Absorption and distribution

Question 1

pKa, pH and absorption

Answer 1

• If the pH is lower than the pKa value the molecule wont be ionised and therefore will have a neutral charge and will be able to pass though the membrane
• If the pH is higher than the pKa value the molecule will be ionsied and and will be charged and so wont be able to pass through the membrane

Question 2

Typical plasma concentration/time profiles

Answer 2

1. Absorbed and enters the bloodstream so concentration rises
2. Compound distributes into tissue and absorption rates start to slow
3. Drug is metabolised and excreted from the systemic circulation
   * Theraputic region between the MEC (minimum effective conc) and MTC (maximum tolerated conc) is where you want it to be

Question 3

Factors affecting absorption

Answer 3

1. Acid stability - tablet has to pass through the stomach before it gets inot the systemic circulation, drug needs to be stable to these acidic conditions at body temp
2. Solubility - the drug requires sufficient aqueous solubility for dissolution, as only dissolved compound can be absorbed
3. Permeability - poor permeability, gut wall metabolism can all lead to poor absorption across the intestinal walll
4. Lipophilicity - drugs which are absorbed passively through the gut wall also need to be sufficiently lipophilic to cross cell membranes but polar enough to be sufficiently water soluble
5. Metabolism

Question 4

Absorption mechanics

Answer 4

• Transcellular absorption - diffusion through one membrane on one side of the cell to the other side, along conc gradient
• Paracellular absorption - drug passes through gaps between cells, restricted to low molecular weight and has to be hydrophillic drugs
• Active transport - drugs carried through a membrane by a transporter, required ATP, against conc gradient

Question 5

Distribution

Answer 5

• The reversible transfer of a drug to and from the systemic circulation
• Factors influencing distribution: pKa, lipophilicity, plasma protein binding
• Tissue pH is slightly lower than plasma pH and therefore basic compound tend to distribute out of plasma into tissue more than acidic compounds

Question 6

Interactions with blood proteins

Answer 6

• Drugs can bind to macromolecules in the blood known as plasma protein binding (PPB)
• Compounds with high PPB are retained in the plasma and cannot therefore distribute inot the tissues
• Only unbound compounds are available for distribution into tissues = bioavalibility

Question 7

Interactions with blood proteins

Answer 7

• Drugs can bind to macromolecules in the blood known as plasma protein binding (PPB)
• Compounds with high PPB are retained in the plasma and cannot therefore distribute inot the tissues
• Only unbound compounds are available for distribution into tissues = bioavalibility

Question 8

Plasma protein binding

Answer 8

• Serum albumin is the most abundant protein in blood and binds with various hydrophobic molecules with a preference for acids
• Albumin binding can also be used to increase the long term solubility and release of hydrophobic drugs
• When multiple drugs are given to a patient at once, they will compete for binding to blood proteins which can make one or both of them more bioavailable, this is usually a risk tho because it can lead to toxicity