Effects of Physicochemical properties on biological activities

=Acid /base properties, partition coefficient, stereochemistry

Determine

Chemical structure Physicochemical properties

Biological activities

Influence

Effects of acid/base properties on biological activity

• The majority of drugs are either weak acids or weak bases.

• According to Bronsted-Lowry theory:- Acids = can give a proton- Base = can accept a proton- Neutral = cannot give or accept proton- Amphoteric = can give and accept protons.

Compound having both acidic and basic groups. It reacts with acids as a base and with bases as an acid

• To reach their targets, drugs have to cross cell membrane.

• Membranes are lipid (lipophilic) in nature, therefore permits only unionized (lipophilic) form of drugs to pass through.

• Hence, degree of ionization of drugs affects their passage through membranes (absorption, distribution and excretion).

• Degree of ionization of drugs depends on their acidic or basic strength.

• Acid/base strength is expressed by pKa• The lower the pKa the higher the acidity, and the

higher the pKa the higher the basicty.

• pKa is the negative logarithm of the dissociation constant “Ka”.

• For acids:CH3COOH + H2O CH3COO- + H3O+

Acid Base Conjugate base Conjugate

acid [CH3COO-][H3O+]

Ka = [CH3COOH]

[CH3COO-][H3O+] [Ionized form]

pKa = -log = -log [CH3COOH] [Unionized form]

• For bases:CH3NH2 + H2O CH3NH3

+ + OH-

Base Acid Conjugate acid Conjugate

base.

[CH3NH2]

Ka = CH3NH3

+ + OH-

[CH3NH2] [Unionized form]

pKa = -log = -log [CH3NH3

+][OH-] [Ionized form]

Q: Why pKa is important??

A: It allows us to predict the degree of ionization of a drug at a given pH. How ??

For acids: 100 % Ionized = 1 + 10(pKa-pH)

For bases: 100 % Ionized = 1 + 10(pH-pKa)

General rules:• An acidic drug at acidic pH will not ionize.• An acidic drug at basic pH will ionize.• A basic drug at basic pH will not ionize.• A basic drug at acidic pH will ionize.

Ionized = poor absorption through GIT, BBB & placenta

Unionized = good absorption through GIT, BBB & placenta

• pH of GIT: stomach 1-3.5, duodenum 4-7, then rise gradually till reach 8 in the colon.

• pH of urine: 4.5 – 5.5• pH of blood: 7.4

Problems1) Assign the relative acid/base strength of each

functional group in ciprofloxacin. Predict its ionization form at different locations in GIT.

NN

O

NH

OF

OHacidic

weak baseweak base

neutral

neutral

basic

NN

O

N+

O

FOH

H

H

NN

O

N+

O

FO

-

H

H

NN

O

NH

O

FO

-

At stomach At duodenum At colon

2) A truck driver complaining of seasonal allergies asks you to recommend an agent that will act as antihistamine but will not cause drowsiness. Choose between “Cetirizine” and “Clemastine”.

N

N O

OH

Cl

O

N

O Cl

CH3 CH3

Cetirizine Clemastine

3) Predict the most suitable location in GIT (stomach or intestine) for absorption of the following drugs:

O

OH

CH3

CH3

CH3

N

O

NH

NH2

CH3

CH3

NHNH

O

O

N

S

N

Cl

CH3

CH3

N

NH

O O

O

CH3

CH3

IbuprofenProcainamide

Phenytoin

Chlorpromazine Phenobarbital

4) If a patient is given thiopental sodium orally instead of IV, will it put him to sleep?

pKa of thiopental sodium is 7.5 and pH of stomach is 2.5.

N

NH

S-

O

O

CH3

CH3

CH3

Na+

100 100 % Ionized = = = 0%

1 + 10(pKa-pH) 1 + 10(7.5-2.5)

http://www.manuelsweb.com/pka.htm

Basic drug

Acidic drug

pH 2.5

pKa 7.4

Solve

Ionized (%) 0

Reset

5) A basic drug with pKa of 9.4 is a suspect teratogen. If given IV to a pregnant woman whose blood pH is 7.4, will this drug cross the placenta and affects the baby?

6) A weakly acidic drug with pKa of 8.4 is a suspect teratogen. If given IV to a pregnant woman whose blood pH is 7.4, will this drug cross the placenta and affects the baby?

http://www.manuelsweb.com/pka.htm