Pharmacokinetics

Question 1

What does pharmacokinetics refer to?

Answer 1

Refers to the journey of drugs around the body.

Question 2

What is the full route of the drug around the body?- starting with administration

Answer 2

Administration

Absorption

Distribution

Metabolism

Excretion

(AADME)

Question 3

What are the 2 systems drugs can be administered through?

Answer 3

Systemic- across the entire organism

Local- restricted to one area

Question 4

What are the sites used for administration?

Answer 4

• Enteral- Gastro-intestinal administration
• Parenteral- Outside the GI tract.
• Remember that IV administration has a rapid onset of action but is invasive and needs training
• Intraperitoneal is not a common route of administration- peritoneal cavity has a rich blood supply which means that the drug has good access to the blood supply.

Question 5

What are the 2 ways a drug moves around the body (from administration to systemic circulation)?

Answer 5

• Bulk flow transfer (i.e. in the bloodstream and, to a degree, in the gut)
• Diffusional transfer (i.e. molecule by molecule over short distances)

Question 6

When drugs move across the body, we think about compartments and barriers- what do they mean?

Answer 6

Compartments= aqueous (e.g. blood, lymph, extra cellular fluid, intra cellular fluid)

Barriers= lipid (i.e. cell membranes- epithelium and endothelium)

Drugs need to exist in aqueous compartments but be able to cross lipid barriers.

Most targets and receptor are on the outside of the cells but the drug molecules still have to get there.

Question 7

What are the different ways to cross lipid barriers?

Answer 7

1. Diffusion- only if the drug is lipid-soluble
2. Diffusion through aqueous pores- this is the least relevant because the molecules have to be very small to go through these pores.
3. Carrier molecules (through active process)
4. Pinocytosis- membrane pinches off with drug embedded in membrane and vesicle enters the cells.

Question 8

Drugs and their ionisation state

Answer 8

Most drugs are either weak acids or weak bases. Therefore, drugs exist in ionised (polar) and non-ionised (non-polar) forms- the ratio depends on the pH. The ionisation state heavily depends on pH.

Question 9

Which ‘form’ of the drug will be more lipid-soluble?

Answer 9

The unionised form of drugs are going to be more lipid-soluble than the ionised form of the drug.

Question 10

Important thing to remember:

Answer 10

Weak acids will be more unionised in acidic environments and weak bases will be more unionised in alkaline environments.

Question 11

What does pKa of a molecule describe?

Answer 11

How readily the molecule dissociates

Question 12

What information do you know if you know the pKa of a drug and the pH of the compartment that it’s in?

Answer 12

You get the proportion of ionised over unionised.

Remember that the pKa of the drug does NOT change but the pH of the drug environment will change

Question 13

how do you interpret the result of the henderson-hasselbalch equation?

Answer 13

If the result is above 1 there is more unionised drug compared to ionised.

As long as the pH is below the pKa, there is more unionised (for acids)

If pH below pKa for bases, there is more unionised

^FOR BASES, THE FRACTION IS THE OTHER WAY ROUND- REMEMBER THAT IT FLIPS!

Question 14

What happens if the pKa and pH are the same?

Answer 14

There is a 50:50 split of unionised and ionised

Question 15

What is ion trapping?

Answer 15

Lipid barriers prevent soluble drugs from moving around

Question 16

What will an Iv of sodium bicarbonate do?

Answer 16

It increases excretion because it raises the pH of the urine. If drugs are ionised, it will stay in the tubules, if it was unionised it’d just diffuse out of the tubules. Sodium bicarbonate helps excretion of acidic drugs.

Question 17

What are the 4 factors affecting drug distribution?

Answer 17

1. Regional blood flow
2. Extracellular binding (plasma-binding protein)
3. Capillary permeability
4. Localisation in tissues

Question 18

Describe the ‘regional blood flow’ factor affecting drug distribution

Answer 18

If there is increased blood flow (e.g. in exercise) there is more delivery of drug per unit time to an organ. At rest, the liver gets a high cardiac output (27%) and the brain gets 14%. Therefore, they will get a larger proportion of the drug. When you eat a meal, there is increased blood flow to the gut, therefore more drug is diverted there.

Question 19

Describe the ‘extracellular binding’ factor affecting drug distribution

Answer 19

Plasma binding proteins (proteins in the blood plasma that bind to molecules of the drug)- provide a reservoir especially for drugs like aspirin and warfarin. If the drug is bound to plasma protein, it is not leaving the blood. Particular problem with acidic drugs, like aspirin (50-80% bound). This can be an issue when there are more than one drugs wanting to bind- they will displace each other. Therefore, there will be a higher dose of drug in the bloodstream.

Question 20

Describe the ‘capillary permeability’ factor affecting drug distribution

Answer 20

Most capillaries are continuous. Small water-filled gap junctions between the endothelium cells. Not too much of an issue with lipid-soluble drugs. If not lipid-soluble, they need a mechanism. This is a particular problem in the brain- there are no water-filled gap junctions- there are tight junctions to form the blood-brain barrier. Water-soluble drugs are dependent on the saturation/ concentration of the carrier proteins on the surface of the tissue itself.

Question 21

What are the different types of capillaries?

Answer 21

You can have fenestrated walls, continuous walls and discontinuous walls.

There are three types of capillary architecture:

1. Fenestrated- more permeable to drugs.
2. Continuous- found in normal vessels (has water-filled gap junctions).
3. Discontinuous- large gaps between endothelial cells.

Question 22

What is the ‘localisation in tissues’ factor affecting drug distribution?

Answer 22

Adipose tissue gets very little blood supply. REALLY Fat-soluble drugs (like general anaesthetic) will still distribute into that tissue, even with the reduced blood supply. This can slow down drug distribution as it will take time to leak back into the blood. This is why general anaesthetic takes a while to wear off.

Question 23

What are the 2 main routes of excretion?

Answer 23

The kidney- into urine

The liver- into bile and into faeces

Question 24

Describe excretion at the kidneys

Answer 24

Blood sent to kidney- low molecular weight drugs filtered at the glomerulus.

The rest sent in the plasma which then undergo active secretion (there are a lot of transporters which recognise the drug molecules). They chuck them into the kidney tubules. If the drug is lipid-soluble however, it will diffuse right back across (this depends on the pH and the pKa of the drug).

Question 25

Describe the route of excretion by the liver?

Answer 25

In the liver there are discontinuous capillaries as it allows for drugs to easily leave the blood and enter the liver tissue. Hepatocytes do the metabolism of the drugs. Key aims here is to make drug more water soluble. This proves problems for lipid barriers. Therefore, you need active protein carriers. It is chucked into the bile and lost in the faeces.

Question 26

What is enterohepatic recycling is a problem?

Answer 26

Enterohepatic recycling is a problem.

Bile containing the metabolised drug enters the gut. The gut bacteria break down the conjugate the lipid-soluble form of the drug is happy to diffuse back into the liver. It can even go back to the systemic circulation.

The drug cycles round and round.

Question 27

What are other routes of excretion?

Answer 27

saliva, sweat, milk, genital secretions

Lungs- excreting alcohol (breathalyser)

Question 28

what does bioavailability mean?

Answer 28

Proportion of the administered drug that is available within the body to exert its pharmacological effect. Linked to absorption. 100% of drug in, into gut, but how much is absorbed there. It is common for 20% bioavailability.

Question 29

What is the apparent volume of distribution

Answer 29

The volume in which a drug appears to be distributed- an indicator of pattern of distribution. Eg fat-soluble drug.

Question 30

What does the biological half-life mean?

Answer 30

Time taken for the concentration of drug (in blood/plasma) to fall to half its original value. How quickly you’re metabolising and excreting drugs. If you take the drug every 6 hours, for example, you are estimating that the drug is being metabolised and excreted all in that time.

Question 31

What does clearance mean?

Answer 31

Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time