Lecture 2 concept notes Flashcards
What do physiochemical properties of a drug influence?
Their pharmacokinetics and their pharmacodynamics
What are some factors that affect the kinetics and dynamics?
The acid/base properties of the drug
the water solubility
the partition coefficient
the stereochemistry
Lipinski’s Rule of Five
A guideline or gold standard for making an ideal drug
Drug should have a Molecular Weight of ____ or below?
500
Drug should have _____ than _____ H-bond donating functional groups ?
Fewer than 5 H-bond donating groups
Drug should have ____ than ____ H-bond accepting functional groups?
Fewer than 10 H- bond accepting groups
Drug should have a calculated ____ of ____than 5?
LogP less than 5
The larger the LogP the ____?
the more hydrophobic the drug is
Life cycle of a drug
Can be taken orally, absorbed through the GI tract or through injections, will have a systemic effect, and then taken to the liver to be metabolized
What happens to a drug if it binds to an unintended receptor?
IF the drug is an ideal drug, it will survive this binding.
Why does a drug need to be hydrophilic as well as lipophilic?
The body has both aqueous and lipid phases that the drug needs to pass through. Aqueous = bodily fluids like blood. Lipid= Bilayer
If a drug binds to an unintended receptor and degrades, is it an ideal drug?
No. an ideal drug needs to be able to survive binding to inert sites.
What does a drug have to do until it reaches the intended receptor or site of action?
Has to penetrate until the site of action
Name the criteria for ideal drugs
Soluble in water
Able to pass through lipid bilayers
Survive binding to inert or unintended receptors
Endure metabolic modifications
Penetrate until the site of action
bind to the right receptor & have the intended biological response
How do functional groups affect a drug?
Can affect the pharmacodynamics and kinetics of the drug
How does the acidity or basicity of a drug affect it?
It will affect the ADME of the drug
Most drugs with a pKa outside of 5-9 tend to be strongly ionized. What does this mean for absorption across the membrane?
The drug will not be permeable to the membrane. It will be too polar to pass, and thus hydrophilic. In order to pass the membrane, the drug needs to be lipophilic and this non-polar.
how can we change the solubility of a drug?
We can modify the drug’s structure by adding functional groups that are acidic or basic.
Salt formation can ___ (increase//decrease) water solubility
Can increase water solubility.
Ionizable drugs
Usually have at least one basic group
Use other deck for acidic and basic drugs
(sengshang lin) memorize now.
acidic drugs?
penicillin
phenobarbital
vitamin c
aspirin
phenytoin
boric acid
Basic drugs
Caffeine
zalcitabine
morphine
erythromycin
amphetamine
Use Anki for functional groups
memorize now.
Acid/base theory
Acid- donates a proton
base- accepts a proton
How to determine percent ionization?
Using the formulas derived from Henderson hasselbach
ionization formula for an acidic drug?
It will have a (-) charge since it donates a proton
% ionization = 100/ 1+ 10^pka-pH
ionization formula for an basic drug
It will have a (+) charge since it accepts a proton
% ionization = 100/ 1+ 10^pH-pKa
Acidic drugs in an acidic environment
will be non-ionized
Acidic drugs in a basic environment
will be ionized
Basic drugs in a basic environment
will be non-ionized
Basic drugs in an acidic enviornment
Will be ionized
Lipophillicity
Important property in the ADME profile
Can affect solubility, adsorption, etc
Partition Coefficient
Helps determine the absorption of the drug in the body
The higher the partition coefficient, the ___ the absorption?
The higher the absorption in the body
The lower the partition coefficient, the ___ the absorption?
the lower the absorption in the body
logP
the partition coefficient
logP is a measure of ____ in the absence of ___?
logP is measured in the ABSENCE of ionization.
It is a measure of how much of the drug has an affinity for the lipid and aqueous phases of a solution.
Why is 1-Octanol is commonly used to measure logP?
It has polar and non polar regions. Mimics the bilayer, and P is easy to measure.
Distribution Coefficient
Takes into account ionization. **
The partitioning of a molecule between the lipid and aqueous phase will depend on the pH.
What does the distribution coefficient take into account?
The lipophillicity of the drug as well as the degree of ionization at a given pH
What does aqueous solubility depend on?
It depends on the ionization of functional groups as well as their H bond properties
How can we improve solubility
Decrease logP. Recall that a higher logP = more hydrophobicity. We want a lower logP so we will have less hydrophobic properties in the drug
How can we decrease logP
By increasing ionizable groups, H-bonding groups and more polar groups
How else can we improve solubility
Reduce crystal packing. Preventing molecules from tightly packing together will make it more soluble
Organic vs Inorganic salts
Organic salts = Carbon containing
Inorganic salts= no-carbons
Which is more soluble? Organic or inorganic?
Inorganic salts are more soluble
What are some factors that will cause a drug to not reach the intended site of action?
Protein binding
Binding to neutral fats
Drug metabolism
and
Excretion
Protein Binding
Drugs can bind to proteins like albumin and it is reversible. However, once bound, the drug cannot pass through lipid membranes and will spend longer in the body without doing anything. When unbound, it can then be metabolized or excreted
Clinical significancee of protein binding
Warfarin can be displaced from its binding site by drugs like sulfonamides. this is a drug drug interaction
Which type of drugs will bind to neutral fats
Drugs that are lipophilic are more likely to deposit in neural fats and then will slowly redistribute to the fattu tissue.
