toxicology: antidepressants & antipsychotics

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TOXICOLOGY: ANTIDEPRESSANTS & ANTIPSYCHOTICS. May 26, 2011 Jason Mitchell Joe McLellan Phil Ukrainetz. INTRODUCTION. 18 yo F 1/52 Fever, otalgia, chills, myalgia, arthralgia Tooth extraction 2/52 ago Meds: Percodan (ASA/Oxycodone) Chlorphenamine Erythromycin - PowerPoint PPT Presentation

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TOXICOLOGY: ANTIDEPRESSANTS & ANTIPSYCHOTICS

TOXICOLOGY: ANTIDEPRESSANTS &ANTIPSYCHOTICSMay 26, 2011Jason MitchellJoe McLellanPhil UkrainetzINTRODUCTION18 yo F1/52 Fever, otalgia, chills, myalgia, arthralgiaTooth extraction 2/52 agoMeds: Percodan (ASA/Oxycodone) Chlorphenamine Erythromycin Something for stressFrequent marijuana, denies cocaine or other rec drugs

2INTRODUCTIONO/E: 39.7oC, 120, 110/75 supine 95/60 standing, 20, 4.7

CNS: Appears distressed Intermittent writhing/agitation/confusion ?volitionalStrange jerking movements and shivering notedHyper-reflexic, nystagmus

HEENT: Hyperemic R TM

CV: II/VI LLSB diastolic murmur

Resp: Clear to bases

Integument: Petechial rash to R thigh

3INTRODUCTIONIx:

CBC/Lytes: WBC 18

CXR: Normal

ECG: Sinus tach

INTRODUCTIONDx: Tentative diagnosis of viral syndrome NYD with hysterical symptomsAdmitted to hospital, routine vitalsAgitation persists25mg Demerol IM Rx for agitation and shivering

Two hours later5INTRODUCTIONAgitation and confusion worsensPt thrashing in bed, ripped out IVsHypertense, tachycardic, ongoing feverResident notified by telephonePhysical restraints1 mg haloperidol1 hour later6Agitation initially resolves, but shortly returnsAxillary temp. 420C Cold compresses and cooling blanket appliedProgresses to respiratory arrest and unable to resuscitatePt dies 7 hours after presentation to hospital2-3 hours later

Think about this case as we discuss antidepressants and antipsychotics7ANTIDEPRESSANTSMultiple ClassesSSRIs (Citalopram, Fluoxatine, Fluvoxamine, Paroxetine, Sertraline)MAOIs (Isocarboxacid, Phenelzine, Moclobemide)TCAs (Amitriptyline, Clomipramine, Imipramine, Desipramine)SNRIs (Desvenlafaxine, Venlafaxine, Duloxetine)NaSSAs (Mirtazapine)NRIs (Strattera)NDRIs (Bupropion)SSREs (Tianeptine)NDDIs (Agomelatine)NaSSAs Noradrenergic and specific serotenergic antidepressantsNDRI Norepinephrine-dopamine reuptake inhibitorsSSRE Selective serotonin reuptake enhancerNDDI Norepinephrine-dopamine disinhibitors8ANTIDEPRESSANTSMultiple ClassesSSRIs (Citalopram, Fluoxatine, Fluvoxamine, Paroxetine, Sertraline)MAOIs (Isocarboxacid, Phenelzine, Moclobemide)TCAs (Amitriptyline, Clomipramine, Imipramine, Desipramine)SNRIs (Desvenlafaxine, Venlafaxine, Duloxetine)NaSSAs (Mirtazapine)NRIs (Strattera)NDRIs (Bupropion)SSREs (Tianeptine)NDDIs (Agomelatine)NaSSAs Noradrenergic and specific serotenergic antidepressantsNDRI Norepinephrine-dopamine reuptake inhibitorsSSRE Selective serotonin reuptake enhancerNDDI Norepinephrine-dopamine disinhibitors9ANTIDEPRESSANTSPHYSIOLOGY

Mechanism of depression incompletely understood

Proposed consequence of low [monoamines]:serotonin (5-HT), norepinephrine (NE), dopamine (DA)

Monoamine hypothesis10ANTIDEPRESSANTSPHYSIOLOGYSSRI:Prevents 5-HTreuptakeMAOI:Prevents 5-HTdeaminationIncreasessynaptic [5-HT]

SSRI Varying degree of pure selectivity of serotonin. Pure SSRIs have weak affinity for NE and DA transporters

MOAI Inhibit MOA which otherwise degrades monoamine transmitters. There are two isoforms: MOA-A and B. MOA-A preferentially degrades 5-HT, NE, and epinephrine. MOA-B preferentially degrades phenethylamine. Both degrade dopamine and tyramine. The degree of isoform inhibition with MAOIs varies with each agent (ie selegiline and rasagiline are delective MAO-Bi in low doses)

COMT Catechol-O-Methyltransferase: degrades dopamine, norepinephrine, and epinephrine11MAOIsPHARMACODYNAMICSPeak plasma concentrations 0.5-2.5 hours

Hepatic metabolism

Minimal urinary excretion

MAOIsTOXICITYMAOI Overdose

MAOI-food/beverage interactions

MAOI-drug interactions13MAOIsTOXICITYMAOI Overdose

ExcessiveMAOI-food/beverage interactions SympatheticActivity

MAOI-drug interactionsMAOIsMAOI OVERDOSEFour phasesAsymptomatic/Latent

CV/CNS excitation with sympathetic hyperactivity

CNS depression and CV collapse

Secondary complicationsOnset of signs and symptoms of acute overdose occurs in 6-24 hours post ingestion and may last for days. Lethal dose 2mg/kg

Clinical manifestations of CNS excitability include headache, agitation (67%), mydriasis (58%), rigidity (58%), hyperthermia (50%), hyperreflexia (33%), nystagmus (33%), seizures (17%)

Clinical manifestations of CV toxicity includes sinus tachycardia (67%), hyper/hypotension (17%).

Severe OD progresses to hypotension, bradycardia, dysrrhythmias, marked hyperthermia, obtundation, DIC, multi-organ failure

Secondary complications include hypoxic brain injury, rhabdomyolysis/hyperkalemia, renal failure, MI, ICH, ARDS15MAOIsMAOI-FOOD/BEVERAGE INTERACTIONSFoods high in tyramine

Tyramine leads to catecholamine release

May potentiate hypertensive crisisTyramine is usually degraded by MAO in the gastrointestinal mucosa or hepatic MAO. Blocked MOA increased [tyramine] which may cause significant catecholamine release16MAOIsMAOI-FOOD/BEVERAGE INTERACTIONSFOODBEVERAGEAged/Fermented MeatsAlesAged CheeseBeersBeansWinesSauerkrautSherryYeastVermouthChocolateFigsRaisinsBananasMAOIsMOAI-DRUG INTERACTIONSOccur minutes to hours after co-ingestion

May cause sympathetic storm/serotonin syndromeProduction of excessive concentrations of monoamines

Examples:SSRIsTCAsSympathomimeticsOpiatesLithiumNon-exhaustive list! Numerous medications have potential MAOI interactions ALWAYS check for interactions before introducing a new drug to a patient on an MAOI18MAOIsMANAGEMENTRecall ABCDEFs of toxicology

ABCs primarily supportiveSinus tachycardia does not usually require treatment Blockers and CCBs relatively contraindicatedHypertensionNitroprusside 0.3 mcg/kg/min titrated to effect (max 10 mcg/kg/min)Nitroglycerine 20 mcg/min titrate q5min to effectPhentolamine 5 mg bolus q5-10minBeta blockers can cause unopposed alpha worsen vasoconstriciton and hypertensionBeta blockers and CCB can potentiate late hypotension and bradycardia19MAOIsMANAGEMENTABCs primarily supportiveBradycardiaCompensatory response to hypertensionTreat if associated with hypotension

Hypotension IV crystalloidAtropine if associated with bradycardiaVasopressors not contraindicatedAvoid dopamineBenzodiazepines agent of choice to control rigidity, seizures, agitation. May also control help manage hypertension20MAOIsMANAGEMENTDEFsMay consider AC

Forced diuresis, hemoperfusion ineffective

No antidote availableMAOIs have large volumes of distribution and high protein affinity. Hemoperfusion ineffective

Very little native drug excreted in urine. Forced diuresis ineffective21MAOIsDISPOSITIONOnset of symptoms may be delayed

Recommended 24 hour observation for asymptomatic pts with MAOI overdose

Recommended 6 hour observation for food interaction

ICU/MTU admit depending on symptom severity SSRIsPHARMACODYNAMICSPeak plasma concentration: 3 10 hours

Liver metabolism: Elimination half-life 15hours 4days

Small amount of urinary excretion

23SSRIsTOXICITYNot as pronounced as TCA toxicity

High ingested dosages required

Toxic SpectrumMild serotonin-related symptomsSerotonin syndromeToxic statesRadomski JW, Dursun SM, Reveley MA, Kutcher SP. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria Pages 218-224Serotonin syndrome and toxic states differentiated by degree of illness and disease-related complications (ie rhabdo, renal failure, DIC)24SSRIsTOXICITY

Typically affect GI, CV, and CNS organ systems

25SSRIsGI TOXICITYAbdominal cramps

Nausea

Vomiting

Diarrhea

Salivation

26SSRIsCV TOXICITIYCutaneous flushing

Hypertension/Hypotension

Tachycardia/Bradycardia

QT Prolongation (rare)Fluoxetine, Citalopram

Ventricular tachycardia (rare)

SSRIsCNS TOXICITY (RARE)AgitationAkathisiaAnxietyClonusComaConfusionDeliriumHeadacheHyper-reflexiaHyperthermiaHypomaniaInsomniaManiaMydriasisMyoclonusNystagmusRigiditySeizuresSedation

Extensive list of CNS results of SSRI toxicity28SSRIsCNS and CV TOXICITY

Hoffman RS, Nelson LS, Howland MA, et al. Goldfrank's Manual of Toxicologic Emergencies. McGraw-Hill Companies, 2007.Risk of seizures and QTc prolongation highest with citalopram and its enantiomar, escitalopram. Typical daily dose of citalopram is 20-60mgThese effects reported in doses as low as 400mg.One case series found seizures typically occurred early, but ECG changes manifested as late as 24 hours29SSRIsDIAGNOSISPrimarily clinicalHistory importantSSRI dosage increaseKnown ingestionCo-ingestion of drugs that potentiate [synaptic serotonin]Eg Cocaine, DM, amphetamines, MAOIs, TCAs, Carbamazepine, Lithium, SumatriptanUrine/Blood tox screens not usefulUnless coingestion suspected.

SSRIsMANAGEMENT

Recall the ABCDEFs of toxicology

SSRI overdose is generally mild and rarely life-threatening

Treatment is largely supportive

31SSRIsMANAGEMENTABCs Mainly supportiveHypertension Not usually indicatedConsider sodium nitroprussideHypotensionIV crystalloid +/- norepinephrine or dopamineVTach/BradycardiaAs per ACLS algorithmsNeurologic complications treated with benzodiazepines32SSRIsMANAGEMENTDecontamination and EliminationAC may be consideredForced diuresis not indicatedMinimal amounts of SSRI excreted in urineHemodialysis not indicatedLarge volumes of distribution, high protein-bindingFind an AntidoteNo specific antidote exists for SSRIs

SSRIsDISPOSITION6-hour monitoring for asymptomatic patients

Psychiatric consultation if intentional ingestion

Citalopram OD warrants 12-24 hour observationLate pres