Week 1: Pharmacokinetics II

Question 1

Why does the plasma concentration of a drug decrease with time? Why does it decrease in a curve rather than in a straight line?

Answer 1

The plasma concentration of a drug decreases because of the ADME effects–Absorption, Distribution, Metabolism and Excretion

It decreases in a curve due to the fact that rate of change depends on enzyme kinetics. When a lot of molecules are available, V_max of an enzyme is approached. As drug concentration falls off, enzyme velocity decreases according to the curve of the enzyme kinetic plot.

Question 2

What are the enzyme kinetics of drug metabolism?

Answer 2

Since the rate of metabolism is dependent on [drug] alone, enzyme kinetics are first order.

Enz + D <=> EnzD –> Enz + metabolite

This means a constant fraction of drug is eliminated per unit time.

Question 3

What is half life (t_1/2)? How long does it take for >90% of a drug to be cleared?

Answer 3

The half life of a drug is the amount of time required to metabolise 50% of the original amount. If the half life of a drug is one day, then…

After 1 day: 50% of original amount

After 2 days: 25% of original amount

After 3 days: 12.5% of original amount

After 4 days: 6.25% of original amount

Thus, it takes 4 days, in this case, to eliminate >90% of the drug

Question 4

What is the equation for the clearance of drug from the body?

Answer 4

C = e^-kt(C₀)

where C = [drug] at time t after administration

e = Euler’s number ~2.7

k = rate constant of elimination

t = time since C₀

C₀ = initial concentration

e^-kt = fraction remaining

Question 5

How can we transform the clearance equation, and what does this give us as far as Y-intercept and slope?

Answer 5

We can transform the clearance equation by taking the natural log of both sides to get:

ln(C) = -kt + ln (C₀)

y = mx + b

Y-int. = ln(C₀)

Slope = -k_e

Question 6

What is k_e? What is its relationship to t_1/2? What is its unit? What does it mean if k_e = 0.1/hr?

Answer 6

k_e is the elimination rate constant

It relates to t_1/2 via t_1/2 = 0.693/k_e

It has a unit of 1/time aka per hour

If k_e = 0.1/hr that means 10% of the drug is eliminated per hour

Question 7

What is another term for k_e, and why do we call it that?

Answer 7

k_e is also referred to as k_beta because alpha = distribution phase of a drug, beta = elimination phase

Question 8

Does k_e remain constant?

Answer 8

The rate, k_e doesn’t stay constant since the concentration is decreasing, so you would actually metabolize less than 10% per hour when k_e = 0.1/hr (because that value assumes that the drug concentration stays constant, when it is in fact decreasing)

Question 9

What happens if the process of drug elimination is saturated? How does this affect enzyme kinetics? How does it affect t_1/2?

Answer 9

If the process/enzyme activity is saturated, the number of molecules of drug removed from the plasma per minute will be constant since the process is working at its maximal rate (V_max).

Because the rate does not depend on the concentration of drug, it is a zero order process. Here, the decay is linear and C is decreasing by a constant amount/time.

THERE IS NO t_1/2 IN ZERO ORDER KINETICS

Question 10

What drugs have zero-order kinetics?

Answer 10

Ethanol (Every)

Phenytoin (Physician)

Fluoxetine (Fills)

Verapamil (Vag’s)

Question 11

What is the volume of distribution and how is it calculated?

Answer 11

Volume of distribution is the apparent volume that the drug is dissolved in. It is calculated via:

D/C₀ = V_d

Where D = dose given, and C₀ = starting concentration

Question 12

How can you calculate the volume that the drug is dissolved in?

Answer 12

C = D/V_d

where C = mass/volume = mg/L = dose/volume, and rearrange to get

V_d = D/C

Question 13

Does the V = D/C calculation give us the actual volume that a drug is dissolved in? Why or why not?

Answer 13

The equation gives us the apparent volume that the drug is dissolved in, not the actual volume. This is because the drug binds to other elements like plasma protein, cell surfaces and more.

Question 14

How do lean and adipose individuals differ in the administration of a lipophilic drug?

Answer 14

In the case of high adipose individuals, much of the drug becomes sequestered in the adipose tissue, instead of actually distributing around the body. With the lean individual, a relatively high percent of the drug remains unsequestered by fat, so they see a higher relative dose in relevant compartments.

Question 15

What is the difference in distribution of two drugs that are given in the same dose, but have different lipophilicity?

Answer 15

Drugs given in the same dose but with differing lipophilicity will sequester and distribute differently. Low lipophilicity drugs will remain in the aqueous compartments, with low levels of the drug sequestering in fat. High lipophilicity drugs will mostly sequester in fat, with low levels of the drug remaining in aqueous compartments.

Question 16

How is it possible for V_d to be larger than *actual* aqueous volume?

Answer 16

V_d refers to a theoretical volume of distribution, not an actual, physical volume. This is because drug distribution in aqueous solutions compared to initial dose depends on how much is sequestered elsewhere, like in fat (i.e. how lipophilic, etc. the drug may be)

Question 17

How do you calculate the relative bioavailability of an oral drug? Given a graph of the physiological concentration vs time, what can you determine from the area under the curve?

Answer 17

Bioavailability = F = AUC_oral/AUCiv

where AUC = Area Under the Curve for oral vs IV delivery method

The area under the curve of a graph of physiological concentration vs time indicates the measure of how much drug the body sees in total. Usually, oral administration has lower bioavailability than IV.

Question 18

What generally occurs when multiple doses of a drug are given?

Answer 18

Drug accumulation can occur during delivery of a repeated dose. If the t_1/2 for a drug is 1 day and you give a dose of 2 mg every other day, attempting to reach a target of 3 mg then…

Day 0: 2 mg (delivery)

Day 1: 1 mg (half eliminated)

Day 2: 3 mg (delivery)

Day 3: 1.5 mg (half eliminated)

Day 4: 3.5 mg (delivery)

The average level begins to approach the target concentration after 4 days

Question 19

How long does it take for a drug to reach steady state?

Answer 19

This depends on the half-time length (when half-time is the time it takes to reach half of the previously delivered amount), but in general it takes about four half-times to reach steady state. This is independent of dosage.

Question 20

What are steady-state drug concentrations dependent upon?

Answer 20

It is proportional to the dose/doseage interval ratio

Also proportional to F (bioavail.) / CL (clearance)

Question 21

What are the concentration fluctuations in a repeatedly administered drug dependent upon?

Answer 21

Fluctuations are proportional to interval (of delivery)/half-time ratio

Fluctuations are blunted by slow absorption

Question 22

What kind of dose do you give if you need the plasma concentration of the drug to reach C_SS (steady state concentration) more quickly than the time required for four half-lives?

Answer 22

You can give a loading dose that fills up V_d that the drug will dissolve in

Question 23

What is the effect of giving smaller doses over shorter intervals of time compared to larger doses over longer intervals?

Answer 23

Giving smaller doses in shorter intervals smoothes out the drug concentration curve, and prevents large spikes in blood [drug] (green curve). In contrast, larger doses create the same C_SS overall when given over larger intervals compared to the small dose + short interval combo, but have large fluctations (pink)

Question 24

Why/how does steady state occur when dosing multiple times?

Answer 24

The rate of drug going in becomes equal to the amount of drug going out

Question 25

What is k_e?

Answer 25

The fraction of drug lost per unit time

Question 26

How do you calculate clearance of a drug? What is clearance, anyway?

Answer 26

Clearance (CL) = k_e x V_d

Clearance is the volume from which drug is completely cleared per unit time

Question 27

How do you calculate the maintenance dosing rate?

Answer 27

CL x C_SS

where CL = clearance and C_SS = desired concentration of drug at steady state

Maintenance dosing rate (amount going in) = CL x Css (amount going out)

Question 28

With orally administered drugs, how do you calculate dosing rate (mg/unit time)?

Answer 28

(C_SS x CL)/F = dose rate (mg/unit time)

where C_SS is desired steady state concentration

CL = clearance

and F = oral bioavailability

F becomes a factor here because you need more drug than is eliminated, since not all of the drug is bioavailable

Question 29

Why is oral dosing formulation different than IV? When does absorption of orally administered drugs become an issue?

Answer 29

Oral dosing formulation does not have instant absorption. We can, however, calculate a rate constant of absorption and factor that in. This is an issue when absorption is REALLY slow, or slow relative to k_e

Question 30

What is the difference between zero and first order kinetics with respect to drugs?

Answer 30

With zero order kinetics, a constant amount of drug is eliminated per unit time, no matter the concentration of the drug.

zeroth order: rate of elimination = k

With first order kinetics, the amount of drug eliminated depends on the concentration of the drug.

first order: rate of elimination = k[D]