L29 - recap of bioavailability, dissolution, membrane transport Flashcards
pharmacodynamics
what the drug does to the body
pharmacokinetics
what the body does to the drug
bioavailability
amount of drug that reaches its site of action and the rate at which it gets there
LADME
- Liberation
- Absorption
- Distribution
- Metabolism
- Excretion
after extravascular administration how does the drug enter the blood?
- release: drug dissolves at administration site
- absorption: drug crosses biomembrane to reach blood
describe what happens if drug is rapidly released but membrane transported is slow?
- this is typical of hydrophilic molecules
- you can increase bioavailability by changing drug structure, e.g increase lipophilicity)
describe how to increase bioavailability of a poorly soluble / slowly released drug that easily permeates membrane?
- typical of lipophilic molecule
- optimisation of dosage form
dissolution process
- salvation of drug at crystal surface to create stagnant layer of saturated solution
- diffusion of dissolved molecules across layer into bulk solution
- observed rate of dissolution depends on slowest of these 2 steps
notes Whitney equation: overall rate of dissolution
dissolution rate = dC/ dt = D x S /h (Cs-Cb)
solubility of weak acids as a function of pH
- solubility (Cs) of weakly acidic drug predicted by:
- pH of sol
- pKa
- solubility of ionised drug (S0)
solubility of weak bases as function of pH
- solubility of weakly basic drugs can be predicted given:
- pH of sol
- pKa
- solubility of unionised drug (S0)
transcellular pathway
- major pathway
- passive diffusion: solutes diffuse down a conc gradient. partiton into lipid bilayer and then out to cytoplasm
- aqueous pore: hydrophilic channel made by aquaporin proteins
- facilitated diffusion: selective, carried protein, down conc gradient
- active transport: selective, against conc gradient
passive diffusion
system not in equilibrium moves towards equilibrium, so flux/flow must occur
equation for flux
J = C x v x A
conc x velocity x area
what is flux proportional to?
change in conc
passive transport: ficks first law
- flux increases with membrane surface area
- SA of the SI is bigger than stomach
- flux is inversely proportional to membrane thickness (Δx).
- flux is correlated to difference between drug conc on either side of memb
partition coefficient (K)
- k quantifies distribution of drug between membrane and aqueous phases which it separates
- K = Coil/Cw
- K= ratio of drug’s solubility in 2 phases
- K= drugs relative affinity for oil compared to water
what is logP?
octanal water partiton coefficient - used to find drugs lipophilicity
what does a drugs lipophilicity affect?
absorption, distribution, elimination
what could happen if drugs are too lipophilic?
deposited in fatty tissue
why are polar functional groups needed on drugs?
to bind to receptors + ensue,es by h bonds
octanal water partition coefficient
- measures drug lipophilicity
- P = [drug]oct / [drug]water
P and log P of drug that is 10x more lipid soluble than water soluble?
P= 10
LogP = 1
P and log P of drug that is 100x more lipid soluble than water soluble?
P= 100
LogP= 2
P and log P of drug that is 5x more water-soluble than lipid-soluble?
P= 1/5 = 0.2
LogP = -0.7
pH partiton hypothesis
drug accumulates on side where pH favours ionisation.
- unionised drug = optimal memb transport as lipophillic
- ionised drug = hydrophilic = reduced transport
limitations of pH partition hypothesis
doesn’t take into account
1. type of epithelium
2. SA of absorption site
3. ionised drugs still absorbed to a small extent
4. AT of drugs
5. residence time of drug at delivery site
6. mass transfer of fluids
7. charged drugs can form ion pairs with oppositely charged species
lipinskis rule of 5
- predicts that good oral bioavailability when:
1. molecular weight ≤ 500
2. log P ≤ 5
3. No more than 5 hydrogen bond donors
4. No more than 10 hydrogen bond acceptors
5. All units are multiples of five
