8/11/14

ACMT Board Review 2014: Cardiovascular

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 blockers

n 2.1.6.1.4 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 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

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 , 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 (Monk’s Hood)

n ( Dart Frog)

n Grayanotoxin (Azalea and sp) n some are antagonists n (Veratrum sp – False Hellebore)

n Zygacine (Zygadenus sp – Death Camus)

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Na+ Channel Agonists

n Clinical consequences n Ventricular dysrhythmias

n

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, , disopyramide

n Ib Antidysrhythmics

n , mexilitine,

n Ic Antidysrhythmics

n , , propafenone

Na+ Channel Modulation: Antagonists n Other sodium channel blocking drugs n Analgesics: propoxyphene

n Anticonvulsants: n Antidepressants: cyclics, bupropion, venlafaxine

n Antimalarials: quinine, chloroquine, hydroxychloroquine n Class II antidysrhythmics: , acebutolol

n Class III antidysrhythmics: n Local anesthetics

n Phenothiazines: ,

n Others: , 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 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’

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

Sodium Channel Blockade: Consequences

ventricular torsades de pointes

n Treatment n Sodium bicarbonate

n Lidocaine (?)

n Cardioversion/defibrillation

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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 (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 : 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: n ADRs limit clinical use n Rash, heptatoxicity, blood dyscrasias

n Class 1b:

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: X Bradycardia Poor cardiac output

Cardiogenic Shock

Ca2+ Channel Agonist

n Levosimendan n Directly opens Ca2+ channel

n treatment

n Experimental treatment of CCB toxicity

n No human overdose

Ca2+ Channel Antagonism

n Class IV drugs n (dihydropyridine)

n (benzothiazepine)

n (phenylalkylamine)

n Bepridil (diarylaminopropylamine) n Cyclic antidepressants n Class 1c agent Propafenone

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Calcium 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 , 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

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K+ Channel Structure n Tetrameric protein in the 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

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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 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 () n Class III (amiodarone, , , ) 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 (diuretics)

n hypomagnesemia (diuretics)

n

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

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

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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

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: 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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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.)

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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)

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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 , visual halos, xanthanopsia GI , 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, , pacing n : 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, 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 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

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: (? testable)

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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: ) 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

K+-sparing

loop agents

Diuretic Factoids 2.1.6.2.4 n Toxicity: 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 nitroprusside

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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 n Treatment: or thiosulfate/

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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

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