ANTI-PSYCHOTIC ANTI-PSYCHOTIC DRUGSDRUGS

DON D. CUA, MDDON D. CUA, MDDepartment of PharmacologyDepartment of Pharmacology

TYPES OF PSYCHOSISTYPES OF PSYCHOSIS

SCHIZOPHRENIASCHIZOPHRENIAAFFECTIVE DISORDERS AFFECTIVE DISORDERS

(DEPRESSION/MANIA)(DEPRESSION/MANIA)ORGANIC PSYCHOSES ORGANIC PSYCHOSES

(CAUSED BY HEAD INJURY, (CAUSED BY HEAD INJURY, ALCOHOLISM, OTHERS)ALCOHOLISM, OTHERS)

SCHIZOPHRENIASCHIZOPHRENIAA clinical syndrome A clinical syndrome

characterized by profound characterized by profound disruption in cognition and disruption in cognition and emotion, affecting the most emotion, affecting the most

fundamental attributes: fundamental attributes: language, thought, perception, language, thought, perception,

affect and sense of self.affect and sense of self.

clear sensorium but marked clear sensorium but marked thinking disturbancethinking disturbance

THE NATURE OF THE NATURE OF SCHIZOPHRENIASCHIZOPHRENIA

1% population, begins at an 1% population, begins at an early age, with strong early age, with strong hereditary factorhereditary factor

SEXSEX: Equally prevalent in men : Equally prevalent in men and womenand women

AGEAGE: MEN-between 15 and 25 : MEN-between 15 and 25

WOMEN-between 25 and 35 WOMEN-between 25 and 35

POSITIVE SYMPTOMSPOSITIVE SYMPTOMS Delusions Disorganized behaviorDelusions Disorganized behavior Hallucinations Disorganized Hallucinations Disorganized

speech/thinkingspeech/thinking Thought disorder Catatonic behaviorsThought disorder Catatonic behaviors

NEGATIVE SYMPTOMSNEGATIVE SYMPTOMS Withdrawal from social contactsWithdrawal from social contacts Flattening of emotional responsesFlattening of emotional responses Alogia, Avolition-Apathy, Anhedonia-Alogia, Avolition-Apathy, Anhedonia-

AsocialityAsociality AttentionAttention

MAJOR AFFECTIVE /MANIC MAJOR AFFECTIVE /MANIC DEPRESSIVE DISORDERSDEPRESSIVE DISORDERS

Abnormal emotion or moodAbnormal emotion or mood Disorders of affect & depression, Disorders of affect & depression,

dysphoria, elation or maniadysphoria, elation or mania Bipolar or non-bipolarBipolar or non-bipolar Can occur as a mild disorder or Can occur as a mild disorder or

can be associated with other can be associated with other psychiatric or medical illnessespsychiatric or medical illnesses

NEUROSES:NEUROSES: Less pervasive psychiatric disordersLess pervasive psychiatric disorders Comprehend reality, suffering & Comprehend reality, suffering &

disability are sometimes severedisability are sometimes severe Acute or transient, persistent or Acute or transient, persistent or

recurrentrecurrent Mood changes- anxiety , panic, Mood changes- anxiety , panic,

depressiondepression Limited abnormalities of thought- Limited abnormalities of thought-

obsessions, irrational fearsobsessions, irrational fears Behavior – rituals, compulsions, Behavior – rituals, compulsions,

hysterical conversionshysterical conversions

Diagnostic Criteria for Diagnostic Criteria for SchizophreniaSchizophrenia

DSM IVDSM IVA. Two or more of the followingA. Two or more of the following ( one-month ( one-month period )period )

delusions, hallucinations, disorganized delusions, hallucinations, disorganized speech, grossly disorganized or catatonic speech, grossly disorganized or catatonic behavior and negative symptoms.behavior and negative symptoms.

B. Social/occupational dysfunctionB. Social/occupational dysfunction: one or : one or major areas of functioning such as work, major areas of functioning such as work, interpersonal relations, or self-care, are interpersonal relations, or self-care, are markedly below the level achieved prior to markedly below the level achieved prior to the onset.the onset.

C. Continuous signs of the disturbanceC. Continuous signs of the disturbance persist for at least SIX months.persist for at least SIX months.

THE DOPAMINE THE DOPAMINE HYPOTHESISHYPOTHESIS SCHIZOPHRENIA: SCHIZOPHRENIA: WITH EXCESSIVE WITH EXCESSIVE

DOPAMINERGIC ACTIVITY; NORe and GABADOPAMINERGIC ACTIVITY; NORe and GABA ANTI-PSYCHOTIC DRUGS BLOCK ANTI-PSYCHOTIC DRUGS BLOCK

POSTSYNAPTIC D2 RECEPTORS IN CNSPOSTSYNAPTIC D2 RECEPTORS IN CNS DRUGS THAT INCREASE DOPA DRUGS THAT INCREASE DOPA

AGGRAVATE AGGRAVATE SCHIZOPHRENIASCHIZOPHRENIA DOPAMINE RECEPTOR DENSITYDOPAMINE RECEPTOR DENSITY ↑ in ↑ in

schizosschizos POSITRON EMISSION TOMOGRAPHY (PETS)POSITRON EMISSION TOMOGRAPHY (PETS) ↑ ↑ Dopamine Receptor DensityDopamine Receptor Density HOMAVANILLIC ACID (HAV)HOMAVANILLIC ACID (HAV) CHANGE IN AMOUNTCHANGE IN AMOUNT

CLASSIFICATION OF CLASSIFICATION OF ANTIPSYCHOTIC DRUGS:ANTIPSYCHOTIC DRUGS:

1.1. TYPICAL ANTIPSYCHOTICS:TYPICAL ANTIPSYCHOTICS:

A. PHENOTHIAZENE DERIVATIVEA. PHENOTHIAZENE DERIVATIVE 3 ring structure, 2 benzene rings 3 ring structure, 2 benzene rings

are linked by sulfur & nitrogen are linked by sulfur & nitrogen atomatom

N position 10 is replaced by carbon N position 10 is replaced by carbon atom with a double bond to the atom with a double bond to the side chainside chain

ALIPHATIC DERIVATIVE:ALIPHATIC DERIVATIVE: CHLORPROMAZINECHLORPROMAZINE TRIFLUPROMAZINETRIFLUPROMAZINE PIPERIDINE DERIVATIVE:PIPERIDINE DERIVATIVE: THIORIDAZINETHIORIDAZINE MESORIDAZINEMESORIDAZINE PIPERACETAZINEPIPERACETAZINE Decrease incidence of EPS Decrease incidence of EPS

side effects due to side effects due to antimuscarinic activityantimuscarinic activity

PIPERAZINE DERIVATIVE:PIPERAZINE DERIVATIVE: FLUPHENAZINEFLUPHENAZINE PERPHENAZINEPERPHENAZINE TRIFLUOPERAZINETRIFLUOPERAZINE Most potent phenothiazene & Most potent phenothiazene &

thioxanthene antipsychotic thioxanthene antipsychotic compoundcompound

EPS but EPS but tendency to produce tendency to produce sedation or autonomic side effectssedation or autonomic side effects

B. THIOXANTHENE B. THIOXANTHENE DERIVATIVESDERIVATIVES::

ALIPHATIC DERIVATIVE:ALIPHATIC DERIVATIVE: CHLORPROTHIXENECHLORPROTHIXENE

PIPERAZINE DERIVATIVE:PIPERAZINE DERIVATIVE: CHLOPENTHIXOLCHLOPENTHIXOL FLUPENTIXOLFLUPENTIXOL THIOTHIXENETHIOTHIXENE

C. BUTYROPHENONEC. BUTYROPHENONE::

HALOPERIDOLHALOPERIDOL

CLASSIFICATION OF CLASSIFICATION OF ANTIPSYCHOTIC DRUGSANTIPSYCHOTIC DRUGS

1. TYPICAL ANTI-PSYCHOTICS1. TYPICAL ANTI-PSYCHOTICS

AA. . Phenothiazine DerivativesPhenothiazine Derivatives Aliphatic DerivativeAliphatic Derivative: : CHLORPROMAZINECHLORPROMAZINE Piperidine DerivativePiperidine Derivative: : THIORIDAZINETHIORIDAZINE Piperazine DerivativePiperazine Derivative: :

FLUPHENAZINE, PERPHENAZINE, FLUPHENAZINE, PERPHENAZINE, TRIFLUOPERAZINETRIFLUOPERAZINE

BB. . Thioxanthene DerivativeThioxanthene Derivative: : THIOTHIXENETHIOTHIXENE

C.C. ButyrophenoneButyrophenone:: HALOPERIDOLHALOPERIDOL

2. ATYPICAL ANTI-2. ATYPICAL ANTI-PSYCHOTICSPSYCHOTICS

CLOZAPINECLOZAPINE LOXAPINELOXAPINE RISPERIDONERISPERIDONE MOLINDONEMOLINDONE SERTINDOLESERTINDOLE ZIPRASIDONEZIPRASIDONE OLANZAPINEOLANZAPINE QUETIAPINEQUETIAPINE PIMOZIDEPIMOZIDE

CLASSIFICATION OF ANTI-CLASSIFICATION OF ANTI-PSYCHOTIC DRUGSPSYCHOTIC DRUGS

DOPAMINE RECEPTORSDOPAMINE RECEPTORSD1 like familyD1 like family

D1: CHROMOSOME 5D1: CHROMOSOME 5; INCREASE ; INCREASE cAMP…>cAMP…>

activation of adenyl cyclaseactivation of adenyl cyclase D5 : CHROMOSOME 4D5 : CHROMOSOME 4; INCREASE cAMP; INCREASE cAMP

D2 like familyD2 like family D2: CHROMOSOMES 11D2: CHROMOSOMES 11: DECREASE : DECREASE

cAMP …>cAMP …>blocks calcium channelsblocks calcium channels …… ……> > opens potassium channelsopens potassium channels D3: CHROMOSOME 11D3: CHROMOSOME 11: DECREASE : DECREASE

cAMPcAMP D4: D4: DECREASE cAMPDECREASE cAMP

DIFFERENCES AMONG DIFFERENCES AMONG ANTI-PSYCHOTIC DRUGSANTI-PSYCHOTIC DRUGS

CHLORPROMAZINECHLORPROMAZINE alpha1=5HT2 > D2 alpha1=5HT2 > D2 >D1>D1

HALOPERIDOL HALOPERIDOL D2>D1=D4>alpha1>5HT2D2>D1=D4>alpha1>5HT2

CLOZAPINECLOZAPINE D4=alpha1>5HT>D2=D1 D4=alpha1>5HT>D2=D1

RISPERIDONE D2=5HT2RISPERIDONE D2=5HT2

OLANZAPINE 5HT2> or= D1, D2, alpha2 OLANZAPINE 5HT2> or= D1, D2, alpha2

DOPAMINERGIC SYSTEMDOPAMINERGIC SYSTEM

1. MESOLIMBIC-MESOCORTICAL 1. MESOLIMBIC-MESOCORTICAL substancia nigra………>limbic system substancia nigra………>limbic system BEHAVIORBEHAVIOR

2. NIGROSTRIATAL2. NIGROSTRIATAL substancia nigra….>caudate & substancia nigra….>caudate &

putamen putamen VOLUNTARY VOLUNTARY MOVEMENTSMOVEMENTS

3. TUBEROINFUNDIBULAR3. TUBEROINFUNDIBULAR arcuate nuclei & periventricular arcuate nuclei & periventricular

neurons,> hypothalamus & post neurons,> hypothalamus & post pituitary pituitary

INHIBITS PROLACTIN SECRETIONINHIBITS PROLACTIN SECRETION

DOPAMINERGIC SYSTEMDOPAMINERGIC SYSTEM

4. MEDULLARY-4. MEDULLARY-PERIVENTRICULAR PERIVENTRICULAR motor motor nuclei of the vagus nuclei of the vagus EATING BEHAVIOREATING BEHAVIOR

5. INCERTOHYPOTHALAMUS5. INCERTOHYPOTHALAMUS from the medial zona incerta to from the medial zona incerta to

the hypothalamus and the the hypothalamus and the amygdala amygdala REGULATE THE REGULATE THE ANTICIPATORY MOTIVATIONAL ANTICIPATORY MOTIVATIONAL PHASE OF COPULATORY PHASE OF COPULATORY BEHAVIOR IN RATSBEHAVIOR IN RATS

ANTI-PSYCHOTIC ANTI-PSYCHOTIC AGENTSAGENTS

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 testlibido, false(-) pregnancy test

>decrease libido in males, gynecomastia>decrease libido in males, gynecomastia

ANTI-PSYCHOTIC ANTI-PSYCHOTIC AGENTSAGENTS

CARDIOVASCULAR EFFECTSCARDIOVASCULAR EFFECTS orthostatic hypotensionorthostatic hypotension high resting pulse ratehigh resting pulse rate increase PR, decrease stroke increase PR, decrease stroke

volume, decrease mean volume, decrease mean arterial pressure arterial pressure

decrease peripheral resistancedecrease peripheral resistance

PHARMACOKINETICSPHARMACOKINETICS READILY BUT INCOMPLETELY READILY BUT INCOMPLETELY

ABSORBEDABSORBED FIRST PASS METABOLISMFIRST PASS METABOLISM HIGHLY LIPID SOLUBLEHIGHLY LIPID SOLUBLE LARGE VOLUME OF DISTRIBUTIIONLARGE VOLUME OF DISTRIBUTIION PROTEIN BOUNDPROTEIN BOUND COMPLETELY METABOLIZED COMPLETELY METABOLIZED Except Except mesoridazinemesoridazine (major metabolites of (major metabolites of

thioridazine)thioridazine) LITTLE EXCRETED UNCHANGEDLITTLE EXCRETED UNCHANGED T ½ is 10 -24 hoursT ½ is 10 -24 hours

CLINICAL INDICATIONSCLINICAL INDICATIONSA. PSYCHIATRY INDICATIONSA. PSYCHIATRY INDICATIONS SCHIZOPHRENIASCHIZOPHRENIA SCHIZO-AFFECTIVE DISORDERSSCHIZO-AFFECTIVE DISORDERS MANIC EPISODES IN BIPOLAR MANIC EPISODES IN BIPOLAR

DISORDERSDISORDERS GILLES DE LA TOURETTE SYNDROMEGILLES DE LA TOURETTE SYNDROME SENILE DEMENTIASENILE DEMENTIA

B. NON-PSYCHIATRIC B. NON-PSYCHIATRIC INDICATIONSINDICATIONS

ANTI-EMETIC EFFECTANTI-EMETIC EFFECT ANTI-PRURITIC EFFECTANTI-PRURITIC EFFECT PRE-OPERATIVE ANESTHESIAPRE-OPERATIVE ANESTHESIA NEUROLEPTIC ANESTHESIANEUROLEPTIC ANESTHESIA

SIDE EFFECTTS OF SIDE EFFECTTS OF NEUROLEPTIC DRUGSNEUROLEPTIC DRUGS

A. NEUROLOGIC EFFECTSA. NEUROLOGIC EFFECTS1. ACUTE DYSTONIA1. ACUTE DYSTONIA : s : spasm of pasm 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: Rx: anti-parkinson’s agentsanti-parkinson’s agents

2. AKATHISIA2. AKATHISIA : m : motor restlessnessotor restlessness 5 -60 days5 -60 days Mechanism unknownMechanism unknown Rx with 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 MechanismMechanism: antagonism of dopamine: antagonism of dopamine

Rx: Rx: anti-parkinson’s agentsanti-parkinson’s agents

4. NEUROLEPTIC MALIGNANT SYNDROME4. NEUROLEPTIC MALIGNANT SYNDROME catatonia, stupor, fever, unstable BP,catatonia, stupor, fever, unstable BP,

myoglobulinemia after weeks of treatmentmyoglobulinemia after weeks of treatment MechanismMechanism: antagonism of dopamine: antagonism of dopamine

Rx: Rx: Stop neuroleptic immediately; Stop neuroleptic immediately; dandrolene; dandrolene; bromocriptine, Anti-bromocriptine, Anti-parkinsons- not effectiveparkinsons- not effective

5. PERIODIC TREMOR RABBIT SYNDROME5. PERIODIC TREMOR RABBIT SYNDROME Peri-oral tremors after months or years of Peri-oral tremors after months or years of

treatmenttreatment Mechanism Mechanism : unknown: unknown Rx: Rx: Anti-parkinson’s DrugsAnti-parkinson’s Drugs6. TARDIVE DYSKINESIA6. TARDIVE DYSKINESIA Supersensivity of D receptors (cholinergic Supersensivity of D receptors (cholinergic

def)def) oral-facial dyskinesia, choreoathetosis, dystoniaoral-facial dyskinesia, choreoathetosis, dystonia After months or years of RXAfter months or years of RX Worse on withdrawalWorse on withdrawal MechanismMechanism: excess function of dopamine: excess function of dopamine Rx: prevention crucial Rx: prevention crucial Rx: unsatisfactoryRx: unsatisfactory

ADVERSE EFFECTSADVERSE EFFECTSB. BEHAVIORAL EFFECTSB. BEHAVIORAL EFFECTS Pseudo-depression; toxic confusional statePseudo-depression; toxic confusional state

C. AUTONOMIC NERVOUS SYSTEM C. AUTONOMIC NERVOUS SYSTEM EFFECTSEFFECTS

urinary retention, dry mouth, loss of urinary retention, dry mouth, loss of accomodation, constipation accomodation, constipation

((MUSCARINIC CHOLINERGIC BLOCKADEMUSCARINIC CHOLINERGIC BLOCKADE)) orthostatic hypotension, impotence, failure to orthostatic hypotension, impotence, failure to

ejaculate ejaculate

( ( ALPHA ADRENORECEPTOR BLOCKADEALPHA ADRENORECEPTOR BLOCKADE))

ADVERSE EFFECTSADVERSE EFFECTSD. METABOLIC & ENDOCRINE D. METABOLIC & ENDOCRINE

EFFECTSEFFECTS Weight gain, hyperglycemia, Weight gain, hyperglycemia,

hyperprolactinemia, amenorrhea-galactorrhea hyperprolactinemia, amenorrhea-galactorrhea syndrome, infertility, impotence in malessyndrome, infertility, impotence in males

E. TOXIC OR ALLERGIC REACTIONSE. TOXIC OR ALLERGIC REACTIONS Agranulocytosis (clozapine) , cholestatic Agranulocytosis (clozapine) , cholestatic

jaundice, jaundice, skin eruptionsskin eruptions

F. CARDIAC TOXICITYF. CARDIAC TOXICITY Ventricular arrythmias (thioridazine)Ventricular arrythmias (thioridazine)

G. OCULAR COMPLICATIONSG. OCULAR COMPLICATIONS: : “ “ browning of vision”browning of vision”

ANTI-MANIC AGENTSANTI-MANIC AGENTS MANIAMANIA-- -- STATE OF ELEVATED STATE OF ELEVATED

MOOD & PSYCHOMOTOR MOOD & PSYCHOMOTOR ACCELERATION,ACCELERATION,

WITH EXCESS CATHECHOLAMINES WITH EXCESS CATHECHOLAMINES ACTIVITYACTIVITY

TREATMENTTREATMENT: : LITHIUM CARBONATELITHIUM CARBONATE

CATHECOLAMINE RELEASE FROM CATHECOLAMINE RELEASE FROM ADRENERGIC NERVE TERMINALS ADRENERGIC NERVE TERMINALS

LITHIUMLITHIUM

INDICATIONS:INDICATIONS:

BIPOLAR DISORDERS BIPOLAR DISORDERS

THYROTOXICOSISTHYROTOXICOSIS

INAPPROPRIATE ADH SECRETIONINAPPROPRIATE ADH SECRETION

LITHIUM LITHIUM PHARMACOKINETICSPHARMACOKINETICS

ABSORPTIONABSORPTION : virtually complete : virtually complete within 6 -8 hrs; peak plasma levels in within 6 -8 hrs; peak plasma levels in 30 min to 2 hrs30 min to 2 hrs

DISTRIBUTIONDISTRIBUTION: in total body water; : in total body water; slow entry into intracellular slow entry into intracellular compartment. No protein bindingcompartment. No protein 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 LITHIUM PHARMACODYNAMICSPHARMACODYNAMICS EFFECTS ON ELECTROLYTES & IONSEFFECTS ON ELECTROLYTES & IONS

TRANSPORTTRANSPORT: : Substitute for sodium in generating action Substitute for sodium in generating action

potentialspotentials EFFECTS ON NEUROTRANSMITTERSEFFECTS ON NEUROTRANSMITTERS Enhance effects of serotonin?Enhance effects of serotonin? Decrease norepinephrine & dopamine Decrease norepinephrine & dopamine

turnoverturnover Block dopamine receptor supersensitivityBlock dopamine receptor supersensitivity Augment synthesis of acetylcholine?Augment synthesis of acetylcholine? EFFECTS ON SECOND MESSENGERSEFFECTS ON SECOND MESSENGERS effect on effect on Inositol 1,4,5 triphospateInositol 1,4,5 triphospate (IP3 )/ (IP3 )/ DiacylglycerolDiacylglycerol (DAG)-needed in alpha a (DAG)-needed in alpha a

andmuscarinic transmissionandmuscarinic transmission

LithiumLithium inhibits several important inhibits several important enzymes in the normal recycling of enzymes in the normal recycling of membrane phosphoinositides.membrane phosphoinositides.

(-) (-) IP2----IP1IP2----IP1

(-) (-) IP1----inositolIP1----inositol

It will lead to a depletion of It will lead to a depletion of PIP2(phosphotidylinositol-4,5-bis-PIP2(phosphotidylinositol-4,5-bis-phosphate) phosphate) which is the membrane which is the membrane precursor of precursor of IP3 and DAGIP3 and DAG

LITHIUMLITHIUM could cause a could cause a selective depression of the selective depression of the overactive circuits.overactive circuits.

LITHIUM ADVERSE LITHIUM ADVERSE EFFECTSEFFECTS

1.1. CNS EFFECTS: CNS EFFECTS: dizziness, mild ataxiadizziness, mild ataxia

2.2. NEUROMUSCULAR EFECTS: NEUROMUSCULAR EFECTS: fine tremorsfine tremors3.3. CVS EFFECTS: CVS EFFECTS: ventricular arrythmiasventricular arrythmias4.4. GIT EFFECTS: GIT EFFECTS: nausea, vomiting, diarrheanausea, vomiting, diarrhea5.5. GUT EFFECTS: GUT EFFECTS: polyuriapolyuria6.6. ENDOCRINE EFFECTS: ENDOCRINE EFFECTS: hypothyroidismhypothyroidism7.7. ALLERGIC REACTION: ALLERGIC REACTION: pruritus, rashpruritus, rash8.8. OVERDOSE TOXICITY: OVERDOSE TOXICITY: vomiting, vomiting,

drowsiness, decrease consciousness and drowsiness, decrease consciousness and seizuresseizures

Rx: Rx: dialysisdialysis

The TWO most common side The TWO most common side effectseffects

UNCOUPLING OF THE UNCOUPLING OF THE VASOPRESSIN and TSH RECEPTORSVASOPRESSIN and TSH RECEPTORS

FROM THEIR G PROTEINSFROM THEIR G PROTEINS

LITHIUM LITHIUM CONTRAINDICATIONSCONTRAINDICATIONS

A. A. MARKED DEHYDRATION OR MARKED DEHYDRATION OR SODIUM DEPLETIONSODIUM DEPLETION

BB. SIGNIFICANT RENAL OR CARDIAC . SIGNIFICANT RENAL OR CARDIAC DISEASESDISEASES

C. C. PREGNANCYPREGNANCY

D. D. RENAL CONCENTRATION ABILITYRENAL CONCENTRATION ABILITY Nephrogenic diabetes insipidus with Nephrogenic diabetes insipidus with

polyuriapolyuria

LITHIUM DRUG LITHIUM DRUG INTERACTIONSINTERACTIONS

A.A. THIAZIDE DIURETICSTHIAZIDE DIURETICS: DECREASE : DECREASE RENAL CLEARANCE OF LITHIUMRENAL CLEARANCE OF LITHIUM

B.B. NSAIDNSAID: DECREASE LITHIUM : DECREASE LITHIUM CLEARANCECLEARANCE

C.C. ANTIPYSCHOTIC AGENTSANTIPYSCHOTIC AGENTS: : INCREASEINCREASE

NEUROTOXICITYNEUROTOXICITY

DEPRESSIONDEPRESSIONII. REACTIVE OR SECONDARY DEPRESSION. REACTIVE OR SECONDARY DEPRESSIONCore Depression Syndrome: depression, Core Depression Syndrome: depression,

anxiety, tension, bodily complaints, guilt anxiety, tension, bodily complaints, guilt (> 60%)(> 60%)

IIII. ENDOGENOUS DEPRESSION. ENDOGENOUS DEPRESSIONCore Depression Syndrome plus ABNORMAL Core Depression Syndrome plus ABNORMAL

vital signs rhythm of sleep, motor activity, vital signs rhythm of sleep, motor activity, libido, decrease appetite ( 25%) libido, decrease appetite ( 25%)

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

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

Pathogenesis of Major Pathogenesis of Major DepressionDepression

DECREASED FUNCTIONAL DECREASED FUNCTIONAL AMINE-DEPENDENT AMINE-DEPENDENT

SYNAPTIC TRANSMISSIONSYNAPTIC TRANSMISSION

ANTI-DEPRESSANTSANTI-DEPRESSANTSAA.TRICYCLIC ANTI-DEPRESSANTS(TCA).TRICYCLIC ANTI-DEPRESSANTS(TCA) THREE-RING NUCLEUS-THREE-RING NUCLEUS- (anti-muscarinic, anti-H and @(-)adrenergic)(anti-muscarinic, anti-H and @(-)adrenergic)

IMIPRAMINE. AMITRYPTYLINEIMIPRAMINE. AMITRYPTYLINE ((mixedNorE and serotonin uptake inhibitorsmixedNorE and serotonin uptake inhibitors)) DOXAPIN, NORTRIPTYLINE , DESIPRAMINE, DOXAPIN, NORTRIPTYLINE , DESIPRAMINE,

CLOMIPRAMINE , PROTRIPTYLINE, CLOMIPRAMINE , PROTRIPTYLINE, TRIMIPRAMINETRIMIPRAMINE

Note: toxicity due alpha adrenergic blocking Note: toxicity due alpha adrenergic blocking activityactivity

BB. . HETEROCYCLIC: SECOND & THIRDHETEROCYCLIC: SECOND & THIRD GENERATIONSGENERATIONS

1. 1. SECOND GENERATIONSSECOND GENERATIONSAMOXAPINE (AMOXAPINE (dopamine receptor antagonistdopamine receptor antagonist) ) MAPROTILINEMAPROTILINETRAZODON, BUPROPIONTRAZODON, BUPROPION

2. 2. THIRD GENERATIONSTHIRD GENERATIONSMIRTAZAPINE, VENLAFAZINE,NEFAZODONEMIRTAZAPINE, VENLAFAZINE,NEFAZODONE

ANTI-DEPRESSANTSANTI-DEPRESSANTSC. C. SELECTIVE SEROTONIN REUPTAKE SELECTIVE SEROTONIN REUPTAKE

INHIBITORSINHIBITORS (SSRI) (SSRI) FLUOXETINEFLUOXETINE PAROXETINEPAROXETINE SERTRALINE, CITALOPRAM, FLUVOXAMINESERTRALINE, CITALOPRAM, FLUVOXAMINE

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

PHENELZINE, TRANYLCYPROMINEPHENELZINE, TRANYLCYPROMINE MOCLOBEMIDE ,SELEGILINEMOCLOBEMIDE ,SELEGILINE NOTE: NOTE: MAO-AMAO-A—amine oxidase responsible for —amine oxidase responsible for

NORe, serotonin and tyramineNORe, serotonin and tyramine

MAO-BMAO-B---selective for ---selective for dopamine(dopamine(SELEGILINESELEGILINE))

ANTI-DEPRESSANTS ANTI-DEPRESSANTS PHARMACODYNAMICSPHARMACODYNAMICS

A.A. ACTION OF ANTIDEPRESSANTS ON ACTION OF ANTIDEPRESSANTS ON BIOGENIC AMINE NEUROTRANSMITTERSBIOGENIC AMINE NEUROTRANSMITTERS

TCATCA(-) NorE and serotonin reuptake pump(-) NorE and serotonin reuptake pump

“ “OFF-SWITCHES” of the amine transmissionOFF-SWITCHES” of the amine transmissionMAO inhibitors MAO inhibitors (-) major degradation pathway (-) major degradation pathway

resultingresulting

to accumulation of amines in presynaptic stores for to accumulation of amines in presynaptic stores for the amino neurotransmitters and increase releasethe amino neurotransmitters and increase release

Trazodone,Nefazodone and MirtazepineTrazodone,Nefazodone and Mirtazepine(-) 5HT2a (-) 5HT2a or 5HT2cor 5HT2c

MirtazepineMirtazepine (-) alpha 2 NorE receptors (-) alpha 2 NorE receptors

((Increase therapeutic effectsIncrease therapeutic effects))

BB. . RECEPTOR & POSTRECEPTOR EFFECTSRECEPTOR & POSTRECEPTOR EFFECTS

Increase in neurotransmitter in the synapse Increase in neurotransmitter in the synapse acting on postsynaptic receptor giving acting on postsynaptic receptor giving ultimate effect.ultimate effect.

by decreasing cAMP rather than by decreasing cAMP rather than increase.increase.

and decreasing postsynaptic B and decreasing postsynaptic B adrenoreceptors as clinical improvement adrenoreceptors as clinical improvement is seen.is seen.

CC. . EFFECTS OF SPECIFIC ANTIDEPRESSANTSEFFECTS OF SPECIFIC ANTIDEPRESSANTS

PHARMACOKINETICSPHARMACOKINETICS A. A. TRICYCLICSTRICYCLICS Incompletely reabsorbedIncompletely reabsorbed First pass metabolismFirst pass metabolism Large volume of distributionLarge volume of distribution Metabolized due Metabolized due to transformation of to transformation of

tricyclic nucleus and alteration of the tricyclic nucleus and alteration of the aliphatic side chainaliphatic side chain

( ( hydroxylation and conjugation and hydroxylation and conjugation and demethylationdemethylation))

B. B. HETEROCYCLICSHETEROCYCLICS Variable bioavailabilityVariable bioavailability High protein bindingHigh protein binding Variable and large volume of distributionVariable and large volume of distribution Active metabolitesActive metabolites

PHARMACOKINETICSPHARMACOKINETICS

C. C. SSRISSRI : FLUOXETINE : FLUOXETINE Well absorbedWell absorbed PPC: 4 – 8 hrsPPC: 4 – 8 hrs Inhibits drug metabolizing enzymesInhibits drug metabolizing enzymes

D. D. MAOIMAOI Readily absorbedReadily absorbed

CLINICAL INDICATIONSCLINICAL INDICATIONSA.A. DEPRESSIONDEPRESSIONB.B. PANIC DISORDER (PANIC DISORDER (ImipramineImipramine))C.C. OBSESSIVE COMPULSIVE(OBSESSIVE COMPULSIVE(SSRI-SSRI-

FluoxetineFluoxetine))D.D. ENURESIS (ENURESIS (TCATCA))E.E. CHRONIC PAIN (CHRONIC PAIN (TCA,PhenothiazineTCA,Phenothiazine))F.F. OTHERS: Eating Disorder (Bulemia)(OTHERS: Eating Disorder (Bulemia)(SSRISSRI))Cataplexy associated with narcolepsy, school Cataplexy associated with narcolepsy, school

phobia, attention deficit syndromephobia, attention deficit syndromeNOTE: Serotonin Syndrome-NOTE: Serotonin Syndrome-

hyperthermia,muscle rigidity and hyperthermia,muscle rigidity and myoclonusmyoclonus

ADVERSE EFFECTSADVERSE EFFECTS TRICYCLICSTRICYCLICS

SedationSedation:: sleepinesssleepinessSympathomimeticSympathomimetic: : tremors, insomniatremors, insomniaAnti-muscarinicAnti-muscarinic: : blurred vision, blurred vision,

constipation confusion, urinary constipation confusion, urinary incontinenceincontinence

PsychiatricPsychiatric: : psychoses aggravatedpsychoses aggravatedCVSCVS: : orthostatic hypotensionorthostatic hypotensionNeurologicNeurologic: : SeizuresSeizuresMetabolic-EndocrineMetabolic-Endocrine: : weight gain, sexual weight gain, sexual

disturbancedisturbance

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 BEANS CHEESECHEESE CHICKEN LIVERCHICKEN LIVER SAUSAGESSAUSAGES RED WINERED WINE YEASTYEAST

MAO INHIBITORSMAO INHIBITORS headache, drowsiness, dry mouth, weight headache, drowsiness, dry mouth, weight

gain, postural hypotension, sexual disturbancegain, postural hypotension, sexual disturbance AMOXAPINAMOXAPIN Tricyclic & anti-psychotic effectsTricyclic & anti-psychotic effects MAPROTILINEMAPROTILINE Tricyclic effectsTricyclic effects TRAZODONE & NEFAZODONETRAZODONE & NEFAZODONE: :

drowsiness, dizziness, insomnia, nausea and drowsiness, dizziness, insomnia, nausea and agitationagitation

BUPROPIONBUPROPION dizziness, dry mouth, tremordizziness, dry mouth, tremor FLUOXETINEFLUOXETINE Anxiety, insomnia, tremors, decrease libido, Anxiety, insomnia, tremors, decrease libido,

GIT effectsGIT effects

OVERDOSE TOXICITYOVERDOSE TOXICITYComa with shock, metabolic acidosis, respiratory Coma with shock, metabolic acidosis, respiratory

depression, sudden apnea, agitation, deliriumdepression, sudden apnea, agitation, delirium

Hypertensive crisisHypertensive crisis

Cardiac conduction defects such as arrhythmiasCardiac conduction defects such as arrhythmias

DRUG INTERACTIONSDRUG INTERACTIONS

MAO Inhibitors and sympathomimetics and MAO Inhibitors and sympathomimetics and opiatesopiates

Anti-hypertensive drugs—exaggerated Anti-hypertensive drugs—exaggerated hypotensionhypotension

TCA—increase concentration with cimetidine and TCA—increase concentration with cimetidine and phenothiazinesphenothiazines

DRUGS WITH SPECIAL DRUGS WITH SPECIAL IMPORTANCEIMPORTANCE

DesipramineDesipramine—less sedating, low anti-—less sedating, low anti-muscarinic effectsmuscarinic effects

AmitryptylineAmitryptyline-more sedating and -more sedating and marked anti-muscarinic effectsmarked anti-muscarinic effects

MaprotilineMaprotiline-seizures-seizuresTrazodoneTrazodone—prolonged penile erection—prolonged penile erectionFluoxetineFluoxetine—minimal sedative effects, —minimal sedative effects,

very low anti-muscarinic effectsvery low anti-muscarinic effectsNefazodoneNefazodone-less sedating, no SSRI-less sedating, no SSRI

Drugs that Interact with Drugs that Interact with MAOIMAOI

A. A. INDIRECTLY ACTINGINDIRECTLY ACTING SYMPATHOMIMETICS:SYMPATHOMIMETICS: amphetamines, amphetamines, ephedrine, metaraminol, ephedrine, metaraminol, phenylpropanolaminephenylpropanolamine

BB. . OTHER ADRENORECEPTOR AGENTS & OTHER ADRENORECEPTOR AGENTS & RELATED AGENTSRELATED AGENTS: levodopa, methyldopa, : levodopa, methyldopa, guanethidine, reserpineguanethidine, reserpine

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

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

Who is wise and understanding Who is wise and understanding among you? Let him show it among you? Let him show it

by his good life, by deeds by his good life, by deeds done in humility that comes done in humility that comes

from wisdom.from wisdom.

James 3: 13James 3: 13