Exam I: Intro, Trials, Partition Coefficient Flashcards
Physico-chemical properties that are related to drug action (8).
- Solubility
- Degree of dissociation (pKa)
- Partition coefficient, ratio of oil to water solubility
- Resonance - induction
- Chelation
- Stereochemistry
- Interatomic distance between functional groups
- Isosterism
Where are strong acids ionized (dissociated) in the body?
Some in stomach
Almost fully in the intestine or in the blood
Where are strong acids absorbed in the body?
May be absorbed from stomach and trapped in blood
Unionized are more easily absorbed
Where are strong bases ionized in the body?
Some in stomach but almost none in intestine or blood
Where are strong bases mostly absorbed?
Intestine
Are ionized or unionized drugs easier to be absorbed?
Unionized drugs absorb more easily.
Weak acids will absorb mostly in an acidic environment
Weak bases will absorb mostly in alkaline environment
Where are weak acids ionized?
None in the stomach
A little in the intestine
Mostly in the blood.
Where are weak acids absorbed?
Stomach
Where are weak bases ionized?
Fully ionized in the stomach
Some in the intestine and blood
Where are weak bases absorbed?
Intestine
Physico-chemical properties of drug molecules are determined by the…?
Kind, number and arrangement of atoms in a drug molecule
These type of lipoproteins are considered “good cholesterol”. What is a good range for levels of these lipoproteins in the body?
HDL - High-density lipoproteins
greater than or equal to ≥ 40 mg/dL
These type of lipoproteins are considered “bad cholesterol”. What is a good range for levels of these lipoproteins in the body?
LDL
Less than < 100 mg/dL
These lipoproteins are not considered good or bad, they contain large amounts of triglycerides. What is a good range for levels of these lipoproteins in the body?
VLDL
5 - 40 mg/dL
What is the maximum amount of cholesterol that can remain free in solution? What happens to the remaining amount?
Max 2 mcg/dL
The rest of the cholesterol is bound to lipid molecule carriers
Total cholesterol in the lipid panel represents the amount of cholesterol that is free in a patient’s blood. (True/False)
False
Only 2 mcg/L of cholesterol can be free in the blood.
This is far less than the total cholesterol in the body.
Ideal range of total cholesterol in the body
< 200 mg/dL
Ideal range of triglyceride in the body.
< 150 mg/dL
Which components of cholesterol be measured alone experimentally?
Total cholesterol
Triglyceride
HDL
Which cholesterol factors must be found using an equation? What are these equations?
VLDL = 1/5 of triglyceride
LDL = Total – (VLDL +HDL)
LDL +VLDL + HDL = ?
Total cholesterol
ADME stands for?
Absorption, Distribution, Metabolism, Excretion
First three steps in the drug discovery and development process.
- Target Identification - usually a biological receptor or enzyme
- Target validation
- Target + Ligand (prototype that binds to the target and is supposed to inhibit its function)
What occurs during the drug and discovery process after a target and ligand are identified?
Structure Activity Relationship (SAR) studies
Design and synthesis of new compounds
Lead Identification
Lead Characterization
Lead Optimization
What results from the SAR studies?
A drug candidate is developed then preclinical studies begin
What occurs during the preclinical studies?
Formulation
Animal pharmacology studies
Pharmacokinetic and safety studies in animals
Target Identified, SAR studies, a drug candidate developed and preclinical trials have been conducted. What is the next step?
Investigational New Drug Application (IND) submitted to the FDA.
FDA has 30 days to reject the IND otherwise clinical trials can begin
Phase I of Clinical Trials
10 - 20 patients
Mainly determine safety and acceptability
Other determinants: Half life, routes of excretion and distribution properties
Phase II of Clinical Trials
100 - 300 patient
Test safety and efficacy
Other determinants: Pharmacodynamics, short term safety, and safe/effective dose ranges
Phase III of Clinical Trials
> 1000 patients
Safety and efficacy
Other determinants: Short and long term toxicity (side effects), mimic how the drug will be used in a clinical setting
What happens after phase III of clinical trials complete?
New Drug Application (NDA) submitted to the FDA to determine if the drug is safe and effective.
Takes 1 -2 years
Phase IIa vs IIb and Phase IIIa vs IIIB
IIb has a larger sample size than IIa
IIIb is conducted after a NDA is submitted and has a larger sample size than IIIa
What is Phase IV of clinical trials?
Rare side effects are found, post marketing surveillance, prescriber behavior of physicians, further assess drug therapeutic effects in special populations (i.e pediatrics vs adults)
About how (long) and how much does it (cost) to put a new drug on the market?
2.6 billion
avg - 12 years
50% of drugs come from natural sources while 50% come from chemical synthesis. What natural sources do drugs come from?
Plants (25%) - morphine
Animals (6%) – Steroids (i.e. hydrocortisone, estradiol)
Minerals (7%) – calcium, potassium, iron
Microorganisms (12%) - antibiotics
Describe structurally non specific drugs.
- Drugs that do not require any specific site of action
- The biological effect of such drugs is closely related to their physico-chemical properties rather than with their chemical structures
Examples: Osmotic diuretics, Gastric antacids, general anesthetics, etc.
Describe structurally specific drugs.
- These agents usually interact with a specific receptor/enzyme to initiate or block the transduction of a signal leading to the observed biological response.
- They are often called ligands, agonists, antagonists, or inhibitors.
- Certain structural features appear to have greater influence on the overall biological effects than their physico-chemical properties.
Give three examples of structurally specific drugs.
- Thymine (-CH3) and 5-fluorouracil (-F)
- Acetylcholine (-CH3) and Carbachol (-NH2)
- Epinephrine (-CH3) and Isoproterenol (-CH(CH3)2)
The result of the interaction of a drug with a functional or organized group of molecules is…?
Biological response
Four strongest molecular bonds.
- Covalent
- Reinforced ionic - NH4 and CO2. Hydrogen attracted to carbonyl O and Nitrogen attracted to O ion
- Ionic
- Ion-dipole
Four weakest molecular bonds.
- Van der waals
- Hydrophobic - between two hydrogen on different carbon atoms
- Dipole-dipole
- Hydrogen bonds
Is there a drug that relies on covalent binding to a drug target?
Yes, alkylating agents used in chemotherapy treatment (ex. cyclophosphamide (cytoxan))
What was Thalidomide used to treat and the major side effect that was missed prior to FDA approval?
Thalidomide is a racemic mixture
Marketed to combat morning sickness in pregnant women
(S) isomer caused birth effects - inhibited angiogenesis and growth of limbs
What is Thalidomide used to treat today?
Treats HIV, leprosy, and multiple myeloma (plasma cell cancer)
2px 2py 2pz within the same energy level are called what?
Degenerate
Aufbau Principle
Lowest energy orbitals are filled first with electrons
Hund’s Rule
Add one electron to each orbital of the same pairing
Criteria for aromaticity
- Cyclic
- Flat ( to allow maximum overlap of p-orbitals)
- Every atoms possesses a p-orbital (sp2)
- 4n + 2 atoms in π system
Criteria for anti-aromaticity
- Cyclic
- Flat
- Full conjugated (sp2)
- 4n atoms in pi system
Constitutional isomers
Same chemical formula
Different connection
Propylene vs cyclopropane
Stereoisomers
Same formula and connectivity but different arrangement in space
Enantiomers - Diastereomer
Cis vs Trans
What has lower priority than hydrogens when assigning E/Z?
Lone pairs have lower priority than hydrogen
Put ortho, meta and para in order from highest to lowest priority
Ortho > meta > para
What is the device used and expression used for optical rotation?
Device - polarimeter
Expressed as specific rotation [α]
Describe how the optical rotation of two enantiomers are the same and different.
Equal magnitude (number) but opposite sign (direction)
What is a mixture called when there is an equal amount of two enantiomers? What would the optical rotation be for the two enantiomers?
Racemic mixture (±) or (dl)
[α] = 0 –> Rotations of the enantiomers cancel out
How to calculate the maximum number of stereoisomers?
2^n
n = number of chiral centers
Note there may be less actual stereoisomers due to meso compounds
Can amines be chiral centers?
No, amines are not configurationally stable
At room temp amines undergo rapid inversion of configuration that equilibrates the isomers.
Amines are not optically active
CH3 - CH3 gauche
energy?
0.9 kcal/mol
H - H eclipse
energy?
1.0 kcal/mol
CH3 - H eclipse
energy?
1.3 kcal/mol
CH3 - CH3 gauche
energy?
4.0 kcal/mol
Partition coefficient (P) equations. What does a low or high P value mean?
P = Conc drug in octanol (fat)/ Conc drug in water (polar)
High value = lipophilic
Low value = water soluble (polar)
What equation is used to measure the effect of a substituent on a drug’s lipophilicity?
Hansch Partition Coefficient (πx)
πx = Log P(x) - Log P(h)
x = coefficient of substituted compound
h = unsubstituted compound
Interpret a positive vs a negative value for a Hansch Partition Coefficient (πx)
πx = positive (+) compound becomes more lipophilic
πx = negative (-) compound becomes more water soluble
How to measure the effect of substituents if there is more than one on a compound?
Add up the πx values for all the substituents
πx = Log P(x) - Log P(h) for each substituent the add
Methoxy group (-OCH3) affect on an alkane vs an aromatic compound.
Makes alkanes more polar than when added to aromatic compounds.
Resonance from aromatic compounds delocalize the electrons on the oxygen decreasing its readiness to form hydrogen bonds with water molecules
How does Log P increase after each addition of a carbon to a chain? (i.e. methane to ethane to propane)
Log P increases 0.5 after each added carbon to the chain
Compound becomes more lipophilic
What are branchless compounds more lipophilic than compounds than their branched isomer?
Branchless compounds decrease water’s entropy
Decreased entropy means there will be an increase in energy
Increased energy means that the K value will be small
The compound will favor the organic phase (fat)
What is the equation for the K value in relation to the concentration of a compound in the organic phase vs water?
K = [compound] H2O/ [compound]organic
Compound (organic) Compound (H2O)
What is the relationship between energy and entropy? What is the gibbs free energy equation?
ΔG = ΔH - TΔS
Inversely proportional
What is the relationship between k and gibbs energy? What is the gibbs free energy equation with k?
ΔG = -RTlnk
Inversely proportional
Halogens - chlorine, bromine, iodine
Effect on partition coefficient (Log P)
Increase - more lipophilic
Fluorine attached to an unsaturated carbon like an aromatic
Effect on partition coefficient (Log P). Why?
Increase - more lipophilic
Electron withdrawing effect of the double doubles pull electron density from the fluorine making it less ready to form hydrogen bonds
Fluorine attached to a saturated carbon.
Effect on partition coefficient (Log P)
Decrease - more water soluble
Trifluoromethyl (-CF3)
Effect on partition coefficient (Log P). Why?
Increase - more lipophilic
Three strong electronegative atoms decrease the compounds readiness to form hydrogen bonds
Thiols (mercaptans) and thioethers (sulfides)
Effect on partition coefficient (Log P). Why?
Increase - more lipophilic
Sulfur is much larger than hydrogen so it cannot readily form a hydrogen bond
Oxygen and nitrogen containing functional groups
Effect on partition coefficient (Log P)
Decrease - more water soluble
Charged functional groups (negative and positive charges)
Effect on partition coefficient (Log P). Why?
Decrease - more water soluble
Negative attracted to the hydrogen in water
Positive attracted to the oxygen in water
Branching of compounds like alkanes.
Effect on partition coefficient (Log P)
Decrease - more water soluble
Unsaturation (adding double or triple bonds)
Effect on partition coefficient (Log P)
Decrease - more water soluble
