AJPTI_118_10_2014_NOVEL_APPROACH_OF_TREATMENT_FOR_BETA_BLOCKER_AND_CAL

Views:
 
Category: Entertainment
     
 

Presentation Description

Research and Review articles

Comments

Presentation Transcript

slide 1:

Sandeep Rajan Kolli et al. Asian Journal of Pharmaceutical Technology Innovation 02 08 2014 121-127 Asian Journal of Pharmaceutical Technology Innovation ISSN: 2347-8810 www.asianpharmtech.com 121 Review Article Received on: 01-10-2014 Accepted on: 09-10-2014 Published on: 15-10-2014 Novel Approach of Treatment for Beta Blocker and Calcium Channel Blocker Toxicity a High Dose Insulin Theraphy Corresponding Author: Sandeep Rajan Kolli B.Lakshmi Durga K.Vineela K.Mohini Kalyani Sandeep Rajan Kolli C.R.R. College of Pharmacy Eluru- 534007 West Godavari DT Andhra Pradesh ABSTRACT Poison-induced cardiogenic shock PICS as a result of beta-blocker β-blocker or calcium channel blocker CCB overdose is a common and highly life-threatening condition. Conventional therapies including fluid resuscitation atropine cardiac pacing calcium glucagon and vasopressors often fail to improve hemodynamic status. High-dose insulin HDI is an emerging theraphy for PICS. In this article we discuss the existing literature and highlight the therapeutic success and potential of HDI. Based on the current literature which is limited primarily to case series and animal models the authors conclude that HDI can be effective in restoring hemodynamic stability and recommend considering its use in patients with PICS that is not responsive to traditional therapies. Future studies should be undertaken to determine the optimal dose and duration of therapy for HDI in PIC. Email Id- sndiprkgmail.com Key-words: High dose insulin Beta-blocker Calcium channel blocker Overdose. Cite this article as: Sandeep Rajan Kolli B.Lakshmi Durga K.Vineela K.Mohini Kalyani Novel Approach of Treatment for Beta Blocker and Calcium Channel Blocker Toxicity a High Dose Insulin Theraphy Asian Journal of Pharmaceutical Technology Innovation 02 08 2014. C.R.R. College of Pharmacy Eluru-534007 West Godavari DT Andhra Pradesh

slide 2:

Sandeep Rajan Kolli et al. Asian Journal of Pharmaceutical Technology Innovation 02 08 2014 121-127 www.asianpharmtech.com 122 INTRODUCTION: Poison-induced cardiogenic shock PICS due to beta-blocker β-blocker or calcium channel blocker CCB overdose is a frequent and potentially lethal occurrence 1. β-blockers are used widely for conditions such as hypertension dysarrhythmias and coronary artery disease. In the developed countries there were millions of prescriptions for β-blockers filled according to IMS Health the united states became fifth most commonly prescribed medication class in the country 2. CCBs are also frequently utilized for patients with cardiovascular disease and other conditions with an estimated 98 million prescriptions filled in 2010 alone in US itself.3. The most common cause of PICS is β-blocker toxicity with 24465 exposures to β-blockers reported by the American Association of Poison Control Centers’ National Poison Data System in 2012 4. While less frequent CCB overdose has been associated with the highest mortality rates amongst cardiovascular agents in the United States 5.In india it was a little higher in use of drugs and deaths of unintentional and overdose which are undetermined. INDIA’S FATE IN TOXICITY: There are lots of cases have reported before and have been reporting at present that many people died due to overdose and toxicity for medicines. This is the problem not only for underdeveloped areas but also in highly developed countries like united states. It was a getting very worst situation in India. Many people are died by drug toxicity due to lack of knowledge and not under proper toxicologists supervision. So treatment of overdose patients is an intense risk and very flaucid chances for survival.My review keeps on alerting to the physicians and patients to have proper knowledge and have proper awareness on intake of medicines. HIGH-DOSE INSULIN HDI: It is using doses 10-fold greater than traditional therapy for hyperglycemia is an emerging therapeutic model for PICS. Although there are sparse of clinical trials and existing data are currently limited to case series or animal models HDI has shown great promise as an effective treatment for β-blocker and CCB toxicity 79-13. HDI is a potentially life-saving therapeutic option however its popularity is not yet widespread and has been mainly restricted to use as a rescue therapy after conventional methods fail 15 IMPORTANCE: Conventional therapies including fluid resuscitation atropine cardiac pacing calcium glucagon and vasopressors often fail to improve hemodynamic status in PICS in β-blocker and CCB overdose. Even if there is a response to such traditional therapies the response is often transient in nature 6-8. Unlike other countries such as Iran where there is a growing trend to treat acutely poisoned patients in specialized tertiary hospitals where the clinical staff is trained specifically in toxicology many poisoned patients in India are not treated by a medical toxicologist 14. As such it is of critical importance that emergency medicine physicians and supporting staff nursing pharmacy are equipped with the knowledge and comfort to utilize HDI.Lack of knowledge and limitation of clinical trials lack of practitioner unfamiliarity are the causes of not employing HDI in useful cases. In this paper we will review the existing literature and highlight the therapeutic success and potential of HDI.

slide 3:

Sandeep Rajan Kolli et al. Asian Journal of Pharmaceutical Technology Innovation 02 08 2014 121-127 www.asianpharmtech.com 123 MECHANISM OF TOXITY: β-blockers act on beta-receptors through competitive inhibition indirectly decreasing the production of cAMP and thereby limiting calcium influx through L-type calcium channels with a resulting negative effect on heart rate and cardiac contractility 11617. CCBs exert their therapeutic and toxic effects by the direct blockade of L-type calcium channels causing relaxation of the vascular smooth muscle with subsequent vasodilation and in the case of verapamil and diltiazem inhibition of the sinoatrial and atrioventricular nodes. Calcium channel blockade concurrently triggers the heart to switch to preferential carbohydrate metabolism as opposed to the free fatty acid oxidation that occurs in the myocardium in the non-stressed state 817-19. The effects of calcium channel antagonism are also seen in other parts of the body 1617. For example in the beta-islet cells of the pancreas calcium channel antagonism inhibits insulin secretion producing insulin resistance and hyperglycemia81718. Calcium flux is crucial to many aspects of normal myocardial activity including contractility pacemaker function and signal propagation. Both CCBs and β-blockers ultimately result in decreased myocardial cytosolic calcium 117. Life- threatening cardiovascular effects such as profound vasodilation with decreased systemic vascular resistance bradycardia conduction delay hypotension and resulting cardiogenic shock have been well established in BB and CCB overdose172021. Other adverse effects include hyperglycemia more common in CCB overdose and lactic acid accumulation leading to metabolic acidosis 692223. In addition altered mental status dysarhythmias seizures and other adverse effects may occur depending upon the specific agent ingested 17. MANAGEMENT OF PCIS: The primary goal in the management of PCIS is to restore hemodynamic stability 9. Treatment tends to be physician dependent given the lack of clinical trials and established guidelines. Once the patients airway breathing and circulation have been stabilized initial therapy for CCB and β-blocker overdose generally includes aggressive gastrointestinal decontamination. Activated charcoal gastric wash and whole-bowel irrigation are potential options for decontamination in hemodynamically stable patients however these therapies are relatively contraindicated in the setting of shock. In patients with evidence of cardiovascular compromise infusions such as normal saline are initially administered . Patients with symptomatic bradycardia can be treated with atropine and cardiac pacing however patients with β- blocker and CCB overdose often do not respond to these interventions 17. Calcium and glucagon administration are often attempted as part of initial resuscitation bringing back efforts. Catecholamines such as norepinephrine can be administered as hemodynamic status warrants. For patients who remain hemodynamically unstable after these initial therapies second line treatment options include HDI lipid emulsion therapy 2425 and mechanical life support including intra-aortic balloon pump cardio pulmonary bypass or extracorporeal membrane oxygenation 1. MECHANISM OF ACTION: HDI has been postulated to improve hemodynamics in CCB and β-blocker overdose by several different mechanisms. Most notably a number of studies have demonstrated that insulin administered in higher doses has strong positive inotropic properties 9111718202126. HDI also assists myocardial uptake of carbohydrates which is the preferred fuel substrate of the heart under stressed conditions 182127 HDI also inhibits free fatty acid metabolism 2728. Additionally exogenous insulin administration can

slide 4:

Sandeep Rajan Kolli et al. Asian Journal of Pharmaceutical Technology Innovation 02 08 2014 121-127 www.asianpharmtech.com 124 help to overcome the insulin resistance and insulin deficiency that occurs in CCB toxicity 1. HDI produces vasodilation which improves local microcirculation1121 and aids systemic perfusion 91120. Studies have demonstrated accelerated oxidation of myocardial lactate and reversal of metabolic acidosis with HDI 926. Response to catecholamines is also improved with addition of HDI 9. While conventional therapy sometimes offers temporary improvement in hemodynamics the hemodynamic stability achieved with HDI does not appear to be as transient in nature 21. DOSING AND ADMINISTRATION: There are no official guidelines regarding insulin dosing in PICS and wide practice variation exists. However one of the most common recommendations consists of a 1 unit/kg bolus dose followed by a continuous infusion at 0.5-1 unit/kg per hour which can be titrated to response. Insulin doses up to 10 units/kg per hour have been successfully used to treat PCIS 29. A dextrose bolus of 0.5 g/kg can be administered with the initial insulin bolus in patients whose blood glucose is less than 400 mg/dL. A continuous dextrose infusion 0.5 g/kg per hour should be initiated. It is preferable to administered concentrated dextrose solutions through a central venous catheter 17. Supplemental intravenous dextrose 110–150 mg/dL or 6–8 mmol/L can be administered as needed to maintain euglycemia however patients with CCB overdose may be hyperglycemic despite HDI 91521. Blood glucose should be checked every twenty minutes during the first hour and can then be checked hourly 9 with the goal of maintaining blood glucose levels in the upper range of normal 15. The onset of action of HDI is thought to be 15–45 minutes but may be delayed several hours 1521. Once initiated HDI therapy is continued until hemodynamic stability is achieved. There are no established recommendations regarding the proper duration of therapy and treatment with HDI should be guided by the patient’s hemodynamic status 21 with the goal of maintaining a heart rate of at least 50 beats/min and a systolic blood pressure of at least 100 mm Hg 9. Case reports have documented variable duration of HDI ranging from 9 hours to 49 hours 71030. ADVERSE EFFECTS: HDI is relatively well tolerated. The most common adverse effects include hypoglycemia and hypokalemia however these are rare and reversible when proper serum monitoring and replacement is undertaken 2131. Supplemental glucose is often required throughout the administration of HDI and for as long as 24 hours after cessation of therapy 21. Some adult patients may need up to 30 g of supplemental glucose per hour to maintain normal calcium levels along with potassium supplements15. Serum potassium should be checked hourly during insulin titration and may be extended to every 6 hr following titration and electrolyte stability 21. Intravenous potassium repletion is required when concentrations drop below 2.8 mEq/L 21 with a target goal of maintaining concentrations at 2.8-3.2 mEq/L 9. In some case reports patients have not required potassium supplementation at all7 while other authors have described the need for potassium supplementation averaging 2.7 mmol/h or 4.1 mmol per 100 units of insulin 31. Hypokalemia during HDI is representative of intracellular shifting of potassium as opposed to total body depletion 21. Practitioners can observe hypokalemia through electrocardiogram changes beginning with decreased T-wave amplitude and progressing to ST segment depression T-wave inversion prolongation of the PR interval

slide 5:

Sandeep Rajan Kolli et al. Asian Journal of Pharmaceutical Technology Innovation 02 08 2014 121-127 www.asianpharmtech.com 125 increased P wave amplitude and U wave appearance 32. Despite the known risk of adverse arrhythmias with hypokalemia there have been few such events recorded in the literature when HDI is used in cases of PICS 21. It is important to note that the adverse effects associated with HDI are also present with the use of insulin at regular doses which physicians pharmacists and nurses are accustomed to addressing in conditions such as diabetic ketoacidosis. EXPERIMENTAL AND CLINICAL DATA: Although prospective clinical studies in human subjects comparing the efficacy of HDI to conventional treatments are lacking several experimental animal studies have demonstrated the utility of HDI in achieving hemodynamic stability. A series of studies in canines by Kline et al. consistently demonstrated improved inotropy when HDI was given after verapamil overdose 8182026. In other studies HDI successfully normalized heart rate 13 and reversed negative inotropy caused by propranolol overdose in canines 1113. Superior survival rates have been witnessed in various animal studies when HDI is administered in PICS 812202633. In humans several case reports have documented successful hemodynamic stabilization with insulin after initial failed treatment attempts with conventional therapy 67253435. To date there are no studies on the most appropriate way to wean HDI once hemodynamic stability has been achieved 21. While some physicians opt for a slow taper others advocate for abrupt cessation of HDI infusion as this method has been postulated to allow insulin concentrations to self-taper as lipid stores slowly release insulin 721. Several case reports have documented worsening hypotension in patients with CCB overdose with early insulin withdrawal that was alleviated when the insulin infusion was subsequently increased 730. In one reported case of verapamil overdose resulting in hypotension and a junctional rhythm HDI was initiated 3.5 hours after presentation 0.5 IU/kg bolus and infusion at 0.5 IU/kg/h following failure of blood pressure stabilization with intravenous fluids and metaraminol boluses with subsequent improvement in blood pressure and conversion to normal sinus rhythm within 30 minutes 30. Following abrupt termination of HDI 5.5 hours after presentation the patient again became hypotensive therefore HDI was restarted at 8.5 hours as well as an adrenaline infusion which again achieved hemodynamic stability. HDI was continued until 30.5 hours and the patient remained stable throughout this time. In another case report of verapamil overdose resulting in initial hypotension and third degree heart block HDI up to 70 units per hour was initiated after 45 minutes of refractory hypotension despite calcium chloride and glucagon with subsequent improvement in blood pressure 7. Eight hours after presentation HDI was gradually weaned while maintaining glucagon and dopamine infusions resulting in recurrent hypotension which was improved when the dose of HDI was increased. HDI was continued for a total of 27.5 hours. Treatment difficulty could be due to delayed initiation of insulin therapy as rare case reports have documented treatment failure with HDI when initiated late for example at the end of cardiopulmonary resuscitation or following multiple hours of alternative therapies 3637. Although many sources recommend a 1 unit/kg bolus dose followed by a continuous infusion at 0.5-1 unit/kg per hour 91521 no ceiling effect has ever been established and higher doses have been postulated to be more effective 38 with good outcomes documented in patients receiving insulin boluses as high as 10 U/kg 39 and infusions as high as 22 U/kg/h 25.

slide 6:

Sandeep Rajan Kolli et al. Asian Journal of Pharmaceutical Technology Innovation 02 08 2014 121-127 www.asianpharmtech.com 126 CONCLUSION: Although clinical trial data in humans are lacking available published reports suggest that HDI is effective at restoring hemodynamic stability in CCB and β-blocker overdose. As such HDI should be considered in patients with PCIS who do not respond to traditional therapies and providers who care for poisoned patients should be familiar with this potentially life-saving therapy. Future studies should be undertaken to determine the optimal dosing regimen and duration of therapy for HDI in PICS. REFERENCES: 1. DeWitt CR Waksman JC: Pharmacology pathophysiology and management of calcium channel blocker and beta blocker toxicity. Toxicol Rev 2004 23:223238. 2. Consumer Reports health best buy drugs: treating high blood pressure and heart disease: the beta-blockers. 2011.http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/CU-Betablockers-FIN060109.pdf webcite 3. The Huffington Post: calcium-channel blockers blood pressure medication might raise breast cancer risk. 2014.http://www.huffingtonpost.com/2013/08/06/calcium-channel-blockers-breast-cancer- bloodpressure_n_3712936.html webcite 4. Mowry JB Spyker DA Cantilena LR Jr Bailey JE Ford M: 2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System NPDS: 30th Annual Report.Clin Toxicol Phila 2013 51:949-1229. Pubmed abstract. 5. Watson WA Litovitz TL Klein-Schwartz W Rodgers GC Jr Youniss J Reid N Rouse WG Rembert RS Borys D: 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System.Am J Emerg Med 2004 22:335-404. PubMed Abstract | Publisher Full Text 6. Boyer EW Duic PA Evans A: Hyperinsulinemia/euglycemia therapy for calcium channel blocker poisoning. Pedatr Emerg Care 2002 18:36-37. Publisher Full Text 7. Yuan TH Kerns WP Tomaszewski CA Ford MD Kline JA: Insulin-glucose as adjunctive therapy of severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999 37:463-474. PubMed Abstract | Publisher Full Text 8. Kline JA Leonova E Raymond RM: Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995 23:1251 1263. PubMed Abstract | Publisher Full Text 9. Mégarbane B Karyo S Baud FJ: The role of insulin and glucose hyperinsulinaemia /euglycaemia therapy in acute calcium channel antagonist and beta-blocker poisoning. Toxicol Rev 2004 23:215-222. PubMed Abstract | Publisher Full Text 10. Marques I Gomes E de Oliveria J: Treatment of calcium channel blocker intoxication with insulin infusion: case report and literature review. Resuscitation 2003 57:211-213. PubMed Abstract | Publisher Full Text 11. Reikerås O Gunnes P Sørlie D Ekroth R Jorde R Mjøs OD: Haemodynamic effects of low and high doses of insulin during beta-receptor blockade in dogs. Clin Physiol 1985 5:455-467. PubMed Abstract | Publisher Full Text 12. Kerns W Schroeder JD Williams C Tomaszewski CA Raymond RM: Insulin improves survival in a canine model of acute beta-blocker toxicity. Ann Emerg Med 1997 29:748-757. PubMed Abstract | Publisher Full Text 13. Krukenkamp I Sorlie D Silverman N Pridjian A Levitsky S: Direct effect of high-dose insulin on the depressed heart after beta-blockade or ischemia. Thorac Cardiovasc Surg 1986 34:305-309. PubMed Abstract | Publisher Full Text 14. Zamani N Mehrpour O: Outpatient treatment of the poisoned patients in Iran may it be a feasible plan DARU J Pharm Sci 2013 211:45. BioMed Central Full Text 15. Lheureux PE Zahir S Gris M Derrey AS Penaloza A: Bench-to-bedside review: hyperinsulinaemia/euglycaemia therapy in the management of overdose of calcium-channel blockers.Crit care 2006 10:212. Pubmed extract. 16. Love JN Howell JM Litovitz TL Klein-Schwartz W: Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol 2000 38:275-281. PubMed Abstract | Publisher Full Text 17. Nelson L Hoffman R Flomenbaum N Goldfrank L Howland MA: Goldfrank’s Toxicologic Emergencies. 9th edition. New York NY: McGraw-Hill 2010. 18. Kline JA Leonova E Williams TC Schroeder JD Watts JA: Myocardial metabolism during graded intraportal verapamil infusion in awake dogs. J Cardiovasc Pharmacol 1996 27:719-726. PubMed Abstract | Publisher Full Text 19. Downing SE: The heart in shock. In Handbook of Shock and Trauma. Edited by Altura BM Lefer AM Schumer W. New York: Raven Press 1983:5-28. 20. Kline JA Tomaszewsi CA Schroeder JD Raymond RM: Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine.J Pharm Exp Ther 1993 267:744-750. 21. Engebretsen KM Kaczmarek KM Morgan J Holger JS: High-dose insulin therapy in beta-blocker and calcium channel- blocker poisoning. Clin Toxicol Phila 2011 49:277-283. PubMed Abstract | Publisher Full Text

slide 7:

Sandeep Rajan Kolli et al. Asian Journal of Pharmaceutical Technology Innovation 02 08 2014 121-127 www.asianpharmtech.com 127 22. Buss WC Savage DD Stepanek J Little SA McGuffee LJ: Effect of calcium channel antagonists on calcium uptake and release by isolated rat cardiac mitochondria. Eur J Pharmacol 1988 152:247-253. PubMed Abstract | Publisher Full Text 23. Rafael J Patzelt J: Binding of diltiazem and verapamil to isolated rat heart mitochondria. Basic Res Cardiol 1987 82:246 251. Pubmed Abstract. 24. Stellpflug SJ Fritzlar SJ Cole JB Engebretsen KM Holger JS: Cardiotoxic overdose treated with intravenous fat emulsion and high-dose insulin in the setting of hypertrophic cardiomyopathy. J Med Toxicol 2011 7:151153. Pubmed Abstract. 25. Stellpflug SJ Harris CR Engebretsen KM Cole JB Holger JS: Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high-dose insulin. Clin Toxicol 2010 48:227-229. Publisher Full Text 26. Kline JA Raymond RM Leonova ED Williams TC Watts JA: Insulin improves heart function and metabolism during non- ischemic cardiogenic shock in awake canines. Cardiovasc Res 1997 34:289-298. PubMed Abstract | Publisher Full Text 27. Farah AE Alousi AA: The actions of insulin on cardiac contractility. Life sci 1981 29:975- 1000. PubMed Abstract | Publisher Full Text 28. Tune JD Mallett RT Downey HF: Insulin improves contractile function during moderate ischemia in canine left ventricle. Am J Physiol 1998 2745 Pt 2:H1574-H1581. PubMed Abstract | Publisher Full Text 29. Holger JS Stellpflug SJ Cole JB Harris CR Engebretsen KM: High-dose insulin: a consecutive case series in toxin-induced cardiogenic shock. Clin Toxicol 2011 49:653-658. Publisher Full Text 30. Boyer EW: 2000 Poisoning Data. Boston: Massachusetts Poison Control Center 2000. 31. Greene SL Gawarammana I Wood DM Jones AL Dargan PI: Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: a prospective observational study. Intensive Care Med 2007 33:2019-2024. PubMed Abstract | Publisher Full Text 32. Levis JT: ECG diagnosis: hypokalemia.PermJ2012 162:57. Pubmed Abstract. 33. Holger JS Engebretsen KM Fritzlar SJ Patten LC Harris CR Flottemesch TJ: Insulin versus vasopressin and epinephrine to treat beat-blocker toxicity.Clin Toxicol 2007 45:396-401. Publisher full text. 34. Vergugge LB van Wezel HB: Pathophysiology of verapamil overdose new insights into the role of insulin. J Cardiothoracic Vasc Anesth 2007 21:406 409. Punlisher full text. 35. Boyer EW Shannon M: Treatment of calcium channel blocker intoxication with insulin infusion. N Eng J Med 2001 344:1721-1722. Publisher Full Text 36. Levine MD Boyer E: Hyperinsulinemia-euglycemia therapy a useful tool in treating calcium channel blocker poisoning. Crit care 2006 10:149. Pubmed Abstract. 37. Herbert J O’Malley C Tracey J Dwyer R Power M: Verapamil overdosage unresponsive to dextrose/insulin therapy. J Toxicol Clin Toxicol 2001 39:293-294. 38. Cole JB Stellpflug SJ Ellsworth H Anderson CP Adams AB Engebretsen KM Holger JS: A blinded randomized controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock. Clin Toxicol Phila. 2013 51:201-207 . pubmed Abstact . 39. Place R Carlson A Leikin J Hanashiro P: Hyperinsulin therapy in the treatment of verapamil overdose. J Toxicol Clin Toxicol 2000 38:576-577.

authorStream Live Help