drugs for psychiatric disorders

8/3/2019 Drugs for Psychiatric Disorders

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DRUGS FORPSYCHIATRIC

DISORDERS

Dr Qodriyah Hj Mohd Saad

Dept of Pharmacology,

Faculty of Medicine,

Universiti Kebangsaan Malaysia

[email protected]


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PSYCHOSISVariety mental disorder

Sx:

distortion of perception

(delusion & hallucination)grossly disorganized behavior &speech

capacity to recognize realitycauses functional

organic


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INFECTION

ORGANICPSYCHOSIS

DRUGS

M ETABOLIC

TRAUMA

SOL

HYPERTENSION

SEIZURE


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CLASSIFICATION OF PSYCHIATRIC/

MENTAL D/O (DSM-IV)

Axis I: major mental disorders schizophrenia,bipolar d/o, depression, anxiety d/o, ADHD

Axis II: underlying pervasive or personality

conditions, developmental disorders, learningdisabilities, mental retardation

Axis III: medical conditions contributing to the

disorder

Axis IV: psychosocial & environmental factors

contributing to the disorder

Axis V: Global Assessment of Functioning


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SCHIZOPHRENIA

positive Sx (distort function)hallucination, delusion, paranoia,

disorganized speech, thought &behavior

negative Sx (diminished function)emotional blunting, social withdrawal,

lack motivation


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Schizophrenia- ?? Pathogenesis- Dopamine hypothesis

Due to >>dopaminergic activity. Evidence:

1. Most antipsychotics block postsynaptic D2

receptor in mesolimbic frontal system

2. Drugs dopaminergic activity produce psychosis

3. dopamine reseptor density treated &

untreated schizophrenics

4. HVA (dopamine metabolite) in CSF, plasma &

urine Rx schizophrenics


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DOPAMINERGIC SYSTEMS

1. Mesolimbic-mesocortical :emotion & behavior

2.

Nigrostriatal : motor coordination3. Hypothalamo-hypophyseal/

Tuberoinfundibular : regulation of

prolactin secretion

4. Medullary-periventricular : eating habit

5. Incertohypothalamic ?


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ANTIPSYCHOTIC AGENTS

Typical/Classic1. Phenothiazines

2. Thioxanthenes3. Butyrophenones

Atypical/ NewerAgents

Clozapine

Risperidone

Olanzapine


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ANTIPSYCHOTIC AGENTS -cont.

Typical/Classic

1.Phenothiazines Derivatives

i. Aliphatic : Chlorpromazine

ii. Piperidine : Thioridazine

iii. Piperazine : Fluphenazine2.Thioxanthenes Derivatives : Thiothixene

3.Butyrophenones Derivatives : Haloperidol


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PHARMACOKINETICS

Oral, rectal, i/m, i/v, depot injection

(fluphenazine, haloperidol, clozapine,

risperidone, olanzapine)

lipid soluble protein bound

metabolism : liver active metabolite

1st pass metabolism

excretion: urine, feces

t 1/2 = 10 -24 h


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MECHANISM OF ACTION

Complex, not well understood

X dopamine receptor subtype

selectively Antipsychotic effect :

X D2 >D1 (after 2 - 3 wks)

X muscarinic

X 1 adrenoceptor side

X 5-HT2 effects

X histamine


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PHARMACOLOGIC EFFECTS

1. CNS

Antipsychotic - X mesolimbic-mesocortical

- agitation- emotional quieting

- paranoid idea block D2- hallucination

- anxiety


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PHARMACOLOGIC EFFECTS -cont.

2. Antiemetic

X DA receptor - CTZ at medulla

eg.: Phenothiazine Derivatives

- promethazine Rx. motion

- meclizine sickness

3. Sedation - anti histamine


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ADVERSE REACTIONS

1. Neurological effects

i. Extrapyramidal - X Nigrostriatal

- parkinsonism - Rx: benztropine

(antimuscarinic)

- akathisia Rx:diphenhydramine

- dystonia (sedative antihistamine

& anticholinergic)


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ADVERSE REACTIONS- cont.

ii.Tardive dyskinesia

- occur late (months/years)

- involuntary facial & limb movement

- Causes:? supersensitivity DA receptor

? dysfunction GABAergic neuron

- Rx : stop antipsychotic/

Clozapine/Olanzapine

iii. Seizure : with CPZ, clozapine


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ADVERSE REACTIONS - cont.

2. Autonomic - antimuscarinic effect

- dry mouth

- blurred vision

- constipation

- urinary retention


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3. Metabolic & endocrine

- X Tuberoinfundibular

(inhibit PIH

hyperprolactinemia)- weight gain

- amenorrhoea-galactorrhoea

- impotence

- infertility

- gynaecomastia


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4. CVS

- postural hypotension anti

- tachycardia adrenergic

- ventricular arrhythmias- conduction block thioridazine

5. Ocular complication- lens & cornea deposit ( CPZ)

- retinal deposit resemble retinitis

pigmentosa (thioridazine)


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6. Allergic reaction

- agranulocytosis ( clozapine)

- cholestatic jaundice (phenothiazine)

7. Pregnancy - relatively safe

- risk dysmorphogenesis

(early pregnancy)


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8. Neuroleptic malignant syndrome- common haloperidol, fluphenazine

- rare but severe, life threatening

- fever, delirium

- muscle rigidity

- muscle damage CPK

-Rx : muscle relaxant

(dantrolene,diazepam)


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BIPOLAR

BIPOLAR


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BIPOLAR Past/present history of manic episode +

depression

MANIA DSM IV criteria

Elevated, expansive or irritable mood

Inflated self-esteem (grandiose) need for sleep without feeling fatigue

>>talkative

Racing thoughts

Easily distracted

physical activity

Negative outcomes (gambling, accidents)


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MANIA

Cause:

? monoamine at CNS (NA)

adrenergic transmission at CNS


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MOOD STABILIZER

Aim:Stabilizes mood abolish excitement,

euphoria & insomniaPrevent relapse

Drugs : lithium carbonate (lithium)

valproic acid

carbamazepine

clonazepam

LITHIUM CARBONATE (Li+)


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LITHIUM CARBONATE (Li+)Pharmacokinetics

Monovalent kation (Li+)

Well absorbed orally

X metabolized, X protein bound,

Cross BBB

t 1/2 = 20 - 24h

Excretion: 95% in urine

80% filtered Li+

reabsorbed by prox. tubule


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Li+ - Pharmacokinetics cont.

therapeutic index - monitor [Li+]

blood, tears, saliva

Effects Li+

several days & 2 4 weeks to fully

develop


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Li+ - MECHANISM OF ACTION

Specific mechanism not known Possible mechanism:

1. Li+ replaces Na+ - equally distributed

in/out cell affect ion flux across brain cell/modify cellular membrane property

2. Li+ X release NA & DA in CNS

3. Li+ X enzyme involve in recycling ofmembrane phosphoinositide 2nd

messenger adrenergic &

muscarinic transmission (refer Katzung 10th ed. Pg 470)


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Li+- SIDE EFFECTS

1. CNS

- tremor, ataxia, choreoathetosis,

- slurred speech/aphasia

- mental confusion, forgetfulness, drowsiness- motor hyperactivity

2. Thyroid dysfunction

- goitre (interfere tyrosine iodination but

normally pt. euthyroid)

- hypothyroidism


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Li+ - SIDE EFFECTS cont.

3. Kidney

- nephrogenic diabetes insipidus

- minimal change glomerulopathy

- chronic interstitial nephritis

4. Electrolyte

- initial Na+ & H20 loss Na+ & H20 retention

oedema (due to aldosterone secretion)

5. CVS

- benign & reversible inversion T wave

(C/I in pt. with sick sinus syndrome)


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Li+ - SIDE EFFECTS cont.

6. Others

- GI disturbances (N, V, D)

- weight gain

- rash

7. Pregnancy & B/Feeding C/I

Pregnancy fetal congenital abnormalities

(cardiacEbsteins anomaly) fetal goitre, hypotonia

Breastfeeding secreted in milk

- baby lethargic, cyanose, abnormal Moro reflex


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DRUG INTERACTIONS

Li+

clearance - thiazide diuretics

- ACE inhibitors

- tetracyclines- NSAIDs (except aspirin & acetaminophen)

Li+ toxicities

All antipsychotics (except clozapine & newer

drugs) + Li+

extrapyramidal Sx

VALPROIC ACID (VALPROATE)


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VALPROIC ACID (VALPROATE) Antiepileptic & antimanic

Widely used 1st

line Rx for mania Advantage

Efficacy = Li+ (early wks Rx) maintenance Rx?

Effective in pt. failed to respond to Li+

Better tolerated than Li+ but > sedating

Can rapidly dose over few days therapeutic

range (S/E: nausea) Indication: Bipolar ( + antipsychotic agt)

?? Valproate + Li+ pt. X respond to either

agent


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CARBAMAZEPINE

Alternative to Li+

Action: ? sensitization of brain to repeated

episode of mood swing

Indication : acute maniamania prophylaxis

- produce stability in rapid cycling patient

- pt who are refractory/intolerant to Li+

- > sedating than Li+

Used alone or + Li

+


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ANTIDEPRESSANT


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DEPRESSION

Depression is a mood disorder affecting

psychomotor functions

Energy, sleep, appetite, libido, abilityto do activity

Intense feeling of sadness,hopelessness, despair, no interest to do

daily activities


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1. REACTIVE - most common

20 to trauma spontaneous recovery

2. ENDOGENOUS

inability to cope with ordinary life events

cause not obvious - genetic3. BIPOLAR DISORDER

depressive d/o + alternate with mania

Types of depression


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Amine Hypothesis:

depression is due to deficiency/decreaseof monoamines such as serotonin and

noradrenaline in the brain

PATHOGENESIS OFDEPRESSION


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Limitation to amine theory:

Post mortem study did not show significant

decreased in NE & 5HT in depressive patients

2nd generation antidepressant (Bupropion) has little

effect on NE & 5HT and yet has antidepressanteffect

Changes in brain amine activity is immediate

however, the antidepressant effect only seen after2-3 weeks

Most antidepressants cause down regulation of

amine receptors

A tid t Cl ifi ti


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Antidepressants - Classification:1.Tricyclic / Polycyclic Antidepressants (TCA)

Prototype imipramine, amitriptylineSecond generation amoxapine, maprotiline,

bupropion

2. Selective Serotonin Reuptake Inhibitors (SSRIs)fluoxetine

paroxetine

sertraline

3. Monoamine Oxidase Inhibitors (MAOIs)

phenelzine

tranylcypromine

Tricyclic / Polycyclic


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Tricyclic / PolycyclicAntidepressants (TCA)

Prototype imipramine

amitriptyline

Second generation amoxapine

maprotiline

bupropion


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Inhibits amine pump

Therefore it block the reuptake of

monoamine NE/5HT

Increase amines at presynaps (immediate)

TCA - Mechanisms of action


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Well absorbed - orally

Widely distributed (lipophilic) Able to penetrate CNS

Long t (imipramine 4-17 hrs)

Undergo 1st past effect

TCA - Pharmacokinetic

Metabolism:


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Metabolism:

liver

Demethylation, aromatic hydroxylation &glucuronide conjugation

Amitriptyline Nortriptyline

Imipramine Desipramine

Excretion:Kidney

Onset of action is late about 2-3 weeks In depressed patient - Elevated mood, improved

mental alertness, improved physical activities

No effect on normal person


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TCA - Adverse effects:

Antimuscarinic effects

dry mouth

blurred vision

constipation

urinary retention

CNS

sedation

seizure

CVS

tachycardia

arrhythmias

posturalhypotension

Othersweight gain

hypersensitivity


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TCA - Drug Interaction

increase TCA side effects by certain drugs:

E.g.CNS depressants sedation

Antipsychotics seizure

Antimuscarinics dry mouth


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TCA Clinical uses

1. Severe major depression

2. Imipramine bedwetting

3. Panic disorder


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Selective Serotonin Reuptake

Inhibitors(SSRI)

- Fluoxetine

- Paroxetine- Sertraline

Less A/E than tricyclic antidepressants(TCA)

Less likely to induce mania


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Orally given with constant dose fluoxetine actively demethylated active

metabolite (norfluoxetine)

Slowly excreted

fluoxetine T = 1-10 days

norfluoxetine T = 3-30 days

steady state after several weeks

Potent inhibitor to cytochrome p450 isoenzyme

SSRI - Pharmacokinetic


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SSRIs - Mechanism Of Action

- Decreased 5-HT reuptake at presynaps

- End result: long-term enhancement of

5-HT neurotransmission


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Anxiety

Insomnia

Anorexia GIT symptoms

Weight loss

Sexual dysfunction, libido Teratogenic (paroxetine)

Overdose - seizure

SSRIs -Adverse effects


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SSRIs Drug interactions

1. SSRI + MAOI serotonin

syndrome

2. SSRI cytoc P450 inhibitor - inhibit

metab. nortriptyline, desipramine

adverse effects of TCA

SSRI Cli i l


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1. Antidepressants

2. Panic disorder

3. Obsessive compulsive

4. Bulimia nervosa

5. Anorexia nervosa

6. Premenstrual syndrome

SSRIs - Clinical uses

M i O id I hibit


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Monoamines Oxidase Inhibitor(MAOI)

Phenelzine

Tranylcypromine


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MAOIs: Mechanism of action

- decreased monoamine oxidase enzyme

- thus increase monoamines at synaps

Enzymes:

- MAO-A: degrade NA, 5-HT

- MAO-B: degrade DA

- phenelzine, tranylcypromine -irreversibleinhibitorsEnzyme regeneration: varies; usually occurs several weeks after

termination of drug, so must wait at least 2 weeks before switching


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MAOIs - Pharmacokinetic

Absorption - good (orally)

Metabolism - liver

Excretion: kidneys


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MAOIs: interactions

1. Tyramine-enriched foodcheese reaction

severe hypertension (throbbing headache, +/-

intracranial haemorrhage)2. Indirectly-acting sympathomimetic amines (eg.

adrenaline, amphetamines) hypertensive

crisis

3. Pethidine severe hyperpyrexia,

restlessness, coma, hypotension

MAOIs Adverse Effects:


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Headache

Drowsiness

Orthostatic hypotension

Blurred vision

Dry mouth

Weight gain

MAOIs - Adverse Effects:

MAOIs Clinical ses


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Patients allergic/unresposive to tricyclicantidepressant.

Patients with low psychomotor activities

Treatment of phobic state

Atypical depression case (+ anxiety,

phobic states, hypochondriasis)

MAOIs - Clinical uses:


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GOOD LUCK IN YOUR EXAM

drugs for psychiatric disorders

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