L2. Clearance

Question 1

What is pharmacokinetics

Answer 1

Pharmokinetics is the study of concentration-time profile of a drug in the body- what happens to the drug over time in the body- measured in the blood, tissues, other bodily fluids (saliva, milk, urine, faeces)

Question 2

Define clearance (CL) and two equations

Answer 2

Volume of plasma irreversibly cleared of drug per unit time : L/ hour. Can be constant, concentration dependent and flow dependent.
Clearance = elimination rate / concentration
Plasma clearance: Cl renal + Cl hepatic + Cl other (sweat/exhalation)

Question 3

What are the 3 ways drug is removed from the body

Answer 3

• Metabolism in the liver where drugs-> metabolites
• Biliary excretion in liver-> to faeces
• Excretion by glomerular filtration or tubular secretion in the kidney

Question 4

What is more important in getting the pharmalogical effect? Drug dosage or free drug concentration in plasma

Answer 4

Free drug conc in plasma because some of the dosage binds to plasma proteins/ storage in tissues, metabolised (made inactive or active) and excreted, rendering it inactive.
Therefore free drug concentration is the only one that directly contributes to the drug conc at site of action.

Question 5

Why is pharmacokinetics important

Answer 5

• Allows rational dosing: helps to identify the therapeutic window= plasma drug conc most benefit/efficacy without adverse effects.
• Optimises the route of drug administration and schedules of dosing.

Question 6

What are the physiological determinants of drug clearance in the kidney/ liver

Answer 6

Both= The amount of blood flow to the organ
Liver: has to be given orally/ travel through digestive system
Renal: how easily filtered- higher if not bound to plasma proteins, can go through active transporters in peritubular capillaries. Ionised, large and non lipophilic drugs not easily reabsorbed by passive diffusion, therefore easily excreted

Question 7

What is maintenance dose rate and how is it calculated.

Answer 7

The dose rate to achieve and maintain a target concentration (therapeutic window). So amount going in plasma = rate of elimination.
Maintanence dose rate = mg/h = CL x target conc

Better managed with IV, compared to oral which gives peaks and troughs.

Question 8

Compare the 3 types of clearance: Constant, concentration dependent and Flow dependent and which types of elimination are they associated with

Answer 8

Constant = independent of organ blood flow and concentration, leaving elimination proportional concentration: 1st order or linear elim

• Concentration dependent: for drugs that the elimination method becomes saturated, CL changes with concentration- tubular active transport, metabolising enzymes : mixed order or non linear elimination
• Flow dependent: CL approximates organ blood flow, so dose adjustment for vascular flow problems

Question 9

What happens during mixed order elimination , what type of clearance is it related to and give eg.

(small increases in dose cause large increases in plasma drug levels for the eg.)

Answer 9

Mixed order kinetics is depending on the concentration compared to KM, the same drug will have different elimination rate profile. Eg. Phenytoin

If the conc is a lot smaller than the KM value, there is no saturation of elimination so it follows first order elimination. Elimination rate becomes effectively [vmax/ km] x C (CL x C) so conc declines exponentially, But clearance is independent of concentration.

If conc is much higher than KM, elimination is saturated, so it is 0 order kinetics. Clearance is concentration dependent. Elimination rate is independent of concentration. (conc has linear decline). so proportional to V max.

Question 10

What are 3 ways to help elimination processes clinically

Answer 10

Haemodialysis = filters blood to remove drug
Haemoperfusion = passing blood through cartridge to absorb drug 

Charcoal bind to drug in the gut to prevent absorption.