Amlodipine Tablet Poisoning in adults.pptx

Amlodipine Tablet Poisoning in adults

1. An Interesting Case of AMLODIPINE POISONING M5 UNIT Chief : Dr. Bharath M.D. Dr . Rajamahendran, M.D. DCH Assistants Professors : Dr. Vivek Raja, M.D. Dr. Maheshwari, M.D. Dr. Gowthaman, M.D.

2. A 65y old female who is a k/c/o SHTN was referred from a Pvt. Hospital with alleged h/o consumption of 20 tablets of T.AMLODIPINE 5mg at morning 8.00am on 15/09/2024 Patient was referred with Unstable Vitals with Poor Hemodynamic Status and Decreased Urine Output and poor General Condition First Point Of Contact - Pvt. Hospital, Manaparai First Aid Given - Gastric Lavage given within 2h of Consumption Referral time - 12h following Consumption Motive Of Consumption - Familial Conflict Toxic Dose - 100mg (Therapeutic Dose - 10mg/day)

3. Treatment given at Referral Hospital Gastric Lavage with Activated Charcoal Aggressively treated with IVF Inj Noradrenaline IV Infusion Inj Dopamine IV Infusion

4. H/o Presenting Illness Pt had H/o headache following consumption Pt had H/o Vomiting 1-2 Episodes following Consumption. Pt developed breathlessness ,insidious in onset, progressive with no aggravating or relieving factors.Breathlessness developed 7 hours following the consumption and following which her sensorium dete ri or at ed. No c/o abdominal pain No c/o loose stools

5. PAST H/o k/c/o SHTN since 5y On Regular treatment with T. AMLODIPINE 5 Mg OD No other Comorbidities

6. Vitals @ Admission BP – 80/? PR - 86/min , irregularly irregular, low volume SpO2 – 90% under RA  95% in NRM 10L O2 CBG – 19 7 mg/dl RR – 26/min

7. Examination General Examination Pt Drowsy/ Disoriented Responding to oral commands Afebrile Dehydration + Tachypnea Pallor + No Pedal Edema Cold Peripheries + Systemic Examination CVS - S1, S2 +, No Murmur RS - BLAE+, B/l fine Crepts + heard predominantly over mammary, infra axillary and sub scapular region P/A - Soft, BS +, Non Tender CNS - Drowsy B/l Pupils - 3. 0mm RTL + B/l Plantar - Flexor DEM - Intact

8. INVESTIGATIONS 15/09/2024 16/09/2024 TC 30,000 22 , 900 Hb 12.0 11.6 Platelets 3,87,000 4,00,000 Hct 36.2% 36% S.Urea 70 82 S.Creatinine 2.2 2.7 Total bilirubin 0.2 0.4 Serum albumin 4.2 4.0 AST/ALT 33 /22 43 /24 ALP 83 91 S.Na /K+ 138 / 3.7 135 / 3.5

9. ABG Analysis 15/9 16/9 PH 7.104 7.34 Pco2 22.8 27 Po2 80.5 66.4 Hco3 7.0 14.5 Lactate 4.96 2.05 Na 120 133.3 K 3.59 3.29 Ca 0.31 0.70 Cl 93 101

10. 15/09/2024 S.Calcium (corrected) 6.8 Plasma acetone Negative Urine acetone Negative

11. Urine routine Albumin - ++ Sug – Nil Deposits – 4 to 6 pus cells

12. ECG @ Admission

13. CXR @ Admission

14. CT Chest (16/9/2024 @ 10.45pm) B/L moderate Pleural effusion Ground glass opacity in bilateral lung fields predominantly in perihilar region with consolidatory changes in left linguilar lobe IMPRESSION – F/S/O Pulmonary edema

15. USG ABDOMEN AND PELVIS (16/09/2024 @ 2.00 pm) Liver: IVC and hepatic vein prominent Gall bladder: Contracted Pancreas : Obscured Spleen: 9cm Right kidney: 9.9 x 3.8 CMD + , increased echoes Left kidney : 10.3 x 3.9 CMD + , increased echoes Urinary bladder : Empty No free fluid in abdomen and pelvis Impression : B/L Pleural effusion,GRADE 1 MRD

16. Echocardiography (16/09/2024) Tachycardia during study Irregular rhythm during study No RWMA Normal LVSF Grade 1 LVDD Trivial MR/ No MS EF – 64% AVS + No AS/ AR No PAH Normal RV function No clot/ Vegetation/ PE IMPRESSION : Normal LVSF Grade 1 LVDD

17. FINAL DIAGNOSIS Intentional Amlodipine tablet poisoning Atrial fibrillation with CVR Renal failure – AKI (oliguric) Severe Metabolic acidosis Type 1 respiratory failure Multifactorial shock

18. Treatment at our Hospital Repeat Stomach Wash with Activated Charcoal Nasal O2 NRM @ 10 L/min Inj PIPTAZ 2.25mg IV TDS Inj Calcium Gluconate (10%) 10ml slow IV 2 times at an interval of 5-10 mins DC cardioversion and Inj Amiodarone infusion Inj .Heparin 5000IU IV QID( CHADVASC – 3) Inj Noradrenaline @ 0.1 mcg/kg/min Inj Dopamine 10 mcg/kg/min Inj Human Insulin Regular 0.5u/kg IV Stat Inj Human Insulin Regular 0.5u/kg/h IV Infusion in D10 Inj Sodium Bicarbonate IV Infusion to correct Acidosis

19. Course in our Hospital Patient was received into our ER in a state of altered sensorium, breathlessness and poor Hemodynmamic Status Patient’s ABG taken outside showed Severe Metabolic Acidosis Patient was immediately kept on Nasal O2 Patient was given Ca gluconate 3 doses Continued on IV Inotrope Infusion and started on IV Insulin Infusion (HIET) in view of Refractory Shock Patient was treated with IV Sodium Bicarbonate Infusion Patient was given DC shock and on IV Amiodarone Infusion to treat Atrial Fibrillation

20. Following Day, Patient’s Hemodynamic status improved and patient was gradually tappered of HIET therapy and IV Inotrope Infusion Following which, in the evening patient’s GC got worsened and she became hemodynamically unstable. Further on, she was intubated and kept under Mechanical ventilation She was started again on IV Inotropes Infusion. Following which, patient’s hemodynamic status didn’t improve.

21. Time BP CBG Comment PR 11.30pm 80/- 197 NA @0.1mcg/kg/min Dopa @10mcg/min HI R @ 0.5u/kg/hr in D10 89 12.30am 80/60 271 “ 114 1.30am 90/40 259 “ 110 2.30am 90/40 214 “ 90 3.30 am 100/50 244 “ 106 4.30am 100/60 274 “ 102 5.30 am 100/60 231 “ 89 8.00am 120/60 241 Downtitrated 90 10.00am 140/70 301 Downtitrated 92 12.00pm 150/90 197 Downtitrated 90 2.00pm 130/70 147 “ 87 4.00 pm 130/90 182 Downtitrated 104 6.00 pm 120/70 194 Downtitrated 106 8.00pm 130/70 172 Infusion stopped 90

22. DISCUSSION

23. Mechanism of Toxicity CCBs inhibit L type Ca Channels Decrease Influx of Ca in Myocardium, AV node and Vascular Smooth Muscle Systemic, Coronary & Peripheral Vasodilation Reduced Cardiac Contractility Depressed SA Node Activity Dimnished AV Nodal conduction

24. AMLODIPINE OVERDOSE Cardiac Vascular Smooth Muscle Tone Metabolic Negative Inotropy Negative Chronotropy Negative Dromotropy Myocardial Depression Bradyarrhythmias AV Nodal Blockade Decreased Afterload Sysytemic Hypotension Coronary Vasodilation Hypoinsulinemia CCBs induced Insulin Resistance

25. CCBs on Cardiac Myocyte

26. Drug Interactions Hypotension is more likely in patients taking - Beta Blockers Nitrates Diuretics Arrhythmias are more common if patients are taking concomitantly - Beta Blockers Verapamil

27. TOXIC DOSES Tablet Maximum Therapeutic Dose/ Day Verapamil 480 mg Diltiazem 360 mg Amlodipine 10 mg Felodipine 30 mg Nifedipine 120 mg Nimodipine 360 mg

28. Clinical Presentation

29. INVESTIGATIONS BEDSIDE - ECG : bradycardia, 2nd and 3rd degree heart block, sinus arrest with nodal escape, asystole hyperglycaemia is a marker of severity blood gas : hyperlactaemia , metabolic acidosis, impaired oxygen delivery LABORATORY - evidence of organ dysfunction due to shock (e.g. increased creatinine)

30. MANAGEMENT Early intubation and ventilation when life-threatening toxicity is anticipated Early invasive blood pressure monitoring, if evolving hypotension and shock Monitor Vital signs and ECG for atleast 6h after alleged ingestion Admit Symptomatic patients for at least 24h Administer Activated Charcoal and Gastric lavage Can be continued upto 48-72h Whole bowel irrigation can also be performed following the administration of activated charcoal if the patient meets these criteria: cooperative presents within 4 hours of ingestion of >10 tablets of verapamil or diltiazem SR no evidence of established toxicity

31. SPECIFIC TREATMENT Fluid resuscitation (up to 20 mL/kg crystalloid) Calcium can be a useful temporising measure to increase HR and BP 10% calcium gluconate 10 mL IV (0.6-1.0 mL/kg in children) 10% calcium chloride 20mL IV (0.2 mL/kg in children) [must be given via CENTRAL VENOUS ACCESS – it burns!] repeat boluses can be given up to 3 times in a 5-10min interval consider calcium infusion to keep serum calcium >2.0 mEq/L Atropine: 0.6mg every 2 min up to 1.8 mg (often ineffective) High dose insulin – euglycaemic therapy (HIET)

32. High-dose insulin euglycaemic therapy (HIET) – A solution to “ metabolic hunger “ of heart The place of HIET in the step-wise approach to managing cardiovascular toxicity has evolved

33. Hypoinsulinemia (insulin release is dependent on calcium uptake into the pancreatic beta cells via L-type calcium channels) Insulin resistance, which is caused by the toxicity of calcium channel blockers Calcium channel blockers act on the heart muscle cells by reducing the utilization of free fatty acids, increasing myocardial dependence on carbohydrates by reducing the intake of free fatty acids and glucose into muscle cells and by reducing the activity of mitochondria, which are essential for carbohydrate catabolism.

34. Insulin itself has several effects related to the repair of toxic effects: It increases the uptake of glucose and lactate into myocardial cells. It improves myocardial function without the need to increase oxygen demand. It increases pyruvate dehydrogenase activity, which improves lactate oxidation and the “cleansing" of cytosols from glycolysis byproducts that may affect calcium turnover and lead to diastolic dysfunction. It improves myocardial contraction due to greater glucose availability. It increases the activity of calcium-dependent ATPase in the sarcoplasmic reticulum. It increases the concentration of calcium in the cytoplasm. It improves calcium inflow into mitochondria.

35. Mechanism of Action - HIET

36. Vasoactive infusions Titrate catecholamines to effect ( inotropy and chronotropy ); options include dopamine, adrenaline and/ or noradrenaline Glucagon if vasoplegic , consider noradrenaline and vasopressin. Consider methylene blue if refractory (to decrease cGMP formation, scavenge nitric oxide, and inhibit nitric oxide synthesis leading to vasoconstriction). Sodium bicarbonate consider in severe metabolic acidosis 50-100 mEq sodium bicarbonate (0.5-1.0 mEq/kg in children) In acidosis , the affinity of calcium channel blocker to L type calcium channel is more

37. Cardiac pacing electrical capture may be difficult to achieve and may not improve overall perfusion ventricular pacing to bypass AV blockade, typical with rates not in excess of 60/min Circulatory support devices consider in refractory cases VA ECMO or cardiac bypass intra-aortic balloon counterpulsation (useful if poor inotropy , will not correct refractory vasoplegia )

38. Lipid emulsion therapy Verapamil is lipophilic and amendable to lipid emulsion therapy It can be considered as an antidotal therapy of last resort in calcium channel blockers overdose Lipid emulsion 20%: 1.5 mL/kg over 1 minute Follow immediately with an infusion at a rate of 0.25 mL/kg/min

39. Citations from Case studies related to amlodipine tablet poisoning

40. “ Our patient presented with giddiness caused by hypotension 2 attributable to generalized vasodilatation due to direct effect on vascular smooth muscle worsened by negative effect on the cardiac pacemaker and myocardial contractility. Hyperglycemia due to reduced insulin release and lactic acidosis seen in CCB overdose also contributes to reduced dromotropic effect. ” “Abdominal pain and vomiting seen in our patient has been described to reduced gastrointestinal motility and stasis of gastric contents” “Oliguric renal failure with features of fluid overload seen in our patient is well described; and is attributable to prolonged hypotension and reduced effective circulatory volume ”

41. “An unusual finding in our case is bilateral exudative pleural effusion caused by amlodipine, that has not been reported earlier. We attribute this to capillary leak syndrome as a result of generalized vasodilatation”

42. “Treatment includes supportive care including maintenance of airway, breathing, and circulation (ABCs)” “Hypotension is initially managed with volume loading; however, as our patient had signs of fluid overload, we did not continue to administer iv fluids . Inotropes (dopamine, norepinephrine, epinephrine) can be added after normalization of CVP. Correction of acid-base disturbances and electrolyte abnormalities optimizes cardiac function. In refractory cases, glucagon (5-10 mg iv) and hyperinsulinemic - euglycemia using dextrose and insulin infusion (with 0.5 IU/kg/hr) as inotropic agents ”

43. Calcium gluconate or chloride in continuous infusion (Ca chloride 0.2 ml/kg/hr) or iv boluses (10 ml of 10% calcium chloride/ 20-30 ml of calcium gluconate , every 15-20 minutes; maximum: 30 g over 12 hours) is given to overcome the competitive blockade of calcium channels. We treated our patient with parenteral calcium and monitored with clinical response, ECG, and serum calcium levels. The course of hospitalization was complicated by oliguric acute renal failure that was managed conservatively though renal replacement therapy may be needed.

44. With an increase in the ingested dose of DHP , selectivity is lost and myocardium and conducting system gets affected resulting in reduced cardiac output and bradycardia. This combination of vasodilation and decreased cardiac output causes hypotension. The patients may also present with pulmonary edema due to myocardial depression. They might have an altered mental status and are often hyperglycemic due to reduced insulin secretion.

45. In recent years hyperinsulinemia - euglycemia therapy (HIET) has gained wide acceptance as a part of the treatment strategy for CCA toxicity . CCA over-dosage results in hyperglycemia from reduction in the insulin production due to blockage of L-type calcium channels in the pancreas. When hypoinsulinemia and acquired insulin resistance occur, the myocardium is unable to utilise glucose thereby reducing its contractility and causing hypotension. HIET reverses the cardiovascular collapse by improving myocardial utilization of carbohydrates and clearance of lactic acid and other glycolytic byproducts. In addition, insulin has direct positive inotropic action

46. ECMO in AMLODIPINE TABLET POISONING

47. Daubin et al. have used ECMO in a series of 17 patients within 6-7 hours of admission for the average duration of 74 hours All patients showed in improvement in hemodynamics following initiation and the dose of vasopressors was reduced. Weinberg et al. used ECMO in two patients with amlodipine poisoning having refractory vasodilatory shock. Vignesh et al. used ECMO for successful outcome in three patients

48. Due to refractory hypotension, VA-ECMO was planned as the rescue therapy. Right femoral vein was cannulated with 25 Fr cannula and placed up to the junction of inferior venacava and right atrium. Left femoral artery was cannulated with 17 Fr cannula and passed up to the abdominal aorta and an additional 7 Fr cannula was used for distal perfusion. Pump flow was maintained at 4.5 L/minute, sweep gas flow of 800 mL/minute, FIO2 of 0.9 and activated clotting time of 180–200 seconds. The ECMO was gradually weaned from 3rd day onward as the blood pressure started improving . Insulin-dextrose and calcium gluconate infusion gradually stopped after 72 hours. Patient was extubated on the 4th day following ECMO decannulation

49. CITATIONS ON HIET

50. We report the case of a patient with calcium channel blocker toxicity who was treated successfully with hyperinsulinemia euglycemia therapy, without prior use of vasopressors. The patient was 60-year-old man with schizoaffective disorder who presented with severe hemodynamic compromise after an intentional overdose of 5,400 mg of extended-release diltiazem . He had been admitted to the hospital twice before for attempted suicide with diltiazem and nifedipine, respectively. During the previous admissions, conventional treatments were used, and complications included hemodynamic compromise, ischemic bowel requiring ileostomy, and a prolonged hospital stay. During the current admission, the patient's clinical condition failed to improve after treatment with charcoal, fluid resuscitation, calcium, and glucagon. Eight hours after admission, hyperinsulinemia euglycemia therapy was initiated; 3 hours later, the patient's hemodynamic status showed sustained improvement.

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