Quantitative Pharmacokinetics

Question 1

What is the definition of first order kinetics? Is this typical of drug metabolism and excretion?

Answer 1

the rate of the process is directly dependent on the drug concentration (a constant percent or fraction is lost per unit time)

This is typical of drug metabolism at therapeutic levels (below Km), and renal excretion (assuming constant GFR and regular filtration)

Question 2

What is the definition of zero order kinetics?

Answer 2

The process is not dependent on drug concentration

Rate = k [Drug]^0 = k

A constant amount is lost per unit time

Question 3

What are two example situations when drug elimination is zero order?

Answer 3

1. Drug elimination in overdose situation (enzymes are working at Vmax)
2. IV drug administration -> plasma concentration is not changing so it is essentially zero order

Question 4

How many beers must you drink to get to zero order kinetics?

Answer 4

About 3 beers, since you are past Km in about 3 beers

Question 5

Other than alcohol, what are two other drugs that show zero-order elimination?

Answer 5

Aspirin overdose -> renal tubule organic acid transport system becomes saturated

Phenytoin (Dilantin) -> liver at almost max capacity when Dilantin is in therapeutic range (anticonvulsant)

Question 6

How is aspirin overdose treated?

Answer 6

Activated charcoal is ingested to adsorb salicylates remaining in stomach, and sodium bicarbonate is given for treatment of metabolic acidosis and increase pH trapping in urine

Question 7

What is the expression for rate of drug input and what are its units?

Answer 7

units are: amount / time (i.e. mg per day)

Rate of drug input = f(D/T)

f = bioavailability / fractional absorption
D = Amount of drug administered
T = Time between doses

Question 8

What is the rate of drug input for IV infusion of 1 mg / hour?

Answer 8

Rate of drug input = 1(1mg / 1 hr) * 24 hr / 1 day = 24 mg / day

Question 9

What type of kinetics does half life apply to?

Answer 9

First order processes only (amount eliminated is dependent on current drug concentration)

Question 10

What is the elimination constant and how is it related to half-life?

Answer 10

Ke = 0.7 / (half life)

They are inversely proportional. Longer half lives will have small elimination constants.

Question 11

What is the Ke for a drug with a halflife of 7 hours?

Answer 11

Ke = 0.7 / (7 hours) = 0.1 per hour

Which means 10% of the amount of the drug in the body will be eliminated per hour

Question 12

What does T(1/2) assume about the patient?

Answer 12

Normal liver and kidney function

Question 13

What is clearance and what are its units? What type of reaction can it be used for?

Answer 13

The volume of plasma from which a drug is entirely removed per unit time (ml/min or L / hr)

CL = (Vd)(ke)

Because Vd has units of volume
Ke has units time^-1

Can only be used for first order kinetics, since it depends on half life

Question 14

What is the steady state equation?

Answer 14

input = output

f(D/T) = (C_ss)(CL)
concentration/time = (concentration/volume)(volume/time)

Where C_ss = Concentration at steady state

Question 15

What is equal to the total body clearance of a drug?

Answer 15

The sum of the clearances from individual organs: liver, kidney, and others

Question 16

Why is clearance useful?

Answer 16

The clearance times the plasma concentration of the drug will predict the rate of elimination (the output)

This is why Css*CL = steady state elimination

Because CL = Rate of elimination / C (concentration of drug in plasma)

Question 17

Should clearance be constant over the concentration range of drugs seen in clinics?

Answer 17

Yes, because elimination is not saturable -> rate of drug elimination is directly proportional to concentration.

Elimination = CL * drug concentration in plasma (elimination is directly proportional to drug concentration when CL is constant)

Question 18

Why do the immediate effects of drugs not simply parallel their action proportionately?

Answer 18

Drug concentrations are often at well over their EC50’s, so even when the drug has dropped to a very low level (i.e. 1/16 of initial dose by the fourth half life), it is still having an appreciable effect

Question 19

What is one major reason why warfarin has a “delayed effect”?

Answer 19

Slow turnover of prothombin complex, takes a while to notice the effect that warfarin is having on clotting factors

Question 20

What are two drug classes with “cumulative effects”?

Answer 20

1. Aminoglycosides - greater renal damage when administered constantly vs intermittent dosing (due to accumulation in renal cortex)
2. Cancer therapeutics - extent of DNA binding is proportional to drug concentration and is irreversible

Question 21

If a drug has a very high distribution, will the required dose be high or low?

Answer 21

High distribution = high dose (lower effective concentrations at any place, due to large Vd)

Question 22

What is the plateau principle?

Answer 22

The principle of drug accumulation which states that steady state is achieved when the rate of drug input and the rate of loss per day are equal

-> rate of elimination will determine how long it takes to get to steady state

Question 23

What is the steady state equation with Vd included?

Answer 23

f(D/T) = (Css)(Vd)(Ke)
or
f(D/T) = (Css)(Vd)(0.7/t-half)

Question 24

Why are there jagged variations in the plasma concentration of a drug when taken orally and how can this be prevented? Why is this a problem?

Answer 24

Because after the dose of drug is administered, it will be slowly cleared until the next dose. This is a problem if the troughs fall below therapeutic levels.

Can be prevented by shortening the dosing interval. (same amount of drug given per day, just at a shorter interval). Can easily be done via IV infusion

Question 25

How long does it typically take to get to a steady state drug concentration and why?

Answer 25

Assuming a regular dosing interval, it should take about 4 half lives (you will be at 93.75% of steady state at this time). This is due to elimination kinetics which govern the accumulation of a drug.

Take for example, drug X: half life 1 hour

If you are giving 10 mg a day with a 5mg pill BID, it will take you four halflives to reach the steady state of maybe 20 mg / L plasma concentration

If you are giving 20 mg a day with a 5 mg pill QID, it will take you about four halflives to reach a steady state concentration of maybe 30 mg / L plasma concentration

Im just illustrating a point, the numbers for Css aren’t right

Question 26

When is a loading dose used?

Answer 26

Used in situations where we have a serious, painful, or even life-threatening condition where we need to reach Css very quickly and can’t afford to wait four half lives.

Question 27

What is the formula for a loading dose?

Answer 27

Loading dose = Css * Vd

Css = desired plasma concentration at steady state
Vd = Volume of distribution, a property of the drug

Question 28

What is a maintenance dose?

Answer 28

The dosage which must be given to maintain steady state concentrations after the loading dose (basically, the dosage which would’ve lead to the steady state concentration if you had waited enough half lives)

Question 29

What is the formula for maintenance dose?

Answer 29

Dose maintenance = Css * CL

Dose maintenance is thus essentially f(D/T), as its units are amount per time. We are usually giving the drug IV as well so f = 1, so it’s just D/T.