Psychotropics G. Patrick Daubert, MD Some (most) material plundered from various mentors and other talented toxicologists, with permission 1 HOWARD n How n Objects/ n Words n Are n Remembered n Daily 2 MENU n 2.1.11.9 Psychotropics n 2.1.11.9.1 Anxiolytics and sedative-hypnotics n 2.1.11.9.2 Antidepressants n 2.1.11.9.3 Antipsychotics n 2.1.11.9.4 Mood stabilizers 3 Anxiolytics and Sedative-hypnotics n Benzodiazepines n Barbiturates n Sedative-Hypnotics 4 Benzodiazepines “There are very few toxicological problems that cannot be solved through the suitable (and liberal) application of benzodiazepines” Suzanne White, MD 5 Benzodiazepines n Roughly 50,000 benzodiazepine OD cases reported annually n 65% intentional n Few deaths n Most are combination exposures n Mixed drug overdose or IV administration = increased morbidity 6 Benzodiazepines n About 15 types marketed in the US n 50 types worldwide n Vary in half-life and metabolism n All rapidly absorbed n CNS redistribution varies n Half-life ≠ duration of action n Conjugation only n Oxazepam, lorazepam, temazepam n IM administration n Lorazepam, midazolam 7 Benzodiazepines n All are indirect agonists at post-synaptic GABA-A channels n Can’t open the channel without GABA n BZD1 receptors n Increase frequency of Cl channel opening n BZD2 receptors (spinal cord) affect muscle relaxation n All produce tolerance with cross-reactivity n Predispose to physical dependence n BZD2 receptors n Withdrawal : worse for short half-life agents 8 Benzodiazepine Overdose n Nonspecific n CNS: drowsiness, dizziness, slurred speech, nystagmus, confusion, ataxia, coma (rare) n Children: 17% isolated ataxia n Other: respiratory depression, hypotension with IV administration 9 Benzodiazepine Pearls n Increase frequency of Cl channel opening n Propylene glycol: lorazepam n Clonazepam: n Anticonvulsant n Mood stabilizer n Flunitrazepam (RoHypnol): “Date Rape” n EMIT: Oxazepam false negatives 10 Barbiturates n GABAA n Direct increase in duration of channel opening n GABA not needed n 4 Categories n Ultrashort: methohexital, thiopental n Short: pentobarbital, secobarbital n Intermediate: butalbital n Long-acting: phenobarbital n Enzyme induction: drug interactions 11 Barbiturate Toxicity n Symptoms similar to other sedatives n More likely to see respiratory depression n CNS tolerance ≠ Respiratory tolerance n Common n Nystagmus, dysarthria, ataxia, drowsiness, respiratory depression, and coma n Less common n hypotension, cardiovascular collapse, and hypothermia n Bullous skin lesions (“barb burns”), noncardiogenic pulmonary edema 12 Phenobarbital (PHB) n Long-acting barbiturate n Normal range 15-40 mg/L n PHB tolerance does not usually involve respiratory tolerance n Levels > 80 mg/L typically result in coma n Death is uncommon with good supportive care n Primidone n Metabolized to PEMA and PHB 13 Treatment n Supportive care n Passive warming n Positive barbiturate on urine drugs of abuse screen n Phenobarbital vs butalbital n IVF, norepinephrine for hypotension n Urinary alkalinization n Stop alkalinization when PHB < 40 mg/L n MDAC n Listed on MDAC position statement (The ‘A’ List) n MDAC demonstrates better elimination than urine alkalinization 14 ‘Z’ Drugs n Zolpidem (Ambien, Stilnox) n Non-benzodiazepine n Zaleplon (Sonata) sedatives n EcZopiclone (Lunesta, n Selective for GABAA BZ-1 Estorra) receptors n Ramelteon (RoZerem) n Less physical dependence n Flumazenil may precipitate withdrawal n Rozerem may alter testosterone and prolactin levels 15 “Z” Drug Overdose n CNS depression, coma n Respiratory depression n Nausea and vomiting n Hypotension n Miosis, mydriasis n Hallucinations n Flumazenil reverses Z agent effect and may precipitate withdrawal n Same precautions as with benzodiazepines 16 Sedative-Hypnotics n Buspirone (Buspar) n Chloral hydrate n Meprobamate n Methaqualone n Glutethimide n Ethchlorvinyl 17 Chloral Hydrate n Commonly used by alcoholics in the late 19th century to induce sleep n Solutions of alcohol and chloral hydrate often called “knockout drops” or “Mickey Finn” n Sedation with minimal respiratory depression and hypotension n Used recreationally only by a small number of people n Common trade names are Noctec, Somnos and Felsules 18 Pharmacology Chloral Hydrate ADH P450 Trichloroacetic Trichloroethanol Acid n Trichlorocetic acid n Highly protein bound n May displace acidic drugs from plasma protein n Trichloroethanol exerts barbiturate-like effects on the GABAA receptor channels n Trichloroethanol inhibits ethanol metabolism 19 Clinical Highlights n Hemorrhagic gastritis n Cardiac arrhythmias n Attributed largely to trichloroethanol n Myocardium sensitized to circulating catecholamines n Radioopaque 20 Sedative-Hypnotic Pearls n Meprobamate (Miltown, Equanil, Meprospan) n Active metabolite of carisoprodol n Concretions/bezoars in overdose n Glutethimide (Doriden) n 2D6 inducer – codeine abuse n “Doors and Fours” with Tylenol#4 21 Sedative-Hypnotic Pearls n Ethchlorvynol (Placidyl) n “Jelly-bellies” n Used by William Rehnquist (oversedation then withdrawal) n Methaqualone n Quaaludes, Mandrax n Recent abuse in South Africa n Can see hyperreflexia, clonus n Residual paresthesias and polyneuropathies after overdose 22 Antidepressants n Cyclic antidepressants n Monoamine oxidase inhibitors (MAOIs) n Serotonin reuptake inhibitors n Miscellaneous/SNRIs n Buproprion n Citalopram/Escitalopram n Duloxetine n Milnacipran n Mirtazapine n Trazadone n Venlafaxine/Desvenlafaxine 23 Cyclic Antidepressants 24 Usual Suspects n Tertiary amines n Secondary amines n Amitriptyline n Desipramine n Clomipramine n Nortriptyline n Doxepin n Protriptyline n Imipramine n Tetracyclic n Trimipramine n Amoxapine n Maprotiline 25 Immunoassay Cross Reactivity n Cyclobenzaprine (Flexeril) n Diphenhydramine (Benadryl) n Cyproheptadine (Periactin) n Carbamazepine (Tegretol) n Thioridazine (Mellaril) n Quetiapine (Seroquel) 26 Pharmacokinetics n Peak serum concentration 1-8 hrs n Antimuscarinic – delayed gastric emptying n Lipophilic – large Vd n Hepatic phase I: Demethylation n Imipramine desipramine n Amitriptyline nortriptyline n Hydroxylation: CYP2D6 n Slow vs Rapid n Desipramine: 81-131 vs 12-23 hours 27 CA Toxicity n Rapid onset of symptoms n Early sedation and coma n Early antimuscarinic symptoms n Cardiovascular “T” =Tremor (seizures) n Hypotension n Dysrhythmias “C” = Cardiovascular “A” = Antimuscarinic 28 Cardiovascular Toxicity n Rapid inward Na+ current n QRS prolongation n RBB more susceptible (leads V1, V2, aVR, I) n Rate dependent n pH dependent n R axis deviation in terminal 40 msec n AV node blocks n K+ channel blockade (Ikr) n Increased QT but TdP uncommon with tachycardia n Seen with therapeutic dosing 29 Cyclic Antidepressants Toxicology n Membrane effects n Blockade of fast Na+ channels phase 0 of the action potential 1 2 3 0 4 30 Axis Change in Toxicity R ’ Terminal R V1 R aVR I 31 32 MAOI pharmacology n Intracellular enzyme found on mitochondrial membrane n Degrades biogenic amines n Increases neurotransmitter activity in CNS, down-regulates post-synaptic 5HT and adrenergic receptors n Post-synaptic DA unaffected 34 MAOI pharmacology n Irreversible binding n Reversible binding n Phenylzine n Moclobemide n Tranylcypromine n Brofaromine n Isocarboxizide n Cimoxatone n Selegiline n Toloxatone n Pargyline n Harmaline 35 MAOI pharmacology n Selective n Nonselective n Clorgyline (A) n Tranylcypromine n Moclobemide (A) n Phenylzine n Toloxatone (A) n Isocarboxazid n Harmaline (A) n Selegiline (B) n Pargyline (B) 36 Signs and Symptoms (Overdose) n Phase I n Phase II n Latent period: 6-12 hrs in n Excitatory phase pts on medication n Hyperadrenergic appearing n 24-36 hrs in “naïve” n “Ping-pong” nystagmus patients n Hyperreflexive with rigidity n Writhing, opisthotonus, facial grimacing n Progression n CNS depression n Fever, diaphoresis, salivation n Rigidity, myoclonus, carpopedal spasm n Myocardial ischemia, ICH, seizures 37 Treatment n Expect prolonged period of toxicity n ICU for 24 hrs after resolution of signs and symptoms n Restricted diet for 2-3 weeks n Check ALL medications for interactions n Treat as signs and symptoms appear n Use SHORT acting agents n Use DIRECT acting agents-COMT metabolism 38 MAO-Tyramine reaction n Not an overdose n Onset within 2 hrs after eating n Ingested tyramines normally inactivated by gut MAO-A n Tyramine releases NE formed by inhibition of neuronal MAO-A n Hyperadrenergic state n Treat symptomatically 39 40 Serotonin Reuptake Inhibitors n Citalopram (Celexa) n Dapoxetine (Priligy) n Escitalopram (Lexapro) n Fluoxetine (Prozac, Sarafem) n Fluoxetine + olanzepine (Symbyax) n Fluvoxamine (Luvox) n Paroxetine (Paxil) n Sertraline (Zoloft) 41 Pearls n SSRI in overdose: CNS depression and tachycardia most common n Citalopram and escitalopram: reports of seizures and widened QT interval n Fluvoxamine inhibits CYP1A and CYP2C n Paroxetine, fluoxetine, and metabolites strong inhibitors of CYP2D6 42 SSNRI and Others n Buproprion n Excitation in overdose, SEIZURES, XL products n Hypotension, cardio collapse 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 n Hypotension, cardio collapse 43 Serotonin Syndrome n Stimulation of post-synaptic 5HT1A and 5HT2 brain receptors n Mechanism n Two or more serotonergic agents n SSRI + neuroleptic n SSRI + agent with serotonergic properties n Change