Pharmacokinetics 3 Flashcards
For most drugs, the rate of metabolism depends on two factors:
the concentration of a drug at the site of metabolism
the intrinsic rate of the metabolic process
The concentration of a drug at the site of metabolism is influenced by
blood flow to the site of metabolism
The intrinsic rate of the metabolic process is influenced by
genetics and enzyme activity
Zero order kinetics describes the situation where there is more
drug than enzyme
Examples of drugs that undergo zero order kinetics include
aspirin, phenytoin, alcohol, warfarin, heparin, and theophylline
First order kinetics describes the situation where there is
less drug than enzyme (no saturation occurs)
Which drugs follow first order kinetics?
nearly all the drugs we administer
If an enzymatic pathway that obeys first order kinetics becomes saturated, then the kinetics can
change from first order to zero order
Which process is a phase 2 reaction?
a. reduction
b. conjugation
c. oxidation
d. hydrolysis
B. conjugation
Drug metabolism is divided into
three phases
Phase 1 of drug metabolism includes
modification (oxidation, reduction, and hydrolysis)
Phase 2 of drug metabolism includes
conjugation
Phase 3 of drug metabolism includes
excretion
Sites of metabolism include
the kidneys, plasma, lung, and intestines
The ______ is the primary metabolic organ
liver
________ is the enzymatic process of altering a molecule’s chemical structure
metabolism
The purpose of metabolism is to change a
lipid-soluble, pharmacologically active compound into a water-soluble, pharmacologically inactive byproduct
Describe oxidation.
removes electrons from a compound
Describe reduction.
adds electrons to a compound
Describe hydrolysis.
adds water to a compound to split it apart (usually an ester)
A phase 2 reaction
conjugates a highly polar, water-soluble substrate to the molecule
A phase 3 reaction involves
ATP dependent carrier proteins that transport a drug across a cell membrane
Describe enterohepatic circulation.
some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation
What drugs undergo enterohepatic circulation?
diazepam and warfarin
Identify the drugs that undergo perfusion-dependent hepatic elimination. select 3
a. diazepam
b. fentanyl
c. rocuronium
d. lidocaine
e. propofol
f. remifentanil
fentanyl (b)
lidocaine (d)
propofol (e)
Drugs that undergo capacity-dependent hepatic elimination include
diazepam & rocuronium
Hepatic clearance is the product of
liver blood flow and hepatic extraction ratio
The extraction ratio is a measure of how much
drug is delivered to the clearing organ vs. how much drug is removed by that organ
An extraction ratio of 1.0 means that
100% of the drug delivered to the clearing organ is removed
An extraction ratio of 0.5 means that
50% of the drug delivered to the clearing organ is removed
For a drug with a high hepatic extraction ratio (>0.7), clearance is dependent on
liver blood flow
Examples of drugs where clearance is dependent on liver blood flow include
fentanyl, sufentanil, morphine, ketamine, and propofol
For a drug with a low hepatic extraction ratio (<0.3), clearance is dependent on
the ability of the liver to extract the drug from the blood
Examples of drugs where clearance is dependent on the ability of the liver to extract the drug from the blood inlcude
rocuronium, diazepam, and methadone
When administered orally, high extraction ratio drugs are subject to
first-pass metabolism
Hepatic extraction ratio is
how much drug is removed by the liver
The extraction ratio is a measure of
how much drug is delivered to the clearing organ vs. how much drug is eliminated by that organ
The extraction ratio equation is
Extraction ratio= (arterial concentration- venous concentration)/arterial concentration
Hepatic clearance is categorized as
perfusion-dependent elimination or capacity-dependent elimination
Increased liver blood flow leads to
increased clearance
Does hepatic enzyme activity have an effect on drugs that have perfusion-dependent elimination?
No
Does hepatic enzyme activity have an affect on drugs that undergo capacity-dependent elimination?
Yes! - changes in hepatic enzyme activity or protein binding have a profound impact on the clearance of these drugs
Do alterations in liver blood flow affect clearance for capacity dependent elimination drugs?
minimally because only a small amount of drug is removed per unit time
If enzyme induction occurs, how does this affect capacity-dependent drugs?
it increases clearance
Drugs with low hepatic extraction ratios include
rocuronium
diazepam
lorazepam
methadone
thiopental
theophylline
phenytoin
Drugs with intermediate hepatic extraction ratios include
midazolam
vecuronium
alfentanil
methohexital
Drugs with high hepatic extraction ratios include
fentanyl
sufentanil
morphine
meperidine
naloxone
ketamine
propofol
lidocaine
bupivacaine
metoprolol
propranolol
alprenolol
nifedipine
diltiazem
verapamil
Enterohepatic circulation describes
a process where the liver excretes a substance into the bile, and then that substance is reabsorbed from the small intestine and transported back to the liver
Drugs that undergo enterohepatic circulation tend to
have a long duration of effect
What drugs undergo enterohepatic circulation?
diazepam, warfarin
