L21: Pharmacokinetics II

Question 1

What is meant by elimination?

Answer 1

Metabolism and excretion

Question 2

Why are drugs removed from the body?

Answer 2

Drugs tend to accumulate in the body and need removing
Body has homeostatic mechanisms to regulate many hundreds of endogenous molecules to ensure they exist within a given concentration range over time
Drugs are recognised and eliminated from the body
Mechanism evolved to deal with xenobiotics which were normally toxic

Question 3

What is metabolism?

Answer 3

Changing of the molecular structure ready for excretion
Split into two phases
1. Phase 1: introduce or unmask more polar groups on the drug molecule (OH or NH2) by oxidation and reduction reactions or hydrolysis
2. Phase 2: addition of a number of molecules that conjugate with the drug molecule

Question 4

Why is metabolism important?

Answer 4

Essential for lipophilic compounds that would otherwise just diffuse through renal cell plasma membranes into the plasma and back into the body
Can also activate an inactive pro-drug

Question 5

What happens during phase 1 metabolism?

Answer 5

Cytochrome P450; CYP450, large family of molecules will optimally metabolise different drug molecules

Question 6

What are CYP450s?

Answer 6

Enzymes
Generalist
Take a long time to metabolise compared to highly specific specialised enzymes

Question 7

What factors can affect metabolism?

Answer 7

Age, gender, general health (heart, renal, hepatic), induction and inhibition by Rx and OTC drugs

Question 8

How does induction affect metabolism?

Answer 8

Increase the transcription and translation or slow the degradation of CYP450s
Over 200 inducers
Increases the rate of metabolism
Typically occurs over 1-2 weeks

Question 9

What impact does induction have?

Answer 9

Alters the rate of metabolism of drugs meaning the dosage of certain drugs may have to be increased

Question 10

How does inhibition affect metabolism?

Answer 10

Elevation of drug plasma levels
Risk of toxic side effects
Occurs over 1-2 days

Question 11

What type of inhibitors are there?

Answer 11

Competitive- Metabolised at the same site

Non competitive- Inhibitor binds to a separate site

Question 12

What happens during phase II?

Answer 12

Carried out by hepatic enzymes
Further increases the ionic charge
Conjugated to other molecules

Question 13

What other molecule are they conjugated to?

Answer 13

• Glucornonide
• Sulphate
• Gluathione
• N-acetyl

Question 14

What is excretion?

Answer 14

Removal of the metabolised drug from the body

Question 15

Where does excretion take place?

Answer 15

Mainly the kidneys but some via the intestines, lungs or skin

Question 16

What are the three stages of renal elimination?

Answer 16

Glomerular filtration
Active Proximal tubular secretion
Passive Distal tubular reabsorption

Question 17

What happens in the glomerulus?

Answer 17

20% of renal blood supply
Unbound free metabolites diffuses out into the Bowman’s capsule
Process is limited by the GFR 125ml/min

Question 18

What happens in the proximal tubules?

Answer 18

Remaining 80% of renal blood flows through the peritubular capillaries
Charged molecules and their polar metabolites are transported through OATs and OCTs
Most effective as it receives 80% blood

Question 19

What happens in the distal tubules?

Answer 19

Water is reabsorbed
Drug concentration increases
If in lipophilic form it is reabsorbed down it concentration gradient

Question 20

Define clearance?

Answer 20

Rate of elimination

The volume of plasma that is completely cleared of drug per unit time

Question 21

How is it calculated?

Answer 21

Total body clearance= Hepatic clearance + Renal clearance

Question 22

What factor affect clearance?

Answer 22

Same as affect elimination
HRH
Heart - cardiovascular/ circulatory factors affecting flow to main organs of elimination
Renal - factors affecting renal elimination
Hepatic - factors affecting hepatic elimination

Question 23

What is the drug half life?

Answer 23

The amount of time over which the concentration a drug in the plasma decreases to one half of that concentration value it had when it was first measured

Question 24

What does the drug half life tell you?

Answer 24

How long the drug will stay in your body

Dosing regime

Question 25

What is the drug half life calculation?

Answer 25

t1/2= 0.693 (or 0.7) x Vd / CL

Question 26

What does linear or first order kinetics mean?

Answer 26

Rate of the process of interest is dependent on the concentration
e.g. relatively few molecules in the plasma (low concentration) rate of elimination is slow
Concentration is high the rate of elimination is high

Question 27

What is zero order or non linear kinetics or saturated kinetics?

Answer 27

For a high concentration of drug the kinetics are no longer concentration dependent and are said to be saturated as they cannot work any faster

Question 28

Is drug clearance linear or non linear kinetics?

Answer 28

Most drugs at therapeutic levels have linear kinetics
At high concentration non linear
Transporters are generalists- sometimes it takes a long time to clear a drug sometimes

Question 29

What drugs display saturated kinetics?

Answer 29

High dose aspirin, phenytoin, verapamil, fluoxetine
Alcohol and MDMA (ecstasy)
Can only occur with polypharamacy