsonism).

Hospital beds occupied by patients with psychiatric disorders

Fig 1. Yearly change in the number of hospitalized patients with psychiatric disorders
(thousands).

Thank you for the attention