Week 2 - Drug Distribution

Question 1

Define distribution & explain the importance of distribution

Answer 1

Distribution - movement of drug from blood into tissues i.e. site of action (across a a membrane)
- distribution allows drug to have therapeutic effect in target tissue BUT can also reach other organs + exert effects

Question 2

What factors affect distribution rate

Answer 2

1. Permeability of tissue membrane (as drug needs to cross it)
2. Binding of dug to plasma proteins
   - ONLY UNBOUND drug can cross membrane
3. Delivery of drug to tissue by perfusion (depends on blood flow)
4. Drug molecule properties
   - lipophilic, hydrophilic, ionised etc.
5. Binding to acidic phospholipids in tissue membranes

Question 3

What is perfusion limited distribution

Answer 3

• MEMBRANE isn’t a barrier to drug distribution
  
  • membrane is permeable = small lipophilic molecules can cross easily from blood into tissue
• DEPENDS on BLOOD FLOW , changes in flow affects distribution
• ONLY applies to small, lipophilic molecules
• Perfusion varies across tissues
  - highly perfused tissues = good blood supply = drug distributed rapidly
  - poorly perfused tissues = poor blood supply = drug distributed slowly + eliminated slowly (equilibrium is reached slower)

Question 4

What is permeability-limited distribution

Answer 4

• MEMBRANE is a BARRIER either its impermeable or drug is large, hydrophilic / polar / ionised molecule
  - changes in blood-flow doesn’t affect distribution
  - more lipophilic molecule = quicker rate of distribution
  - ionised / polar drug = slower rate of distribution
• Drug requires transporters (AT) to move across membrane

Question 5

What is “volume of distribution” ( V or Vd)

Answer 5

Is the theoretical volume necessary to contain the total amount of drug (in body tissue) at the same conc. observed in the blood plasma (equilibrium)
(volume required in order to have same conc. of drug in tissue compared to in blood plasma)

V = amount of drug in body (at equilibrium) / measured drug conc. in blood plasma
V varies depending on tissue binding, plasma protein binding and binding to blood cells

IMPORTANCE: V helps determine loading dose
loading dose = initial high dose to achieve target conc. quick
loading dose is followed by maintenance dose

Question 6

What affects volume of distribution

Answer 6

1. Acidic drugs = low V
   - have high affinity for plasma protein
   - bind to plasma protein = not distributed outside of plasma
2. Basic drugs = high V
   - have high affinity for acidic phospholipids in tissues = distributed
3. Monoclonal antibodies = low V

Question 7

Explain the role of plasma protein binding (in drug distribution)

Answer 7

• ONLY UNBOUND drug (fu) can cross membrane + enter tissues
  - drug binding is reversible (forms complex when bound)
  - fu can change in diseases, impairment, pregnancy etc.
• Plasma proteins inc. Albumin (acid drugs), a1-acid GP (basic drugs), Globulins (steroids)

fu IMPORTANCE:
- depends on; affinity of protein for drug, conc. of protein and drug
- highly bound drugs = low fu (fu = fraction unbound)
- drugs that dint bind = high fu