Lecture 14: Pharmacology of Drug Treatment in the Liver Flashcards
what do LFTs (liver profiles) measure
measure serum levels of liver enzymes
what does elevated ALP/GGT indicate
obstructive (cholestatic) condition e.g. PSC, PBC, biliary obstruction
what does elevated AST/ALT indicate
hepatitic condition i.e. hepatitis
what is the most common cause for isolated T. bilirubin
Gilbert’s disease
why might a very cirrhotic liver give a relatively normal liver profile
not enough hepatocytes to release any transaminases (enzymes) anymore
what liver functions are measured in a liver profile
- protein formation of albumin
- prothrombin time/INR –> good measure of vit K activity of coagulation factors
name 3 reasons albumin levels might decrease
- not enough in diet
- losing albumin in gut and kidneys
- liver not making enough albumin
what is the bioavailability of a drug
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
what is meant by phase 1 reactions? what is its purpose?
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
name the enzyme enducers
PC BRAGS
- phenytoin
- carbamazepine/cigs
- barbituates (brussel sprouts)
- rifampicin
- alcohol
- glucocorticoids
- St John’s Wort
how can water-soluble molecules be eliminated
in bile and urine
how do enzyme inducers work
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
what are phase 2 reactions
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
substitute groups conjugated in phase 2 reactions
- glucuronyl
- sulfate
- methyl
- acetyl
- glycyl
what enzymes carry out conjugation reaction of phase 2
transferase enzymes
summarise liver drug metabolism
- 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
what enzymes do hepatotoxic drugs tend to affect most
transaminases ALT and AST
name some common hepatotoxic drugs
- alcohol
- excessive paracetamol
- statins
- methotrexate
- amiodarone
- chlorpromazine (obstructive jaundice)
- halothane (immune mediated)
- isoniazid
what is the most common cause of drug induced liver failure
paracetamols
how does paracetamol cause liver failure
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
manifestations of cirrhosis
- ascites
- encephalopathy
- coagulation
- spider nevi
- hepatorenal syndrome
- varices/ portal hypertension
define ascites
build up of fluid in abdominal cavity
name the system for determining how severe their cirrhosis is
Child-Turcotte-Pugh Scoring System
- Child class A –> 5-6points
- Child class B –> 7-9points
- Child class C –> 10-15points
name some non-pharmacological treatments for ascites
- sodium restriction
- paracentesis
- bonnano catheter
- transjugular intrahepatic portosystemic shunt (TIPS)
name a pharmacological treatment for ascites
diuretics
name two diuretics used for ascites treatment and their MoA
- 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
outline some possibilities for hepatic encephalopathy
- 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
outline some treatment methods for hepatic encephalopathy
- 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
define cirrhosis-related coagulopathy
increased prothrombin time
how is coagulopathy treated
treated w/ vit k (phytomenadione) or if bleeding give prothrombin complex (activated clotting factors)
name on issue of hepatorenal syndrome
splanchnic vasodilatation (decreased vascular resistance) which increase portal hypertension, changing direction of blood flow away from kidneys
outline a treatment for hepatorenal syndrome
can use ADH receptor selective vasoconstriction to redirect blood flow and reduce splanchnic vasodilatation
