Download I. ANTIPSYCHOTIC (AP)

PSYCHOPHARMACA
Sulistia 1209
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
- tend to drowse off but easily arouse,
and respond to question
- strongly inhibit aggressive tendencies
- < hallucination & delusion
• Antiemetic activity : ~ block. D3 rec.
Th/effect
70% of pts
30% resistant
EFFECT ON RECEPTRS
• Vary among different AP
* Chlorpromazine:
α1=5-HT2A>D2>D1
* Haloperidol:
D2> α1>5-HT2A>D1>H1
* Clozapine:
D4= α1>5-HT2A>D2=D1
* Olanzapine:
5-HT2A>H1> D4>D2 > α1 >D1
* Aripiprazole:
D2= 5-HT2A>D4> α1=H1>>D1
* Quetiapine :
H1> α1>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 t½ (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 : amenorrhoea-galactorrhea,
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 291. 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 hypnoticsedatives and tricyclic antidepressant
Cytochrome P450 enzymes involved in
psychopharmacological drug
2D6
: - amitriptyline, desipramine, imipramine,
haloperidol, nortriptyline
- risperidone, thioridazine
- venlafaxine
3A4
:
2C19 :
amitriptyline, imipramine
bupropion
clonazepam, diazepam
fluoxetine, sertraline
zolpidem
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
:
2C19 :
amitriptyline, imipramine
bupropion
clonazepam, diazepam
fluoxetine, sertraline
zolpidem
amitriptyline, clomipramine, imipramin,
diazepam, moclobemide
• Drug Interaction

highly protein bound :  free drug in comb. :
aspirin, phenylbutazone


inhibitor of Cyp 2D6 :
- nortriptyline
- desipramin
 conc. by
- 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:
hyperthermia, CVS collaps  † reported
 common : nausea
anorexia
insomnia
loss of libido, failure of orgasm
tremor,
Indication :




(OCD)
major depression
anxiety disorder
panic attacks
obsessive-compulsive disorder
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
- pargiline
- tranylcypromine
Main ADR :
- postural hypotension
- atropin like action
- weight gain
- CNS stimulation
acute overdose  convulsions
- cheese reaction : severe hypertension
(tyramine containing food > 10 mg)
- hyperpyrexia
in comb. with pethidine
hypotension
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
short acting
- temazepam
! 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