ACES: CV Drugs / Pesticides

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  • Cardiac myocytes, as well as many other cells, have a Na+-Ca++ exchanger (not an active energy-requiring pump) that is essential for maintaining sodium and calcium homeostasis. The exact mechanism by which this exchanger works is unclear.  It is known that calcium and sodium can move in either direction across the sarcolemma. Furthermore, three sodium ions are exchanged for each calcium, therefore an electrogenic potential is generated by this exchanger.  The direction of movement of these ions (either inward or outward) depends upon the membrane potential and the chemical gradient for the ions. We also know that an increase in intracellular sodium concentration competes for calcium through this exchange mechanism leading to an increase in intracellular calcium concentration. As intracellular sodium increases, the concentration gradient driving sodium into the cell across the exchanger is reduced, thereby reducing the activity of the exchanger, which decreases the movement of calcium out of the cell. Therefore, mechanisms that lead to an accumulation of intracellular sodium cause a subsequent accumulation of intracellular calcium because of decreased exchange pump activity.By inhibiting the Na+/K+-ATPase, cardiac glycosides cause intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium via the Na+-Ca++ exchange system. In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy). Inhibition of the Na+/K+-ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction and vasoconstriction.By mechanisms that are not fully understood, digitalis compounds also increase vagal efferent activity to the heart. This parasympathomimetic action of digitalis reduces sinoatrial firing rate (decreases heart rate; negative chronotropy) and reduces conduction velocity of electrical impulses through the atrioventricular node (negative dromotropy).
  • Note cardioselectivity is lost in overdose. Cardioselectivity portends a lower mortality rate compared to propanolol
  • ACES: CV Drugs / Pesticides

    1. 1. CV Drug Toxicity Pesticides CHAPTER 150 CHAPTER 161 20 November 2013
    2. 2. 1. Which of the following poisoningantidote therapeutic pairings is correct? A.Anticholinergic-atropine A.Beta-blocker- octreotide A.Calcium-channel blocker-insulin A.Digoxin-Calcium
    3. 3. 2. A 70 year-old patient with a history of CHF on digoxin presents with weakness. Which is correct with regard to her EKG? A. EKG findings suggest the emergent need for digiFAB B. EKG findings are most likely due to ischemia C. EKG findings are expected with therapeutic digoxin levels. D. EKG findings are diagnostic of chronic vs. acute digoxin toxicity
    4. 4. 3. A 29 year old patient is brought in to the ED by EMS in full cardiac arrest. The medics found an empty bottle of digoxin next to his bed. What is the most appropriate initial dose of DigiFab for this patient? A. 2 Vials B. 4-6 Vials C. 10 Vials D. 20 Vials E. It needs to be calculated based on the digoxin level.
    5. 5. 4. Which of the following is correct regarding Beta Blocker overdose? A. Beta blocker overdose universally causes AV block. B. Seizures and obtundation are seen more often with propanolol compared to metroprolol. C. Octreotide is an important component of treatment D. Unlike calcium channel blocker toxicity, high-dose insulin/glucose is not effective for beta-blocker toxicity.
    6. 6. 5. High dose insulin treatment in beta-blocker overdose increases cardiac output primarily by increasing heart rate. • A. True • B. False
    7. 7. 6. Which is correct regarding the EKG? • A. This EKG shows a common finding in acute digoxin toxicity. • B. Salvage treatment should include administering of intravenous lipid emulsion (ILE). • C. This EKG is highly suggestive of Class I sodium channel blockade (TCA, beta blocker (sotalol) • D. This EKG is diagnostic for Digoxin Toxicity
    8. 8. 7. Which statement is not correct with regard to the theoretical mechanism-of-action of intravenous lipid emulsion (ILE) therapy for beta blocker overdose? A. Directly activates cardiac calcium channels. B. Acts as a “sink” for lipid-soluble beta blockers C. Provides a substrate for cardiac myocytes. D. Activates Adenyl cyclase by a C-AMP process. E. It would be appropriate to use in a massive propanolol overdose.
    9. 9. 8. Which calcium channel blocker has the highest fatality rate after overdose? • • • • • A. Diltiazem B. Verapamil C. Nifedipine D. Nicardipine E. Bepridil
    10. 10. 9. Which is correct regarding the clinical endpoint for atropine administration in Organophosphate toxicity? A. Pupillary dilatation @ 10mm is the best endpoint. B. Heart rates exceeding 140 are a relative contraindication to continued atropine administration. C. Drying of airway secretions is always the best clinical endpoint. D. Total bolus dosing should never exceed 200 mg .
    11. 11. 10. Which is true with regard to intubation of a patient with a significant organophosphate exposure? • A. Succinylcholine in OGP is associated with malignant hyperthermia. • B. Succinylcholine will cause a worsening of airway secretion production. • C. Succinylcholine is contraindicated in OGP. • D. Succinylcholine’s activity lasts longer than that of rocuronium. • E. There is little risk of exposure to ED staff during airway management.
    12. 12. A. C. Which painting does not have any connection to a cardiotoxic medication? B. D.
    13. 13. 1. Which of the following poisoning-antidote therapeutic pairings is correct? A.Anticholinergic-atropine A.Beta-blocker- octreotide A.Calcium-channel blocker-insulin A.Digoxin-Calcium
    14. 14. 1. Which of the following poisoning-antidote therapeutic pairings is correct? A.Anticholinergic-atropine A.Beta-blocker- octreotide A.Calcium-channel blocker-insulin A.Digoxin-Calcium
    15. 15. A. C. Which painting does not have any connection to a cardiotoxic medication? B. D.
    16. 16. Cardiovascular Drugs David E. Slattery, MD
    17. 17. Digoxin Toxicity • Derived from Digitalis lanata (Foxglove plant) • Drug looking for an indication – 1797 • Most common cause of preventable iatrogenic cardiac arrests
    18. 18. Na/K ATPase & Ca2+ exchanger
    19. 19. Pharmacologic Effects • Inotrope – Increased contractility due to increase intracellular calcium concentrations • Parasympathomimetic – Decreased AV Conduction – Due to increased vagal efferent activity – Slowed ventricular rate in afib
    20. 20. Digoxin at Toxic levels • Paralysis of Na/K ATPase – Hyperkalemia • SA Nodal blockade • AV nodal blockade • Increased sensitivity of SA node to catecholamines
    21. 21. Digoxin effects on Pukinje fibers • Decreased resting potential (slowed phase 0) • Decreased action potential duration – Increased sensitivity to electrical stimuli • Enhanced automaticity (increased phase 4 repolarization) Most common manifestation of Digoxin toxicity= Increased PVC’s
    22. 22. NB! Digoxin can produce any dysrhythmia or conduction block
    23. 23. Digoxin Toxicity • Elimination half-life – Digoxin=36 hours; multi-dose charcoal not effective – Digitoxin=7 days; multi-dose charcoal very effective • Highly protein bound – Dialysis is not effective
    24. 24. 2. A 70 year-old patient with a history of CHF on digoxin presents with weakness. Which is correct with regard to her EKG? A. EKG findings suggest the emergent need for digiFAB B. EKG findings are most likely due to ischemia C. EKG findings are expected with therapeutic digoxin levels. D. EKG findings are diagnostic of chronic vs. acute digoxin toxicity
    25. 25. 2. A 70 year-old patient with a history of CHF on digoxin presents with weakness. Which is correct with regard to her EKG? A. EKG findings suggest the emergent need for digiFAB B. EKG findings are most likely due to ischemia C. EKG findings are expected with therapeutic digoxin levels. D. EKG findings are diagnostic of chronic vs. acute digoxin toxicity
    26. 26. EKG - Digoxin • Causes increased automaticity with conduction block (PAT with block) • Therapeutic levels may cause – T wave depression – ST down sloping (Salvador Dali moustache) – QT shortened • Toxic levels – PVCs (most common dysrhythmia) – Sinus / AV node blocks – AV dissociation – SVT (especially with blocks) – Sinus bradycardia
    27. 27. Paroxysmal Atrial Tachycardia with Block
    28. 28. Aflutter with block
    29. 29. Clinical Manifestations • Acute Toxicity: – – – – GI: Nausea and vomiting CNS: Headache, dizziness, confusion, coma Cardiac: bradyarrhythmias SVT with block Electrolytes- potassium elevated • Chronic Toxicity – Hx: elderly patients taking diuretics – GI: nausea and vomiting – Cardiac: Almost any arrhythmia, Ventricular are common. – Potassium normal or low
    30. 30. Elderly patient with altered mental status and cardiac arrhythmia • Think Digoxin toxicity
    31. 31. Putting it all together http://manicgrandiosity.blogspot.com
    32. 32. NB! Indications for Fab Fragments • Ventricular dysrhythmias (beyond PVC’s) • Hemodynamically significant bradycardia unresponsive to atropine • Potassium >5.0 • Worsening rhythm disturbances/rapidly rising K+
    33. 33. 3. A 29 year old patient is brought in to the ED by EMS in full cardiac arrest. The medics found an empty bottle of digoxin next to his bed. What is the most appropriate initial dose of DigiFab for this patient? A. 2 Vials B. 4-6 Vials C. 10 Vials D. 20 Vials E. It needs to be calculated based on the digoxin level.
    34. 34. 3. A 29 year old patient is brought in to the ED by EMS in full cardiac arrest. The medics found an empty bottle of digoxin next to his bed. What is the most appropriate initial dose of DigiFab for this patient? A. 2 Vials B. 4-6 Vials C. 10 Vials D. 20 Vials E. It needs to be calculated based on the digoxin level.
    35. 35. Calculation of DigiFab dosing • Step 1: Calculate total body-load (TBL) – TBL= amt ingested (mg) x 0.80 – TBL= dig level (ng/ml)x 5.6 x wt (kg) 1,000 Step 2: Calculate # vials of DigFab 1 vial=40 mg DigFab Number of vials= TBL/0.5
    36. 36. Simple math! # Vials = Dig level (ng/ml)X wt (kg) 100
    37. 37. Empiric Administration • Acute with indications – 10 vials over 30 minutes • Chronic – 4-6 vials • Cardiac arrest – 20 vials undiluted IV bolus
    38. 38. Digoxin Toxicity Treatment • • • • IV Access Continuous monitoring Activated Charcoal Bradyarrhythmias – Atropine – DigiFAB – Pacing (external; avoid transvenous pacing) – • Ventricular arrhythmias – Digifab – Magnesium – Lidocaine (1-1.5 mg/kg IV bolus followed by 1-4 mg/min) and/or phenytoin (15-20 mg/kg)
    39. 39. Summary • Think of dig toxicity in any patient with GI or visual disturbances and new onset dysrhythmia or conduction abnormality • Use DigFab before pacing or other antidysrhythmics • Hyperkalemia best definitively treated with digfab
    40. 40. 4. Which of the following is correct regarding Beta Blocker overdose? A. Beta blocker overdose universally causes AV block. B. Seizures and obtundation are seen more often with propanolol compared to metroprolol. C. Octreotide is an important component of treatment D. Unlike calcium channel blocker toxicity, high-dose insulin/glucose is not effective for beta-blocker toxicity.
    41. 41. 4. Which of the following is correct regarding Beta Blocker overdose? A. Beta blocker overdose universally causes AV block. B. Seizures and obtundation are seen more often with propanolol compared to metroprolol. C. Octreotide is an important component of treatment D. Unlike calcium channel blocker toxicity, high-dose insulin/glucose is not effective for beta-blocker toxicity.
    42. 42. Beta Blocker toxicity • Initially used to treat dysrhythmias • Antihypertensive effects discovered later • Used for – SV dysrhythmias – HTN – Angina – Thyrotoxicosis – Migraine – Glaucoma
    43. 43. Pathophysiology • Competitively inhibit endogenous catecholamines at beta-adrenergic receptors. • Beta 1 blockade – Blocks inotropy, dromotropy (conduction) chronotropy • Beta 2 blockade – Blocks Vascular smooth muscle relaxation and vasodilation – Inhibits gluconeogenesis – Inhibits release of Free fatty acids
    44. 44. Unique Characteristics. • Cardioselctivity (atenolol, metoprolol, esmolol= lower mortality in OD) • Membrane stabilization (Na channel blockade) • Lipophilicity • Intrinsic sympathomimetic
    45. 45. Glucagon MOI
    46. 46. Beta Blocker Pharmacokinetics • Rapidly absorbed • Peak effect 1-4 hours • Hemodialysis not effective except for “ANTS” – Acebutolol – Atenolol – Nadolol – Timolol – Sotalol
    47. 47. Manifestations of complications • • • • • Bradycardia and Hypotension Unconscious Respiratory arrest Hypoglycemia (uncommon in adults) Others: seizures, VT/VF, mild hyperkalemia
    48. 48. NB! Propanolol • Non-selective • Most fatalities • Lipophilic and readily crosses BB barrier – Altered mental status – Seizures • Hypoglycemia common in children
    49. 49. Sotalol • Class III (K ch) and Class II (beta blockers) antidysrhythmic • Torsades de pointes • Dialyzable (Remember ANTS) • QT prolongation – Sotalol – Acebutolol
    50. 50. Treatment • Phase I: – – – – Fluids Atropine Calcium Glucagon • Phase II: – – – – – High-dose insulin/glucose (inotrope) Glucagon Pressors (epi, NE, isoproterenol) Consider dialysis of lipophilic beta blockers Pacing /SWAN-Ganz • Phase III: Salvage – Intravenous fat emulsion – IAB pump – LVAD
    51. 51. Glucagon • Inotropic and chronotropic effects not dependent on beta receptors – Stimulates C-AMP • Helps counteract hypoglycemia • Dose: 5-10 mg IV bolus (0.1 mg/kg) – Followed by response dosing (over 1 hour) – Short half-life (20 minutes) • Less effective than insulin-glucose
    52. 52. 5. High dose insulin treatment in beta-blocker overdose increases cardiac output primarily by increasing Heart rate. • A. True • B. False
    53. 53. 5. High dose insulin treatment in beta-blocker overdose increases cardiac output primarily by increasing Heart rate. • A. True • B. False
    54. 54. 5. High dose insulin treatment in beta-blocker overdose increases cardiac output primarily by increasing Heart rate. • A. True • B. False
    55. 55. High Dose Insulin-Glucose • HDI is a potent inotrope – Optimizing of the use of carbohydrates – And modulation of IC calcium • NB! Improve in CO due more to increase in stroke volume vs. HR • 1U/kg Bolus • 1 -10 U/kg/hr drip • Preceded with amp D50 and followed by D10 or D25 drip.
    56. 56. Adjuncts for specific agents • Sodium Bicarb – Use for QRS widening • Propanolol • Sotalol • Magnesium – Prolonged QT interval • Sotalol • Acebutelol
    57. 57. 6. Which is correct regarding the EKG? • A. This EKG shows a common finding in acute digoxin toxicity. • B. Salvage treatment should include administering of intravenous lipid emulsion (ILE). • C. This EKG is highly suggestive of Class I sodium channel blockade (TCA, beta blocker (sotalol) • D. This EKG is diagnostic for Digoxin Toxicity
    58. 58. 6. Which is correct regarding the EKG? • A. This EKG shows a common finding in acute digoxin toxicity. • B. Salvage treatment should include administering of intravenous lipid emulsion (ILE). • C. This EKG is highly suggestive of Class I sodium channel blockade (TCA, beta blocker (sotalol) • D. This EKG is diagnostic for Digoxin Toxicity
    59. 59. Bi-directional Ventricular Tachycardia Rare but specific for dig toxicity
    60. 60. 7. Which statement is not correct with regard to the theoretical mechanism-of-action of intravenous lipid emulsion (ILE) therapy for beta blocker overdose? A. Directly activates cardiac calcium channels. B. Acts as a “sink” for lipid-soluble beta blockers C. Provides a substrate for cardiac myocytes. D. Activates Adenyl cyclase by a C-AMP process. E. It would be appropriate to use in a massive propanolol overdose.
    61. 61. 7. Which statement is not correct with regard to the theoretical mechanism-of-action of intravenous lipid emulsion (ILE) therapy for beta blocker overdose? A. Directly activates cardiac calcium channels. B. Acts as a “sink” for lipid-soluble beta blockers C. Provides a substrate for cardiac myocytes. D. Activates Adenyl cyclase by a C-AMP process. E. It would be appropriate to use in a massive propanolol overdose.
    62. 62. Intravenous Fat emulsion • Lipid sink • Optimization of cardiac metabolism – Provides substrate for myocytes – Free fatty acids • Direct activation of cardiac calcium channels • Dose: 1.5 ml/kg 20% solution over 3 minutes, then drip at 0.25ml/kg/min
    63. 63. Calcium channel blocker toxicity • Earliest – Verapamil Nifedipine • Many indications – Antihypertensive – SV tachy – Hypertrophic cardiomyopathy – Migraine prophylaxsis
    64. 64. Calcium channel blockers • Rapidly absorbed • Peak effect earliest with nifedipine • Highly protein bound not conducive to dialysis
    65. 65. 8. Which calcium channel blocker has the highest fatality rate after overdose? • • • • • A. Diltiazem B. Verapamil C. Nifedipine D. Nicardipine E. Bepridil
    66. 66. 8. Which calcium channel blocker has the highest fatality rate after overdose? • • • • • A. Diltiazem B. Verapamil C. Nifedipine D. Nicardipine E. Bepridil
    67. 67. Pathophysiology • Block slow L-type calcium channels – Coronary and peripheral vasodilation – Reduction of contractility – Slow AV conduction • NB! Verapamil – Deadliest, severe vasodilation and myocardial depression
    68. 68. Calcium channel blocker toxicity • • • • Hypotension Bradycardia All degrees of AV block Nifedipine (Dihydropyridines) – Reflex tachycardia • • • • NB! No QRS widening is seen. Pulmonary edema Lethargy, confusion, seizures Metabolic: hyperglycemia, lactic acidosis, mild hyperkalemia.
    69. 69. Treatment Phase I: IV fluids Calcium atropine No data to support glucagon. Phase II: Calcium HDI Pressors Pacing Phase III: Intravenous Fat Emulsion LVAD
    70. 70. Ca Channel blocker toxitiy Pediatric PEARLS • • • • Seizures are more common Death is rare Refractory shock can be treated with IABP Verapamil IV is contraindicated for SVT in infants.
    71. 71. Know these two • Nifedipine – Single pill can kill a child – Shortest onset – Has Reflex tachycardia • Verapamil – Highest fatality rates
    72. 72. Nitrates/Nitrites • Know – Nitroprusside (renal failure patients) – PDI contraindication • Viagra et al – Found in rural well water – Patients with G-6PD deficiency= hemolysis • Methemoglobinemia – Treatment methylene blue 1-2 mg IV over 5 minutes
    73. 73. 9. Which is correct regarding the clinical endpoint for atropine administration in Organophosphate toxicity? A. Pupillary dilatation @ 10mm is the best endpoint. B. Heart rates exceeding 140 are a relative contraindication to continued atropine administration. C. Drying of airway secretions is always the best clinical endpoint. D. Total bolus dosing should never exceed 200 mg .
    74. 74. 9. Which is correct regarding the clinical endpoint for atropine administration in Organophosphate toxicity? A. Pupillary dilatation @ 10mm is the best endpoint. B. Heart rates exceeding 140 are a relative contraindication to continued atropine administration. C. Drying of airway secretions is always the best clinical endpoint. D. Total bolus dosing should never exceed 200 mg .
    75. 75. Pesticides • Organophosphates – Highly lipid soluble – Rapidly absorbed through skin • Metabolites are ACHesterase inhibitors
    76. 76. Autonomic Nervous system Muscarinic Nicotinic
    77. 77. Muscarinic vs. Nicotinic • Muscarinic – – – – Not an ion channel G-protein-coupled receptor Activate ion channels via second messenger system. Blocked by atropine • Nicotinic – – – – Ion gated channel Post-synaptic neuromuscular junction Ach causes Na entry and leads to depolorization. Stimulation (tremor, seizures, temp, etc)
    78. 78. Muscarinic Receptors • Gland excretion • Smooth muscle relaxation
    79. 79. Nicotinic Receptors • • • • • • Skeletal muscle hyperstimulation Fasciculations Twitches Seizures Muscle fatigue and paralysis Delayed resp failure
    80. 80. Cholinesterase inhibitors can result in : • Tachycardia, bradyardia • Hypertension or hypotension • Mydriasis, miosis
    81. 81. OGP Aging • Irreversible conformational change when OGP bound to cholinesterase enzyme • Becomes irreversible • Varies with agent • Importance of 2PAM
    82. 82. OGP Aging • Irreversible conformational change when OGP bound to cholinesterase enzyme • Becomes irreversible • Varies with agent • Importance of 2-PAM (give regardless of time from ingestion)
    83. 83. Diagnosis • Clinical syndrome • Cholinesterase levels – RBC – Plasma-these decrease first • RBC cholinesterase levels correlate best with ACH activity at nerve terminal. • RBC cholinesterase recovers slowly
    84. 84. 10. Which is true with regard to intubation of a patient with a significant organophosphate exposure? • A. Succinylcholine in OGP is associated with malignant hyperthermia. • B. Succinylcholine will cause a worsening of airway secretion production. • C. Succinylcholine is contraindicated in OGP. • D. Succinylcholine’s activity lasts longer than that of rocuronium. • E. There is little risk of exposure to ED staff during airway management.
    85. 85. 10. Which is true with regard to intubation of a patient with a significant organophosphate exposure? • A. Succinylcholine in OGP is associated with malignant hyperthermia. • B. Succinylcholine will cause a worsening of airway secretion production. • C. Succinylcholine is contraindicated in OGP. • D. Succinylcholine’s activity lasts longer than that of rocuronium. • E. There is little risk of exposure to ED staff during airway management.
    86. 86. Management • 1. Decontamination – Remove clothes, soap and water • 2. Supportive Care – Airway management (rocuronium better choice) • 3. Reversal of ACH excess at muscarinic sites • 4. reversal of toxin binding at active sites on the ACH molecule
    87. 87. Treatment • Atropine 1-2 mg IV and double dose q 5 minutes until secretions dry • Patients may need 200-300 mg • Follow with continuous infusion: • 5-100 mg/hr
    88. 88. 2-PAM • Pralidoxime • Regenerates ACHesterase complex and restores ACHesterase activity at nicotinic and muscarinic sites. • Dose: 1-2 g IV over 30 minutes repeat q 4 hours • Benzodiazepines for seizures
    89. 89. Carbamates • • • • Differentiated from OGP by short half-life Reversible inhibition Lasts ~48 hours Symptoms – Twitching, hyperdynamic, rhabdo, altered MS • Treatment – Decontamination – Cooling measures – Benzos
    90. 90. Phenols • • • • • • DNP Insecticides, herbicides Absorbed through skin Uncouple oxidative phosphorylation Hyperthermic, tachycardia, diaphoresis TX: early skin decon; control body temp, fluids, glucose, supportive care.
    91. 91. Summary • • • • Decon all! Patients die from airway compromise V/S and pupil findings variable 2-PAM should be given if you are giving atropine • Rapid cooling and glucose the most important therapies for phenol toxicity

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