Lecture 14: Pharmacology of Drug Treatment in the Liver

Question 1

what do LFTs (liver profiles) measure

Answer 1

measure serum levels of liver enzymes

Question 2

what does elevated ALP/GGT indicate

Answer 2

obstructive (cholestatic) condition e.g. PSC, PBC, biliary obstruction

Question 3

what does elevated AST/ALT indicate

Answer 3

hepatitic condition i.e. hepatitis

Question 4

what is the most common cause for isolated T. bilirubin

Answer 4

Gilbert’s disease

Question 5

why might a very cirrhotic liver give a relatively normal liver profile

Answer 5

not enough hepatocytes to release any transaminases (enzymes) anymore

Question 6

what liver functions are measured in a liver profile

Answer 6

• protein formation of albumin

- prothrombin time/INR –> good measure of vit K activity of coagulation factors

Question 7

name 3 reasons albumin levels might decrease

Answer 7

• not enough in diet
• losing albumin in gut and kidneys
• liver not making enough albumin

Question 8

what is the bioavailability of a drug

Answer 8

the fraction of the drug that makes it through the gut wall, through the portal system and into the liver, then eventually through to the SYSTEMIC SYSTEM

Question 9

what is meant by phase 1 reactions? what is its purpose?

Answer 9

preparation reaction carried out by large isoenzyme family (74) of CYP450 monooxygenase –> catalyse redox or hydrolytic reactions to a molecule to form more chemically reactive products

• may be pharmacologically active
• may be toxic/carcinogenic

enables easy conjugation of a substituent group (phase 2 reaction) to make the molecule more water soluble and ready for excretion

Question 10

name the enzyme enducers

Answer 10

PC BRAGS

• phenytoin
• carbamazepine/cigs
• barbituates (brussel sprouts)
• rifampicin
• alcohol
• glucocorticoids
• St John’s Wort

Question 11

how can water-soluble molecules be eliminated

Answer 11

in bile and urine

Question 12

how do enzyme inducers work

Answer 12

work at a genetic level –> induce hepatocytes at a nuclear level to transcribe more CYP450s –> takes time to impact likewise takes time to calm down

• more catalytic enzymes –> faster processing of molecules

Question 13

what are phase 2 reactions

Answer 13

conjugation of water-soluble moiety to another molecule, making the original molecule change its shape, structures and function…it becomes more water soluble (polar)

• tends to reduce activity of original parent compound

Question 14

substitute groups conjugated in phase 2 reactions

Answer 14

• glucuronyl
• sulfate
• methyl
• acetyl
• glycyl

Question 15

what enzymes carry out conjugation reaction of phase 2

Answer 15

transferase enzymes

Question 16

summarise liver drug metabolism

Answer 16

• drugs undergo phase 1 and 2 reactions
• phase 1 CYP450 monooxygenases create more reactive molecule
• phase 2 conjugation sticks water soluble (polar) moiety onto molecule to enable excretion in bile or urine

Question 17

what enzymes do hepatotoxic drugs tend to affect most

Answer 17

transaminases ALT and AST

Question 18

name some common hepatotoxic drugs

Answer 18

• alcohol
• excessive paracetamol
• statins
• methotrexate
• amiodarone
• chlorpromazine (obstructive jaundice)
• halothane (immune mediated)
• isoniazid

Question 19

what is the most common cause of drug induced liver failure

Answer 19

paracetamols

Question 20

how does paracetamol cause liver failure

Answer 20

in excessive doses (overdose) usual conjugation pathways become overwhelmed and remaining paracetamol is oxidised into toxic metabolite NAPBQI (N-Acetyl-p-benzoquinoneimine)

• normal doses safe

Question 21

manifestations of cirrhosis

Answer 21

• ascites
• encephalopathy
• coagulation
• spider nevi
• hepatorenal syndrome
• varices/ portal hypertension

Question 22

define ascites

Answer 22

build up of fluid in abdominal cavity

Question 23

name the system for determining how severe their cirrhosis is

Answer 23

Child-Turcotte-Pugh Scoring System

• Child class A –> 5-6points
• Child class B –> 7-9points
• Child class C –> 10-15points

Question 24

name some non-pharmacological treatments for ascites

Answer 24

• sodium restriction
• paracentesis
• bonnano catheter
• transjugular intrahepatic portosystemic shunt (TIPS)

Question 25

name a pharmacological treatment for ascites

Answer 25

diuretics

Question 26

name two diuretics used for ascites treatment and their MoA

Answer 26

• spironolactone –> blocks the aldosterone receptor in distal tubule
• furosemide –> loop diuretic; inhibits Na/K/2Cl carrier in luminal membrane in Loop of Henle

work together very well

Question 27

outline some possibilities for hepatic encephalopathy

Answer 27

• excess ammonia from bacteria in GIT not being converted to urea therefore making it into systemic circulation
• excess GABA (neuroinhibitory substance) or neurosteroids building up in brain

Question 28

outline some treatment methods for hepatic encephalopathy

Answer 28

• treat precipitant –> avoid high protein meals, avoid GI bleeding, avoid constipation (large doses of lactulose - reduce time bacteria has to make ammonia and inhibits formation of ammonia)
• treat malnutrition –> high doses of thiamine, vit B and C to protect brain - Pabrinex
• antibiotics –> if pain in abdomen and suspect spontaneous bacterial peritonitis
• hepa merz (L-ornithine-L-aspartate) –> dietary supplement that promote urea reduction

Question 29

define cirrhosis-related coagulopathy

Answer 29

increased prothrombin time

Question 30

how is coagulopathy treated

Answer 30

treated w/ vit k (phytomenadione) or if bleeding give prothrombin complex (activated clotting factors)

Question 31

name on issue of hepatorenal syndrome

Answer 31

splanchnic vasodilatation (decreased vascular resistance) which increase portal hypertension, changing direction of blood flow away from kidneys

Question 32

outline a treatment for hepatorenal syndrome

Answer 32

can use ADH receptor selective vasoconstriction to redirect blood flow and reduce splanchnic vasodilatation