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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 and sedative- n 2.1.11.9.2 n 2.1.11.9.3 n 2.1.11.9.4 Mood stabilizers

3 Anxiolytics and Sedative-hypnotics n n 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 OD cases reported annually n 65% intentional n Few deaths n Most are combination exposures n Mixed 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 , , temazepam n IM administration n Lorazepam, midazolam

7 Benzodiazepines n All are indirect 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, with IV administration

9 Benzodiazepine Pearls n Increase frequency of Cl channel opening n Propylene glycol: lorazepam n : n 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: , secobarbital n Intermediate: butalbital n Long-acting: n Enzyme induction: drug interactions

11 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, 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 and vomiting n Hypotension n Miosis, mydriasis n n Flumazenil reverses Z agent effect and may precipitate withdrawal n Same precautions as with benzodiazepines

16 Sedative-Hypnotics n (Buspar) n Chloral hydrate n 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 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 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- Pearls n Meprobamate (Miltown, Equanil, Meprospan) n Active metabolite of 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 inhibitors n Miscellaneous/SNRIs n Buproprion n / n n Milnacipran n n Trazadone n /Desvenlafaxine

23 Cyclic Antidepressants

24 Usual Suspects n Tertiary amines n Secondary amines n n n n n n n n n n n

25 Immunoassay Cross Reactivity n (Flexeril) n (Benadryl) n (Periactin) n (Tegretol) n (Mellaril) n (Seroquel)

26 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

0 3 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 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 (Overdose) n Phase I n Phase II n Latent period: 6-12 hrs in n Excitatory phase pts on 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 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 (Prozac, Sarafem) n Fluoxetine + olanzepine (Symbyax) n (Luvox) n (Paxil) n (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 agents n SSRI + neuroleptic n SSRI + agent with serotonergic properties n Change in dose n Metabolic inhibition

44 Serotonin Syndrome n Modified Sternbach criteria: A, B, C must be met: n A. Syndrome occurs after addition of known serotonergic agent n B. List of symptoms to be met (at least 3) and other causes ruled out n C. No neuroleptic involved n NEJM M. Shannon article n Hyperthermia n Mental status changes n Autonomic instability n CLONUS

45 SS vs NMS

Signs/Symptoms SS NMS Onset Rapid Gradual Resolution < 24 hour Days Myoclonus ++ -- Hyperreflexia ++ -- Metabolic acidosis +/- ++++ Muscle rigidity ++ ++++ Altered mental status ++ ++++ Autonomic dysfunction +++ ++++

46 Serotonin Syndrome-Treatment n Good supportive care n Benzodiazepines n External cooling n Paralysis with a nondepolarizing agent n 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 : 5HT1A antagonism (1-5 mg IV)

n : 5HT2 antagonist

47 Neonatal SSRI Withdrawal n Fetus exposed to an SRI late in the third trimester n Symptoms n Respiratory distress (apnea) n Cyanosis, apnea n Feeding difficulties n Vomiting n Hypoglycemia n Tremors, jitteriness, irritability n Onset hours to days after delivery, which resolved in days or weeks n Prolonged hospitalization, respiratory support, and tube feeding

48 Question

Acute overdose of selective serotonin reuptake inhibitor (SSRI) medications most often result in A. Cardiac dysrhythmias B. CNS depression and tachycardia C. Hallucinations and delirium D. Profound hyperthermia and rigidity E. Seizures

49 Question

Acute overdose of selective serotonin reuptake inhibitor (SSRI) antidepressant medications most often result in A. Cardiac dysrhythmias B. CNS depression and tachycardia C. Hallucinations and delirium D. Profound hyperthermia and rigidity E. Seizures

50 Antipsychotics

51 Antipsychotics n Traditional antipsychotics n D2 antagonists n Atypical n Selective for limbic vs EP sites n Mixed DA receptor affinities (D1,D2 etc) n Looser binding to D2, less EPS n Mixed affinity for DA, 5HT, alpha

52 Classification n Low potency (sedating, antimuscarinic, miosis) n Chlorpromazine (most sedating in overdose) n n n Thioridazine (most cardiotoxic in overdose) n Medium potency n n (more seizures in overdose) n n n High potency (more EPS, less sedation) n n (most common cause of NMS) n n Thiothixene

53 Reversible EPS: Acute Dystonia n Intermittent spasmodic and involuntary contractions of face, neck, trunk n Facial grimacing n Tongue protrusion n Trismus n Torticollis n Blepharospasm n Opisthotonis n Oculogyric crisis n Abnormal posture, gait n Idiosyncratic n Males 5-45 years n Depot preps n Resolves during sleep

54 Reversible EPS n Akathesia n Parkinsonism n Subjective unease n Muscle rigidity n Motor restlessness n Bradykinesia n Dose related n Tremor n Women n Elderly women n High potency n High potency n -cholinergic basal ganglia balance disrupted n Excess with dopamine depletion

55 Irreversible EPS: Tardive n Involuntary movements of orofacial structures n Lip smacking n Facial grimacing n Eye blinking n Grunting n Late onset > 2 years after therapy onset n More common in women > 50 years

56 Antipsychotic Pearls n Thioridazine n Peak serum level can be delayed 120 hours n QTc but not QRS correlates closely with peak concentration n Most lethal in overdose n Most common cause of NMS (> 90%) n Haloperidol n Agranulocytosis n Chlorpromazine (Thorazine) n Cholestatic jaundice n Chlorpromazine (Thorazine) n Acute reversible oliguria n Chlorprothixene (Taractan)

57 Atypical Antipsychotics n (Solian) n (Zyprexa) n (Abilify) n (Invega) n (Saphris) n (Lullan) n (Lonasen) n Quetiapine (Seroquel) n (Prazinil) n (Roxiam) n (Clofekton) n (Risperdal) n (Entumine) n (Serdolect) n (Clozaril) n (Sulpirid, Eglonyl) n (Fanapt) n (Geodon, n (Latuda) Zeldox) n (Cremin) n (Nipolept)

58 Atypical Antipsychotics n Aripiprazole (Abilify) n Longest potential elimination half-life in overdose (146 hrs) n Clozapine (Clozaril) n Aplastic anemia, seizures, drug-induced DM, myocarditis, fever n Olanzapine (Zyprexa) n Highest incidence of NMS n Highest antimuscarinic activity but salivation common n Drug-induced DM n Classically resembles opiate toxidrome

59 Atypical Antipsychotics n Paliperidone (Invega) n Active metabolite of risperidone n Risperidone (Risperdal) n Highest rate of dystonia n Most reported seizures n Potent alpha blockade n No antimuscarinic effects; miosis n Unusual dysrhythmias for class (aflutter, heart blocks) n Ziprasidone (Geodon) n Highest rate of increased QT n Miosis common

60 Quetiapine Pearls n CNS depression, prolonged QT, tachycardia n 3 grams predicted ICU/prolonged LOS n Cross reacts with TCA assay n Most sedating of class n Highest activity n High alpha blockade n Less miosis n Half-life longer in overdose

61 Olanzapine Pearls n Long half-life in overdose n Highest anticholinergic, but salivation, miosis; physostigmine? n Most cases of NMS n Chronic therapy associated with: n Hyperglycemia n Overdose may resemble opiate toxidrome with miotic pupils

62 Risperidone Pearls n Highest rate of dystonia n High rate of seizures n High rate of alpha blockade n No antimuscarinic effects; miosis n Electrolyte depletion n Unusual dysrhythmias for class (aflutter, heart blocks)

63 Overdose: Atypical effects n Hypersalivation n clozapine, olanzapine n Miosis n Clozapine, olanzapine, risperidone, ziprasodone n Pancreatitis/Hyperglycemia n Clozapine/olanzapine n Electrolyte depletion (Mg, Na, K) n Risperidone n Antimuscarinic n Olanzapine, clozapine, aripiprazole

64 New! Improved! n Asenapine n Hypotension n Agitation, altered n QT? n Iloperidone n Hypotension, antimuscarinic n QT prolongation n Lurasidone n Hypotension, confusion, leukopenia

65 Mood Stabilizing Lithium n Main therapy for bipolar disorder n Narrow therapeutic index (0.6-1.2 mEq/L) n Slow distribution across cell membranes n Delay between peak blood levels and CNS effects n Most cases chronic due to a reduction in GFR n Volume loss n NSAIDs, diuretics, ACE inhibitors n Age

66 Acute vs Chronic Lithium n Increased intake n Decreased n Delayed toxicity due to n Serum levels lower since delayed distribution intracellular levels high n High serum levels initially do n Subacute/nonspecific not correlate with toxicity neurologic symptoms n GI symptoms more severe n GI symptoms less severe n Tremor, muscle weakness, n Encephalopathy, myoclonus, ataxia, hyperreflexia severe rigidity n ECG n Bradycardia n T-wave flattening/inversion n QT prolongation

67 Lithium Management n Discontinue lithium and offending drugs n Improve GFR n 20% reduction in Li over 6 hours n Hemodialysis (guidelines vary) n Renal failure n Encephalopathy, myoclonus, severe rigidity, seizures n Acute > 4.0 mEq/L? n Chronic > 2.5 mEq/L?

68 Question

A 23-year-old woman is taking ziprasidone for her schizoaffective disorder. Her ECG reveals a QRS 86 msec, and QTc 560 msec. Her physician wants to know what medication you would recommend in place of her ziprasidone? A. Chlorpromazine (Thorazine) B. Haloperidol (Haldol) C. Olanzapine (Zyprexa) D. Quetiapine (Seroquel) E. Thioridazine (Mellaril)

69 Question

A 23-year-old woman is taking ziprasidone for her schizoaffective disorder. Her ECG reveals a QRS 86 msec, and QTc 560 msec. Her physician wants to know what medication you would recommend in place of her ziprasidone? A. Chlorpromazine (Thorazine) B. Haloperidol (Haldol) C. Olanzapine (Zyprexa) D. Quetiapine (Seroquel) E. Thioridazine (Mellaril)

70 Questions?

Good Luck!!

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