lecture 1 - pharmacokinectics Flashcards
First pass metabolism. what is it?
a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. when a drug is absorbed across the GI membrane, it enters the hepatic portal system, which carries the drug molecules directly to the liver.
absorption of sublingual/buccal - goes where?
drains to vena cava. (bypasses GI tract)
absorption of sublingual/buccal - speed?
rapid
sublingual/buccal drugs must be
highly lipid soluble and potent
if you have poor blood flow to a cut and put a topical on it you will have poor
absorption
p-glycoproteins- where are they?
membranes. they are found all over the kidney, color, BBB, jejunum, liver, pancreas, etc.
p-glycoproteins- what are they?
family of transfer proteins. important for med interactions and drug resistance.
what do p-gloycoproteins require for transport
ATP
total body water
.65L/kg
average adult plasma volume is
Vd= 3 liters
what does volume of distribution assume?
that a sample of peripheral blood is homogenous throughout the body. sometimes called “apparent” volume of distribution
volume of distribution definition
size of compartment necessary to account for the total amount of drug in the body if it were present throughout the body at the same concentration found in the plasma.
are SQ and IM lipophilic or hydrophilic ?
lipo
injectable meds are absorbed by what process
simple diffusion
bioavailability of subcutaneous meds is
100
inhaled meds absorption
rapid due to large surface area, avoid first pass, local site of action, difficult to control
how does temp affect absorption
increases
topical meds need to be
highly lipophilic
first pass metabolism
the concentration of a drug is greatly reduced before it reaches the systemic circulation
how to figure out new dose if you have the current dose, its bioavailability, and the new dose’s bioeval
new dose = f old (current dose) / f (new)
concept of bioavailability as a percentage
so (f) is a percentage of the oral dose that is becoming into the general circulation. and because you’re giving IV meds right into the circulation pt gets the whole dose
100 mcg PO, 75% bioavailable. whats the IV dose?
75mcg
salts at the end of the drug like tartrate
can change bioavailability and duration of action
100 mcg IV, 50% bioavailable IV–>PO dose?
200mcg
factors that affect bioavailability
dissolution and absorption characteristics, route, stability in GI tract, metabolism prior to blood stream
absorption definition
the movement of drug molecules a cross membrane and into the bloodstream
bioavailability (F) definition
% of med that reaches systemic circulation
pharmacodynamics
the effects of a drug on the body
pharmacokinetics
the effect of the body on a drug
ADME
absorption, distribution, metabolism, excretion
oral admin- considerations in GI tract
gastric ph and contents. surface area. blood flow. GI mobility. complete GI tract. flora
gastric ph and contents affects what?
absorption of certain meds like ca supplements
what limits transport into placental transfer
p-glycoproteins
placental transfer -describe fetal plasma
acidic, ion trapping of basic drugs
blood brain barrier is made up of
very tight junctions
to cross BBB, meds need to be highly
lipophilic
CNS inflammation (meningitis) does what to BBB
increases the space between the junctions (look this up more)
hydrophillic
water loving water is an ionized. meds need a transport molecule or carrier protein
membrane permeability
in order to enter an organ, a drug must permeate all membranes that separate the organ from the site of drug administration
tissue binding
where is the drug most likely to be used
what meds live in the bones
tetracyclines
the less albumin you have
the more unbound medication, and greater risk of toxicity
what do basic drugs bind to
Alpha 1 acidic glycoprotein
what do acidic drugs bind to
albumin
why are free levels drawn
want to know how much of the med is actually active
protein binding affects
the amount of free drug that can actually effect the body
two compartment model
- redistribution before elimination
- slow rate of administration for secondary re-distribution
- target organ may be in the initial or secondary “compartment”
does passive diffusion require energy
no
does passive diffusion require a carrier
no
what molecules use passive diffusion
rapid for lipophilic, non-ionic, small molecules
does facilitated diffusion require energy
no
does facilitated diffusion require a carrier
yes
what is facilitated diffusion
drugs bind to carrier by noncovalent mechanisms.
chemically similar drugs compete for carrier
do aqueous channels require energy
no
do aqueous channels require a carrier
no
how do aqueous channels work
small hydrophilic drugs diffuse along concentration gradient by passing thru aqueous channels/pores. electrolytes love these
does active transport require energy
yes
does active transport require a carrier
yes
how does active transport work
identical to facilitated diffusion except that ATP powers drug transport against concentration gradient
metabolism
breakdown for ease of elimination
prodrug
an inactive substance that is converted to a drug within the body by the action of enzymes or other chemicals.
phase 1 metabolism
- induce or expose a functional group on the parent compound.
- generally lose activity, rare instances of preserved.
phase 1 metabolism - how are they eliminated
often hydrolyzed or ester linked for rapid elimination thru kidneys
phase 2 metabolism
conjugation reactions… links parent compound or phase 1 metabolite with a functional group via covalent linkage.
most enzymes that break down medications come from
liver
cyp450
terminal oxidase in a multicomponent electron transfer chain.
phase 1 type reactions.
“most common enzymes that break down meds into something more ionized, polar water loving, so that they get eliminated”
CYP3A4
isoform. responsible for the metabolism of more than 50% of all medications. found in liver and small intestine
med metabolized by a CYP is a
substrate
inhibition of enzyme
-Will keep the enzyme from
working properly
-Ability to increase amount of parent compound
induction of enzyme
- will enhance the capability of the enzyme
- Ability to quickly metabolize the parent compound
so you need more!
factors affecting metabolism
genetics, environment, diet, disease factors, age, sex
hydrolysis
often provide a site for conjugation, or may inactivate P450 metabolites for excretion. “a chemical process of decomposition involving the splitting of a bond and the addition of the hydrogen cation and the hydroxide anion of water.”
conjugation
Phase I metabolite joining to another compound.
elimination is easier when a med is
polar, hydrophillic
3 processes of renal elimination
glomerular filtration, active tubular secretion, passive tubular reabsorption
glomerular filtration is for
unbound medications
active tubular secretion is for
p-gp and other transport proteins
passive tubular reabsorption is for
weak acids and bases via concentration gradients
first order kinetics
A constant fraction of the drug in the body is eliminated per unit time. so length of half life is constant.
zero order kinetics
half life decreases with decreasing concentration.
elimination rate (k)
fraction or % of the total amount of drug in the body removed per unit of time.
formula: k= Cl/V
elimination rate = clearance / volume
formula: k = ln (C1-C2) / time
elimination rate = natural log times the change in concentration divided by time.
how many half lives do you need to get to steady state
5
what do half lifes and elimination rates do
- estimate the time to steady state
- estimate the time to eliminate the med from the body
- predict non-steady state plasma levels
- predict steady state from a non-steady state level
- determine dosing intervals
