Physico-Chemical properties and Drug Action

________ is a description of the events that a given drug

undergoes from the minute of oral administration until it is

excreted from the body. The chemistry and functional groups that

exist in the drug molecule controls its ADME properties.

ADME (A: Absorption, D: Distribution, M: Metabolism, E:

Excretion)

f given orally; the drug has to go through two processes:

1. _____ from the dosage form into the aqueous environment

of the GIT; and;

2. _______ of the GIT to reach blood stream,

and this requires lipophilic properties to be able cross the bi-lipid

layer of bio-membranes.

Dissolution, Crossing the bio-membrane

Eventually; if the drug is given by injection; no ______ is

involved.

dissolution

3. After the lipophilic drug is absorbed and reaches the blood stream; the drug is bound to plasma proteins (______) forming a water soluble complex that will allow the lipophilic drug to be compatible with the blood aqueous environment.

The drug is distributed (as a water soluble complex with albumin) to reach different sites as shown below. Notice the two half arrows indicate that all movements are reversible including plasma protein binding.

mainly albumin, a water soluble protein

A. Absorption

* Bio-membranes:

Absorption occurs through membranes which are comprised

primarily of bi-lipid layer making it easier for lipophilic drugs to

cross these barriers (recall “like dissolves like”). One of those

barriers is the blood brain barrier (BBB) differs from other

membranes by having much thicker lipid membrane that allows

only very highly lipophilic materials to get into the brain.

Because drugs that are absorbed must first undergo dissolution

from dosage form to the aqueous environment of the GIT fluids;

drugs are expected to have balance of both lipophilicity and

hydrophilicity. A drug that is ________ and those with highly hydrophilic

properties will have the opposite.

At this point; it is very important to know which functional groups

that will give lipophilic (non-polar) or hydrophilic (polar)

characteristics to a drug.

very lipophilic will have good absorption but poor dissolution

Functional groups that increase the polarity and dissolution

of drugs:

* Very polar groups; each group increases solubility of 5-6

carbons in a given molecule. This includes:

1. Hydroxyl group:

a. Alcoholic hydroxyl (if linked to aliphatic chain)

b. Phenolic hydroxyl (if linked to aromatic ring system)

2. Aliphatic amines:

Only primary or secondary amines (Why not tertiary? → they lack the ability to form hydrogen bonds with themselves)

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

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

solubilize only 2-3 carbons.

Functional groups that increase lipophilicity of drugs:

1. Alkyl groups (the bigger the alkyl, the higher the lipophilicity)

2. Phenyl group

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

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

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

Alcoholic hydroxyl if linked to aliphatic chain

Phenolic hydroxyl if linked to aromatic ring

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

Aliphatic amine = alcoholic amine

Aromatic amine ( aniline type amine)

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

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

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

Ester

The presence of more carbons makes esters more lipophilic and

therefore better absorbed.

Esters also make good leaving groups.

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

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

Sulfonamide weakly polar, increase solubility of 2-3 carbons

Ether , very weakly polar, and more lipophilic than alcohol

Alkyl groups: very lipophilic, the more carbons, the more the lipophilicity and 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

Aromatic radicals: very lipophilic, highly absorbed

Benzyl

Aromatic radicals: very lipophilic, highly absorbed

Notice that benzyl group is a phenyl attached to CH2 attached to

a heteroatom (X= O, or N, or S).

Fluoro

Aromatic radicals: very lipophilic, highly absorbed

Notice that benzyl group is a phenyl attached to CH2 attached to

a heteroatom (X= O, or N, or S).

Chloro

Aromatic radicals: very lipophilic, highly absorbed

Notice that benzyl group is a phenyl attached to CH2 attached to

a heteroatom (X= O, or N, or S).

Bromo

Aromatic radicals: very lipophilic, highly absorbed

Notice that benzyl group is a phenyl attached to CH2 attached to

a heteroatom (X= O, or N, or S).

Iodo

Aromatic radicals: very lipophilic, highly absorbed

Notice that benzyl group is a phenyl attached to CH2 attached to

a heteroatom (X= O, or N, or S).

Remember that drugs before absorption; must first undergo dissolution into the aqueous GIT fluids and this requires certain degree of polar properties. The balance between polar and nonpolar properties requires is a major issue in drug absorption process.

You can see that we are faced with a problem for orally

administered drugs: If the polar functional groups will dominate,

we will have good dissolution from the dosage form, but poor

absorption through the membrane. On the other hand, if we have

highly lipophilic functional groups; the drug will have very poor

dissolution from the oral dosage form and will get good absorption

through the GIT membranes if it comes in contact with the bio-

membrane.

This dilemma, was solved by the presences of acidic or basic

functional groups in the drug molecule. Acidic and basic functional

groups allow back and forth equilibrium between ionic form

(hydrophilic) for good dissolution, and non-ionic forms (lipophilic

forms) for absorption.

Does that explain why most of the drugs with acidic or basic

functional groups are administered as salts? (very soluble in

aqueous media therefore dissolute well) due to the charge, then

reverts back to unionized form in the GIT for absorption. Fully

charged molecules are water soluble no matter how many

lipophilic entities exists.

A. Acidic Functional groups:

We have 4 functional groups that are considered as acidic

functional groups that are capable to ionize in the body fluids; with

different degree of ionization power:

1. Carboxylic group 2. Imides 3. Sulfonamides 4. Phenolic…

(check functional groups structures above).

For all acidic or basic functional groups; Unionized form is

needed for Absorption and the ionized one is needed for

Dissolution.

B. Basic Functional groups:

In our drug world; nitrogen atoms are the source of donating

electrons to a proton. Nitrogen atoms donate electrons (same like

accept protons) depends on the adjacent functional groups to the

nitrogen atom. This results in presence of several subclasses of

nitrogen atom functional groups:

1. Basic nitrogen atoms where there is no electron withdrawing

functional groups attached to it. We have 3 subtypes of this

nitrogen atoms conditions with different range of pKb values:

Basic Functional Group

1. Aliphatic Amines: PKb:3-5: (primary, secondary, tertiary, please

review the structure in the table), saturated nitrogen atom with no

adjacent electron withdrawing groups.

Basic Functional Group

2. Pyridine type nitrogen, PKb:7-9 are sp2 hybridized and are 1

million times weaker bases than aliphatic amines. This is due to

the larger s orbitals % (closer to the nucleus and as such, e- are

more tightly held).

Basic Functional Group

3. Anilino type nitrogen :PKb 7-9, have reduced basicity The

nitrogen’s lone pair of e- interacts easily with the aromatic ring

through resonance, making the e- pair less likely to be donated

and as such the nitrogen is less likely to accept a proton.

C. Neutral Nitrogen atoms (cannot donate electrons to a proton):

We have four of those groups:

1. Cyano (nirile) the lone pair of electrons are rotating in SP

hybridized orbital (50% S character, closely attracted to the

nucleus).

C. Neutral Nitrogen atoms (cannot donate electrons to a proton):

We have four of those groups:

2. AMIDES: The presence of an adjacent carbonyl group (electron

withdrawing group) makes the nitrogen lone pair unavailable to be

donated.

C. Neutral Nitrogen atoms (cannot donate electrons to a proton):

We have four of those groups:

3. Pyrrole-like nitrogen (the nitrogen lone pair is part of the

   aromatic system, highly involve in resonance).

Recall Huckle’s equation to determine aromaticity:

4n + 2 = π ; if n=integer then the system is aromatic.

There are 6 pi electrons (2 from each double bond

and 2 from the lone pair).

4n+2= π

n= (π-2)/4 = (6-2)/4= 1

1”, an integer indicates that the

system is aromatic.

The lone pair is completely involved in the

conjugated ring’s pi bonding. The e-s cannot be donated to an

incoming proton.

C. Neutral Nitrogen atoms (cannot donate electrons to a proton):

We have four of those groups:

4. Quaternary Ammonium nitrogen (the nitrogen is attached to 4

   carbon atoms and there is no lone pair).

D. Nitrogen atoms capable of losing protons (acidic functional

groups with nitrogen atoms):

1. Imides: 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.

D. Nitrogen atoms capable of losing protons (acidic functional

groups with nitrogen atoms):

2. Sulfonamides: 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.

Bio-isosteres The term bioisosteres 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.

Metabolism is the process through which the biological system

eliminates and/or deactivates the endogenous chemicals (like

hormones) and foreign chemicals like drugs (xenobiotics) from the

system after exerting the biological effects.

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

As sated above the process of Metabolism aims to eliminate and deactivate chemicals from the body. The liver as the major site of metabolism conducts this process in two phases: one phase to render the drug a little polar, this call phase I metabolism that creates a single polar group on the drug molecule, the second is to take the created polar functionality produce by phase I and conjugate it through covalent bonding with a very polar entity in the liver such as glucouronic acid to produce a conjugate the is water soluble ready to be excreted in urine, this phase is called phase II metabolism or the conjugation phase metabolism.

A. Phase-I microsomal reactions: Three types:

1. Hydroxylation: 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.

A. Phase-I microsomal reactions: Three types:

2. De-alkylation metabolic reactions: 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.

A. Phase-I microsomal reactions: Three types:

3. Oxidative deamination: as the name indicates; cyp450 can remove an NH2 group connected to a secondary carbon atom (must be secondary carbon, not primary nor tertiary). The resulting products are a ketone and ammonia

B. Phase I Non-microsomal reactions

1. Monoamine oxidase removes a primary amino group connected to primary carbon.

Substrate: primary amines, with primary carbon next to it.

Product: aldehyde & ammonia

B. Phase I Non-microsomal reactions

2. Esterases hydrolyze esters. Estrases 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.

• Substrate: must have ester group

• Product: carboxylic acid & alcohol (or phenol)

• This is the fastest metabolic reaction that occurs in the

biological system, it occurs everywhere in the body including

GIT,Liver, Plasma.

B. Phase I Non-microsomal reactions

3. Amidases hydrolyze amides. are localized mainly in the

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

   • Substrate: amide

   • Product: carboxylic acid & amine (primary or secondary, not

   tertiary; why?)

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

3. COMT (catechol-O-methyl transferase):

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

Function: converts catechol into 3-methoxy derivative as a deactivation mechanism of catechol-amines

1. First pass metabolism: Some drugs (mostly highly lipophilic drugs) undergo rapid metabolism before reaching circulation, this type of metabolism is called first pass metabolism. You cannot predict it from the structure, it is just a phenomenon that occurs with some drugs.

Important terminologies you should be familiar with regarding phase 1 drug metabolism:

2. Enterohepatic circulation: Some drugs (mostly highly lipophilic drugs) undergo rapid

   excretion in bile after being conjugated by phase II (explained below) after returning to the liver from circulation. The bile acid conjugate is hydrolyzed in the intestine back into the original drug which is reabsorbed again and undergoes another cycle of action. This kind of enterohepatic circulation results in long duration of action for the drug. This type of metabolism is called enterohepatic circulation metabolism. You cannot predict it from the structure, it is just a phenomenon that occurs with some

   drugs.

Important terminologies you should be familiar with regarding phase 1 drug metabolism:

3. Bioavailability of drugs: Bioavailability is defined as how much of a drug will reach the circulation intact (as is) without metabolism if given orally. Bioavailability is affected by two important drug properties:

   a. Lipophilicity, that affects the absorption % from the GIT, and;

   b. First pass metabolism

   If the drug is with polar functional groups, its absorption will be decrease and it will have low bioavailability. If the drug is highly lipophilic, it will be well absorbed and have high bioavailability unless it undergoes first pass metabolism. In conclusion, for a drug to have good bioavailability; it must be highly lipophilic and does not undergo first pass metabolism.

D. EXCRETION: Phase II metabolism (or Phase 2, the same)

Occurs primarily in the liver and somewhat in the kidney. Its

purpose is to make the polar molecule created during one of the

reactions from phase 1 into a water soluble molecule. This is

achieved by attaching a water soluble molecule to the polar group

of the drug phase I metabolite. The water soluble molecules

include:

• Glucuronic acid (primarily)

• Sulfates

• Glycine

• Glutathione

• The most commonly water soluble molecule involved in

phase II metabolism is Glucouronic acid (oxidized glucose

molecule at C-6 into carboxylic group). We will focus on that

conjugating agent for now, and address other conjugating

agents with drug classes.