ANTI-PSYCHOTIC DRUGSANTI-PSYCHOTIC DRUGS

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ANTI – PSYCHOTIC DRUGSANTI – PSYCHOTIC DRUGS

•NEUROLEPTIC DRUGSNEUROLEPTIC DRUGS

•ANTI-SCHIZOPHRENIC ANTI-SCHIZOPHRENIC DRUGSDRUGS

•MAJOR TRANQUILIZERSMAJOR TRANQUILIZERS

•DOPAMINE RECEPTOR DOPAMINE RECEPTOR ANTAGONISTSANTAGONISTS

TYPES OF PSYCHOSISTYPES OF PSYCHOSIS

•SCHIZOPHRENIASCHIZOPHRENIA

•AFFECTIVE DISORDERS AFFECTIVE DISORDERS (DEPRESSION/MANIA)(DEPRESSION/MANIA)

•ORGANIC PSYCHOSES ORGANIC PSYCHOSES (CAUSED BY HEAD INJURY, (CAUSED BY HEAD INJURY, ALCOHOLISM, OTHERS)ALCOHOLISM, OTHERS)

THE NATURE OF SCHIZOPHRENIATHE NATURE OF SCHIZOPHRENIA• Begins at an early ageBegins at an early age

• Strong hereditary factorStrong hereditary factor

POSITIVE SYMPTOMSPOSITIVE SYMPTOMS Delusions / HallucinationsDelusions / HallucinationsThought disorderThought disorder

NEGATIVE SYMPTOMSNEGATIVE SYMPTOMSWithdrawal from social contactsWithdrawal from social contactsFlattening of emotional responsesFlattening of emotional responses

THE DOPAMINE HYPOTHESISTHE DOPAMINE HYPOTHESIS• SCHIZOPRENIA: WITH EXCESSIVE SCHIZOPRENIA: WITH EXCESSIVE

DOPAMINIERGIC ACTIVITYDOPAMINIERGIC ACTIVITY

1. ANTIPSYCHOTIC DRUGS BLOCK 1. ANTIPSYCHOTIC DRUGS BLOCK POSTSYNAPTIC D2 RECEPTORS IN POSTSYNAPTIC D2 RECEPTORS IN CNSCNS

2. DRUGS THAT INCREASE DOPA 2. DRUGS THAT INCREASE DOPA AGGRAVATE SCHIZOPHRENIAAGGRAVATE SCHIZOPHRENIA

THE DOPAMINE HYPOTHESISTHE DOPAMINE HYPOTHESIS3. DOPAMINE RECEPTOR DENSITY ↑ in 3. DOPAMINE RECEPTOR DENSITY ↑ in

schizophreniaschizophrenia

4. POSITRON EMISSION TOMOGRAPHY 4. POSITRON EMISSION TOMOGRAPHY (PETS) ↑ DRD(PETS) ↑ DRD

5. HOMAVANILLIC ACID (HAV) change 5. HOMAVANILLIC ACID (HAV) change in amountin amount

CLASSIFICATION OF ANTIPSYCHOTIC CLASSIFICATION OF ANTIPSYCHOTIC DRUGSDRUGS

1. TYPICAL ANTIPSYCHOTICS1. TYPICAL ANTIPSYCHOTICSa. Phenothiazine derivativesa. Phenothiazine derivatives• Aliphatic Derivative: CHLORPROMAZINEAliphatic Derivative: CHLORPROMAZINE• Piperidine Derivative: THIORIDAZINEPiperidine Derivative: THIORIDAZINE• Piperazine Derivative: FLUPENAZINE, Piperazine Derivative: FLUPENAZINE,

PERPHENAZINE, TRIFLUOPERAZINEPERPHENAZINE, TRIFLUOPERAZINEb. Thioxanthene Derivative: THIOTHIXENEb. Thioxanthene Derivative: THIOTHIXENEc. Butyrophenone: HALOPERIDOLc. Butyrophenone: HALOPERIDOL

2. ATYPICAL ANTIPSYCHOTICS2. ATYPICAL ANTIPSYCHOTICS

•CLOZAPINE LOXAPINECLOZAPINE LOXAPINE

•OLANZAPINE QUETIAPINEOLANZAPINE QUETIAPINE

•RISPERIDONE MOLINDONERISPERIDONE MOLINDONE

•ZIPRASIDONEZIPRASIDONE

•SERTINDOLE ARIPIPRAZOLESERTINDOLE ARIPIPRAZOLE

•PIMOZIDEPIMOZIDE

CLASSIFICATION OF ANTIPSYCHOTIC CLASSIFICATION OF ANTIPSYCHOTIC DRUGSDRUGS

PHARMACOKINETICSPHARMACOKINETICS•READILY BUT INCOMPLETELY READILY BUT INCOMPLETELY

ABSORBEDABSORBED•FIRST PASS METABOLISMFIRST PASS METABOLISM•HIGHLY LIPID SOLUBLEHIGHLY LIPID SOLUBLE•LARGE V d > 7 L / kgLARGE V d > 7 L / kg•PROTIEN BOUNDPROTIEN BOUND•COMPLETELY METABOLIZEDCOMPLETELY METABOLIZED•LITTLE EXCRETED UNCHANGEDLITTLE EXCRETED UNCHANGED•T ½ is 10 -24 hoursT ½ is 10 -24 hours

MECHANISM OF ACTIONMECHANISM OF ACTION• DOPAMINE RECEPTOR-BLOCKING DOPAMINE RECEPTOR-BLOCKING

ACTIVITY IN THE BRAINACTIVITY IN THE BRAIN

• SEROTONIN RECEPTOR-BLOCKING SEROTONIN RECEPTOR-BLOCKING ACTIVITY IN THE BRAINACTIVITY IN THE BRAIN

• BLOCK CHOLINERGIC, BLOCK CHOLINERGIC, ADRENERGIC & HISTAMINERGIC ADRENERGIC & HISTAMINERGIC RECEPTORSRECEPTORS

DOPAMINERGIC SYSTEMDOPAMINERGIC SYSTEM1.1. MESOLIMBIC-MESOCORTICAMESOLIMBIC-MESOCORTICAL : L :

substancia nigra………>limbic substancia nigra………>limbic system BEHAVIORsystem BEHAVIOR

2. 2. NIGROSTRIATAL NIGROSTRIATAL : substancia : substancia nigra,,,……...>caudate & putamen nigra,,,……...>caudate & putamen VOLUNTARY VOLUNTARY MOVEMENTS MOVEMENTS

3.T3.TUBEROINFUNDIBULARUBEROINFUNDIBULAR: arcuate : arcuate nuclei & periventricular neurons,,,> nuclei & periventricular neurons,,,> hypothalamus & post pituitary; hypothalamus & post pituitary; INHIBITS PROLACTIN SECRETIONINHIBITS PROLACTIN SECRETION

DOPAMINERGIC SYSTEMDOPAMINERGIC SYSTEM4.MEDULLARY-PERIVENTRICULAR :4.MEDULLARY-PERIVENTRICULAR :

motor nuclei of the vagus motor nuclei of the vagus EATING BEHAVIOREATING BEHAVIOR

5. 5. INCERTOHYPOTHALAMUSINCERTOHYPOTHALAMUS : from the : from the medial zona incerta to the medial zona incerta to the hypothalamus and the amygdala hypothalamus and the amygdala REGULATE THE ANTICIPATORY REGULATE THE ANTICIPATORY MOTIVATIONAL PHASE OF MOTIVATIONAL PHASE OF COPULATORY BEHAVIOR IN RATS COPULATORY BEHAVIOR IN RATS

DOPAMINE RECEPTORSDOPAMINE RECEPTORS•D1: CHROMOSOME 5; D1: CHROMOSOME 5; ↑↑ cAMP… cAMP…

> activation of adenyl cyclase> activation of adenyl cyclase

•D5 : CHROMOSOME 4; D5 : CHROMOSOME 4; ↑↑ cAMP cAMP

•D2: CHROMOSOMES 11: D2: CHROMOSOMES 11: ↓ ↓ cAMP…cAMP…> blocks Ca > blocks Ca ++++ channels…> opens channels…> opens K K + + channels channels

•D3: CHROMOSOME 11: D3: CHROMOSOME 11: ↓ ↓ cAMP cAMP

•D4: D4: ↓↓ cAMP cAMP

DIFFERENCES AMONG DIFFERENCES AMONG ANTIPSYCHOTIC DRUGSANTIPSYCHOTIC DRUGS

CHLORPROMAZINE: a1=5HT2 >D2 CHLORPROMAZINE: a1=5HT2 >D2 >D1>D1

HALOPERIDOL: D2>D1=D4>a1>5HT2HALOPERIDOL: D2>D1=D4>a1>5HT2

CLOZAPINE : D4=a1>5HT>D2=D1 CLOZAPINE : D4=a1>5HT>D2=D1

DIFFERENCES AMONG DIFFERENCES AMONG ANTIPSYCHOTIC DRUGSANTIPSYCHOTIC DRUGS

OLANZAPINE: 5HT2A >D4 >D2 >a1 OLANZAPINE: 5HT2A >D4 >D2 >a1 >D1>D1

ARIPIPRAZOLE: D2 = 5HT 2A > D4 > ARIPIPRAZOLE: D2 = 5HT 2A > D4 > a1a1

=H1 > > D1=H1 > > D1

QUETIAPINE: H1 >a1 > M1,3 > D2 > 5 QUETIAPINE: H1 >a1 > M1,3 > D2 > 5 HT2aHT2a

ANTIPSYCHOTIC AGENTSANTIPSYCHOTIC AGENTS• PSYCHOLOGICAL EFFECTSPSYCHOLOGICAL EFFECTS

> sleepiness, restlessness, impaired > sleepiness, restlessness, impaired performance & judgmentperformance & judgment

• NEUROPHYSIOLOGIC EFFECTSNEUROPHYSIOLOGIC EFFECTS

> hypersyncrony focal /unilateral> hypersyncrony focal /unilateral

• ENDOCRINE EFFECTSENDOCRINE EFFECTS

> amenorrhea, galactorrhea, increase > amenorrhea, galactorrhea, increase libido, false( +) pregnancy testslibido, false( +) pregnancy tests

• ↓↓ libido in males, gynecomastialibido in males, gynecomastia

ANTIPSYCHOTIC AGENTSANTIPSYCHOTIC AGENTS•CARDIOVASCULAR EFFECTSCARDIOVASCULAR EFFECTSorthostatic hypotensionorthostatic hypotension high resting pulse ratehigh resting pulse rate↑ ↑ PR, PR, ↓ ↓ stroke volume, stroke volume, ↓ mean ↓ mean

arterial pressure, arterial pressure, ↓ ↓ peripheral resistanceperipheral resistanceNAUSEA & VOMITINGNAUSEA & VOMITINGBlock the chemoreceptor trigger Block the chemoreceptor trigger

zonezone

CLINICAL INDICATIONSCLINICAL INDICATIONSA. PSYCHIATRY INDICATIONSA. PSYCHIATRY INDICATIONS• SCHIZOPHREMIASCHIZOPHREMIA• SCHIZOAFFECTIVE DISORDERSSCHIZOAFFECTIVE DISORDERS• MANIC EPISODES IN BIPOLAR MANIC EPISODES IN BIPOLAR

DISORDERSDISORDERS• GILLES DE TOURETTE SYNDROMEGILLES DE TOURETTE SYNDROME• SENILE DEMENTIASENILE DEMENTIAB. NONPSYCHIATRIC INDICATIONSB. NONPSYCHIATRIC INDICATIONS>ANTI-EMETIC EFFECT >ANTI-EMETIC EFFECT

(prochlorperazine)(prochlorperazine)>ANTI-PRURITIC EFFECTIphenothiazines)>ANTI-PRURITIC EFFECTIphenothiazines)>PREOPERATIVE >PREOPERATIVE

ANESTHESIA.promethazineANESTHESIA.promethazine>NEUROLEPTIC ANESTHESIA..droperidol>NEUROLEPTIC ANESTHESIA..droperidol

SIDE EFFECTTS OF SIDE EFFECTTS OF NEUROLEPTIC DRUGSNEUROLEPTIC DRUGS

A. NEUROLOGIC EFFECTSA. NEUROLOGIC EFFECTS1. ACUTE DYSTONIA : 1. ACUTE DYSTONIA : Spasm of Spasm of muscles tongue, face, neck, back, may muscles tongue, face, neck, back, may mimic seizuresmimic seizures

• During the first 1 -5 days of RxDuring the first 1 -5 days of Rx• Mechanism unknownMechanism unknown• Rx: antiparkinson’s agentsRx: antiparkinson’s agents

2. AKATHISIA : 2. AKATHISIA : Motor restlessnessMotor restlessness• 5 -60 days5 -60 days• Mechanism unknown; Rx with Mechanism unknown; Rx with

diphenhydraminediphenhydramine

3. PARKINSONISM3. PARKINSONISM bradykinesia, rigidity, tremor, mask facies, bradykinesia, rigidity, tremor, mask facies,

shuffling gait seen in 5-30 daysshuffling gait seen in 5-30 days

Mechanism is antagonism of DopamineMechanism is antagonism of Dopamine

Rx: Antiparkinson’s AgentsRx: Antiparkinson’s Agents

4. NEUROLEPTIC MALIGNANT 4. NEUROLEPTIC MALIGNANT SYNDROME:SYNDROME:

catatonia, stupor, fever, unstable BP, catatonia, stupor, fever, unstable BP, myoglobulinemia after weeks of treatmentmyoglobulinemia after weeks of treatment

Mechanism: Antagonism of DopamineMechanism: Antagonism of DopamineRx: Stop neuroleptic immediately; Rx: Stop neuroleptic immediately;

Dandrolene; Bromocriptine, Antiparks not Dandrolene; Bromocriptine, Antiparks not effectiveeffective

5. PERIODIC TREMOR (RABBIT SYNDROME)5. PERIODIC TREMOR (RABBIT SYNDROME)Perioral tremorsPerioral tremors after months or years of treatmentafter months or years of treatmentMechanism : unknownMechanism : unknownRx Antiparkinson’s DrugsRx Antiparkinson’s Drugs

6. TARDIVE DYSKINESIA6. TARDIVE DYSKINESIAoral-facial dyskinesia, choreoathetosis, oral-facial dyskinesia, choreoathetosis,

dystoniadystoniaAfter months or years of RxAfter months or years of RxWorse on withdrawalWorse on withdrawalMechanism: excess function of dopamineMechanism: excess function of dopamineRx: prevention crucial Rx unsatisfactoryRx: prevention crucial Rx unsatisfactory

ADVERSE EFFECTSADVERSE EFFECTS

II. BEHAVIORAL EFFECTS:II. BEHAVIORAL EFFECTS:

• Pseudo-depression; toxic confusional statePseudo-depression; toxic confusional state

III. AUTONOMIC NERVOUS SUSTEM III. AUTONOMIC NERVOUS SUSTEM EFFECTS : EFFECTS :

• urinary retention,dry mouth, loss of urinary retention,dry mouth, loss of accommodation, constipation accommodation, constipation (MUSCARINIC CHOLINERGIC BLOCKADE)(MUSCARINIC CHOLINERGIC BLOCKADE)

• orthostatic hypotension, impotence, orthostatic hypotension, impotence, failure to ejaculate ( ALPHA failure to ejaculate ( ALPHA ADRENORECEPTOR BLOCKADE)ADRENORECEPTOR BLOCKADE)

ADVERSE EFFECTSADVERSE EFFECTSIV. METABOLIC & ENDOCRINE EFFECTSIV. METABOLIC & ENDOCRINE EFFECTSWeight gain, hyperglycemia, hyper - Weight gain, hyperglycemia, hyper - prolactenemia, amenorrhea-galactorrhea prolactenemia, amenorrhea-galactorrhea

syndrome, infertility, impotence in malessyndrome, infertility, impotence in malesV. TOXIC OR ALLERGIC REACTIONSV. TOXIC OR ALLERGIC REACTIONSAgranulocytosis (clozapine) , cholestatic Agranulocytosis (clozapine) , cholestatic

jaundice, skin eruptionsjaundice, skin eruptionsVI. CARDIAC TOXICITYVI. CARDIAC TOXICITYVentricular arrythmias (thioridazine)Ventricular arrythmias (thioridazine)VII. OCULAR COMPLICATIONS: “ browning VII. OCULAR COMPLICATIONS: “ browning

of vision”of vision”

ANTIMANIC AGENTSANTIMANIC AGENTS• MOOD STABILIZING AGENTMOOD STABILIZING AGENT

• BIPOLAR DISORDERS (MANIC-BIPOLAR DISORDERS (MANIC-DEPRESSIVE)DEPRESSIVE)

• DISORDER WITH PREPONDERANCE DISORDER WITH PREPONDERANCE OF CATHECHOLAMINE RELATED OF CATHECHOLAMINE RELATED ACTIVITYACTIVITY

• LITHIUM CARBONATELITHIUM CARBONATE

• CARBAMAZEPINE, VALPROIC ACIDCARBAMAZEPINE, VALPROIC ACID

LITHIUM P’KINETICSLITHIUM P’KINETICSABSORPTIONABSORPTION : : virtually complete virtually complete

within 6 -8 hrs; peak plasma levels in 30 within 6 -8 hrs; peak plasma levels in 30 min to 2 hrsmin to 2 hrs

DISTRIBUTIONDISTRIBUTION: in total body water; slow : in total body water; slow entry into intracellular compartment. No entry into intracellular compartment. No protein bindingprotein binding

METABOLISMMETABOLISM: None: None

EXCRETIONEXCRETION: virtually entirely in urine; : virtually entirely in urine; plasma half life is about 20 hoursplasma half life is about 20 hours

LITHIUM ‘ DYNAMICSLITHIUM ‘ DYNAMICS• EFFECTS ON ELECTROLYTES & IONS EFFECTS ON ELECTROLYTES & IONS

TRANSPORT: TRANSPORT: Substitute for sodiumSubstitute for sodium• EFFECTS ON NEUROTRANSMITTEREFFECTS ON NEUROTRANSMITTER enhance effects of serotonin?enhance effects of serotonin?Decrease norepinephrine & dopamine Decrease norepinephrine & dopamine

turnoverturnoverBlock dopamine receptor Block dopamine receptor

supersensitivitysupersensitivityAugment synthesis of acetylcholine?Augment synthesis of acetylcholine?

LITHIUM LITHIUM PHARMACODYNAMICSPHARMACODYNAMICS

• EFFECTS ON SECOND MESSENGEREFFECTS ON SECOND MESSENGEReffect on IP3/ DAGeffect on IP3/ DAG

EFFECTS ON PHOSPHOINOSITOL EFFECTS ON PHOSPHOINOSITOL TURNOVER…..> EARLY RELATIVE TURNOVER…..> EARLY RELATIVE REDUCTION OF MYOINOSITOL IN REDUCTION OF MYOINOSITOL IN HUMAN BRAINHUMAN BRAIN

LITHIUM ADVERSE EFFECTSLITHIUM ADVERSE EFFECTS1.1. CNS EFFECTS; dizziness, mild ataxiaCNS EFFECTS; dizziness, mild ataxia2.2. NEUROMUSCULAR EFECTS: fine tremorsNEUROMUSCULAR EFECTS: fine tremors3.3. CV EFFECTS: ventricular arrythmiasCV EFFECTS: ventricular arrythmias4.4. GIT EFFECTS: nausea, vomiting, GIT EFFECTS: nausea, vomiting,

diarrheadiarrhea5.5. GUT EFFECTS: polyuriaGUT EFFECTS: polyuria6.6. ENDOCRINE EFFECTS: hypothyroidismENDOCRINE EFFECTS: hypothyroidism7.7. ALLERGIC REACTION: pruritus, rashALLERGIC REACTION: pruritus, rash8.8. OVERDOSE TOXICITY: vomiting, OVERDOSE TOXICITY: vomiting,

drowsiness, decrease consciousness drowsiness, decrease consciousness seizuresseizures

Rx: dialysisRx: dialysis

LITHIUM CONTRAINDICATIONLITHIUM CONTRAINDICATION

A. MARKED DEHYDRATION OR SODIUM A. MARKED DEHYDRATION OR SODIUM DEPLETIONDEPLETION

B.SIGNIFICANT RENAL OR CARDIAC B.SIGNIFICANT RENAL OR CARDIAC DISEASESDISEASES

C. PREGNANCY(W)C. PREGNANCY(W)

D. RENAL CONCENTRATION ABILITY(W)D. RENAL CONCENTRATION ABILITY(W)

•Nephrogenic diabetes insipidus with Nephrogenic diabetes insipidus with polyuriapolyuria

DRUG INTERACTIONSDRUG INTERACTIONS

A.A. THIAZIDE DIURETICS: THIAZIDE DIURETICS: ↓ ↓ RENAL CLEARANCE OF RENAL CLEARANCE OF LITHIUMLITHIUM

B.B. NSAID: NSAID: ↓ ↓ LITHIUM LITHIUM CLEARANCECLEARANCE

C.C.ANTIPYSCHOTIC AGENTS: ANTIPYSCHOTIC AGENTS:

↑ ↑ NEUROTOXICITYNEUROTOXICITY

DEPRESSIONDEPRESSIONI.REACTIVE OR SECONDARY DEPRESSIONI.REACTIVE OR SECONDARY DEPRESSION

Core Depression Syndrome: depression, Core Depression Syndrome: depression, anxiety, tension, bodily complaints, guilt anxiety, tension, bodily complaints, guilt (> 60%)(> 60%)

II.ENDOGENOUS DEPRESSIONII.ENDOGENOUS DEPRESSION

Core Depression Syndrome plus ABNORMAL Core Depression Syndrome plus ABNORMAL VS rhythm of sleep, motor activity, livido, VS rhythm of sleep, motor activity, livido, decrease appetite ( 25%)decrease appetite ( 25%)

III. DEPRESSION ASSOCIATED WITH BIPOLAR III. DEPRESSION ASSOCIATED WITH BIPOLAR AFFECTIVE DISORDER AFFECTIVE DISORDER

(10-15%)(10-15%)

ANTIDEPRESSANTSANTIDEPRESSANTSI.TRICYCLIC ANTIDEPRESSANTSI.TRICYCLIC ANTIDEPRESSANTS

IMIPRAMINE. AMITRYPTYLINE, DOXAPIN, IMIPRAMINE. AMITRYPTYLINE, DOXAPIN, NORTRIPTYLLINE ,DESIPRAMINE. NORTRIPTYLLINE ,DESIPRAMINE. CLOMIPRAMINE , PROTIPTYLINE, CLOMIPRAMINE , PROTIPTYLINE, TRIMIPRAMINETRIMIPRAMINE

B. HETEROCYCLIC, SECOND & THIRD B. HETEROCYCLIC, SECOND & THIRD DEGENERATIONSDEGENERATIONS

1. SECOND GENERATIONS1. SECOND GENERATIONSAMOXAPINE, MAPROTILINEAMOXAPINE, MAPROTILINETRAZODON, BUPROPIONTRAZODON, BUPROPION

2. THIRD GENERATIONS2. THIRD GENERATIONSMIRTAZAPINE, VENLAFAZINEMIRTAZAPINE, VENLAFAZINENEFAXODONENEFAXODONE

ANTIDEPRESSANTSANTIDEPRESSANTSC. C. SELECTIVE SEROTONIN REUPTAKE SELECTIVE SEROTONIN REUPTAKE

INHIBITORS (SSRI)INHIBITORS (SSRI)

• FLUOXETINE FLUVOXAMINE FLUOXETINE FLUVOXAMINE

• PAROXETINE ESCITALOPRAMPAROXETINE ESCITALOPRAM

• SERTRALINE CITALOPRAM SERTRALINE CITALOPRAM

D. D. MONOAMINE OXIDASE INHIBITORSMONOAMINE OXIDASE INHIBITORS (MAOI)(MAOI)

• PHENELZINE, TRANYLCYPROMINEPHENELZINE, TRANYLCYPROMINE

• MOCLOBEMIDE MOCLOBEMIDE

ANTIDEPRESSANTS PHARMADYNAMICSANTIDEPRESSANTS PHARMADYNAMICS

A.A. ACTION OF ANTIDEPRESSANTS ON ACTION OF ANTIDEPRESSANTS ON BIOGENIC AMINE BIOGENIC AMINE NEUROTRANSMITTERSNEUROTRANSMITTERS

TRICYCLICS: BLOCK AMINE REUPTAKE TRICYCLICS: BLOCK AMINE REUPTAKE PUMPSPUMPS

MAOI: BLOCK DEGRADATIVE PATHWAY MAOI: BLOCK DEGRADATIVE PATHWAY FOR THE AMINE NEUROTRANSMITTERSFOR THE AMINE NEUROTRANSMITTERS

TRAZODON, NEFAZODONE & TRAZODON, NEFAZODONE & MIRTAZAPINE: SERETONIN RECEPTORS MIRTAZAPINE: SERETONIN RECEPTORS ANTAGONISTANTAGONIST

B.RECEPTOR & POSTRECEPTOR B.RECEPTOR & POSTRECEPTOR EFFECTSEFFECTS

•SSRI: SSRI: ↓↓ in norepinephrine in norepinephrine cAMP & in beta -adrenoreceptor cAMP & in beta -adrenoreceptor bindingbinding

•MAOI: mixed action with MAOI: mixed action with norepinephrine & serotoninnorepinephrine & serotonin

•↑↑ serotonergic transmission serotonergic transmission mediated through diverse mediated through diverse mechanismsmechanisms

DrugDrug SedatiSedativeve

MuscaMuscarinicrBlrinicrBlockock

NE NE reuptakereuptake

BlockBlock

5HT reuptake 5HT reuptake blockblock

AmitryptylineAmitryptyline ++++++ ++++++ ++++ ++++++

ImipramineImipramine ++++ ++ ++ ++++

AmoxapineAmoxapine ++++ ++ ++++ ++

BupropionBupropion - -

-- -- --

TrazodoneTrazodone ++++++ - - -- ++++

MirtazepineMirtazepine ++++++ -- -- --

VenlafaxineVenlafaxine -- -- ++++++ ++++

FluoxetineFluoxetine -- ++ - - ++++++

PHARMACOKINETICSPHARMACOKINETICS• A. TRICYCLICSA. TRICYCLICSIncompletely reabsorbedIncompletely reabsorbedFirst pass metabolismFirst pass metabolismLarge VdLarge VdMetabolizedMetabolizedHETEROCYCLICSHETEROCYCLICSVariable bioavailabilitiyVariable bioavailabilitiyHigh protein bindingHigh protein bindingVariable and large VdVariable and large VdActive metabolitesActive metabolites

PHARMACOKINETICSPHARMACOKINETICS•SSRI : FLUOXETINESSRI : FLUOXETINE

•Well absorbedWell absorbed

•PPC: 4 – 8 hrsPPC: 4 – 8 hrs

• Inhibits drug metabolizing Inhibits drug metabolizing enzymesenzymes

•MAOIMAOI

•Readily absorbedReadily absorbed

CLINICAL INDICATIONSCLINICAL INDICATIONS

A.A. DEPRESSIONDEPRESSIONB.B. PANIC DISORDERPANIC DISORDERC.C.OBSESSIVE COMPULISVEOBSESSIVE COMPULISVED.D.ENURESISENURESISE.E. CHRONIC PAINCHRONIC PAINF.F. OTHERS: Eating Disorder(Bulemia)OTHERS: Eating Disorder(Bulemia)Cataplexy asstd with Narcolepsy, Cataplexy asstd with Narcolepsy,

School Phobia, Attention Deficit School Phobia, Attention Deficit SyndromeSyndrome

ADVERSE EFFECTSADVERSE EFFECTS

•TRICYCLICSTRICYCLICSSedation:Sedation: Sleepiness SleepinessSynpathomimetic; tremors, Synpathomimetic; tremors,

insomniainsomniaAntimuscarinic; blurred Antimuscarinic; blurred

vision. vision. constipation confusion,constipation confusion,

urinary urinary incontinenceincontinence

TRICYCLICSTRICYCLICS

Psychiatric: psychoses Psychiatric: psychoses aggravatedaggravated

CVS: orthostaticCVS: orthostatic hypotensionhypotension

Neurologic: SeizuresNeurologic: SeizuresMetabolic-Endocrine: weight gain, Metabolic-Endocrine: weight gain,

sexualsexual disturbance disturbance

ADVERSE EFFECTSADVERSE EFFECTS

MAO INHIBITORSMAO INHIBITORSheadache, drowsiness, dry mouth, headache, drowsiness, dry mouth,

weight gain, postural hypotension, weight gain, postural hypotension, sexual distnsexual distn

AMOXAPINAMOXAPIN Tricyclic & antipsychotic effectsTricyclic & antipsychotic effects

MAPROTILINEMAPROTILINETricyclic EffectsTricyclic Effects

ADVERSE EFFECTSADVERSE EFFECTSTRAZODONE & NEFAZODONE: TRAZODONE & NEFAZODONE:

drowsiness, dizziness, insomnia, drowsiness, dizziness, insomnia, nausea, agitationnausea, agitation

BUPROPIONBUPROPIONdizziness, dry mouth, tremordizziness, dry mouth, tremor

FLUOXETINEFLUOXETINEAnxiety, insomnia, tremors, decr Anxiety, insomnia, tremors, decr

libido, GIT effectslibido, GIT effects

Foods that interact with Foods that interact with MAOIMAOI

• High in tyramine content:High in tyramine content:BEER. BEER. BROAD BEANS, LAVA BEANSBROAD BEANS, LAVA BEANSCHEESE.CHEESE.CHICKEN LIVERCHICKEN LIVER SAUSAGESSAUSAGES SNAILS WINE, RED WINESNAILS WINE, RED WINEYEASTYEAST

Drugs that Interact with Drugs that Interact with MAOIMAOIA.INDIRECTLY ACTINGA.INDIRECTLY ACTING SYMPATHOMIMETICS: amphetamines, SYMPATHOMIMETICS: amphetamines, ephedrine, metaraminol, ephedrine, metaraminol, phenylpropanolaminephenylpropanolamine

B. B. OTHER ADRENORECEPTOR AGENTSOTHER ADRENORECEPTOR AGENTS & & RELATED AGENTS: levodopa, methyldopa, RELATED AGENTS: levodopa, methyldopa, guanethidine, reserpineguanethidine, reserpine

C. C. OPIOID ANALGESICS & DERIVATIVESOPIOID ANALGESICS & DERIVATIVES: : morphine, codeine, meperidine, morphine, codeine, meperidine, dextromethorphamdextromethorpham

D.MISCELLANEOUS DRUGSD.MISCELLANEOUS DRUGS: buspirone, : buspirone, fluoxetine, LSDfluoxetine, LSD