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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.