Pharmacokinetics Flashcards
4 actions of the body on a drug
- absorption
- distribution
- metabolism
- excretion / elimination
two ways drugs can be absorbed into body?
- transported across membrane through carrier protein / endocytosis
- diffuse across lipid bilayer
partition coefficient
amount in oil vs amount in H2O
drugs that have highest oil / water coefficient… (high or low lipid solubility?)
are the most lipid soluble
high partition coefficient = (high or low absorption rate?)
high absorption rate
ionization
many drugs are week acids or bases… ionization makes a polar molecule (not good, will not cross membrane)
weak acid
unionized form has proton on it and then can lose H+ to become ionized
when pH = pKa…
50% ionized
weak acids have (high or low) pKa
high
if 3 pH units above above pKa…
almost 100% ionized
if 3 pH units below the pKa…
alost 100% in nonionized state
pH trapping
ideal for the drug to be in the nonionized form in stomach and then be able to be in ionized form in the plasma
once drug gets into blood plasma… it becomes _____
ionized (it is INHIBITED from crossing over through the lipid bilayer)
local anesthetics block ______ that carry APs down the axon
voltage gated Na+ channels
drug must bind ______ portion fo the voltage gated Na+ channel
intracellular
three important properties of anesthetics
- solubility
- ability to cross membrane
- charge
if anesthetic is poorly hydrophobic (hydrophilic)…
can’t cross so the anesthetic block can’t occur
if anesthetic is moderately hydrophobic…
crosses, so block can occur (we want this!)
if anesthetic is extremely hydrophobic…
tries to cross and then gets stuck in membrane… block cannot occur
are weak bases (low pH) ionized or nonionized?
ionized
are weak acids (high pH) ionized or nonionized?
nonionized
the lower the pH of weak base…
more likely to become ionized
inflamed tissues are more (basic or acidic)?
acidic (lower pH)
might need larger dose of anesthetic to inflamed tissue
Solutes must be ______ to cross BBB and enter the brain
lipid soluble
the more vascular the tissue is…
the more distribution of drug
(also easier to wash out of those areas)
Which tissue is least vascular?
adipose
metabolism
inactivation of drug by enzymes
primary organ for metabolism
liver
cytochrome P450 enzymes
make it easier to excrete in urine
each enzyme can metabolize _____. Each drug can be metabolized by ______.
different drugs
different enzymes
CYP3A4
most common metabolic enzyme involved in drug interactions
phase I reaction
oxidation, reduction, hydrolysis
small changes to the functional group
phase II reactions
conjugation (larger, bulkier molcules)
do molecules have to undergo both phase reactions sequentially?
no! can go through one or the other (or both)
general purpose of metabolism reactions
makes molecules more water soluble to allow excretion in urine
1st order kinetics
drug concentration affects rate (higher concentration = higher rate) (exponential decrease)
zero order kinetics
drug concentration does not affect metabolic rate (linear decrease in concentration)
zero order reactions are due to
saturation
enzyme induction
more of the enzyme = more of a drop in drug concentration because metabolized faster
alcohol will cause induction of ___ mediated pathways which is one way to get enhanced ____
P450
NADPQI
if you take too much _____ and overwhelm the ______ and _____ pathways, get more NADPQI
acetaminophen
glucuronidation
sulfation
at what point does NAPQI become toxic?
have a limited pool of glutathione
when you run out of GSH, NAPQI becomes toxic
GSH
glutathione is detoxified and allowed to be released from the body
inhibition
decreased enzyme capacity
less metabolism (impact on drugs)
drug accumulation
notorious inhibiting agents
grapefruit juice
medications
warfarin (coumadin)
oral anticoagulate
warfarin requires
active vitamin K for synthesis of clotting factors
warfarin prevents vitamin K from
reactivating by inhibiting vitamin K epoxide reductase complex (VKORC)
CYP2C9 impact on warfarin (steps)
- reduces warfarin metabolism
- allows more prevention of Vit K re-activation
- decrease synthesis of clotting factors
- increased bleeding
prodrugs
administered in inactive form (to promote absorption)
prodrugs require
metabolic activation by the body
codeine
prodrug of morpheine
what is the only enzyme that can cause codeine to become active?
CYP2D6
excretion
removal of metabolites or unchanged active drug from body
two main organs for excretion
kidney and liver
biliary excretion
occurs through bile duct
enterohepatic cycling helps to…
maintain a higher drug level than what would be maintained if excretion was a one way path
sequence for enterohepatic cycling
- drug in the liver secreted into bile
- stored in the gallbladder
- released into small intestine
- drug reabsorbed back into circulation and subsequently returned to liver
excretion = filtration ____ secretion ____ reabsorption
lipid soluble drugs are reabsorbed in the ____ by _____
renal tubules
passive diffusion
can ionized / hydrophilic drugs be reabsorbed?
no - excreted in urine
what does alkalization of urine lead to?
excretion of weak acids
maintaining ideal drug concentration can be affected by
-administration route
-dose amount
-dose interval
-drug half life
-tissue distribution
intrinsic drug toxicity
reproducible (all patients at risk)
is intrinsic drug toxicity dose dependent?
yes
the results of actions of intrinsic drug toxicity happen at …
the target receptor (or affects other receptors)
idiosyncratic drug toxicity
not widely reproducible (in small subset of patients)
idiosyncratic drug toxicity example
hypersensitivity / allergic reactions
clearance is a way to…
collectively quantify all of the processes that make active drugs disappear from the body
clearance is calculated by
rate of elimination relative to drug concentration
amount of plasma that would have been cleared in order to account for disappearance of drug
volume of distribution
how much drug is dissolved in body
half life
time it takes for drug concentration to decrease by half
how many half lives does it take to remove drug completely from system?
5
bioavailability
fraction of original dose that reaches systemic circulation
bioavailability for IV
100%
main obstacle with oral administration of drug
concentration is greatly reduced before it reaches systemic circulation
