8/13/14

1

1

Psychotropics

Andrew Stolbach, MD

Thanks to G. Patrick Daubert and others for this slideset

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

8/13/14

2

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

8/13/14

3

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

8/13/14

4

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

8/13/14

5

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  Zaleplon (Sonata) n  EcZopiclone

(Lunesta, Estorra) n  Ramelteon (RoZerem)

n  Non-benzodiazepine sedatives

n  Selective for GABAA BZ-1 receptors

n  Less physical dependence

n  Flumazenil may precipitate withdrawal

n  Ramelteon 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

8/13/14

6

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

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

Chloral Hydrate

Trichloroacetic Acid Trichloroethanol

ADH P450

8/13/14

7

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

8/13/14

8

22

Antidepressants n  Cyclic antidepressants n  Monoamine oxidase inhibitors (MAOIs) n  Serotonin reuptake inhibitors n  Miscellaneous

n  Buproprion n  Citalopram/Escitalopram n  Mirtazapine n  Trazadone n  Venlafaxine

23

Usual Suspects n  Tertiary amines

n  Amitriptyline n  Clomipramine n  Doxepin n  Imipramine n  Trimipramine

n  Secondary amines n  Desipramine n  Nortriptyline n  Protriptyline

n  Tetracyclic n  Amoxapine n  Maprotiline

24

TCA Screen Cross Reactivity n  Cyclobenzaprine (Flexeril) n  Diphenhydramine (Benadryl) n  Cyproheptadine (Periactin) n  Carbamazepine (Tegretol) n  Thioridazine (Mellaril) n  Quetiapine (Seroquel)

8/13/14

9

25

Pharmacokinetics n  Peak serum concentration 1-8 hrs n  Antimuscarinic – delayed gastric emptying n  Lipophilic – large Vd n  Hepatic phase I: Demethylation

n  Imipramine g desipramine n  Amitriptyline g nortriptyline

n  Hydroxylation: CYP2D6 n  Slow vs Rapid n  Desipramine: 81-131 vs 12-23 hours

26

CA Toxicity n  Rapid onset of symptoms n  Early sedation and coma n  Early antimuscarinic symptoms n  Cardiovascular

n  Hypotension n  Dysrhythmias

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

“A” = Antimuscarinic

27

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

8/13/14

10

28

Cyclic Antidepressants Toxicology

n  Membrane effects n  Blockade of fast Na+ channels phase 0 of the

action potential

1

0

2

3

4

29

Axis Change in Toxicity

V1 R

R’

I

aVR Terminal R

30

8/13/14

11

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

33

MAOI pharmacology n  Irreversible binding

n  Phenylzine n  Tranylcypromine n  Isocarboxizide n  Selegiline n  Pargyline

n  Reversible binding n  Moclobemide n  Brofaromine n  Cimoxatone n  Toloxatone n  Harmaline

8/13/14

12

34

MAOI pharmacology n  Selective

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

n  Nonselective n  Tranylcypromine n  Phenylzine n  Isocarboxazid

35

Signs and Symptoms (Overdose)

n  Phase I n  Latent period: 6-12

hrs in pts on medication

n  24-36 hrs in “naïve” patients

n  Phase II n  Excitatory phase

n  Hyperadrenergic appearing n  “Ping-pong” nystagmus n  Hyperreflexive with rigidity n  Writhing, opisthotonus,

facial grimacing n  Progression

n  CNS depression n  Fever, diaphoresis,

salivation n  Rigidty, myoclonus,

carpopedal spasm n  Myocardial ischemia, ICH,

seizures

36

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

8/13/14

13

37

MAO-Tyramine reaction n  Not an overdose n  Onset within 2 hrs after eating n  Ingested tyramine normally inactivated by gut

MAO-A n  Inhibition of gut MAO-A: absorption of dietary

tyramine and byproducts n  Tyramine releases NE formed by inhibition of

neuronal MAO-A n  Hyperadrenergic state n  Treat symptomatically

38

39

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)

8/13/14

14

40

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

41

SSNRI and Others n  Buproprion

n  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

42

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 in dose n  Metabolic inhibition

8/13/14

15

43

Serotonin Syndrome n  Modified Sternbach criteria (all 3 must be met)

n  Syndrome occurs after addition of known serotonergic agent

n  List of symptoms to be met (at least 3) and other causes ruled out

n  No neuroleptic involved n  NEJM M. Shannon article

n  Hyperthermia n  Mental status changes n  Autonomic instability n  CLONUS

44

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

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 +++ ++++

8/13/14

16

46

Neonatal SSRI Withdrawal n  Fetus exposed to an SSRI 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

47

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

48

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

8/13/14

17

49

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

50

Antipsychotic Classification n  Low potency (sedating, antimuscarinic, miosis)

n  Chlorpromazine (most sedating in overdose) n  Chlorprothixene n  Mesoridazine n  Thioridazine (most cardiotoxic in overdose)

n  Medium potency n  Droperidol n  Loxapine (more seizures in overdose) n  Molindone n  Perphenazine

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

51

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)

8/13/14

18

52

Atypical Antipsychotics n  Aripiprazole (Abilify)

n  Longest 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

53

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

54

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 antihistamine activity n  High alpha blockade n  Less miosis n  Half-life longer in overdose

8/13/14

19

55

New! Improved! n  Asenapine (Saphris®)

n  Hypotension n  Agitation, altered n  QT?

n  Iloperidone (Fanapt®) n  Hypotension, antimuscarinic n  QT prolongation

n  Lurasidone (Latuda®) n  Hypotension, confusion, leukopenia

56

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

57

Acute vs Chronic Lithium n  Increased intake n  Delayed toxicity due to

delayed distribution n  High serum levels initially

do not correlate with toxicity

n  GI symptoms more severe

n  Tremor, muscle weakness, ataxia, hyperreflexia

n  Decreased excretion n  Serum levels lower since

inracellular levels high n  Subacute/nonspecific

neurologic symptoms n  GI symptoms less severe n  Encephalopathy,

myoclonus, severe rigidity, seizures

n  ECG n  Bradycardia n  T-wave flattening/inversion n  QT prolongation

8/13/14

20

58

Lithium Management n  D/C 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?

59

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.  hioridazine (Mellaril)

60

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.  hioridazine (Mellaril)

8/13/14

21

61

Questions? Good Luck!!