Flashcards in Lecture 2 (Intro to MedChem) Deck (76):
Free bases or acids are often ____
Are they better or worse than a salt?
-less water soluble than ionized form
-difficult to measure (because they are hygroscopic)
-difficult to make into a dosage form
Why do we want to make a salt out of the free acids/bases?
because they are easier/better to work with (see previous card) and are more stable
Drug absorption across biological membranes is better in the ______ state
T or F: good drugs have only either lipid or water solubility
-most efficient drugs have some degree of water and lipid solubility
for a chemical to dissolve in a particular solvent the compound must be able to form attractive forces with the molecules of the solvent
it is possible to estimate the solubility properties of drug by examining its _____
Can we alter the solubility of a drug?
explain the 3 ways
-use acid or base to make the drug into a salt
-add substituents that are very water soluble:
-adding groups that are H bond donors and acceptors
-adding groups that can ionize
-changing dose form
Are dispersion forces strong or weak?
Dispersion forces are called ??
(wrongly called van der waals attraction)
Where do dispersion forces occur?
between induced and instantaneous formed dipoles
As molecule gets larger, dispersion forces get _____
(disperson forces increase as the total area for interaction between molecules increases)
Why do larger molecules become liquids? (ex. butane, hexanes, and octane are liquids but methane, ethane, and propane are gases)
increasing size = increasing dispersion forces
(also increasing weight is a factor)
What is stronger: dispersion forces or dipole-dipole bonds?
Where does a dipole-dipole bond occur?
happens between permanent dipoles
note** these are not formal charges (that would be an ionic rxn)
H-bonding is a special kind of ??
H-bonding is _____ than ordinary dipole-dipole bonding
When does H-bonding happen?
-happens between atoms with highly electronegative atoms attached to H
H-bonding plays a big role in making things more ??
hydrophilic (water soluble)
Molecules with many H-bond donors and acceptors are more ____ soluble
What is the H-bond donor?
electronegative atom with an attached hydrogen
What is the H-bond acceptor?
electronegative atom with a FREE (not tied up in resonance) lone pair of electrons
Are S, Cl, and F, weak or strong H-bond acceptors?
SH is NOT an H-bond ____
Amide N is NOT an H-bond _____
acceptor (lone pair on amide N cannot accept H-bonding due to resonance)
Why are intermolecular H-bonds between drug molecules in solution very uncommon?
Because H2O molecules will out compete the other drug molecules
in order to form a H-bond between drug molecules, it would first have to break the H-bonds formed with water (and this would require energy)
Explain how intramolecular H-bonds form in water (Note** very different than intermolecular H-bonds which we just previously deduced were very uncommon in water)
Bc the H-bonding pair are always super close in proximity it is easier to form H-bonds
What is intramolecular H-bonds forming in water known as?
effect of local concentration
(bc it is similar to having high concentrations of each other)
How does having too many H-bonds affect absorption?
those H-bonds have to be broken in order to cross the lipid membrane
**this represents the idea of having a practical limit H-bonds
Breaking H-bonds with water (in order to cross membranes) is _____
You don't want to have too many H-bond donors and acceptors or the drug will not _____
What is an ionic bond?
electrostatic interaction between cations and anions
Are ionic bonds strong?
What is an ion-dipole bond?
electrostatic interaction between a nation/anion and a dipole
When are ion-dipole bonds important?
between drugs and water
Can covalent bonds happen between drugs and solvent?
NO WAY JOSE
Where can covalent bonds be present?
can be part of drug receptor interactions (but this is rare)
Why is a covalent interaction between a drug and receptor BAD?
-because if the receptor is covalently attached to the drug - the receptor is not the receptor anymore
-it is now a foreign protein that the body attacks
What is the solubility o fa drug a function of?
It is a function of the lipophilic and hydrophilic groups within its STRUCTURE
How can we determine the relative solubility of a drug?
-can be determined with the PARTITION COEFFICIENT
What is the partition coefficient?
P = [drug in hydrophobic/lipophilic solvent (ex. octanol)]/ [drug in hydrophilic solvent (water)]
logP = ?
pi (not actual pi) - different kind of pi
What are the 2 very common functional groups that often increase water solubility?
N and O
-they polarize the molecule and act as H-bond acceptors and donors (with an attached hydrogen)
Ionizable groups increase ____ solubility
Give 3 examples of groups that increase lipid solubility
Hydrophilic groups have a _____ pi value
Lipophilic groups have a _____ pi value
LogPcalc value greater than +0.5 = ?
LogPcalc values less than +0.5 = ?
understand slide 21
one of the most important factors effecting the ____ of drugs is the LogP
Explain the 3 types of ways to cross biological membranes
-passive diffusion through aqueous channels
-passive diffusion through lipid (most important mechanism of absorption across membranes)
-facilitated transport (energy required)
What is 1 other important thing to consider when thinking about the ways that molecules can move through biological membranes?
**once a drug crosses the membrane and if the blood takes it away then it will make an equilibrium so as to drag more drug across the membrane
Why do drugs need to be hydrophilic?
-needs to have sufficient solubility so they dissolve out of solid dosage forms
-needs to have some solubility in biological fluids to transport to site of action
Why won't drugs that are too hydrophilic be absorbed across biological membranes?
-because they form too many H-bonds that need to be broken (which causes energy) in order for absorption to occur
When _____ there is sufficient lipophilicity to cross membranes
When ____ there is sufficient water solubility for dissolution and distribution
About 85 % of drugs have functional groups that are ___ to some extent
What is ionization controlled by?
pKa and external pH
pH of blood
pH of sweat/saliva
pH of fasting stomach
pH of fed stomach
pH of fasting duodenum
pH of fed duodenum
pH of colon
Why don't we absorb too many drugs in the stomach?
due to mucous layer
Where does a lot of absorption occur?
small intestine (specifically duodenum)
When you put an acidic drug into a decreasing pH (acidic environment) it will increase the ____ form
The unionized form of the drug is better at ???
crossing biological membranes
*remember the unionized form is more lipophilic (i.e. can cross those lipid membranes better than the ionized form which is more water soluble)
When you put a basic drug into an increasing pH (basic environment) it will increase the ____ form
addition of base or hydroxide ion will ___ pH
addition of acid or hydrogen ion will ___ pH
unionized form of the drug ____ better
Describe interfacial tension
-when you put a lipophilic compound into water - you get few but stronger water-water H bonds at the non-polar/water interface