Pharmacokinetics 3

Question 1

Assumptions we make regarded LogP and ionisation of a drug

Answer 1

• Only lipid soluble molecules can cross the GI membrane
• Most drugs are weak acids or bases which can ionise to form charged, water soluble species
• Therefore, it is expected that only the UNIONISED form of a drug will easily cross the membrane to any significant extent

Question 2

What is the henderson-hasselbalch equation used to work out

Answer 2

• The exact % of a drug that is ionised at a given ph

Question 3

What does the pKa of a drug tell us

Answer 3

• pKa is when half the drug is charged (ionised) and half is uncharged (neutral)
  Tells us about:
• Absorption and permeability: e.g. weak acids (low pKa) absorb better in stomach, but weak bases (high pKa) absorb better in intestine
• Solubility and disturbance: drugs tend to dissolve better in water when ionised

Question 4

Interpret this graph in terms of ionisation

Answer 4

• At low pH, aspirin is mainly unionised (no charge) as theres lots of H+, so acid groups of the API cant dissociate
• At high pH, its ionised due to low H+ conc, so the acid groups of the API can dissociate easily

Question 4

Interpret this graph for chloropromazine in terms of ionisation

Answer 4

• At low pH, chlorpromazine is largely ionised – this is not surprising, as concentration of H+ in solution is high, so the basic groups of the APIs will take up H+
• At high pH, chlorpromazine is largely unionised – this is not surprising, as concentration of H+ in solution is low, so there is no driving force pushing H+ onto the basic groups of the APIs

Question 5

You only need to go BLANK pH units either side of the pKa value to get almost complete ionisation or almost complete lack of ionisation

Answer 5

You only need to go + or - 2 pH units either side of the pKa value to get almost complete ionisation or almost complete lack of ionisation

Question 6

Aspirin has a pKa = 3.5
What pH will this be unionised and ionised

Answer 6

Question 7

What is the major limiting factor in GIT absorbtion

Answer 7

• Surface area regardless of ionisation state
• e.g. weak acids are in the optimal non-ionized state for absorption in the acidic environment of the API of the stomach, but the surface area of the stomach is so small that in practice, the extent of absorption is negligible
• Whilst in a non-optimal ionized state for absorption in the neutral environment of the small intestine, absorption is extensive due to massive surface area and equilibrium

Question 8

What is lipinskis rule of five

Answer 8

• Candidate drugs that conform to the “rule of five” stand a better chance of progressing to market
• RULE 1: Molecule should have fewer than 5 H-bond donor groups (e.g. –OH)
• RULE 2: Molecule should have fewer than 10 H-bond acceptor groups (e.g. the oxygen atom of -C=O)
• RULE 3: Molecule should have a total MWt of less than 500
• RULE 4: Molecule should have a log P value less than 5

Question 9

Biopharmaceutical classification system - What are the four classes

Answer 9

• Most widely used drugs are class I, II and III
• Class IV drugs (low solubility, low permeability) are more problematic and less well represented in therapeutic use