L6. Absorption and Half life

Question 1

What is drug absorption

Answer 1

Transfer of drug from administration site to systemic circulation (and then target site) in order to cause pharmalogical effect
-Requires passage through biological membranes
More relevant for orally administered drugs where
- not all the drug will enter circulation (incomplete absorption), which can delay onset on effect.

Question 2

When is the maximum concentration achieved after administration for oral vs IV and how does this affect clearance

Answer 2

IV; instantaneously as 100% absorbed
Oral: takes some time to be absorbed: max at rate of absorption = rate of clearance, this max is lower than IV
Clearance will be the same between them but can look different for oral because absorption is delayed

Question 3

Compare definition of Rate of absorption vs extent

Answer 3

Rate: how fast does the drug get from the site of administration to the systemic circulation- how fast does it reach its max conc

Extent: How much of the administered dose enters the systemic circulation. -Bioavailability (F)
-area under the curve of conc of drug in the plasma vs time- determines intensity and duration

Question 4

What are the factors that affect the extent of absorption

Answer 4

The fraction absorbed across the gut wall into the portal vein (f). Depending on
1. Ability to cross cell membranes : small, lipophilic, non ionised, and soluble in the gut fluid.
2. The metabolism of drugs by enzymes present in the gut wall (eg. simvastatin by CYP3A4).
3. Efflux transporters in gut epithelia that transport drugs back out into the lumen to get excreted
Then First pass metabolism in liver- ER
4. Hepatic extraction ratio (ER): fraction of drug entered the liver that is extracted, dependent on organ blood flow and clearance

Question 5

Define hepatic extraction ratio (ER) and what it is dependent on

Answer 5

Fraction of drug entering the liver that is extracted

• dependent on intrinsic clearance of the liver : high clearance = high ER
• blood flow to liver- slow flow allows more time to metabolise = high ER

Question 6

What is the formula for calculating extent (F)

Answer 6

F = (fraction absorbed) x (1 - Extraction Ratio)
F= f x (1-ER)
All in decimals

Question 7

What are the 3 different input processes that affect the rate of absorption

Answer 7

1. Bolus: administered directly into systemic circulation (IV)
2. Zero order: rate of absorption is constant (not dependent on concentration)
   eg. constant rate IV infusion
3. First order: rate of absorption is dependent of the conc of drug at the site of absorption
   eg. intramuscular injection

Question 8

Give 2 examples of what zero order input drugs are like

Answer 8

• The rate of absorption is dependent on the rate of stomach emptying- delivery of drug from stom to small intestine-because its absorption in the small intestine is so rapid.
• Slow release formulation: drugs released from formulation at a controlled rate over time so rate of absorption is dependent on pharmacological formulation

Question 9

What is Ka for first order absorption

intestinal absorption

Answer 9

Proportionality constant showing relationship between drug concentration at the site of absorption and the rate of absorption.
(0.7/absorption halflife)
This is limited by diffusion

Question 10

What is the relationship between the rate of absorption vs the plasma conc for First order absorption in the intestine

Answer 10

As the plasma conc goes up (due to drug being absorbed), the rate of absorption drops.
The plasma conc reaches its peak when the rate of absorption= rate of elimination

Question 11

What are the clinical applications of rate and extent of absorption

Answer 11

• Extent helps to work out equivalent dose of IV drug for oral dose - IV dose/ F (same area under the curve/exposure)
• rate of absorption: determine time to peak concentration/ effect.
• allows standards for generic medicines to be judged to be safe by

Question 12

What is elimination half life - for drugs that follow 1st order elimination.
What is it used for

Answer 12

Time required for drug concentration to fall by half.
T(half)= (0.7 x VD) / CL
Dependent on volume of distribution and clearance- usually constant irrespective of drug concentration.
Used to find the amount of drug in the body at any time, the time taken to reach steady state.

Question 13

What is steady state concentration and how is achieved

Answer 13

Steady state is where drug concentrations have plateaued after accumulation. This is achieved with repeated dosing/infusion until input rate = elimination rate. It takes time for concentration to increase so that elimination rate will increase.
The time to reach steady state is after 4-5 half lives.
So to stop accumulation have to wait >5 half lives

Question 14

What is the difference between oral dosing and iv for accumulation to steady state concentration

Answer 14

For oral dosing there are peaks and troughs so there is initial time taken to reach Cmax and then the half life starts, whereas for IV, the c max is constant

Question 15

What is accumulation factor

Answer 15

The ratio of concentration of steady state to the concentration after the first dose - at the same time after the dose

Question 16

What is the application of half life of absorption

0.7/ Ka

Answer 16

The time all of the drug has been absorbed = 4/5 half lives

The time to reach peak conc T max) is shorter than that = around 3 half lives.