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Psychotropics

G. Patrick Daubert, MD

Some (most) material plundered from various mentors and other talentedtoxicologists, with permission

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MENU

n 2.1.11.9 Psychotropicsn 2.1.11.9.1 Anxiolytics and sedative-hypnoticsn 2.1.11.9.2 Antidepressantsn 2.1.11.9.3 Antipsychoticsn 2.1.11.9.4 Mood stabilizers

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Anxiolytics and Sedative-hypnotics

n Benzodiazepinesn Barbituratesn Sedative-Hypnotics

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Benzodiazepines

“There are very few toxicological problems thatcannot be solved through the suitable (and liberal)

application of benzodiazepines” Suzanne White, MD

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Benzodiazepines

n Roughly 50,000 benzodiazepine OD casesreported annually

n 65% intentionaln Few deathsn Most are combination exposuresn Mixed drug overdose or IV administration =

increased morbidity

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Benzodiazepines

n About 15 types marketed in the USn 50 types worldwiden Vary in half-life and metabolism

n All rapidly absorbedn CNS redistribution variesn Half-life � duration of actionn Conjugation only

n Oxazepam, lorazepam, temazepamn IM administration

n Lorazepam, midazolam

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Benzodiazepines

n All are indirect agonists at post-synaptic GABA-Achannelsn Can’t open the channel without GABAn BZD1 receptorsn Increase frequency of Cl channel opening

n BZD2 receptors (spinal cord) affect muscle relaxationn All produce tolerance with cross-reactivityn Predispose to physical dependence

n BZD2 receptorsn Withdrawal : worse for short half-life agents

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Benzodiazepine Overdose

n Nonspecificn CNS: drowsiness, dizziness, slurred speech,

nystagmus, confusion, ataxia, coma (rare)n Children: 17% isolated ataxian Other: respiratory depression, hypotension with IV

administration

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Benzodiazepine Pearls

n Increase frequencyfrequency of Cl channel openingn Propylene glycol: lorazepamn Clonazepam:

n Anticonvulsantn Mood stabilizer

n Flunitrazepam (RoHypnol): “Date Rape”n EMIT: Oxazepam false negatives

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Barbiturates

n GABAAn Direct increase in durationduration of channel openingn GABA not needed

n 4 Categoriesn Ultrashort: methohexital, thiopentaln Short: pentobarbital, secobarbitaln Intermediate: butalbitaln Long-acting: phenobarbital

n Enzyme induction: drug interactions

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Barbiturate Toxicity

n Symptoms similar to other sedativesn More likely to see respiratory depression

n CNS tolerance � Respiratory tolerancen Common

n Nystagmus, dysarthria, ataxia, drowsiness, respiratorydepression, and coma

n Less commonn hypotension, cardiovascular collapse, and hypothermia

n Bullous skin lesions (“barb burns”), noncardiogenicpulmonary edema

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Phenobarbital (PHB)

n Long-acting barbituraten Normal range 15-40 mg/Ln PHB tolerance does not usually involve

respiratory tolerancen Levels > 80 mg/L typically result in coman Death is uncommon with good supportive caren Primidone

n Metabolized to PEMA and PHB

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Treatment

n Supportive caren Passive warmingn Positive barbiturate on urine drugs of abuse screen

n Phenobarbital vs butalbitaln IVF, norepinephrine for hypotensionn Urinary alkalinization

n Stop alkalinization when PHB < 40 mg/Ln MDAC

n Listed on MDAC position statement (The ‘A’ List)n MDAC demonstrates better elimination than urine

alkalinization

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‘Z’ Drugs

n Zolpidem (Ambien,Stilnox)

n Zaleplon (Sonata)n EcZopiclone (Lunesta,

Estorra)n Ramelteon (RoZerem)

n Non-benzodiazepinesedatives

n Selective for GABAA BZ-1receptors

n Less physical dependencen Flumazenil may precipitate

withdrawaln Ramelteon may alter

testosterone and prolactinlevels

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“Z” Drug Overdose

n CNS depression, coman Respiratory depressionn Nausea and vomitingn Hypotensionn Miosis, mydriasisn Hallucinationsn Flumazenil reverses Z agent effect and may precipitate

withdrawaln Same precautions as with benzodiazepines

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Sedative-Hypnotics

n Buspirone (Buspar)n Chloral hydraten Meprobamaten Methaqualonen Glutethimiden Ethchlorvinyl

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Chloral Hydrate

n Commonly used by alcoholics in the late 19th centuryto induce sleep

n Solutions of alcohol and chloral hydrate often called“knockout drops” or “Mickey Finn”

n Sedation with minimal respiratory depression andhypotension

n Used recreationally only by a small number of peoplen Common trade names are Noctec, Somnos and

Felsules

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Pharmacology

n Trichlorocetic acidn Highly protein boundn May displace acidic drugs from plasma protein

n Trichloroethanol exerts barbiturate-like effects on theGABAA receptor channels

n Trichloroethanol inhibits ethanol metabolism

Chloral Hydrate

TrichloroaceticAcidTrichloroethanol

ADH P450

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Clinical Highlights

n Hemorrhagic gastritisn Cardiac arrhythmias

n Attributed largely to trichloroethanoln Myocardium sensitized to circulating catecholamines

n Radioopaque

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Sedative-Hypnotic Pearls

n Meprobamate (Miltown, Equanil, Meprospan)n Active metabolite of carisoprodoln Concretions/bezoars in overdose

n Glutethimide (Doriden)n 2D6 inducer – codeine abusen “Doors and Fours” with Tylenol#4

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Sedative-Hypnotic Pearls

n Ethchlorvynol (Placidyl)n “Jelly-bellies”n Used by William Rehnquist (oversedation then

withdrawal)n Methaqualone

n Quaaludes, Mandraxn Recent abuse in South African Can see hyperreflexia, clonusn Residual paresthesias and polyneuropathies after

overdose

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Antidepressants

n Cyclic antidepressantsn Monoamine oxidase inhibitors (MAOIs)n Serotonin reuptake inhibitorsn Miscellaneous

n Buproprionn Citalopram/Escitalopramn Mirtazapinen Trazadonen Venlafaxine

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Usual Suspects

n Tertiary aminesn Amitriptylinen Clomipraminen Doxepinn Imipraminen Trimipramine

n Secondary aminesn Desipraminen Nortriptylinen Protriptyline

n Tetracyclicn Amoxapinen Maprotiline

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TCA Screen Cross Reactivity

n Cyclobenzaprine (Flexeril)n Diphenhydramine (Benadryl)n Cyproheptadine (Periactin)n Carbamazepine (Tegretol)n Thioridazine (Mellaril)n Quetiapine (Seroquel)

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Pharmacokinetics

n Peak serum concentration 1-8 hrsn Antimuscarinic – delayed gastric emptyingn Lipophilic – large Vdn Hepatic phase I: Demethylation

n Imipramine g desipraminen Amitriptyline g nortriptyline

n Hydroxylation: CYP2D6n Slow vs Rapidn Desipramine: 81-131 vs 12-23 hours

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CA Toxicity

n Rapid onset of symptomsn Early sedation and coman Early antimuscarinic symptomsn Cardiovascular

n Hypotensionn Dysrhythmias

“T” =Tremor (seizures)“C” = Cardiovascular“A” = Antimuscarinic

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Cardiovascular Toxicity

n Rapid inward Na+ currentn QRS prolongation

n RBB more susceptible (leads V1, V2, aVR, I)n Rate dependentn pH dependent

n R axis deviation in terminal 40 msecn AV node blocks

n K+ channel blockade (Ikr)n Increased QT but TdP uncommon with tachycardian Seen with therapeutic dosing

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Cyclic Antidepressants Toxicology

n Membrane effectsn Blockade of fast Na+ channels phase 0 of the action

potential

1

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2

3

4

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Axis Change in Toxicity

V1 R

R’

I

aVR Terminal R

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MAOI pharmacology

n Intracellular enzyme found on mitochondrialmembrane

n Degrades biogenic aminesn Increases neurotransmitter activity in CNS,

down-regulates post-synaptic 5HT andadrenergic receptorsn Post-synaptic DA unaffected

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MAOI pharmacology

n Irreversible bindingn Phenylzinen Tranylcyprominen Isocarboxiziden Selegilinen Pargyline

n Reversible bindingn Moclobemiden Brofarominen Cimoxatonen Toloxatonen Harmaline

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MAOI pharmacology

n Selectiven Clorgyline (A)n Moclobemide (A)n Toloxatone (A)n Harmaline (A)n Selegiline (B)n Pargyline (B)

n Nonselectiven Tranylcyprominen Phenylzinen Isocarboxazid

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Signs and Symptoms (Overdose)

n Phase In Latent period: 6-12 hrs in

pts on medicationn 24-36 hrs in “naïve”

patients

n Phase IIn Excitatory phase

n Hyperadrenergic appearingn “Ping-pong” nystagmusn Hyperreflexive with rigidityn Writhing, opisthotonus, facial

grimacing

n Progressionn CNS depressionn Fever, diaphoresis, salivationn Rigidty, myoclonus, carpopedal

spasmn Myocardial ischemia, ICH,

seizures

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Treatment

n Expect prolonged period of toxicityn ICU for 24 hrs after resolution of signs and

symptomsn Restricted diet for 2-3 weeksn Check ALL medications for interactionsn Treat as signs and symptoms appear

n Use SHORT acting agentsn Use DIRECT acting agents-COMT metabolism

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MAO-Tyramine reaction

n Not an overdosen Onset within 2 hrs after eatingn Ingested tyramine normally inactivated by gut MAO-An Inhibition of gut MAO-A: absorption of dietary

tyramine and byproductsn Tyramine releases NE formed by inhibition of neuronal

MAO-An Hyperadrenergic staten Treat symptomatically

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Serotonin Reuptake Inhibitors

n Paroxetine (Paxil)n Fluoxetine (Prozac, Sarafem)n Citalopram (Celexa) n Escitalopram (Lexapro) n Sertraline (Zoloft)n Fluvoxamine (Luvox)n Fluoxetine + olanzepine (Symbyax)

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Pearls

n SSRI in overdose: CNS depression andtachycardia most common

n Citalopram and escitalopram: reports of seizuresand widened QT interval

n Fluvoxamine inhibits CYP1A and CYP2Cn Paroxetine, fluoxetine, and metabolites strong

inhibitors of CYP2D6

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SSNRI and Others

n Buproprionn Excitation in overdose, SEIZURES, XL products

n Mirtazepine (Remeron)n Sedation, mild symptoms in toxicity

n Nefazadone (Serzone), Trazadone (Desyrel)n Prolonged QT, orthostatic hypotension, priapism

n Venlafaxine (Effexor, aka side-effectsor)n Seizures, QRS prolongation

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Serotonin Syndrome

n Stimulation of post-synaptic 5HT1A and5HT2 brain receptors

n Mechanismn Two or more serotonergic agentsn SSRI + neurolepticn SSRI + agent with serotonergic propertiesn Change in dosen Metabolic inhibition

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Serotonin Syndrome

n Modified Sternbach criteria: A, B, C must be met:n A. Syndrome occurs after addition of known serotonergic

agentn B. List of symptoms to be met (at least 3) and other causes

ruled outn C. No neuroleptic involved

n NEJM M. Shannon articlen Hyperthermian Mental status changesn Autonomic instabilityn CLONUS

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Serotonin Syndrome-Treatment

n Good supportive caren Benzodiazepinesn External coolingn Paralysis with a nondepolarizing agentn Specific agents

n Cyproheptadine: nonspecific 5HT1-2 antagonist (4-8 mg q1h)n NTG: nitric acid mediated downregulation of 5HT (drip

titrated to effect)n Propranolol: 5HT1A antagonism (1-5 mg IV)n Chlorpromazine: 5HT2 antagonist

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SS vs NMS

++++

++++

++++

++++--

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Days

GradualNMS

+++Autonomic dysfunction

++Altered mental status

++Muscle rigidity

+/-Metabolic acidosis

++Hyperreflexia

++Myoclonus

< 24 hourResolution

RapidOnset

SSSigns/Symptoms

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Neonatal SSRI Withdrawal

n Fetus exposed to an SRI late in the third trimestern Symptoms

n Respiratory distress (apnea)n Cyanosis, apnean Feeding difficultiesn Vomitingn Hypoglycemian Tremors, jitteriness, irritability

n Onset hours to days after delivery, which resolved indays or weeks

n Prolonged hospitalization, respiratory support, and tubefeeding

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Question

Acute overdose of selective serotonin reuptakeinhibitor (SSRI) antidepressant medicationsmost often result in

A. Cardiac dysrhythmiasB. CNS depression and tachycardiaC. Hallucinations and deliriumD. Profound hyperthermia and rigidityE. Seizures

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Question

Acute overdose of selective serotonin reuptakeinhibitor (SSRI) antidepressant medicationsmost often result in

A. Cardiac dysrhythmiasB. CNS depression and tachycardiaC. Hallucinations and deliriumD. Profound hyperthermia and rigidityE. Seizures

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Antipsychotics

n Traditional antipsychoticsn D2 antagonists

n Atypicaln Selective for limbic vs EP sitesn Mixed DA receptor affinities (D1,D2 etc)n Looser binding to D2, less EPSn Mixed affinity for DA, 5HT, alpha

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Antipsychotic Classification

n Low potency (sedating, antimuscarinic, miosis)n Chlorpromazine (most sedating in overdose)n Chlorprothixenen Mesoridazinen Thioridazine (most cardiotoxic in overdose)

n Medium potencyn Droperidoln Loxapine (more seizures in overdose)n Molindonen Perphenazine

n High potency (more EPS, less sedation)n Fluphenazinen Haloperidol (most common cause of NMS)n Trifluoperazinen Thiothixene

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Reversible EPS: Acute Dystonia

n Facial grimacingn Trismusn Blepharospasmn Oculogyric crisis

n Tongue protrusionn Torticollisn Opisthotonisn Abnormal posture, gait

n Intermittent spasmodic and involuntary contractions offace, neck, trunk

n Idiosyncraticn Males 5-45 yearsn Depot prepsn Resolves during sleep

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Reversible EPS

n Akathesian Subjective uneasen Motor restlessnessn Dose relatedn Womenn High potency

n Parkinsonismn Muscle rigidityn Bradykinesian Tremorn Elderly womenn High potency

n Dopamine-cholinergic basal ganglia balance disruptedn Excess choline with dopamine depletion

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Irreversible EPS: Tardive Dyskinesia

n Involuntary movements of orofacial structuresn Lip smackingn Facial grimacingn Eye blinkingn Grunting

n Late onset > 2 years after therapy onsetn More common in women > 50 years

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Antipsychotic Pearls

n Thioridazinen Peak serum level can be delayed 120 hoursn QTc but not QRS correlates closely with peak concentrationn Most lethal in overdose

n Most common cause of NMS (> 90%)n Haloperidol

n Agranulocytosisn Chlorpromazine (Thorazine)

n Cholestatic jaundicen Chlorpromazine (Thorazine)

n Acute reversible oligurian Chlorprothixene (Taractan)

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Atypical Antipsychotics

n Aripiprazole (Abilify)n Longest potential e-half-life in overdose (146 hrs)

n Clozapine (Clozaril)n Aplastic anemia, seizures, drug-induced DM, myocarditis,

fevern Olanzapine (Zyprexa)

n Highest incidence of NMSn Highest antimuscarinic activity but salivation commonn Drug-induced DMn Classically resembles opiate toxidrome

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Atypical Antipsychotics

n Paliperidone (Invega)n Active metabolite of risperidone

n Risperidone (Risperdal)n Highest rate of dystonian Most reported seizuresn Potent alpha blockaden No antimuscarinic effects; miosisn Unusual dysrhythmias for class (aflutter, heart blocks)

n Ziprasidone (Geodon)n Highest rate of increased QTn Miosis common

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Quetiapine Pearls

n CNS depression, prolonged QT, tachycardian 3 grams predicted ICU/prolonged LOSn Cross reacts with TCA assayn Most sedating of class

n Highest antihistamine activityn High alpha blockaden Less miosisn Half-life longer in overdose

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New! Improved!

n Asenapinen Hypotensionn Agitation, alteredn QT?

n Iloperidonen Hypotension, antimuscarinicn QT prolongation

n Lurasidonen Hypotension, confusion, leukopenia

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Mood Stabilizing Lithium

n Main therapy for bipolar disordern Narrow therapeutic index (0.6-1.2 mEq/L)n Slow distribution across cell membranes

n Delay between peak blood levels and CNS effectsn Most cases chronic due to a reduction in GFR

n Volume lossn NSAIDs, diuretics, ACE inhibitorsn Age

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Acute vs Chronic Lithium

n Increased intaken Delayed toxicity due to

delayed distributionn High serum levels initially do

not correlate with toxicityn GI symptoms more severen Tremor, muscle weakness,

ataxia, hyperreflexia

n Decreased excretionn Serum levels lower since

inracellular levels highn Subacute/nonspecific

neurologic symptomsn GI symptoms less severen Encephalopathy, myoclonus,

severe rigidity, seizuresn ECG

n Bradycardian T-wave flattening/inversionn QT prolongation

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Lithium Management

n D/C lithium and offending drugsn Improve GFR

n 20% reduction in Li over 6 hoursn Hemodialysis (guidelines vary)

n Renal failuren Encephalopathy, myoclonus, severe rigidity, seizuresn Acute > 4.0 mEq/L?n Chronic > 2.5 mEq/L?

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Question

A 23-year-old woman is taking ziprasidone for herschizoaffective disorder. Her ECG reveals a QRS 86msec, and QTc 560 msec. Her physician wants toknow what medication you would recommend inplace of her ziprasidone?

A. Chlorpromazine (Thorazine)B. Haloperidol (Haldol)C. Olanzapine (Zyprexa)D. Quetiapine (Seroquel)E. hioridazine (Mellaril)

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Question

A 23-year-old woman is taking ziprasidone for herschizoaffective disorder. Her ECG reveals a QRS 86msec, and QTc 560 msec. Her physician wants toknow what medication you would recommend inplace of her ziprasidone?

A. Chlorpromazine (Thorazine)B. Haloperidol (Haldol)C. Olanzapine (Zyprexa)D. Quetiapine (Seroquel)E. hioridazine (Mellaril)

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Questions?

Good Luck!!