2012 BRC BW Day One Cover Page

American College of Medical Toxicology 2012 www.acmt.net

ACMT Medical Toxicology Board Review Course

ARE YOU PREPARED? Astor Crowne Plaza Hotel New Orleans, LA September 8-10, 2012 SYLLABUS

Day One - 3 slides per page

Sponsored by the University of Alabama School of Medicine Division of Continuing Medical Education American College of Medical Toxicology Medical Toxicology Board Review Course September 8-10, 2012 - New Orleans, LA

Day 1 - Saturday, September 8, 2012 7:00-7:50am Breakfast & Stimulus Room 7:50-8:20am Welcome & Introductions 8:20-9:10am Pharmacokinetics/Toxicokinetics Howard A. Greller, MD, FACMT 9:10-10:00am Molecular Mechanisms William P. “Russ” Kerns II, MD, FACMT 10:00-10:20am Break 10:20-11:10am Analytical/Forensics Evan S. Schwarz, MD 11:10-12:00pm Autonomics/Neurotransmitters G. Patrick Daubert, MD 12:00-1:30pm Lunch –n-Learn: Mushrooms & Fish-borne Howard A. Greller, MD, FACMT 1:30-2:20pm Psychotropics G. Patrick Daubert, MD 2:30-3:20pm Cardiovascular Toxins Trevonne M. Thompson, MD 3:20-3:40pm Break 3:40-4:05pm Hydrocarbons Trevonne M. Thompson, MD 4:05-4:30pm Pharmaceutical Additives G. Patrick Daubert, MD 4:30-4:55pm Endocrine Trevonne M. Thompson, MD 6:00-7:30pm Welcome Reception - Napoleon House, 500 Chartres Street in the French Quarter

Day 2 - Sunday, September 9, 2012 7:00-8:00AM Breakfast & Stimulus Room 8:00-8:50am Pesticides J. Dave Barry, MD, FACMT 8:50-9:15am Terrorism Hazmat J. Dave Barry, MD, FACMT 9:15-9:40am Antimicrobials Michael Policastro, MD 9:40-10:00am Break 10:00-10:50am GI/Heme Michael Policastro, MD 10:50-11:15am Chemotherapeutics Michael Policastro, MD 11:15-12:05pm Plants Thomas C. Arnold, MD, FACMT 12:05-1:30pm Lunch-n-Learn: Historical Outbreaks Stephen W. Munday, MD, MPH FACMT 1:30-2:20pm Envenomations Thomas C. Arnold, MD, FACMT 2:20-3:10pm Carcinogens Stephen W. Munday, MD, MPH, FACMT 3:10-3:30pm Break 3:30-4:20pm Misc Toxins 1 Brandon K. Wills, DO, FACMT 4:20-4:45pm Misc Toxins 2 Brandon K. Wills, DO, FACMT

Day 3 - Monday, September 10, 2012 7:00-8:00am Breakfast & Stimulus Room 8:00-8:50am Anesthetics; Drugs of Abuse & Withdrawal Kurt C. Kleinschmidt, MD, FACMT 8:50-9:15am Herbal/Supplemental Tox Kurt C. Kleinschmidt, MD, FACMT 9:15-10:05am Industrial Poisons Jefrey Brent, MD, PhD, FACMT 10:05-10:25am Break 10:25-11:15am Assessment/Population Health/Risk Jefrey Brent, MD, PhD, FACMT 11:15-12:05pm Metals/Metalloids 1 Cyrus Rangan, MD 12:05-12:30pm Metals/Metalloids 2 Cyrus Rangan, MD John G. Benitez, MD, MPH, FACMT 12:30-3:00pm Stimulus Room Russ Kerns, MD, FACMT Pharmacokinetics and Toxicokinetics

Pharmacokinetics and Toxicokinetics

Howard A. Greller, MD FACEP FACMT North Shore University Department of Emergency Medicine Division of Medical Toxicology 1

WHAT WE’LL COVER TODAY

• Pharmacokinetics/Toxicokinetics • Absorption

• Distribution • Metabolism

• Elimination • Pharmacodynamics/Toxicodynamics

• Xenobiotic interactions • Pharmacogenomics/Toxicogenomics 2

OVERVIEW

Tissue Therapy Toxicity

Absorption Elimination Dose Drug Excretion Liberation

Metabolite Protein

Biotransformation

3 1 Pharmacokinetics and Toxicokinetics

ABSORPTION

•Process by which a xenobiotic enters body

•Rate of absorption (ka) determined by:

•Route of administration

•Dosing form

•Bioavailability 4

ROUTE OF ABSORPTION

•Affects rate and extent

•IV, inhalation > IM, SQ, IN, PO> SQ, PR

•Onset dependent on route

ROUTE OF ABSORPTION

Oral, onset approximately 20 minutes

6 2 Pharmacokinetics and Toxicokinetics

ROUTE OF ABSORPTION

Smoking ~10 seconds, IV ~30 seconds

DISSOLUTION

DIFFUSION

9 3 Pharmacokinetics and Toxicokinetics

DISINTEGRATION

EROSION

OSMOTIC PUMPS

12 4 Pharmacokinetics and Toxicokinetics

ION EXCHANGE RESINS

BIOAVAILABILITY

•Amount reaches systemic circulation, unchanged

•Extent of absorption

•Predicts intensity of effect

•First pass effects modify bioavailability 14

FIRST PASS EFFECTS

• Prevention of absorption • Decon / chelation (+/-)

• P-glycoprotein • Bezoars, mod preps

• Pre-systemic metabolism • Hepatic, gastric mucosa, intestinal BB

• Bacterial • Saturable in overdose 15 5 Pharmacokinetics and Toxicokinetics

FIRST PASS EXAMPLES

• Gastric emptying time

• Food, medications

• Gastric ADH

• Age, sex, H2

• “worst case”

• High FP (“low bioavailability”)

• Propranolol, cyclosporine, morphine, TCAs 16

IONIZATION

• Uncharged, non-polar cross membranes

• pH + pKa (dissociation constant) determine ionization (HH)

- • Log (HA/A ) = pKa - pH

• HA/A- = 10pKa-pH

- • pH < pKa ➡ HA/A > 1

• Favors non-ionized

- • pH > pKa ➡ HA/A < 1

• Favors ionized 17

SALICYLATE

• Weak acid (pKa 3.5)

Brain Blood Urine pH ~ 6.8 pH ~ 7.4 pH variable SH SH SH

H+ + S- H+ + S- H+ + S-

What is HA/A- in urine for pH=3.5? 7.5? 18 6 Pharmacokinetics and Toxicokinetics

ION TRAPPING

•HA/A- = 10pKa-pH

•pH 3.5 = (103.5-3.5) = 100 = 1 = 1:1

•pH 7.5 = (103.5-7.5) = 10-4 = 1/10,000

•With alkalinization, ionized, “trapped”

LIPID SOLUBILITY

• Partition coefﬁcients (oil/water)

• Higher lipid solubility, higher absorption

• Even with similar pKa

• Thiopental >> secobarbital >> barbital

• All with pKa of ~7.8 20

SURFACE AREA

•Affected by blood ﬂow

•Hypotension

•Vasoconstriction

21 7 Pharmacokinetics and Toxicokinetics

SPECIALIZED TRANSPORT

• Active (energy dependent)

• Transport against a concentration gradient

• Facilitated (energy independent)

• Xenobiotics utilize native systems

• 5-FU resembles pyrimidine

• Thallium/Pb resemble K+ and Ca2+ 22

P-GLYCOPROTEIN (PGP)

• Active efﬂux transporter (inside out) - “ABC” family

• BBB, BTB, brush border Digoxin, protease inhibitors, vinca alkaloids, S paclitaxel Amiodarone, ketoconazole, quinidine, verapamil St. John’s wort 23

24 8 Pharmacokinetics and Toxicokinetics

DISTRIBUTION

VOLUME OF DISTRIBUTION

• Where the drug goes

• Vd (L/kg) = amount/Cp = SxFxdose/C0

[C]=(S x F x dose)/(Vd x kg)

• Apparent proportionality constant

• Not a real volume (i.e. chloroquine ~185 L/kg) 26

SOME EXAMPLES Large Vd (>1 L/kg) Small Vd (<1 L/kg)

• Antidepressants • Alcohols

• Camphor • Lithium

• Digoxin • Phenobarbital

• Opioids • Phenytoin

• Phencyclidine • Salicylate

• Phenothiazines • Valproic acid 27 9 Pharmacokinetics and Toxicokinetics

ONE COMPARTMENT MODEL

Change in [plasma] = change [tissue]

Ke 28

TWO COMPARTMENT MODEL

• Measure #1

• Effects in #2

• Examples

K a • Digoxin k 12 #2 • Lithium

k21 • There can be multiple, multiple #1 compartments . . .

Ke 29

MODIFIERS

•Lavage, AC and WBI ⬇Ka

•MDAC, ion-trapping, chelation ⬆Ke

•Decrease Cmax, tmax and AUC

•Extracorporeal techniques ⬆Ke 30 10 Pharmacokinetics and Toxicokinetics DISTRIBUTION ≠ SITE OF TOXICITY / ACTION

•Lead ➡ bone •CO ➡ Hgb vs •DDT ➡ fat •Paraquat ➡ type II alveolar

PROTEIN BINDING

• Phenytoin 90% bound with normal albumin

• Albumin decreases, more free active drug

• [phenytoin] = 14 mg/L (10-20 mg/L)

• Sick (2 g/dL) vs. Healthy (4 g/dL)

• [adjusted] = [measured] / ((0.25 x albumin) + 0.1)

• 23.33 mg/L vs. 12.73 mg/L 32

PROTEIN BINDING - ASA

•Overdose increases apparent Vd

•⬆ free drug ➞ lower pH ⬆ HA ⬆ diffusion •More drug in tissues, more toxicity

•Other drugs with high protein binding

•Carbamazepine, valproate, warfarin, verapamil 33 11 Pharmacokinetics and Toxicokinetics

POOR LITTLE JOHNNY . . .

• Johnny got dumped

• He went home and took grandma’s digoxin

• Grandma calls poison control

• Do we have to be worried?

• Johnny weighs 50 kg

• Grandma’s pills are 250 mcg each

• There were 25 of them left . . . 35

WORST CASE SCENARIO . . .

• [C] = (S x F x dose) / (Vd x kg) = (1 x 0.7 x 25 x 0.25mg) / (6 L/kg x 50kg) = (4.38mg) / (300L) = 0.015mg/L

• Units, units, units . . . = (0.015mg/L) x (106ng/mg) x (1L/1000mL)

• [digoxin] = 15 ng/mL (worry) 36 12 Pharmacokinetics and Toxicokinetics

HOW MUCH FAB?

• TBL (total body load) = S x F x dose

• 1 x 0.7 x (25 x 0.25 mg) = 4.375 mg

• Each vial binds 0.5 mg digoxin

• Therefore, need 9 vials based on dose

• Worst case ([C] x kg)/100 = 8 vials (round up) 37

HIS LEVEL IS 4 NG/ML . . .

• Dose = Vd x Cp; Vd = 6 L/kg; wt = 50 kg; 0.5mg digoxin bound / vial Dose = (6 L/kg) x (50 kg) x (4 ng/mL) = 1200 . . . 1200 what? (103 mL/1 L) x (6 L/kg) x (50 kg) x (4 ng/mL) x (1 mg/106 ng) = 1.2 mg

• 0.5 mg/vial = 3 vials (round up)

• Shorthand ([C] x kg)/100 = 2 vials 38

39 13 Pharmacokinetics and Toxicokinetics

METABOLISM

• “Morally” neutral • Toxicate vs detoxify vs biotransform

• LEO GER (CYP 450) • Oxidize substrate (lose e-)

• Reduce electrophile (gain e-) • Cyclical oxidation co-factor

• i.e. NADH / NAD+ • Links catabolism to synthesis 41

PHASE I (PREPARATORY)

• Add/expose polar groups •HHydrolysis • Esterase, peptidase, epoxidase •OOxidation • P450, ADH, MAO, etc. •RReduction • Azo-, Nitro-, Carbonyl-, Quinone •DeDe-alkylation 42 14 (A1) Carboxylic acid ester (delapril) (A2) Carboxylic acid ester (procaine)

O NH2 NH2

C OC2H5 O O H2O H2O N CH CH NH CH CNCH COOH C OH C H OH + 2 2 2 + 2 5 HO hCE1 hCE2 CH3 R N C O COOH

(B) Amide (procainamide) (C) Thioester (spironolactone) O Pharmacokinetics and ToxicokineticsO NH2 NH2 O O H2O H O + N 2 H N + CH3COOH N 2 C NH COOH OPHASE I EXAMPLES O SCOCH3 O SH

(D) Phosphoric acid ester (paraoxon) + + (E) Acid anhydride (diisopropylfluorophosphate) CH3CH2OH + NADPH + H + O2 CH3CHO + NADP + 2H2O O CYP2E1

C2H5 O P O C2H5 O OH O O H O CH3 CH3 2 CH3 CH3 O CH OP OCH CH OP OCH + HF + + CH CH CH CH CH3CH2OH + NAD H 2O CH3CHO + NADH + H 3 3 3 3 C H C H F OH Alcohol Dehydrogenase + 2 5 OP O 2 5 hPON1 OH

NO2 NO2

(F) Transesterification (cocaine) (G) Lactone (spironolactone)

O methyl ester ethanol ethyl ester COOH O CH CH OH O 3 2 O OH H3C COCH H C 3 3 C OCH2CH3 N N H2O O hCE1 O hPON3 OC OO CH3OH methanol SCOCH O SCOCH3 O 3 Casarett & Doull’s 7th Edition 43

(H) Phosphate prodrugs (fosamprenavir) OH OH O P OH O H O 2 H H O N N NH2 + H PO O N N NH2 3 4 Alkaline Phosphatase O S O S O O O O O O

Figure 6-4.PHASE Examples of reactions II catalyzed (SYNTHETIC) by carboxylesterases, cholinesterases, organophosphatases, and alkaline phosphatase. hCE1 and hCE2, human carboxylesterases 1 and 2; hPON1 and hPON3 (human) paraoxonase 1 and 3.

•Conjugation polar groups •⬆ hydrophilicty

•Glucuronide, acetate, sulfate, methyl, amino acids and glutathione •GAS MAG

CYP 450 INTERACTIONS Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007) http://medicine.iupui.edu/clinpharm/ddis/table.aspx Accessed 3/2012

45 15 Pharmacokinetics and Toxicokinetics

CYP 1A2 Inducers broccoli'&'brussel'sprouts,' Aryl Hydrocarbon Hydroxylase cigare,es,'char1grilled'meat,' 15% pharmaceuticals insulin,'modaﬁnil,'omeprazole Linked with cancer Inhibitors

Substrates ﬂuvoxamine,6ciproﬂoxacin6 • Caffeine amiodarone,'cime8dine,' • Carvedilol clarithromycin,'interferon,' • Clozapine 8clodipine • Theophylline Toxica9on • R-warfarin

• APAP APAP,'benzo[a]pyrene,' dichloromethane • Haloperidol 46

CYP 2C9 Inducers rifampin,'secobarbital Most abundant CYP2C Inhibitors Substrates

•NSAID’s ﬂuconazole,6amiodarone,' •S-warfarin ﬂuvoxamine,'isoniazid,'lovasta8n,' sertraline,'sulfamethoxazole •Sulfonylureas •Phenytoin Toxica9on •ARBs Phenytoin'&'warfarin'(decreased' metabolism) 47

Inducers CYP 2C19 Absent 20% Asians carbamazepine,'prednisone,' “PPIs & Seizures” rifampicin Substrates Inhibitors •Diazepam omeprazole,6cime8dine,' ﬂuoxe8ne,'indomethacin,' •Phenytoin ketoconazole,'modaﬁnil,' •Phenobarbital oxcarbazepine,'8clodipine,' topiramate •Omeprazole Toxica9on •R-warfarin •Carvedilol 48 16 Pharmacokinetics and Toxicokinetics

CYP 2D6 Inducers 25% drugs, 50% antipsych dexamethasone,'rifampin 10% W, 8% AA poor metab Ethiopian ultra-rapid metab Inhibitors Substrates bupropion,6ﬂuoxe9ne,6 •β-blockers paroxe9ne,6quinidine,6sertraline,' •Codeine duloxe-ne,'amiodarone,' •Methadone, oxycodone, cime8dine,'citalopram,'cocaine,' codeine doxorubicin,'h1'antagonists,' •Tamoxifen methadone,'metoclopramide,' •TCAs, SSRIs ritonavir,

•Haloperidol Toxica9on 49

CYP 2E1 Inducers ethanol6(chronic),'fomepizole,' 7% total CYP in liver isoniazid,'phenobarbital,' Only other CYP cancer phenytoin,'cigareGe'smoke (1A2) Inhibitors •NP CA in Chinese smokers disulﬁram,'diethyl1 dithiocarbamate,'ethanol'(acute),' Substrates fomepizole

•Acetaminophen Toxica9on •Anesthetics acetaminophen,'ifosphamide,'

•Ethanol acrylonitrile,'CCl4,'aniline,' benzene,'dichloromethane,'vinyl' •Theophylline chloride 50

Inducers CYP 3A4 • Most abundant CYP in liver carbamazepine,'efavirenz,' • Most common intestinal modafinil,'glucocor8coids,' • 50-60% all pharmaceuticals oxcarbazepine,'phenobarbital,' • Terfenadine + erythromycin phenytoin,'rifampin,'st.'john’s'wort Substrates Inhibitors protease6inhibitors,6clarithromycin,6 ketoconazole,6erythromycin,3 fluconazole,3grapefruit3juice,3 verapamil,3dil-azem,3cime8dine,' amiodarone.'ciprofloxacin,' fluvoxamine,'starfruit Toxica9on acetaminophen,'aflatoxin 51 17 Pharmacokinetics and Toxicokinetics

Inducers P-GLYCOPROTEIN rifampin,'st.'john’s'wort Substrates Inhibitors •Cyclosporine

•Digoxin amiodarone,'cyclosporine,' •Diltiazem ketoconazole,'quinidine,'ritonavir,' •Loperamide tamoxifen,'verapamil • Lovastatin Toxica9on

ELIMINATION

54 18 Pharmacokinetics and Toxicokinetics

ELIMINATION

•Biotransformation, clearance, excretion

•Clearance(ss) = elimination ~ concentration

•Cl = ke/C

•Clearance is additive

•Hepatic + renal + GI + etc. 55

ELIMINATION

• Clearance constant over concentration

• i.e. elimination not saturated

• Rate is proportional to concentration

• ke = Cl x C

• First order elimination

• Calculate clearance from AUC (dose/AUC) 56

FIRST ORDER

•Percentage eliminated / time is constant

•Linear on semi-log paper

•t1/2 is time for 50% reduction

•t1/2 = 0.693/ke = 0.693 x Vd/Cl

57 19 Pharmacokinetics and Toxicokinetics

FIRST ORDER Magic #5

Katzung – Basic & Clinical Pharmacology 9th Edition 58

MICHAELIS-MENTEN

• “In between” elimination

• Elimination related to concentration

• ke=(Vmax x C)/(km + C)

• Vmax – maximum elimination capacity

• km – concentration at 50% of Vmax

• Non-linear 59

FIRST ORDER

•When concentration is low (C <<< km)

•ke = (Vmax x C)/(km + C) = Vmax/km

•Process is not saturated

•First order

60 20 Pharmacokinetics and Toxicokinetics

ZERO ORDER

• When concentration is high (C >>> km)

• ke = (Vmax x C)/(km + C) = Vmax

• Fixed amount eliminated per time

• Elimination saturated, capacity limited

• Non-linear; no “half-life”

• Dose >> elimination, no steady state

• Concentration keeps rising with dose 61

GRAPHS YOU SHOULD KNOW Concentration Concentration Concentration

Time Time Time First Order Zero Order Michaelis Menten Log concentration Log concentration Log concentration Time Time Time 62

“ENHANCED” ELIMINATION

• Johnny takes dad’s Enditall™

• His serum concentration is 1000 ng/mL

• Vd = 40 L/kg

• PCC recommends hemodialysis

• Dialysis ﬂow rate = 300 mL/min

• Cout (HD) = 340 ng/mL

• Johnny weighs 100 kg 63 21 Pharmacokinetics and Toxicokinetics

“HALF LIFE” ON HD?

• Clearance = ﬂow x ER (extraction ratio)

• ER = (Cin – Cout)/Cin = (1000-340)/1000

• ﬂow x ER = 300 x 2/3 = 200 mL/min

• So what’s the half-life on HD?

• t1/2 = 0.693 x Vd/Cl = (0.693 x 40L/kg x 100 kg)/(200 mL/min x 60 min/hr x 0.001 L/mL)

• 231 hours! 64

WHAT DID WE MISS?

•Clearance is sum of ALL clearances

•Cltotal= Clnative + ClHD

•= (90 L/hr) + (12 L/hr) = 102

•t1/2 = (0.693 x 4000 L)/(102 L/hr) =

•27.2 hours (better) 65

WHAT ABOUT CRRTS?

• Cl = (Volume/time of UF) x (CUF/Cp)

• Usual renal clearance for lithium is 25-35 mL/min

• HD adds about 100-150 mL/min

• Only 4 hours at a time, plus rebound

• CVVH adds 20-35 mL/min, continuously

• Clear ~ 50 L/day vs. 36 L/day with 4 hr HD

• Plus, no rebound 66 22 Pharmacokinetics and Toxicokinetics

Board Review Course 67

PHARMACODYNAMICS AND TOXICODYNAMICS

TIME COURSE DRUG ACTION

•Drug (D) - receptor (R) interaction

•[D] + [R] [DR]

•Kdissociation = [D][R]/[DR]

•Effect (E) proportional to occupancy . . .

•E = [D]/(Kd+[D]) 69 23 Pharmacokinetics and Toxicokinetics

DOSE RESPONSE CURVE

•log-log plot of E = [D] / (Kd+[D])

•Sigmoid shaped, linear in middle

•When E = 50%, dose = Kd

100%

50% Response

0% Dose 70

KINETICS VS. DYNAMICS

•Dynamics = time course of effect at receptor

•Kinetics = concentration in central compartment

•When xenobiotic is bound to receptor, it no longer participates in kinetic process

PENTOBARBITAL

• Terminal half-life is long (6-48 hours)

• Yet, patients wake up minutes after bolus

• Highly lipid soluble

• Rapidly highly perfused tissues (brain)

• Redistributes to low-perfusion, high volume tissue (fat)

• Central concentration is not reﬂective of receptor concentration (clinical effect) 72 24 Pharmacokinetics and Toxicokinetics

ORGANOPHOSPHATE

• Half-life of parathion is short

• Cholinesterase inhibited days to weeks

• Binding functionally irreversible

• Kinetics at receptor not reﬂected by serum concentration

• Irreversible binding or sequestration separates kinetic from dynamic process 73

APAP

• Dynamic time ≠ equal kinetic time

• APAP half-life is ~ 4 hours

• Toxicity manifests days later

• Kinetics depends on metabolism

• Dynamics is a function of the time course of interactions

• Cellular injury, immune response, etc 74

OTHER EXAMPLES OF PK≠PD

•OPIDN (“Jake Leg”, disrupted neuronal transport)

•Delayed axonal injury in CO (demyelination)

•Carcinogenesis (multifactorial)

•Physostigmine (hysteresis) 75 25 Pharmacokinetics and Toxicokinetics

RECEPTORS

• Agonism – mimics natural ligand

• Antagonism – opposes natural ligand

• Agonist/antagonist (partial effect)

• Less effective ligand than natural ligand

• Natural ligand missing, mostly activation

• Natural ligand present, mostly antagonism 77

RECEPTOR LIGAND INTERACTIONS

• Competition - naloxone

• Fight for the same receptor site

• More of either overwhelms the other

• Non-competitive - ﬂumazenil

• Binding to different sites changes the effect

• Adding more does not result in more effect 78 26 Pharmacokinetics and Toxicokinetics RECEPTOR LIGAND INTERACTIONS

•Un-competitive inhibition - lithium

•Inhibitor binds enzyme-substrate complex

•The more substrate, the more inhibited

RECEPTOR REGULATION

• Cell surface and nuclear receptors

• Self-regulate in response to signals

• Over-stimulated down-regulate, etc

• Important in tolerance and withdrawal

• Chronic cocaine dopamine receptors

• GABA , NMDA with chronic ethanol 80

81 27 Pharmacokinetics and Toxicokinetics

TOLERANCE AND WITHDRAWAL

BIOLOGIC TOLERANCE

• Diminished effect with repeat administration

• Withdrawal

• Physiologic symptoms after discontinuation

• Physiologic tolerance

• Receptor regulation / metabolic changes

• Behavioral (independent of physiology) 83

TOLERANCE VS. ADDICTION

•Tolerance = physiologic adaptation

•Addiction = behavior directed at avoiding withdrawal

•Usually in tolerant individuals

•Continued use, seeking behavior despite adverse consequences 84 28 Pharmacokinetics and Toxicokinetics

ADVERSE EFFECTS XENOBIOTIC INTERACTIONS

ADVERSE DRUG EVENTS

•1.5 million ADE/yr in U.S. (>1/d/pt)

•Predictable

•Pharmacokinetic/dynamic

•Immunologic

•I-IV, hepatitis 87 29 Pharmacokinetics and Toxicokinetics UNPREDICTABLE (IDIOSYNCRATIC)

•Polymorphisms (“fast metabolizers”)

•epoxide hydrolase + phenytoin = anticonvulsant hypersensitivity

•N-acetyl-transferase + INH = neuropathy, hepatitis

•G6PD + pyridium = hemolysis 88

XENOBIOTIC INTERACTIONS

• Food

• Fluoroquinolone (FQ) + antacid = decreased absorption of FQ

• Tyramine and MAOI = hypertensive crisis

• Warfarin and cruciferous veggies = INR

• Flora

• ABX + e. lentum + digoxin = increased digoxin (less digestion)

• Distribution

• Amiodarone + phenytoin = protein binding 89

XENOBIOTIC INTERACTIONS

• Metabolism

• Rifampin + carbamazepine (CBZ) = decreased CBZ (3A4)

• Grapefruit + 3A4 substrate = levels

• Excretion

• NSAIDs + lithium = lithium

• Pharmacodynamics

• PGE-5 inhibitor (sildenaﬁl) + nitrates = hypotension

• SSRI & MAOI = serotonin syndrome

• Terfenadine and erythromycin = prolonged QT 90 30 Pharmacokinetics and Toxicokinetics

TOXICOLOGY 91

GENOMICS PROTEOMICS

LIFE EXPLAINED . . . • Step 1

• Genomics

• “Possiblities”

• Step 2

• Transcriptomics

• Selected outcomes

• Step 3

• Proteomics

• Equipment

• Step 4

• Metabolomics • Results (biochem) 93 31 Pharmacokinetics and Toxicokinetics

PROFILING (THE FUTURE . . .)

• Applied genomics, proteomics, etc. • Identify mechanisms of toxicity

• Reduced animal testing • Genotype patients

• Early diagnosis of disease or predisposition • Predict ADRs, idiosyncratic reactions

• Custom therapeutics, correct dosing • CYP2D6 and codeine 94

95 Questions?

96 32 Pharmacokinetics and Toxicokinetics

33 Molecular Mechanisms

ACMT Board Review 2012: Molecular Mechanisms

Russ Kerns, MD, FACMT Carolinas Medical Center Charlotte, NC 1

Objectives: Cover Core Content

! 1.2 Molecular components/mechanisms ! 1.2.1 Glycolysis & oxidative phosphorylation

! 1.2.2 Other metabolic pathways (β-oxidation)

! 1.2.4 Transport proteins (hemoglobin)

! 1.2.5 Channels

! 1.3 Cytotoxic mechanisms

! Provide key example toxins

1.2.1 Glycolysis & Oxidative Phosphorylation

1 Molecular Mechanisms

Oxidative Phosphorylation

! Energy is released when ATP → P + ADP ! Restoration of ATP (energy stores) involves phosphorylation of ADP via coupling of oxidation + of H to form H20.

Oxidative Phosphorylation

ADP carbohydrate/fatty acid ATP H O P 2 ADP antiporter acetyl-CoA

TCA

NADH/FADH2

H+ + e- e- + O2- + H+

electron transport chain ATP synthase

H+ H+ H+ 5

glucose ATP glucose-6-P Glycolysis

fructose-6-P ATP fructose-1,6-diP ! Main carb metab path

glyceraldehyde-3-P + DHA-P ! Cytosolic process ! 6C cmpd → 2 X 3 C cmpd 2 [glyceraldehyde-3-P] ! Net 2 ATP molecules

2 [1,3-diphosphoglycerate] ! Make pyruvate for Krebs ATP 2 [P intermediates] ATP 2 [pyruvate] 6

2 Molecular Mechanisms

Glycolysis: Toxins

glyceraldehyde-3-P + DHA-P

! Arsenic (V) 2 [glyceraldehyde-3-P] ! Substitutes for P ! Fail to make 1,3-diP intermed 2NAD+ + 2 P As5+ X ! Fail to make ATP ! Fail to make pyruvate 2 [1,3-diphosphoglycerate]

ATP

2 [P intermediates] 7

Glycolysis

CH3COCOOH pyruvate

NADH pyruvateCoA, decarboxylase NAD+

thiamine

NAD+ NADH, CO2

pyruvate dehydrogenase

CH3CH2OCOOH CH3CO-CoA lactate acetyl-CoA

Glycolysis: Toxins

CH3COCOOH pyruvate As3+

pyruvatelipoamide decarboxylase X

thiamine dihydrolipoamide

CH3CO-CoA acetyl-CoA

3 Molecular Mechanisms

Krebs TCA Cycle pyruvate acetyl-CoA

oxaloacetate citrate

NADH NAD+ maleate cis-aconitate

fumarate isocitrate NAD+ NADH FADH2 FADH succinate oxalosuccinate

NAD+ Succinyl-CoA α-ketoglutarate

NADH 10

Krebs TCA Cycle: Toxins

acetyl-CoA

oxaloacetate fluorocitrate X X

monofluoroacetate cis-aconitate

fluoroacetamide isocitrate Rodenticides

! Sodium monofluoroacetate

! Fluoroacetamide

Electron Transport Chain

! Mitochondrial process ! Series of oxidation-reduction reactions ! Cytochrome enzymes

! FADH2 and NADH electron sources

! Produce H2O and ATP

4 Molecular Mechanisms

ETC: Toxins

! Enzyme inhibitors ! Uncouplers

cytochrome oxidase aa3 NADH-CoQ reductase X X X

Cytochrome Oxidase Inhibitors

lactate lactate glucose lactate lactate lactate pyruvate lactate lactate lactate

H+ acetyl CoA ATP

X X -X TCA cycle e transport

ETC: Toxins ! Uncouplers ! Salicylate ! Dinitrophenol (explosives & wood preservative) ! Pentachlorophenol (fungicide)

! Cytochrome aa3 inhibitors ! Cyanide

! H2S ! CO ! Methanol ! Phosphine gas ! Sodium azide (propellant in airbags) ! NADH-CoQ reductase ! Rotenone (plant derived fish poison) 15

5 Molecular Mechanisms

1.2.2 β-Oxidation of FFA CoA ATP ADP + P (CH) COOH (CH) CO-CoA n acyl-CoA synthetase n fatty acyl-CoA fatty acyl-CoA fatty acylcarnitine fatty acyl-CoA

carnitine-palmitoyltransferase

CoA carnitine CoA

NADH, FADH2

(CH)nCO-CoA (CH)n-2CO-CoA + CH3CO-CoA CoA acetyl-CoA 16

β-Oxidation of FFA: Toxins fatty acyl-CoA fatty acylcarnitine fatty acyl-CoA

CoA carnitine CoA

valproate

NADH, FADH2

(CH)nCO-CoA (CH)n-2CO-CoA + CH3CO-CoA CoA acetyl-CoA

etoh, hypoglycin 17

β-Oxidation of FFA: Toxins

! ↑ NADH/NAD+ ratio ! ethanol ! Hypoglycin(?)

! Carnitine ! Valproate

! Undefined mechanism ! Aflatoxin ! Amiodarone ! cereulide ! dimethylformamide ! tetracycline

www.australianprescriber.com18

6 Molecular Mechanisms

Mitochondrial DNA: NRTIs

! Nucleoside reverse transcriptase inhibitors ! Mechanism

! Inhibit mitochondrial DNA replication ! Inhibit ADP/ATP antiporter(?)

! Result

! Lactic acidosis ± steatosis

! Agents ! Stavudine

! Didandosine ! Zalcitobine X ! Zidovudine

! Tenofovir (nucleotide) 19

1.2.4 Transport Proteins

Hemoglobin

! iron-based tetrameric protein ! α- and β-globin chains (2 each) ! Heme complex in each chain (4 total) ! protoporhyrin ring ! central iron atom

7 Molecular Mechanisms

Hemoglobin: Toxins

! Site of action of toxins

! Heme synthesis ! Erythropoiesis

! Hemorrhage

! Oxidant stress

! Competition for oxygen binding

Heme Synthesis: Direct Toxin

23 Harrisons On-Line

Heme Synthesis: Indirect Toxins

! Acute Intermittent Porphyria ! Hepatic

! Autosomal dominant

! Reduced HMB synthase activity

! Some drugs may exacerbate AIP by increasing ALA-synthase activity

! Poorly defined mechanism

8 Molecular Mechanisms

Heme Synthesis: AIP

! Barbiturates ! Carisoprodol dark red urine

! Danazol

! Ethchlorvinyl

! Meprobamate

! Primidone

! Pyrazolones

! Trimethadione www.porphyriafoundation.com

Hemoglobin: Toxins

! Erythropoiesis ! Nephrotoxins - ↓ erythropoietin ! Pure rbc aplasia – rare ! INH ! Hypoglycemics (chlorpropamide, tolbutamide) ! Phenytoin ! Sulfasalazine ! Valproate (single case report)

Hemoglobin: Aplastic Anemia aplastic marrow normal marrow

www.hopkinsmedicine.org 27

9 Molecular Mechanisms

Hemoglobin: Aplastic Anemia

TNF

interferon-γ

! Immune mediated ! T lymphocytes release cytokines ! Suppress hematopoietic stem cells

! Apoptosis (↑ Fas receptors on stem cells)

Hemoglobin: Aplastic Anemia metaphase arrest

! DNA injury ! Direct DNA injury ! Ionizing radiation metaphase.wordpress.com ! Inhibition of DNA replication ! Folate inhibitors (methotrexate)

! Intermediary metabolite that binds DNA ! Benzene (quinone + free radicals)

! Tubulin inhibition during cell replication ! Antimitotics (colchicine, vincristine, vinblastin)

Hemoglobin: Aplastic Anemia

! Antibiotics ! Chloramphenicol

! Anti-convulsants

! Carbamazepine, phenytoin ! Anti-inflammatory agents

! Diclofenac, D-penicilamine, gold salts, indomethicin, phenylbutazone

! Anti-neoplastic agents ! Alkylating agents (nitrogen mustards)

! Antibiotics (danorubicin, adriamycin)

! Antimitotics (colchicine, vinblastin, vincristine)

! Antimetabolites (purine and pyrimidine analogues)

! Antipsychotics ! Chlorpromazine, clozapine 30

10 Molecular Mechanisms

Hemoglobin: Aplastic Anemia

! Chemicals ! Benzene, lindane

! Metals

! Arsenic

! Miscellaneous

! Acetazolamide, captopril, cimetidine, chlorpromazine, dapsone, fluoxetine, meprobamate, nifedipine, PTU, ticlopidine, tocainide

! Radiation 31

Hemoglobin: Toxins

www.pathology.vcu.edu

Hemoglobin: Toxins

! Megaloblastic anemia

! ↓ Vit B12 absorption ! Colchicine, metformin, neomycin

! ↓ folate absorption ! Etoh

! Impaired dihydrofolate reductase ! Methotrexate

! Pyrimethamine ! Pyridium

! Trimethoprim 33

11 Molecular Mechanisms

Hemoglobin: Oxidant Stress

! Heme: deoxyhgb → Methgb (Fe2+→Fe3+)

! Prophyrin ring by sulfur: Sulfhgb

! Globin: Heinz body hemolytic anemia

Hemoglobin: Oxidant Stress

! Protection from oxidant stress ! Ascorbic acid (Vit C)

! Glutathione (intact HMP, G6PD)

! Enzymatic

! NADH-dependent reductase (Cytochrome b5 reduc) ! NADPH-dependent reductase (intact HMP, G6PD)

! Catalase

! Hydrogen peroxidase

Hemoglobin: Methemoglobin

! Fe2+ state: deoxyhemoglobin carries oxygen ! Fe3+ state: methemoglobin results from oxidation and does not carry hemoglobin

2+ 3+ 2+ 3+ - HgbFe + O2 → HgbFe O2 → HgbFe + O2 > HgbFe + O2

12 Molecular Mechanisms

Hemoglobin: Methemoglobin

! Cyt b5 or NADH dependent reductase ! NADPH-dependent reductase

+ 2+ + NAD cyt b5 HgbFe LMB NADP

Cyt b5 reductase NADPH- dep reductase

+ 3+ + NADH cyt b5 HgbFe MB NADPH

glycolysis hexose monophosphate shunt 37

Hemoglobin: Methemoglobin

! Chemicals ! aniline aniline ! arsine ! chlorates (old strike matches) ! chlorobenzene ! copper sulfate ! napthalene chloro- & nitrobenzene ! nitrites (food contaminants & poppers) ! nitrates (food & well water) ! NOx (oxides of nitrogen) ! phenol phenol 38

Hemoglobin: Methemoglobin

! Medications benzocaine ! -caines (benzo-, lido-, prilo-) ! dapsone (sulfonamide deriv) ! methylene blue ! nitrites, nitrates aniline ! phenacetin phenacetin ! phenazopyridine ! -quines (chloro-, prima-) ! sulfonamide antibiotics

sulfanilamide39

13 Molecular Mechanisms

Hemoglobin: Sulfhemoglobin

! Characteristics ! Same agents that induce methgb

! Not reversible

! Shifts O2-hgb dissociation curve to right

! H2S arguable, probably does not cause sulfhgb, and hopefully would not be a great test item.

Heinz Body

vettech.vet.ku.edu 41

Hemoglobin: Hemolysis

! Mechanism ! Oxidation of the globin chain

! Glutathione depletion or membrane injury

! Characteristics

! Extravascular: mild forms

! Intravascular: severe forms ! Anemia

! Free hgb (in serum and urine) ! Reticulocytosis

! Decreased haptoglobin

42 www.residents.pathology.pitt.edu

14 Molecular Mechanisms

Hemoglobin: Hemolysis

! Hemolysis > methemoglobin

! Arsine (AsH3)

! Stibine (SbH3) ! Napthalene

! Copper sulfate

Hemoglobin: Non-oxidant, Immune-mediated Hemolysis

! Type I (IgG-mediated) ! penicillin

! Type IV (Cell-mediated)

! α-methyldopa

Hemoglobin: Toxins

! Competition for oxygen binding ! COHgb ! MetHgb ! SHgb

15 Molecular Mechanisms

1.2.5 Channels

! Sodium Channels

! Calcium channels

! Potassium channels

1.2.5 Sodium Channel

Na+ Channel Structure

! Found in neurons, glial cells & myocytes ! 9 subtypes

! Tetrameric protein

! Transmembrane

! SCN gene ! SCN5 – Brugada Syndrome

! Voltage-gated (myocardial)

! Ligand-gated (nicotinic)

16 Molecular Mechanisms

Na+ Channel Function

! Resting (Closed)

! Open

! Inactivated (Closed)

! Refractory to opening

Myocardial Na+ Channel Function

Na+ Channel Modulation

! Agonists – channel openers ! Aconitine (Monks Hood)

! Batrachotoxin (Poison Dart Frog)

! Ciguatoxin

! Grayanotoxin (Azalea & Rhododendron)

! Veratridine (Hellebore sp)

17 Molecular Mechanisms

Na+ Channel Modulation

! Antagonists ! Ia Antidysrhythmics

! Procainamide, quinidine, disopyramide ! Ib Antidysrhythmics

! Lidocaine, phenytoin

! Ic Antidysrhythmics ! Encainide, flecainide, propafenone

! Others

! Amiodarone, carbamazepine, cocaine, diphenhydramine, propranolol, propoxyphene, thioridazine and metabolite

Ca in, K out

Na in K out

Na+ Channel Modulation

18 Molecular Mechanisms

Na+ Channel Modulation: Rate-Dependent

baseline 2:50 min

QRS – 140 ms; BP - 145/78 mmHg QRS – 160 ms; BP - 151/68 mmHg

5:50 min 7:50 min

QRS – 180 ms; BP -164/65 mmHg QRS – 220 ms; BP - 0 mmHg 55

Na Channel Recovery

! Class Ia: τrecovery 1-10 sec

! Class Ib: τrecovery < 1 sec

! Class Ic: τrecovery > 10 sec

1.2.5 Ca2+ Channels

! L-type

! N-type (neuronal)

! P-type (Purkinje)

! T-type (muscular)

19 Molecular Mechanisms

L-type Ca2+ Channel

! Four proteins ! Span cell membranes ! Regulates calcium entry ! Closed in resting state ! Require activation to open ! Channel location determines the functional result of calcium entry 58

L-type Ca2+ Channel

endocrine non-vascular smooth muscle59

Ca2+ Channel Activation - Myocardial

! Ca2+- mediated Ca2+ - release ! Result ! ↑HR ! ↑contractility ! Modulators ! Catecholamines ! G protein

! cAMP

! protein kinase

20 Molecular Mechanisms

Ca2+ Channel Activation - Vascular

! Result ! vasoconstriction ! Maintenance of BP ! Modulators

! α1 stimulation ! β2 stimulation ! angiotensin ! endothelin

Ca2+ Channel Antagonism

Consequences: X Hypotension Bradycardia Poor cardiac output

Cardiogenic Shock

Ca2+ Channel Antagonism

! CCB drugs ! Nifedipine (dihydropyridine)

! Diltiazem (benzothiazepine)

! Verapamil (phenylalkylamine)

! Bepridil (diarylaminopropylamine)

! Cyclic antidepressants

! Propafenone 63

21 Molecular Mechanisms

Ca2+ Channel Agonist

! Levosimendan ! Directly opens Ca2+ channel

! Heart failure treatment

! Experimental treatment of CCB toxicity

! No human overdose

1.2.5 Potassium Channels

K+ Channel Structure

! Tetrameric protein in the cell membrane ! Central pore through which K+ flows ! Normally closed ! Opening leads to K+ efflux from the cell

22 Molecular Mechanisms

K+ Channel Function

! Inhibition of cell function ! Acts to prevent overuse of the cell

! Opening stimuli ! ↓intracellular energy molecules (ATP) ! ↑intracellular Na+ ! ↑intracellular Ca2+

ATP-Dependent K+ Channel

Ca2+ + ins K -ATP ins

ins ins

ins Ca2+ Ca2+ ins

ATP ADP + Pi 68

ATP-Dependent K+ Channel + K Ca2+ K+ + Ca2+ K K+ Ca2+

K+ Xins ins ins ins ATP ADP + Pi 69

23 Molecular Mechanisms

ATP-K+ Channel Modulation

Sulfonylurea (glipizide, glyburide) ins ins Ca2+ ins K+ channel ins ins

ins ins

ins Ca2+ Ca2+ ins 70

ATP-K+ Channel Modulation

somatostatin 2+ receptor Ca (octreotide)

G + K ins ins ins ins ins ins 71

Normal Function: Myocardial K+ Channel

2+ Ca + mV

Na+ - mV

24 Molecular Mechanisms

Normal Function: Myocardial K+ Channel

! Effective Refractory Period ! Depolarization not possible

! Relative Refractory Period

! Depolarization possible with sufficient electrical stimulus ERP RRP

K+ Channel Modulation

! K+ channel inhibition (Class III drugs) ! Prolongs action potential (phase 3) ! Equalizes refractoriness of ischemic and non- ischemic tissues

Na+! X

Prolonged QTc / TdP

! Antidysrhythmic ! Class I (quinidine and quinine) ! Class III (amiodarone, bretylium, dofetilide, ibutilide) ! Antidepressants ! Serotonin agonists ! Antihistamine ! terfenadine, astemizole ! Antipsychotic ! haloperidol - butyrophenone ! thioridazine - phenothiazine ! sertindole - atypical 75

25 Molecular Mechanisms

Prolonged QTc / TdP

! GI agents ! cisapride

! Metabolic

! hypokalemia (diuretics)

! hypomagnesemia (diuretics)

! Metals

! arsenic

www.torsades.org

1.3 Cytotoxic Mechanisms

26 Molecular Mechanisms

1.3 Antimitotics

! Mitosis www.cancerquest.emory.edu ! Forming of identical daughter cells by replicating and dividing the chromosomes ! Replication occurs centrally in the parent cytoplasm ! Spindle apparatus attach to the chromosomes (metaphase) and pull them towards the centromere (anaphase) prior to completion of cell division 79

Antimitotics

! Spindle apparatus is composed of tubulin ! polymerized subunits ! polymerization ↔ depolymerization ! Antimitotics interfere with spindle function ! Inhibit polymerization ! colchicine, vincristine, vinblastine (vinca alkaloids) ! Inhibit depolymerization ! taxol (alkaloid from Yew) ! Result: metaphase arrest

1.3 Apoptosis: Programmed Cell Death

! Homeostatic mechanism for removal of: ! damaged, infected, aged cells

! activated immune cells (no longer needed) ! Non-inflammatory

! Extrinsic triggers

! Intrinsic triggers

27 Molecular Mechanisms

Apoptosis

Extrinisic Intrinisic ! TNF-R ! Nuclear p53

! Fas (CD95) ! Mitochondrial cyt C

! Death receptor 3-5 82

Apoptosis

Results ! Caspase family activation (3,7,8,9,10) ! Cleaves DNA, protein ! Apoptotic protein activation (BH3 family) ! Initiates mitochondrial pore formation 83

Apoptosis: Programmed Cell Death

! Progressive condensation of nuclear contents ! Nucleus lyses (karyorhexis)

! Cell shrinkage, cytoplasmic condensation

! Apoptotic bodies, budding formed

! Macrophages remove apoptotic bodies

Normal lymphocyte

apoptotic lymphocyte

28 Molecular Mechanisms

Apoptosis

29 8/26/12!

Analytical and Forensic Toxicology!

Evan S. Schwarz, MD! Washington University! St. Louis, MO! Barnes Jewish Hospital!

Special Thanks!!

• Howard Greller!

• Jeffrey Brent! • Adhi Sharma! • Chuck McCay! • Kent Olson!

It was the break they had been waiting ! for; prints left at the crime scene!

Content! • Core Content of Medical Toxicology! • Part 5: Analytical and Forensic Toxicology! • LLSA Articles! • Post-mortem Toxicology: What the dead can and cannot tell us. Clin Tox 2003;41(1):47-56.! • Is this urine really negative? J of Sub Abus Treat 207;33:33-42.!

1! 8/26/12!

Laboratories!

• Clinical Laboratory Improvement Amendments of 1988 (CLIA)! • Medical Lab Testing governed by federal regulations since 1992! • Regulations apply to all lab testing of human specimens for medical purposes! • All tests require the possession of an appropriate certiﬁcate!

Testing!

Moderate! Record Keeping! Written Procedures! • Waived! Laboratory Director! Competency Testing! • Moderate complexity! Proﬁciency Testing! Controls! • High complexity! Inspection! High! Qualiﬁed onset supervisor! Daily review of all results!

Magic Answer Box?!

• Low volume, often old methodologies! • Limits to every technique! • Implies conﬁrmation or exclusion! • More toxic xenobiotics than named diseases!

2! 8/26/12!

Magic Answer Box?!

• Low volume, often old methodologies! • Limits to every technique! • Implies conﬁrmation or exclusion! • More toxic xenobiotics than named diseases!

Basics of analysis!

• Screening ! • Conﬁrmation! • Separation! • Detection! • Quantiﬁcation!

Assay Methods!

• Spot & spectrochemical! • Immunoassays! • Non-competitive! • Competitive! • Enzyme-multiplied immunoassay (EMIT)! • Magnetic microparticle chemiluminescent competitive immunosassay! • Microparticle capture immunoassay!

3! 8/26/12!

Assay Methods!

• Chromatography! • Thin layer liquid (TLC)! • High performance (pressure) liquid (HPLC)! • Gas chromatography (GC)! • Mass spectroscopy (MS)! • Inductively coupled plasma mass spectroscopy!

Testing!

“You’re ﬁred, Jack. The lab results! just came back, and you tested positive for Coke.”!

Spot tests !!

• Simple!

• Rapid Reaction!

• Color change!

• Ferric chloride for salicylate!

• Unreliable (FP & FN)!

• Visual interpretation!

4! 8/26/12!

Spot Testing!

• Salicylates!

• Ferric chloride!

• Mercuric chloride!

• Meixner Test!

Spectrochemical!

• Sophisticated spot tests!

• Chemical reaction to form light- absorbing substance!

• Carefully controlled!

• Spectrophotometer vs eyeball!

Co-oximetry!

• Spectrophotometry used to measure various forms of hemoglobin! • Measurement of light absorbance at multiple wavelengths allows allows several hemoglobin species to be quantiﬁed! • Need more wavelengths than types of hemoglobin!

5! 8/26/12!

Spectrochemical!

• Older tests waited until complete conversion! • Modern tests measure rate of conversion! • Initial phase, rate is constant and proportional to the initial concentration of the analyte! • Nonreacting substances that absorb light! • Don’t affect results!

Spectrochemical!

• Produce light absorbing substances! • Ex: High concentrations of lactate! • Inhibit the assay reaction or that consume reagents! Oh, a drug test. That’s a relief.! • Ex: ascorbic acid in I thought you were going to test ! oxidation reactions! my ethics.!

Spectrochemical!

• Improve Selectivity! • Enzymes that can catalyze highly selective reactions! • Assays for ethanol use alcohol dehydrogenase! • Rate of change of NAD+ to NADH! • Rate of increase in light absorption is proportional to ethanol concentration!

6! 8/26/12!

Immunoassays!

• Created due to need to measure a very low concentraiton of an analyte! • Quick, inexpensive! • Combination of ! • High afﬁnity! • High selectivity! • 2 common types!

Immunoassays! • Non-competitive! • Analyte is sandwiched b/w 2 antibodies! • Difﬁcult with small drugs! • Competitive! • Analyte from specimen competes for number of Ab binding sites with a labeled version of the analyte!

Non-competitive! “Sandwich” assay!

7! 8/26/12!

8! 8/26/12!

Competitive! “Inverse” assay!

9! 8/26/12!

Competitive!

From Goldfranks 9th edition!

Immunoassays!

• Nonisotopic immunoassays are common! • Limited to those in high demand! • Lots of effort, high development cost! • Low production cost! • Homogenous immunoassays! • Measure differences in bound and free labels!

10! 8/26/12!

Immunoassays! • Old - radio immunoassays! • New - spectrophotometric! • Enzyme multiplied immunoassay technique (EMIT)! • Fluorescence polarization immunoassay (FPIA)! • Kinetic inhibition of microparticles in solution (KIMS)! • Cloned enzyme donor immunoassay (CEDIA)!

EMIT !

Goldfranks 9th edition!

Magnetic Microparticle!

Goldfranks 9th edition!

11! 8/26/12!

Chromatography! Separation and Detection! • Encompasses several related techniques where analyte specificity is achieved by physical separation! • Partition analytes between a stationary and mobile phase! • Stationary: very fine particles aranged in a thin layer! • Mobile (moving): phase flows thru spaces between particles! • After separation--need a detection phase! • However, can have provisional identification based on their characteristic velocities, distance traveled, or time to traverse the chromatography column! • Not specific!

Rf!

• Retention time! • Time required to traverse the column! • Retardation (planar) or retention (column)! • Separation based on polarity, afﬁnity, solubility, etc.! • Standard for each analyte!

Thin Layer Chromatography! • Extracts dissolved in a solvent! • Placed on thin layer of silica gel! • Plates placed vertically in closed tank! • Solvent drawn upwards thru the gel! • Xenobiotics are drawn up the gel! • Hydrophobic rapidly! • Hydrophilic slowly!

12! 8/26/12!

TLC!

Goldfranks 9th edition!

Thin Layer Chromatography! • Fast, easy, inexpensive! • Polar silica medium! • Low sensitivity (~ 1000 ug/L)! • Low speciﬁcity! • Used in drug screens! • Requires large amount of material! • Done on urine, gastric aspirate!

TLC Drawbacks!

• Multiple steps! • Slow, labor intensive! • Interpretation of spots! • Difﬁcult to quantitate! • Used to demonstrate the presence of a drug!

13! 8/26/12!

High-Performance Liquid Chromatography! • Stationary phase packed in a column! • Mobile phase pumped through under pressure! • Allows better separation in less time! • Identiﬁcation by retention time in a column! • Also use ultraviolet spectroscopy ! • Measuring light absorbance allows the amount of the xenobiotic to be determined!

Reverse phase chromatography! • Non-polar stationary phase and hydrophilic mobile phase! • Polar out ﬁrst, non-polar retained! • Hydrophobic stationary! • Hydrophilic mobile phase! • Most common HPLC technique! • TLC can be done this way too!

High-Performance Liquid Chromatography! • Expensive, complex, fast! • Separation under pressure! • Quantitation, detection > 10 ug/L (10 fold difference)! • Low speciﬁcity for same class! • One at a time; narrow range of polarity! • Measure serum concentration for which no immunoassay is available! • Can’t analyze multiple specimens!

14! 8/26/12!

HPLC!

Gas Chromatography! • Similar to HPLC except the moving phase is a gas! • Nitrogen, helium! • Low ﬂow resistance of gas! • High ﬂow rates! • Less time! • Temperature gradient allows multiple xenobiotics to be analyzed at once! • Partitioning depends on natural volatility! • Temp < 572°F (300°C)!

Gas Chromatography!

• Expensive! • Screening or conﬁrmatory! • High speciﬁcity and sensitivity! • Quantitation and broad screening ! • Temperature gradient! • Analyte volatilized in injector, column kept hot ! • Heat labile cannot be assessed!

15! 8/26/12!

Gas Chromatography!

• Substances have characteristic retention times! • Column outﬂow detectors! • Flame-ionization - organic compounds! • Most common detector! • Nitrogen-phosphorous - N or P compounds (many drugs)!

Mass Spectrometry!

• Can serve as highly sensitive GC detector! • Analyte separated from the gas carrier and then ﬁltered to a detector! • Extremely high speciﬁcity! • Unparalleled ID of organic chemicals! • Shoots electrons → fragment ions! • Characteristic of the parent molecule!

Mass Spectrometry!

16! 8/26/12!

MS Limits!

• Cannot separate enantiomers! • D-methamphetamine (DOA)! • L-methamphetamine (inhalers)! • Vick’s inhalers, metabolite of selegiline ! • “L” = legal! • Can separate by a chiral analysis !

LC/MS/MS!

• High sensitivity and speciﬁcity extended by the related hybrid technique of liquid chromatography/tandem mass spectrometry!

GC/MS!

• Expensive equipment! • Most common gold standard, in ~1 hour! • Most speciﬁc and sensitive! • Sensitivity 2 – 10 ug/L!

17! 8/26/12!

Relative Comparison!

Method! Speed! Cost! Spot Test! Fast! $! Spectrochemical! Medium! $! Immunoassay! Medium! $$! TLC! Slow! $$! HPLC! Medium! $$! GC! Medium! $$! GC/MS! Slow! $$$! LC/MS/MS! Medium! $$$$!

*Reproduced from Goldfranks 9th edition!

Hair Analysis!

• Hair grows ~1 cm/month ! • Can utilize any methodology! • Contamination is greatest ﬂaw!

Drug Screens!

18! 8/26/12!

NIDA-5!

• Amphetamines!

• Cannabinoids!

• Cocaine!

• Opiates!

• Phencyclidine!

Cocaine!

• Highly speciﬁc!

• Benzoylecgonine!

• Inactive metabolite!

• No false positives!

• Acute: 2-3 days!

• Chronic: 1 week!

Tetrahydrocannabinol!

• Tetrahydrocannabinoic acid!

• Inactive metabolite!

• Occassional use: 3 days!

• Chronic use: > 1 month!

• 11-OH THC!

19! 8/26/12!

The “second hand smoking” defense! • Studies of passive exposure!

• Conﬁned areas!

• Mixed results!

• Cutoffs: 20 ng/ml!

• Levels: ~6 ng/ml!

• NIDA 50 ng/ml!

THC! False Positives!

• Dronabinol!

• Efavirenz!

• NSAIDs!

• Promethazine!

• Riboﬂavin!

• Ethacryinc acid!

Opioids!

• Morphine, codeine, heroin!

• Cross reactivity depends on assay!

• Synthetics showlittle or nocross-reactivity!

• Speciﬁc directed assays available!

20! 8/26/12!

“Poppy Seed” Defense!

6-MAM!

Challenges! Dextromethorphan!

• Dextrorphan – major metabolite! • Levorphanol – “L” enantiomer, also opioid! • Can’t differentiate optical enantiomers by MS!

Methadone! False Positives!

• Quetiapine! • Doxylamine! • Olanzapine! • Diphenhydramine & Verapamil metabolites!

*Tests for other sythetic and semisynthetics are available!

21! 8/26/12!

PCP!

• Phencyclidine! • False Positives! • DXM, Ketamine ! • Diphenhydramine! • Venlafaxine, bupropion! • Metabolites of PCP! • False Negatives?!

Benzodiazepines!

• Metabolized to oxazepam!

• Chlordiazepoxide!

• Diazepam!

• Temazepam!

• Glucuronides (lorazepam)!

Amphetamines!

• Amphetamine assay plagued with false positives!

• Fails to detect “designer” amphetamines!

• Bupropioin (cathinone)!

• Pseudoephedrine!

22! 8/26/12!

Nasal Inhalers!

• Can contain l-methamphetamine! • less potent isomer of d-methamphetamine! • Both turn immunoassays positive! • Difﬁcult to distinguish with mass spec! • Optical enantiomers!

TCA Challenges!

• Cross react with ringed xenobiotics! • Carbamazepine! • Phenothiazines! • Diphenhydramine!

• Major challenge is timing!

Federal Cutoffs (ng/mL)!

23! 8/26/12!

Adulteration! • 2004: First mandatory guidelines for federal workplace testing (SAMHSA)! • Tampering! • In vivo adulteration ! • In vitro adulteration! • Urine substitution! • Little evidence to support any product working consistently !

Specimen Validity! • Appearance! • Temperature! • 90-100oF! • pH testing! • pH 3-11! • Speciﬁc gravity! • Cr < 20 mg/dl! • > 1.003! • Creatinine! • > 20 ppm!

In Vivo Adulteration" “Ingest prior to urination”! • Primary mechanisms: dilution and excretion! • Water and diuretics! • Fool visual inspection! • Interfere with creatinine level checks! • Water, Naturally Klean herbal tea, golden seal, HCTZ! • B-vitamins, riboflavin, creatinine! • Riboflavin may cause fluorescent urine!

24! 8/26/12!

In Vitro Adulteration" “Add after urination”! • Interfere with an immunoassay or convert a target drug to a different compound! • Sold under many names but contain:! • Glutaraldehyde! • Sodium or potassium nitrate! • Pyridinium chlorochromate! • Peroxide/peroxidase! • Household products, too!

In Vitro Adulteration" “Add after urination”! • Glutaraldehyde: interferes with immunoassay, denatures! • Nitrite: decreased ion concentration! • Pyridinium: decrease in pH levels! • Peroxidase: oxidizing drugs and metabolites! • Bleach: decreases detection! • Vinegar: interferes with detection; lowers pH!

Others!

• Acids and bases (i.e. lemon juice, NaOH)! • Oxidizing agents (i.e. bleach, peroxide)! • Denaturants (i.e. glutaraldehyde)! • Eyedrops (i.e. benzalkonium chloride)! • Reduces binding of immunoassay! • Soap (created FP and FN)!

25! 8/26/12!

Urine Substitution! Ontario Smith!

Questions?!

Cholinesterases!

• Butyrylcholinesterase (plasma cholinesterase)! • Metabolizes cocaine, succinylcholine! • Falls first, recovers first! • Red Cell Acetylcholinesterase! • Reflects activity at the NMJ ! • Low concentrations in people! • Serve as markers for poisonings!

26! 8/26/12!

Cholinesterases! Butrylcholinesterase! Red Cell!

• Malnutrition!

• Hereditary deﬁciency!

• Iron deﬁciency anemia!

• Hepatic disease!

• Chronic Illness!

• Succ, codeine, morpine!

• Pernicious anemia!

Anion Gap Reliability!

+ - - AG = Na - (Cl + HCO3 )! • MUDPILES! • Cyanide, CO, Acetaminophen, Toluene, Theophylline, Hydrogen Sulﬁde! • Increase unmeasured anions! • Dehydration, sodium salts, antibiotics! • Decreased unmeasured cations! • Mag, Ca, and K!

Anion Gap Reliability! Low Anion Gap! • Hypercalcemia! • Hypermagnesemia! • Hyperkalemia! • Lithium! • Multiple myeloma! • Hypoalbuminemia!

27! 8/26/12!

Forensic Toxicology!

Forensics!

• Aid medical / legal investigation of death, poisoning, and drug use! • Concern is not legal outcome, but obtaining and interpreting results! • Chain of Custody! • List everyone who handled a specimen (special couriers)! • Where specimen was at any given time!

DEA Schedule!

• Controlled Substances Act (1970)! • I - High abuse potential, no medical use! • Heroin, PCP, LSD, GHB, MDMA, etc. ! • II - High abuse potential, but has medical use! • Most opioids, barbiturates, methylphenidate, etc.! • No reﬁlls! • III - Ketamine, buprenorphine, GHB! • IV - BZD, long acting barbiturates, modaﬁnil! • V - Codeine cough suppressants, pregabalin, diphenoxylate!

28! 8/26/12!

Medical Review Ofﬁcer!

• Licensed physician! • “Expert in drug and alcohol testing and the application of federal regulations to the process.”! • Consultant! • Business, industry, labor, government or academia! • Relating to prevention, detection and control of drug abuse in the workplace!

Drug Abuse Testing!

• Strict, invariable procedures, federally mandated (DOT)! • Certiﬁed lab, separate from all other testing! • MRO interpretation required! • COAT-PE! • ‘SAMHSA 5’ - cocaine, opioids, amphetamine, THC, PCP! • ETOH breath testing! • Screening, then conﬁrmatory if + by cutoffs!

Post Mortem Toxicology!

29! 8/26/12!

Post Mortem Changes" “Necrokinetics”! • Postmortem interval! • Deﬁned by the degree of decomposition! • Decomposition! • Autolysis: enzymes are released and chemicals move down gradients! • Putrefacation: digestion by bacteria! • Anthropophagia: feeding on remains!

Specimens! • Blood! • Reported as “blood concentrations”! • From femoral or subclavian (low glucose)! • Right heart blood (elevated glucose)! • Vitreous! • Avascular, acellular so well protected! • Aqueous content > blood! • Urine! • Bladder serves as a “reservoir”!

Interpretation Confounders!

• Postmortem redistribution! • Postmortem metabolism! • Continuous absorption! • Xenobiotic stability! • Chemical interactions! • Expected clinical effects! • Comorbid, tolerance, genetics!

30! 8/26/12!

Other sources!

Redistribution Doesn’t Occur!

Leikin JB. Clin Tox 2003;41(1):47-56.!

Legal Ethanol!

31! 8/26/12!

Legal Ethanol!

• State determines own legal driving limit! • DWI, DUI, DWAI, etc.! • Zero tolerance! • “Illegal per se”! • What is “drunk”?! • ~ 150 mg/dL!

The Barman’s Paradox!

• Legally drunk 50-80 mg/dL or 0.05-0.08 g/dL [%]! • Serving to intoxicated is prohibited! • No better at determining “drunk”!

Blood Ethanol Testing! • The law = whole blood! • The lab = serum / plasma! • [serum] = [plasma]! • ETOH does not enter RBCs well! • [serum]/[blood] ~ 1.15! • The lab measures higher than the law! • [Breath ethanol] mmol/L X 2100 = [Blood ethanol] mmol/L!

32! 8/26/12!

The Clues" 1. Wide turns!

2. Straddling / driving on lane marker!

3. Nearly striking object or another vehicle!

4. Weaving / swerving!

5. Going too slow (> 10 MPH below speed limit)!

6. Stopping inappropriately / without cause!

7. Following too closely!

8. Erratic braking!

9. Driving into opposing / crossing trafﬁc!

10. Slow response to trafﬁc signals!

*NHTSA Top 10 in descending order of probability of intoxication!

Goldfranks 9th edition!

What’s in a Drink?! Approximately! • 10 oz beer (5%)! • 4 oz of wine (12%)! • 1 oz liquor (50%)! • All ~ 15 g ETOH! • 100-125 mg/kg/hr! • Avg adult: 7-10 g/hr or 15-20 mg/dL/hr! • Tolerance: 30 mg/dL/hr!

33! 8/26/12!

Laboratory Methods!

• Enzymatic! • ADH + ETOH = NADH (340 nm)! • FP with elevated lactate (lactate converted to pyruvate increases NADH formation)! • GC! • Can detect other volatiles (“toxic”)!

The Numbers!

• Speciﬁc gravity 0.8 g/ml! • Vd 0.6 L/kg! • 1-1.5 shot(s) = 30 ml! • mmol/L = (mg/dL)/4.6 ! • % = grams/100 ml!

Sample Calculation! 50 kg man drinks 1 shot of 80 proof alcohol!

1.5 oz (30 ml/oz) = 45 ml! 40% of 45 ml = 18 ml! 18 ml X 0.8 g/ml = 16 g which is 16,000 mg!

50 kg (0.6 L/kg) = 30 L (10 dL /L) = 300 dL!

16,000 mg/300 dL = 80 mg/dL!

34! 8/26/12!

“Breathanol” !

• [expired air] surragote for [blood] (sort of)! • Henry’s law! • [ethanol] remains constant throughout respiratory tract! • Mean breath:blood ratio 1:2100 used in forensics! • Many confounders! • [Breath ethanol] mmol/L X 2100 = [Blood ethanol] mmol/L ! • Breath units underestimate BAC!

References! 1. Goldfranks 9th Edition! 2. Jaffee WB et al. Is this urine really negative? A systematic review of tampering methods in UDS and testing. J of Subs Abu Treat 2007;33:33-42.! 3. Leikin JB, et al. Post-mortem toxicology: What the dead can and cannot tell us. Clin Tox 2003;41(1):47-56.! 4. Shannon: Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, 4th edition 2007!

Photo References!

1. http://www.offthemark.com/cartoons/1998-12-22.gif! 2. http://www.ecardica.com/ecards/postcards%5Cfunny%20pictures/drug_testing_at_pepsi.jpg! 3. http://www.ﬂickr.com/photos/cornellfungi/2828851149/sizes/z/in/photostream/!

4. http://www.cartoonstock.com/newscartoons/cartoonists/jlv/lowres/jlvn386l.jpg! 5. http://cdn1.images.videobash.com/photos/000/022/977/22977.jpg! 6. http://26.media.tumblr.com/tumblr_lykxob8LmS1qfcutbo1_500.jpg! 7. http://www.thcfinder.com/uploads/files/marijuana-mcdonalds.jpg! 8. http://www.cannabisculture.com/v2/files/images/2493-homer-phish.jpg!

9. http://www.myfreewallpapers.net/movies/pages/the-good-the-bad-and-the-ugly.shtml! 10. http://www.sodahead.com/entertainment/bristol-palin-gets-her-own-reality-show-laughable-or-legit/question-1778221/?page=4&link=ibaf&q=meth +mouth&imgurl=http://farm4.static.ﬂickr.com/3063/2780829321_9f3f10177b.jpg! 11. http://images.teamsugar.com/ﬁles/upl0/1/13254/08_2008/headline.preview.jpg! 12. http://www.cdc.gov/Features/AlcoholConsumption/!

13. http://sharetv.org/shows/seinfeld/episodes/346227! 14. http://ourweed.com/funny-marijuana-pictures/! 15. http://cdn.bleacherreport.net/images_root/slides/photos/000/840/267/52000365_display_image.jpg?1302153389! 16. http://www.4aceswholesale.com/cart/images/New-Whizzinator-w.jpg! 17. http://theestreet.com/wp-content/uploads/2012/01/entourage.jpg!

18. http://thebeautybrains.com/2007/08/16/the-scandalous-secret-beauty-companies-dont-want-you-to-know/! 19. http://2pep.com/funny%20pics/cool_funniest_hilarious_pictures/super_funny_hilarious_pictures_of_25_epic_drunk_shaming_photos_20090603_1483976130.jpg! 20. http://www.cartoonstock.com/newscartoons/cartoonists/mba/lowres/mban1080l.jpg! 21. http://www.thecrimsoncrow.com/wp-content/uploads/2011/05/heroin-up-his-butt-billboard-12835-1306154078-11.jpg! 22. http://images3.wikia.nocookie.net/__cb20111221073446/simpsons/images/7/7b/Eliza_Simpson_Detective.png!

23. http://amazingdata.com/mediadata57/Image/crazy_funny_amazing_shocking_awesome_sexy_200907311639075608.jpg! 24. http://mimg.ugo.com/201103/3/8/7/176783/cuts/charlie-sheen-crazy-eyes_288x288.png!

35! Autonomics/Neurotransmitters

Autonomics/ Neurotransmitters G. Patrick Daubert, MD Sacramento, CA

Some (most) material plundered from various mentors and other talented toxicologists, with permission 1

Autonomic Nervous System

ACh ACh

ACh ACh ACh NE NMJ Hollow end-organs CNS

Muscarinic Nicotinic

2 Courtesy Cynthia Aaron, MD

ACh ACh CNS

ACh NE Sympathetic Secreting ACh innervation hollow end- ACh to heart, lungs, etc organs: Sympathetic Heart ganglion Lungs GI Striated muscle ACh Muscarinic Nicotininc

3 Courtesy Cynthia Aaron, MD

1 Autonomics/Neurotransmitters

Acetylcholine

ACh Receptors n Nicotinic Receptors n CNS (mainly spinal cord) n Preganglionic autonomic neurons (sympathetic and parasympathetic) n Adrenal neuronal receptors n Skeletal muscle neuromuscular junction

ACh Receptors n Muscarinic Receptors n CNS (mainly brain) n Postganglionic parasympathetic nerve endings n Postganglionic sympathetic receptors for most sweat glands

2 Autonomics/Neurotransmitters

Agents that Induce ACh Release

n Aminopyridines n Latrodectus venom n Carbachol n Guanidine

n Alpha2-adrenergic antagonists ( ACh release from parasympathetic nerve endings)

Acetylcholinesterase Inhibitors

n  [ACh] at both nicotinic and muscarinic receptors n Produce a variety of CNS, sympathetic, parasympathetic, and NMJ effects n Carbamates n Organophosphorus compounds n Nerve agents n ‘Central’ AChE inhibitors (donepezil)

Autonomic Nervous System

ACh ACh

HTN, tachycardia, ACh ACh ACh NE mydriasis NMJ Seizures, coma Hollow end-organs DUMBBELS CNS Fasciculations, Muscarinic Nicotinic respiratory paralysis

9 Courtesy Cynthia Aaron, MD

3 Autonomics/Neurotransmitters

Question n Which one of the following agents inhibits acetylcholine release? A. Bupropion B. Disulfiram C. Mirtazapine D. Tizanidine E. Yohimbine

Answer n Which one of the following agents inhibits acetylcholine release? A. Bupropion B. Disulfiram C. Mirtazapine D. Tizanidine E. Yohimbine

Agents that Block ACh Release n Alpha2-adrenergic agonists n Botulinum toxin n Crotalinae venoms n Elapidae beta-neurotoxins n Hypermagnesemia

4 Autonomics/Neurotransmitters

Nicotinic Receptor Agonists n Initial activation of receptors n Prolonged depolarization leads to inhibition n Initial sympathomimetic, GI distress, fasciculations, seizures n Then  BP,  HR, paralysis, coma

Nicotinic Receptor Agonists n Nicotine alkaloids (nicotine, coniine) n Carbachol (mainly muscarinic effects) n Methacholine (minimal effects) n Succinylcholine (initial effects)

Nicotinic Receptor Antagonists n NMJ blockers: weakness, paralysis n Curare, atracurium, alpha-bungarotoxin n Peripheral neuronal blockers: autonomic ganglionic blockade n Trimethaphan (not entirely specific, may produce NMJ blockade)

5 Autonomics/Neurotransmitters

Nicotinic Indirect Agonists n Bind to distinct allosteric sites on the nicotinic receptor, not ACh binding site (enhanced channel opening) n Physostigmine n Tacrine n Galantamine

Nicotinic Indirect Antagonists n Bind to distinct allosteric sites on the nicotinic receptor, not ACh binding site (decreased channel opening) n Chlorpromazine n Ketamine n Phencyclidine (PCP) n Local anesthetics n Ethanol n Corticosteroids

Buzzwords n Nicotine alkaloids (nicotine, coniine) n Trick to remember the hemlocks – n Water Gate Candidate Scandal (Water hemlock, GABA, Cicutoxin, Seizures) n Poison Control Network (Poison hemlock, Coniine, Nicotine)

6 Autonomics/Neurotransmitters

Muscarinic Agonists n Peripheral: DUMBBELS n Central: Sedation, dystonia, coma, seizures n Muscarine n Bethanachol n Pilocarpine

Question n A 35-year-old man presents to hospital with vomiting, diarrhea, profuse sweating, and mild bradycardia. What is the most likely mushroom he ingested A. Amanita phalloides B. Clitocybe dealbata C. Cortinarius orellanus D. Gyromitra esculenta E. Tricholoma equestre

7 Autonomics/Neurotransmitters

Muscarinic Antagonists n Peripheral: mydriasis, anhidrosis, tachycardia, urinary retention, ileus, dry and flushed skin n Central: delirium, agitation, hallucinations, coma n Atropine n Benztropine n Scopolamine n Phenothiazines n Cyclic antidepressants

Histamine

H1 Receptor Antagonists n 1st generation n 2nd generation n Cross the BBB n Classified as non-sedation n Diphenhydramine n Selectively bind peripheral H1 receptors n Lower binding affinity for cholinergic receptors n Reduced antimuscarinic effects and CNS depression

8 Autonomics/Neurotransmitters

H1 Receptor Antagonists

CYP3A4 Terfenadine  terfenadine carboxylate

CYP3A4 Astemizole  desmethylastemizole n Parent compounds block Ikr n Increased risk of TdP n Withdrawn from market in 1998

H1 Receptor Antagonists n Clinical manifestations n CNS depression n Antimuscarinic effects n Cardiac n Na and Ikr blockade with diphenhydramine (QRS and QT prolongation)

H2 Receptor Antagonists n Hydrophilic – poor access to CNS n Alter gastric pH n May impact absorption of acid-labile drugs n e.g., ketoconazole

9 Autonomics/Neurotransmitters

Cimetidine n Only H2 receptor antagonist to inhibit P450 isozymes (specifically CPY3A4) n Useful in dapsone-induced methemoglobinemia n Useful in toxicity from Gyromitra esculenta n Associated with myelosuppression if taken with drugs associated with BM suppression n Rapid IV dosing has resulted in bradycardia, hypotension, and cardiac arrest

Serotonin

Serotonin n Indole alkylamine n Synthesis from tryptophan n Central neurotransmitter n Precursor for melatonin n Serotonergic neurons lie in or near midline nuclei in brainstem and project to various parts of cerebrum n 7 classes of receptors with at least 15 subtypes

10 Autonomics/Neurotransmitters

Serotonin Synthesis & Metabolism

Tryptophan

tryptophan hydroxylase (rate limiting)

5-OH-Tryptophan

l-aromatic acid decarboxylase

Serotonin

MAO, aldehyde dehydroxylase

5HIAA

5HIAA: 5-OH-indoleacetic acid 31

Serotonin Agonists

n Enhanced synthesis n L-tryptophan (associated with eosinophilia myalgia syndrome) n 5-OH-tryptophan

Increased Serotonin Release

n Amphetamines (MDMA) n Cocaine n Codeine derivatives n Dexfenfluramine n Fenfluramine n L-Dopa

11 Autonomics/Neurotransmitters

Other Serotonins n Inhibit Serotonin Metabolism n MAO-I n Unknown Serotonin Effect n Lithium

Inhibit Serotonin Uptake

Amphetamines Meperidine

Cocaine Dextromethorphan

Cyclic antidepressants Carbamazepine

SSRIs Lamotragine

St. John’s Wart (Hypericum perforatum)

Direct Serotonin Antagonists

5-HT1 Methysergide, cyproheptadine

5-HT2

5-HT2 Trazadone, nefazodone

5-HT2A Risperidone, olanzapine, ziprasidone, quetiapine, cyclic antidepressants 5-HT2C

5-HT3 Ondansetron, granisetron, metoclopramide

12 Autonomics/Neurotransmitters

Adenosine

Adenosine Receptor Antagonists n Methylxanthines n Theophylline n Caffiene n Theobromine

Normal Adenosine Accumulation and Physiologic Response n Adenosine accumulates in the extracellular space during conditions of fatigue n ATP utilization > ATP synthesis n Seizures, hypoxia or ischemia promotes accumulation n Hypoxia  adenosine kinase activity n  Adenosine promotes sleepiness

13 Autonomics/Neurotransmitters

Adenosine A1 Receptors - CNS

n Presynaptic n Inhibits adenylyl cyclase   cAMP levels n Inhibits presynaptic N-type Ca2+ channels n  Neurotransmitter release n GABA, NE, 5-HT and Ach n Strongest inhibition on glutamate release

Neuroscience. 112(2):319-329 (2002) 40

Adenosine AutoReceptors and Glutamate Neurotransmission

Adenosine R1 Ca

Glu Ca R

Glu AP A Glu

Post Pre

Adenosine A1 Receptors - CNS n Postsynaptic n Enhances outward K+ channels n Enhances inward Cl- influx n Results in induced hyperpolarization

Adenosine R 1 Pre

K+ (-) A Cl- Glu

Post 42

14 Autonomics/Neurotransmitters

Adenosine A2 Receptors - CNS n Presynaptic n Activates adenylyl cyclase   cAMP levels n Inhibits L-type & N-type calcium channels n Vasodilation n Only the A2A subtype of A2 receptors have significant activity n Effects of A1 receptors predominate over A2A

n A1 receptors are more numerous

n Adenosine affinity for A1 > A2A receptors 43

Adenosine A2A Receptors n Adenosine A2A receptors are prominent in endothelial cells (vasodilation) n A2A receptor activity inhibits locomotor activity by inhibiting dopamine at D2 receptors n A2A receptors serve as check-balance for A1

Adenosine A1 Antagonism n Cardiac n  HR n  Atrial inotropicity n  Response to epinephrine n CNS n  Excitatory amino acid (EAA) release n Renal n Diuresis

15 Autonomics/Neurotransmitters

Question n Which of the following laboratory abnormalities is consistent with acute theophylline toxicity? A. Hyperchloremia B. Hypernatremia C. Hyperphosphatemia D. Hypokalemia E. Hypoglycemia

Questions?

Good Luck!!

16 1 AUTONOMIC HOMEOSTASIS

CORE CONTENT 2.1.11.4 Drugs That Affect Autonomic Homeostasis 2.1.11.4.1 Anticholinergics 2.1.11.4.2 Antihistamines 2.1.11.4.3 Antiserotinergics 2.1.11.4.4 Cholinergics (eg, nicotine) 2.1.11.4.5 Ergot and derivatives 2.1.11.4.6 Methylxanthines 2.1.11.4.7 Sympathomimetics AUTONOMIC NERVOUS SYSTEM (ANS) The ANS is a neuronal network that enables us to function without consciously controlling and managing our bodies. In order to accomplish this specific neurotransmitters and neuromodulators are involved working through many different pathways. The system is also an integral part of neuroendocrine and immunomodulary systems.

LLCDoc Quit 2007 2 ACETYLCHOLINE Acetylcholine (ACh) was the first neurotransmitter (NT) discovered and is the major NT in the peripheral nervous system (PNS) • Acetylcholine o Produced from acetyl-CoA (glucose metabolism) and choline o Acetyl-CoA and choline are independently synthesized in the neuronal cell body and transported along the axon to the synapse for conjugation into ACh o Release is mediated via Ca influx and presynaptic vesicles interacting with cell membrane docking complex (process disrupted by botulinum toxin) o In order to allow repolarization, ACh must be removed rapidly (ie, AChE) o Two classes of ACh receptors . Nicotinic . Muscarinic Nicotinic Receptors (nAChRs) o CNS (mainly spinal cord) o Preganglionic autonomic neurons (sympathetic and parasympathetic) o Adrenal neuronal receptors o Skeletal muscle neuromuscular junction • Nicotinic Receptor Agonists o Initial activation of nicotinic receptors . Prolonged depolarization leads to inhibition . Initial sympathomimetic, GI distress, fasciculations, seizures . Then i BP, i HR, paralysis, coma o Nicotine alkaloids (nicotine, coniine) . Trick to remember the hemlocks – • Water Gate Candidate Scandal (Water hemlock, GABA, Cicutoxin, Seizures) • Poison Control Network (Poison hemlock, Coniine, Nicotine) o Carbachol (mainly muscarinic effects, primarily in ophthalmic use) o Methacholine (minimal effects, does not cross BBB, methacholine test in asthma) o Succinylcholine (initial effects) • Nicotinic Receptor Antagonists o Neuromuscular junction (NMJ) blockers: weakness, paralysis . Curare, atracurium, alpha-bungarotoxin (prevents AChR channel opening) o Peripheral neuronal blockers: autonomic ganglionic blockade . Trimethaphan (not entirely specific, may produce NMJ blockade) • Nicotinic Indirect Agonists o Bind to distinct allosteric sites on the nicotinic receptor, not ACh binding site (enhanced channel opening) . Physostigmine . Tacrine . Galantamine 3 • Nicotinic Indirect Antagonists o Bind to distinct allosteric sites on the nicotinic receptor, not ACh binding site (decreased channel opening) . Chlorpromazine . Local anesthetics . Ketamine . Ethanol . Phencyclidine (PCP) . Corticosteroids • Muscarinic Receptors o CNS (mainly brain) o Postganglionic parasympathetic nerve endings o Postganglionic sympathetic receptors for most sweat glands • Muscarinic Agonists o Peripheral: DUMBBELS o Central: Sedation, dystonia, coma, seizures o Muscarine o Bethanachol o Pilocarpine • Muscarinic Antagonists o Peripheral: mydriasis, anhidrosis, tachycardia, urinary retention, ileus, dry and flushed skin o Central: delirium, agitation, hallucinations, coma . Atropine . Phenothiazines . Benztropine . Cyclic antidepressants . Scopolamine • Agents that Induce ACh Release o Aminopyridines o Latrodectus venom (acts as a transmembrane pore and allows Ca influx into cells) o Carbachol o Guanidine o Alpha2-adrenergic antagonists (h ACh release from parasympathetic nerve endings) • Acetylcholinesterase Inhibitors o h [ACh] at both nicotinic and muscarinic receptors o Produce a variety of CNS, sympathetic, parasympathetic, and NMJ effects (DUMBBELS) o Carbamates o Organophosphorus compounds o Nerve agents o ‘Central’ AChE inhibitors (donepezil) • Agents that Block ACh Release o Alpha2-adrenergic agonists o Botulinum toxin (prevents NT vesicle from docking with cell membrane) o Crotalinae venoms o Elapidae beta-neurotoxins o Hypermagnesemia (blocks presynaptic N-subtype calcium channels) 4 HISTAMINE

Histamine interacts with four types of receptors H1-4. H1 receptors use G-protein second messenger systems. H1 receptors are diverse and have the most clinical toxicity in overdose. They are located in the CNS, heart and vasculature, airways, sensory nerves, Gastrointestinal smooth muscles cells, immune cells, and adrenal medulla. H2 receptors are located mainly in the gastric mucosa, but also exist in the heart, lungs, CNS, uterus, and immune cells. H3 receptors serve as neuromodulators for the release of other NT, including histamine. H4 receptors are involved in hematopoietic functions and eosinophil chemotaxis. • Antihistamines o 1st generation . Cross the BBB . Diphenhydramine most clinically relevant for boards o 2nd generation . Classified as non-sedating . Selectively bind peripheral H1 receptors . Lower binding affinity for cholinergic receptors . Reduced antimuscarinic effects and CNS depression • H1 Receptor Antagonists o Historical perspective . Terfenadine gCYP3A4g terfenadine carboxylate . Astemizole gCYP3A4gdesmethylastemizole • Parent compounds block Ikr • Increased risk of TdP • Withdrawn from market in 1998 o Clinical manifestations . Rapid onset with potential for long duration . CNS depression . Antimuscarinic effects . Cardiac • Sodium channel and Ikr blockade with diphenhydramine (QRS and QT prolongation) o H2 Receptor Antagonists . Hydrophilic – poor access to CNS . Alter gastric pH . May impact absorption of acid-labile drugs • e.g., ketoconazole . Cimetidine • Only H2 receptor antagonists to inhibit P450 isozymes (specifically CPY3A4) • Useful in dapsone-induced methemoglobinemia • Useful in toxicity from Gyromitra esculenta • Associated with myelosuppression if taken with drugs associated with BM suppression • Rapid IV dosing has resulted in bradycardia, hypotension, and cardiac arrest 5 ADENOSINE Adenosine is a neuromodulator primarily involved in the reduction of excitatory NT release including glutamate, GABA, norepinephrine, serotonin, and ACh. Its greatest effect is in the inhibition of glutamate release and neuronal excitation. • Adenosine receptor antagonism o CNS: excitation due to sustained and unmodulated release of glutamate and other excitatory neurotransmitters (A1 receptors) o Cardiac: tachycardia due to an increase rate of signaling in pacemaker cells (A1 receptors) o Vasculature: vasoconstriction of CNS, cardiac, and peripheral vascular (A2 receptors) • Adenosine A1 Receptors - CNS o Postsynaptic o Enhances outward potassium channels o Enhances inward Chloride influx o Results in induced hyperpolarization • Adenosine A2 Receptors - CNS o Presynaptic o Activates adenylyl cyclase increasing cAMP levels o Inhibits L-type & N-type calcium channels o Vasodilation o Only the A2A subtype of A2 receptors have significant activity • Effects of A1 receptors predominate over A2A o A1 receptors are more numerous o Adenosine affinity for A1 > A2A receptors o Adenosine A2A Receptors o Adenosine A2A receptors are prominent in endothelial cells (vasodilation) o A2A receptor activity inhibits locomotor activity by inhibiting dopamine at D2 receptors o A2A receptors serve as check-balance for A1 • Adenosine A1 Antagonism o Cardiac . h HR . h Atrial inotropicity . h Response to epinephrine o CNS . h Excitatory amino acid (EAA) release o Renal . Diuresis • Other methylxanthine effects o Increased catecholamine release o Phosphodiesterase (PDE) inhibition: results in increased levels of cyclic adenosine monophosphate (cAMP) that serves to augment adrenergic effects o Increased intracellular calcium uptake and storage: clinical significance is unknown 6 SEROTONIN Serotonin is an indole alkylamine synthesized from tryptophan. Serotonergic neurons lie in or near midline nuclei in brainstem and project to various parts of cerebrum. There are 7 current serotonin receptor classes (5-HT1-7) with at least 15 subtypes. Serotonin has a wide variety of functions including vasoconstriction, inhibition of gastric secretion, enhanced platelet aggregation, stimulation of smooth muscle, and is naturally present in the central nervous system (CNS) as a neurotransmitter. Hallucinogenic drugs produce their electrophysiologic effects primarily through partial agonism at 5-HT2 receptors. Serotonin syndrome involves 5-HT1A and 5-HT2A receptors. • Serotonin synthesis and metabolism Tryptophan

tryptophan hydroxylase (rate limiting) 5-OH-Tryptophan

l-aromatic acid decarboxylase Serotonin

MAO, aldehyde dehydroxylase 5HIAA

• Serotonin Agonists o Enhanced synthesis . L-tryptophan (associated with Eosinophilia Myalgia Syndrome – see Pharmaceutical Additives handout) . 5-OH-tryptophan • Direct Serotonin Agonists

5-HT1A Buspirone

5-HT1B Triptans 5-HT1D

Ergot alkaloids, LSD, mescaline, 5-HT2A psylocibin

Metoclopramide 5-HT4 Cisapride

• Increased Serotonin Release o Amphetamines (MDMA) o Dexfenfluramine o Cocaine o Fenfluramine o Codeine derivatives o L-Dopa 7 • Inhibit Serotonin Metabolism o MAO-I • Unknown Serotonin Effect o Lithium • Inhibit Serotonin Uptake

Amphetamines Meperidine

Cocaine Dextromethorphan

Cyclic antidepressants Carbamazepine

SSRIs Lamotragine

St. John’s Wart

(Hypericum perforatum)

• Direct Serotonin Antagonists

5-HT1 Methysergide, cyproheptadine

5-HT2

5-HT2 Trazadone, nefazodone

5-HT2A Risperidone, olanzapine, ziprasidone, quetiapine, cyclic antidepressants 5-HT2C

5-HT3 Ondansetron, granisetron, metoclopramide

8 BUZZWORDS AND KEYPOINTS – AUTONOMIC HOMEOSTASIS

• Nicotine and similar alkaloids first stimulate then inactive nAChRs • Botulinum toxin prevents release of ACh • Alpha-latrotoxin (black widow) stimulates release of ACh and NE • Cimetidine CYP3A4 inhibitor o Useful in dapsone-induced methemoglobinemia o Useful in toxicity from Gyromitra esculenta • Terfendine and astemizole withdrawn for increased risk of TdP • Hallucinogenic drugs produce their effects primarity through 5-HT2 receptors • Serotonin syndrome primarily involves 5-HT1A and 5-HT2A receptors • Methysergide (serotonin antagonist) linked to retroperitoneal fibrosis • Fenfluramine and phentermine: weight loss drugs linked thickening of the leaflet and chordae tendineae of aortic and mitral valves, withdrawn from U.S. market in 1997 • Nicotine alkaloids (nicotine, coniine) o Trick to remember the hemlocks – . Water Gate Candidate Scandal (Water hemlock, GABA, Cicutoxin, Seizures) . Poison Control Network (Poison hemlock, Coniine, Nicotine)

9 QUESTIONS 1. A 22-year-old woman with resistant depression discontinued her phenelzine (Nardil) last week and arrives to hospital after using crack cocaine with complaints of abdominal pain. The medical resident prescribes the patient meperidine. She becomes agitated, hyperthermic, rigid, and hyperreflexic with a profound startle response. What best explains her reaction? A. Excessive GABA release from the meperidine B. Excessive glutamate stimulation in the cerebellum from cocaine C. Excessive serotonin release from the cocaine and meperidine D. Serotonin antagonism from the phenelzine E. Probable concomitant methamphetamine abuse

This patient’s symptoms are consistent with excessive serotonin or serotonin syndrome. The recent use of phenelzine along with the exposure to cocaine and administration of meperidine likely lead to significant amounts of serotonin in the CNS.

2. Which of the following statements is correct regarding neurotransmitters? A. Acetylcholine release is mediated via transmembrane pores unlike other neurotransmitters that use synaptic vesicles B. Adenosine antagonism leads to reduction in glutamate transmission C. Hallucinogenic drugs produce their effects primarily through partial agonism at 5-HT4 receptors D. Nicotine first stimulates but then blocks nicotinic receptors both in the CNS and in skeletal muscle E. Norepinephrine is the neurotransmitter of preganglionic sympathetic neurons

Nicotine first stimulates but then blocks nicotinic receptors both in the CNS and in skeletal muscle. Acetylcholine uses synaptic vesicles primarily for its release. Adenosine antagonism leads to an increase glutamate transmission. Hallucinogenic drugs primarily stimulate 5-HT2 receptors. Norepinephrine is a neurotransmitter of postganglionic sympathetic neurons.

3. Which of the following systems is involved with an organophosphate poisoning but not encountered in a diphenhydramine overdose? A. Central nervous system B. Glands (salivary, sweat, lacrimal) C. Skeletal muscle D. Stomach and intestines E. Urinary (bladder)

All of the organ systems listed except skeletal muscles contain muscarinic receptors. The nicotinic receptors of skeletal muscles would no be effected with an exposure to a drug with antimuscarinic properties such as diphenhydramine.

4. The antagonism of adenosine A1 receptors is most likely to result in which of the following clinical manifestations? A. Bradycardia B. Diaphoresis C. Hyperkalemia D. Hypotension 10 E. Seizures

Adenosine is primarily involved in the reduction of excitatory neurotransmitter release including glutamate, GABA, norepinephrine, serotonin, and acetylcholine. Its greatest effect is in the inhibition of glutamate release and neuronal excitation. Seizures are a manifestation of this excitation and may occur with adenosine A1 antagonism.

5. Which of the following best explains the mechanism of action for the botulinum toxin? A. Blockes presynaptic N-subtype calcium channels B. Inhibits magnesium binding at the NMDA receptor C. Phosphodiesterase (PDE) inhibition with increase cyclic adenosine monophosphate (cAMP) D. Prevents neurotransmitter vesicle from docking with cell membrane E. Sodium channel and Ikr blockade The botulinum toxin enters the presynaptic terminal as two chains. Its primary mechanism of action is preventing synaptic vesicles containing acetylcholine from binding to the terminal membrane. This results in a reduction of acetylcholine release and post-synaptic acetylcholine receptor changes.

1C 2D 3C 4E 5D

ANTICONVULSANTS

G. Patrick Daubert, MD; Michelle Burns-Ewald, MD CORE CONTENT 2.1.11.2 Anticonvulsants ANTICONVULSANTS

• Traditional Anticonvulsants o Phenobarbital (Luminol) o Clonazepam (Klonopin) o Phenytoin (Dilantin) o Ethosuximide (Zarontin) o Carbamazepine (Tegretol) o Primidone (Mysoline) o Valproic acid (Depakote, Depakene) o Trimethadione (Tridione) • Mechanisms of Action o Sodium channel inhibition . Inhibit Na+ influx g i rate of firing . PHT, CBZ, OxCBZ, VPA, lamotragine, felbamate o GABA-A receptor augmentation . Increase inhibition g i neuronal activity . PHB, benzos, VPA, gapapentin, vigabatrin o Calcium channel (T-type) inhibition . Inhibit Ca2+ mediated NT release . Ethosuximide, VPA, trimethadione • Phenytoin (PHT) o Na+ channel blocker (Class IB) o Delayed absorption, highly protein bound o Therapeutic level 10-20 mg/L o Propylene glycol diluent in IV forms o P450 inducer/inhibitor o Saturation kinetics (Michaelis-Menton) • Oral Phenytoin Overdose o Toxic effects common at levels > 30 mg/L o Nystagmus, ataxia, slurred speech, confusion o Oral PHT does not cause cardiac toxicity o Supportive care in most cases o Multidose AC may help eliminate PHT faster but outcome data is lacking o Paradoxical seizures and death are rare • Fetal hydantoin syndrome o Microcephaly, developmental delay, telecanthus, short nose and flat nasal bridge, anteverted nares, long shallow filtrum, thin upper lip, hypoplastic nails 2

• Carbamazepine (CBZ) o Structurally similar to imipramine o Only given orally o Erratic absorption common o Therapeutic level 8-12 mcg/ml o Estimated toxic dose 5-10 mg/kg o Active metabolite – 10,11 epoxide . Less anticonvulsant activity but equally as toxic o CBZ Receptor Promiscuity . Type 1A antidysrhythmic • Prolonged QRS g seizures, VT/Vfib . Cardiac K+ channel blocker • Prolonged QT g TdP . Antimuscarinic • Classic toxidrome with hHR and AMS . Adenosine type 1 blockade • Seizures o CBZ Treatment . Cardiac monitor - . NaHCO3 for wide QRS and > 3mm terminal R wave in aVR . Lidocaine for VT/Vfib . Magnesium for wide QTc and TdP . BZD for seizures . Multidose AC – be aware of gut motility . Hemodialysis/Hemoperfusion may be effective • Valproic Acid o Branched chain fatty acid o It is available as Depakene (sodium VPA) or an enteric coated form of two molecules of VPA linked (divalproex or Depakote) o Therapeutic level 50 – 100 mg/L o Highly protein bound o Onset and peak levels often delayed in overdose o Saturation kinetics above 90 mg/L o Metabolism . Many of the VPA metabolites (hydroxyvalproate, 2-propylgluturate, 2- propylpent-4-enoate, 5-hydroxyvalproate, and 4-hydroxyvalproate) contribute to toxicity without having any therapeutic benefit. Most of the toxicity can be linked to carnitine depletion and increase ω-oxidation. Carnitine is necessary for transport of fatty acids into the mitochondria and to maintain the ratio of acyl CoA to CoA across the mitochondria. Without this balance, toxic acyl groups accumulate in the cell and destabilize the membrane, which can impair several enzymatic processes. Hepatotoxicity and hyperammonemia also occur due to carnitine depletion and increase ω-oxidation. ω-oxidation increases levels of 4-en- VPA which inhibits carbamyl phosphate synthetase (CPS1) and enzyme necessary in converting ammonia to urea. As the metabolism shifts from β to ω-oxidation, there is a decrease in acetyl-CoA and ATP. Acetyl- 3

CoA is needed to synthesize N-acetyl glutamic acid (NAGA). NAGA activates CPS1, which again is an enzyme necessary in converting ammonia to urea. • Clinical Presentation o CNS depression/coma . Common with ingestions > 30 mg/kg . Ataxia, nystagmus, slurred speech generally do not occur o Other less common findings . Hypernatremia, hypoglycemia, hypoglycemia, QT prolongation . Pancreatitis . Bone marrow suppression days 3-5 after ingestion • VPA Hepatitis o Transient elevation of enzymes o Reversible elevation of ammonia o Frank hepatitis o Reye-like steatosis • Treatment o Supportive care for CNS depression o Multi-dose charcoal o Hemodialysis for levels 800-1000 mg/L o L-carnitine o Probably not beneficial in CNS depression alone o Children < 2, multiple anticonvulsants, ketogenic diet, malnourished o Elevated ammonia, CNS depression, hepatitis deserve consideration • Anticonvulsant Hypersensitivity Syndrome o Insufficient detoxification of epoxide hydrolase o Aromatic stuctures . Carbamazepine (HLA link?) . Phenytoin . Phenobarbital/Primidone o Onset 4 weeks to 3 months o Clinical picture . Mucocutaneous erruptions (may progress to TEN) . Fever . Hepatitis (ominous finding) . BM suppression . Pneumonitis o Diagnosis: lymphocyte killing assay with mouse microsomes • New Anticonvulsants o Felbamate (Felbatol) o Oxcarbazepine (Trileptal) o Fosphenytoin (Cerebyx) o Tiagabine (Gabitril) o Gabapentin (Neurontin) o Topiramate (Topamax) o Lamotragine (Lamictal) o Vigabatrin (Sabril) o Levetiracetam (Keppra) o Zonisamide (Zonegran) 4

• New Anticonvulsant Pearls o Felbamate (Felbatol) . Mild CNS depression . Aplastic anemia o Gabapentin (Neurontin) . Decreased bioavailability in OD . Not metabolized - no interactions o Lamotragine (Lamictal) . Coma, seizures, QRS prolongation . Hypersensitivity Syndrome o Oxcarbazepine (Trileptal) . Inhibits CYP2C19 . Hyponatremia (SIADH), seizures o Tiagabine (Gabitril) . Coma, seizures o Topiramate (Topamax) . Removed by hemodialysis . Renal nephrolithiasis-calcium phosphate . Acute angle closure glaucoma . Hyperammonemia - carbonic anhydrase inhibition slows ammonia urinary excretion o Vigabatrin (Sabril) . Agitation and psychosis o Zonisamide (Zonegran) . Carbonic anhydrase Inhibitor . Nephrolithiasis QUESTIONS 1. A 37-year-old male is transported to the emergency department via ambulance because of decreased mentation. His vital signs are normal and his physical exam is unremarkable except for a decreased level of consciousness and asterixis. His ammonia level is 145 ug/dL (normal < 20 ug/dL). His friend tells you that he is on a medication for seizures. Which anticonvulsant is he most likely taking? A. Carbamazepine (Tegretol) B. Lamotrigine (Lamictal) D. Phenytoin (Dilantin) C. Phenobarbital (Luminal) E. Valproic acid (Depakote)

The patient’s presentation is consistent with valproic acid toxicity. The most distinctive feature is the elevated ammonia level. None of the other medications would produce this in acute toxicity.

2. What is the diluent found in intravenous phenytoin that is responsible for cardiotoxicity with rapid infusions and production of lactic acid with prolonged infusions? 5

A. Ethylene glycol B. Propylene glycol C. Polyethylene glycol D. Diethylene glycol E. Ethylene glycol monobutyl ether

The diluent in intravenous phenytoin is propylene glycol. Ethylene glycol would not be used as a pharmaceutical diluent. Diethylene glycol has been used as a diluent with disastrous results. Diethylene glycol poisoning causes severe renal failure and acidosis following exposure.

3. Which of the following anticonvulsant drugs is most likely to require cardiac monitoring in acute oral overdose? A. Carbamazepine B. Gabapentin C. Levetiracetam D. Phenytoin E. Valproic acid

Carbamazepine is the most cardiac active of the medications listed with its cyclic antidepressant structure. Valproic acid can cause prolonged QT intervals but is not expected to be as problematic as carbamazepine. Gabapentin and levetiracetam are not known to cause cardiac toxicity. Oral exposures to phenytoin do not result in cardiac toxicity as apposed to rapid intravenous administration of phenytoin (due to propylene glycol).

4. A patient presents to you from an outside clinic where she was receiving follow-up for post-traumatic seizures. She was taking phenytoin (Dilantin) 300 mg TID but developed break-through seizures prompting the family physician to increase her dose to 400 mg TID. She is now ataxic, with slurred speech, notable incoordination, and horizontal nystagmus. Her phenytoin level is 48 mg/L. What is the likely cause of this patient’s phenytoin toxicity? A. Auto-inhibition of phenytoin on P450 due to the increase in dose resulting in elevated levels B. Her symptoms are likely due to the diluent propylene glycol C. Poor outpatient compliance with her medication D. She has been consuming alcohol with her medication E. She is demonstrating Michaelis-Menton kinetics with the increase dose of phenytoin

Phenytoin demonstrates Michaelis-Menton kinetics at serum levels greater that approximately 20 mg/L. Serum levels will decrease at a much slower rate than levels in the therapeutic range.

1E 2B 3A 4E M & M Mushrooms and Marine Howard A. Greller

Introduction

• Mushrooms are the fruiting body of a fungus

• More than 40,000 species worldwide

• 5000 species in U.S., < 2% poisonous

• 79% poison < 6 years old

• Raw >> cooked

• Allergy and anaphylaxis more common than poisoning Mushroom Anatomy and identiﬁcation

General properties of mushrooms. Not everyone has the “cup”

(pileus)

(lamella)

(annulus)

cup (volva)

(stape) (mycelial threads)

Mushroom ID

• Books

• Location

• Size, color, shape

• Spore print

• Spore ID

• Mycologist Melzer’s reagent (mycologist prefers) - 20 mL H2O, 1.5 g K iodide, 0.5 g iodine, 20 g chloral hydrate - Defines presence of amatoxin = dark blue Meixner reaction (reliability = doubtful) - http://namyco.org/ Several drops 10-12 N HCl on newspaper to amatoxin-containing spore - blue reaction

Tricksy mushrooms yeeesssss. . . precious . . . Cortinarius speciosissimus. Nephrotoxic (non-US). Wound up with a renal transplant (from his daughter). His wife and pssst. . . Nicholas . . . the Lord he was dining eat these. they’re yummy. with are still on dialysis. . .

Famous mushroom quote number one

There are old mushroom hunters, and there are bold mushroom hunters. But there are no old, bold mushroom hunters. Mushroom Taxonomy Classiﬁcation

Famous mushroom quote number two

Falling in love is like eating (poisonous) mushrooms. You never know if it is the real thing until it’s too late.

Cyclopeptides Group I Amanita phalloides Amanita verosa

Modern series have a lower case fatality rate

Amanita species - cyclopeptides - A. phalloides (death cap), A. virosa (death angel) - 95% mushroom related fatalities, 50% case fatality - One mushroom enough to kill an adult

Galerina autumnalis Lepiota helveola Galerina & Lepiota species - cyclopeptides - G. autumnalis, G. marginata, G. venenata - L. helveola, L. josserandi, Lbrunneoincarnata

Cyclopeptides Amatoxins (cyclic octapeptides) - α-amanitin - heat stabile - poorly absorbed, enterohepatic recirculation - interferes with RNA polymerase II, protein translation - sodium-taurocholate co-transporter polypeptide - centrilobular hepatic necrosis with intact architecture Cyclopeptides Phallotoxins (cyclic heptapeptides) - Phalloidin - limited absorption - interrupts actin polymerization - impairs cell membrane function

Cyclopeptides Virotoxins (cyclic heptapeptides) - Virotoxin - ? human toxicity Toxicity - cyclopeptides Phase I - not earlier than 6 hours, lasts up to 24 hours - initial cholera-like diarrhea, then nausea/vomiting Phase II - “quiescent” phase (no n&v) - hepatotoxicity Phase III - hepatic, renal, pancreatic - death 2-3 days after ingestion

thioctic acid is a co-enzyme in TCA cycle, free radical scavenger Therapeutics - cyclopeptides PCN displaces amanitin from albumin, Early blocks uptake, binds circulating - volume resuscitation amatoxins, prevents amanitin from - ? MDAC - ? hemodialysis / hemoperfusion binding to RNA polymerase Late(r) Silymarin block amatnitin uptake - thioctic (α-lipoic) acid NAC is good for what ails the liver - penicillin G (1.6 million U/kg/day) Cimetidine potentially inhibits - silymarin (silibinin) from milk thistle metabolism - n-acetylcysteine - cimetidine Bioartificial Liver (“bridge” to recovery or T/P) Therapeutics Liver Transplant (EARLY > late)

•Bioartiﬁcial liver •Liver transplant •Early >> late

Gyrometrin Group II gyromitra esculenta morchella esculenta

Gyromitra species - gyromitrin - G. esculenta, G. californica, G. brunnea, G. infula - found in spring under conifers - often confused for the edible morel

Gyromitrin - N-methyl-N-formyl hydrazone - hydrolyzed to monomethylhydrazine - heat sensitive (although fumes have ? toxicity)

➜➜➜

gyromitrin monomethylhydrazine Toxicity - gyromitrin - asymptomatic for at least 6 hours - initial GI symptoms - seizures

GAD - glutamic acid decarboxylase, PPK - pyridoxal phosphokinase hydrazines ! - inactivate pyridoxal 5’ phosphate ! - inhibit pyridoxal phosphokinase ! - complex with and lead to increased urinary excretion of pyridoxine GAD glutamic acid GABA pyridoxal 5’ phosphate

PPK hydrazines

pyridoxine Therapeutics - gyromitrin Early - ? GI decontamination Seizures - benzodiazepines - pyridoxine (vit B6) - 70 mg/kg up to 5 grams - anesthetic barbiturates

pyridoxine Muscarine Group III

clitocybe clavipes inocybe geophylia

Clitocybe species - muscarine - C. dealbata (‘the sweater’),C. illudens Inocybe species - muscarine - I. Iacera, I. geophylla

Muscarine Quarternary ammonium compound - Does not cross BBB (no CNS) - Not nicotinic - Not susceptible to ACHase hydrolysis

acetylcholine muscarine

When you think of rain, always bring a “sweater” Toxicity - muscarine - Rapid onset of toxicity (within 30 minutes) - SLUDGE - NO nicotinic ﬁndings (i.e. mydriasis, tachycardia, weak)

Therapeutics - muscarine - Atropine (infrequently required) - ACLS doses to start - titrate until relief of symptoms, dry secretions - NO oximes (i.e. 2-PAM) Coprine Group IV

Coprinus atramentarius Coprinus comatus Coprinus - coprine - C. comatus, C. atramentarius - Undergo “autodigestion” - inky caps - pleasant tasting, edible mushrooms - problematic with ethanol (disulﬁram like reaction)

Coprine Toxicity comes from primary metabolite - 1-aminocyclopropanol - ethanol present or ingested within 24-48 hours - usually okay if done together (delayed toxicity)

➜➜➜

coprine 1-aminocyclopropanol

Toxicity - coprine - rapid onset of toxicity (within 1 hour) - inhibits aldehyde dehydrogenase - disulﬁram reaction - ﬂushing - nausea & vomiting - tachycardia - headache

disulﬁram Therapeutics - coprine - intravenous ﬂuids - antiemetics - analgesics - time (for ethanol to be metabolized)

+ = Ibotenic acid / Muscimol Group V

Amanita muscaria Amanita gemmata

Modern series have a lower case fatality rate

Amanita muscaria - ibotenic acid / muscimol - A. muscaria (ﬂy agaric), A. pantherina, A. gemmata - popular children’s books and games - Babar, Super Mario Bros.

NOT MUSCARINIC, NOT ANTI MUSCARINIC Ibotenic acid / muscimol Ibotenic acid - structurally similar to glutamic acid Muscimol - decarboxylated metabolite of ibotenic acid - similar to GABA

ibotenic acid muscimol

glutamic acid GABA

Toxicity - ibotenic acid / musicmol - rapid onset (0.5 - 2 hours), resolves 6-12 hours - mild GI upset - ibotenic acid stimulates glutamic acid receptors - hallucinosis, excitation - musicmol acts as a GABA agonist - somnolence, ataxia

- seizures rare (GABAB agonism) - adults manifest more GABA-ergic symptoms - pediatrics excitatory transmission predominates Therapeutics - ibotenic acid / muscimol - supportive care - benzodiazepines for seizures, excitation - no role for ﬂumazenil for sedation

Psilocybin / Psilocin Group VI Psilocybe cubensis Psilocybe cyanescens

Gymnopilus spectabilis, Psathyrella foenisecii

Psilocybe species - psilocybin / psilocin - P. cyanescens, P. cubensis, G. spectabilis, P. foenisecii - “magic mushrooms” - Native american religious customs, drug culture - when handled, develop blue bruises

Psilocybin / psilocin Structural similarity to serotonin - interact with serotonin receptors, no adrenergic effects - rapid onset, medium duration (1 - 6 hours) - psilocybin is rapidly hydrolyzed to psilocin

psilocybin serotonin psilocin illusion hallucination

pallinopsia synesthesia

Toxicity - psilocybin / psilocin - Early GI effects (0.5 - 1 hour) - illusions - synesthesias - “heightened perceptions” - true hallucinations are rare and dose dependent - autonomic response to altered perceptions Therapeutics - psilocybin / psilocin Primary supportive care - benzodiazepines - avoid neuroleptics - risk hallucinogen persistent perceptive disorder (HPPD)

Little Brown Mushrooms Group VII russula emetica Chlorophyllum molybdites

Little Brown Mushrooms (LBM) - GI toxins - Boletes, Lactarius sp., Omphalotus sp., Tricholoma sp. - Lycoperdon sp., Agaricus, Entoloma, Chlorophyllum sp. - Largest group of mushrooms - Often mistaken for edible or hallucinogenic

LBM - GI toxins Heterogenous toxins - terpenes and lactones - unknown speciﬁc mechanism or toxin - direct irritant? allergic phenomenon? Toxicity - LBM - Early GI effects (0.5 - 3 hours) - rapid resolution without signiﬁcant consequence - Paxillus Syndrome (rare) - P. involutus, Clitocybe claviceps, Boletus luridus - involutin? (diphenylcyclopenteneone) - immune-mediated hemolytic anemia, renal failure - repeated long term exposure

Therapeutics - LBM Primary supportive care - intravenous hydration - antiemetics - antidiarrheals Prevention Orelline / Orellanine Group VIII

cortinarius speciosissimus cortinarius archeri

Cortinarius sp. - orelline / orellanine - C. orellanus, C. speciosissimus, C.rainierensis (NA) - Only recent recognition of toxicity Oreline / Orellanine Bipyridyl agents - similar to paraquat/diquat - heat stable - direct irritant? allergic phenomenon?

orellanine paraquat

Toxicity - orelline / orellanine - asymptomatic for 24 - 26 hours - headache, chills, anorexia, n/v (ﬂu-like) - oliguric renal failure - ATN - similar prognosis to other causes of ATN

Therapeutics - LBM Primary supportive care - intravenous hydration - hemodialysis - transplantation reported, but very rare Prevention Allenic norleucine Group IX

amanita smithiana tricholoma magnivelare Amanita smithiana - allenic norleucine - mistaken for tricholoma magnivelare (matsutake) - Paciﬁc N.W. US

Allenic norleucine 2-amino-4,5-hexadienoic acid - limited mechanistic information - may be the compound

Toxicity - allenic norleucine Phase I - early GI distress (0.5 - 12 hours) - malaise, diaphoresis, dizzy Phase II - 4-6 days after ingestion - acute renal failure - ALT, LDH elevated - renal tubular toxin Therapeutics - allenic norleucine Primary supportive care - no known antidote - ? AC - consider hemodialysis given location/history, etc. Prevention

Myotoxin Group X tricholoma equestre tricholoma ﬂavovirens

Tricholoma equestre - myotoxin - T. ﬂavovirens - “man on horseback” (Fr), “yellow knight” (US)

Toxicity - myotoxin - unknown what the toxin is - delayed symptoms 24-72 hours after ingestion - fatigue, myalgia, weakness - nausea, diaphoresis, facial erythema - CPK elevations and rhabdomyolysis - biopsy shows acute myopathy - acute myocarditis, dysrhythmias, CHF possible - mortality as high as 25% - therapy is supportive N Engl J Med 2001;345

mushroom philosophy

• Color, odor, taste, location DO NOT predict toxicity

• Symptoms NOT always from mushroom toxin

• pesticides, allergies, other (i.e. sauce)

• Early symptoms good, late symptoms bad

• exception Group IX allenic norleucine

• not always just one type of mushroom wrap up

• Identiﬁable early symptoms (< 6 hours)

• Supportive care

• Delayed onset of symptoms

• MDAC

• Admission

• More aggressive therapy?

All mushrooms are edible . . . once. Goldfrank’s Far greatest proportion of foodborne illness is bacterial and viral related

Goldfrank’s OVERVIEW

CIGUATERA Amber jack, red snapper, grouper, sea bass, barracuda, sturgeon, parrot fish Ciguatera - endemic to warm waters, bottom reef dwellers - more than 500 species - large ﬁsh (more than 4 lbs) - viscera and gonads - > 50k cases in U.S./year - Hawaii & Florida > 90% of cases

Parrot fish and giant sea bass

35 degrees north to 35 degrees south

from May through August Amberjack and red snapper

Ciguatoxin - bioaccumulated & concentrated dinoﬂagellates - gambierdiscus toxicus - heat stable, lipid soluble - odorless, tasteless, colorless

Grouper SYMPTOMS

• diaphoresis, chills • temperature reversal

• abdominal pain • dental pain (“loose”)

• nausea / vomiting / • paresthesias diarrhea • lingual, perioral, • dysuria extremity

• painful defecation / • arthralgia, myalgias ejaculation • vertigo, ataxia

Lipophilic sodium channel activators, bind site 5. Other toxins include brevitoxins. Binding VOLTAGE SENSITIVE SODIUM CHANNEL leads to prolonged firing, persistent activation & increased axonal volume.

CONCERNING SYMPTOMS

• t-wave abnormalities

• bradycardia

• hypotension

• pulmonary edema

• respiratory paralysis

• coma Toxicity - ciguatoxin - most prominent symptoms are neurologic - dysesthesias (i.e. hot/cold reversal) - “dental pain” (i.e. tooth are loose or “itch) - small percentage with bradycardia / hypotension

- Bagnis, Am J Trop Med Hyg, 1979

Barracuda

Ciguatoxin - symptoms 2-6 hours after eating - more than 75% within 12 hours - GI and diaphoresis - neurologic symptoms between 2 and 24 hours

- There is an ELISA assay Sturgeon

Reduce axonal edema, Therapeutics - ciguatoxin dissociate ciguatoxin binding, - GI decon (self) free radical scavenger, Na - consider AC - Symptomatic therapy channel blockade - antihistamines Case reports for (early - atropine for bradycardia better??), 2002 RCT = no - Mannitol - unknown mechanism, ? reverse neuro ? benefit (maybe late present??) - early >> late Other treatments: ?TCAs = - 1 g/kg of 20% solution over 30min / 2-6 hr - theories block Na channels yellofin tuna

Nonscobroid (mahi mahi, amberjack) much more often implicated than Scombroidae Scombroid (skipjack, tuna, mackerel) - temperate or tropical waters - non-scombroidae (most common) - mahi mahi, amberjack - scombroidae - skipjack, tuna, mackerel - ﬁrst described cases

properly frozen and preserved tuna Elaborated by Enterobacteriaceae (Proteus, Morganella, Klebsiella, Aerobacter, Scombroid - histamine Escherichia) and Clostridium, Lactobacillus - improper refrigeration (> 20℃ / 68℉) - bacteria on ﬁsh skin - histidine decarboxylated to histamine - heat stable - peppery tasting - “honeycomb” appearance rare

histidine decarboxylase histidine histamine

truncal and facial flushing

Symptoms - scombroid - within 5 to 90 minutes - ﬂushing (face, neck, torso) - n/v/d, dizziness, palps, hypotension - rarely puritis, urticaria, angioedema - bronchospasm, visual loss - lasts 12-24 hours untreated mahi mahi

Differential - scombroid - Allergic reaction - MSG reaction - Disulﬁram reaction - Tyramine reaction - Carcinoid - Zollinger-Ellison syndrome

Goldfrank’s Toxicologic Emergencies Therapeutics - scombroid - Supportive

- H1 / H2 blockers - Serious reactions - bronchodilators, epi, etc - Reassurance and education

diphenhydramine

TETRODOTOXIN

fugu and blue-ringed octopus

fugu hapalochlaena maculosa 50-100 species implicated Pufferfish, Blowfish Tetrodotoxin - puffer ﬁsh and blue-ringed octopus - fresh and saltwater - frogs, horseshoe crabs/eggs, salamanders - puffer ﬁsh skin and gut make toxin - octopus is small (< 5”) and non-aggressive - venom expressed by beak

60x more toxic than strychnine or curare, 1250x than cyanide Toxicity - tetrodotoxin - highest concentrations in liver and ovary Blue ringed octopus venom also contains a mixture of hyaluronidases, tyramine, - female more toxic than male acetylcholine, histamine, dopamine, - blocks voltage-gated Na channels tryptamine, octopine, taurine. - blocks axonal neurotransmission - PNS, CNS, autonomic, cardiac HA, dizziness, “floating”, early miosis & later mydriasis, salivation/diaphoresis/ Symptoms - tetrodotoxin bronchospasm - GI within 3 hours - n/v/d, abd pain - Neurologic minutes to hours - progressive parasthesias - progressive weakness (bulbar), ataxia - Ascending paralysis, respiratory depression - Preserved mental status - Death reported within 17 minutes! - Survival beyond 24 hours excellent prognosis

JAPANESE 4 STAGES

• Oral paresthesias, ? GI

• Advanced paresthesias, ext paralysis, + DTR

• Gross incoordination, aphonia, dysphagia, resp distress, hypotension, fully conscious

• Mental impairment, resp paralysis, ↓BP HA, dizziness, “floating”, early miosis & later mydriasis, salivation/diaphoresis/ Differential Dx - tetrodotoxin bronchospasm - Botulism - Guillan-Barré - Progressive supranuclear palsy (PSP) - Ciguatera

“I want to eat fugu, but I don’t want to die”

> 1,500 restaurants in Tokyo Avg. 150 people/year with s&s. (61% death rate)

FUGU WA KUITASHII, INOCHI WA OSHISHII

HA, dizziness, “floating”, early miosis & later mydriasis, salivation/diaphoresis/ Therapeutics - tetrodotoxin bronchospasm - aggressive supportive care - diagnostic testing to exclude other causes - no speciﬁc laboratory study - admission, observation SHELLFISH POISONING

Shellfish poisoning - dinoflagellate or algae contamination - paralytic shellfish poisoning - protogonyaulax catanella & tamarensis - neurotoxic shellfish poisoning - ptychodiscus brevis (gymnodinium breve) - amnestic shellfish poisoning - nitzschia pungens - “diarrhetic” shellfish poisoning - dinophysis or prorocentrum Paralytic shellfish poisoning http://www.whoi.edu/

Toxicity - saxitoxin - blocks voltage-sensitive Na channel - similar to tetrodotoxin

saxitoxin s.aks-itoxin

Algae “bloom” at certain times and under certain conditions. Red Tide associated with PSP, but can be other colors. Symptoms - saxitoxin - neurologic (within 30 min) - paresthesias, numbness, “ﬂoating”, HA, vertigo - ataxia, muscular weakness - dysphagia, dysarthria, dysphonia, blindness - paralysis - weakness can last weeks - GI symptoms less common Therapeutics - saxitoxin - supportive

Neurotoxic shellfish poisoning http://www.whoi.edu/ Toxicity - brevetoxin - stimulates voltage-sensitive Na channel - similar to ciguatera

brevetoxin

ciguatera

Clams

Symptoms - brevetoxin - GI symptoms - n/v/d, abd pain, rectal burning - neurologic - paresthesias, “hot/cold reversal”, myalgias, HA - vertigo, ataxia, tremor - dysphagia, bradycardia, ⬇ DTRs, mydriasis - NO paralysis - GI with neuro symptoms simultaneously - incubation ≈ 3 hr (15 min - 18 hr) - duration ≈ 17 hr (1 - 72 hr) Amnestic shellfish poisoning

Amnestic shellfish poisoning http://www.whoi.edu/

Toxicity - domoic acid - glutamate agonist - analog of glutamic and kainic acids - AMPA & kainate receptor damage ➜ Ca inﬂux

domoic acid kainic acid Symptoms - domoic acid - onset within 5 hr (15 min - 36 hr) - neurologic - memory loss (10% long term anterograde) - chewing/grimacing - ophthalmoplegia - seizures, hemiparesis - GI symptoms less common - carries mortality of ~ 2% (older)

diarrhetic shellfish poisoning Diarrhetic shellfish poisoning http://www.whoi.edu/

Phosphorylation of proteins controlling Na secretion of intestinal cells or influencing Toxicity - okadoic acid permeability of cell membranes - phosphatase a1 & a2 inhibitor S. intestine: degeneration of absorp epith - phosphorylates proteins control Na secretion - permeability of intestinal cell membranes - degeneration of absorptive epithelium

okadoic acid

may through august most prominent times Symptoms - okadoic acid - GI symptoms (30 min - 2 hours) - n/v/d, abd pain - self limited (2 - 3 days) Therapeutics - okadoic acid - supportive Psychotropics

Psychotropics

G. Patrick Daubert, MD

Some (most) material plundered from various mentors and other talented toxicologists, with permission 1

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

Anxiolytics and Sedative-hypnotics n Benzodiazepines n Barbiturates n Sedative-Hypnotics

1 Psychotropics

Benzodiazepines

“There are very few toxicological problems that cannot be solved through the suitable (and liberal) application of benzodiazepines”

Suzanne White, MD

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

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

2 Psychotropics

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

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

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

3 Psychotropics

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

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

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

4 Psychotropics

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

‘Z’ Drugs n Zolpidem (Ambien, n Non-benzodiazepine Stilnox) sedatives n Selective for GABA BZ-1 n Zaleplon (Sonata) A receptors n EcZopiclone (Lunesta, n Less physical dependence Estorra) n Flumazenil may precipitate n Ramelteon (RoZerem) withdrawal n Ramelteon may alter testosterone and prolactin levels

“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

5 Psychotropics

Sedative-Hypnotics n Buspirone (Buspar) n Chloral hydrate n Meprobamate n Methaqualone n Glutethimide n Ethchlorvinyl

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

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

6 Psychotropics

Clinical Highlights n Hemorrhagic gastritis n Cardiac arrhythmias n Attributed largely to trichloroethanol n Myocardium sensitized to circulating catecholamines n Radioopaque

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

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

7 Psychotropics

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

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

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

8 Psychotropics

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

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

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

9 Psychotropics

Cyclic Antidepressants Toxicology n Membrane effects n Blockade of fast Na+ channels phase 0 of the action potential 1 2

0 3 4

Axis Change in Toxicity

R ’ Terminal R V1 R aVR

10 Psychotropics

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

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

11 Psychotropics

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)

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 Rigidty, myoclonus, carpopedal spasm n Myocardial ischemia, ICH, seizures

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

12 Psychotropics

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

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)

13 Psychotropics

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

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

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

14 Psychotropics

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

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

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 +++ ++++

15 Psychotropics

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

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

Question

16 Psychotropics

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

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

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

17 Psychotropics

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

Irreversible EPS: Tardive Dyskinesia 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

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)

18 Psychotropics

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, 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

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

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

19 Psychotropics

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

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

Acute vs Chronic Lithium n Increased intake n Decreased excretion n Delayed toxicity due to n Serum levels lower since delayed distribution inracellular 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, seizures n ECG n Bradycardia n T-wave flattening/inversion n QT prolongation

20 Psychotropics

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?

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)

Question

21 Psychotropics

Questions?

Good Luck!!

22 1 PSYCHOTROPICS

G. Patrick Daubert, MD; Michelle Burns-Ewald, MD CORE CONTENT 2.1.11.2 Psychotropics 2.1.11.9.1 Anxiolytics and sedative-hypnotics 2.1.11.9.2 Antidepressants 2.1.11.9.3 Antipsychotics 2.1.11.9.4 Mood stabilizers ANXIOLYTICS AND SEDATIVE-HYPNOTICS Benzodiazepines • Background o Roughly 50,000 benzodiazepine OD cases reported annually o 65% intentional o Few deaths o Most are combination exposures o Mixed drug overdose or IV administration = increased morbidity o About 15 types marketed in the US o 50 types worldwide Generic Trade T ½ (hrs) M Alprazolam Xanax 6-26 I Clorazepate Tranxene 1.1-2.9 A Chlordiazepoxide Librium 5-30 A Clonazepam Klonopin 39 I Diazepam Valium 20-70 A Estazolam Prosom 10-24 I Flurazepam Dalmane 2-3 A Lorazepam Ativan 9-19 I Midazolam Versed 2-5 I Oxazepam Serax 5.4-9.8 I Temazepam Restoril 10-16 I Triazolam Halcion 1.6-5.4 I

• Kinetics o Vary in elimination half-life and metabolism o All rapidly absorbed o CNS redistribution varies o Half-life ≠ duration of action o Conjugation only BZDs = oxazepam, lorazepam, temazepam o IM administration = lorazepam, midazolam 2 • Dynamics o All are indirect agonists at post-synaptic GABAA channels . Can’t open the channel without GABA . BZD1 receptor subtype . Increase frequency of chloride channel opening o BZD2 receptors (HC, spinal cord) affect muscle relaxation o All produce tolerance with cross-reactivity o Predispose to physical dependence . BZD2 receptor agonism • Benzodiazepine Overdose o Nonspecific – sedative-hypnotic symptoms o CNS changes without vital sign changes: drowsiness, dizziness, slurred speech, nystagmus, confusion, amnesia, ataxia, coma (rare) o Patients look “drunk” o Children: 17% isolated ataxia o Other: respiratory depression, hypotension with IV administration • Benzodiazepine withdrawal o Worse for short half-life agents o Agitation, tremor, headache, weight loss, seizures o Mild symptoms start in 1-3 days with peak in 5-9 days. Symptoms taper over 3-4 weeks o May be precipitated by flumazenil • Flumazenil (Romazicon) o Competitive BZD antagonist o Reverses CNS depression but not respiratory depression o Withdrawal symptoms more likely in doses > 1 mg o Safest patient populations . Children with single dose ingestions . Reversal of iatrogenic sedation (procedural sedation) • Benzodiazepine Pearls o Increase frequency of GABAA chloride channel opening o Propylene glycol: lorazepam, diazepam o Clonazepam: Anticonvulsant, mood stabilizer, sounds like “clonidine” o Flunitrazepam (RoHypnol): “Date Rape” drug o In-house urine qualitative EMIT toxicology screen may not detect BZDs that do not produce oxazepam metabolite (false negative) . Midazolam, alprazolam, lorazepam, triazelam, clonazepam Barbiturates • 4 Categories o Ultrashort: methohexital, thiopental o Short: pentobarbital, secobarbital o Intermediate: butalbital o Long-acting: Phenobarbital o Combination products . Donnatal: phenobarbital, atropine, hyoscyamine . Fiorinal/cet: butalbital, caffeine, ASA/APAP 3 • Pharmacology o GABAA agonist with direct increase in duration of channel opening o Contrast to BZD, GABA not needed with barbiturates o Pharmacology secondary to decrease in central sympathetic tone and direct myocardial depression • Barbiturate Toxicity o Symptoms similar to other sedatives with CNS depression and cerebellum symptoms o More likely to see respiratory depression . CNS tolerance ≠ Respiratory tolerance o Medullary effect: cardiovascular collapse, miosis o Hypothermia, bullae at pressure points (“barb burns”), concretions o Noncardiogenic pulmonary edema • Barbiturate withdrawal o Life threatening o Agitation, tremor, seizures, insomnia, delirium o Occurs 3 days after cessation of drug and lasts 10-14 days • Phenobarbital (PHB) o Long-acting barbiturate o Normal range 15-40 mg/L o PHB CNS tolerance does not usually involve respiratory tolerance o Death is uncommon with good supportive care o Remember primidone metabolized to PEMA and PHB o Treatment . Supportive care . Passive warming . IVF, norepinephrine for hypotension . Urinary alkalinization • Phenobarbital is only barbiturate effectively eliminated with urine alkalinization • Stop alkalinization when PHB < 40 mg/L . Multidose activated charcoal • Stop MDAC when PHB < 40 mg/L • MDC demonstrates better elimination than urine alkalinization • Listed as one of five drugs in position statement for MDAC with best data for enhanced elimination (NOT outcome data) o Carbamazepine, dapsone, phenobarbital, quinine, theophylline) o Caveat . Positive barbiturate (qualitative) on urine drugs of abuse screen: PHB vs butalbital are typically only barbiturates available for use by general patient population. If PHB level is zero, likely butalbital overdose, which means also ordering ASA and APAP (Fiorinal/cet) 4 ‘Z’ Drugs • Zolpidem (Ambien, Stilnox) • Non-benzodiazepine sedatives • Zaleplon (Sonata) • Selective for GABAA BZ-1 • EcZopiclone (Lunesta, Estorra) receptors • Ramelteon (RoZerem) • Less physical dependence • Flumazenil may precipitate withdrawal • Ramelteon ay alter testosterone and prolactin levels

• “Z” Drug Overdose o Nausea/vomiting, respiratory depression, hypotension o Can see both miosis and mydriasis and fixed pupils o CNS depression and hallucinations o Flumazenil reverses ‘Z agent’ effect and precipitates withdrawal with same precautions as with benzodiazepines Sedative-Hypnotics • Buspirone o Non-benzodiazepine, anxiolytic . Does not stimulate GABAA receptors . Acts act 5-HT1A o No reported withdrawal syndrome o CNS depression, miosis o Serotonin syndrome potential • Chloral Hydrate o Commonly used by alcoholics in the late 19th century to induce sleep o Solutions of alcohol and chloral hydrate often called “knockout drops” or “Mickey Finn” o Sedation with minimal respiratory depression and hypotension o Used recreationally only by a small number of people o Common trade names are Noctec, Somnos and Felsules o Pharmacology . Trichlorocetic acid • Highly protein bound • May displace acidic drugs from plasma protein . Trichloroethanol exerts barbiturate like effects on the GABAA receptor channels . Trichloroethanol inhibits ethanol metabolism Chloral Hydrate

ADH P450

Trichloroethanol Trichloroacetic Acid 5 o Chloral hydrate clinical highlights . Hemorrhagic gastritis . Cardiac arrhythmias • Sensitized myocardium to circulating catecholamines • Attributed largely to trichloroethanol . Radioopaque • Sedative-Hypnotic Pearls o Meprobamate (Miltown,, Equanil, Meprospan) . Active metabolite of carisoprodol . Concretions/bezoars in overdose o Glutethimide (Doriden) . 2D6 inducer – codeine abuse . “Doors and Fours” with Tylenol#4 o Ethchlorvynol (Placidyl) . “Jelly-bellies” . Used by William Rehnquist (oversedation then withdrawal) o Methaqualone . Quaaludes, Mandrax . Recent abuse in South Africa . Can see hyperreflexia, clonus . Residual paresthesias and polyneuropathies effects after overdose ANTIDEPRESSANTS Cyclic Antidepressants (CAs) • Account for nearly 50% of all cardiovascular deaths in the U.S. CAs are widely available for medical conditions other than depression (e.g., chronic pain, pediatric enuresis) • Usual Suspects o Tertiary amines o Secondary amines . Amitriptyline . Desipramine . Clomipramine . Nortriptyline . Doxepin . Protriptyline . Imipramine . . Trimipramine o Tetracyclic . Amoxapine (high risk of intractable seizures) . Maprotiline (high risk of intractable seizures) • TCA Urine Drug Screen Cross Reactivity o Cyclobenzaprine (Flexeril) o Carbamazepine (Tegretol) o Diphenhydramine (Benadryl) o Thioridazine (Mellaril) o Cyproheptadine (Periactin) o Quetiapine (Seroquel) 6 • Pharmacokinetics o Peak serum concentration 1-8 hrs (symptoms in 1-2 hours) o Antimuscarinic – remember delayed gastric emptying o Lipophilic – large Vd o Elimination almost entirely hepatic o Hepatic phase I: Demthylation (CAs remain active until hydroxylation occurs) . Imipramine g desipramine . Amitriptyline g nortriptyline o Hydroxylation of some CAs affected by genetic polymorphism at the CYP2D6 allele. For example, 90-95% of U.S. population are rapid hydroxylators producing shorter desipramine elimination half-lives 12-23 hours than slow hydroxylators (81-131 hours) • Clinical Toxicity o Rapid onset of symptoms o Early sedation and coma o Early antimuscarinic symptoms o Cardiovascular . Hypotension . Dysrhythmias • Blockade of fast Na+ channels phase 0 of the action potential g QRS prolongation • RBB more susceptible (leads V1, V2, aVR, I) o Rate dependent – increase in CA binding with h HR o pH dependent - increase in CA binding with i pH • R axis deviation in terminal 40 msec • AV node blocks • K+ channel blockade (Ikr) o Increased QT but TdP uncommon with tachycardia o Can be seen with therapeutic dosing 1 2

0 3 R ’ ’ Terminal 4 V R aVR R 1

• Treatment caveats o Airway management early o Multi-dose charcoal may be beneficial with amitriptyline o Levels generally not useful in acute overdose. However, levels > 1000 ng/mL will likely result in significant toxicity (remember to order both tertiary and secondary CA levels) o Sodium bicarbonate (no outcome data comparing infusion vs IV bolus) o Lidocaine most commonly advocated for VT/VFib but efficacy data is lacking 7 o Seizures usually resolve spontaneously – but resulting lowered pH may increase risk of dysrhythmias . Phenytoin not to be used for seizures • Hypotension and dysrhythmias from rapid infusions • Seizure most likely due to GABA and adenosine inhibition, not sodium channel effects • Animal models suggest phenytoin is prodysrhythmic in CA toxicity o Physostigmine . Not currently advocated . Most likely risk of asystole and death is in the treatment of patients with severe toxicity with seizures and bradycardia. QRS widening has not been directly linked to asystolic risk Monoamine Oxidase Inhibitors • Isoniazid and its isopropyl derivative, iproniazid (Marsilid, no longer marketed), were used in 1951 for the treatment of tuberculosis. Patients on these drugs were noted to have elevated mood, secondary to both drugs having the ability to inhibit MAO. MAOIs were widely used for nearly a decade until a tyramine reaction (see below) resulted in a death in 1962. • MAOI pharmacology o Intracellular enzyme found on mitochondrial membrane o Degrades intracellular biogenic amines with H2O2 as a free radical byproduct o Increases neurotransmitter activity in CNS, down-regulates post-synaptic serotonin and adrenergic receptors o Post-synaptic DA unaffected o Liver has highest concentration of MAO with equal amounts of each isozymes. Brain has both with MAO-B more prominent in glial cells. Selectively often lost in overdose. Serotonin primarily metabolized by MAO-A. Phenethylamines (including designer drugs) primarily metabolized by MAO-B. o Isocarboxazid and phenelzine derived from hydrazine and are therefore acetylated with risk of slow and rapid acetylators (NAT2 enzyme) o Herbals such as Ephedra (Ma Huang) and St. John’s Wart (Hypericum perforatum) may interact with MAOIs o Selegiline (MAOI) metabolized to methamphetamine and amphetamine • MAOI pharmacology o Irreversible binding o Reversible binding . Phenylzine . Moclobemide . Tranylcypromine . Brofaromine . Isocarboxizide . Cimoxatone . Selegiline . Toloxatone . Pargyline . Harmaline o Selective o Nonselective . Clorgyline (A) . Tranylcypromine . Moclobemide (A) . Phenylzine . Toloxatone (A) . Isocarboxazid . Harmaline (A) . St. Johns Wort . Selegiline (B) . Pargyline (B) 8 • Signs and Symptoms (MAOI Overdose) o Phase I . Latent period: 6-12 hrs in pts on medication . 24-36 hrs in “naïve” patients o Phase II . Excitatory phase • Hyperadrenergic appearing • “Ping-pong” nystagmus • Hyperreflexive with rigidity • Writhing, opisthotonus, facial grimacing . Progression • CNS depression • Fever, diaphoresis, salivation • Rigidty, myoclonus, carpopedal spasm • Myocaridal ischemia, ICH, seizures • MAOI Treatment o Expect prolonged period of toxicity o ICU for 24 hrs after resolution of signs and symptoms o Restricted diet for 2-3 weeks o Check ALL medications for interactions o Treat as signs and symptoms appear o Use SHORT acting agents o Use DIRECT acting agents-COMT metabolism • MAO-Tyramine reaction o Not an overdose o Onset within 2 hrs after eating o Ingested tyramine is normally inactivated by gut MAO-A o Inhibition of gut MAO-A: absorption of dietary tyramine and byproducts o Tyramine releases NE formed by inhibition of neuronal MAO-A o Hyperadrenergic state o Treat symptomatically Serotonin Reuptake Inhibitors • In overdose, have been less toxic in overdose than previous generation antidepressants. Death with SSRI alone is rare. • Types include selective serotonin reuptake inhibition as well as some with norepinephrine, dopamine, and alpha-adrenergic blockade • Current SSRIs o Paroxetine (Paxil) o Sertraline (Zoloft) o Fluoxetine (Prozac, Sarafem) o Fluvoxamine (Luvox) o Citalopram (Celexa) o Fluoxetine + olanzepine (Symbyax) o Escitalopram (Lexapro) o Dapoxetine (Priligy) - Europe • Pearls o SSRI in overdose: CNS depression and tachycardia most common o Citalopram and escitalopram: reports of seizures and widened QT interval o Fluvoxamine inhibits CYP1A and CYP2C o Paroxetine, fluoxetine, and metabolites strong inhibitors of CYP2D6 9 • SSNRI and Others o Buproprion . Excitation in overdose, seizures common, sustained release product o Duloxetine (Cymbalta) o Mirtazepine (Remeron) . Sedation, mild symptoms in toxicity o Nefazadone (Serzone), Trazadone (Desyrel) . Prolonged QT, orthostatic hypotension, priapism o Venlafaxine (Effexor) . Seizures, QRS prolongation Serotonin Syndrome • Stimulation of post-synaptic 5HT1A and 5HT2 brain receptors • Mechanism o Two or more serotonergic agents (eg, meperidine and MAOI [Libby Zion case]) o SSRI + neuroleptic o SSRI + agent with serotonergic properties o Change in dose of serotonergic drug o Metabolic inhibition of serotonergic drug • Modified Sternbach criteria: A, B, C must be met: o A. Syndrome occurs after addition of known serotonergic agent to established regimen or increase in dose of a serotonergic agent o B. At least 3 of the following: . Uncontrollable shivering, incoordination, restlessness in feet while sitting, initial involuntary ctx followed by myoclonic-like movements in legs, hyperreflexia, frightened hyperarousal state, agitation, oculogyric crises, diarrhea, fever . Other causes ruled out (sympathomimetics, MAOI, lithium, ASA, anticholinergics, withdrawal, CNS infection, SIRS, NMS, etc.) o C. A neuroleptic has not been started or increased in dosage prior to onset of symptoms • NEJM M. Shannon article on serotonin syndrome o Hyperthermia o Mental status changes o Autonomic instability o CLONUS • Treatment o Good supportive care o Benzodiazepines o External cooling o Paralysis with a nondepolarizing agent o Specific agents . Cyproheptadine: nonspecific 5HT antagonist (4-8 mg q1h) – no trials showing cyproheptadine more efficacious than BZD . NTG: nitric acid mediated down regulation of 5HT (drip titrated to effect) . Propranolol: 5HT1A antagonism (1-5 mg IV) . Chlorpromazine: 5HT2 antagonist 10 • Neonatal SSRI Withdrawal o Fetus exposed to an SSRI late in the third trimester o Symptoms . Respiratory distress (apnea) . Cyanosis, apnea . Feeding difficulties . Vomiting . Hypoglycemia . Tremors, jitteriness, irritability o Onset hours to days after delivery, which resolved in days or weeks o Prolonged hospitalization, respiratory support, and tube feeding • Serotonin syndrome vs neuroleptic malignant syndrome Signs/Symptoms SS NMS Onset Rapid Gradual Resolution < 24 hour Days Myoclonus ++ -- Hyperreflexia ++ -- Metabolic acidosis +/- ++++ Muscle rigidity ++ ++++ Altered mental status ++ ++++ Autonomic dysfunction +++ ++++

ANTIPSYCHOTICS

• Traditional antipsychotics o D2 antagonists • Atypical antipsychotics o Selective for limbic vs EP sites o Mixed DA receptor affinities (D1,D2 etc) o Looser binding to D2, less EPS o Mixed affinity for DA, 5HT, alpha • Antipsychotic Classification o Low potency (sedating, antimuscarinic, miosis) . Chlorpromazine (most sedating in overdose) . Chlorprothixene . Mesoridazine (very cardiotoxic in overdose) . Thioridazine (most cardiotoxic in overdose) o Medium potency . Droperidol . Loxapine (more seizures in overdose) . Molindone . Perphenazine 11 o High potency (more EPS, less sedation) . Fluphenazine . Haloperidol (most common cause of NMS) . Trifluoperazine . Thiothixene • Reversible EPS: Acute Dystonia o Idiosyncratic and occurs more commonly in males 5-45 years with depot preps. Increased risk with family history of AD and recent ethanol or cocaine use. Dystonia is known to resolve during sleep. o Symptoms . Facial grimacing . Tongue protrusion . Trismus . Torticollis . Blepharospasm . Opisthotonis . Oculogyric crisis . Abnormal posture, gait • Reversible EPS o Akathesia o Parkinsonism . Subjective unease . Muscle rigidity . Motor restlessness . Bradykinesia . Dose related . Tremor . Women . Elderly women . High potency Drugs . High potency • Irreversible EPS: Tardive Dyskinesia o Involuntary movements of orofacial structures o Lip smacking o Eye blinking o Facial grimacing o Grunting o Late onset > 2 years after therapy onset o More common in women > 50 years who have had their long-term meds discontinued. Cessation of therapy leads to increased number of DA receptors in the nigrostriatal system (DA excess, cholinergic underactivity) • Antipsychotic Pearls o Thioridazine (Mellaril) . Peak serum level can be delayed 120 hours . QTc but not QRS correlates closely with peak concentration . Most lethal in overdose o Pimozide (Orap®) . Akathisia most characteristic adverse effect o Most common cause of NMS (> 90%) . Haloperidol o Agranulocytosis . Chlorpromazine (Thorazine) o Cholestatic jaundice . Chlorpromazine (Thorazine) o Acute reversible oliguria . Chlorprothixene (Taractan) 12 • Atypical Antipsychotic Pearls o Aripiprazole (Abilify®) . Longest half-life in overdose . Sedation and mild antimuscarinic symptoms reported o Clozapine (Clozaril®) . Prototypic atypical antipsychotic . Long half-life in overdose . Highest alpha-1 blockade . Highest rate of seizures . Central antimuscarinic (delirium) but salivation, miosis common . Chronic therapy associated with agranulocytosis and hyperglycemia o Olanzapine (Zyprexa® Zydis®) . Long half-life in overdose . Highest antimuscarinic, but salivation, miosis . No reported cardiac effects . Most cases of NMS of atypicals . Chronic therapy associated with: . Hyperglycemia (drug-induced diabetes) . Waxing and waning sedation . Overdose resembles opiate toxidrome with miotic pupils o Quetiapine (Seroquel®) . Tachycardia, sedation, prolonged QT . Highest antihistamine activity . > 3 grams predicted ICU and prolonged length of stay . Cross reacts with TCA drug assay o Risperidone (Risperdal®) . Highest rate of dystonia . High rate of seizures . High rate of alpha blockade . No antimuscarinic effects; miosis . Electrolyte depletion . Unusual dysrhythmias for class (a flutter, heart blocks) o Paliperidone (Invega®) . Major active metabolite of risperidone . Observed signs and symptoms included EPS and ataxia . Other potential signs and symptoms: sedation, tachycardia, and hypotension . QT prolongation (12.5-62 msec in pre-clinical trials) . Overdose experience reported similar to risperidone o Ziprasidone (Geodon®) . Highest rate of increased QT prolongation . Miosis common . Not as sedating as others (no H1 block) 13 MOOD STABILIZERS - LITHIUM

• Mood Stabilizing Lithium o Main therapy for bipolar disorder o Narrow therapeutic index (0.6-1.2 mEq/L) o Slow distribution across cell membranes o Delay between peak blood levels and CNS effects o Most cases chronic due to a reduction in GFR . Volume loss . NSAIDs, diuretics, ACE inhibitors . Age • Acute vs chronic toxicity. Most cases involve chronic poisoning due to a reduction in renal elimination of lithium. Role of hemodialysis continues to be controversial. o Acute o Chronic . Increased intake . Decreased excretion . Delayed toxicity due to . Serum levels lower since delayed distribution inracellular levels high . High serum levels initially . Subacute/nonspecific do not correlate with neurologic symptoms toxicity . GI symptoms less severe . GI symptoms more severe . Encephalopathy, . Tremor, muscle weakness, myoclonus, severe rigidity, ataxia, hyperreflexia seizures • ECG o Bradycardia o T-wave flattening/inversion o QT prolongation • Other effects of lithium o Nephrogenic diabetes insipidous o Hypothyroidism o Teratogenic: Ebstein’s anomaly • Lithium Management o Discontinue lithium and offending drugs o Improve GFR – normal saline . 20% reduction in Li over 6 hours o Hemodialysis (guidelines vary) . Renal failure . Stage III neurotoxicity: encephalopathy, myoclonus, severe rigidity, seizures . Acute > 4.0 mEq/L? . Chronic > 2.5 mEq/L? o Kayexelate (Na polystyrene sulfonate) . Some newer data to suggest improved clearance . Theoretical risk of worsening cardiac effects due to hypokalemia

14 QUESTIONS 1. 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

Patients with acute exposures to SSRI medications typically due very well with CNS depression and tachycardia being the most common symptoms encountered. Cardiac dysrhythmias, seizures, and hallucinations and delirium are not routinely seen in acute overdose. Hyperthermia and rigidity may be seen as a part of the serotonin syndrome but is not common after a single acute overdose of an SSRI. 2. A 14-year-old girl presents to the emergency department after two witnessed generalized, tonic-clonic seizures. In resuscitation she is comatose and requires ventilatory support. Her initial vitals signs are BP 80/43 mmHg, HR 133 bpm, RR 14 (vent), temperature 99.6oF, and pulse oximetry 100% on FiO2 1.0. Her ECG is provided below.

What is the next best course of management in this patient?

A. Octreotide B. Glucagon C. Naloxone D. Sodium bicarbonate E. Calcium chloride

The patient’s presentation is consistent with cyclic antidepressant toxicity. The antidote of choice from the above options is sodium bicarbonate. Octreotide is used in sulfonylurea exposure. Naloxone is the antidote for opiates. Calcium chloride is not expected to improve this patient’s hypotension or cardiac conduction disturbance. 15

3. A 23-year-old woman with schizoaffective disorder presents to the emergency department for chest pain. She is currently taking ziprasidone (Geodon) for her psychiatric disorder. In the evaluation of her complaint, a 12-lead ECG is completed. It reveals a normal sinus rhythm, normal T waves, normal ST segments, QRS 86 msec, and QTc 560 msec. You diagnose her with musculoskeletal pain, but are concerned by her ECG. What medication would you recommend in place of her ziprasidone? A. Chlorpromazine (Thorazine) B. Haloperidol (Haldol) C. Olanzapine (Zyprexa) D. Quetiapine (Seroquel) E. Thioridazine (Mellaril)

The greatest concern in this patient is the prolonged QT interval. From the above choices, the medication with the least amount of IKr blockade and subsequent QT prolongation is olanzapine.

4. A young woman presents with chronic lithium intoxication. Which of the following clinical signs is the most likely indication for hemodialysis in this patient? A. Ataxia B. Diabetes insipidus C. Hyperreflexia D. Tremor E. Seizures

Although uncommon, seizures represent severe lithium toxicity (Stage III neurotoxicity) and are an indication for hemodialysis. Ataxia, hyperreflexia, and tremor are common clinical manifestations that occur even at baseline in patients on chronic lithium. Diabetes insipidus is seen in both acute and chronic lithium toxicity and managed through fluid restriction and not hemodialysis.

5. Which of the following agents is the most appropriate treatment for a patient with severe hypertension due to MAO-I toxicity? A. Clonidine B. Diltiazem C. Labetalol D. Nitroprusside E. Verapamil

Patient’s blood pressure is often unpredictable after MAO-I toxicity. Shorter acting antihypertensive agents are preferred in case of precipitous drops in blood pressure. Nitroprusside is the agent of choice among those listed due to its rapid onset and offset.

1B 2D 3C 4E 5D

1 PSYCHOTROPICS

ADH P450

0 3 R ’ ’ Terminal 4 V R aVR R 1

ANTIPSYCHOTICS

What is the next best course of management in this patient?

A. Octreotide B. Glucagon C. Naloxone D. Sodium bicarbonate E. Calcium chloride

The greatest concern in this patient is the prolonged QT interval. From the above choices, the medication with the least amount of IKr blockade and subsequent QT prolongation is olanzapine.

5. Which of the following agents is the most appropriate treatment for a patient with severe hypertension due to MAO-I toxicity? A. Clonidine B. Diltiazem C. Labetalol D. Nitroprusside E. Verapamil

1B 2D 3C 4E 5D

Cardiovascular Toxins

Cardiovascular Toxins 2.1.6 Trevonne M. Thompson, MD

2.1.6 Drugs that affect the cardiovascular system 2.1.6.1 Antidysrhythmics 2.1.6.1.1 Calcium channel blockers 2.1.6.1.2 Cardiac glycosides 2.1.6.1.2 Potassium channel blockers 2.1.6.1.3 Sodium channel blockers 2.1.6.2 Antihypertensives 2.1.6.2.1 Angiotensin system modulators 2.1.6.2.2 Beta (and mixed alpha, beta) antagonists 2.1.6.2.3 Centrally acting alpha receptor agonists 2.1.6.2.4 Diuretics 2.1.6.2.5 Vasodilators 2.1.6.3 Inotropes

Fundamentals

1 Cardiovascular Toxins

Cardiac Action Potential

• Phase 0: depolarization • Phase 1: overshoot • Phase 2: plateau • Phase 3: repolarization • Phase 4: resting

Cardiac Action Potential

• Phase 0 • Begins with excitation from a stimulus • Fast sodium channels open • Rapid depolarization

Cardiac Action Potential

• Phase 1 • Sodium channels close • Partial outward potassium current occurs • Partial repolarization of the membrane

2 Cardiovascular Toxins

Cardiac Action Potential

• Phase 2 • Inward calcium current • Outward potassium current

Cardiac Action Potential

• Phase 3 • Calcium channels close • Continuation of potassium inﬂux

Cardiac Action Potential

• Phase 4 • Resting state for much of the myocardium

3 Cardiovascular Toxins

Image courtesy of Wikimedia Commons

Goldfrank’s Toxicologic Emergencies, 8th ed

Antidysrhythmics

• Vaughn-Williams classiﬁcation • Based on electrophysiologic properties • The Sicilian Gambit • Developed by European cardiologists • Based on mechanisms by which antidysrhythmics modify dysrhythmogenic mechanism

4 Cardiovascular Toxins

Classes

• Class I: sodium channel blockers • Subclasses IA, IB, IC • Class II: beta-adrenergic antagonists • Class III: potassium channel blockers • Class IV: calcium channel blockers

Goldfrank’s Toxicologic Emergencies, 8th ed

Class I

• IA: block Na channels in the resting state • IB: block Na channels in the inactivate state • IC: block Na channels in the activated state

5 Cardiovascular Toxins

Class I

• Examples of class IA • Disopyramide • Procainamide • Quinidine

Class I

• Examples of class IB • Lidocaine • Mexiletine • Moricizine • Phenytoin • Tocainide

Class I

• Examples of class IC • Flecainide • Propafenone

6 Cardiovascular Toxins

Class III

• Prevent and terminate reentrant dysrhythmias by prolonging the action potential duration and effective refractory period without slowing conduction velocity during phase 0 or 1 of the action potential. • Amiodarone, dofetilide, ibutilide

Calcium Channel blockers 2.1.6.1.1

Classiﬁcation

• Phenylalkylamines • Benzothiazepines • Dihydropyradines • Diarylaminopropylamine ethers • T-channel blockers

7 Cardiovascular Toxins

Classiﬁcation

• Phenylalkylamines • Verapamil • Benzothiazepines • Diltiazem

Classiﬁcation

• Dihydropyridines • Nifedipine, isradipine • Amlodipine, felodipine • Nimodipine, nisoldipine, nicardipine

Classiﬁcation

• Diarylaminopropylamine ether • Bepridil • T-channel blocker • None (mibefradil withdrawan)

8 Cardiovascular Toxins

Uses

• Hypertension, angina, dysrhythmias • Migraine headaches, Raynaud’s phenomenon • Subarachnoid hemorrhage

Pharmaco/ Toxicokinetics

• All well absorbed orally • Metabolized via CYP3A4 • Saturated in overdose, reducing effect of 1st pass, increasing bioavailability in OD • All CCBs are highly protein bound

Verapamin & Diltiazem

• In contrast to other, much potential for drug interactions • CYP3A4 substrate and inhibitors • Decreases clearance of many drugs • Also inhibit P-glycoprotein mediated drug transport

9 Cardiovascular Toxins

Drugs with decreased clearance with verapamil and diltiazem

• Carbamazepine

• Cisapride

• Quinidine

• Many HMG-CoA reductase inhibitors

• Cyclosporine

• Tacrolimus

• Most HIV-protease inhibitors

• Theophylline

• Digoxin

Pathophysiology

• Ca++ is integral to excitation-contraction coupling • L-type (voltage-dependent) Ca++ channels are located in the plasma membrane of all types of muscle cells

Pathophysiology

• L-type Ca++ channels • Composed of homologous protein subunits

• The α1 subunit is the pore-forming portion of the channel • Where all CCBs bind to prevent Ca++ inﬂux

10 Cardiovascular Toxins

Pathophysiology

• Other Ca++ channels • N, P, T, Q, R • Found on sarcoplasmic reticulum (SR) or cell membranes (mainly neuronal and secretory tissue) • Can be stretch-operated, receptor- operated, or voltage sensitive

Pathophysiology

• Skeletal muscle depends exclusively on intracellular Ca++ stores for E-C coupling • Intracellular inﬂux is inconsequential • Cardiac and smooth muscle • Intracellular inﬂux is critical

Pathophysiology

• Smooth muscle cells • Ca++ binds calmodulin, resulting complex stimulates myosin light-chain kinase (MLCK) • MLCK phosphorylates/activates myosin • Myosin binds actin, causing contraction

11 Cardiovascular Toxins

Pathophysiology

• Myocardial cells • Inﬂux of Ca++ creates phase 2 of the AP • Ca++ binds to and opens Ca++ channels on the SR • Releases Ca++ from the vast store within the SR (Ca++ mediated Ca++ release)

Pathophysiology

• Myocardial cells • Ca++ then binds troponin C, causes conformational change • Displaces troponin & tropomyosin from actin • Allows actin and myosin to bind causing contraction

Pathophysiology

• Ca++ inﬂux also important in myocardial conduction • Ca++ inﬂux plays a role in phase 4 spontaneous depolarization in the SA node

12 Cardiovascular Toxins

Epinephrine Ca++ L-type VDCC β receptor

Ca++ ++ Ca ++ Gs protein Ca ++ Ca Ca++ AC PKA

ATP cAMP Ca++ Ca++ ++ Ca++ Ca++ Ca ++ Ca++ Ca++ Ca Ca++ Ca++ Ca++

Sarcoplasmic Myofibril Reticulum

Pathophysiology

• All commercially available CCBs antagonize L-type Ca++ channels • Differences in pharmacologic effect result of receptor afﬁnity and type of antagonism

Pathophysiology

• Vascular smooth muscle • Cytosolic [Ca++] maintains basal tone • Decrease in Ca++ inﬂux = arterial vasodilation

13 Cardiovascular Toxins

Pathophysiology

• Myocardium • Decrase in Ca++ inﬂux • Reduced contractility • Reduced heart rate • Reduced conduction velocity

Pathophysiology

• Each group of CCBs bind slightly different regions of the α1 subunit • Hence the different clinical effects • See Goldfranks 8th Ed, page 915 for discussion of therapeutic effects of different classes of CCBs

Clinical Manifestations

• In overdose, receptor selectivity is lost • Hypotension, bradycardia, (death) • There are subtle variations in presentations among the classes

14 Cardiovascular Toxins

Clinical Manifestations

• Hyperglycemia • Numerous reports of hyperglycemia in severe poisoning • B islet cell insulin release is dependent on Ca++ inﬂux from L-type Ca++ channel • This channel is blocked in severe CCB overdose

Management

• Usual measures typically ineffective in severe poisoning • Atropine, calcium salts, inotropes, vasopressors • No role for glucagon • Insulin

Management

• Insulin • Under stress, myocardium changes from free fatty acid energy substrate to carbohydrate (CHO) • Cannot use CHOs because of insulin resistance • High dose insulin seems to be effective

15 Cardiovascular Toxins

Cardiac Glycosides 2.1.6.1.2

Cardioactive Steroids 2.1.6.1.2

Chemistry

• All cardioactive steroids (CAS) contain • Aglycone or “genin” nucleus • Steroid core • Unsaturated lactone ring at C-17 • Additional sugar groups at C-3

16 Cardiovascular Toxins

Oleandrin lactone ring

steroid core

sugar groups

Aglycone (“genin”) nucleus

Image courtesy of Jeff Dahl via Wikimedia Commons

Uses

• Congestive heart failure • Arial tachydysrhythmias

Uses

• Most commonly prescribed CAS in US is digoxin • Internationally available but less commonly used • Digitoxin, ouabain, lanatoside C, deslanoside, gitalin

17 Cardiovascular Toxins

Other Sources

• Oleander

• Nerium oleander, Thevetia peruviana

• Foxglove (Digitalis spp.)

• Lily of the Valley (Convallaria majalis)

• Dogbane (Apocynum cannabinum)

• Bufo marinus toad (bufadionolide cardioactive steroid)

Pharmaco/ Toxicokinetics

• Intravascular distribution & elimination of digoxin from plasma are described using the 2-compartment model • Further discussion on page 973 of GF’s

Pharmaco/ Toxicokinetics

• Many drug-drug interactions • These increase digoxin concentration • Quinidine, verapamil, diltiazem, carvedilol, amiodarone, spironolactone, macrolide antibiotics

18 Cardiovascular Toxins

Mechanism of Action/ Pathophysiology

• CAS increase the force of cardiac contraction (inotropy) by increasing cytosolic Ca++ during systole.

Mechanism of Action/ Pathophysiology • Inhibit active transport of Na+/K+ across cell membranes during repolarization • Binds and inhibits the Na+-K+-ATPase • The Na+-Ca++ antiporter doesn’t use ATP, relies on Na gradient from the Na+-K+- ATPase • Ca++ extrusion is reduced

Goldfrank’s Toxicologic Emergencies, 8th ed

19 Cardiovascular Toxins

Goldfrank’s Toxicologic Emergencies, 8th ed

Mechanism of Action/ Pathophysiology

• Electrophysiologic effects • Increase excitability • Increase automaticity • Decrease conduction velocity • Decrease refractoriness

Goldfrank’s Toxicologic Emergencies, 8th ed

20 Cardiovascular Toxins

Clinical Manifestations

• Noncardiac • Acute • Nausea, vomiting, lethargy, confusion, weakness • Hyperkalemia • Marker of lethality

Clinical Manifestations

• Chronic • Insidious and protean

Chronic effects

• Anorexia, nausea, vomiting, abdominal pain, weight loss

• Delirium, headache, hallucinations

• Amblyopia, photophobia, blurry vision

• Scotomata

• Photopsia, reduced visual acuity

• Chromatopsia, xanthopsia

21 Cardiovascular Toxins

Clinical Manifestations

• Cardiac • Every known type of dysrhythmia • Except rapidly conducted SVT • Bidirectional ventricular tachycardia is nearly diagnostic

Diagnostic Testing

• Serum concentration >2ng/mL 6 hours post ingestion • >40ng/mL for digitoxin • Assay may cross react with other CAS

Management

• Aggressive supportive care • If life-threatening toxicity, treat with digoxin-speciﬁc antibody fragments (Fab)

22 Cardiovascular Toxins

Potassium Channel Blockers 2.1.6.1.2

Amiodarone

• Iodinated benzofuran derivative • Structurally similar to both thyroxine and procainamide • 40% of molecular weight is iodine • Weak alpha-, beta-adrenergic antagonism • Some blockade of Na and L-type Ca channels

23 Cardiovascular Toxins

Amiodarone

• Metabolized by CYP3A4 to desethylamiodarone (active metabolite) • Competes for P-glycoprotein • Increases serum concentrations of digoxin, cyclosporin, warfarin

Amiodarone

• Therapeutic use • Various dysrhthmias, particularly atrial ﬁbrillation • EKG manifestations • Prolong PR and QTC intervals (not QRS)

Amiodarone

• Few reported cases of overdose • Complications associated with long term use, dose related • Pulmonary, thyroid, corneal, hepatic, cutaneous toxicity • (all organs where amiodarone bioaccumulates)

24 Cardiovascular Toxins

Amiodarone

• Pulmonary • Pneumonitis, up to 5% of patients • Typically occurs after years of therapy • May be hastened by supplemental O2 • CT most useful to make diagnosis

Amiodarone

• Thyroid • Approximately 4% of patients • Amiodarone-induced thyrotoxicosis (AIT) • Amiodarone-induced hypothyroidism (AIH) • AIH more common

Amiodarone

• Corneal microdeposits extremely common • May lead to vision loss • Abnormal hepatic enzymes occur in >30% of patients • Slate gray or bluish discoloration of the skin is common

25 Cardiovascular Toxins

Sodium Channel Blockers 2.1.6.1.3

Class I

• IA: block Na channels in the resting state • IB: block Na channels in the inactivate state • IC: block Na channels in the activated state

Class I

• Examples of class IA • Disopyramide • Procainamide • Quinidine

26 Cardiovascular Toxins

Class I

• Examples of class IB • Lidocaine • Mexiletine • Moricizine • Phenytoin • Tocainide

Class I

• Examples of class IC • Flecainide • Propafenone

Management

• Aggressive supportive care with attention to dysrhythmias • Sodium bicarbonate for widened QRS

27 Cardiovascular Toxins

Antihypertensives 2.1.6.2.1

Angiotensin System Modulators

Classes

• Angiotensin-converting enzyme inhibitors (ACE-I) • Antiotensin II receptor blockers

28 Cardiovascular Toxins

Angiotensin Converting Enzyme Inhibitors

Uses

• Most widely prescribed antihypertensives

Pharmaco/ Toxikokinetics

• Well absorbed by GI tract • Peak plasma concentration in 1-4 hours • Enalapril & ramipril are prodrugs • Require hepatic metabolism • Elimination via kidneys

29 Cardiovascular Toxins

Pathophysiology

• Core 2-methyl-propranolol-L-proline moiety • Binds to active site of angiotensin converting enzyme (ACE) • In lungs and vascular endothelium • Prevents conversion of angiotensin I to angiotensin II

Captopril

2-methyl-propranolol-L-proline moiety

Image courtesy of Yikrazuul via Wikimedia Commons

Pathophysiology

• Antiogensin II is a potent vasoconstrictor and activator of aldosterone secretion • ACE inhibition results in • Vasodilation, reduced peripheral vascular resistance, reduced blood pressure, increased cardiac output

30 Cardiovascular Toxins

Pathophysiology

• Side effects • Rash, dysgeusia, neutropenia, hyperkalemia, chronic cough, angioedema • Teratogen • Should not be prescribed in the pregnant or those wanting to be pregnant

Angioedema

• ACE inactivates bradykinin and substance P • ACE inhibition results in increased bradykinin concentration • Primary cause of angioedema (and cough)

Angioedema

• Incidence is 0.1% • 1/3 within hours of 1st dose • 1/3 within 1st week • No dose-response relationship

31 Cardiovascular Toxins

Clinical Effects

• Overdose • May present with hypotension • Rare deaths in isolated overdose

Management

• Intravenous crystalloid • Naloxone? • ACE-Is may inhibit metabolism of enkephalins and potentiate their opioid effects, including BP reduction

Angiotensin II Receptor Blockers

32 Cardiovascular Toxins

Uses

• Antihypertensive • Introduced in 1995 • Six member of the class

Pharmaco/ toxicokinetics

• Rapidly absorbed via GI tract • Peak concentration in 1-4 hours • Eliminated • unchanged in feces or • hepatic metabolism (CYP), bile excretion

Pathophysiology

• Antagonize angiotensin II at the type I angiotensin receptor (AT-1 receptor) • Allows inhibition of angiotensin II without bradykinin effect • Reduced incidence of cough • Rare cases of angioedema reported • Teratogen

33 Cardiovascular Toxins

Management

• Crystalloid

Beta (and mixed alpha) Antagonists 2.1.6.2.2

Uses

• 18 FDA approved beta blockers • Used in the treatment of • Hypertension, coronary artery disease, tachydysrhythmias, congestive heart failure, benign essential tremor • Panic attacks, stage fright, hyperthyroidism, glaucoma

34 Cardiovascular Toxins

Pharmaco/ Toxicokinetics

• Wide range of • Bioavailability, volume of distribution, elemination half-life, duration of effect • Depends on which agent

Pathophysiology

• Already discussed myocyte pathophysiology as it relates to the Ca++ channel • 3 types of beta receptors • beta-1, beta-2, beta-3 • Focus on beta-1 (main type in heart)

Pathophysiology

• Beta receptors are coupled to Gs proteins • When triggered, activate adenylate cyclase (AC), which converts ATP to cAMP • cAMP activated protein kinase A (PKA)

35 Cardiovascular Toxins

Pathophysiology

• PKA then phosphorylates important myocyte proteins • Voltage dependent calcium channel • Enhancing Ca++ inﬂux • Sarcoplasmic reticulum Ca++ channels • Enhancing Ca++ release

Epinephrine Ca++ L-type VDCC β receptor

Ca++ ++ Ca ++ Gs protein Ca ++ Ca Ca++ AC PKA

ATP cAMP Ca++ Ca++ ++ Ca++ Ca++ Ca ++ Ca++ Ca++ Ca Ca++ Ca++ Ca++

Sarcoplasmic Myofibril Reticulum

Pathophysiology

• Beta blockade responsible for • Reduced chronotropy, dromotropy, ionotropy, blood pressure

36 Cardiovascular Toxins

Pathophysiology

• Membrane stabilizing effects • Beta-antagonists that inhibit fast Na+ channels • Type I antidysrhythmic effects • Only occurs in overdose • Clinical effect is QRS widening

Pathophysiology

• Membrane stabilizing effects (MSE) • Agents: • Propranolol, oxprendolol, betaxolol, acebutolol

Pathophysiology

• Intrinsic sympathomimetic activity (ISA) • Agents that have partial agonism at beta receptors • No clinical beneﬁt demonstrated • Agents • Acebutolol, oxprenolol, penbutolol, pindolol

37 Cardiovascular Toxins

Pathophysiology

• Potassium channel blockade • Sotalol • Non-selective beta antagonist • No ISA, MSE, low lipophilicity • Blocks the delayed rectiﬁer K channel

Pathophysiology

• Sotalol • Prolongs action potential • Increases QTc • Predisposes to torsades de pointes and ventricular dysrhythmias

Pathophysiology

• Vasodilation • Agents that are also vasodilators • Labetalol/carvedilol • Nonselective beta blockers that are also alpha-adrenergic antagonists

38 Cardiovascular Toxins

Pathophysiology

• Vasodilation • Nebivolol • Selective beta-1 activity • Causes NO release to produce vasodilation

Pathophysiology

• Vasodilation • Bucindolol/carteolol • Beta-1 blockers • Beta-2 agonists • Carteolol also has NO effects (but only available as ocular preparation)

Pathophysiology

• Betaxolol • Has Ca++ blocking effects

39 Cardiovascular Toxins

Clinical Manifestations

• Hypotension, bradycardia • Refractory in severe cases • Propranolol • Disproportionate number of deaths • Related to prevalence of use and lipophilicity and MSE

Management

• Aggressive supportive care • Usual measures may be ineffective in severe cases • Atropine, inotropes, pressors • Glucagon • High-dose insulin

Management

• Glucagon • Humans have cardiac glucagon receptors

• Coupled to Gs proteins • Trigger the same cascade of events at the beta receptor

40 Cardiovascular Toxins

Centrally Acting Alpha Receptor Agonists 2.1.6.2.3

Classiﬁcation

• Imidazolines • Clonidine, oxymetazoline, tetrahydrozoline • Others • Methyldopa, guanfacine, granabenz • Structurally different but work similarly

Uses

• Antihypertensives • Clonidine • Most commonly used in this category • Hypertension, ADHD, peripheral nerve & spinal anesthesia, adjunct in withdrawal (opioids, nicotine, ethanol)

41 Cardiovascular Toxins

Uses

• Other imidazolines • Oxymetazoline, tetrahydrozoline • ocular topical vasoconstrictors and nasal decongestants • Similar effects as clonidine when ingested

Pathophysiology

• Clonidine • Well absorbed in the GI tract • Onset of action is 30-60 minutes • Peak plasma concentration in 2-3 hours • Lasts up to 8 hours • Eliminated unchanged in the kidneys

Pathophysiology

• Guanabenz & guanfacine • Structurally and pharmacologically similar • Well absorbed orally • Peak plasma concentration in 3-5 hours • No signiﬁcant active metabolite

42 Cardiovascular Toxins

Pathophysiology

• Methyldopa • Is a prodrug • 3 active metabolites • alpha-methylnorepinephrine • alpha-methyldopamine • alpha-methylepinephrine

Pathophysiology

• All drugs in this category exert hypotensive activity via stimulation of presynaptic alpha-2-adrenergic receptors in the brain • Enhances activity of inhibitory neurons in the nucleus tractus solitarius in the medulla

Pathophysiology

• Results in reduced norepinephrine release • Reduction in heart rate, peripheral vascular tone and blood pressure

43 Cardiovascular Toxins

Clinical Manifestations

• Exaggeration of clinical effects • CNS depression, bradycardia, hypotension

Clinical Manifestations

• Abrupt cessation can lead to excess sympathetic activity • Agitation, insomnia, palpitations, hypertension • Typically 16-48 hours after cessation

Management

• Supportive care • Naloxone • Data are mixed

44 Cardiovascular Toxins

Diruretics 2.1.6.2.4

Uses

• Antihypertensives

Classiﬁcation

• 3 classes: thiazides, loops, potassium- sparing • Thiazides • hydrochlorothiazide, chlorthalidone • Loops • Furosemide, bumetanide, ethacrynic acid

45 Cardiovascular Toxins

Classiﬁcation

• Potassium sparing • Amiloride, triampterene, spironolactone

Pathophysiology

• Thiazides • Inhibit Na/Cl reabsorption in the distal convoluted tubule • Loops • Inhibit coupled transport of Na/K/Cl in the ascending loop of Henle

Pathophysiology

• Potassium-sparing • Act as aldosterone antagonists (spironolactone) or epithelial Na channel antagonists (triampterene) in the last distal tubule and collecting duct

46 Cardiovascular Toxins

Clinical Manifestations

• Hyponatremia predominately • May have hyperkalemia with potassium- sparing diuretics • Thiazides may increase hyperglycemia in diabetics (secondary to hypokalemia) • Thiazides increase hyperurecemia, renal calculi, gout

Management

• Supportive care

Vasodilators 2.1.6.2.5

47 Cardiovascular Toxins

Vasodilators

• Hydralazine, minoxidil, diazoxide, nitroprusside • All stimulate the release of NO from vascular endothelium resulting in vasodilation

Clinical Manifestations

• Reduction in blood pressure • Hydralazine adverse effects • Hemolytic anemia, vasculitis, glomerulonephtiris, lupus-like syndrome • Nitroprusside adverse effects • Cyanide, thiocyanate toxicity

Inotropes 2.1.6.3

48 Hydrocarbons

Hydrocarbons/ Solvents/Fuels 2.2.5 Trevonne M. Thompson, MD

2.2.5 Hydrocarbons/Solents/Fuels 2.2.5.1 Aldehydes 2.2.5.2 Alcohols & glycols 2.2.5.2.1 Diethylene glycol 2.2.5.2.2 Ethylene glycol 2.2.5.2.3 Glycol ethers 2.2.5.2.4 Isopropanol 2.2.5.2.5 Methanol 2.2.5.3 Aliphatic hydrocarbons 2.2.5.3.1 Hexane and congeners 2.2.5.3.2 Mixtures (eg. gasoline and kerosene) 2.2.5.4 Aromatic hydrocarbons 2.2.5.4.1 Benzene 2.2.5.4.2 Polycyclic aromatic hydrocarbons 2.2.5.4.3 Toluene 2.2.5.5 Halogenated hydrocarbons 2.2.5.5.1 Carbon tetrachloride 2.2.5.5.2 Chloroform 2.2.5.5.3 Methylene chloride 2.2.5.5.4 Perchloroethylene 2.2.5.5.5 Trichlororoethylene 2.2.5.5.6 Vinyl chloride 2.2.5.6 Hydrazines 2.2.5.7 Ketones 2.2.5.8 Peroxides 2.2.5.9 Terpenes

2.2.5 Hydrocarbons/Solents/Fuels 2.2.5.3 Aliphatic hydrocarbons 2.2.5.3.1 Hexane and congeners 2.2.5.3.2 Mixtures (eg. gasoline and kerosene) 2.2.5.4 Aromatic hydrocarbons 2.2.5.4.1 Benzene 2.2.5.4.2 Polycyclic aromatic hydrocarbons 2.2.5.4.3 Toluene 2.2.5.5 Halogenated hydrocarbons 2.2.5.5.1 Carbon tetrachloride 2.2.5.5.2 Chloroform 2.2.5.5.3 Methylene chloride 2.2.5.5.4 Perchloroethylene 2.2.5.5.5 Trichlororoethylene 2.2.5.5.6 Vinyl chloride

1 Hydrocarbons

Hydrocarbons

• Hydrocarbon • Organic compound made up primarily of carbon and hydrogen atoms • 2 basic types • Aliphatic - straight or branched chain • Cyclic - closed ring

Hydrocarbons

• Miscellany • Many products are mixtures of hydrocarbon (eg. gasoline) • More lipid soluble products cause more CNS depression • Aromatic, aliphatic, chlorinated

Goldfrank’s Toxicologic Emergencies, 8th ed

2 Hydrocarbons

Goldfrank’s Toxicologic Emergencies, 8th ed

Pathophysiology

• Pulmonary toxicity • Mechanism unclear • Aspiration pneumonitis • 3 risk factors • Viscosity, surface tension, volatility

Pathophysiology

• Pulmonary • Absence of tachypnea on initial evaluation has an 80% negative predictive value for aspiration pneumonitis

3 Hydrocarbons

Pathophysiology

• Cardiotoxicity • Halogenaged hydrocarbons, benzene, and toluene are more frequently implicated • Tachydysrhythmias • Sudden snifﬁng death syndrome

Pathophysiology

• CNS • CNS depression with acute toxicity • Irreversible damage with chronic use • White mater degeneration (leukoencephalopathy)

Pathophysiology

• Peripheral nervous system • Peripheral neuropathy • n-hexane, methyl-n-butyl ketone, carbon disulﬁde, acrylamide, ethylene oxide, trichloroethylene

4 Hydrocarbons

Pathophysiology

• Hepatotoxicity • Mainly with chlorinated hydrocarbons • Nephrotoxicity • Halogenated hydrocarbons • Chloroform, carbon tetrachloride, ethylene dichloride, tetrachloroethane, 1,1,1 trichloroethane

n-Hexane

• 6 carbon simple aliphatic hydrocarbon • Used in • Brake cleaning ﬂuid, rubber cement, glues, spray paint, silicones

n-Hexane

• Produces “dying back” peripheral neuropathy • Begins in stocking glove distribution • (Methyl-n-butyl ketone also produces similar neuropathy) • Toxicity is from metabolic intermediate • 2,5-hexadione

5 Hydrocarbons

Goldfrank’s Toxicologic Emergencies, 8th ed

Methylene Chloride

• Found in paint removers, cleaning & degreasing agents, aerosol propellants • Metabolized by CYP2E1 to CO • Signiﬁcant, delayed, and prolonged carboxyhemoglobinemia

Carbon Tetrachloride

• Industrial solvent and reagent • Undergoes Phase I dehalogenation in the liver, produces free radicals causing lipid peroxidation • Centrilobular hepatic necrosis • Suspected carcinogen

6 Hydrocarbons

Vinyl Chloride

• Hepatic angiosarcoma • Acroosteolysis

Trichloroethylene

• Solvent, previously used as general anesthetic

• In presence of CO2, produces phosgene • CNS depression • Cardiotoxic and hepatotoxic

Camphor

• Monoterpene ketone • Inhibits cellular respiration, mainly in CNS • N/V, headache, agitation, and seizures

7 Hydrocarbons

Other Monoterpene Ketones

• All produce CNS depression • Oil of wormwood • Oil of Clove • Oil of eucalyptus • Oil of pennyroyal

Pennyroyal Oil

• Main component • Pulegon • Hepatotoxic—centrilobular necrosis

Chloroform

• Also known as • Trichloromethane and methyltrichloride • Once used as general anesthetic • Currently used as intermediary in industry • Cardiotoxic, hepatotoxic (centrilobular necrosis)

8 Pharmaceutical Additives

Pharmaceutical Additives

G. Patrick Daubert, MD Sacramento, CA

Some (most) material plundered from various mentors and other talented toxicologists, with permission 1

MENU n 2.1.12 Pharmaceutical Additives n 2.1.13 Veterinary Products n 2.1.14 Vitamins

Pharmaceutical Additives n Propylene glycol n Chlorbutanol n Polyethylene glycol n Parabens n Benzyl alcohol n Diethylene glycol n Vit E ferol n Thallium n Benzalkonium chloride n Thorotrast n Thimerosol n Thalidomide n Tryptophan n DES n Sorbitol

1 Pharmaceutical Additives

Pharmaceutical Additives n Propylene glycol n IV preps pushed rapidly n Hypotension, bradycardia, asystole n Prolonged infusions n Lactic acid production n Polyethylene glycol n Toxicity concern with low MWs (< 400) n Risk of renal tubular necrosis

Gasping Syndrome n In 1981 16 neonatal deaths occurred in a NICU n All were pre-term neonates < 2500 gm n Symptoms included severe AGMA, respiratory depression with gasping, and encephalopathy n All neonates had received bacteriostatic NaCl or water flushes containing 0.9% benzyl alcohol

Gasping Syndrome n Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid n This metabolic pathway is well developed in premature infants n The benzyl alcohol was metabolized to benzoic acid causing metabolic acidosis

2 Pharmaceutical Additives

DEG and Sulfanilamide n September-October 1937 n S.E. Massengill Co., used DEG diluent in sulfanilamide elixir n Vomiting, abdominal pain, anuria, seizures, coma n 105 deaths in 15 states n 34 children n Hydropic tubular nephrosis n Development of the Food, Drug, and Cosmetic Act

Polysorbate 80 and E-Ferol n Polysorbate 80 = polyproblems n Released december 1983 n IV form of a vitamin E preparation (E-Ferol) n Fatalities among low birth weight (< 1,500 g) and premature infants n 38 deaths and 43 cases of severe morbidity n Thrombocytopenia n Renal failure n Cholestasis n Ascites n Inhibitory effect by this vitamin E preparation on the in vitro response of human lymphocytes to phytohemagglutinin

Eosinophilia Myalgia Syndrome n October 1989, the health department in New Mexico was notified of 3 patients with an unexplained acute illness n Characterized by intense myalgia, dyspnea, extremity edema, neuropathy, and peripheral blood eosinophilia n By July 1991, 1543 cases and 31 deaths were attributed to EMS n Some L-tryptophan may have been produced by a new bacteria causing an unknown bi-product n EMS lead to the Dietary Supplement Health and Education Act of 1994 n Syndrome resembled Toxic Oil Syndrome (rapeseed oil)

3 Pharmaceutical Additives

Pharmaceutical Additives n Benzalkonium chloride n Most common ophthalmic preservative n Cytotoxic to corneal epithelium n Compromised cornea (keratoconjunctivitis) n Chlorbutanol n Structure similar to trichloroethanol n Chloral hydrate active metabolite n IV thiamine preps

Pharmaceutical Additives n Thorotrast (thorium dioxide 25%) n IV radiocontrast medium (1928-1955) n Delayed hepatic angiosarcoma n Thalidomide n Antiemetic (1960s) n 5,000 infants born with severe congenital abnormalities (phocomelia) n DES (Diethylstilbestrol) n DES mothers – breast CA n DES daughters – vaginal clear cell adenoCA

Question

Which of the following pharmaceutical additives is associated with acute renal dysfunction? A. Chlorobutanol B. Polysorbate 80 C. Thimerosol D. Vit E ferol E. Xylitol

4 Pharmaceutical Additives

Question

Which of the following pharmaceutical additives is associated with acute renal dysfunction? A. Chlorobutanol B. Polysorbate 80 C. Thimerosol D. Vit E ferol E. Xylitol

Vitamins

Vitamin A n Binds retinal binding proteins to maintain vision, epithelial cell integrity n Deficiency: night blindness, Bitot spots on conjunctiva with corneal drying (xerosis) n Acute toxicity defined > 12,000 IU/kg n Chronic toxicity > 25,0000 IU/day for 2-3 weeks n Pseudotumor cerebri (IIH): n Hepatoxicity potential n Teratogenic

5 Pharmaceutical Additives

Vitamin D n Ca/Phos intestinal absorption, bone development, parathyroid gland function n Deficiency: adults - osteomalacia, peds – rickets (craniotabes, rachitic rosary, genu varum) n Toxicity n Acute: hypercalcemia, muscle weakness n Chronic: nephrocalcinosis, renal failure

Vitamin E n Antioxidant n Deficiency: preterm infants have large requirement (ROP, BPD, IVH, hemolytic anemia) n Recall polysorbate 80 and E-Ferol in Pharmaceutical Additives n Toxicity n Antagonizes epoxidation of vitamin K (anticoagulant effect) n Muscle weakness, nausea, diarrhea, headache

Vitamin K1 n Vitamin K1 = phytonadione (vitamin K3 is not clinically relevant) n Synthesis of factors II, VII, IX, X, protein C n Deficiency: rare except in newborns (bleeding episodes) n Hemorrhagic disease of the newborn occurs if vit K1 is not given at birth n Toxicity n Jaundice in premature infants n IV preps associated with anaphylaxis

6 Pharmaceutical Additives

Vitamin B1 (Thiamine) n Coenzyme (TTP) in oxidative metabolism of glucose and ketoacid decarboxylation n Deficiency: n Wet beriberi – high output cardiac failure n Dry beriberi – Wernicke-Korsakoff syndrome: oculomotor changes, ataxis, global confusion. Seen in malnourished such as alcoholism and gastric bypass n Toxicity: antiquated literature reported anaphylactoid reactions with IV dosing. May be due to previous formulations containing chlorbutanol

Vitamin B2 (Riboflavin) n FAD coenzyme in oxidative-reduction reactions n Deficiency: anorexia, mucositis, cheilosis, nasolabial seborrhea n Toxicity: n Yellow urine n Increased riboflavin excretion with boric acid toxicity (blue-green vomit, boiled lobster appearance)

Vitamin B3 (Niacin or Nicotinic acid) n NAD coenzyme for oxidative-reduction reactions n Deficiency: pellagra (4 Ds: diarrhea, dermatitis, dementia, death) n Toxicity: n Niacin flush (skin flush, headache, pruritis, vasodilation). Mediated by prostaglandins, not histamine n Use aspirin to treat n Used by some young adults to adulterate urine to “beat” drug tests n Vacor (PNU) antidote

7 Pharmaceutical Additives

Vitamin B6 (Pyridoxine) n Cofactor for GAD in GABA synthesis n Converted to active form pyridoxal phosphate by pyridoxine phosphokinase n Deficiency: Seizures n Isoniazid, Gyromitra esculenta (false morel), hydrazines (high output fuels) n Toxicity: peripheral sensory neuropathy with excessive chronic dosing or large acute ingestions n Antidote: INH, G. esculenta, hyrdrazines, ethylene glycol poisoning

Vitamin B12 (Cyanocobalamin)

n Coenzyme for 5-methyltetrahydrofolate formation, DNA synthesis, myelin n Deficiency: megaloblastic anemia with peripheral neuropathy (post/lat columns, foot drop) n Toxicity: probably none n Nitrous oxide abusers (dentists): bone marrow suppression, and pernicious anemia. Histochemistry reveals inactive cobalt and inhibition of methionine synthetase n Antidote: CN – Hydroxycobalamin (synthetic B12)

Vitamin C n Reducing agent and antoxidant, Cr6+  Cr3+, collagen metabolism n Deficiency: scurvy (poor wound healing, bleeding gums, bone pain) n Toxicity: > 1.5 grams IV or chronic oral intake > 4 grams/day n Calcium oxalate with ARF (urinary acidification), chronic nephropathy n G6PD hemolysis n Gouty arthritis due to decreased urate excretion n  Fe absorption leading to hemochromatosis n Antidote: congenital methemoglobinemia

8 Pharmaceutical Additives

Question

Which of the following clinical manifestations is associated with excessive vitamin C use? A. Esophagitis B. Flushing of the skin C. Megaloblastic anemia D. Nephrolithiasis E. Peripheral neuropathy

Question

Which of the following clinical manifestations is associated with excessive vitamin C use? A. Esophagitis B. Flushing of the skin C. Megaloblastic anemia D. Nephrolithiasis E. Peripheral neuropathy

Food Additives

9 Pharmaceutical Additives

Food Additives n Regulated by FDA and categorized into 5 groups n Enhance texture n Improve nutritional value (ie, vitamins) n Maintain freshness/safety n Regulate acidity n Provide flavoring/coloring

Food Additives n Sulfites (red wines): hypersensitivity reactions n Nitrates n Hypotension (hotdog syndrome) n Infants convert nitrates to nitrites – methemoglobinemia n NaOH and KOH: skin, mucous membrane irritation

Food Additives n MSG: “Chinese restaurant syndrome” – flushing, headache, chest pain, vomiting, rare angioedema, bronchospasm n Yellow dye #5: hypersensitivity reactions n Aspartame: three metabolites – aspartic acid, phenylalanine, methanol (minute) n Patients with PKU unlikely to accumulate toxic levels of phenylalanine n Saccharin: bladder CA in animals

10 Pharmaceutical Additives

Question

A young boy presents to the hospital with acute urticaria after eating lemon cake. What was the likely food additive to which he is allergic? A. Aspartame B. Metabisulfite C. Monosodium glutamate D. Saccharin E. Tartrazine

Question

Questions?

Good Luck!!

11 PHARMACEUTICAL ADDIVITES, VETERINARY PRODUCTS, VITAMINS

G. Patrick Daubert, MD; Michelle Burns-Ewald, MD CORE CONTENT 2.1.12 Pharmaceutical Additives 2.1.13 Veterinary Products 2.1.14 Vitamins PHARMACEUTICAL ADDITIVES

• Pharmaceutical Additives o Benzalkonium chloride o Benzyl alcohol o Chlorbutanol o Diethylene glycol (DEG) o Diethylstilbestrol (DES) o Parabens o Polyethylene glycol o Propylene glycol o Sorbitol o Thalidomide o Thallium o Thimerosol o Thorotrast o Tryptophan o Vit E ferol • Benzalkonium chloride o Most common ophthalmic preservative o Cytotoxic to corneal epithelium o Compromised cornea (keratoconjunctivitis) • Gasping Syndrome o In 1981, 16 neonatal deaths occurred in a NICU o All were pre-term neonates < 2500 gm o Symptoms included severe anion gap metabolic acidosis, respiratory depression with gasping, and encephalopathy o All neonates had received bacteriostatic NaCl or water flushes containing 0.9% benzyl alcohol . Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid . This metabolic pathway is well developed in premature infants . The benzyl alcohol was metabolized to benzoic acid causing metabolic acidosis • Chlorbutanol o Structure similar to trichloroethanol (chloral hydrate active metabolite) o IV thiamine preps in past

1 • DEG o Sulfanilamide . September-October 1937 . S.E. Massengill Co., used DEG diluent in sulfanilamide elixir . Vomiting, abdominal pain, anuria, seizures, coma . 105 deaths in 15 states with 34 pediatric fatalities • Multiple other epidemics in Nigeria, Bangladesh, South Africa, Haiti • Hydropic tubular nephrosis . Development of the Food, Drug, and Cosmetic Act o Oxidative metabolism by ADH/ ALDH to hydroxyethoxy acetic acid (HEAA) o Ether bond probably does not break o Renal biopsy typically reveals tubular necrosis and vacuolization o DEG has high fatality rate o Management with early hemodialysis in otherwise normal patients is still controversial • DES (Diethylstilbestrol) o DES mothers – breast CA o DES daughters – vaginal clear cell adenoCA • Parabens o Hypersensitivity reactions o 2nd most common ingredient (2nd to water) in medications • Polysorbate 80 and E-Ferol o Polysorbate 80 = polyproblems o Released December 1983 o IV form of a vitamin E preparation (E-Ferol) o Fatalities among low birth weight (< 1,500 g) and premature infants o 38 deaths and 43 cases of severe morbidity . Thrombocytopenia . Renal failure . Cholestasis . Ascites o Inhibitory effect by E-Ferol on the in vitro response of human lymphocytes to phytohemagglutinin • Propylene glycol o IV preps pushed rapidly (> 50 mg/min for IV phenytoin (Dilantin) can result in toxicity . Hypotension, bradycardia, asystole o Prolonged infusions . Lactic acid production • Polyethylene glycol o Toxicity concern with low MWs (< 400) o Risk of renal tubular necrosis • Sorbitol (D-glucitrol) o Widely used as sweetening agent (activated charcoal)

2 o Case reports of fatalities in patients with hereditary fructose intolerance (sorbitol metabolized to glucose and fructose) receiving IV formulation of sorbitol • Thalidomide o Antiemetic (1960s) o 5,000 infants born with severe congenital abnormalities (phocomelia) • Koremlu (thallium acetate) o 1920-1940 Koremlu was used topically as a treatment for ringworm (depilatory agent) o Patients were experiencing various aliments including losing all scalp hair, neuritis, myalgias, and arthralgias o Many of the nation’s leading department stores sold the product, and Vogue and Cosmopolitan carried its advertizing o By 1934, 692 cases of thallium poisoning with 31 deaths • Eosinophilia Myalgia Syndrome (EMS) o October 1989, the health department in New Mexico was notified of 3 patients with an unexplained acute illness o Characterized by intense myalgia, dyspnea, extremity edema, neuropathy, and peripheral blood eosinophilia o By July 1991, 1543 cases and 31 deaths were attributed to EMS o Some L-tryptophan may have been produced by a new bacteria causing an unknown bi-product o EMS Histology . Endothelial cell hyperplasia in the capillaries, with evidence of swelling and necrosis . Inflammatory cell infiltrate of predominantly monocytes, histiocytes, lymphocytes, macrophages, and plasma cells and occasionally eosinophils in nerve, muscle, and connective tissue, including the subdermal fascial layer (fasciitis) . Increased fibrosis, mostly in the fascia o EMS lead to the Dietary Supplement Health and Education Act of 1994 • Thorotrast (thorium dioxide 25%) o IV radiocontrast medium (1928-1955) o Delayed hepatic angiosarcoma o Leukemia and skeletal sarcomas (thorotrastomas at sites of extravasation) VETERINARY PRODUCTS

• Xylazine o Animal sedative with central alpha-agonist and imidazoline properties similar to clonidine o CNS depression, miosis, respiratory depression, bradycardia symptoms • Ivermectin: o Antiparasitic drug that potentiates GABA release • 4-aminopyridine o Avian pesticide

3 o Potassium channel blocker and enhances release of ACh from nerve endings o Marketed in humans as Fampridine and Neurelan . Muliple sclerosis therapy . Shown to reverse tetrodotoxin toxicity in animal models o Seizures: probably the only drug-induced seizures that respond to phenytoin VITAMINS

• Fat soluble = A, D, E, K • Vitamin A o Binds retinal binding proteins to maintain vision, epithelial cell integrity o Deficiency: night blindness, Bitot spots on conjunctiva with corneal drying (xerosis) o Acute toxicity defined > 12,000 IU/kg, chronic toxicity > 25,0000 IU/day for 2-3 weeks . Pseudotumor cerebri (IHH): also consider tetracycline, steroids, OCPs . Hepatoxicity – uptake into Ito cells, cirrhosis, alcohol may potential . Teratogenic – facial and ear deformities, rare CNS/CV . Misc – dry skin, alopecia, premature epiphyseal closure in infants • Vitamin D o Ca/Phos intestinal absorption, bone development, parathyroid gland function o Deficiency: adults - osteomalacia, peds – rickets (craniotabes, rachitic rosary, genu varum) o Toxicity . Acute: hypercalcemia, muscle weakness . Chronic: nephrocalcinosis, renal failure • Vitamin E o Antioxidant o Deficiency: preterm infants have large requirement (i ROP, BPD, IVH, hemolytic anemia) o Review polysorbate 80 and E-Ferol in Pharmaceutical additives o Toxicity . Antagonizes epoxidation of vitamin K (anticoagulant effect) . Muscle weakness, nausea, diarrhea, headache • Vitamin K1 o Vitamin K1 = phytonadione (vitamin K3 is not clinically relevant) o Essential cofactor in hepatic synthesis of coagulation factors II, VII, IX, X, protein C o Deficiency: rare except in newborns (bleeding episodes) . Hemorrhagic disease of the newborn occurs if vit K1 is not given at birth o Toxicity

4 . Jaundice in premature infants, elevated levels could impair effects of anticoagulants . IV preps uncommonly cause anaphylaxis, IM preps hematomas • Vitamin B1 (Thiamine) o Coenzyme (TTP) in oxidative metabolism of glucose and ketoacid decarboxylation o Deficiency: . Wet beriberi – high output cardiac failure . Dry beriberi – Wernicke-Korsakoff syndrome: oculomotor changes, ataxis, global confusion. Seen in malnourished such as alcoholism and gastric bypass o Toxicity: antiquated literature reported anaphylactoid reactions with IV dosing. May be due to previous formulations containing chlorbutanol • Vitamin B2 (Riboflavin) o FAD coenzyme in oxidative-reduction reactions o Deficiency: anorexia, mucositis, cheilosis, nasolabial seborrhea o Toxicity: Yellow urine. Increased riboflavin excretion with boric acid toxicity (blue-green vomit, boiled lobster appearance). No evidence that riboflavin is useful in the treatment of boric acid toxicity. • Vitamin B3 (Niacin or Nicotinic acid) o NAD coenzyme for oxidative-reduction reactions o Deficiency: pellagra (4 Ds: diarrhea, dermatitis, dementia, death) o Toxicity: . Niacin flush (skin flush, headache, pruritis, vasodilation). Mediated by prostaglandins, not histamine. Use aspirin to treat. . Used by some young adults to adulterate urine to “beat” drug tests o Vacor (PNU) antidote • Vitamin B6 (Pyridoxine) o Cofactor for GAD in GABA synthesis. Converted to active form pyridoxal phosphate by pyridoxine phosphokinase o Deficiency: Seizures . Isoniazid, Gyromitra esculenta (false morel), hydrazine rocket fuel o Toxicity: peripheral sensory neuropathy with excessive chronic dosing or large acute ingestions o Antidote: INH, G. esculenta, hyrdrazines, ethylene glycol poisoning • Vitamin B12 (Cyanocobalamin) o Coenzyme for 5-methyltetrahydrofolate formation, DNA synthesis, myelin o Deficiency: megaloblastic anemia with peripheral neuropathy (post/lat columns, foot drop) o Toxicity: probably none o Nitrous oxide abusers (dentists): bone marrow suppression, and pernicious anemia. Histochemistry reveals inactive cobalt and inhibition of methionine synthetase o Antidote: CN – Hydroxycobalamin (synthetic B12) exchanges hydroxyl group with free CN to produce cyanocobalamin (renally excreted)

5 • Vitamin C o Reducing agent and antoxidant, Cr6+ g Cr3+, collagen metabolism o Deficiency: scurvy (poor wound healing, bleeding gums, bone pain) o Toxicity: > 1.5 grams IV or chronic oral intake > 4 grams/day . Calcium oxalate with ARF (urinary acidification), chronic nephropathy . G6PD hemolysis . Gouty arthritis due to i urate excretion . h Fe absorption leading to hemochromatosis o Antidote: congential methemoglobinemia FOOD ADDITIVES

• Regulated by FDA and categorized into 5 groups o Enhance texture o Improve nutritional value (ie, vitamins) o Maintain freshness/safety . Sulfites (red wines): hypersensitivity reactions . Nitrates • Hypotension (hotdog syndrome) • Infants convert nitrates to nitrites – methemoglobinemia o Regulate acidity . NaOH and KOH: skin, mucous membrane irritation o Provide flavoring/coloring . MSG: “Chinese restaurant syndrome” – flushing, headache, chest pain, vomiting, rare angioedema, bronchospasm . Yellow dye #5: hypersensitivity reactions . Aspartame: three metabolites – aspartic acid, phenylalanine, methanol (minute). Patients with PKU unlikely to accumulate toxic levels of phenylalanine . Saccharin: bladder CA in animals

6 QUESTIONS 1. The structure of chlorobutanol most closely resembles which of the following compounds? A. Chloral hydrate B. Dibromochloropropane C. Hexachlorobenzene D. Hydroxyethoxy acetic acid E. Trichloroethanol

The structure of chlorobutanol most closely resembles trichloroethanol, the metabolite of chloral hydrate. Hydroxyethoxy acetic acid is the metabolited of DEG. The other choices are note related to chlorobutanol. Dibromochloropropane is a pesticide that causes sterility and altered sex ratio in offspring. Hexachlorobenzene is a fungicide associated with porphyria, pemba yara, and spongiform encephalopathy.

2. Which of the following statements best describes the pathophysiology of the neonatal “gasping” syndrome? A. Benzyl alcohol metabolized to benzoic acid resulting in metabolic acidosis B. Chlorobutanol in thiamine preparation resulting in coma C. Diethylene glycol metabolized to HEAA resulting in renal failure D. Hydrogen peroxide in the dialysate resulting in severe hemolysis E. Propylene glycol infusions producing hypotension, bradycardia, asystole

The gasping syndrome in 1981 was due to bacteriostatic NaCl or water flushes containing 0.9% benzyl alcohol. The benzyl alcohol was metabolized to benzoic acid resulting in severe metabolic acidosis.

3. Propylene glycol is metabolized by alcohol dehydrogenase to which of the following? A. Acetone B. Ethylene glycol C. Lactic acid D. Oxalic acid E. Trichloroethanol

Propylene glycol is metabolized to lactic acid in a complex metabolic pathway. This is most likely to be of clinical importance during prolonged infusions. Oxalic acid is the metabolite of ethylene glycol. Trichloroethanol is the metabolite of chloral hydrate. Acetone is the metabolite of isopropyl alcohol

7 4. Which of the following toxicological disasters lead to the Dietary Supplement Health and Education Act of 1994? A. Diethylstilbestrol clear cell adenocarcinoma B. Eosinophilia Myalgia Syndrome C. Gasping syndrome D. Sulfanilamde and DEG E. Vitamin E-Ferol-induced renal failure

Eosinophilia Myalgia Syndrome was caused by L-tryptophan and lead to the Dietary Supplement Health and Education Act of 1994. The sulfanilamide disaster with DEG lead to the development of the Food, Drug, and Cosmetic Act. Gasping syndrome, vitamin E-ferol and diethylstilbestrol were tragic toxicologic events but did not lead to any national legislation.

5. Which of the following pharmaceutical additives is second only to water as the most common ingredient in medications? A. Benzalkonium chloride B. Parabens C. Polyethylene glycol D. Propylene glycol E. Sorbitol

The parabens are very common ingredients in medications and cosmetics. They probably have little toxicity other than allergic reactions.

1E 2A 3C 4B 5B

8 Endocrine

Drugs that Affect the Endocrine System 2.1.7 Trevonne M. Thompson, MD

2.1.7 Drugs that affect the endocrine system 2.1.7.1 Antidiabetic drugs 2.1.7.1.1 Insulin 2.1.7.1.2 Oral hypoglycemics 2.1.7.1.2 Others 2.1.7.2 Bone active drugs 2.1.7.3 Electrolytes and minerals 2.1.7.4 Glucocorticoids 2.1.7.5 Sex hormones, growth hormones, anabolic steroids 2.1.7.6 Thyroid drugs 2.1.7.7 Vasopressin and somatostatin analogues

Antidiabetic Drugs 2.1.7.1

1 Endocrine

Insulin

• Released from pancreas, binds to receptors on cell surface of insulin-sensitive tissue • Hepatocytes, myocytes, adipocytes

Sulfonylureas

• Stimulate pancreatic insulin release • Bind to receptors that result in closure of the KATP channels • Results in multistep process that increases insulin release

Meglitinides

• Structurally different from sulfonylureas • Bind to same receptors that result in closure of the KATP channels • Results in multistep process that increases insulin release

2 Endocrine

Biguanides

• Inhibits gluconeogenesis, decreasing hepatic glucose output • Also enhances peripheral glucose uptake

Thiazolidinediones

• Decrease insulin resistance by potentiating insulin sensitivity in the liver, adipose, and skeletal muscle • Also reduce hepatic glucose production

Glucosidase Inhibitors

• Acarbose, miglitol • Oligosaccharides that inhibit alpha- glucosidase enzymes in small intestine • Blunts postprandial blood glucose concentration

3 Endocrine

Goldfrank’s Toxicologic Emergencies, 8th ed

4 Endocrine

Pharmacokinetics

• Many sulfonylureas have long durations of action

Clinical Manifestations

• Insulin, sulfonylureas, meglitinides • All cause hypoglycemia • CNS effects predominate with hypoglycemia • Brain uses glucose almost exclusively as energy source (ketones in starvation)

Management

• Supportive care • Reversal of hypoglycemia • Insulin • Titrate dextrose infusion as needed

5 Endocrine

Management

• Sulfonylureas • Feed patient when appropriate, • Octreotide • Somatostatin analogue, blocks insulin release from pancreas

Special Consideration

• Metformin associated lactic acidosis (MALA) • Metformin inhihibits hepatic lactate update and conversion of lactate to glucose • 2 entities

Special Consideration

• MALA • Lactic acidosis associated with underlying medical disease (especially renal insufﬁciency) • Metformin overdose

6 Endocrine

Bone Active Drugs 2.1.7.2

Bone Active Drugs

• Calcitonin & bisphosphonates

Calcitonin

• Inhibits osteoclast activity, reduces bone reabsorption • Used to treat hypercalcemia • Can cause hypocalcemia

7 Endocrine

Bisphosphonates

• Inhibits osteoclast activity, reduces bone reabsorption • Can be used to treat hypercalcemia, osteoporosis • Associated with osteonecrosis of the jaw

Electrolytes & Minerals 2.1.7.3

Calcium

• Ca++ homeostasis is regulated by the endocrine system • Interaction between vitamin D, parathyroid hormone, and calcitonin • Ca++ essential in maintaining function of heart, vascular smooth muscle, skeletal muscle and nervous system

8 Endocrine

Calcium

• Hypocalcemia • Paresthesias, muscle cramps, carpopedal spasm, tetany, seizures, prolonged QTc • Hypercalcemia • Lethargy, muscle weakness, nausea, vomiting, constipation, altered mental status, dysrhythmias

Glucocorticoids 2.1.7.4

Glucocorticoids

• Class of steroid hormones that bind to the glucocorticoid receptor (present in nearly all vertebrate animal cells) • Both metabolic and immunologic effects

9 Endocrine

Adverse Effects

• Immunosuppression

• Hyperglycemia

• Skin fragility

• Osteoporosis

• Weight gain

• Adrenal insufﬁciency

• Anovulation

• Irregular menses

• Growth retardation

• CNS excitation

• Cararacts

• Many others Sex Hormones, Growth Hormones, and Anabolic steroids 2.1.7.5

Anabolic Steroids

• Androgenic anabolic steroids (AAS) • Increase muscle mass, lean body weight, cause nitrogen retention • Responsible for secondary sex characteristics (hair, voice, etc) • Testosterone is the prototype

10 Endocrine

Anabolic Steroids

• 1990 Anabolic Steroid Control Act • Amended the Substance Control Act • Made AAS schedule III • 2004 Anabolic Steroid Control Act • Added certain precursors (like androstenedione) to the list of substances

Anabolic Steroids • Testosterone is rapidly degraded in the liver • For clinical usefulness: • Esterify the 17-hydroxy position to form a hydrophobic compound suitable for injection • Alkylate the 17-hydroxy position for an oral preparation

Goldfrank’s Toxicologic Emergencies, 8th ed

11 Endocrine

Goldfrank’s Toxicologic Emergencies, 8th ed

Terminology

• Cycling • AAS use intervals (2 months on/2 off) • Stacking • Combining several AAS at one time • Plateauing • Developing tolerance

Terminology

• Pyramiding • Start with low dose, increase, then decrease • Bridging • Changing to short acting agents just prior to drug testing

12 Endocrine

Clinical Manifestations

• Musculoskeletal • Increase muscle mass and size • Hepatic • Hepatic subcapsular hematoma, peliosis hepatis

Clinical Manifestations

• Infectious • Local complications from injecting • Dematologic • Keloids, sebaceous cysts, comedones, seborrheic furunculosis, folliculitis, striae

Clinical Manifestations

• Endocrine • Gynecomastia, testicular atrophy, reduced spermatogenesis, breast atrophy in women

13 Endocrine

Clinical Manifestations

• Cardiovascular • Acute MI, sudden cardiac death, biventricular hypertrophy, myocardial ﬁbrosis, contraction band necrosis • Psychiatric • Depression, mania, delirium, insomnia, aggression

Clenbuterol

• Beta-2 agonist with anabolic properties • Overdose will have beta-2 agonist characteristics

Human Growth Hormone • Anabolic peptide hormone • Stimulates protein synthesis • Adverse effects • Myalgias, arthralgias, carpel tunnel syndrome, edema, acromegaly, hyperglycemia

14 Endocrine

Thyroid Drugs 2.1.7.6

Thyroid Function

• Inﬂuenced by hypothalamus, pituitary gland, thyroid gland, and target organs

Thyroid Function

• Hypothalamus releases thyrotropin releasing hormone (TRH) • TRH causes pituitary gland to release thyroid stimulating hormone (TSH) • TSH causes thyroid to release T3 and T4 • T3 and T4 affect end organs (metabolic consequences)

15 Endocrine

Thyroid Function

• 95% of circulating hormone is T4 • T3 has 3x hormonal activity • T4 is de-iodinated intracellulary to T3

Pharmacology

• Desiccated thyroid • Animal derived, contains T3 and T4 • Levothyroxine • Synthetic T4 • Most widely used for hypothyroidism

Toxicity

• 7-10 day delay • Most remain asymptomatic or only mildly symptomatic • Treatment • Supportive care, beta-blockers

16 Endocrine

Thioamides

• PTU and methimazole • Used to treat hyperthyroidism • Both inhibit T3/T4 release • PTU also blocks peripheral deiodination of T4 to T3 • Little data on overdose

Iodides

• Iodide salts were used before Thioamides were available • Inhibit T3/T4 release

Iodism

• Rash, laryngitis, bronchitis, esophagitis, conjunctivitis, drug fever, metallic taste, salivation, headache, bleeding diathesis

17 Accreditation Statement The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The University of Alabama School of Medicine designates this educational activity for a maximum of 22.5 AMA PRA Category 1 credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The University of Alabama School of Medicine is an equal opportunity/afﬁrmative action institution.

Program Objectives: • Present study content speciﬁcally designed for the medical toxicology subspecialty exam offered jointly by ABEM,ABP, and ABPM • Present a comprehensive review of medical toxicology • Allow attendees to gain new insight into current clinical issues

Target Audience: Physicians preparing for the biennial certiﬁcation and recertiﬁcation examination in Medical Toxicology, and others with an interest in medical toxicology.

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