PSYCHOPHARMACA

classification
I. Antipsychotics
II. Antidepressants
III. Antianxiety and Drug for
insomnias
IV. Drug for bipolar disorder

I. ANTIPSYCHOTIC (AP)
SYNONIMS:
antischizophrenic drug, neuroleptics,
mayor tranquilizer
CLASSIFICATION:
Typical AP : chlorpromazine, fluphenazine
haloperidol, thioridazine
Atypical AP :
clozapine,olanzapine,risperidone
quetiapine, aripriprazol

 MECHANISM OF ACTION
- Blocking the D2-receptors > D1
(mesolimbic / mesocortical dep. pathway)
- ! Atypical : clozapine
weak D2 blocker ,potent
antipsychotic
block D4-receptor and 5-HT2
- Varying pattern of selectivity in rec. blocking
effect
- Take several weeks to clinical response even
though their rec. blocking is immediate
- The connection between rec. block. activity to
clin.
response : remains unclear

PHARMACOLOGICAL EFFECTS
Slow response to external stimuli :
- apathy
- reduce initiative
- display few emotion
Th/effect
70% of pts
- tend to drowse off but easily arouse,
30% resistant
and respond to
question
- strongly inhibit aggressive tendencies
- < hallucination & delusion
Antiemetic activity : ~ block. D3 rec.

EFFECT ON RECEPTRS
Vary among different AP
* Chlorpromazine:
1=5-HT2A>D2>D1
* Haloperidol:
D2> 1>5-HT2A>D1>H1
* Clozapine:
D4= 1>5-HT2A>D2=D1
* Olanzapine:
5-HT2A>H1> D4>D2 > 1 >D1

* Aripiprazole:
D2= 5-HT2A>D4> 1=H1>>D1
* Quetiapine :
H1> 1>M1,3>D2>5-HT2A

PSYCHOLOGICAL EFFECTS
In nonpsychotic patients
Sleepiness, restlessness, autonomic
effect unlike sedative-hypnotics and
impaired performance in
psychomotor and psychometric tests
In Psychotic patients: alleviate
psychosis and improve performance

ELECTROENCEPHALOGRAPHIC
EFFECTS
Shift the pattern of EEG frequencies:
slowing and increasing their
synchronization erroneous
diagnostic interpretation
some lower seizure threshold , but
can be use safely in epileptic
patients with careful dosage titration

Pharmacokinetic
Absorption and Bioavailabily
Chlorpromazine absorption erratic
interindividual variation up to 90 fold ,
bioavailability:
chlorpromazine: 25%
thioridazine 35%,both undergo first pass
metabolism
haloperidol 65%
- relation between plasma conc clin. effect :
highly variable tailored individually!
- long t (15-30 hours) 1 2 dd.
- Depot preparation : heptanoic or decanoic
acid in oil : IM given each 2-4 weeks
overcome compliance problems

DISTRIBUTION

Highly lipid soluble

widely distributed. Vd >7L/kg
Highly protein bound(92-99%)
Prolonged binding to receptors
duration of action> than plasma
t 1/2

Metabolism and Excretion

Most AP are completely metabolized
Metabolites usually not active except
mesoridazine which is more active
than thioridazine
Excreted in the urine as inactive
metabolites

ADE
A. 2 kind of motor disturbance :
1)Acute dystonias & Parkinson-like
symptoms ~ nigrostriatal block D2 rec.,
tremor, rigidity (esp. eck muscle),
akatisia(uncontrollable restlessness)
Th/ anticholiergic drugs: trihexyphenidyl
beperiden ,
diphenhydramine
* Levodopa and dopaminergic agonist
should never be use (why?)

ADE
2)
Tardive diskinesia
- involuntary movement of face
& limbs, appearing months/years after
treatment
Th/ usually unsuccessful
Extrapyramidal ADE are less likely to occur with
atypical AP
clozapine : strong antimusc.
more selective D block in
mesolimbic vs nigrostriatal

B.Cardiovascular adverse
effects
Chlorpromazine, thioridazine:
orthostatic hypotension;mean
arterial pressure, peripheral
resistance and stroke volume <;
H Rate , prolonged QT interval
sertindole, withdrawn from the
market
ziprazidone warning about the risk

C.Endocrine ADE
In women : amenorrhoeagalactorrhea, increase libido and false
positive pregn. Test.
In men: decrease libido, gynecomastia
a part cause by hyperprolactinemia
due to dopaminergic blocking effect
and increase peripheral conversion of
androgens to estrogens(>typical AP)

D. Other ADE
antimuscarinic adverse effects :
! - Alzheimer (memory impairment)
- prostate hypertrophy
- glaucoma,
orthostatic hypotension : associated w alfa
adrenergic blocking effect ~ fall and fracture
in the elderly
weigh gain : > atypical
agranulocytosis : clozapine to be monitored by
blood count
idiosyncratic : antipsychotic malign. syndrome,
rare but dangerous
relation of chemical structure to potency & toxicity
Table 29-1. p 461.Bertram G Katzung 10th ed.

- Indonesian population : as
common with other drug tolerate
AP less than caucasian
- ? poor metabolizer
- ! Start with lower dose

DRUG CHOICE
Based mainly on differences and ADE
In using typical AP knowledge of
chlorpromazine and haloperidol
remains relevant
One should be familiar w 3 subfamily
of phenothiazine,a member of
thioxanthine and butyrophenone
group and all the newer compound

 A representative group of AP drugs is

presented in:
Table 29-1. p 461.Bertram G
Katzung 10th ed.

Summary
AP are very useful : for pats & care givers
less hospitalization
Effective in 70% of pts
Atypical : problem with dystonia S.E.
Atypical :
- sign less motor disturbance
- claimed > effective to control neg.
symptoms :* emotional flattening
* social withdrawal and
* lack of motivation

Summary
Atypical :
- > metabolic side effects :
* weight gain
* hyperglycemia
- clozapine : efficacy in treatment
resistant pts.
- not more effective in every patients
- first line drug for those who could
afford the cost
AP are safe in acute overdose compare to
hypnotic-sedatives and tricyclic antidepressant

Cytochrome P450 enzymes involved in

psychopharmacological drug
2D6 : - amitriptyline, desipramine, imipramine,
haloperidol, nortriptyline
- risperidone, thioridazine
- venlafaxine
3A4 : amitriptyline, imipramine
bupropion
clonazepam, diazepam
fluoxetine, sertraline
zolpidem
2C19 : amitriptyline, clomipramine, imipramin,
diazepam, moclobemide

Question to be answered
1. mention classification of
AP(antipsychotic) and 3 examples of
each class
2. explain the differences of
pharmacodynamic action of each class
3. explain important pharmacokinetic
issue of AP
4. Explain difference in ADE of special
drugs

 5. Explain factors influencing the use

of drugs

I. ANTIDEPRESSANT
CLASSIFICATION
A.First Generation Tricyclic AD

Imipramine

Amitriptyline
* Clomipramine
B. Second Generation:
* Amoxapine, Maprotiline, Trazodone,
Bupropion
C. Third Generation:Venlafaxine, Mirtazapine,
Nefazodone & Duloxetine

 D. Selective Serotonin Reuptake

Inhibitor (SSRI)
Fluoxetine, Sertraline,
Fluvoxamine, Citalopram
E. Monoamine Oxydase Inhibitors
Phenelzine, Tranylcypromine,
moclobemide

A. Tricyclic Antidepressant
Mechanism of action
Block the amine transporters (uptake pump)
Block reuptake of NE (NET), 5HT (SERT) (<<
dopamin)
catecholamine: mania;
catecholamine :depression
Not clearly understood why blocking transporter
occurs rapidly but clinical result is delayed for a
few weeks

B.. Second generation of

Antidepressant
AD that exhibit less CVS side effects
* desimipramine: metabolit of
imipramine
* nortriptyline: metabolit of triptyline
AD that exhibit less CVS side effects but
more sedation: trazodone and bupropion
Amoxapine a metabolite of
antipsychotic loxapine: retain AP action
of the parent drug

 Maprotyline,structure resembles
desimipramine is a potent NE
reuptake inhibitor, causing
<sedation,antimuscarinic and
CVS side effects .

C. Third Generation of AD
Venlafaxine:
- potent inhibitor of serotonin transporter; &
weak inhibitor of NE transporter;
in low dose= SSRI, high doses (> 225 mg/d)

mild-moderate increase HR & BP

Nefazodone: as trazodone, but less sedation.

potent inhibitor of CYP 3A4

Duloxetine=SSRI,free of autonomic SE and
sedation

Mirtazapine
more rapid in action
no more efficacious than
other AD
likely to cause weight gain
substantial sexual side effect

>> sedating because of

strong antihistaminergik effect

 ADE

Interference with autonomic control

- Atropine like : dry mouth
blurred vision
constipation
urinary retention
- Orthostatic hypotension : central NE
effect
- CNS : * sedation, seizure
* diff. in concentrating
- CVS : prolongation Q-T interval
: risk of sudden cardiac

Cytochrome P450 enzymes involved in

psychopharmacological drug
2D6 : - amitriptyline, desipramine,
imipramine,
haloperidol, nortriptyline
- venlafaxine
3A4 :

amitriptyline, imipramine
bupropion
clonazepam, diazepam
fluoxetine, sertraline
zolpidem

2C19 : amitriptyline, clomipramine,

imipramin,
diazepam,
moclobemide

Drug Interaction

highly protein bound : free drug in

comb. :
aspirin,
phenylbutazone

inhibitor of Cyp 2D6 :

- nortriptyline conc. by
- desipramin
- fluvoxamine
- paroxetine
TCA + alcohol severe Resp. depression

TCA + antihypertensive adrenergic

neuron
blocking agents (guanadrel): BP
! Should be monitored clinically

D. SSRI (Selective Serotonin Reuptake

Inhibitor)

Fluoxetine
Fluvoxamine
Paroxetine
Sertralin
Mechanism of action

More selective 5 HT-reuptake Inhibitor

more 5 HT at rec.

desensitization of autorec normal firing rt.

No influence to cholinergic nerves / NE, dopamin

less side effects

ADE

<< than TCA : CVS, antimusc.

acute toxicity : << dangerous than TCA
combination with MAOI serotonin
syndrome: tremor, hyperthermia, CVS collaps
reported
common : nausea
anorexia
insomnia
loss of libido, failure of orgasm

Indication :

major depression
anxiety disorder
panic attacks
obsessive-compulsive
disorder (OCD)

ADE
Paroxetine:
highest affinity to serotonin
receptors.indirectly result in a net decline
in dopaminergic transmission leading to
extrapyramidal side effects (distonia,
akathisia)
Sexual function(delayed ejaculation and
anorgasmia)
paroxetine>fluoxetine, sertraline>
flufoxamine

D. Monoamine oxidase Inhibitors

Moclobemide : selective MAOI ( type A),reversible
less interaction
Than older MAOI :
less CNS ADR
Main ADR :

- pargiline
- tranylcypromine

- postural hypotension
- atropin like action
- weight gain
- CNS stimulation
acute overdose convulsions
- cheese reaction : severe hypertension
(tyramine containing food > 10 mg)
- hyperpyrexia
hypotension in comb. with pethidine

III. ANXIOLYTIC & HYPNOTIC

DRUGS
A. BENZODIAZEPINES
Mechanism of action
- facilitate GABA action ( receptor binding) :
hyperpolarization, Cl channel opening
- safe because its action depend on
endogenous GABA
barbiturate : direct action in overdose

Pharmacological effects
- reduction of anxiety and aggression
- sedation and induction of deep
- reduction of muscle tonus and coordination
- anticonvulsant effect

ADE
Acute overdosage
- less dangerous, only rarely
- in the present of other CNS depressant
esp. alcohol : severe resp. disorder or
in COPD
! could be counteract by antagonist flumazenil
Common side effect :
- drowsiness
- confusion
- impaired coordination
- amnesia
esp. with long acting drug

impairment of job performance and driving

skill

Chronic use :
Tolerance : less than barbiturate
Dependence demonstrate by
- symptoms of anxiety
- tremor
after withdrawal
- dizziness
withdrawal symptoms : slower in onset
than
barbiturates
with triazolam : a short acting BDZ
occurred within a few hours :
- early morning insomnia
- daytime anxiety
Addiction : not a mayor problem

Indication

Hypnotic :
- lorazepam
- temazepam short acting
! not for chronic use tolerance

Anxiolytic :
acute anxiety state e.g. panic disord. agoraphobia
choice : alprazolam 2-3 times daily 0.25-0.5 mg
altern. : diazepam 2 times daily 2-5 mg

Muscular relaxant in muscle spasm : diazepam

Other :
- Alprazolam : anxiety in major depressive
disorder
- Clobazam :
claimed to cause less sedation
as
antianxiety drug