PHARMACOVIGILANCE CASE

Dr Pranesh PawaskarFirst Year Resident

Department Of PharmacologyL.T.M.M.C. Sion, Mumbai

400022Date = 14/10/2016

HALOTHANE INDUCED HEPATITIS

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

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)

COURSE OF REACTIONOn 17 SEP 2016:-• Pain abdomen and Fever.• Generalised Malaise.On 19 SEP 2016:-• Nausea Vomiting• Yellow scleraOn 20 SEP 2016:-• Constipation• Refered

COURSE OF REACTION20 SEP 2016 –

• Patient refered to Sion Hospital in view of –

TAH + B/L Salpingo- oophorectomy

With Post Operative Icterus

EVALUATION• Temp – Normal CVS - Normal• Pulse – 80/min CNS – Conscious ,

Oriented• B.P.- 130/86 mmHg RS - Normal• Icterus – Present GIT - Hepatomegaly• Pallor - Present

COURSE OF REACTIONON 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.

DOCTORS IMPRESSIONBLOOD 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

DOCTORS IMPRESSIONPREANAESTHETIC 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.

COURSE OF REACTION• ADR REPORTED > 22 Sep 2016

• Patient = Improved

• Discharge = 30 Sep 2016

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 (0.1-1.0mg/dl

)

0.3 (0.1-0.5mg/dl

)-

19 SEP 2016

169 (0-40IU/L)

188 (0-40IU/L)

1168 (225-450

IU/L)

10.8 (0.1-

1.0mg/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-

1.0mg/dl)

2.4 (0.0-0.5mg/dl

)-

24 SEP 2016

87 (0-40IU/L)

50 (0-40IU/L)

700 (225-450

IU/L)

7.7 (0.1-1.0mg/dl

)

2.0 (0.1-1.0mg/dl

)-

27 SEP 2016

37 (0-40IU/L)

30 (0-40IU/L) -

2.1 (0.1-1.0mg/dl

)

1.2 (0.1-1.0mg/dl

)28 (9-37IU/l)

30 SEP 2016

25 (0-40IU/L)

31 (0-40IU/L)

360 (225-450

IU/L)

0.9 (0.1-1.0mg/dl

)

0.2 (0.1-1.0mg/dl

)-

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

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)

SERIOUSNESS OF REACTION • Reaction was serious as it prolonged hospitalisation

of patient.

OUTCOME • Patient recovered.

DIAGNOSIS• Halothane induced Hepatitis.

NARANJO SCALE

CAUSALITY ASSESSMENTAccording to NARANJO CAUSALITY assessment scale –

POSSIBLE(Score = 4)

Because-----1) Reasonable Drug-Event temporal relationship.2) De-challange response POSITVE.

HEPATITIS

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

HEPATITISSIGNS 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,EParasiticBacterialAlcoholicToxic and Drug induced- PCM, INH,VLP, PHN, CTXAutoimmuneIschemic

VIRAL HEPATITIS

ALCOHOLIC HEPATITIS• Very high Mortality.

• M > F ….But….

• Other Factors …

• Obesity And AH

• AH > Cirrhosis

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

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

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

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.

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

DRUG INDUCED HEPATITIS• Chemicals, medicines, industrial toxins, herbal

remedies, dietary suppliments.

• Mechanisms = Direct cell damage, Cell membrane disruption, Structural changes.

DRUG INDUCED HEPATITISDrugs 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

MECHANISMSPARACETAMOL –• Centrilobular necrosis.• Fatal = >25 g • Phase 2 > Phase 1• NAPQI ~ Glutathione = Mercapturic acid• Antidote =

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

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

MECHANISMMETHYLDOPA • Minor alteration = 5%• 15% = mod to severe chr. Hepatitis.• Chollestatic Injury / Hepatocellular Injury.

MECHANISMAMIODARONE• ultrastructural phospholipidosis• <5% • Desethyl-amiodarone• Injury = Pseudo alcoholic Injury• idiosyncracy > Metabolite generated

MECHANISMERYTHROMYCIN • Children > adults• Cholestatic reaction • Bx = Cholestasis, portal inflammation, PMNs

Eosinophils

MECHANISMOC PILLS• Intrahepatic cholestasis • Susceptible = recurrent idiopathic jaundice of

pregnancy, severe pruritis of pregnancy, Family history.• Bx = cholestasis with bile plugs.• Estrogen > progesterone (synergistic).

MECHANISMSULFA DRUGS• Unpredictable• Uniform latency period.• Hepatocellular necrosis > cholestatic injury• Attribute = Sulpha group• Risk more = HIV

MECHANISMCHLORPROMAZINE • Well known = ALI • Cholestatic• 1 : 1500• Onset = within 1 week• Vanishing Bile Duct Syndrome.• Hypersensitivity

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

HALOTHANE

HALOTHANE

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

HALOTHANE• 60-70% = eliminated unchanged.

• Rest = Hepatic CYP

• Tri-Fluoroacetic Acid.

• Excreted in Urine

• Protein (tri-fluoro)Acetylation.

• Immune reaction = Hepatic necrosis

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

SIDE EFFECTS1) Cardiovascular – mean arterial blood pressure,

cardiac output, brady cardia normal heart rate.

2) Respiratory - alveolar ventilation, no compensatory ventilation.

3) CNS – intra cranial pressure, cerebral metabolism

SIDE EFFECTS4) Muscular System – Relaxation of Sk. Muscle,

potentiation of non depolarisers, Malignant hyperthermia

5) Smooth Muscle – Uterus relaxed

6) Kidney – Less vol. more conc. Urine, GFR reduced.

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.

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.

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

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.