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Pharmaceutical Chemistry > Exam I: Intro, Trials, Partition Coefficient > Flashcards

Exam I: Intro, Trials, Partition Coefficient Flashcards

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1
Q

Physico-chemical properties that are related to drug action (8).

A
  1. Solubility
  2. Degree of dissociation (pKa)
  3. Partition coefficient, ratio of oil to water solubility
  4. Resonance - induction
  5. Chelation
  6. Stereochemistry
  7. Interatomic distance between functional groups
  8. Isosterism
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2
Q

Where are strong acids ionized (dissociated) in the body?

A

Some in stomach

Almost fully in the intestine or in the blood

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3
Q

Where are strong acids absorbed in the body?

A

May be absorbed from stomach and trapped in blood

Unionized are more easily absorbed

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4
Q

Where are strong bases ionized in the body?

A

Some in stomach but almost none in intestine or blood

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5
Q

Where are strong bases mostly absorbed?

A

Intestine

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6
Q

Are ionized or unionized drugs easier to be absorbed?

A

Unionized drugs absorb more easily.

Weak acids will absorb mostly in an acidic environment

Weak bases will absorb mostly in alkaline environment

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7
Q

Where are weak acids ionized?

A

None in the stomach

A little in the intestine

Mostly in the blood.

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8
Q

Where are weak acids absorbed?

A

Stomach

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9
Q

Where are weak bases ionized?

A

Fully ionized in the stomach

Some in the intestine and blood

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10
Q

Where are weak bases absorbed?

A

Intestine

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11
Q

Physico-chemical properties of drug molecules are determined by the…?

A

Kind, number and arrangement of atoms in a drug molecule

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12
Q

These type of lipoproteins are considered “good cholesterol”. What is a good range for levels of these lipoproteins in the body?

A

HDL - High-density lipoproteins

greater than or equal to ≥ 40 mg/dL

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13
Q

These type of lipoproteins are considered “bad cholesterol”. What is a good range for levels of these lipoproteins in the body?

A

LDL

Less than < 100 mg/dL

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14
Q

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?

A

VLDL

5 - 40 mg/dL

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15
Q

What is the maximum amount of cholesterol that can remain free in solution? What happens to the remaining amount?

A

Max 2 mcg/dL

The rest of the cholesterol is bound to lipid molecule carriers

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16
Q

Total cholesterol in the lipid panel represents the amount of cholesterol that is free in a patient’s blood. (True/False)

A

False

Only 2 mcg/L of cholesterol can be free in the blood.

This is far less than the total cholesterol in the body.

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17
Q

Ideal range of total cholesterol in the body

A

< 200 mg/dL

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18
Q

Ideal range of triglyceride in the body.

A

< 150 mg/dL

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19
Q

Which components of cholesterol be measured alone experimentally?

A

Total cholesterol

Triglyceride

HDL

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20
Q

Which cholesterol factors must be found using an equation? What are these equations?

A

VLDL = 1/5 of triglyceride

LDL = Total – (VLDL +HDL)

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21
Q

LDL +VLDL + HDL = ?

A

Total cholesterol

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22
Q

ADME stands for?

A

Absorption, Distribution, Metabolism, Excretion

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23
Q

First three steps in the drug discovery and development process.

A
  1. Target Identification - usually a biological receptor or enzyme
  2. Target validation
  3. Target + Ligand (prototype that binds to the target and is supposed to inhibit its function)
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24
Q

What occurs during the drug and discovery process after a target and ligand are identified?

A

Structure Activity Relationship (SAR) studies

Design and synthesis of new compounds

Lead Identification
Lead Characterization
Lead Optimization

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25
Q

What results from the SAR studies?

A

A drug candidate is developed then preclinical studies begin

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26
Q

What occurs during the preclinical studies?

A

Formulation

Animal pharmacology studies

Pharmacokinetic and safety studies in animals

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27
Q

Target Identified, SAR studies, a drug candidate developed and preclinical trials have been conducted. What is the next step?

A

Investigational New Drug Application (IND) submitted to the FDA.

FDA has 30 days to reject the IND otherwise clinical trials can begin

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28
Q

Phase I of Clinical Trials

A

10 - 20 patients

Mainly determine safety and acceptability

Other determinants: Half life, routes of excretion and distribution properties

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29
Q

Phase II of Clinical Trials

A

100 - 300 patient

Test safety and efficacy

Other determinants: Pharmacodynamics, short term safety, and safe/effective dose ranges

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30
Q

Phase III of Clinical Trials

A

> 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

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31
Q

What happens after phase III of clinical trials complete?

A

New Drug Application (NDA) submitted to the FDA to determine if the drug is safe and effective.

Takes 1 -2 years

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32
Q

Phase IIa vs IIb and Phase IIIa vs IIIB

A

IIb has a larger sample size than IIa

IIIb is conducted after a NDA is submitted and has a larger sample size than IIIa

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33
Q

What is Phase IV of clinical trials?

A

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)

34
Q

About how (long) and how much does it (cost) to put a new drug on the market?

A

2.6 billion

avg - 12 years

35
Q

50% of drugs come from natural sources while 50% come from chemical synthesis. What natural sources do drugs come from?

A

Plants (25%) - morphine

Animals (6%) – Steroids (i.e. hydrocortisone, estradiol)

Minerals (7%) – calcium, potassium, iron

Microorganisms (12%) - antibiotics

36
Q

Describe structurally non specific drugs.

A
  1. Drugs that do not require any specific site of action
  2. 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.

37
Q

Describe structurally specific drugs.

A
  1. These agents usually interact with a specific receptor/enzyme to initiate or block the transduction of a signal leading to the observed biological response.
  2. They are often called ligands, agonists, antagonists, or inhibitors.
  3. Certain structural features appear to have greater influence on the overall biological effects than their physico-chemical properties.
38
Q

Give three examples of structurally specific drugs.

A
  1. Thymine (-CH3) and 5-fluorouracil (-F)
  2. Acetylcholine (-CH3) and Carbachol (-NH2)
  3. Epinephrine (-CH3) and Isoproterenol (-CH(CH3)2)
39
Q

The result of the interaction of a drug with a functional or organized group of molecules is…?

A

Biological response

40
Q

Four strongest molecular bonds.

A
  1. Covalent
  2. Reinforced ionic - NH4 and CO2. Hydrogen attracted to carbonyl O and Nitrogen attracted to O ion
  3. Ionic
  4. Ion-dipole
41
Q

Four weakest molecular bonds.

A
  1. Van der waals
  2. Hydrophobic - between two hydrogen on different carbon atoms
  3. Dipole-dipole
  4. Hydrogen bonds
42
Q

Is there a drug that relies on covalent binding to a drug target?

A

Yes, alkylating agents used in chemotherapy treatment (ex. cyclophosphamide (cytoxan))

43
Q

What was Thalidomide used to treat and the major side effect that was missed prior to FDA approval?

A

Thalidomide is a racemic mixture

Marketed to combat morning sickness in pregnant women

(S) isomer caused birth effects - inhibited angiogenesis and growth of limbs

44
Q

What is Thalidomide used to treat today?

A

Treats HIV, leprosy, and multiple myeloma (plasma cell cancer)

45
Q

2px 2py 2pz within the same energy level are called what?

A

Degenerate

46
Q

Aufbau Principle

A

Lowest energy orbitals are filled first with electrons

47
Q

Hund’s Rule

A

Add one electron to each orbital of the same pairing

48
Q

Criteria for aromaticity

A
  1. Cyclic
  2. Flat ( to allow maximum overlap of p-orbitals)
  3. Every atoms possesses a p-orbital (sp2)
  4. 4n + 2 atoms in π system
49
Q

Criteria for anti-aromaticity

A
  1. Cyclic
  2. Flat
  3. Full conjugated (sp2)
  4. 4n atoms in pi system
50
Q

Constitutional isomers

A

Same chemical formula

Different connection

Propylene vs cyclopropane

51
Q

Stereoisomers

A

Same formula and connectivity but different arrangement in space

Enantiomers - Diastereomer

Cis vs Trans

52
Q

What has lower priority than hydrogens when assigning E/Z?

A

Lone pairs have lower priority than hydrogen

53
Q

Put ortho, meta and para in order from highest to lowest priority

A

Ortho > meta > para

54
Q

What is the device used and expression used for optical rotation?

A

Device - polarimeter

Expressed as specific rotation [α]

55
Q

Describe how the optical rotation of two enantiomers are the same and different.

A

Equal magnitude (number) but opposite sign (direction)

56
Q

What is a mixture called when there is an equal amount of two enantiomers? What would the optical rotation be for the two enantiomers?

A

Racemic mixture (±) or (dl)

[α] = 0 –> Rotations of the enantiomers cancel out

57
Q

How to calculate the maximum number of stereoisomers?

A

2^n

n = number of chiral centers

Note there may be less actual stereoisomers due to meso compounds

58
Q

Can amines be chiral centers?

A

No, amines are not configurationally stable

At room temp amines undergo rapid inversion of configuration that equilibrates the isomers.

Amines are not optically active

59
Q

CH3 - CH3 gauche

energy?

A

0.9 kcal/mol

60
Q

H - H eclipse

energy?

A

1.0 kcal/mol

61
Q

CH3 - H eclipse

energy?

A

1.3 kcal/mol

62
Q

CH3 - CH3 gauche

energy?

A

4.0 kcal/mol

63
Q

Partition coefficient (P) equations. What does a low or high P value mean?

A

P = Conc drug in octanol (fat)/ Conc drug in water (polar)

High value = lipophilic

Low value = water soluble (polar)

64
Q

What equation is used to measure the effect of a substituent on a drug’s lipophilicity?

A

Hansch Partition Coefficient (πx)

πx = Log P(x) - Log P(h)

x = coefficient of substituted compound

h = unsubstituted compound

65
Q

Interpret a positive vs a negative value for a Hansch Partition Coefficient (πx)

A

πx = positive (+) compound becomes more lipophilic

πx = negative (-) compound becomes more water soluble

66
Q

How to measure the effect of substituents if there is more than one on a compound?

A

Add up the πx values for all the substituents

πx = Log P(x) - Log P(h) for each substituent the add

67
Q

Methoxy group (-OCH3) affect on an alkane vs an aromatic compound.

A

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

68
Q

How does Log P increase after each addition of a carbon to a chain? (i.e. methane to ethane to propane)

A

Log P increases 0.5 after each added carbon to the chain

Compound becomes more lipophilic

69
Q

What are branchless compounds more lipophilic than compounds than their branched isomer?

A

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)

70
Q

What is the equation for the K value in relation to the concentration of a compound in the organic phase vs water?

A

K = [compound] H2O/ [compound]organic

Compound (organic) Compound (H2O)

71
Q

What is the relationship between energy and entropy? What is the gibbs free energy equation?

A

ΔG = ΔH - TΔS

Inversely proportional

72
Q

What is the relationship between k and gibbs energy? What is the gibbs free energy equation with k?

A

ΔG = -RTlnk

Inversely proportional

73
Q

Halogens - chlorine, bromine, iodine

Effect on partition coefficient (Log P)

A

Increase - more lipophilic

74
Q

Fluorine attached to an unsaturated carbon like an aromatic

Effect on partition coefficient (Log P). Why?

A

Increase - more lipophilic

Electron withdrawing effect of the double doubles pull electron density from the fluorine making it less ready to form hydrogen bonds

75
Q

Fluorine attached to a saturated carbon.

Effect on partition coefficient (Log P)

A

Decrease - more water soluble

76
Q

Trifluoromethyl (-CF3)

Effect on partition coefficient (Log P). Why?

A

Increase - more lipophilic

Three strong electronegative atoms decrease the compounds readiness to form hydrogen bonds

77
Q

Thiols (mercaptans) and thioethers (sulfides)

Effect on partition coefficient (Log P). Why?

A

Increase - more lipophilic

Sulfur is much larger than hydrogen so it cannot readily form a hydrogen bond

78
Q

Oxygen and nitrogen containing functional groups

Effect on partition coefficient (Log P)

A

Decrease - more water soluble

79
Q

Charged functional groups (negative and positive charges)

Effect on partition coefficient (Log P). Why?

A

Decrease - more water soluble

Negative attracted to the hydrogen in water

Positive attracted to the oxygen in water

80
Q

Branching of compounds like alkanes.

Effect on partition coefficient (Log P)

A

Decrease - more water soluble

81
Q

Unsaturation (adding double or triple bonds)

Effect on partition coefficient (Log P)

A

Decrease - more water soluble

Pharmaceutical Chemistry (3 decks)

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