2013-08-22 Pharmacokinetics I & II Flashcards
What is pharmacokinetics?
how drugs get into and distribute within the body
define and explain mech of drug absorption and distribution
absorption: mov’t of drug from admin site to blood
distribution: delivery of drug from blood to tissues/target site(s);
—IN BLOOD: affected by binding to plasma prots (Esp albumin), ionization, tissue storage (e.g. teeth, bone, fat), metabolism (first-pass), and excretion
IMAGE Slide 6
discuss key factors affecting drug absorption and distribution
see cards w/ specifics re: absorption via different routes
distribution affected by:
cap perm, perfusion rate, extent of plasma prot binding, regional ∆s in pH, transport mech available, perm characteristics of particular tissues
describe pharmacokinetic concepts and models and how they can be used to determine dose and the length of time the drug remains effective
It's all to do with ADME: Absorption Distribution Metabolism Excretion
list and define the concept of equation for half-life (include equation!)
t_1/2** = 0.693*/K_el
OR = 0.693* (V_d/Cl_p)
- 0.693 is ln(2) for first order kinetcs
- *in either mins or hrs
list and define the concept of equation for volume of distribution (include equation!)
V_d = D/C_o (L/kg)
The volume of distribution (V_d) is the volume of the compartment that contains the drug
—in practice based on serum volume
—theoretical number!
—do it b/c we can use it to estimate
THIS WOMAN IS CRAZY
list and define the concept of equation for clearance (include equation!)
CL_p = (K_el)(V_d) [L/hr or L/min, right?]
Primary parameter that defines the elimination rate.
“the amount of swimming pool cleared per unit time” NOT the amount of drug removed
In actual fact: additive of all the total systemic clearance Cl(liver) + Cl(kidney) + Cl(plasma) etc.
Clearance numbers in PDR are generic and do not hold true for everybody. Depends on: —sex —weight —age —hepatic/renal function ——Cockcroft-Gault equation helpful
list and define the concept of equation for oral fraction (include equation!)
Which parameters in this equation change w/ dose? Which ones don’t?
F_oral = AUC_oral/AUC_i.v. [range 0.0-1.0]
—in PDR; derived from data about IV injection
concerns:
—t_max (time to peak conc)
—c_max (maximum attained conc; i.e. conc that occurs at t_max)
—AUC (area under the curve)
Shape, especially time to peak, is usually the same for a drug regardless of dose
—c_max and AUC change w/ dose
You can infer something about the chemistry of the drug based on the shape of the curve. E.g. in notes: high c_max at quick t_max is likely a weak acid that is absorbed very quickly
list and define the concept of equation for loading dose (include equation!)
D* = (C_ss)( V_d) [mg]
—can give after a loading dose often (e.g. pain meds for cancer; azithromycin) if you can’t wait 4 half-lives to get to C_ss
define the concept of steady state concentration
Maintenance Dose (MD) is the dose at a specified dosing-interval required to achieve a specific steady state concentration (CSS)
**Will have spikes (sawtooth pattern?) with oral dosing in between doses
Recall, the plasma conc is dependent on the amount admin, the frequency of admin and the half-life. If you give a fixed amount of drug at fixed intervals then you will achieve steady state concentration after about 4 half-lives (4 x t1/2).
list and define the concept of equation for maintenance dose (include equation!)
MD = (C_ss)(V_d)(K_el)
= (C_ss)(Cl_p)(time interval)
[in mg/min or mg/hr]
explain the theory of one-compartment and multi-compartment models of drug distribution and elimination (include equation!)
one comparment seems to not redistribute much; exhibits 1st order exponential decay that straightens out when plotted on log-linear scale
multi-compartment are those that are distributed rapidly to highly perfused tissues and more slowly to other tissues; displays alpha- and beta-elimination slopes on curve (two slopes on one curves giving L-shaped curve) when you measure concentration from central compartment
——initial step alpha-slope is mostly showing rapid redistribution, have to wait for beta slope to get real elim rate
—appears as a curve on log-linear scale.
distinguish between first-order, zero-order and dose-dependent kinetics of drug elimination and list examples of commonly used drugs in each class.
first-order kinetics is when a constant FRACTION (exponential relationship of X = (X_o)e^-kt) is removed by elim per unit time
zero-order is when route of elim saturated therefore constant AMOUNT is eliminated
define bioavailability
amt of drug that actually reaches the target site in active form
partition coeff; what is common for most drugs?
lipid-water test for polarity; determines how readily it will diffuse
—most drugs amphiphilic
—some (those give per ET tube) are non-polar
ionization
most drugs are weak bases
—pH of compartment determines their ionization
—ionized drugs usually not well absorbed
Which is harder to absorb through stomach, weak acids or weak bases?
weak bases, because pH < their pKa so they are ionized; THINK THROUGH THIS
acids are ionized at basic pH’s
bases are ionized at acidic pH’s
The [lower/higher] the pKa for an acid is, the stronger it is.
lower
The [lower/higher] the pKa for a base is, the stronger it is.
higher
In overdoses where should you sample for acidic drugs vs. basic drugs? Why?
sample for acidic drugs in the blood
sample for basic drugs in the stomach (ion trapping)
REGARDLESS of original route of administration
What pH of antibiotic would you want to use to tx an intestinal infection?
a more basic one.
—pH in tum is 1.4
—in intestines is 5.0
–therefore a basic abx will be
What are the mechs of drug transport across membranes?
—passive diffusion (down conc gradient in non-ionized form)
—filtration (if wicked small, e.g. urea, ethylene glycol)
—bulk flow?? (across capillary wall)
—active transport
—facilitated transport
—ion-pair transport
—endocytosis
tell me about absorption in alimentary tract
most abs in prox jejunum
—passive diffusion so pKa of drug and pH of lumen (depends on what you eat) matter
—shortened transit (diarrhea) matters
tell me about abs in large intestine
<sm intest b/c less s.a. and less vasc; more solid
**RECTAL AVOIDS hepatic metabolism
tell me about abs in lungs
inhaled gases, anesthetics, aerosols, smokes, dusts, etc.
—large s.a. w/thin cell layer, high vasc, high flow
—lipophilic good
—difficult to get rid of once in!
—diesel fumes
tell me abs thru skin
usual to topical only
—little systemic but some skin patches (e.g. nicotine and scop)
—certain creams (e.g. DMSO in farmers) can make it easier for meds to get into systemic circ via skin
IM vs SC
IM faster
—can combine drugs with vasodilator or constrictor to increas abs
IV vs IA vs IP
IV direct to blood (so doesn’t need to go thru abs process at all), rapid, good for narrow ther range
never IA or IP in humans; both used in animal studies though (harder to compare to humans then)
albumin
many binding sites, most important plasma prot, net negative charge,
BBB
only non-ionized, high partition-coeff free drugs can cross;
crossing incr w/ inflamm
blood-testis barrier
similar to BBB; hard to get chemo in, e.g.
What is the rate of elimination?
a constant FRACTION that is removed from the body and NOT a constant amount! it is proportional to the amt of drug in the body (X:
X = (X_o)e^-kt
Where -k is the elimination rate constant
t is time
X_o is amount of drug at time zero
general rule of thumb: how often and by how much can you change a dose?
No more than 50% per change
—no quicker than every 3-4 half-lives
What is a general rule of thumb dosing schedule strategy? Talk about what happens to C_p.
schedule = to half life
—means there is a 50% fluctuation in C_p
100kg man and drugs with:
- -Vd - 1 L/kg for the drug
- -Cl_p - 0.06 L/hr/kg for this drug
- -C_p(ther) - 8-10 mg/L
- -F_p.o. - 0.8 (means ~80% bioavailable)
- -t_1/2 - 6hrs
- -no significant toxicity, so shoot for top of the therapeutic range
What loading dose (D*) for IV? For oral?
What maintenance dose for IV? For oral?
- -Vd…since this man weighs 100kg and the Vd given is 1L/kg, the V_d is 100L
- -Cl_p for him is 6L/hr
- -C_p(ther) is want we want as our C_ss
INTRAVENOUS DOSING
D* = Vd X Cp
= 100 L X 10mg/L
= 1000mg (large amt, so admin IV over 30min)
MD = Cl_p X Css
= 6 L/hr X 10 mg/L
= 60 mg/hr or 1 mg/min (so admin 1/mg/min IV)
ORAL DOSING
D* = (Vd X Cp)/F_p.o.
= (100 L X 10mg/L)/0.8
= 1250 mg
MD = (Cl_p X Css)/F_p.o.
= (6 L/hr X 10 mg/L)/0.8
= 75mg/hr
So admin 450mg SR tab q6h (the half life)
potency vs. efficacy
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