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/effect70% of pts30% 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

PharmacokineticAbsorption 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

ADEA. 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 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 costAP 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, imipraminebupropionclonazepam, diazepamfluoxetine, sertralinezolpidem

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

* ClomipramineB. 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 mouthblurred visionconstipationurinary 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, imipraminebupropionclonazepam, diazepamfluoxetine, sertralinezolpidem

2C19 : amitriptyline, clomipramine, imipramin, diazepam, moclobemide

• Drug Interaction

highly protein bound : free drug in comb. : aspirin, phenylbutazone

inhibitor of Cyp 2D6 :- nortriptyline- desipramin

TCA + alcohol severe Resp. depression

TCA + antihypertensive adrenergic neuron

blocking agents (guanadrel): BP

! Should be monitored clinically

conc. by- fluvoxamine- paroxetine

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 : nauseaanorexiainsomnialoss 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 less CNS ADR

Main ADR :- postural hypotension- atropin like action- weight gain- CNS stimulation

acute overdose convulsions- cheese reaction : severe hypertension

(tyramine containing food > 10 mg) - hyperpyrexia hypotension

Than older MAOI :- pargiline- tranylcypromine

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 flumazenilCommon 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- dizziness

withdrawal symptoms : slower in onset than barbiturates

with triazolam : a short acting BDZoccurred within a few hours :

- early morning insomnia- daytime anxiety

Addiction : not a mayor problem

after withdrawal

Indication

Hypnotic :- lorazepam- 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 mgaltern. : 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

short acting