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Physicochemical Principles of
Drug Action

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Physicochemical principles of drug action

• Physicochemical properties that allow drug molecules to
exert their desired pharmacodynamic and
pharmacokinetic effects are:
• Water solubility.
• Lipid solubility.
• Partition coefficient.
• Acid–base properties.
• Degree of ionization.
• Steric factors.
• Stereochemistry.

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Features Governing Drug Action at Active

Site

• Depending upon the degree to which chemical

structure affects biological action, drugs can be
classified as:
o Structurally specific
o Structurally non-specific

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Structurally Specific Drugs

• They act at specific sites, such as a receptor or an

enzyme.
• Biological action is related to the chemical
structure.
• Minor alterations in groups in parent structure
bring about appreciable difference in activity.
• Effective in a relatively low concentration.
• Stereoisomers differ greatly in activity.
• The physical properties also play an important
role in the biological activity.

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Structurally Non-specific Drugs

• They have no specific site of action.

• The biological activity depends on the physical
properties of the molecules rather than the
chemical structure.
• Minor modifications do not affect the activity.
• Effective only in high concentrations
• Examples: general anesthetics ( gaseous: diethyl
ether, N2O, CHCl3), hypnotics, few bactericidal
compounds and insecticides.

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Acid–Base Properties

• Bronsted-Lowery theory.
o Proton donor (acid).
o Proton acceptor (base).

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The principle points

• The gastrointestinal and other biological membranes
act like lipid barriers.

• Most drugs (Orally) are absorbed from the

gastrointestinal tract by a process of passive
diffusion.

• The un-ionized form of the acidic or basic drug is

preferentially absorbed.

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Acid–Base Properties
• Have a direct effect on:
o Absorption.
Un-ionized form (lipid soluble).
o Distribution:
Ionized form (soluble in plasma).
o Excretion.
o Drug-Receptor interaction
o Compatibility with other drugs in solution.

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Acidic functional groups

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Basic functional groups

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Neutral functional groups

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Acid-Base properties
• A molecule can contain multiple functional groups
with acid–base properties and, therefore, can
possess both acidic and basic character.

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• Once in GIT, it behaves as an acid or a base.

• Factors:
o pH (variable).
o pKa (constant).

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Ionization and pH at Absorption Site

• The fraction of the drug existing in its un-ionized
form in a solution is a function of both:

– The dissociation constant of a drug (expressed as

the pKa).
– The pH of the solution at the absorption site.
• You should calculate the degree of ionization.

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Degree of ionization

• Drugs pass through membranes in a unionized form.

• Drugs act as ions (if ionization is a possibility).
• Ideal pKa (6-8; weak acid or weak base).
• Assumption passive diffusion.
• This consideration does not relate to compounds
that are actively transported through such
membranes.

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Importance of ionization of drugs

1. The lower the pH relative to the pKa, the greater is
the fraction of protonated drug.

2. Weak acid at acidic pH: more lipid-soluble, because

it is uncharged—the uncharged form more readily
passes through biological membranes.

3. Weak base at alkaline pH: more lipid-soluble,

because it is uncharged—the uncharged form more
readily passes through biological membranes.

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Predicting the degree of ionization:

Acids

Henderson-Hassalbach equation

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Predicting the degree of ionization:

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Aspirin

• Orally administered drug (pKa 3.5).

• Stomach (acidic):
o Un-ionized form ( partial absorption).
• Intestinal tract (Basic).
o Ionized form.
o Microvilli.
o Huge surface area.
o Absorption.

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Aspirin

• pKa 3.5.
• Orally administered.
• Absorbed in Stomach.

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Predicting the degree of ionization:

Bases

Henderson-Hassalbach equation

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Predicting the degree of ionization:

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Amine
• pKa 9-10.
• Stomach (acidic):
o Ionized form (BH+) will not be absorbed.
• Intestinal tract (Basic pH ~ 8 ).
o Equilibrium system is obtained.

o B and BH+ are absorbed.

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Question
• What is the percentage ionization of indomethacin
(pKa 4.5) in an intestinal tract buffered at pH 8.0?

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• K+/H+ ATPase inhibitor.

• Used for treatment of peptic ulcer.
• pKa ≈ 4 (not protonated in the stomach).
• Can be absorbed into the parietal cells.
• Is protonated inside the parietal cells (pH < 1).

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• A possible protonation mechanism leading to

formation of intermediate A is shown below:

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Acid-Base properties/ Compatibility

• What is the chemical consequence of mixing

aqueous solutions of these two drugs in the same
IV bag?
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Electronic effects of substituents

• Have an effect on a drug’s ionization or polarity.

• This in turn may have an effect on how easily a drug
can pass through cell membranes or how strongly it
can bind to a receptor.
• It is therefore useful to have some measure of the
electronic effect a substituent can have on a
molecule.

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The Hammett substitution constant (σx)

• The Hammett substitution constant (σx) is a measure

of the electron withdrawing or electron donating
ability of a substituent on the molecules.
• For the effect of substituents on an aromatic ring,
The Hammett substitution constant is used.
• It has been determined by measuring the
dissociation of a series of substituted benzoic acids
compared to the dissociation of benzoic acid itself.

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Hammett Substitution Constant (σx)

• As soon as a substituent is strategically positioned

on the aromatic (phenyl) ring.
• Equilibrium gets imbalanced.

• At this juncture two situations may crop up distinctly

by virtue of the fact that :
o An electron-withdrawing moiety.
o An electron-releasing moiety.
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• Electron-withdrawing moiety
o Stabilize the carboxylate anion, hence, the
overall equilibrium will be shifted more to the
ionized form, (larger σX value).

• Electron-Donating Moiety
o render the aromatic ring much less stable to
stabilize the carboxylate ion, hence, the overall
equilibrium will be shifted more to the
unionized form, (smaller σX value).

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The Hammett Substitution Constant (σx)

• The Hammett constant takes into account both

resonance (R) and inductive effects (F).
• Therefore, the value of σ for a particular
substituent will depend on whether the
substituent is meta or para.
• This is indicated by the subscript m or p after the σ
symbol.

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The Hammett Substitution Constant (σx)

• The nitro group has two values for σ.

o For para position, σp is 0.78.
o For meta position, σm is 0.71.
• The hydroxyl group has two values for σ.
o For para position, σp is −0.37.
o For meta position, σm is 0.12.

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The Hammett substitution constant (σx)

• There are limitations to the electronic constants.

• For example, Hammett Substituent Constants cannot
be measured for ortho substituents since such
substituents have an important steric, as well as
electronic, effect.
• They are only suitable for drugs containing aromatic
rings.

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