Liver- Flashcards
What is first pass metabolism?
- Orally administered drugs that are absorbed travel through the portal system and the liver before entering systemic circulation
- If a percentage of the drug is metabolised by the liver only the remainder of that drug will be able to enter systemic circulation to exert its effect (reduced bioavailability)
- requires a larger dose orally than parenterally
Metabolism
- The process of chemical modification of a drug
- Mainly via enzymes
- Liver primary site of metabolism
- other sites include: kidneys, lungs, intestines
- For the majority of drugs metabolism results in the formation of a more water-soluble compound or metabolite that can be more readily excreted
- clears the parent compound from circulation and promotes excretion
Prodrug - drugs that require activation (metabolism) to elicit a therapeutic action
**CYP enzymes
- CYP enzymes responsible for Phase 1 (functionalisation) metabolism
- CYP enzymes found in the smooth endoplasmic reticulum
- Abundant in hepatocytes
- More than 50 varieties. Three main families
- Genetic polymorphisms occur altering clearance of particular medications
- Responsible for many drug interactions
- Liver disease can effect the performance of these enzymes
Hepatic clearnace
- Depends on hepatic blood flow (Q) and extraction ratio (EH)
- Hepatic extraction ratio (EH):
- the fraction of drug entering the liver in the blood that is irreversibly removed by metabolism on each pass through the liver. (0.7 = 70% removed)
- Hepatic clearance (Cl)= Q. EH
- Hepatic clearance can be:
- low extraction:
- clearance capacity by limited by liver enzymes to clear drug (clearance is independent of blood flow)
- high extraction
- clearance capacity limited by delivery of drug to the liver (blood flow)
- low extraction:
Cause of AKI
- Viral cause
- Hepatitis A, B, C, D, E; cytomegalovirus, Epstein- Barr virus, yellow fever
- other infective causes
- leptospirosis, syphilis
- non-infective causes
- auto-immune
- drug-induced
- metabolic eg Wilson disease
Viral hepatitis
Acute:
- supportive care
- sometimes antiviral therapy
- monitoring of liver function (INR is most readily available measure marker)
Chronic:
- Major cause of advanced liver disease and hepatocellular carcinoma. Usually hepatitis B or C
Hepatitis A
- Acute disease and does not progress to chronic.
- Vaccination or previous exposure provides long-term immunity
- Symptoms are non-specificand include anorexia, nausea, vomiting, abdominal pain and mild fever. Jaundice may not be a feature, especially in the young.
Hepatitis B
- Acute:
- Less than 1% infected develop acute liver failure
- Chronic
- All patients who are HBsAg positive should be fully assessed to determine the stage of disease, and regularly reassessed over the course of their infection.
- Antiviral treatment is directed at patients in theimmune clearancephase (phase 2);and theimmune escapephase (phase 4)
Hepatitis B treatment
- Aim is prolonged suppression of viral replication - preferably undetectable HBV-DNA. Ultimately HBsAg seroconversion is the goal, but infrequently achievable.
- two main drug classes used to treat hepatitis B include: interferon (rarely prescribed due to compliance) and nucleoside/nucleotide analogues
Nucleoside analogues
Nucleoside analogues (entecavir) and nucleotide analogues (tenofovir) - mainstay of Hep B treatment
- Entecavir: Guanosine analogue inhibiting hepatitis B polymerase preventing viral DNA synthesis
- Tenofovir: inhibits viral polymerases and terminates the DNA chain after incorporation into viral DNA
- easy oral administration
- Well tolerated and high barrier to resistance
- Often required life-long
Interferon
(peginterferon alfa-2a) - not commonly used in practice
- Not recommended in cirrhosis due to risk of hepatitis exacerbation and hepatic decompensation
- Weekly injection and more side effects than oral therapy
- No drug resistance
- Defined treatment duration (48 weeks)
- Antiviral and immunomodulator activity
HepC treamte
- To achieve a sustained virologic response (SVR), ie. virus undetectable 12weeks after finishing treatment; this indicates treatment success (cure)
- The newinterferon-free antiviral regimens use combinations of direct-acting antiviral drugs.
- cure rate >95%
- highly effective and well tolerated
- significant drug interactions. Drug interactions are particularly relevant for patients receiving concomitant treatment for HIV. Always take a detailed medication history, including non-prescribed medications, to check for interactions.
Targets of direct acting antivirals for Hepatitis C
- Protease Inhibitors (…previr)
- A virus-specific proteaseconverts polyproteins into various structural and functional proteins.
- The protease does not occur in the host, and isuseful target for therapy
- Nucleotide (NS5B) polymerase inhibitor (…buvir)
- Non-nucleotide (NS5B) polymerase inhibitor (…buvir)
- NS5A inhibitors (asvir)
sUMMARY of AKI causes
- Viral causes
- Hepatitis A, B, C, D, E; cytomegalovirus, Epstein- Barr virus, yellow fever
- other infective causes
- leptospirosis, syphilis
- non-infective causes
- auto-immune
- drug-induced
- metabolic eg Wilson disease
D
DILI
Drug-induced liver injury (DILI) is almost certainly underdiagnosed. DILI can be difficult to identify because there may be a long period (latency) between exposure to the drug and onset of symptoms or abnormal liver biochemistry.
For any patient with abnormal liver biochemistry consider a drug cause (including herbal and dietary supplements, and complementary and alternative therapies)
- check for reports of hepatotoxicity caused by any of the patient’s medications
- Stop drugs if possible, and exclude other causes of liver dysfunction
- Monitor blood tests until there is clinical and biochemical evidence of improvement.
- Do not rechallenge with a drug suspected of causing DILI because the recurrent injury may be more severe.
- Up to 20% of DILI cases are associated with herbal and dietary supplements
- Paracetamol is the most common cause of severe DILI (Dose related and predictable)
- Pharmacological risk factors for DILI include:
- Drug factors: dose, lipophilicity and extent of hepatic metabolism of the drug.
- Patient factors:age, gender [F>M], genetic predisposition, pre-existing liver damage, alcohol intake, obesity, fasting/malnutrition)
- Idiosyncratic hepatotoxicity is unpredictable, not dose-related, and can occur at any time after exposure (or re-exposure) to a drug.
DILI classification and symps
Classification
Hepatocellular
Cholestatic
Mixed - many drugs cause this
Symptoms
Malaise, abdominal pain, jaundice
Jaundice, pruritus
Any of the above
LFT picture
Elevated ALT and AST
Elevated ALP and GGT
Mixed pattern of liver dysfunction, resulting in elevated ALT and ALP concentrations.
Paracetamol poisoning
Paracetamol poisoning is common and the treatment of the majority of acute overdoses is well-defined.
Potential for toxicity with a single ingestion of 10 g or 200 mg/kg (whichever is less)
N-acetylcysteine (NAC) is the antidote and if administered appropriately (timely and appropriate dosing)it maypreventhepatotoxicity completely
Whennormal conjugation reactions are saturated, the drug is metabolised instead by mixed function oxidases. The resulting toxic metabolite,N-acetyl-_p_-benzoquinone imine (NABQI), is normally inactivated by conjugation with glutathione, but when this is depleted the toxic intermediate accumulates in the liver and the kidney tubules and causes necrosis.
Paracetamol metabolism:
- depletes glutathione stores
- if glutathione levels are 30% of normal, NAPQI levels rise and cause damage
- NAC ‘replaces’ glutathione
