Hepato Toxicity

8/12/2019 Hepato Toxicity

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NAME/ID :SATHISWARAN ARUMUGAM 17328747SANDRA KUMARI JAGANADAN 17327952

SHOBA SEKARAN 17327716

SAKTHIRUBINI GOONASEKARAN 17327969

GROUP NAME : THE APOTHECARISTSUBJECT : PRACTICE & THERAPEUTICS B

LECTURER : MR. PRABHU & MDM.SASIKALA

PHA THB : CASE STUDY 6


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HEPATOTOXICITY INDUCED BY

DRUG


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INTRODUCTION

Hepatotoxicity is defined as injury to the liver that is associated with impaired liverfunction caused by exposure to a drug or any non infectious agents.

Factors :

Age Ethnicity and race Gender Nutritional status Underlying liver disease

Renal function Pregnancy Duration and dosage of drug Enzyme induction Drug-to-drug interaction


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Symptoms Nausea Vomiting Abdominal pain Loss of appetite Diarrhea

Tiredness Weakness Jaundice Yellow eyes Yellow skin Enlarged liver Abnormal liver function test results Swelling in feet Weight increase due to water retention Prolonged bleeding time


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Test

Liver function test Liver biopsy Urine test Blood test


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Treatments Discontinuation of causative medication, or removal from exposure to the

causative agent Monitoring of patient and regular review of liver function - where liver

dysfunction is mild to moderate, and liver function is improving Abstinence from alcohol and avoidance of medication that may contribute to

further liver damage N-Acetylcysteine for paracetamol toxicity Management of symptoms of liver dysfunction Nutrition - with vitamin supplementation as required Regular exercise to maintain muscle mass

Ursodeoxycholic acid Management of pruritus Cholestyramine Antihistamines


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Management of acute liver failure from hepatotoxicity Supportive care, often in and intensive care unit - airway protection, fluid

and electrolyte management Management of complications such as bleeding problems and hepatic

encephalopathy Liver transplantation - for acute fulminant liver failure or end stage

cirrhosis


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Non pharmacological

Anti oxidant Milk thistle Dandelion Grape fruit Raw tomato


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Miss OD is a 23 year old female, who is a casual employee at Big W andpresents to the ED with abdominal pain and nausea and vomiting. She hadrecently been to her GP for a chest infection for which she was prescribed acourse of Augmentin Duo Forte and adivised to take paracetamol for hercold that she told her would be good for her cough and stuffy nose.After 7 days she presented with a low-grade fever, nausea and vomiting andright upper quadrant pain. Bloods were taken for liver function tests andwere found to be grossly elevated. A serum paracetamol level was requestedalong with other blood tests including glucose, urea and creatinine.

When questioned she admitted to take paracetamol tablets regularly and theother tablets to help with her congestion and cough.It was estimated that she had taken 6 to 8g of paracetamol daily for the past5 to 7 days.Following the results of the blood tests she was commenced on N-acetylcysteine 9g diluted in 200ml of 5% glucose and infused intravenouslyover 60 minutes. She developed a rash and became a little breathless forwhich she was given promethazine 25 mg IM and salbutamol 5mg nebulised.The second dose of 3g in 500ml of 5% glucose was given over the next 6hours and the third dose of 6g in 100ml of % glucose given over the next 16hours


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Patient Name: Miss OD Age: 23 years old

Occupation: Casual Employee at Big W Weight: 60 kgPast Medical History: AsthmaticSocial History

Non-smokerModerate alcohol


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Chief Complain Abdominal painNausea and vomiting

Recently Chest pain Fever Cough Stuffy nose

Low-grade feverNausea and vomiting

Right upper quadrantpain After 7 days


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OBJECTIVE Current medication:

Salbutamol inhaler Augmentin Duo ForteParacetamol tablets

Codral Cold and Flu tablets

Past Medication Microgynon 30ED Seretide 250/25

Vital signsHeart rate : 100bpmBlood pressure : 100/65HgWeight : 60kg


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Blood pressure is normal range.


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Analyte Normal range Result Remarks

ALT 8-40u/L 1500u/L Elevated

INR 0.8-1.2 1.8 Elevated

Creatinine 60-120 mol/L 105 mol/L Normal

Urea 3.8-9.6mmol/L 7.6mmol/L Normal

Glucose


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Normal creatinine, urea, glucosenormal renal function

Any more than 6g or 150mg/kg of Paracetamol dailyOver dose (Toxic)

Serum ALT levels greater than 1000 U/LIndication of severe hepatic injury .

Elevated INRIndicates Paracetamol toxicity

Serum Paracetamol >(90mg/L)Treatment is essential


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Factors that might have increased the risk of liver injury in patientinclude: Concurrent drugs ( Codral Cold and Flu tablets)

Not recommended for asthmatic patients.


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PLANNING


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C: AcetaminophenI: Headache, fever, pain,

discomfort due to cold&flu,dentalSP: Renal & Hepatic failureMax dose: 8 tabs/day or 4

gramOver dosage:1) no symptomsin first 24hr2) Vague abdominal pain&nausea3) Sign of liver failure, low BP,low blood pH, easy bleeding,right upper quadrant pain ,hepatic encelophalopathy

STOP TAKING / GIVINGTHIS


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C:Paracetamol,pseudoephedrine, Codeine phosphate

I: Strong body aches & pain,sorethroat,headaches,fever,blockednose,runny noseDO NOT take when: any

medicine containingparacetamol ,pseudoephedrine,codeine phosphateDO NOT take when you have:

high blood pressuresevere coronary artery diseasetaken MOAinhibitors,bronchitis, unstable asthma

emphysema

chronic constipation

C: loratadine 5mg,pseudoephedrine sulfate120mgI: relieve nasal congestioncaused by colds, allergies,and hay feverCI: MAOI, narrow-angleglaucoma, urinary retention,severe HTN, severe coronaryartery disease,hyperthyroidism


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C: amoxicillin and clavulanatepotassium

I: short-course treatment ofbacterial infections caused bysusceptible bacteriaCI: Hepatic dysfunction

SP: Renal and hepaticimpairmentAR: Diarrhea, indigestion,nausea, vomiting, rash,hepatitis, toxic epidermalneccrolysis, haemolyticanaemia, CNS disturbancesDI: aminoglycosides,anticoagulants, OC

It is IMPORTANT to finish upthe course Stopping it too soon couldlead to the development ofmedication-resistant bacteria.


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C: salmeterol 25mcg,fluticasone propionate 250mcgI: treat reversible obstructiveairways disease, such as

asthma and COPDSP: not for acute, unstable oracutely deteriorating asthma

To be continued


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C:Levonorgestrel 150mcg,

ethinylestradiol 30mcgI: OCCI: pregnancy, severedisturbances of liver function,

jaundice or severe pruritus,Dubin-jonson, previous orexisting liver diseaseSP: diabetes, HTN, benign&rarely malignant liver tumours,

liver enlargement, a livertumour

Stop for at least one or twocycles Monitor LFT Can continue once LFT hasbecome normal

EMERGENCY CONTRACEPTIONC: levonorgestrelI: Taken within 72 hr


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NON-PHARMACOLOGICAL TREATMENTFOR ASTHMA

a) Breathing exercise- Take breaths less often Take slower breaths Breathe through your nose rather than yourmouth Use your abdominal muscles to take deep"belly breaths" (diaphragmatic breathing)

A few breathing techniques Buteyko breathing technique

yoga breathing (pranayama ).


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b) Inspiratory muscle training helps strengthen lung muscles with a series of breathingexercises used for other lung diseases, such as chronic obstructivepulmonary disease (COPD), and after certain types of surgery

C) Vitamins and supplements

Antioxidants. People with severe asthma appear to havedecreased levels of these protective nutrients found in fruitsand vegetables. Antioxidants such as vitamin C, vitamin A andmagnesium may have some effect on asthma by boosting theimmune system.


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Omega-3 fatty acids. Reduce the inflammation that leads toasthma symptoms. Found in fish.

Vitamin D. Some people with severe asthma have a vitamin Ddeficiency. Researchers are exploring whether vitamin D mayreduce asthma symptoms in some people


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NON-PHARMACOLOGICAL TREATMENTFOR LIVER DAMAGE

Simephar Milk thirstle

alpha-lipoic acid antioxidant STOP ALOCHOL


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Q1.What is the mechanism for paracetamol overdose in causinghepatic necrosis and describe what symptoms are predictive ofthis presentation?

When taken in normal therapeutic doses, paracetamol has been shown to

be safe. Following a therapeutic dose, it is mostly converted to nontoxic

metabolites via Phase II metabolism by conjugation with sulfate andglucuronide, with a small portion being oxidized via the cytochrome P450

enzyme system. Cytochromes P450 2E1 and 3A4 convert approximately

5% of paracetamol to a highly-reactive intermediary metabolite, N-acetyl-

p-benzoquinoneimine (NAPQI). Under normal conditions, NAPQI is

detoxified by conjugation with glutathione to form cysteine and

mercapturic acid conjugates.


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In cases of paracetamol overdose, the sulfate and glucuronide pathways

become saturated, and more paracetamol is shunted to the cytochrome

P450 system to produce NAPQI. As a result, hepatocellular supplies of

glutathione become depleted, as the demand for glutathione is higherthan its regeneration. NAPQI therefore remains in its toxic form in the liver

and reacts with cellular membrane molecules, resulting in widespread

hepatocyte damage and death, leading to acute hepatic necrosis.

h h f l d


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Question 2: What is the management of paracetamol overdoseand describe mechanism of the antidote and the rationale for theduration of therapy along with any complications of suchtherapy?

First treat with activated charcoal if overdose occur within anhour

If overdose occurs for more than 24 hours, patient is admittedinto hospital and given N-acetylcysteine

Antihistamine and salbutamol should be given to patient ifpatient has asthma

Fluid replacement for nausea and vomiting treatment

Surgery for liver transplantation if patient gets worse


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Ample supplies of GSH, are secured by NAC cysteineadministration, this ensure that NAPQI will bind to thethiol groups of GSH instead of binding to hepatocytes

thiol group bound to NAPQI, produces cysteine andmercapturic acid conjugates, which are no longerreactive and pose less danger to the liver cells

NAC seems to increase the sulfation of Acetamenophento nontoxic metabolites and may reverse the formationof NAPQI

Improved oxygen delivery by means of increasedhepato-splanchnic circulation and increased oxygenextraction have been proposed as mechanisms to explainimproved outcomes of late presenters


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Rationale for the duration of therapy along withany complications of such therapy

Most effective when started early based on history of toxicacetamenophen doseBetter survival rateFewer complication

Next few hoursCheck risk and blood test Add acetylcysteine dose if plasma paracetamol level is above thelines on nomogram

Continues until acetamenophen level are no longer detectableTo ensure patient is no longer in danger or risk of liver failureIf plasma paracetamol remains the same, perform surgery for livertransplantation


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Q3. How is the potential toxicity assessed and what monitoring isneeded in the management of the condition including any follow-up assessment?

2 types of assessments- susceptibility assessment (patientsrisk of toxicity)

- dose assessment (estimate the dose

ingested)

SUSCEPTIBILTY ASSESSMENT


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SUSCEPTIBILTY ASSESSMENTa) 6 to 8g of paracetamol daily for th past 5 to 7 days

Max 4g per day/1500mg in the effective one) A dose of 6g per day over the preceding 48 hours couldpotentially lead to toxicity

b) LFT. ALT level increase about three times the normal value,the increasing liver damage alters biochemical markers of

liver function ALT 1500u/L ( 8-400 u/L)- paracetamol inducedhepatoxicity

c) Risk factor: alcohol consumption can induce CYP2E1, thus increasing the potential toxicityof paracetamol

d) Glucose: hypoglycaemia is common in hepatic necrosis &capillary blood glucose should be checked regularly


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Management and follow-up assessment AST,ALT, bilirubin, BU, prothrombin time & creatinine

should be done daily for 3 days It is important to monitor or signs and symptoms of

hepatic failure and provide appropriate supportive care NAC is usually continued if blood test are still significantly

abnormal after the first course

Prior to discharge it is sensible to re-check the INR, renaltests and LFT. Patient should be adviced to return if vomitingoccurs after discharge


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Q4. How is this presentation different to an acute ingestion of PanadolOsteo and what additional information needs to be obtained fromthe patient to assist management?

The Paracetamol Osteo contain 665mg of acetaminophen. Panadol Osteo

is a sustained release formulation that can provide long-lasting relief from

persistent pain such as that associated with Osteoarthritis. Panadol Osteo

can be a convenient choice, containing a higher dose of paracetamol thanregular Panadol tablets. With only 3 daily doses, each lasting up to 8

hours. So the extend of damage might occur in short period of time.

The additional information need to be obtained from patient the period of

time patient had been taking Panadol Osteo, frequency of ingestion and

any other drugs taken for other health condition, any alcohol

consumption to identify any possible drug interaction.


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ALT elevations (>1,000 U/L)

Jaundice or even mildhyperbilirubinemia (bilirubin >2xULN)

Increased plasma prothrombin time, orits international normalized ratio

(INR)- a consequence of reduced hepaticproduction of Vitamin K-dependentclotting factors

Potentially useful measure of liver function that might suggest the

potential for severe liver injury :


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Extra Questions


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1)Which of the following are the symptoms that follows in druginduced hepatotoxicity?

a)Nauseab)Swelling in feetc)Prolonged bleeding timed)All the above

2)Which one of the following is not the pharmacological treatment fordrug induced hepatotoxicity?

a)Antioxidantsb)Antihistaminesc)Acetoaminophend)Cholestyramine

Reference


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Reference http://emedicine.medscape.com/article/820200-treatment http://www.who.int/selection_medicines/committees/subcommittee/2/a

cetylcysteine_rev.pdf http://www.patient.co.uk/doctor/paracetamol-poisoning http://www.npis.org/paracetamolposter.pdf https://www.mja.com.au/journal/2008/188/5/guidelines-management-

paracetamol-poisoning-australia-and-new-zealand-explanation?0=ip_login_no_cache%3D2028eabeb075d33d4bdbc7e9f95c8

4f9 http://www.collemergencymed.ac.uk/Shop-

Floor/Clinical%20Guidelines/Clinical%20Guidelines/Paracetamol%20Overdose/

http://emj.bmj.com/content/19/3/202.full http://www.bmj.com/content/342/bmj.d2218?utm_content=1150708638

&utm_medium=email&utm_campaign=101217&keytype=ref&utm_source=Emailvision&siteid=bmjjournals+&ijkey=xX0nExX6P9oIA http://www.imvs.sa.gov.au/wps/wcm/connect/5eebbd49-e07b-421b-

9034-bcd076e3eebe/Paracetamol+overdose.pdf?MOD=AJPERES


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Hepato Toxicity

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