Clinical pharmacodynamcis. Changes in drug pharmacokinetics and pharmacodynamics in patients with liver and heart failure: Flashcards
dose response relationship
dosage is proportionsl to magnitude of desired effect until a max effect is reached
dose response curve
derived from a number of pts to estimate the 1st dose in a pt w/o prior exposure to drug
after this obvs of pt response to dose is used
conc response relationship
conc of drug is unque to indivuduals d/2 diff phK by the pt making it less predictable but more acc
interpatient variation
drugs have a standard dose however pt’s vary in terms of their phD and phK
E.G.
acylation speed
renal / liver dysfunction
concomitant disease
effect of acute liver failure on drug phK
impaired metabolism
impaired elimination
effect of chronic liver failure on drug phK
impairment affects all parameters of pharmacokinetic.
guidlines in suspected liver failure
check for signs of hepatotoxicity
- nausea
- hepatomegaly
- jaundice
avoid hepatotoxic drugs where possible
- alcohol
- aspirin
- methotrexate
- phenytoin
- statins
oral drugs in cirrhosis
decreased first pass met
drug directly introduced into circ
require reduced dose
Phase 1 liver metabolism
oxidation (most common, CYP ez’s,
reduction
hydrolysis.
pharm activity of metabolites after first phase
- inactive metabolites
- less active metabolites than initial drug
- prodrug inactive but has active metabolites
Phase 2 metabolism
chemically changes phase 1 metabolites into compounds that are soluble enough to be excreted in urine.
usually inactive
done via conjugation
methods of conjugation
glucoronidisation
acetylation
General inducers of CYP metabolism
anticonvulsants and antibiotics (Rifampin).
General inhibitors of CYP metabolism:
acute alcohol
cimetidine
omeprazole
factors determining the liver’s metabolic activity
⦁ Hepatic blood flow.
⦁ Liver enzyme activity.
⦁ Binding of a drug to plasma proteins.
how does decreased hepatic flow impair drug met
-⦁ drug delivery to the hepatocytes decreases,
⦁ Drug metabolism decreases,
⦁ drug toxicity increases.
effect of low protein binding on metabolism
⦁ impaired liver is unable to synthesize plasma proteins (albumin)
⦁ Liver impairment causes accumulation of substances (bilirubin) that displace drugs from protein-binding sites.
⦁ protein binding decreases so the free drug increases,
⦁ peak blood levels and adverse effects increase.
principles of dose adjustment in liver impairment
⦁ Starting therapy with low doses and monitoring response or plasma levels
⦁ In case of a high-clearance drug: reduce the initial dose by 50%
⦁ In case of a low-clearance drug: reduce the maintenance dose by 35%
why is dose adaptation harder in liver impairment than renal
no endogenous marker for hepatic clearance that can be used as a guide for drug dosing. Unlike creatinine clearance for the kidney
phK effects of liver imparment
⦁ Absorption increased bioavailability.
⦁ Distribution decreased plasma binding and increased distribution.
⦁ Metabolism impaired.
⦁ Excretion impaired.
define heart failure
inability of the heart to keep up with the demands on it and, specifically, failure of the heart to pump blood with normal efficiency.
what is elimination half life
time it takes for the concentration of the drug in the plasma or the total amount in the body to be reduced by 50%
changes to phK in CHF
reduced distrinution
impaired drug clearance
elimination half life depends on the first 2
how does CHF affect drug plasma conc
increased compared to healthy pt
which drugs are important to monitor in CHF phK
drugs w/ narrow therapeutic index (Anti arrythmics)
- digoxin
- lidocaine
- procainamide
how to manage drugs w/ narraw therapeutic ratio in CHF
reduce loading and maintenance doses
measure plasma conc of drugs
