Halothane induced hepatitis

ADVERSE DRUG REACTION, HALOTHANE, HEPATITIS, DRUG INDUCED HEPATITIS

1. PHARMACOVIGILANCE CASE Dr Pranesh Pawaskar First Year Resident Department Of Pharmacology L.T.M.M.C. Sion, Mumbai 400022 Date = 14/10/2016

2. HALOTHANE INDUCED HEPATITIS

3. CASE Female 42 years Post Operative > Uterine Fibroid ~ 4d c/o Fever, Pain Abdomen ~ 3d Nausea and Vomiting ~ 2d Yellow Sclera ~ 2d Constipation ~ 1d

4. COURSE OF REACTION Asymptomatic ( prior 4 mo. ) Prior h/o Appendix Operation 15 yrs back. Now C/o :- Heavy Menses, Dysmenorrhoea…. 4 mo. Fullness of Abdomen, Increased frequency of Urination…. 3 mo. Progressive Enlargement of abdomen…. 2 mo. 15 days back….. Abdo USG > 17 x 7 x 4 cm Subserosal Fibroid and Cystic Ovary ( Rt /Lt). On 16 SEP 2016 :- Surgery:- TAH + B/l salpingo oophorectomy by Inhal . Halothane (1%) General Anaesthesia. (5 pints BT)

5. COURSE OF REACTION On 17 SEP 2016:- Pain abdomen and Fever. Generalised Malaise. On 19 SEP 2016:- Nausea Vomiting Yellow sclera On 20 SEP 2016:- Constipation Refered

6. COURSE OF REACTION 20 SEP 2016 – Patient refered to Sion Hospital in view of – TAH + B/L Salpingo - oophorectomy With Post Operative Icterus

7. EVALUATION Temp – Normal CVS - Normal Pulse – 80/min CNS – Conscious , Oriented B.P.- 130/86 mmHg RS - Normal Icterus – Present GIT - Hepatomegaly Pallor - Present

8. COURSE OF REACTION ON 20 SEP 2016:- At SION Hospital Pt admitted in Wd 20 under Dr. THT Treatment started was - Inj. Taxim 1 gm TDS (infection) Inj. Metro 100 mg TDS (infection) Inj. Pan 40 mg OD (gastritis) Inj. Ondem 4 mg TDS (vomiting) Vit K 10 mg OD (haemolysis) Blood sent for analysis.

9. DOCTORS IMPRESSION BLOOD ANALYSIS :- Raised > SGPT, SGOT, LDH, T. Bili, D. Bili, GGT. Normal > ALP, T. Prot , Blood Urea, Creatinine, BUN, UA. HBsAg = Negative Hep C Ag = Negative ELISA = Negative. Abdo USG = Mild Hepatomegaly. OTHER :- Addiction (x) No h/o BT

10. DOCTORS IMPRESSION PREANAESTHETIC MEDICATIONS – Inj. Atropine 0.5 mg i.m . T. Chlorpromazine 50 mg p.o. Inj. Midaz 1mg i.v. Inj. Pan 40mg i.v. Inj. Ondem 4mg i.v. SUSPICION – Drug induced Hepatitis. Probably HALOTHANE .

11. COURSE OF REACTION ADR REPORTED > 22 Sep 2016 Patient = Improved Discharge = 30 Sep 2016

12. INVESTIGATIONS Date SGPT SGOT LDH Tot. Bili Dir. Bili GGT 15 SEP 2016 34 (0-40IU/L) 23 (0-40IU/L) 312 (225-450 IU/L) 0.9 (0.1-1.0 mg/dl) 0.3 (0.1-0.5 mg/dl) - 19 SEP 2016 169 (0-40IU/L) 188 (0-40IU/L) 1168 (225-450 IU/L) 10.8 (0.1-1.0 mg/dl) 2.8 (0.0-0.5mg/dl) 39 (9-37IU/l) 21 SEP 2016 105 (0-40IU/L) 70 (0-40IU/L) - 10.0 (0.1-1.0 mg/dl) 2.4 (0.0-0.5 mg/dl) - 24 SEP 2016 87 (0-40IU/L) 50 (0-40IU/L) 700 (225-450 IU/L) 7.7 (0.1-1.0 mg/dl) 2.0 (0.1-1.0 mg/dl) - 27 SEP 2016 37 (0-40IU/L) 30 (0-40IU/L) - 2.1 (0.1-1.0 mg/dl) 1.2 (0.1-1.0 mg/dl) 28 (9-37IU/l) 30 SEP 2016 25 (0-40IU/L) 31 (0-40IU/L) 360 (225-450 IU/L) 0.9 (0.1-1.0 mg/dl) 0.2 (0.1-1.0 mg/dl) -

13. INVESTIGATIONS Date Hb WBC Plt 15 SEP 2016 10.1 mg/dl 7500 / uL 200000 / uL 19 SEP 2016 8.6 mg/dl 8500 / uL 180000 / uL 21 SEP 2016 9.0 mg/dl 9000 / uL 225000 / uL 24 SEP 2016 10.8 mg/dl 8600 / uL 154000 / uL 27 SEP 2016 11.6 mg/dl 9700 / uL 170000 / uL 30 SEP 2016 12.0 mg/dl 6600/ uL 210000 / uL

14. INVESTIGATIONS ALP Albumin Sr. Tot. Prot. Blood Urea Sr. Creat 113 (37-147 IU/L) 4.2 (3.4-5.5gm/dl) 6.7 (6-8 gm/dl) 32.5 (17-50 mg/dl) 0.82 mg/dl (0.5-1.5mg/dl) BUN Sr. Ca Sr. UA Sr. IP 12.9 (6-21mg/dl) 9.0 (8.5-10.0mg/dl) 3.0 (2.4-5.7 mg/dl) 3.96 (3.5–5.5mEq/L)

15. SERIOUSNESS OF REACTION Reaction was serious as it prolonged hospitalisation of patient. OUTCOME Patient recovered. DIAGNOSIS Halothane induced Hepatitis.

16. NARANJO SCALE

17. CAUSALITY ASSESSMENT According to NARANJO CAUSALITY assessment scale – POSSIBLE ( Score = 4 ) Because----- Reasonable Drug-Event temporal relationship. De- challange response POSITVE.

18. HEPATITIS

19. HEPATITIS Hepa = Liver, Itis = Inflammation Inflammatory Cells Symptoms = Jaundice, Poor Appetite, Fatigue Hepatitis Acute Chronic Scarring = Cirrhosis. M/c/c = Viral > Alcoholic > non Alcoholic Others

20. HEPATITIS SIGNS AND SYMPTOMS - Fatigue, Nausea, Vomiting, Poor Appetite, Headache, Yellowing of skin and sclera, Deranged liver enzyme values. CAUSES OF HEPATITIS - Viral – A,B,C,D,E Parasitic Bacterial Alcoholic Toxic and Drug induced- PCM, INH,VLP, PHN, CTX Autoimmune Ischemic

21. VIRAL HEPATITIS

22. ALCOHOLIC HEPATITIS Very high Mortality. M > F ….But…. Other Factors … Obesity And AH AH > Cirrhosis

23. NON ALCOHOLIC HEPATITIS NASH > Liver Transplant Prevalance = 3-5% NASH and Hepatocellular Carcinoma Hepatocellular Carcinoma Prevalance = 15 – 30 %

24. BACTERIAL AND PARASITIC PYOGENIC = M/c by E.Coli , K. pneumonia. ACUTE = N. meningitis, N. gonorrhoea, Bartonella , Borellia CHRONIC = Mycobacteria, Treponema Pallidum Parasitic = Acute Hepatitis = Increased IgE M/c = E. histolytica Worms = Cestodes Liver Flukes = C. Sinensis

25. AUTOIMMUNE HEPATITIS Abn immune response. HLA Ab M/c ANA, SMA, p-ANCA Drugs = Nitrofurantoin, Hydralazine, Methyldopa Viruses = Hep A, EBV, measles

26. GENETIC Causes = Alpha 1 anti-trypsin deficiency, Haemochromatosis , Wilsons disease. A1AtD = mutation in gene… abn prot accumulation Haemochromatosis And Wilsons = Autosomal Recessive… abn storage of minerals.

27. ISCHEMIC HEPATITIS Insufficient blood/ oxygen. Shock Liver M/C in Heart failure AST ALT ….Very High Permenant Damage = Rare

28. DRUG INDUCED HEPATITIS Chemicals, medicines, industrial toxins, herbal remedies, dietary suppliments . Mechanisms = Direct cell damage, Cell membrane disruption, Structural changes.

29. DRUG INDUCED HEPATITIS Drugs which can lead to Hepatitis are :- Paracetamol Methyldopa Amiodarone Isoniazid Methotrexate Anabolic steroids OC Pills Statins Sulfa drugs Chlorpromazine Erythromycin Anti HIV drugs Halothane Amoxicillin- clavulanate Sodium Valproate

30. MECHANISMS PARACETAMOL – Centrilobular necrosis. Fatal = >25 g Phase 2 > Phase 1 NAPQI ~ Glutathione = Mercapturic acid Antidote =

31. MECHANISMS ISONIAZIDE – 10% T.B. 1% = Viral Hepatitis(?) CFR = 10% Age > 35 … highest = >50yr. Isoniazid Acetylhydrazine Rapid Acetylators .

32. MECHANISM VALPROATE Children > Adult Asymptomatic elevations = 45% patients. No major hepatotoxicity….continue Tissue = microvesicular fat and hepatic necrosis. 4 - pentanoic acid L - carnitine

33. MECHANISM METHYLDOPA Minor alteration = 5% 15% = mod to severe chr. Hepatitis. Chollestatic Injury / Hepatocellular Injury.

34. MECHANISM AMIODARONE ultrastructural phospholipidosis <5% Desethyl -amiodarone Injury = Pseudo alcoholic Injury idiosyncracy > Metabolite generated

35. MECHANISM ERYTHROMYCIN Children > adults Cholestatic reaction Bx = Cholestasis, portal inflammation, PMNs Eosinophils

36. MECHANISM OC PILLS Intrahepatic cholestasis Susceptible = recurrent idiopathic jaundice of pregnancy, severe pruritis of pregnancy, Family history. Bx = cholestasis with bile plugs. Estrogen > progesterone (synergistic).

37. MECHANISM SULFA DRUGS Unpredictable Uniform latency period. Hepatocellular necrosis > cholestatic injury Attribute = Sulpha group Risk more = HIV

38. MECHANISM CHLORPROMAZINE Well known = ALI Cholestatic 1 : 1500 Onset = within 1 week Vanishing Bile Duct Syndrome. Hypersensitivity

39. OTHER DRUGS STATINS = Idiosyncratic Mixed Hepatocellular and Cholestatic Reaction. ANABOLIC STEROIDS = Cholestatic Reaction TOTAL PARENTERAL NUTRITION = Steatosis, Cholestasis ALTERNATIVE AND COMPLEMENTARY MEDICINES = Idiosyncratic Hepatitis, Steatosis HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) FOR HIV INFECTION = Mitochondrial Toxic, Idiosyncratic, Steatosis; Hepatocellular, Cholestatic , and Mixed

40. HALOTHANE

41. HALOTHANE

42. HALOTHANE High blood: gas partition coefficient High fat: blood partition coefficient MAC = 0.75 Slow induction Soluble = fat & tissues = the speed of recovery is more

43. HALOTHANE 60-70% = eliminated unchanged. Rest = Hepatic CYP Tri- Fluoroacetic Acid. Excreted in Urine Protein (tri- fluoro )Acetylation. Immune reaction = Hepatic necrosis

44. CLINICAL USE Since 1958 Maintainance Anaesthesia. Child > Adult. Low cost

45. SIDE EFFECTS Cardiovascular – mean arterial blood pressure, cardiac output, brady cardia normal heart rate. Respiratory - alveolar ventilation, no compensatory ventilation. CNS – intra cranial pressure, cerebral metabolism

46. SIDE EFFECTS Muscular System – Relaxation of Sk. Muscle, potentiation of non depolarisers, Malignant hyperthermia Smooth Muscle – Uterus relaxed Kidney – Less vol. more conc. Urine, GFR reduced.

47. SIDE EFFECTS ON LIVER Fulminant Necrosis = Minority Fever, Anorexia , Nausea, Vomiting > 3-14 d If Rapid Progression = 50% fatality 1~10000 Halothane Hepatitis. Trifluoroacetylated proteins.

48. MANAGEMENT AND CONCLUSION Most important aspect of management is Avoid Repeat Exposure within next 3 months . History of Unexplained Jaundice following Halothane use is an Absolute Contraindication for its further usage. Concern for hepatitis resulted in a dramatic reduction in the use of halothane for adults and it is replaced by  Enflurane , Isoflurane, Sevoflurane etc. But caution is must for all Halothane hepatitis patients for future exposure to Fluorinated Hydrocarbons .

49. REFERENCES Chalasani et al: Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135:1924, 2008[PMID: 18955056]  [Full Text] Chang CY, Schiano TD: Review article: drug hepatotoxicity. Aliment Pharmacol Ther 25:1135, 2007[PMID: 17451560]  [Full Text] Navarro VJ, Senior JR: Drug-related hepatotoxicity. N Engl J Med 354:731, 2006[PMID: 16481640]  [Full Text] Lee WM: Drug-induced hepatotoxicity. N Engl J Med 349:474, 2003[PMID: 12890847]  [Full Text] Kaplowitz N, Deleve LD ( eds ): Drug-Induced Liver Disease . 2nd ed , New York, Informa Healthcare, 2007

50. REFERNCES Bahlman SH, Eger EI, Holsey MJ, et al. The cardiovascular effects of halolthane in man during spontaneous ventitation . Anesthesiology , 1972 , 36 :494–502. [PMID: 5021951] Hirshman CA, McCullough RE, Cohen PJ, Weil JV. Depression of hypoxic ventilatory response by halothane, enflurane and isoflurane in dogs. Br J Anaesth , 1977 , 49 :957–963. [PMID: 921874] Study SotNH . Summary of the National Halothane Study. Possible association between halothane anesthesia andpostoperative hepatic necrosis. JAMA , 1966 , 197 :775–788. Urbinati G, Figliuzzi M. [Jaundice caused by chlorpromazine.] Clin Ter 1960; 18: 611-39. Italian.