Canonical Question
PainPharm – Non-Opiates
Master answer
Liver:
- Largest abdominal solid organ
- 25 % CO at rest. approx 1,500 mls/min
- 15% of total blood volume at rest
Functions of Liver
| Filtration | |
| Immune defence | (via Kuppfer cells) against agents entering the portal circulation |
| 80% of circulating cholesterol | → bile salt |
| Biliary excretion of drugs/hormones | penicillins, amp, erythro |
| thyroxine, cortisol, estrogen | |
| calcium | |
| Immune | |
| Filtration of portal circulation | |
| Kuppfer cells | bacteria/ virus/ endotoxins/ immune complexes/ thrombin/ tumour |
| Phagocytosed, fused with lysozomes and degraded by lysosomal enzymes | |
| Antigen presentation | |
| Endotoxin neutralisation = pinocytosed | |
| Complement/CRP production | |
| Storage of metabolic substrate/fluids | |
| glycogen ~ 400g | |
| fat | |
| Fe++, B12, folate, Cu | |
| Vitamin A | |
| Blood Reservoir | |
| Metabolic | |
| CHO and intermediary metabolism | Hepatic Glucostat |
| gluconeogenesis, glycogen storage and utilisation, galactose/fructose to glucose | |
| Conversion to fat, AA’s and ketones | |
| Protein metabolism | amino acids utilisation |
| protein synthesis | |
| production of ketones | |
| deamination of fatty acids | |
| urea formation for ammonia removal | |
| plasma protein formation | |
| Fat homeostasis | metabolism (beta oxidation (rapid in hepatic cells)), synthesis and transport as lipoprotein |
| cholesterol homeostasis | |
| Endocrine | hormone synthesis & metabolism |
| Synthesis of 25 OH cholecalciferol, Metabolism of steroid hormones, Synthesis of somatomedins, Erythropoietin | |
| biotransformation | ammonia & urea cycle |
| drugs & toxins | |
| Acid-Base | Lactate metabolism |
| Synthetic functions | |
| Bile production | bile salts (incr fat absorption) |
| bilirubin (incr haem excretion) | |
| Protein synthesis | albumin 120-300mg/kg/d |
| alpha1/2 & beta globulins (transport) | |
| coagulation & fibrinolytic factors (fibrinogen, prothrombin, II, V, VII,VII, IX, X, XI, XII, XIII, antithrombin) | |
| Lymph synthesis | Up to 50% |
| Erythropoietin (10%) | |
Gladwin / JC / Bianca 2019
Paracetamol Overdose
Hepatotoxicity
Toxic daily dose > 4-6 g (while lethal dose occurs at > 10-15 g (or > 300 mg/kg LBM)) → but the toxic and lethal doses are lower in “at-risk” groups:
- EtOH abuse (due to CYP450 induction (↑ toxic metabolite produced) and ↓ glutathione stores)
- Malnutrition (due to ↓ glutathione stores)
- Elderly (due to ↓ glutathione stores)
- Preexisting liver dysfunction
Mechanism:
- At therapeutic doses – “N-acetyl-p-amino-benzoquinoneimine” (highly toxic metabolite) is produced in small amounts, but is rapidly conjugated with hepatic glutathione (anti-oxidant) into a harmless metabolite
- BUT with toxic doses – Hepatic conjugation pathway is saturated and ↑↑↑ N-acetyl-p-amino-benzoquinoneimine is produced → this depletes hepatic glutathione stores, causing remaining N-acetyl-p-aminobenzoquinoneimine to then forms covalent bonds with sulphydryl groups on hepatocytes → results in centrilobular hepatic necrosis
Clinical features:
- Generally conscious and c/o N/V, epigastric pain, erythema, sweating → later developing:
- Acute haemolytic anaemia
- Develop hepatic failure (Ie. jaundice and cholestasis) after 48 hrs
- LFT/INR derangements at 3-5 days
- Fulminant hepatic failure at 3-7 days
- With severe OD, can present with hypotension/shock
Diagnosis :
Serum paracetamol levels → correlate with “nomogram” to predict likelihood of liver damage → used as a guide to dictate therapy
Treatment:
- Activated charcoal/gastric lavage→ limit paracetamol absorption
- Replace hepatic glutathione store within 12 hrs of OD → permits glucuronidation of toxic metabolite
- Oral methionine → ↑ glutathione synthesis
- IV N-acetylcysteine → hydrolysed to cysteine (which is a glutathione precursor)
- Nb. IV NAC is preferred b/c of N/V a/w toxicity (Ie. ↓ oral methionine absorption)
- IV glucose → due to risk of ↓ BGL with liver dysfunction
- Serial monitoring of LFTs and coagulation studies
- Referral to a specialist centre
Gladwin / JC / Bianca 2019
Exam appearances
| Exam | Exact wording | Relationship | Success |
|---|---|---|---|
| 2011B Q12 | List the functions of the liver (60% marks). Discuss the metabolism of paracetamol in toxicity and the pharmacologic management of this overdose (40% marks). | historical_member | 20.00% |