Halothane induced hepatitis
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ADVERSE DRUG REACTION, HALOTHANE, HEPATITIS, DRUG INDUCED HEPATITIS
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Halothane induced hepatitis
- 2. PHARMACOVIGILANCE CASE Dr Pranesh Pawaskar First Year Resident Department Of Pharmacology L.T.M.M.C. Sion, Mumbai 400022 Date = 14/10/2016
- 4. CASE • Female • 42 years • Post Operative > Uterine Fibroid ~ 4d • c/o Fever, Pain Abdomen ~ 3d Nausea and Vomiting ~ 2d Yellow Sclera ~ 2d Constipation ~ 1d
- 5. 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)
- 6. 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
- 7. COURSE OF REACTION 20 SEP 2016 – • Patient refered to Sion Hospital in view of – TAH + B/L Salpingo- oophorectomy With Post Operative Icterus
- 8. EVALUATION • Temp – Normal CVS - Normal • Pulse – 80/min CNS – Conscious , Oriented • B.P.- 130/86 mmHg RS - Normal • Icterus – Present GIT - Hepatomegaly • Pallor - Present
- 9. 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.
- 10. 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
- 11. 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.
- 12. COURSE OF REACTION • ADR REPORTED > 22 Sep 2016 • Patient = Improved • Discharge = 30 Sep 2016
- 13. 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) -
- 14. 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
- 15. 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)
- 16. SERIOUSNESS OF REACTION • Reaction was serious as it prolonged hospitalisation of patient. OUTCOME • Patient recovered. DIAGNOSIS • Halothane induced Hepatitis.
- 17. NARANJO SCALE
- 18. CAUSALITY ASSESSMENT According to assessment scale – POSSIBLE (Score = 4) Because----- 1) Reasonable Drug-Event temporal relationship. 2) De-challange response POSITVE.
- 19. HEPATITIS
- 20. 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
- 21. 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
- 22. VIRAL HEPATITIS
- 24. ALCOHOLIC HEPATITIS • Very high Mortality. • M > F ….But…. • Other Factors … • Obesity And AH • AH > Cirrhosis
- 25. NON ALCOHOLIC HEPATITIS • NASH > Liver Transplant • Prevalance = 3-5% • NASH and Hepatocellular Carcinoma • Hepatocellular Carcinoma Prevalance = 15 – 30 %
- 26. 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
- 27. AUTOIMMUNE HEPATITIS • Abn immune response. • HLA Ab • M/c ANA, SMA, p-ANCA • Drugs = Nitrofurantoin, Hydralazine, Methyldopa • Viruses = Hep A, EBV, measles
- 28. 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.
- 29. ISCHEMIC HEPATITIS • Insufficient blood/ oxygen. • Shock Liver • M/C in Heart failure • AST ALT ….Very High • Permenant Damage = Rare
- 30. DRUG INDUCED HEPATITIS • Chemicals, medicines, industrial toxins, herbal remedies, dietary suppliments. • Mechanisms = Direct cell damage, Cell membrane disruption, Structural changes.
- 31. 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
- 32. MECHANISMS PARACETAMOL – • Centrilobular necrosis. • Fatal = >25 g • Phase 2 > Phase 1 • NAPQI ~ Glutathione = Mercapturic acid • Antidote =
- 33. MECHANISMS ISONIAZIDE – • 10% T.B. • 1% = Viral Hepatitis(?) • CFR = 10% • Age > 35 … highest = >50yr. • Isoniazid Acetylhydrazine • Rapid Acetylators.
- 34. MECHANISM VALPROATE • Children > Adult • Asymptomatic elevations = 45% patients. • No major hepatotoxicity….continue • Tissue = microvesicular fat and hepatic necrosis. • 4 - pentanoic acid • L - carnitine
- 35. MECHANISM METHYLDOPA • Minor alteration = 5% • 15% = mod to severe chr. Hepatitis. • Chollestatic Injury / Hepatocellular Injury.
- 36. MECHANISM AMIODARONE • ultrastructural phospholipidosis • <5% • Desethyl-amiodarone • Injury = Pseudo alcoholic Injury • idiosyncracy > Metabolite generated
- 37. MECHANISM ERYTHROMYCIN • Children > adults • Cholestatic reaction • Bx = Cholestasis, portal inflammation, PMNs Eosinophils
- 38. 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).
- 39. MECHANISM SULFA DRUGS • Unpredictable • Uniform latency period. • Hepatocellular necrosis > cholestatic injury • Attribute = Sulpha group • Risk more = HIV
- 40. MECHANISM CHLORPROMAZINE • Well known = ALI • Cholestatic • 1 : 1500 • Onset = within 1 week • Vanishing Bile Duct Syndrome. • Hypersensitivity
- 41. 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
- 42. HALOTHANE
- 43. HALOTHANE
- 44. 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
- 45. HALOTHANE • 60-70% = eliminated unchanged. • Rest = Hepatic CYP • Tri-Fluoroacetic Acid. • Excreted in Urine • Protein (tri-fluoro)Acetylation. • Immune reaction = Hepatic necrosis
- 46. CLINICAL USE • Since 1958 • Maintainance Anaesthesia. • Child > Adult. • Low cost
- 47. SIDE EFFECTS 1) 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
- 48. SIDE EFFECTS 4) 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.
- 49. 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.
- 50. 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.
- 51. 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
- 52. 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.
Editor's Notes
- Our case is 42 yrs old female she has been operated for uterine fibroid 4 days prior to admission to our institute, at rajawadi hospital, since the next day of operation patient started getting mild fever and right upper quadrent abdominal pain , next day she started getting nausea and 3-4 episodes of non bilious non projectile vomiting and doctors noticed yellowish discolouration of skin esp. sclera, since one day she was having constipation.
- Asymptomatic prior 4 mo. No other c/o except sometimes excessive menses … h/o prior appendix operation Since last 4 months Some times even pain during coitus Senstion of fullness in abdomen
- Hepatitis is a disease of the liver characterized by the presence of inflammatory cells in the tissue of the organ. Hepatitis may occur without symptoms, but can lead to jaundice (a yellow discoloration of the skin,mucous membranes, and conjunctiva of the eyes), poor appetite, and fatigue. Acute hepatitis can be self-limiting(resolving on its own), can progress to chronic hepatitis, or can cause acute liver failure in rare instances. Scarring of Liver in case of Chronic Hepatitis is called as Cirrhosis. Worldwide, viral hepatitis is the most common cause, followed closely by alcoholic liver disease and non-alcoholic liver disease. Other less common causes of hepatitis include autoimmune diseases, ingestion of toxic substances, certain medications (such as paracetamol), some industrial organic solvents, and plants.
- Alcoholic hepatitis (AH) in its severe form has a one-month mortality as high as 50% Most people who develop AH are men but women are at higher risk of developing AH and its complications likely secondary to high body fat and differences in alcohol metabolism. Other contributing factors include younger age <60, binge pattern drinking, poor nutritional status, obesity and hepatitis C co-infection Obesity increases the likelihood of progression to cirrhosis in individuals with alcoholic hepatitis.[7] It is estimated that a high proportion of individuals (70%) who have AH will progress to cirrhosis.[7]
- Non-alcoholic steatohepatitis (NASH) is projected to become the top reason for liver transplantation by the year 2020, supplanting chronic liver disease due to hepatitis C.[6] About 20–45% of the U.S. population have NAFLD and 6% have NASH.[21][31] The estimated prevalence of NASH in the world is 3–5%.[112] Of NASH patients who develop cirrhosis, about 2% per year will likely progress to hepatocellular carcinoma.[112] Worldwide, the estimated prevalence of hepatocellular carcinoma related to NAFLD is 15–30%.[113] NASH is thought to be the primary cause of cirrhosis in approximately 25% of patients in the United States, representing 1–2% of the general population.
- Bacterial infection of the liver commonly results in pyogenic abscesses, acute hepatitis, or granulomatous (or chronic) liver disease.[23] Pyogenic abscesses commonly involve enteric bacteria such as Escherichia coli andKlebsiella pneumoniae and are composed of multiple bacteria up to 50% of the time.[23] Acute hepatitis is caused by Neisseria meningitidis, Neisseria gonorrhoeae, Bartonella henselae, Borrelia burgdorferi, salmonella species,brucella species and campylobacter species.[23] Chronic or granulomatous hepatitis is seen with infection from mycobacteria species, Tropheryma whipplei, Treponema pallidum, Coxiella burnetii, and rickettsia species.[23] Parasites can also infect the liver and activate the immune response, resulting in symptoms of acute hepatitis with increased serum IgE (though chronic hepatitis is possible with chronic infections).[22] Of the protozoans,Trypanosoma cruzi, Leishmania species, and the malaria-causing Plasmodium species all can cause liver inflammation.[22] Another protozoan, Entamoeba histolytica, causes hepatitis with distinct liver abscesses.[22]Of the worms, the cestode Echinococcus granulosus, also known as the small dog tapeworm, infects the liver and forms characteristic hepatic hydatid cysts.[22] The liver flukes Fasciola hepatica and Clonorchis sinensis live in the bile ducts and cause progressive hepatitis and liver fibrosis
- abnormal immune response against liver cells …genetic predisposition as it is associated with certain human leukocyte antigens….. circulating auto-antibodies…. Auto-antibodies found in patients with autoimmune hepatitis include the sensitive but less specific anti-nuclear antibody (ANA), smooth muscle antibody (SMA), and atypical perinuclear antineutrophil cytoplasmic antibody (p-ANAutoimmune hepatitis can also be triggered by drugs (such as nitrofurantoin, hydralazine, and methyldopa), after liver transplant, or by viruses (such as hepatitis A, Epstein-Barr virus, or measles) CA). Other autoantibodies that are less common but more specific to autoimmune hepatitis are the antibodies against liver kidney microsome 1 (LKM1) and soluble liver antigen (SLA)
- Genetic causes of hepatitis include alpha-1-antitrypsin deficiency, hemochromatosis, and Wilson disease.[21] In alpha-1-antitrypsin deficiency, a co-dominant mutation in the gene for alpha-1-antitrypsin results in the abnormal accumulation of the protein within liver cells, leading to liver disease.[38] Hemochromatosis and Wilson disease are both autosomal recessive diseases involving abnormal storage of minerals.[21] In hemochromatosis, excess amounts of iron accumulate in multiple body sites, including the liver, which can lead to cirrhosis.[21] In Wilson disease, excess amounts of copper accumulate in the liver and brain, causing cirrhosis and dementia.[21] When the liver is involved, alpha-1-antitrypsin deficiency and Wilson disease tend to present as hepatitis in the neonatal period or in childhood.[21] Hemochromatosis typically presents in adulthood, with the onset of clinical disease usually after age 50
- injury to liver cells due to insufficient blood or oxygen results in ischemic hepatitis (or shock liver).[14] The condition is most often associated with heart failure but can also be caused by shock or sepsis. Blood testing of a person with ischemic hepatitis will show very high levels of transaminase enzymes (AST and ALT). The condition usually resolves if the underlying cause is treated successfully. Ischemic hepatitis rarely causes permanent liver damage.[39]
- Many chemical agents, including medications, industrial toxins, and herbal and dietary supplements, can cause hepatitis.  Toxins and medications can cause liver injury through a variety of mechanisms, including direct cell damage, disruption of cell metabolism, and causing structural changes. Some drugs such as acetaminophen (paracetamol) exhibit predictable dose-dependent liver damage. isoniazid cause idiosyncratic and unpredictable reactions that vary among individuals.
- Acetaminophen can cause severe centrilobular hepatic necrosis when ingested in large amounts in suicide attempts or accidentally by children. Fatal fulminant disease is usually (although not invariably) associated with ingestion of 25 g. Acetaminophen is metabolized predominantly by a phase II reaction to innocuous sulfate and glucuronide metabolites; however, a small proportion of acetaminophen is metabolized by a phase I reaction to a hepatotoxic metabolite formed from the parent compound by the cytochrome P450 CYP2E1. This metabolite, N-acetyl-benzoquinone-imine (NAPQI), is detoxified by binding to "hepatoprotective"Â glutathione to become harmless, water-soluble mercapturic acid. the administration of sulfhydryl compounds (e.g., cysteamine, cysteine, or N-acetylcysteine) reduces the severity of hepatic necrosis. These agents appear to act by providing a reservoir of sulfhydryl groups to bind the toxic metabolites or by stimulating synthesis and repletion of hepatic glutathione.
- In 10% of adults treated with the antituberculosis agent isoniazid, elevated serum aminotransferase levels develop during the first few weeks of therapy In 1% of treated patients, an illness develops that is indistinguishable from viral hepatitis The disease may be severe, with a case-fatality rate of 10%. liver injury appears to be age-related, increasing substantially after age 35 A reactive metabolite of acetylhydrazine, a metabolite of isoniazid, may be responsible for liver injury rapid acetylators would be more prone to such injury
- associated with the development of severe hepatic toxicity and, rarely, fatalities, predominantly in children but also in adults. Asymptomatic elevations of serum aminotransferase levels have been recognized in as many as 45% of treated patients major hepatotoxicity is not seen in the majority of patients despite continuation of drug therapy examination of liver tissue reveals microvesicular fat and bridging hepatic necrosis, predominantly in the centrilobular zone sodium valproate is not directly hepatotoxic, but its metabolite, 4-pentenoic acid, may be responsible for hepatic injury. Hepatotoxicity ameliorated by IV administration of carnitine
- Minor alterations in liver tests are reported in 5% of patients treated with this antihypertensive agent …In 15% of patients with methyldopa hepatotoxicity, the clinical, biochemical, and histologic features are those of moderate to severe chronic hepatitis, with or without bridging necrosis and macronodular cirrhosis. for hepatotoxicity (primarily cholestasis and cholestatic hepatitis, but also hepatocellular injury).
- clinically important liver disease develops in <5% of patients The cationic amphiphilic drug and its major metabolite desethylamiodarone accumulate in hepatocyte lysosomes and mitochondria and in bile duct epithelium. liver injury resembling that seen in alcoholic liver disease is observed. The so-called pseudoalcoholic liver injury This category of liver injury appears to be a metabolic idiosyncrasy that allows hepatotoxic metabolites to be generated.
- The most important adverse effect associated with erythromycin, more common in children than adults occurrence of a cholestatic reaction Liver biopsy reveals variable cholestasis; portal inflammation comprising lymphocytes, polymorphonuclear leukocytes, and eosinophils The precise mechanism remains ill-defined
- The administration of oral contraceptive combinations of estrogenic and progestational steroids leads to intrahepatic cholestasis with pruritus and jaundice Especially susceptible seem to be patients with recurrent idiopathic jaundice of pregnancy, severe pruritus of pregnancy, or a family history of these disorders Liver biopsy reveals cholestasis with bile plugs in dilated canaliculi and striking bilirubin staining of liver cells The two steroid components appear to act synergistically on hepatic function, although the estrogen may be primarily responsible
- its occasional hepatotoxicity is being recognized with growing frequency. Its likelihood is unpredictable, but when it occurs, trimethoprim-sulfamethoxazole hepatotoxicity follows a relatively uniform latency period of several weeks and is often accompanied by eosinophilia, rash, and other features of a hypersensitivity reaction. Biochemically and histologically, acute hepatocellular necrosis predominates, but cholestatic features are quite frequent. Occasionally, cholestasis without necrosis occurs, and, very rarely, a severe cholangiolytic pattern of liver injury is observed The hepatotoxicity is attributable to the sulfamethoxazole component of the drug and is similar in features to that seen with other sulphonamides risk of trimethoprim-sulfamethoxazole hepatotoxicity is increased in persons with HIV infection
- Chlorpromazine is also a well known cause of acute cholestatic liver injury. Numerous instances of clinically apparent acute liver injury due to chlorpromazine have been reported in the literature, which is estimated to occur in 1:500 persons exposed. Chlorpromazine was formerly the most common cause of drug induced liver injury in the United States, but with the decrease in its use, chlorpromazine associated jaundice is now rarely reported. The clinical presentation and course are well defined. The onset of jaundice is usually within 1 to 5 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed (Case 1). Immunoallergic manifestations (fever, rash and eosinophilia) occur in some but not all cases, and these manifestations are usually mild and self-limited. Autoantibody formation is rare. Most importantly, chlorpromazine jaundice can be prolonged and associated with vanishing bile duct syndrome…The clinically apparent liver injury due to chlorpromazine is likely due to hypersensitivity, based upon the clinical features of a short latency period, fever, eosinophilia, and rapid recurrence upon reexposure.
- Halothane is 2-bromo-2-chloro-1,1,1-trifluoroethane. Halothane is a volatile liquid at room temperature. Because halothane is a light-sensitive compound that also is subject to spontaneous breakdown, it is marketed in amber bottles with thymol added as a preservative. Mixtures of halothane with O2 or air are neither flammable nor explosive
- Minimum alveolar concentration or MAC is the concentration of a vapour in the lungs that is needed to prevent movement (motor response) in 50% of subjects in response to surgical (pain) stimulus. MAC is used to compare the strengths, or potency, of anaesthetic vapours.
- Approximately 60-80% of halothane taken up by the body is eliminated unchanged by the lungs in the first 24 hours after its administration. A substantial amount of the halothane not eliminated in exhaled gas is biotransformed by hepatic CYPs. The major metabolite of halothane is trifluoroacetic acid, which is formed by removal of bromine and chlorine ions. Trifluoroacetic acid, bromine, and chlorine all can be detected in the urine. Trifluoroacetylchloride, an intermediate in oxidative metabolism of halothane, can trifluoroacetylate several proteins in the liver. An immune reaction to these altered proteins may be responsible for the rare cases of fulminant halothane-induced hepatic necrosis.
- 1.The most predictable side effect of halothane is a dose-dependent reduction in arterial blood pressure. Mean arterial pressure typically decreases ~20-25% at MAC concentrations of halothane. This reduction in blood pressure is primarily the result of direct myocardial depression leading to reduced cardiac output. 2.The decreased alveolar ventilation results in an elevation in arterial CO2 tension from 40 mm Hg to >50 mm Hg at 1 MAC (Figure 19–7). The elevated CO2 does not provoke a compensatory increase in ventilation, because halothane causes a concentration-dependent inhibition of the ventilatory response to CO2 3.Halothane dilates the cerebral vasculature, increasing cerebral blood flow and cerebral blood volume. This can result in an increase in intracranial pressure. Supress cerebral metabolism
- 1. Halothane causes some relaxation of skeletal muscle by its central depressant effects. Halothane also potentiates the actions of non-depolarizing muscle relaxants. Halothane and the other halogenated inhalational anesthetics can trigger malignant hyperthermia, a syndrome characterized by severe muscle contraction, rapid development of hyperthermia, and a massive increase in metabolic rate in genetically susceptible patients
- Halothane can produce fulminant hepatic necrosis in a small number of patients. This syndrome generally is characterized by fever, anorexia, nausea, and vomiting, developing several days after anesthesia and can be accompanied by a rash and peripheral eosinophilia. There is a rapid progression to hepatic failure, with a fatality rate of ~50%. This syndrome occurs in ~1 in 10,000 patients receiving halothane and is referred to as halothane hepatitis (Study, 1966). Current thinking is that halothane hepatitis is the result of an immune response to hepatic proteins that become trifluoroacetylated as a consequence of halothane metabolism
-  The severity and prognosis may relate in part of patient age, being more severe in the elderly and both milder and less common in children. Obesity may also be both a predisposing factor and predictor of outcome. Chronic liver injury from repeated halothane exposure has been described in health care workers repeatedly exposed to the agent, but the injury does not appear to lead to a chronic hepatitis if the exposure is terminated. Patients with halothane induced hepatitis should be cautioned against future exposure to a fluorinated hydrocarbon anesthetic such as isoflurane, enflurane, desflurane or sevoflurane.