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ACMT Board Review 2014: Cardiovascular Toxins

Russ Kerns, MD, FACMT Carolinas Medical Center

Charlotte, NC

Objectives: 2.1.6 Drugs that affect the cardiovascular system

n  2.1.6.1 Antidysrhythmics n  2.1.6.1.1 calcium channel blockers n  2.1.6.1.2 cardiac glycosides n  2.1.6.1.3 potassium channel blockers n  2.1.6.1.4 sodium channel blockers

n  2.1.6.2 Antihypertensives n  2.1.6.2.1 Angiotensin modulators n  2.1.6.2.2 β-adrenergic receptor antagonists n  2.1.6.2.3 central α-agonists n  2.1.6.2.4 diuretics n  2.1.6.2.5 vasodilators

n  2.1.6.3 Inotropes n  Provide key example toxins and visual stimuli

Key Principles

n  Cardiac action potential n  Sodium channels n  Potassium channels n  Na+-K+ ATPase

n  Electromechanical coupling n  Calcium channels

n  Modulators n  Β-adrenergic receptors

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Cardiac Action Potential

n  Phase 0 n  electrical stimulus n  sodium influx via fast

Na+ channels n  ↑ resting membrane

potential n  depolarization

Cardiac Action Potential

n  Phase 1 n  Repolarization of

membrane begins n  Na+ channels close n  Potassium efflux

(outward rectifying current)

Cardiac Action Potential

n  Phase 2 n  plateau phase n  calcium influx n  potassium efflux

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Cardiac Action Potential

n  Phase 3 n  repolarization n  Calcium channels

close n  Potassium efflux

continues

Cardiac Action Potential

n  Phase 4 n  Resting state

Sodium Channel

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Na+ Channel Structure

n  Found in neurons, glial cells & myocytes n  9 subtypes n  Tetrameric protein n  Transmembrane n  SCN gene

n  SCN5 – Brugada Syndrome n  Voltage-gated (myocardial) n  Ligand-gated (nicotinic)

Na+ Channel Function

n  Resting (Closed) n  Open n  Inactivated (Closed)

n  Refractory to opening

Na+ Channel Modulation

n  Agonists – channel openers n  Aconitine (Monk’s Hood) n  Batrachotoxin (Poison Dart Frog) n  Grayanotoxin (Azalea and Rhododendron sp)

n  some are antagonists n  Veratridine (Veratrum sp – False Hellebore) n  Zygacine (Zygadenus sp – Death Camus)

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Na+ Channel Agonists

n  Clinical consequences n  Ventricular dysrhythmias n  Bradycardia

n  Treatment n  Na+ channel antagonists n  Cardioversion/defibrillation

Na+ Channel Modulation: Antagonists

n  Antidysrhythmics 2.1.6.1.4 n  Ia Antidysrhythmics

n Procainamide, quinidine, disopyramide n  Ib Antidysrhythmics

n Lidocaine, mexilitine, phenytoin n  Ic Antidysrhythmics

n Encainide, flecainide, propafenone

Na+ Channel Modulation: Antagonists

n  Other sodium channel blocking drugs n  Analgesics: propoxyphene n  Anticonvulsants: carbamazepine n  Antidepressants: cyclics, bupropion, venlafaxine n  Antimalarials: quinine, chloroquine, hydroxychloroquine n  Class II antidysrhythmics: propranolol, acebutolol n  Class III antidysrhythmics: amiodarone n  Local anesthetics n  Phenothiazines: diphenhydramine, thioridazine n  Others: cocaine, propylene glycol

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Na+ Channel Modulation: Antagonists

n  Natural toxins n Grayanotoxins

n Some are agonists n Taxine (Taxus sp – Yew)

X

Widened QRS

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Wide QRS: ECG as Prognostic Tool for Cyclic Antidepressant OD

n  Reflects activity at the sodium channel n  Limb lead QRS duration

n  > 100 ms risk of seizures n  > 160 ms risk of ventricular dysrhythmias

Boehnert. NEJM 1985;313:474-9

Na+ Channel Antagonism: Rate-dependent baseline

7:50 min

2:50 min

QRS – 140 ms; BP - 145/78 mmHg

5:50 min

QRS – 160 ms; BP - 151/68 mmHg

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

Terminal Axis Deviation

7 mm R’

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Sodium Channel Blockade: Rightward Terminal Axis

n  R’ wave in aVR > 3 mm n  R’:S ratio in aVR > 0.7

normal right axis deviation

Liebelt et al. Ann Emerg Med 1995;26:195-201

Brugada ECG Pattern

u  Terminal right axis deviation u  Coved (saddle) ST segment elevation precordium

Littmann et al. Am Heart J 2003;145:768-78; Beberta et al. Clin Toxicol 2007;45:186-8

Sodium Channel Blockade: Consequences

n  Treatment n  Sodium bicarbonate n  Lidocaine (?) n  Cardioversion/defibrillation

ventricular tachycardia torsades de pointes

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Sodium Channel Blockade: Hypertonic Sodium Bicarbonate

n  Sodium ion n  Reverses competative Na+ channel antagonism

n  Alkalinization n  Increased drug-protein binding (↓ free drug) n  decreased drug binding at the Na+ channel

Sodium Channel Blockade Treatment: Why Lidocaine?

n  Class 1a n  Blocks in resting state n  Recovery: 1-10 ms

n  Class 1b n  Blocks in inactive state n  Recovery: <1 ms

n  Class 1c n  Blocks in inactive state n  Recovery: >10 ms

Lidocaine is “fast on and fast off” so there is a greater chance of channel opening

Antidysrhythmic Factoids

n  Class Ia: procainamide n  Metabolism via acetylation

n  NAPA: K+ channel blockade n  Polymorphic metabolism

n  Acute OD: seizures, dysrhythmias n  Chronic use: SLE, myopathy,

thrombocytopenia, agranulocytosis n  False positive amphetamine on enzyme-

based urine drug screens

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Antidysrhythmic Factoids n  Class Ia: quinidine

n  Torsades de pointes (K+ channel blockade) n  Qunidine syncopy

n  Cinchonism (abdominal pain, tinnitus, AMS) n  d-isomer of quinine

n  Hypoglycemia n  dis-inhibited pancreatic insulin release due to K+ channel

blockade

n  Class 1a: disopyramide n  Anticholinergic n  Hypoglycemia (pancreatic K+ blockade)

Antidysrhythmic Factoids n  Class Ib: lidocaine

n  Acute toxicity: CNS and dysrhythmias n  Lidocaine wraps and liposuction

n  Metabolism n  Hepatic CYP3A4 (saturable/drug interactions) n  Active metabolite (MEGX) n  Adverse drug event risks:

n  Advanced age n  Hepatic insufficiency n  Prolonged infusion (>3 mg/min for 24-72 hr)

Antidysrhythmic Factoids

n  Class Ib: tocainide n  ADRs limit clinical use

n  Rash, heptatoxicity, blood dyscrasias

n  Class 1b: mexiletine n  CYP2D6 interactions n  False positive amphetamine on enzyme-based

urine drug screens

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Antidysrhythmic Factoids n  Class Ic: flecainide

n  Procainamide derivative n  Prolonged PR and QRS duration with minimal

QT prolongation n  Negative inotrope

n  Class 1c: propafenone n  Also β-blocker and calcium channel antagonist n  Bradycardia, wide QRS, negative inotropy

Ca2+ Channels

n  L-type n  N-type (neuronal) n  P-type (Purkinje) n  T-type (muscular)

L-type Ca2+ Channel

n  Four proteins n  Span cell membranes n  Regulates calcium entry

n  Closed in resting state n  Require activation to open

n  Channel location determines the functional result of calcium entry

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L-type Ca2+ Channel

endocrine non-vascular smooth muscle

Ca2+ Channel Activation - Myocardial

n  Ca2+- mediated Ca2+ - release n  Result

n  éHR n  écontractility

n  Modulators n  Catecholamines n  G protein n  cAMP n  protein kinase

Ca2+ Channel Activation - Vascular

n  Result n  vasoconstriction n  Maintenance of BP

n  Modulators n  α1 stimulation n  β2 stimulation n  angiotensin n  endothelin

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Ca2+ Channel Antagonism

Consequences: Hypotension Bradycardia Poor cardiac output Cardiogenic Shock

X

Ca2+ Channel Agonist

n  Levosimendan n  Directly opens Ca2+ channel n  Heart failure treatment n  Experimental treatment of CCB toxicity n  No human overdose

Ca2+ Channel Antagonism

n  Class IV drugs n  Nifedipine (dihydropyridine) n  Diltiazem (benzothiazepine) n  Verapamil (phenylalkylamine) n  Bepridil (diarylaminopropylamine)

n  Cyclic antidepressants n  Class 1c agent Propafenone

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Calcium Channel Blocker Factoids

n  Class IV observations n  Pharmacokinetics

n  Hepatic metabolism n  Highly protein bound

n  Drug interactions n  CYP3A4 and P-glycoprotein inhibitors n  Digoxin, theophylline, OTHERS!!!

n  Acute toxicity n  Bradycardia, hypotension, decreased contractility n  Diabetogenic state

X

Class IV Toxicity: Treatment n  Decontamination

n  Charcoal for sustained release formulations n  Pharmacotherapy

n  Calcium salts n  Glucagon n  High-dose insulin n  Intravenous lipid emulsion (too recent for exam) n  Phosphodiesterase inhibitors n  Vasopressors

n  Technological therapy – novel (except pacing) n  Aortic balloon pump, ECMO, MARS, Pacing, LVADs

Potassium Channels

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K+ Channel Structure n  Tetrameric protein in the cell membrane

n  Central pore through which K+ flows

n  Normally closed n  Opening leads to K+ efflux from the cell

K+ Channel Function n  Inhibition of cell function

n  Acts to prevent overuse of the cell n  Opening stimuli

n êintracellular energy molecules (ATP) n éintracellular Na+

n éintracellular Ca2+

+ mV

- mV

Normal Function: Myocardial K+ Channel

Na+

Ca2+

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Normal Function: Myocardial K+ Channel

n  Effective Refractory Period n  Depolarization not possible

n  Relative Refractory Period n  Depolarization possible with sufficient

electrical stimulus

RRP ERP

K+ Channel Modulation n  K+ channel inhibition

n  Prolongs action potential (phase 3) n  Equalizes refractoriness of ischemic and non-

ischemic tissues without slowing conduction n  ↑RRP allows for dysrhythmias (TdP)

X Na+

Prolonged QTc / TdP n  Antidysrhythmic

n  Class I (procainamide, quinidine and quinine) n  Class II (sotalol) n  Class III (amiodarone, bretylium, dofetilide, ibutilide)

n  Antidepressants n  Serotonin agonists

n  Antihistamine n  terfenadine, astemizole

n  Antipsychotic n  haloperidol - butyrophenone n  thioridazine - phenothiazine n  sertindole - atypical

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Prolonged QTc / TdP n  GI agents

n  cisapride n  Metabolic

n  hypokalemia (diuretics) n  hypomagnesemia (diuretics)

n  Metals n  arsenic

www.torsades.org

Antidysrhythmic Factoids n  Class III: Amiodarone

n  Pharmacology n  Structurally similar to T3 and is 40% iodine n  Class Ic, II, IV activity

n  Competes for p-glycoprotein n  ↑ digoxin and cyclosporine concentrations n  ↑ warfarin anticoagulation

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Antidysrhythmic Factoids

n  Class III: Amiodarone n  ADRs with chronic therapy

n  Pneumonitis n  dose dependent >400 mg/day n  Oxygen sensitive

n  Hypo- or hyperthyroidism n  Hepatic transaminitis n  Corneal deposits n  Sun-sensitive blue skin discoloration

Antidysrhythmic Factoids

n  Class III: dofetilide and ibutilide n  Pharmacology

n  Primarily affect atrial tissues n  Chemical conversion of afib/aflutter

n  Ibutilide may enhance electrical cardioversion n  Ibutilide is parenteral only

n  ADRs n  3-20% TdP (ibutilide > dofetilide) n  Hospitalize during initial therapy

Sodium-Potassium Pump

www.mhhe.com

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Sodium-Potassium Pump

Image down-loaded from www.mhhe.com

Intracellular Na+ binding

Phosphorylation Confirmation change

Dephosphorylation Original confirmation Release of K+

Extracellular K+ binding Na+ release to extracellular space

Na-K Pump Modulation: Antagonists

www.cvpharmacology.com

Na-K Pump Modulation: Antagonists

n  Altered electrophysiology n  ↑ inotropy n  ↑ automaticity/excitability n  ↓ refractory period n  ↓ conduction velocity

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Na-K Pump Antagonists: Clinical Expressions

n  Therapeutic cardiac effects n  Inotrope n  Rate control of tachydysrhythmias

n  Adverse effects n  Atrial and ventricular tachydysrhythmias

n  SVTs with high degree of block n  Excessive conduction blocks

n  Bradycardia especially in acute toxicity

Na-K Pump Modulation: Antagonists

www.cvpharmacology.com

Serum K+ is a direct marker of degree of pump blockade K+ > 5.5 mEq/L high mortality K+ > 5.0 mEq/L treatment indicator

K+

Na-K Pump Antagonists: Digitalis Glycosides/Cardioactive Steroids

2.1.6.1.2

n  Pharmaceutical n  Digitoxin n  Digoxin n  Ouabain

n  Natural n  Plant-derived cardioactive steroids n  Animal-derived cardioactive steroids

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steroid glucose

5-member lactone ring: plant

digoxin

6-member lactone ring: animal

bufodienolide

aglycone lactone

ploysaccharide

steroid

Common Foxglove Digitalis purpurea

Oleander (Nerium sp.)

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Lilly of the Valley Convallaria majalis

Squill Drimia (or Urginea) maritima

www.flickr.com www.flowerpictures.net

Cane Toads (Rhinella marina; formerly Bufo sp.) Colorado River Toads (Incilius alvarius)

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Digoxin Kinetics n  Bioavailability: 80% n  Peak serum concentration: 6 hr n  Protein binding: 25% n  Vd: 6 L/kg n  Elimination:

n  Renal n  t1/2 elimination 24-30 hr (assumes normal GFR)

n  Therapeutic drug monitoring: n  Therapeutic range: 0.5-2.0 ng/ml n  Interference: renal disease, liver disease, pregnancy,

spironolactone

Digoxin Factoids n  Drug interactions

n  Any agent that decreases GFR n  Drug-drug increased [digoxin] concentration

n  Amiodarone, cyclosporine, diltiazem, itraconazole, propafenone, quinidine, verapamil

n  Drugs that alter gut absorption n  Clarithromycin, erythromycin

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Digoxin Toxicity: Clinical Effects

Acute Chronic

CNS normal confusion, visual halos, xanthanopsia

GI nausea, vomiting abdominal pain, anorexia, vomiting

Potassium increased variable; often decreased

Digoxin level increased variable; increased - therapeutic

Bottom ECG from www.lifeinthefastlane.com

Digoxin Toxicity: ECG Manifestations

Digoxin Toxicity: Treatment Options

n  Bradycardia: digoxin Fab, atropine, pacing n  Hyperkalemia: digoxin Fab, insulin/glucose

n  Calcium salts: controversial; avoid on test n  Hypotension: digoxin Fab, dopamine n  Ventricular dysrhythmias: digoxin Fab,

cardioversion, lidocaine, phenytoin, potassium correction, magnesium correction

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Digoxin Toxicity: Digoxin Fab Treatment Indications

n  Life-threatening dysrhythmia in the setting of acute or chronic toxicity

n  Hyperkalemia: K+ > 5.0 mEq/L n  [digoxin] > 15 ng/ml or > 10 ng/ml 6 hr PI n  Adult acute ingestion of 10 mg n  Child acute ingestion of 4 mg n  Poisoning by non-digoxin cardiac glycoside

Goldfrank’s

Digoxin Toxicity: Digoxin Fab Dosing

n  Amount ingested n  # vials needed = n  (mg amount)(0.8 bioavailable)/(0.5 mg/vial)

n  Serum [digoxin] n  # vials needed = n  ([digoxin ng/ml])(kg weight)/(100)

Digoxin Toxicity: Digoxin Fab ADRs

n  Allergic reaction in atopic individuals n  Hypokalemia n  Worsening CHF n  Rashes n  Transient apnea in a neonate

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Cardiac Action Potential and Vascular Tone Modulators

Myocardial Ca2+ Entry Modifiers

n  Enhance calcium entry n  Catecholamines n  Glucagon n  PDE inhibitors

n  Inhibit calcium entry n  Β-ARA

Vascular Ca2+ Entry Modulators

n  Enhance (vasoconstrictors) n  α1 agonists n  β2 antagonists

n  Inhibit (vasodilators) n  α1 antagonists n  β2 agonists n  Calcium channel antagonists n  Angiotensin II n  Endothelin/NO

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Angiotensin Modulators 2.1.6.2.1

angiotensinogen

renin

ACE

angiotensin II angiotensin I

Angiotensin Modulators 2.1.6.2.1

angiotensinogen

renin

ACE

angiotensin II angiotensin I

X X

X

Angiotensin Modulators: Factoids

n  Name recognition n  ACE inhibitors: -pril n  ARB: -sartan

n  Acute toxicity – not exciting n  Hypotension

n  Accumulation of vasodilators n  Accumulation of enkephalins

n  Supportive care n  Novel treatment: naloxone (? testable)

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Angiotensin Modulators: adrs

ACE

angiotensin II angiotensin I

inactivation bradykinin

vasodilator (nitric oxide-mediated) non-vascular smooth muscle constrictor

Angiotensin Modulators: adrs

ACE

angiotensin II angiotensin I

inactivation bradykinin

vasodilator (nitric oxide-mediated) non-vascular smooth muscle constrictor

↑ X

X

angioedema bronchospasm

Angiotensin Modulators: adr Factoids n  Angioedema

n  Idiosyncratic n  Timing: 1/3 immediate, 1/3 1st week, 1/3 years n  ACE inhibitors > ARBs n  Supportive care (novel: methylene blue)

n  Chronic cough n  Hypotension during anesthesia

n  ARBs n  Vasopressin responsive

n  Teratogens (class D)

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Calcium and Vascular Tone Modulators: β-Adrenergic Receptor

Antagonists (βARA) 2.1.6.2.2

βARA Factoids 2.1.6.2.2 n  30 βARAs n  Pharmacological/toxicological effect is a

balance between: n  Receptor selectivity (β1, β2, α1) n  Sodium/potassium channel effects n  Water vs lipid solubility

n  βARAs pharmacological profiles n  Goldfrank’s 9th edition p. 897 n  Tintinalli’s 7th edition p. 1266

βARA Factoids 2.1.6.2.2

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βARA Toxicity n  Cardiovascular – Cardiogenic shock

n  Bradycardia n  Hypotension n  Decreased contractility

n  CNS n  Psychosis n  Coma n  Seizures

n  Metabolic - Hypoglycemia n  Exceedingly rare (masking of diabetic hypoglycemic symptoms) n  βARAs actually stimulate carbohydrate use during shock

n  Pulmonary – bronchospasm (patients with RAD)

βARA Toxicity Factoids 2.1.6.2.2

n  Sodium channel blockade n  Wide-complex bradycardia n  Additive negative inotropic effect n  Acebutolol, betoxolol, carvedilol, oxprenolol, propranolol

n  Potassium channel blockade n  Ventricular dysrhythmis (torsades) n  Sotalol

n  Β1 selectivity: lost in large overdoses n  Intrinsic sympathomimetic activity: non-player in OD

βARA Toxicity: Treatment Options n  Glucagon n  Vasopressors n  High-Dose Insulin n  Calcium (least evidenced-based support) n  Novel treatments

n  Lipid rescue n  vasopressin

n  Technology n  Electrical pacing n  IABP n  ECMO n  Hemodialysis (acebutolol, atenolol, nadolol, and sotalol)

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Adrenergic Vasodilators 2.1.6.2.5

n  Pharmacological mechanism n  Peripheral α1 antagonists

n  Acute toxicity: hypotension n  Agents

n  Phentolamine n  Effective in cocaine chest pain

n  Doxazosin, prazosin, terazosin n  Urological indications (BPH) n  ADR: priapism

Central α-Agonists 2.1.6.2.3

n  Imidazoline derivatives n  Clonidine - prototype n  Guanabenz, guanfacine, tizanidine, oxymetazoline,

tetrahydrozaline n  Dexmedetomidine (too recent for exam) n  Methyldopa (pro-drug)

imidazoline clonidine

Central α-Agonists Factoids

n  Pharmacological mechanism n  Central α2 agonists

n  Negative feedback with decreased catecholamine release n  Receptors concentrated in solitary tract nucleus (medulla)

n  Central imidazoline receptor agonists n  Ventromedial nucleus (medulla)

n  Minimal peripheral α effects n  Interaction with nocireceptors/opioid receptors (?)

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Central α-Agonists ADRs

n  Withdrawal n  Abrupt cessation of clinidine and guanabenz

n  Can occur with other agents n  Down regulation/decreased receptor sensitivity

n  Manifestations (resembles mild etoh withdrawal) n  Hypertension n  Tachycardia n  Tremor n  Agitation, insomnia

Central α-Agonists Toxicity: Treatment Options

n  Cardiovascular n  Bradycardia: atropine n  Hypertension: self-limited n  Hypotension: iv fluids, dopamine

n  CNS n  Naloxone

n  Rebound hypertension possible

n  α antagonists – theoretic, but not practical

Diruetics 2.1.6.2.4

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Diruetics Mechanism of Action

thiazides

K+-sparing

loop agents

Diuretic Factoids 2.1.6.2.4 n  Toxicity: mineral and electrolyte abnormalities

n  Hyponatremia, hypomagnesemia, hypokalemia n  Thiazides:

n  hyperglycemia (in diabetics) n  Hyperuricemia (gout) n  Hypercalciuria (renal stones) n  Pancreatitis, cholecystitis, hemolytic anemia,

thrombocytopenia n  K+-sparing agents:

n  Hyperkalemia (especially with coincident use of aldosterone-promoting drugs like ACE inhibitors)

Non-Adrenergic Vasodilators 2.1.6.2.5

hydralazine minoxidil nitroprusside

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Non-Adrenergic Vasodilators 2.1.6.2.5

eNOS

NO

GTP cGMP Vasodilation

Endothelial Cell

Vascular Smooth Muscle Cell

NO NO NO sGC-Fe2+

sGC-Fe3+-NO

Non-Adrenergic Vasodilators: Factoids n  Mechanism action:

n  NO pathway: hydralazine, minoxidil, nitroprusside n  K+ channel agonist: minoxidil

n  Acute toxicity: hypotension n  Hydralazine

n  ADRs: immune-mediated SLE, hemolytic anemia, glomerulonephritis

n  Minoxidil n  ADRs: repolarization ECG changes and subacute,

multifocal myocardial necrosis

Non-Adrenergic Vasodilators: Factoids

n  Nitroprusside ADRs: Due to CN moieties n  Setting: depleted sulfur stores

n  Poor nutrition, surgery, critical illness, liver disease n  Cyanide toxicity

n  Altered mental status, lactate accumulation, hypotension (tachyphylaxis to vasopressors)

n  Prevention: co-administration of thiosulfate n  Treatment: hydroxocobalamin or thiosulfate/sodium

nitrite

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Non-Adrenergic Vasodilators: Factoids n  Nitroprusside ADRs (cont) n  Thiocyanate toxicity

n  Metabolite of sulfurtransferase metabolism n  Renal elimination n  Accumulates 3-6 days in renal insufficiency n  Manifestations

n  Altered mental status, seizures, increased ICP n  Nausea, vomiting n  Hypertension n  NO ACIDOSIS

n  Treatment n  Hemodialysis

Summary Case Visual Stimulus Quiz

n  What did this patient overdose on? n  hypotensive

before after