pharmacology of antidepressants

1. ANTIDEPRESSANTS

3. CLASSIFICATION
Majority affects Monoamine transmission
 I. Reversible inhibitors of MAO-A (RIMAs) Moclobemide, Clorgyline
 II. Tricyclic antidepressants (TCAs) (I generation)
 A NA + 5·HT reuptake inhibitors - Imipramine, Amitriptyline, Trimipramine, Doxepin, Dothiepin,
Clomipramine
 B. Predominantly NA reuptake inhibitors - Desipramine, Nortriptyline, Amoxapine, Reboxetine
 III. Selective serotonin reuptake inhibitors (SSRIs) - Fluoxetine, Fluvoxamine, Paroxetine, Sertraline,
Citalopram, Escitalopram
 IV. Serotonin & Na Reuptake Inhibitor SNRIs – Venlafaxine, Duloxetine
 V. Atypical antidepressants - Trazodone, Mianserin, mirtazapine, Venlafaxine, Duloxetine, Tianeptine,
Amineptine, Bupropion

4. MAOI
 MAO-A : Deaminates 5HT & NA
 MAO-B : Deaminates phenylethylamine
 Dopamine equally degraded
Non Selective MAOIs : HIT AND RUN
 Cheese Reaction
 Cold & cough remedies
 Reserpine, guanethidine, TCAs
 Levodopa
 Antiparkinsonian anticholinergic
 Barbs, alcohol, opioids, antihistamine

5. RIMAs
MOCLOBEMIDE
 Reversible
 Recovery within 1-2 days
 Dietary restrictions not needed
 Lacks ADRs of typical TCAs
 Preferable in elderly and cardiac cases
 ADRs – nausea, headache, dizziness, insomnia, liver damage
 150 mg BD/TDS

6. TCAs
ACTIONS
CNS
 In normal individuals – no mood elevation or euphoria
 In depressed – in 2-3 weeks gradual mood elevation
 More sedative ones for depressed with anxiety
 Less sedative TCAs for withdrawn & retarded
 Proconvulsants – clomipramine & bupropion most
 Amitryptyline & imipramine depress respiration

7. MOA

8. ANS
 Most are potent anticholinergics
 Potentiate exogenous & endogenous NA by blocking uptake
 Amitriptyline, doxepin & trimipramine slight H1 antihistaminic
CVS
 Tachycardia
 Postural hypotension
 ECG changes & arrhythmias
TOLERANCE & DEPENDENCE
 To anticholinergics & hypotensive

9. KINETICS
 Good oral absorption
 High plasma protein binding
 Vd 20L/kg
 Metabolized in liver, excreted in urine
 Therapeutic window

10. ADRs
 Anticholinergic
 Sedation
 Weight gain
 Switch over to dysphoria or mania
 Sweating
 Seizures
 Postural hypotension
 Sexual distress
 Cardiac arrhythmia
 Hypersensitivity reactions

11. ACUTE POISONING
 Self attempted
 Supportive treatment
 Diazepam i.v for convulsions
 Cardiac arrhythmia – propranolol/lidocaine
 IA, IC contraindicated

12. INTERACTIONS
 Sympathomimetic amines potentiated
 Abolish antihypertensive effects of guanethidine & clonidine
 Potentiates CNS depressants
 Displaced by phenytoin, phenylbutazone, aspirin & CPZ
 Phenobarbitone comp inhibits & induce imipramine metabolism
 SSRIs inhibit metabolism of TCA
 Delays gastric emptying by anticholinergic action
 MAO inhibitors

13. AMOXAPINE
 D2 blockade with NA
 Related to loxapine
 Psychotic depression
 Extrapyramidal s/e & seizures
REBOXETINE
 Weak 5HT blockade with NA blockade
 s/e insomnia, palpitation, dry mouth, constipation, sexual distress

14. SSRIs
 Relative safety, better acceptability
 No interference with cognitive or psychomotor functions
 No anticholinergic s/e
 No postural hypotension
 No ppt of seizure or slowing of cardiac conduction
 s/e mainly GI – nausea, loose motions
 Epistaxis, ecchymosis
 Interfere with ejaculation/orgasm
 Nervousness, restlessness, insomnia

15.  Inhibit CYP2D6 & CYP3A4
 SEROTONIN SYNDROME
 Preferred for prophylaxis of recurrent depression

16. SSRI PROPERTIES
FLUOXETINE First SSRI introduced, longest acting (t 1/2 - 2 days), active demethylated
metabolite, in children 7 yrs or older & adults, agitation & dermatological
reactions, slower onset, stimulant so c/I in agitated
FLUVOXAMINE Shorter acting, t ½ 18 hrs, no active metabolites, for GAD & OCD, higher s/e
PAROXETINE t ½ - 20 hrs no active metabolites, higher s/e
SERTRALINE Juvenile depression, PTSD, t ½ - 26 hrs, longer metabolite, lower interactions
CITALOPRAM PMS, suicidal, t ½ - 33 hrs
ESCITALOPRAM S enantiomer of citalopram , twice potent
DAPOXETINE Delays premature ejaculation

17. USES
 OCD
 PMS
 Social phobias
 PTSD
 Panic disorder
 ADHD
 Eating disorder
 Enuresis

18.  Smoking cessation
 Impulse disorders
 Neuropathic pain
 Premature ejaculation
 Migraine
 Pruritus

19. SNRIs – 5HT & NA
VENLAFAXINE
 No effect on cholinergic, adrenergic or histaminergic
 Faster onset
 Menopausal syndrome benefited
 S/e nausea, sweating, anxiety, dizziness, impotence
DULOXETINE
 Non sedative/anticholinergic/ histaminergic/ α blocking
 Increases urethral tone - SUI
 Panic attacks, neuropathic pain, fibromyalgia

20. S No RECEPTOR ACTION DRUG DISORDER
1 5HT1A PARTIAL AGONIST BUSPIRONE ANXIETY, DEPRESSION
2 5HT1D AGONIST SUMATRIPTAN MIGRAINE
3 5HT2A/2C ANTAGONIST METHYSEGIDE MIGRAINE, DEPRESSION, SCHIZOPHRENIA
4 5HT3 ANTAGONIST ONDANSETRON CHEMO EMESIS
5 5HT4 AGONIST CISAPRIDE GI DISORDERS

21. S. No DRUG PROPERTIES
1 TRAZODONE BLOCKS 5HT2A/α1, PRIAPISM, OCD
2 MIANSERIN BLOCKS PRESYNAPTIC α2 ALSO 5HT2/1c /H1 , SEDATIVE, SEIZURES, BLOOD DYSCRASIAS
& LIVER DYSFUNCTION
3 MIRTAZAPINE BLOCKS α2 AUTO & HETERO, BLOCKS 5HT2c/3/H1 SEDATIVE, NSSA, WEIGHT GAIN
4 BUPROPION DA /NA REUPTAKE INHIBITION, EXCITANT, SMOKING CESSATION, SEIZURES, NO SEXUAL
S/E, C/I IN EATING DISORDERS & MDP
5 TIANEPTINE INCREASES 5HT UPTAKE, S/E DRY MOUTH, EPIGASRTIC PAIN, FLATULENCE, TREMOR
6 AMINEPTINE ENHANCE 5HT UPTAKE, ANTICHOLINERGIC S/E, CONDUCTION ABNORMALITIES
7 ATOMOXETINE SELECTIVE NA REUPTAKE INHIBITOR, ADHD ONLY INDICATION
ATYPICAL ANTIDEPRESSANTS

22. ANXIOLYTICS

23.  Emotional state, associated with uneasiness, discomfort and concern or fear
about some defined or undefined future threat
ANXIOLYTICS -
 Have no therapeutic effect to control thought disorder of schizophrenia.
 Do not produce extra pyramidal side effects
 Have anticonvulsant property.
 Produce physical dependence and carry abuse liability.
 Do not selectively block conditioned avoidance response in animals

24. CLASSIFICATION
BENZODIAZEPINES-Diazepam Chlordiazepoxide
Oxazepam Lorazepam, Alprazolam
AZAPIRONES-Buspirone, Gepirone, Ispapirone
Sedative antihistaminic- Hydroxyzine
β blocker - Propranolol

25. BZDs
 One of the most widely used class
 Have little effect on other body systems
 Have lower dependence producing liability
 Withdrawal syndrome is milder and delayed due to their long half lives
 Are relatively safe even in gross over dosage

26. S No DRUG PROPERTIES
1 CHLORDIAZEPOXIDE CHRONIC ANXIETY , ALCOHOL WITHDRAWAL, T ½ 6-12 HRS, ACTIVE METABOLTE
LONGER ACTING
2 DIAZEPAM BIPHASIC DECAY CURVE, IN ACUTE PANIC & ANXIETY ASSOCIATED WITH ORGANIC
DISEASES, 5-30 mg - VALIUM
3 OXAZEPAM ABSORPTION SLOW, T1/2 10 HRS, METABOLIZED BY GLUCURONIDE CONJUGATION,
SHORT DURATION, PREFERED IN ELDERLY AND LIVER DISESAE
4 LORAZEPAM SLOW ABSORPTION, T ½ 10-20 HRS, GLUCURONIDE CONJUGATION, MARKED
SEDATION, ONLY I.M BZD, SHORT LASTING ANXIETY, PANIC, OCD, I.V IN STATUS,
1-2 mg TAB, 4mg/2ml INJ
5 ALPRAZOLAM ANXIOLYTIC WITH MOOD ELEVATION, ANXIETY WITH DEPRESSION, T1/2 12 HRS,
ACTIVE METABOLITE, HYPNOTIC, WITHDRAWAL SYMPTOMS, 0.25-1 mg

27. BUSPIRONE
 Does not produce significant sedation or cognitive/ functional impairment
 Does not interact with BZD receptor or modify GABAergic transmission
 Does not produce tolerance or physical dependence
 Does not suppress BZD or barbiturate withdrawal syndrome
 Has no muscle relaxant or anticonvulsant activity
 Mild-to-moderate generalized anxiety
 Therapeutic effect develops slowly: maximum benefit may be delayed up to 2weeks
 Not effective in acute anxiety
 Stimulating presynaptic 5-HT1A autoreceptors, partial agonism at postsynaptic
 Mild mood elevating action has been noted occasionally-may be due to facilitation of central
noradrenergic system.

28.  Rapidly absorbed orally undergoes extensive first pass metabolism; (bioavailability <5%)
 One metabolite is active and excretion occurs both in urine and feces
 T1/2 is 2-3.5 hrs
 Side effects are minor: dizziness, nausea, headache ,light-headedness, rarely excitement.
 It may cause rise in BP in patients on MAO inhibitors
 Does not potentiate CNS depressants
 Though most patients on buspirone remain alert, those operating machinery/motor vehicles should
be cautioned

29. HYDROXYZINE
 An H1 antihistaminic with sedative, antiemetic, antimuscarinic and spasmolytic properties
 It is claimed to have selective anxiolytic action
 Accompanying sedation is quite marked
 May be used in reactive anxiety or that associated with marked autonomic symptoms
 Due to antihistaminic and sedative property, it is effective in pruritus and urticaria
 Daily dose 50-200 mg

30. BETA BLOCKERS
 Many symptoms of anxiety (palpitation, rise in BP, shaking, tremor, gastrointestinal hurrying, etc.) are
due to sympathetic overactivity
 These symptoms reinforce anxiety
 Propranolol and other nonselective β blockers help anxious patients troubled by these symptoms, by
cutting the vicious cycle and provide symptomatic relief
 They do not affect psychological symptoms such as worry, tension and fear
 Valuable in acutely stressful situations (examination fear, unaccustomed public appearance, etc)
 They may be used for PERFORMANCE/ situational anxiety or as adjuvant to BZDs

31. TREATMENT OF ANXIETY
 It should be treated with drugs only when excessive and disabling
 The established drugs are BZDs which should be used in the smallest possible dose
 Dose titration with symptoms of anxiety
 Acute anxiety states generally respond better
 The drug should be withdrawn as soon as it is no longer needed
 When large doses have been used for longer periods-withdrawal should be gradual
 The usual practice is to give 1/2 to 2/3 of the daily dose at bed time to ensure good nightly rest
 The remaining is divided in 2-3 doses given at day time
 Buspirone is a non sedating alternative to BZDs for less severe forms of generalized anxiety

32.  SSRIs are now DOC for social anxiety in which BZDs, though effective, carry abuse potential
 Acute management of GAD - BZD
 Panic attacks - Lorazepam