Pharmacokinetics Flashcards
(31 cards)
What does pharmacokinetics refer to?
Refers to the journey of drugs around the body.
What is the full route of the drug around the body?- starting with administration
Administration
Absorption
Distribution
Metabolism
Excretion
(AADME)
What are the 2 systems drugs can be administered through?
Systemic- across the entire organism
Local- restricted to one area
What are the sites used for administration?
- 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.
What are the 2 ways a drug moves around the body (from administration to systemic circulation)?
- 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)
When drugs move across the body, we think about compartments and barriers- what do they mean?
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.
What are the different ways to cross lipid barriers?
- Diffusion- only if the drug is lipid-soluble
- Diffusion through aqueous pores- this is the least relevant because the molecules have to be very small to go through these pores.
- Carrier molecules (through active process)
- Pinocytosis- membrane pinches off with drug embedded in membrane and vesicle enters the cells.
Drugs and their ionisation state
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.
Which ‘form’ of the drug will be more lipid-soluble?
The unionised form of drugs are going to be more lipid-soluble than the ionised form of the drug.
Important thing to remember:
Weak acids will be more unionised in acidic environments and weak bases will be more unionised in alkaline environments.
What does pKa of a molecule describe?
How readily the molecule dissociates
What information do you know if you know the pKa of a drug and the pH of the compartment that it’s in?
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
how do you interpret the result of the henderson-hasselbalch equation?
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!
What happens if the pKa and pH are the same?
There is a 50:50 split of unionised and ionised
What is ion trapping?
Lipid barriers prevent soluble drugs from moving around
What will an Iv of sodium bicarbonate do?
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.
What are the 4 factors affecting drug distribution?
- Regional blood flow
- Extracellular binding (plasma-binding protein)
- Capillary permeability
- Localisation in tissues
Describe the ‘regional blood flow’ factor affecting drug distribution
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.
Describe the ‘extracellular binding’ factor affecting drug distribution
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.
Describe the ‘capillary permeability’ factor affecting drug distribution
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.
What are the different types of capillaries?
You can have fenestrated walls, continuous walls and discontinuous walls.
There are three types of capillary architecture:
- Fenestrated- more permeable to drugs.
- Continuous- found in normal vessels (has water-filled gap junctions).
- Discontinuous- large gaps between endothelial cells.
What is the ‘localisation in tissues’ factor affecting drug distribution?
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.
What are the 2 main routes of excretion?
The kidney- into urine
The liver- into bile and into faeces
Describe excretion at the kidneys
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).
