Waqas Tahir GPST2. Overview Introduction Introduction Mechanism of action Mechanism of action Therapeutic uses Therapeutic uses Pharmacokinetics Pharmacokinetics.

Waqas TahirWaqas TahirGPST2GPST2

OverviewOverview

IntroductionIntroduction Mechanism of actionMechanism of action Therapeutic usesTherapeutic uses PharmacokineticsPharmacokinetics Adverse effects Adverse effects Discontinuation SyndromeDiscontinuation Syndrome PrecautionsPrecautions InteractionsInteractions

IntroductionIntroduction

TCAs discovered in 1950sTCAs discovered in 1950s

22ndnd member of TCA , amitriptyline introduced in member of TCA , amitriptyline introduced in 19611961

- Classification -- Classification - Tertiary aminesTertiary amines : : imipramine , amitriptyline , imipramine , amitriptyline ,

clomipramine , doxepin and trimipramineclomipramine , doxepin and trimipramine

Secondary aminesSecondary amines : : desipramine , nortriptyline , desipramine , nortriptyline , protriptylineprotriptyline

Mechanism of actionMechanism of action

1.1. Inhibition of neurotransmitter reuptakeInhibition of neurotransmitter reuptake

2.2. Blocking of receptorsBlocking of receptors Serotonergic receptorSerotonergic receptor Alpha-adrenergic receptorAlpha-adrenergic receptor Histamine (HHistamine (H11 receptor) receptor) Muscarinic receptorMuscarinic receptor

Therapeutic usesTherapeutic uses

DepressionDepression : initially 75mg , increased gradually : initially 75mg , increased gradually to 150-200mgto 150-200mg

Nocturnal EnuresisNocturnal Enuresis : child (7-10 yrs) 10-20 mg , : child (7-10 yrs) 10-20 mg , (11-16 yrs) 25-50mg at night(11-16 yrs) 25-50mg at night

Neuropathic painNeuropathic pain : initially 10-25mg at night , : initially 10-25mg at night , increased if necessary to 75mgincreased if necessary to 75mg

Migraine prophylaxisMigraine prophylaxis : initially 10mg at night , : initially 10mg at night , increased if necessary to maintenance of 50-increased if necessary to maintenance of 50-75mg75mg

PharmacokineticsPharmacokinetics Lipophilic nature & readily penetrate CNSLipophilic nature & readily penetrate CNS

Therapeutic lagTherapeutic lag

BioavailabilityBioavailability Peak plasma Peak plasma levellevel

Plasma half -Plasma half -lifelife

Active Active metabolitesmetabolites

EliminationElimination

Very variableVery variable

30 – 60%30 – 60%

4 to 8 hours4 to 8 hours 15 hours 15 hours

(10 – 28 hrs)(10 – 28 hrs)

importantimportant ExtrarenalExtrarenal

RenalRenal

Adverse effectsAdverse effects

Blockade of Blockade of MuscarinicMuscarinic receptors receptors blurred vision , xerostomia , urinary retention , constipation & blurred vision , xerostomia , urinary retention , constipation &

aggravation of narrow angle glaucomaaggravation of narrow angle glaucoma

Blockade of Blockade of Alpha-adrenergicAlpha-adrenergic receptors receptorsorthostatic hypotension , dizziness & reflex tachycardiaorthostatic hypotension , dizziness & reflex tachycardia

Blockade of Blockade of Histamine (HHistamine (H11)) receptors receptorsSedationSedation

Blockade of Blockade of Sodium channelsSodium channelsslow cardiac conduction slow cardiac conduction precipitate life threatening precipitate life threatening

arrhythmias as seen in ODarrhythmias as seen in OD

Adverse EffectsAdverse Effects

Discontinuation syndromeDiscontinuation syndrome

Group of symptoms that occurs upon the abrupt Group of symptoms that occurs upon the abrupt discontinuation/withdrawal of anti-depressantsdiscontinuation/withdrawal of anti-depressants

Higher risk for agents with the shorter half-lives Higher risk for agents with the shorter half-lives and inactive metabolitesand inactive metabolites

In tricyclics, discontinuation syndrome symptoms In tricyclics, discontinuation syndrome symptoms include include anxietyanxiety, , insomniainsomnia, , headacheheadache, , nauseanausea, , malaisemalaise, or , or motor disturbancemotor disturbance

PrecautionsPrecautions an alcohol probleman alcohol problem bipolar disorderbipolar disorder or or schizophreniaschizophrenia difficulty passing urine, prostate troubledifficulty passing urine, prostate trouble glaucomaglaucoma heart disease or previous heart attackheart disease or previous heart attack liver diseaseliver disease over active thyroidover active thyroid seizuresseizures thoughts or plans of suicide, a previous suicide attempt, thoughts or plans of suicide, a previous suicide attempt,

or family history of suicide attemptor family history of suicide attempt an unusual or allergic reaction to amitriptyline, other an unusual or allergic reaction to amitriptyline, other

medicines, foods, dyes, or preservativesmedicines, foods, dyes, or preservatives pregnant or trying to get pregnantpregnant or trying to get pregnant breast-feedingbreast-feeding

InteractionsInteractions

MAO inhibitors MAO inhibitors mutual enhancement ; HTN , mutual enhancement ; HTN , hyperpyrexia , convulsions , and comahyperpyrexia , convulsions , and coma

Direct-acting adrenergic drugs Direct-acting adrenergic drugs potentiate potentiate effectseffects

Ethanol ,other CNS depressants Ethanol ,other CNS depressants toxic toxic sedationsedation

Indirect –acting adrenergic drugs Indirect –acting adrenergic drugs blocks the blocks the effect effect

All TCAs lower seizure thresholdAll TCAs lower seizure threshold

Grapefruit juice may interact with amitriptylineGrapefruit juice may interact with amitriptyline

Thank YouThank You