Drugs and the liver

Question 1

What is bioavailability/ the first pass effect?

Answer 1

Drug given po, absorbed through gut, metabolised in liver (phases 1 and 2)
bioavailability is that which gets through hepatic system, rest excreted out

Question 2

Phase 1 metabolism reactions

Answer 2

CYP450 (redox catalysis) m.oxygenase inhibitors
74 haem protein isoenzymes
Designated CYP450 2D6, 3A4 etc
Overlapping substrate specificities
Large genetic/ species/ environmental activity variation

Question 3

Characteristics of phase 1 reactions

Answer 3

Drug A may increase metabolism of drug B:
use redox and hydrolysis, may be pharm. active or toxic/carcinogenic to form more chem. reactive products
Enables easy joining for P2 (PRIMERS) to make molecule more water sol (ready for excretion)

Question 4

PC BRAGS- enzyme inducers ( ^ synthesis or dec. breakdown of CYP isoenzymes)

Answer 4

Phenytoin
Carbamazepine/ cigs
Barbituates/ brussel sprouts
Rifampicin
Alcohol
Glucocorticoids
St John's wort

Question 5

Phase 2 reactions

Answer 5

conjugate almost always inactive- substitute groups: Glucuronyl, sulphate, methyl, acetyl,glycyl (water sol moieties)
More polar, excreted bia urine or bile

Question 6

What sort of molecules do P1 CYP450 monooxygenases and P2 Conjugation create?

Answer 6

P1- “Sticky” molecules- more reactive

P2- polar (water soluble) moiety onto the molecule to enable excretion (urine/ bile)

Question 7

What are some examples of hepatotoxic drugs?

Answer 7

AST ^ > hepatitis > liver failure
alcohol, XS paracetamol, isoniazid, statins, methotrexate, amiodarone, chlorpromazine (obstructive jaundice), halothane (immune mediated)

Question 8

Why is paracetamol dangerous in excess?

Answer 8

Usual conjugation pathways become overwhelmed and remaining paracetamol oxidised to toxic metabolite NAPBQI by CYP450 oxidation, causes hepatic and renal damage when no glutathione

Question 9

What are the signs of cirrhosis?

Answer 9

Ascites in peritoneum, encephalopathy, coagulopathy, hepatorenal syndrome, varices/ portal HT
Muscle atrophy

Question 10

What are some non-pharmacological measures in the treatment of ascites?

Answer 10

Sodium restriction, paracentesis > bonnano catheter, transjugular intrahepatic portosystemic shunt (TIPS)

Question 11

How do diuretics help in the treatment of ascites?

Answer 11

Spironolactone- blocks aldosterone receptor in distal tube (hypoaldosteronism)
Furosemide- Loop diuretic, inhibits Na/K/2Cl carrier in luminal LOH membrane

Question 12

What causes hepatic encephalopathy?

Answer 12

XS ammonia from bacteria in GIT not being converted to urea > systemic circulation
XS gaba (neuroinhibitory substance) or neurosteroids building up in brain

Question 13

How to treat hepatic encephalopathy?

Answer 13

Treat precipitant e.g metabolic disturbances, GI bleeding, infection, constipation
Lactulose, stim passage of ammonia from tissue into gut lumen and inhbits intestinal ammonia production
Malnutrition- thiamine, riboflavin, pyridoxine and ascorbic acid

Question 14

What medication to administer to those suffering from hepatic encephalopathy?

Answer 14

Antibiotics- rifaximin: GIT bacteria, blocks RNA transcription: reduces frequency of episodes
Hepa merz (L-ornithine- L- aspartate)- important substrates in urea > ammonia

Question 15

Hepatorenal syndrome

Answer 15

Multifactorial- 1 is splanchnic vasodilation ( red. vasc. res)
limited succesful treatments, difficult fluid balance
some success w vasopressin (adh) anaolgues eg terlipressin