Absorption and half life

Question 1

What are the two factors which drug absorption can be described by?

Answer 1

1. The extent of absorption (how much drug is entering the body) - not time dependent. This varies when drug is taken orally.
2. The rate of absorption of the drug (how quickly the drug enters the body)

Question 2

What is the equation for the extent of absorption and what do the factors contributing to the equation mean>

Answer 2

F oral (extent) = f (1 - ER)

f = the fraction of the drug absorbed i.e how much drug can actually get across the gut wall into the portal vein

ER = extraction ratio. This refers to the fraction of drug that is extracted/removed from the blood by the liver.

Question 3

What two factors determine a drugs extent of absorption in terms of (f) - the fraction absorbed when taken orally?

Answer 3

1. The physiochemical properties of the drug -
   size/ ionisation. For small unionized drugs like theophylline they are almost completely absorbed across the gut wall whereas large ionized molecules such as gentamicin have difficulty with only a small fraction getting absorbed.
2. Whether the drug is metabolized by enzymes in the gut wall or transported back out into the gut lumen -
   Eg. CYP3A4 metabolizes simvastatin
   and a P-glyco protein transports digoxin back out of the gut cells

Question 4

What is the extent of absorption for IV administed drugs?

Answer 4

100% - they enter directly into the plasma

Question 5

What factors determine the extraction ratio (ER) of a drug taken orally?

Answer 5

The extraction of a drug metabolized by the liver depends on both hepatic blood flow and by the intrinsic clearance.

First pass extraction - if the liver is producing enough/ a lot of the required enzymes to metabolize the drug then most of the drug entering the liver will be extracted. Morphine has a high intrinsic hepatic clearance and about 60% of morphine is removed by first pass extraction after an oral dose.

Blood flow - if the blood flow is low then this gives the liver lots of time to extract the drug and so extraction conc will be high. If clearance is high then more drug will be metabolized per unit time and so the extraction will be high.

Question 6

Using ethanol as an example, describe extraction ratio.

Answer 6

The extraction of ethanol largely depends on the rate at which you drink it.

If you drink really fast (scull a drink) then there will be a higher conc of ethanol in the portal vein and so the liver wont have as much to clear it as it passes through so extraction will be low (10%).

If you drink really slow (over an hour or two) then there is a slow input and the conc in portal vein is very low therefore the liver enzymes arent saturated and so the ethanol is extracted more easily. Extraction can be up to 70% - hence very little ethanol ends up in the systemic circuit so little effect on the body.

Rate of delivery of the ethanol to the liver is also determined by the rate of absorption in the gut. If you eat while drinking then it slows the rate of absorption of the alcohol so the liver has enough time to extract more ethanol from the blood so less ethanol reaches the systemic circulation.

Question 7

What is the overall extent of absorption called?

Answer 7

Bioavailability
- this is the fraction of the administered drug that reaches the systemic circulation. (because once absobred from gut wall this blood drains directly to the liver via the portal vein)

Question 8

Name some of the ways drugs can be administered.

Answer 8

IV (intravenously), IM (intramuscular), orally, suppository (drug put up the rectum or vagina), topical cream, drops in the ear eye or nose, sublingual (under the tongue).

Question 9

What are some of the input processes of drugs? and what method of administration results in this input process?

Answer 9

1. Bolus (by rapid IV infusion)
2. Zero order (constant rate IV infusion and slow release oral medicine can be approximated to this)
3. First order (intra muscular injection)

Question 10

What do each of the input processes mean in terms of how fast is the drug absorbed? (rate of absorption)

Answer 10

Bolus - the absorption is instantaneous

Zero order - the absorption rate is constant.

First order - the absorption rate is proportional to the amount of drug at the absorption site. This therefore means that when the drug is first administered the absorption rate is high and then after some time the rate decreases as the drug is absorbed.

Question 11

For oral drugs, what is the limiter of their rate of absorption?

Answer 11

1. The stomach emptying time. Most drugs are absorbed in the duodenum (small intestine) not the stomach and the absorption once at the small intestine is usually rapid. Therefore the limiting factor of their absorption is the rate at which the stomach empties/rate at which drug is delivered to the duodenum.

It is approximated that the stomach empties at a constant rate and so often the rate of absorption of some drugs is the same because it is the gastric emptying not the drug that determines how quickly the drug gets into the blood.

Some drugs are speshially designed as slow release so they dont dissolve very quickly.

Question 12

Why does taking food with paracetamol help with its rate of absorption?

Answer 12

Eating increases the gastric emptying of the stomach and so will be delivered to the duodenum much faster.

In contrast, when taking paracetemol in a fasting state the stomach will enter much slower and so it may take up to 30mins for the drug to exit the stomach.

Question 13

The rate limiting step of first order absorption is the rate of absorption from the intestinal wall. What does the proportionality constant KA relate? (in terms of first order absorption)

Answer 13

The amount of drug at the absorption site to the rate of absorption.

Half life of absorption can be calculated from this. Absorption is more than 90% complete after 4 half life. This is very different from elimination half life. Absorption half lives are typically 0.5 hours whereas elimination half lives are often several hours/days.

Question 14

When does peak concentration of the drug (in the blood) occur after oral administration?

Answer 14

A little time after 4 half lives of the absorption half life. (by 4 half lifes there is approx 90% of absorption complete).

For a constant rate drug such as paracetamol we can approximate it to gastric emptying time.

Question 15

Why is F (extent of absorption) important for when patients get transferred home from hospital with drugs?

Answer 15

To convert IV dose to oral dose you have to divide by F. Eg if on 500mg IV then to convert to oral dose divide by the drugs F eg 67% - oral dose = 500/100 x 67 = 750mg

Question 16

Why is knowing extent and rate of absorption important for developing generic drugs?

Answer 16

Drug companies are always trying to make cheaper forms of the same generic medicines. If a drug has the same rate (based on Cmax and Tmax) and same extent (judged on equiv area under conc/time curve), then is is bioequivalent and can be marketed as having the same effect as the original drug.

Question 17

What absorption process can half life be used to describe? and what are these processes often called (in terms of the relationship they have with absorption and time graphically)

Answer 17

First order processes.

Exponential - an exponential function can be used to predict the time course of a first order process.

Question 18

What are the elimination and accumulation half lives?

Answer 18

The elimination and accumulation half life are the same thing but they are used to describe different processes

The elimination half life describes how quickly a drug accumulates and vice versa.

Question 19

What is the equation from determining half life?

Answer 19

T 1/2 = 0.7 x V / CL

Question 20

After how many half lives can we assume that almost all drug has been eliminated (after given a single dose or after constant input stops) or the drug has accumulated to reach a steady state (after constant rate infusion)?

Answer 20

4

Question 21

What does the extent of accumulation depend on?

Answer 21

The dosing interval and the half life.

Question 22

What is the accumulation of a drug given every half life? comparatively, what would the accumulation be of a drug given every 2 half lives.

Answer 22

The steady state concentration will be double what was started with. (AF = 2)
A drug given every two half lives would accumulate to much less than the original starting dose concentration.

Question 23

What does the accumulation factor show the ratio of?

Answer 23

The conc at steady state to the conc after the first dose (at the same time after the initial dose and a dose at steady state).

Question 24

At what point of drug absorption can we predict the time of peak concentration (Tmax)?

Answer 24

3x the absorption half life.