Lecture 2 (Intro to MedChem) Flashcards
Free bases or acids are often ____
liquid (oils)
Are they better or worse than a salt?
WORSE
- less water soluble than ionized form
- difficult to measure (because they are hygroscopic)
- difficult to make into a dosage form
- less stable
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
unionized
T or F: good drugs have only either lipid or water solubility
FALSE
-most efficient drugs have some degree of water and lipid solubility
explain 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 _____
structure
Can we alter the solubility of a drug?
explain the 3 ways
YES
-use acid or base to make the drug into a salt
OR
-add substituents that are very water soluble:
-adding groups that are H bond donors and acceptors
-adding groups that can ionize
OR
-changing dose form
Are dispersion forces strong or weak?
weak
Dispersion forces are called ??
london forces (wrongly called van der waals attraction)
Where do dispersion forces occur?
between induced and instantaneous formed dipoles
As molecule gets larger, dispersion forces get _____
larger
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?
dipole-dipole bonding
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 ??
dipole-dipole bonding
H-bonding is _____ than ordinary dipole-dipole bonding
stronger
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
water
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?
weak
SH is NOT an H-bond ____
donator
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 _____
unfavorable
You don’t want to have too many H-bond donors and acceptors or the drug will not _____
absorb
What is an ionic bond?
electrostatic interaction between cations and anions
Are ionic bonds strong?
yeah man
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?
Explain yourself
N and O
-they polarize the molecule and act as H-bond acceptors and donors (with an attached hydrogen)
Ionizable groups increase ____ solubility
water
Give 3 examples of groups that increase lipid solubility
alkyl chains
alkyl rings
aromatic groups
Hydrophilic groups have a _____ pi value
negative
Lipophilic groups have a _____ pi value
positive
LogPcalc value greater than +0.5 = ?
lipophilic
LogPcalc values less than +0.5 = ?
hydrophilic
understand slide 21
ok man
one of the most important factors effecting the ____ of drugs is the LogP
potency
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?
blood flow
**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?
Dissolution:
-needs to have sufficient solubility so they dissolve out of solid dosage forms
Distribution:
-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
unionized
When ____ there is sufficient water solubility for dissolution and distribution
ionized
About 85 % of drugs have functional groups that are ___ to some extent
ionized
What is ionization controlled by?
pKa and external pH
pH of blood
7.4
pH of sweat/saliva
6
pH of fasting stomach
1
pH of fed stomach
3-7
pH of fasting duodenum
5
pH of fed duodenum
6
pH of colon
7-8
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
unionized
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
unionized
addition of base or hydroxide ion will ___ pH
increase
addition of acid or hydrogen ion will ___ pH
decrease
unionized form of the drug ____ better
absorbs
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
Water molecules at the interface are more orientation ally restricted which results in a ____ of entropy (change in S)
decrease
