L13- OPTIMISING DRUG PROPERTIES TO ENSURE GOOD ORAL BIOAVAILABILITY

list some of the requirements for an effective drug molecule

• efficacy 

• must achieve intended therapeutic effect 

• appropriate size and structure 

• chemical stability 

• solubility

• suitable log_p value ( 1→3) -lipophilicity 

explain the importance of log_^p in drug absorption

• a balance is needed between the solubility of a drug and its ability to partition ( go from solid→ aqueous→ lipid→ aqueous )

• hydrophilic character is needed to dissolve in the water but if too hydrophilic then it’ll be poor at partitioning into the cell membrane 

• lipophilic character is needed to allow the drug to partition into the cell membrane but if its too high it’ll affect the drugs solubility and the drug will also struggle to partition back out of the cell membrane-it can they accumulate into the fatty tissue  

what are the factors that afftect the lipophilicity and the log_p 

• the chemical structure of the drug- different functional groups have different lipophilic and hydro 

• more specifically ionisation and hydrogen bonding 

what are the majority of drugs ( weak or strong acids/bases )

weak acids and bases 

what affects the ionisation of a drug

varying pH of the environment and their own pka ( pka=how easiliy a drug will ionise or not)

explain the difference between ionised and unionised drugs when considering oral drug absorption

• unionised drugs- have increased lipophilicity and are more optimal for membrane permeability

• ionised drugs- have increased drug absorption and have a reduced membrane permeability

between strong and weak acids/bases, which is better absorbed and why 

weak is better absorbed as…

strong acids and bases are less absorbed as only a small percentage of them will remain unionised which the optimum for drug absorption

strong acids and bases exists in mostly the ionised form  

what is something that an ionised drug can do to be absorbed though the membrane

it can pair with an ion of the opposite charge to neutralise and pass through

explain the effect of hydrogen bonding on drub absorption

• before a drug can be absorbed de-solvation must occur-when a molucule’s loses its bound water molecules before crossing the membrane 

• the hydrogen bond must be broken before the drug enters the cell membrane

• the more of the hydrogen bonds the more energy required to break them 

• so molecules with more hydrogen bonds are less favourable as more energy is required to allow them desolvate which is needed before they can pass through 

when considering molecules proton donors and acceptors which elements are considered

OH AND NH= proton doners

N AND O = proton acceptors

what is lupinskis rule of 5

its a rule that predicts that poor absorption is likely is 2 or more of the criteria regarding:

• lipophilicity- log_p

• size-molecular weight

• hydrogen bonding- number of acceptors and donors

what are the exceptions to the rule 

drugs which are substrates of transporters 

as the rule only applies for passive diffusion 

also the rues just act as a guide as some drugs break the rules but are still well absorbed

explain other rules/ factors that could  affect/ decide the likehood of a drug being absorbed 

verbers rules- it sates that the number of rotational bonds should be less than or equal to 10 as the more roattional bonds the more conformational forms and this incares the chances of finding the optimum 

also the total polar surface area needs to be less than or equal to 140A²

what are things that can be done to increase how well a drug is absorbed 

• modify the polarity to change the log_p 

• this can be done by including ionisable groups to increase solubility 

• change the pka of functional groups to increase lipophilicity 

• reduce the number of hydrogen acceptors and donators 

• pro drug strategies- making the drug more lipophilicity by adding functional  groups that are later cleaved off

explain the pro-drug approach of increasing a drugs absorption

• this includes taking a drug that is quiet hydrophilic and making it more lipophilic so that it can diffuse across the membrane

• they are modified with lipophilic groups after absoption metabolic process within the cells remove the groups to reveal the parent drugs