1. Waqas Tahir GPST2

2. Overview Introduction Introduction Mechanism of action Mechanism of action Therapeutic uses Therapeutic uses Pharmacokinetics Pharmacokinetics Adverse effects Adverse effects Discontinuation Syndrome Discontinuation Syndrome Precautions Precautions Interactions Interactions

3. Introduction TCAs discovered in 1950s 2 nd member of TCA, amitriptyline introduced in 1961 - Classification - - Classification - Tertiary amines : imipramine, amitriptyline, clomipramine, doxepin and trimipramine Tertiary amines : imipramine, amitriptyline, clomipramine, doxepin and trimipramine Secondary amines : desipramine, nortriptyline, protriptyline Secondary amines : desipramine, nortriptyline, protriptyline

4. Mechanism of action 1. Inhibition of neurotransmitter reuptake 2. Blocking of receptors Serotonergic receptor Serotonergic receptor Alpha-adrenergic receptor Alpha-adrenergic receptor Histamine (H 1 receptor) Histamine (H 1 receptor) Muscarinic receptor Muscarinic receptor

7. Therapeutic uses Depression : initially 75mg, increased gradually to 150-200mg Depression : initially 75mg, increased gradually to 150-200mg Nocturnal Enuresis : child (7-10 yrs) 10-20 mg, (11-16 yrs) 25-50mg at night Nocturnal Enuresis : child (7-10 yrs) 10-20 mg, (11-16 yrs) 25-50mg at night Neuropathic pain : initially 10-25mg at night, increased if necessary to 75mg Neuropathic pain : initially 10-25mg at night, increased if necessary to 75mg Migraine prophylaxis : initially 10mg at night, increased if necessary to maintenance of 50- 75mg Migraine prophylaxis : initially 10mg at night, increased if necessary to maintenance of 50- 75mg

8. Pharmacokinetics Lipophilic nature & readily penetrate CNS Lipophilic nature & readily penetrate CNS Therapeutic lag Therapeutic lag Bioavailability Peak plasma level Plasma half - life Active metabolites Elimination Very variable 30 – 60% 4 to 8 hours 15 hours (10 – 28 hrs) importantExtrarenalRenal

9. Adverse effects Blockade of Muscarinic receptors Blockade of Muscarinic receptors blurred vision, xerostomia, urinary retention, constipation & aggravation of narrow angle glaucoma Blockade of Alpha-adrenergic receptors Blockade of Alpha-adrenergic receptors orthostatic hypotension, dizziness & reflex tachycardia Blockade of Histamine (H 1 ) receptors Blockade of Histamine (H 1 ) receptorsSedation Blockade of Sodium channels Blockade of Sodium channels slow cardiac conduction precipitate life threatening arrhythmias as seen in OD

10. Adverse Effects

11. Discontinuation syndrome Group of symptoms that occurs upon the abrupt discontinuation/withdrawal of anti-depressants Group of symptoms that occurs upon the abrupt discontinuation/withdrawal of anti-depressants Higher risk for agents with the shorter half-lives and inactive metabolites Higher risk for agents with the shorter half-lives and inactive metabolites In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance

12. Precautions an alcohol problem an alcohol problem bipolar disorder or schizophrenia bipolar disorder or schizophrenia bipolar disorderschizophrenia bipolar disorderschizophrenia difficulty passing urine, prostate trouble difficulty passing urine, prostate trouble glaucoma glaucoma glaucoma heart disease or previous heart attack heart disease or previous heart attack heart disease heart disease liver disease liver disease liver disease liver disease over active thyroid over active thyroid seizures seizures thoughts or plans of suicide, a previous suicide attempt, or family history of suicide attempt thoughts or plans of suicide, a previous suicide attempt, or family history of suicide attempt an unusual or allergic reaction to amitriptyline, other medicines, foods, dyes, or preservatives an unusual or allergic reaction to amitriptyline, other medicines, foods, dyes, or preservativesallergic reactionallergic reaction pregnant or trying to get pregnant pregnant or trying to get pregnant pregnant breast-feeding breast-feeding breast-feeding

13. Interactions MAO inhibitors mutual enhancement ; HTN, hyperpyrexia, convulsions, and coma MAO inhibitors mutual enhancement ; HTN, hyperpyrexia, convulsions, and coma Direct-acting adrenergic drugs potentiate effects Direct-acting adrenergic drugs potentiate effects Ethanol,other CNS depressants toxic sedation Ethanol,other CNS depressants toxic sedation Indirect –acting adrenergic drugs blocks the effect Indirect –acting adrenergic drugs blocks the effect All TCAs lower seizure threshold Grapefruit juice may interact with amitriptyline

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