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Transcript of 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
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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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ADVERSE REACTIONS - cont.
3. Metabolic & endocrine
- X Tuberoinfundibular
(inhibit PIH
hyperprolactinemia)- weight gain
- amenorrhoea-galactorrhoea
- impotence
- infertility
- gynaecomastia
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ADVERSE REACTIONS - cont.
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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ADVERSE REACTIONS - cont.
6. Allergic reaction
- agranulocytosis ( clozapine)
- cholestatic jaundice (phenothiazine)
7. Pregnancy - relatively safe
- risk dysmorphogenesis
(early pregnancy)
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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)
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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