DRUGS FOR PSYCHIATRIC

DISORDERS
Dr Qodriyah Hj Mohd Saad Dept of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia qodryrz@ymail.com

PSYCHOSIS
Variety Sx:

mental disorder

of perception (delusion & hallucination) grossly disorganized behavior & speech capacity to recognize reality causes functional organic

distortion

DRUGS M ETABOLIC

HYPERTENSION ORGANIC PSYCHOSIS SEIZURE INFECTION SOL

TRAUMA

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, learning disabilities, 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

SCHIZOPHRENIA
positive

Sx (distort function)

hallucination, delusion, paranoia,

disorganized speech, thought & behavior
negative

Sx (diminished function)

emotional blunting, social withdrawal, lack motivation

Schizophrenia- ?? Pathogenesis - Dopamine hypothesis

1.

Due to >>dopaminergic activity. Evidence: 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

DOPAMINERGIC SYSTEMS
1.

2. 3.

4.
5.

Mesolimbic-mesocortical : emotion & behavior Nigrostriatal : motor coordination Hypothalamo-hypophyseal/ Tuberoinfundibular : regulation of prolactin secretion Medullary-periventricular : eating habit Incertohypothalamic ?

ANTIPSYCHOTIC AGENTS

Typical/Classic
1. Phenothiazines

Atypical/ Newer Agents

Clozapine
Risperidone

2. Thioxanthenes
3. Butyrophenones

Olanzapine

ANTIPSYCHOTIC AGENTS -cont.

Typical/Classic
1.Phenothiazines Derivatives

i. Aliphatic : Chlorpromazine
ii. Piperidine : Thioridazine
iii.

Piperazine : Fluphenazine

2.Thioxanthenes Derivatives : Thiothixene 3.Butyrophenones Derivatives : Haloperidol

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

MECHANISM OF ACTION
Complex,

not well understood

dopamine receptor subtype selectively Antipsychotic effect : X D2 > D1 (after 2 - 3 wks) muscarinic X 1 adrenoceptor X 5-HT2 X histamine
side effects

PHARMACOLOGIC EFFECTS
1. CNS

Antipsychotic - X mesolimbic-mesocortical - agitation - emotional quieting - paranoid idea block D2 - hallucination - anxiety

PHARMACOLOGIC EFFECTS cont.

2. Antiemetic
X DA receptor - CTZ at medulla eg.: Phenothiazine Derivatives - promethazine - meclizine Rx. motion sickness

3.

Sedation - anti histamine

ADVERSE REACTIONS
1.
i.

Neurological effects

Extrapyramidal - X Nigrostriatal
(antimuscarinic)

- parkinsonism - Rx: benztropine

- akathisia
- dystonia

Rx:diphenhydramine
(sedative antihistamine & anticholinergic)

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 Seizure : with CPZ, clozapine

iii.

ADVERSE REACTIONS - cont.

2.

Autonomic - antimuscarinic effect

- dry mouth
- blurred vision - constipation

- urinary retention

ADVERSE REACTIONS - cont.

3.

Metabolic & endocrine - X Tuberoinfundibular (inhibit PIH hyperprolactinemia) - weight gain - amenorrhoea-galactorrhoea - impotence - infertility - gynaecomastia

ADVERSE REACTIONS - cont.

4.

CVS - postural hypotension - tachycardia - ventricular arrhythmias - conduction block

anti adrenergic
thioridazine

5.

Ocular complication - lens & cornea deposit ( CPZ) - retinal deposit resemble retinitis pigmentosa (thioridazine)

ADVERSE REACTIONS - cont.

6.

Allergic reaction

- agranulocytosis ( clozapine) - cholestatic jaundice (phenothiazine)

7.

Pregnancy - relatively safe

- risk dysmorphogenesis (early pregnancy)

ADVERSE REACTIONS - cont.

8.

Neuroleptic malignant syndrome

- common haloperidol, fluphenazine

- rare but severe, life threatening - fever, delirium - muscle rigidity - muscle damage CPK

-Rx : muscle relaxant

(dantrolene,diazepam)

BIPOLAR

BIPOLAR

Past/present history of manic episode + depression 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)

MANIA DSM IV criteria

MANIA
Cause:
?

monoamine at CNS (NA) adrenergic transmission at CNS

MOOD STABILIZER
Aim:
Stabilizes

mood abolish excitement, euphoria & insomnia relapse

Prevent

Drugs

: lithium carbonate (lithium) valproic acid carbamazepine clonazepam

LITHIUM CARBONATE (Li+) Pharmacokinetics

Monovalent
Well

kation (Li+)

absorbed orally

metabolized, X protein bound, Cross BBB

1/2 = 20 - 24h

Excretion:

95% in urine 80% filtered Li+ reabsorbed by prox. tubule

Li+ - Pharmacokinetics cont.

therapeutic index - monitor [Li+] blood, tears, saliva Li+ several days & 2 4 weeks to fully develop

Effects

+ - MECHANISM Li

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 of membrane phosphoinositide 2nd messenger adrenergic & muscarinic transmission (refer Katzung 10th ed. Pg 470)

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

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)

Li+ - SIDE EFFECTS cont.

6. Others - GI disturbances (N, V, D) - weight gain

- rash

7. Pregnancy & B/Feeding C/I

Pregnancy fetal congenital abnormalities (cardiac Ebsteins anomaly) fetal goitre, hypotonia
Breastfeeding secreted in milk - baby lethargic, cyanose, abnormal Moro reflex

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)

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

CARBAMAZEPINE

Alternative to Li+

Action: ? sensitization of brain to repeated episode of mood swing Indication : acute mania mania prophylaxis - produce stability in rapid cycling patient - pt who are refractory/intolerant to Li+ - > sedating than Li+
Used alone or + Li+

ANTIDEPRESSANT

DEPRESSION
Depression

is a mood disorder affecting psychomotor functions Energy, sleep, appetite, libido, ability to do activity feeling of sadness, hopelessness, despair, no interest to do daily activities

Intense

Types of depression
1. REACTIVE - most common
20 to trauma spontaneous recovery

2. ENDOGENOUS
inability to cope with ordinary life events cause not obvious - genetic 3. BIPOLAR DISORDER depressive d/o + alternate with mania

PATHOGENESIS OF DEPRESSION

Amine Hypothesis:

depression is due to deficiency/decrease of monoamines such as serotonin and noradrenaline in the brain

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 antidepressant effect Changes in brain amine activity is immediate however, the antidepressant effect only seen after 2-3 weeks

Most antidepressants cause down regulation of amine receptors

Antidepressants - Classification:
1.Tricyclic / Polycyclic Antidepressants (TCA) Prototype imipramine, amitriptyline Second generation amoxapine, maprotiline, bupropion 2. Selective Serotonin Reuptake Inhibitors (SSRIs) fluoxetine paroxetine sertraline 3. Monoamine Oxidase Inhibitors (MAOIs) phenelzine tranylcypromine

Tricyclic / Polycyclic Antidepressants (TCA)

Prototype imipramine amitriptyline
Second generation amoxapine maprotiline bupropion

TCA - Mechanisms of action

Inhibits amine pump Therefore it block the reuptake of monoamine NE/5HT Increase amines at presynaps (immediate)

TCA - Pharmacokinetic

Well absorbed - orally

Widely distributed (lipophilic)

Able to penetrate CNS

Long t (imipramine 4-17 hrs)

Undergo 1st past effect

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

TCA - Adverse effects:

Antimuscarinic effects dry mouth blurred vision constipation urinary retention
CNS sedation seizure

CVS
tachycardia arrhythmias postural

hypotension Others weight gain hypersensitivity

TCA - Drug Interaction

increase TCA side effects by certain drugs:

E.g.
CNS

depressants sedation

Antipsychotics

seizure
dry mouth

Antimuscarinics

TCA Clinical uses

1.

Severe major depression

2.
3.

Imipramine bedwetting
Panic disorder

Selective Serotonin Reuptake Inhibitors (SSRI)

Fluoxetine - Paroxetine - Sertraline
-

Less A/E than tricyclic antidepressants (TCA) Less likely to induce mania

SSRI - Pharmacokinetic

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

SSRIs - Mechanism Of Action

- Decreased 5-HT reuptake at presynaps - End result: long-term enhancement of 5-HT neurotransmission

SSRIs - Adverse effects

Anxiety Insomnia

Anorexia
GIT symptoms

Weight loss
Sexual dysfunction, libido

Teratogenic (paroxetine)
Overdose - seizure

SSRIs Drug interactions

1.

SSRI + MAOI serotonin

syndrome

2.

SSRI cytoc P450 inhibitor - inhibit

metab. nortriptyline, desipramine

adverse effects of TCA

SSRIs - Clinical uses

1.
2.

Antidepressants
Panic disorder

3.
4. 5. 6.

Obsessive compulsive
Bulimia nervosa Anorexia nervosa

Premenstrual syndrome

Monoamines Oxidase Inhibitor (MAOI)

Phenelzine
Tranylcypromine

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 -irreversible inhibitors
Enzyme regeneration: varies; usually occurs several weeks after termination of drug, so must wait at least 2 weeks before switching

MAOIs - Pharmacokinetic

Absorption - good (orally) Metabolism - liver

Excretion: kidneys

MAOIs: interactions
1. Tyramine-enriched food cheese 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:

Headache Drowsiness

Orthostatic
Blurred Dry

hypotension

vision

mouth

Weight

gain

MAOIs - Clinical uses:

Patients

allergic/unresposive to tricyclic

antidepressant.
Patients

with low psychomotor activities

of phobic state

Treatment Atypical

depression case (+ anxiety,

phobic states, hypochondriasis)

GOOD LUCK IN YOUR EXAM