8/11/14
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
1 8/11/14
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
2 8/11/14
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
3 8/11/14
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)
4 8/11/14
Na+ Channel Agonists
n Clinical consequences n Ventricular dysrhythmias
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
5 8/11/14
Na+ Channel Modulation: Antagonists n Natural toxins
n Grayanotoxins
n Some are agonists
n Taxine (Taxus sp – Yew)
X
Widened QRS
6 8/11/14
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 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
Terminal Axis Deviation
7 mm R’
7 8/11/14
Sodium Channel Blockade: Rightward Terminal Axis
normal right axis deviation
n R’ wave in aVR > 3 mm
n R’:S ratio in aVR > 0.7
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
ventricular tachycardia torsades de pointes
n Treatment n Sodium bicarbonate
n Lidocaine (?)
n Cardioversion/defibrillation
8 8/11/14
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
9 8/11/14
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
10 8/11/14
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
11 8/11/14
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
12 8/11/14
Ca2+ Channel Antagonism
Consequences: X Hypotension Bradycardia Poor cardiac output
Cardiogenic Shock
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
13 8/11/14
Calcium Channel Blocker Factoids n Class IV observations n Pharmacokinetics n Hepatic metabolism
n Highly protein bound n Drug interactions X n CYP3A4 and P-glycoprotein inhibitors n Digoxin, theophylline, OTHERS!!!
n Acute toxicity n Bradycardia, hypotension, decreased contractility
n Diabetogenic state
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
14 8/11/14
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+
Normal Function: Myocardial K+ Channel
2+ Ca + mV
Na+ - mV
15 8/11/14
Normal Function: Myocardial K+ Channel
n Effective Refractory Period n Depolarization not possible
n Relative Refractory Period
n Depolarization possible with sufficient electrical stimulus ERP RRP
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)
Na+ X
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
16 8/11/14
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
17 8/11/14
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
18 8/11/14
Sodium-Potassium Pump
Intracellular Na+ binding
Dephosphorylation Original confirmation Phosphorylation Release of K+ Confirmation change
Extracellular K+ binding Na+ release to extracellular space Image down-loaded from www.mhhe.com
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
19 8/11/14
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
K+ 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
www.cvpharmacology.com
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
20 8/11/14
lactone 5-member lactone ring: plant aglycone
steroid 6-member lactone ring: animal
ploysaccharide
digoxin
steroid glucose bufodienolide
Common Foxglove Digitalis purpurea
Oleander (Nerium sp.)
21 8/11/14
Lilly of the Valley Convallaria majalis
Squill Drimia (or Urginea) maritima
www.flowerpictures.net www.flickr.com
Cane Toads (Rhinella marina; formerly Bufo sp.) Colorado River Toads (Incilius alvarius)
22 8/11/14
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
23 8/11/14
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
Digoxin Toxicity: ECG Manifestations
Bottom ECG from www.lifeinthefastlane.com
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
24 8/11/14
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
25 8/11/14
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
26 8/11/14
Angiotensin Modulators 2.1.6.2.1
ACE angiotensinogen angiotensin I angiotensin II
renin
Angiotensin Modulators 2.1.6.2.1 X ACE angiotensinogen angiotensin I X angiotensin II
renin 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)
27 8/11/14
Angiotensin Modulators: adrs
angiotensin I angiotensin II
ACE
bradykinin inactivation
vasodilator (nitric oxide-mediated) non-vascular smooth muscle constrictor
Angiotensin Modulators: adrs
angiotensin I X angiotensin II ACE ↑ bradykinin X inactivation
vasodilator (nitric oxide-mediated) angioedema non-vascular smooth muscle constrictor 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)
28 8/11/14
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
29 8/11/14
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)
30 8/11/14
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 (?)
31 8/11/14
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
32 8/11/14
Diruetics Mechanism of Action
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
33 8/11/14
Non-Adrenergic Vasodilators 2.1.6.2.5
eNOS Endothelial Cell
NO NO NO NO sGC-Fe2+
Vascular Smooth Muscle Cell sGC-Fe3+-NO
GTP cGMP Vasodilation
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
34 8/11/14
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
35