2013-08-22 Pharmacokinetics I & II

Question 1

What is pharmacokinetics?

Answer 1

how drugs get into and distribute within the body

Question 2

define and explain mech of drug absorption and distribution

Answer 2

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

Question 3

discuss key factors affecting drug absorption and distribution

Answer 3

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

Question 4

describe pharmacokinetic concepts and models and how they can be used to determine dose and the length of time the drug remains effective

Answer 4

It's all to do with ADME:
Absorption
Distribution
Metabolism
Excretion

Question 5

list and define the concept of equation for half-life (include equation!)

Answer 5

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

Question 6

list and define the concept of equation for volume of distribution (include equation!)

Answer 6

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

Question 7

list and define the concept of equation for clearance (include equation!)

Answer 7

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

Question 8

list and define the concept of equation for oral fraction (include equation!)

Which parameters in this equation change w/ dose? Which ones don’t?

Answer 8

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

Question 9

list and define the concept of equation for loading dose (include equation!)

Answer 9

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

Question 10

define the concept of steady state concentration

Answer 10

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).

Question 11

list and define the concept of equation for maintenance dose (include equation!)

Answer 11

MD = (C_ss)(V_d)(K_el)
= (C_ss)(Cl_p)(time interval)

[in mg/min or mg/hr]

Question 12

explain the theory of one-compartment and multi-compartment models of drug distribution and elimination (include equation!)

Answer 12

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.

Question 13

distinguish between first-order, zero-order and dose-dependent kinetics of drug elimination and list examples of commonly used drugs in each class.

Answer 13

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

Question 14

define bioavailability

Answer 14

amt of drug that actually reaches the target site in active form

Question 15

partition coeff; what is common for most drugs?

Answer 15

lipid-water test for polarity; determines how readily it will diffuse
—most drugs amphiphilic
—some (those give per ET tube) are non-polar

Question 16

ionization

Answer 16

most drugs are weak bases
—pH of compartment determines their ionization
—ionized drugs usually not well absorbed

Question 17

Which is harder to absorb through stomach, weak acids or weak bases?

Answer 17

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

Question 18

The [lower/higher] the pKa for an acid is, the stronger it is.

Answer 18

lower

Question 19

The [lower/higher] the pKa for a base is, the stronger it is.

Answer 19

higher

Question 20

In overdoses where should you sample for acidic drugs vs. basic drugs? Why?

Answer 20

sample for acidic drugs in the blood
sample for basic drugs in the stomach (ion trapping)
REGARDLESS of original route of administration

Question 21

What pH of antibiotic would you want to use to tx an intestinal infection?

Answer 21

a more basic one.
—pH in tum is 1.4
—in intestines is 5.0
–therefore a basic abx will be

Question 22

What are the mechs of drug transport across membranes?

Answer 22

—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

Question 23

tell me about absorption in alimentary tract

Answer 23

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

Question 24

tell me about abs in large intestine

Answer 24

<sm intest b/c less s.a. and less vasc; more solid

**RECTAL AVOIDS hepatic metabolism

Question 25

tell me about abs in lungs

Answer 25

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

Question 26

tell me abs thru skin

Answer 26

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

Question 27

IM vs SC

Answer 27

IM faster

—can combine drugs with vasodilator or constrictor to increas abs

Question 28

IV vs IA vs IP

Answer 28

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)

Question 29

albumin

Answer 29

many binding sites, most important plasma prot, net negative charge,

Question 30

BBB

Answer 30

only non-ionized, high partition-coeff free drugs can cross;

crossing incr w/ inflamm

Question 31

blood-testis barrier

Answer 31

similar to BBB; hard to get chemo in, e.g.

Question 32

What is the rate of elimination?

Answer 32

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

Question 33

general rule of thumb: how often and by how much can you change a dose?

Answer 33

No more than 50% per change

—no quicker than every 3-4 half-lives

Question 34

What is a general rule of thumb dosing schedule strategy? Talk about what happens to C_p.

Answer 34

schedule = to half life

—means there is a 50% fluctuation in C_p

Question 35

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?

Answer 35

• -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)

Question 36

potency vs. efficacy

Answer 36

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