Biopharmaceutical considerations in drug discovery

Question 1

what are structure activity relationships

Answer 1

the relationship between chemical structure and pharmacological activity for a series of compounds

Question 2

what do structure property relationships include

Answer 2

1. structure activity relationships
2. factors affecting pharmacokinetic behaviour
3. factors affecting formulation

Question 3

give examples of drugs which are transported across membranes by active transport

Answer 3

• methyldopa
• levodopa

Question 4

how do most drugs cross membranes

Answer 4

by passive diffusion

Question 5

what is the rate of diffusion

Answer 5

rate of diffusion= f(membrane factors + drug molecule factors)

Question 6

what do membrane factors affect

Answer 6

differences in structure of membranes affect rate of passage into various organs
- variation between individuals

Question 7

give examples of drug related factors

Answer 7

• concentration
• RMM
• chemical structure and functional groups
• lipophilicity

Question 8

what is Ficks 1st law

Answer 8

a molecule will tend to move from an area of high concentration to one of a lower concentration

Question 9

describe the effect of concentration on transport across a membrane

Answer 9

the rate of diffusion of a drug molecule across a membrane is proportional to the difference in concentration on either side of the membrane

Question 10

describe the effect of molecular mass on rate of diffusion

Answer 10

• 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

Question 11

describe the effect of chemical structure and functional groups on the rate of diffusion

Answer 11

• 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

Question 12

describe the effect of lipophilicity on rate of diffusion

Answer 12

• 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

Question 13

how is lipophilicity measured

Answer 13

partitioning between an aqueous environment and a lipid environment

Question 14

describe the process of measuring partition coefficient

Answer 14

1. place equal volumes of water and organic solvent in seperating funnel
2. add drug substance
3. measure concentration of drug in each phase
4. express partition coefficient, K, as ratio of drug in one phase to drug in second phase

Question 15

what is log P

Answer 15

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

Question 16

give the equation representing log P

Answer 16

log P= log[drug in organic phase]/[drug in aqueous phase]

Question 17

describe the polarity of small drug molecules

Answer 17

most small organic molecules are non polar unless
- they carry a charge
- they have several polar functional groups (glucose)

Question 18

what are the implications of lipophilicity

Answer 18

1. extremely important parameter affecting passage across membranes
2. implications for both pharmacodynamic and pharmacokinetic properties of drug molecules
3. important for aqueous solubility

Question 19

describe the properties of ionisable salt forms of drugs

Answer 19

1. are more polar than corresponding non ionised form
2. have higher melting point and better crystallinity
   - better for formulation purposes
   - eg. codeine phosphate

Question 20

describe the equilibria in ionisation

Answer 20

organic acids and bases don’t fully dissociate in aqueous solution
HA – H+ + A-
B + H+ — BH+

Question 21

What is log D

Answer 21

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

Question 22

give the equation which represents log D

Answer 22

log D= log[drug in organic phase]/[drug in aqueous phase]

Question 23

what is the bronsted Lowry model

Answer 23

• acids are proton donors
• bases are proton acceptors
• on loosing or accepting a proton, a molecule becomes ionised

Question 24

what are the biological considerations of nicotine

Answer 24

free base nicotine will be more rapidly absorbed than ionised forms

Question 25

what are the formulation considerations of nicotine

Answer 25

• free base nicotine has a lower boiling point and is more volatile
• concentration of nicotine is high in higher pH smoke

Question 26

describe the pH differences between organs

Answer 26

• 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

Question 27

what is forced alkaline diuresis

Answer 27

pH of urinary fluid is raised

Question 28

describe the lipophilicity of the blood brain barrier

Answer 28

• lipid in nature
• hydrophilic drugs penetrate with difficulty

Question 29

what are the quaternised derivatives of atropine

Answer 29

N methyl atropine is a quaternary ammonium compound
- atropine has hallucinogenic activity but quaternised derivative does not

Question 30

what is the partitioning behaviour of drugs important for

Answer 30

• important in drug action
• important consideration in the design of new drugs