Pharmacogenetics + Hepatic Disease Flashcards
What are the two routes of hepatic clearance?
- Metabolism (phase I, phase II) in hepatocytes
- Excretion in bile
What does induction of drug metabolism cause?
Clint = vmax/Km
Increase Vmax = Increase Clint
- Effect is gradual (days to weeks) and reversible ( can be slower to reverse)
What does inhibition of drug metabolism cause? How is it different between non-competitive and competitive
Clint = Vmax/Km
- No change in the amount of enzyme but reduced amount of available enzyme
Non-competitive (block)
- Decreased Vmax = decreased CLint
Competitive affinity
-Increased Km = decreased CLint
For CLint = Vmax /Km
What does Vmax and Km mean?
Vmax = maximum rate of drug elimination
Km = affinity of drug for enzyme
What are some normal liver functions?
- Plasma protein production
- Clotting factor synthesis
- Bile production
- Bilirubin conjugation & excretion
- Enterohepatic circulation of bile salts
- Hormone inactivation
- Metabolism & excretion of drugs & toxins
What are some examples of liver disease and dysfunction? What are some causes?
- Hepatocellular disease – hepatitis, cirrhosis, fibrosis
- Cholestasis
causes include
- alcohol
- viral infections
- drugs and toxins
What are some standard liver function tests?
- Transaminases (ALT, AST)
- Alkaline phosphatase
- Bilirubin (conjugated & unconjugated)
- Albumin (& AAG)
- Clotting screen
What two types of liver function tests are used for PK evaluation? How are changes in these tests significant?
Transaminases: Increased ALT reflects hepatocyte damage (may indicate impairment of metabolism)
Albumin: Decreased albumin reflects reduced synthetic capacity (may be best reflection of drug handling)
How does liver disease have an impact on PK in the following scenarios;
A) Absorption
B) Distribution
C) Elimination (how does cirrhosis affect elimination)
A)
- Decreased first pass loss (Increased AUC and plasma concentrations)
B)
- Protein binding –> decreased albumin may result in increased free fraction (fu)
C)
Related to liver blood flow and/or enzyme function
Cirrhosis
- Altered architecture = increased vascular resistance = decreased blood flow (decreased drug access to hepatocytes)
- Hepatocyte loss and reduced function = decreased intrinsic clearance
What are some patient factors that have an effect on CLhepatic?
Induction = increased metabolism
Gender
- No significant difference (corrected for body weight)
Ethnicity
- Polymorphisms
Age
- 5-10% decline in blood flow per decade
- Enzyme activity unchanged but O2 limitations related to blood flow
- Immature Phase I & II in neonates
Hormones
- Thyroid –> hyperthyroidism –> increased clearance of some drugs (e.g., paracetamol)’
Diet
- BBQs & cruciforms = induction of metabolism
Alcohol
- Induction (early)
- Decreased metabolism (late)
Smoking
- Induction
What is the significance of genetic factors in drug clearance?
- Drug efficacy
- Adverse effects
- Drug interactions
What type of distribution does some P450 metabolism processes have?
Bimodal distribution but not all are due to decreased amounts of enzymes
What are some examples of phase 1 and phase 2 enzyme pharmacogenetics? What is clearance compared to?
Phase I
- CYP2D6 (codeine)
- CYP2C9 (Warfarin, Phenytoin);
- CYP2C19 (Omeprazole)
Phase II
- N-acetyletransferase (Isoniazid)
- Glucuronosyltransferase
- Thiopurine S-methyltransferase (Mercaptopurine, Azathioprine)
- Catechol O-methyltransferase
Clearance is compared to wild type
For CYP2D6, what is meant by;
A) Extensive metabolizer
B) Poor metaboliser (caucasians and asian populations)
C) Ultra-extensive metaboliser (europeans, ethiopians, saudi arabians)
A)
- Wildtype
B)
- homozygous mutant alleles
- delayed drug clearance
- increased adverse effects with standard doses (tricylic depressants)
C)
- multiple copies (3 - 13)
- extremely rapid drug clearance
- therapeutic failure, increased dose
For TPMT;
A)What is high activity?
B) What is intermediate activity?
C) What is low/deficient activity?
A)
- Homozygous wildtype (normal)
- Normal dose 50-100 mg/day
B)
- Heterozygous
- 1/3 - 2/3 of normal dose
C)
- Homozygous variant
- <1/20th normal dose
