Drug Absorption
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What is meant by pharmacokinetics?
Pharmacokinetics is what our body does to the drugs that enter it
What is ADME?
• A - absorption • D - distribution • M - metabolism • E - excretion
Why is ADME important?
• Essential for safe and intelligent use of medicines by doctors • Designing dosage regimens • Monitoring treatment compliance • Substance of abuse monitoring • Medicine licensing requirement
What is the biggest key reason for withdrawal of candidate drugs from development?
A lot of drugs never actually made it due to poor pharmacokinetic properties - anything on the ADME list, eg. poor absorption orally, or metabolism too quick so too many toxic products etc.
What is meant by bioavailability?
The proportion of the administered drug reaching systemic circulation
What method of administering drugs has 100% bioavailability?
Drugs given intravenously
What is the more convenient way of drug admin: oral or i.v.?
oral
What are some routes of drug administration?
• Inhalation • Intravenous injection • Subcutaneous Injection • Intramuscular injection • Oral
What is the difference between facilitated diffusion and active transport?
Both use transporters but facilitated diffusion works along conc gradient whereas active transport is AGAINST
What method of transport do most medicines move by?
Passive diffusion (most) Facilitated diffusion (few) Active transport (v few)
What 3 components are important factors stated by Fick’s Law for rate of diffusion?
• Surface area • Conc difference • Permeability (lipid sol / ionisation)
If a drug is ionised / charged, is it more or less likely to pass through the lipid bilayer?
Less likely, neutral or unionised drugs are better are passing through
How will a weak acid react in an acidic environment?
It will remain unionised (AH)
How will a weak basic drug react in an acidic environment?
It will ionise (from B) -> BH+ and OH-
Will a lipophillic drug be absorbed effectively or not?
Yes, it will be absorbed effectively
What is meant by pKa?
It is the dissociation constant for a drug, used in Henderson-Hasselbach equations
Aspirin (pKa=3.5) is a weak acid, when it reaches the stomach (pH = 1) what should happen?
Aspirin will remain unionised (HAsp) so will be able to cross the gastric mucosa membrane
Are basic or acidic drugs better absorbed in the stomach?
Acidic as the stomach environment is acidic also so allows the drug to remain unionised
What is meant by ‘ion trapping’?
When the drug becomes ionised after crossing a membrane into circulation, so remains as charged particles within the blood so can’t go anywhere (temporarily)
In what (2) instances can basic drugs not be given orally?
• If very basic • or permanently ionised
Can basic drugs be given orally? How?
Even though they are poorly absorbed from the stomach, they are better absorbed from the intestine (pH7), the SA of intestine compensates for low absorption efficacy. Many drugs are absorbed in the intestines.
What do the Lipinski Rules suggest about orally-active drugs?
That they be in violation of no more than one of the following: • Molecular weight < 500 • No more than 5 H bond donors • No more than 10 H bond acceptors • Log P < 5
What are the Lipinski Rules there for?
ADME optimization
Will a higher urinary pH increase or decrease excretion of weak bases?
Decrease, the weak base remains unionised in the alkaline urine so therefore can be reabsorbed back at the kidney - so less excreted.