Cardiac Contractility

1. Cardiac Contractility Dapo Odujebe, MD Toxicology Fellow NYC Poison Control Center

2. Overview • Review & Cases • Cardiac Electrophysiology • Cardiac Contractility • Cardiac Medications • Overdose Management • Questions?

3. Case #1 • 45-year old woman PMHx s/f depression presents to the ED after allegedly ingesting all of her anti-HTN medication. • Prescription filled 3 days prior for 30 tablets of diltiazem CD 240 mg. • Patient alert & oriented, mildly diaphoretic and complaining of generalized weakness.

4. Case #1 • Vital signs: • BP: 76/36, HR: 46, RR: 14, Temp: 98.6 • pOx: 100% RA, AccuChk: 154 • Rest of physical examination is benign. • Patient placed on a cardiac monitor, O2 via nasal cannular and IV access established.

5. Case #1 • What is the next step in her management?

6. Case #3 • An 86-year old woman presents with increased confusion and vomiting. • Per family, she’s had increasing weakness, nausea & anorexia over the last 3 days. • Medications: • hydrochlorothiazide • digoxin • furosemide • enteric-coated aspirin • metformin • PMHx: • hypertension • congestive heart failure (CHF) • diabetes mellitus

7. Case #3 • In the hospital, she is alert, but oriented only to person. • Vital signs are normal, except for a heart rate of 46 beats/minute. She weighs 143 lbs (65 kg). • Her physical examination demonstrates: • bibasilar rales • irregular S1, S2 with a S3 gallop • bilateral LE 2+ pitting edema, up to her shins

8. Case #3 • ECG: • atrial flutter with variable block • ventricular rate of 40-50 beats/minute with occasional premature ventricular contractions (PVCs). • Laboratory results were within limits except: • potassium - 3.2 mEq/L • creatinine - 1.6 mg/dL • glucose - 235 mg/dL • Initial digoxin serum concentration (SDC): • 3.4 ng/mL (> 6 hours since last dose).

9. Case #3 • What is the next step in her management?

10. Cardiac Electrophysiology

11. Cardiac Electrophysiology • Actions potentials • SA node • Cardiac muscle • (atria, ventricles & Purkinje fibers) • Channels • Ca2+ channel • β-adrenergic receptor • Na+/K+-ATPase

12. Ca2+ Pacemaker Cell Cycle Phase 0 Phase 3 0 mV -50 mV -70 mV Phase 4 Phase 4

13. Action potential (SA Node) • Pacemaker of the heart • Unstable resting potential • Exhibits automaticity • AV node & His-Purkinje system are latent pacemakers • Phase 1 & 2 are not present in pacemaker action potentials

14. Ca2+ Cardiac Muscle Cell Cycle Phase 0 Phase 1 Phase 2 +30 mV 0 mV Phase 3 -70 mV -90 mV Resting Potential Phase 4

15. 2 K+ 3 Na+ SR (Mitochondria) Ryanodine receptor Na+/K+ ATPase Na+/Ca2+ Antiporter Voltage dependent L-typeCa2+ channel Na+ channel Na+/K+ ATPase K+ channel(s) Ca2+ 3 Na+ β-adrenergic receptor Na+/Ca2+ exchanger Heart muscle Representative Cardiac Cell

16. Cardiac Contractility

17. Contractility • Intrinsic ability of cardiac muscle • Also called ‘inotropism’ or ‘inotropy’ • Related to the intracellular [Ca2+] • Inotropic agents • positive: increase contractility • negative: decrease contractility

18. Factors Increasing Contractility • Increased intracellular [Ca2+] • increased heart rate • cardiac glycosides (e.g. digoxin) • Stimulation of β1-adrenergic receptor • sympathomimetic agents • catecholamines

19. Contractility - Other Factors • Chronotropy • rate of contraction • also affected by intracellular [Ca2+] • Dromotropy • rate of impulse conduction • noted particularly at AV node

20. Cardiac Medications & Receptors

21. Cardiac Medications • Some examples: • Ca2+ channel antagonists/blockers • β-adrenergic antagonists/blockers • Cardiac glycosides (digoxin)

22. Ca2+ Channel Antagonists

23. Calcium Channel • Cardiac calcium channels • L-type calcium channel • ryanodine (RyR2) calcium channel • located on the sarcoplasmic reticulum • Critical for: • conduction velocity (AV node) • duration of depolarization • cardiac muscle contraction

24. Ca2+ Channel Antagonists • Block the L-type calcium channel • negative inotropy in cardiac muscle • decrease available intracellular Ca2+ • negative chronotropy in pacemaker cells • negative dromotropy at the AV node • relaxation of vascular smooth muscle • decreased afterload • decreased systemic blood pressure • increased coronary vascular dilatation

25. Ca2+ Channel Antagonists • Phentylalkylamines • e.g. verapamil • Benzothiazepines • e.g. diltiazem • Dihydropyridines • e.g. nifedipine • Diarylaminopropylethers • e.g. bepridil • Tetralene Derivatives • e.g. mibefradil

26. Ca2+ Channel Antagonists • Overdose of CCB • extension of therapeutic effects • Lose their selectivity (mostly) • Negative inotropy (bradycardia) • Negative chronotropy (hypotension) • Vasodilation (hypotension) • Negative dromotropy (AV blocks, brady) • +/- hyperglycemia (depressed insulin) CCB = calcium channel blocker

27. β-Adrenergic Antagonists

28. β-Adrenergic Receptors • There are 3 known subtypes of β-adrenergic receptors, namely β1, β2 & β3. • The human heart has predominantly β1 receptors • β2 & β3 exist in ‘small’ quantities

29. β-Adrenergic Receptors • Stimulation on β1 receptors • increases heart rate • increases contractility • increases conduction velocity • increases automaticity • The effect of adrenergic agents on the heart is mediated through a secondary messenger – cAMP

30. β-Adrenergic Receptors • Intracellular cAMP concentrations are regulated by 3 components: • adrenergic receptor on the cell surface • a “G-protein” complex • adenyl cyclase – enzyme synth. cAMP • cAMP acts as a secondary messenger • interacts with protein kinase A to increase phosphorylating activity

31. β-Adrenergic Receptors • Protein kinases transfer a phosphate group from ATP to serine • Thereby, phosphorylating various cellular proteins • phospholamban ( activity) • troponin ( activity) • L-type calcium channels ( activity)

32. β-Adrenergic Receptors Bers DM. Cardiac excitation-contraction coupling. Nature 2002 415;198 - 205

33. β-Adrenergic Antagonists • β-Adrenergic antagonists • effects similar to blockade of L-type calcium channel • Clinical effects • decrease contraction (hypotension) • decrease chronotropy (bradycardia) • decrease dromotropy (AV blocks, brady)

34. β-Adrenergic Antagonists • Extra-cardiac signs of toxicity • neurological disturbances • drowsiness, non-agitated coma • dilated pupils • respiratory depression • Treatment of toxicity is based on: • stimulation of glucagon receptor • restoring intracellular Ca2+ stores

35. Overdose Management

36. Overdose Management • Decontamination • Emesis not recommended • Activated charcoal should be considered • Gastric lavage with 36-40 Fr tube • contraindicated in patients w/ bradycardia • consider particularly in patients a/ SR preps • Whole bowel irrigation • particularly a/ SR preps

37. Overdose Management • Atropine • Adult: 0.5 – 1.0 mg IVP (max 3 mg) • Children: 0.02 mg/kg IVP • given every 2 – 3 minutes • Should be held in patients getting WBI because of anticholinergic effects

38. Overdose Management • Calcium salts • increases extracellular Ca2+ • calcium gluconate: 1 gm = 4.3 mEq • calcium chloride: 1 gm = 13.4 mEq • Dose • 10 – 20 mL of 10% CaCl2 • 30 – 60 mL of 10% Ca gluconate

39. Overdose Management • Dose (cont’d) • effect is transient, redose q15 – 20 mins • in adults, can give 50 mL of 10% CaCl2 (5 gm) before having to check a Ca2+ serum concentration • (i.e. 150 mL of 10% Ca gluconate) • CaCl2 is causes sclerosis of peripheral veins and should be given centrally

40. Overdose Management • Glucagon • activates adenyl cyclase directly via glucagon receptor • adult dose: 2-5 mg slowly IV • can be repeated every 5-10 minutes • total dose should not exceed 10 mg • follow bolus with an infusion of the dose that produced an effect

41. Overdose Management • Catecholeamines • attempt to competitively antagonize β-adrenergic antagonist at the receptor • no convincing evidence • chance of stimulating other receptors in the required dose to produce competive displacement • if one is used – norepinephrine is probably the best choice

42. Overdose Management • Insulin & Glucose • growing evidence that used correctly, this increases inotropy and chronotropy • theory: improved Ca2+ entry & improved myocardial carbohydrate use • Dose: 0.5 – 1 Unit/kg/hr regular insulin • give 0.5 gm/kg/hr dextrose (glu > 100) • check glucose every 30 mins initially

43. Overdose Management • Amrinone • inhibits breakdown of cAMP by phosphodiasterase III • thereby increasing intracellular [] of cAMP • this increases inotropy and chronotropy • BUT, causes vasodilation & hypotension • should be used with a vasopressor

44. Cardiac glycosides (digoxin)

45. Therapeutic • Digoxin inhibits Na+/ K+-ATPase • This increases cytosolic Ca2+ which increases inotropy. • Therapeutically: • digoxin increases automaticity • shortens the repolarization intervals of the atria and ventricles

46. Therapeutic • Decreases depolarization & conduction through the SA and AV nodes. • These changes are reflected on ECG by: • decrease in ventricular response rate • PR interval prolongation • QT interval shortening • ST segment & T-wave opposite major QRS forces • scooped ST segment • Both these effects result in the characteristic “digitalis effect”

47. Therapeutic • Some characteristic signs of digoxin therapy and toxicity. Digitalis effect Atrial flutter with PVC

48. Clinical Toxicity

49. Toxicologic • Effects mirror its therapeutic actions. • Bradydysrhythmias • (from increased VAGAL TONE) • Ventricular tachydysrhythmias • (from myocardial “irritability”) • Rapid atrial rhythms with slow ventricular response • (slowed AV conduction)

50. 2 K+ 3 Na+ SR (Mitochondria) Phase 2 Ca2+ Ca2+ 3 Na+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Cell Electrophysiology