Physico-Chemical properties and Drug Action

Functional groups that increase the polarity and dissolution of drugs:

* Very polar groups; each group increases solubility of ____

carbons in a given molecule. This includes:

1. _____ group:

a. _______ (if linked to aliphatic chain)

b. ______(if linked to aromatic ring system)

2. _____

3. All other functional groups including carboxylic acid, amides,

imides, CN, NO2 , sulfonamide, are weakly polar that can

solubilize only 2-3 carbons.

5-6, Hydroxyl (Alcoholic, Phenolic), primary and secondary amines 

Functional groups that increase lipophilicity of drugs:

1. ____ (the bigger the alkyl, the higher the lipophilicity)

2. _____ group

3. _____ groups (I>Br>Cl>F)

4. _____ functions (the more carbons in the group, the more lipophilic the drug will be)

alkyl groups, phenyl, halogen (I> Br, Cl, F), ester

Hydroxyl: very polar, increase solubility of 5-6 carbons

Amino (very polar)

Carboxylic acid: weakly polar, increase solubility of 2-3 carbons, and acidic

Cyano: weakly polar, increase solubility of 2-3 carbons

Nitro (weakly polar)

Ester (more carbons= more lipophilic=better absorbed)

name polarity

Amide (weakly polar)

name, polarity

Imide (weakly polar)

Sulfonamide weakly polar, increase solubility of 2-3 carbons

Ether (weakly polar)

Alkyl groups: very lipophilic (more carbons = more lipophilicity= better absorption)

Methyl

Ethyl

n-propyl

iso-propyl

n-butyl

iso-butyl, 1° butyl

2°-butyl

3°-butyl, t-butyl

Cyclohexyl & other cyclic alkyls: very lipophilic, highly absorbed

Phenyl (very lipophilic)

Benzyl (very lipophilic) (x=ONS)

Fluoro (very lipophilic)

Chloro (very lipophlic)

Bromo (lipophilic)

Iodo (lipophilic)

Acidic Functional groups: are capable to ionize in the body fluids

Carboxylic, Imides, Sulfonamides, Phenolic

Basic Functional Group

Aliphatic Amines (pkb 3-5), Pyridine type nitrogen (pkb 7-9), Anilino type nitrogen (pkb 7-9)

name (acidic, basic, neutral)

Aliphatic Amines (basic)

name, a b n

Amides (basic)

name, acid basic neutral

Pyrrole (basic)

name, acid basic neutral

Pyridine type nitrogen (basic)

Neutral Nitrogen atoms

cyano, amides, Pyrrole-like nitrogen, Quaternary Ammonium nitrogen 

anilino type nitrogen (weakly basic)

cyano (neutral)

amides (neutral)

Recall Huckle’s equation to determine aromaticity: 4n+2=π

pyrrole like nitrogen (neutral)

Quaternary Ammonium nitrogen (neutral)

D. Nitrogen atoms capable of losing protons (acidic functional groups with nitrogen atoms):

1. _____: two carbonyl groups around the nitrogen strongly

   withdraw electrons from the nitrogen and the nitrogen in turn

   withdraw electron from the hydrogen leading to acidic property.

Imides

D. Nitrogen atoms capable of losing protons (acidic functional

groups with nitrogen atoms):

______: the sulfone group next to the nitrogen strongly

withdraw electrons from the nitrogen and the nitrogen in turn withdraw electron from the hydrogen leading to acidic property.

Sulfonamides

The term _____ refers to the replacement of an atom or functional group with certain number of electrons in the outer most shell with another atom or group with the same number of electrons in the outermost shell.

bioisosteres

The major site in our system that conducts metabolism is the ___, however some metabolic reactions occur also in different organs and tissues such as plasma, nerve endings, and lungs.

liver

metabolism

Phase I: makes drug polar by creating a single polar group
Phase II: conjugates drugs to enhance water solubility.

A. Phase-I microsomal reactions: Three types:

1. _____: CYP450 inserts an “O” between aliphatic or aromatic C-H bonds. If the compound is aromatic, the para position is preferred for oxidation. If it is an aliphatic compound, the last (ω) or second to last carbon (ω-1) is preferred.

Hydroxylation

A. Phase-I microsomal reactions: Three types:

2. ______: removal of an alkyl group form a heteroatom on the drug molecule. If the heteroatom is oxygen, we call O-de-alkylation, Nitrogen; we call it N-de-alkylation, Sulfur, we call it S-de-alkylation. The alkyl groups that are fast to remove are the small groups such as methyl or ethyl. Once the alkyl group becomes bigger than 4 carbons, it unlikely to be removed by de-alkylation. The name of the alkyl group may be added to the de-alkylation reactions so we say O-demethylation, of N-de-ethylation, etc.

De-alkylation metabolic reactions

A. Phase-I microsomal reactions: Three types:

3. ____

Oxidative deamination (remove NH2 group from secondary carbon → ketone and ammonia)

B. Phase I Non-microsomal reactions

1. _____ removes a primary amino group connected to primary carbon.

Monoamine oxidase (MAO) (primary amines → aldehyde and ammonia)

B. Phase I Non-microsomal reactions

2. _____ . are the most abundant enzymes in our system and exist in multiple areas throughout the body fluids in all organs including the GIT, Plasma, liver, lungs, CNS.

• This is the fastest metabolic reaction that occurs in the

biological system, it occurs everywhere in the body including

GIT,Liver, Plasma.

Esterases (hydrolyze esters) (ester → carboxylic acid and alcohol or phenol)

B. Phase I Non-microsomal reactions

are localized mainly in the enzyme is localized mainly in the he liver and very little, if any, in the GIT or plasma.

• This reaction is slower than ester hydrolysis and occurs mostly in the liver and to less extent in plasma.

Amidases (hydrolyze amides) (amide → carboxylic acid and primary or secondary amine)

3. :

The enzyme is localized mostly at the adrenergic nerve endings, and to much less extend in the liver cells cytosol.

COMT (catechol-O-methyl transferase) (converts catechol into 3-methoxy derivative as a deactivation mechanism of catechol-amines)

The water soluble molecules include:

Glucuronic acid (primarily), Sulfates, Glycine, Glutathione

The most commonly water soluble molecule involved in phase II metabolism is _____ (oxidized glucose molecule at C-6 into carboxylic group).

Glucouronic acid

Uridine diphosphate glucuronic acid (UDPGA)

Drug-Drug interactions related to ADME

C. Enzyme inhibitors and activator drugs

• Another potential source of drug-drug-interactions is through the

  activation/deactivation of ____

cyp450.

Enzyme inducers activate/speed up an enzyme, results in faster metabolism of drugs that are metabolized by CYP450.

As a result, a drug may be metabolized more rapidly to metabolites that are more potent, more toxic, or less active than the parent drug.

Phenobarbital, carbamazepine (Tegretol)

Enzyme inhibitors deactivate/slow an enzyme, resulting in slower metabolism of drugs that metabolized by CYP450.

• This will cause the drug to stay in the system longer than their normal duration of action.

Tagamet (cimetidine), Valproic acid, Erythromycin, Grape fruits