Biopharmaceutical considerations in drug discovery Flashcards
what are structure activity relationships
the relationship between chemical structure and pharmacological activity for a series of compounds
what do structure property relationships include
- structure activity relationships
- factors affecting pharmacokinetic behaviour
- factors affecting formulation
give examples of drugs which are transported across membranes by active transport
- methyldopa
- levodopa
how do most drugs cross membranes
by passive diffusion
what is the rate of diffusion
rate of diffusion= f(membrane factors + drug molecule factors)
what do membrane factors affect
differences in structure of membranes affect rate of passage into various organs
- variation between individuals
give examples of drug related factors
- concentration
- RMM
- chemical structure and functional groups
- lipophilicity
what is Ficks 1st law
a molecule will tend to move from an area of high concentration to one of a lower concentration
describe the effect of concentration on transport across a membrane
the rate of diffusion of a drug molecule across a membrane is proportional to the difference in concentration on either side of the membrane
describe the effect of molecular mass on rate of diffusion
- rate of diffusion is inversely proportional to RMM
- most drugs are small molecules
- differences in RMM between members of a congeneric series tend to be small
describe the effect of chemical structure and functional groups on the rate of diffusion
- rate of diffusion depends on interaction between drug molecule and lipid bilayer
- comparisons usually made between structurally related molecules
- some functional groups are associated with problems in bioavailability
describe the effect of lipophilicity on rate of diffusion
- lipid soluble drugs have high permeability constants and penetrate membranes easily
- highly polar dugs have low permeability constants and don’t penetrate membranes easily
- increasing lipophilicity increases rate of passage across membrane
how is lipophilicity measured
partitioning between an aqueous environment and a lipid environment
describe the process of measuring partition coefficient
- place equal volumes of water and organic solvent in seperating funnel
- add drug substance
- measure concentration of drug in each phase
- express partition coefficient, K, as ratio of drug in one phase to drug in second phase
what is log P
describes partition coefficient in an octanol/water system
- log of the partition coefficient of the compound between an organic solution and an aqueous phase at a pH where all the compound molecules are in neutral form
- drugs with log P< 2 don’t generally penetrate BBB
give the equation representing log P
log P= log[drug in organic phase]/[drug in aqueous phase]
describe the polarity of small drug molecules
most small organic molecules are non polar unless
- they carry a charge
- they have several polar functional groups (glucose)
what are the implications of lipophilicity
- extremely important parameter affecting passage across membranes
- implications for both pharmacodynamic and pharmacokinetic properties of drug molecules
- important for aqueous solubility
describe the properties of ionisable salt forms of drugs
- are more polar than corresponding non ionised form
- have higher melting point and better crystallinity
- better for formulation purposes
- eg. codeine phosphate
describe the equilibria in ionisation
organic acids and bases don’t fully dissociate in aqueous solution
HA – H+ + A-
B + H+ — BH+
What is log D
log of the distribution coefficient of a compound between an organic solvent and an aqueous phase at a specified pH
- a portion of the compound molecules may be in neutral form and a portion in ionic form
give the equation which represents log D
log D= log[drug in organic phase]/[drug in aqueous phase]
what is the bronsted Lowry model
- acids are proton donors
- bases are proton acceptors
- on loosing or accepting a proton, a molecule becomes ionised
what are the biological considerations of nicotine
free base nicotine will be more rapidly absorbed than ionised forms
what are the formulation considerations of nicotine
- free base nicotine has a lower boiling point and is more volatile
- concentration of nicotine is high in higher pH smoke
describe the pH differences between organs
- the intracellular pH (7) is slightly lower than extracellular pH (7.4)
- basic drugs will be concentrated slightly intracellularly
- pulmonary tissue has a pH= 6.8 to 6.5, so several basic drugs achieve higher concentrations in this organ
what is forced alkaline diuresis
pH of urinary fluid is raised
describe the lipophilicity of the blood brain barrier
- lipid in nature
- hydrophilic drugs penetrate with difficulty
what are the quaternised derivatives of atropine
N methyl atropine is a quaternary ammonium compound
- atropine has hallucinogenic activity but quaternised derivative does not
what is the partitioning behaviour of drugs important for
- important in drug action
- important consideration in the design of new drugs
