Transcript Lecture 2.P2

CH3
H3C CH3
+
N
N
HO
O
Morphine
OH
HO
O
Inactive
CH3
CH2CH=CH2
N
OH
AcO
O
N
OAc
Heroin (more potent)
HO
O
OH
Nalorphine(morphine antagonist)
Physicochemical properties and Pharmacokinetics of the drug
Some of the physicochemical properties that affect
drug action are partition coefficient, dissociation constant,
steric factors, solubility, polymorphism…etc.
Storage sites
Parentral route
Site of action
GIT
Circulation
Metabolism
Excretion
Physicochemical properties affect Absorption
Distibution A D M E
Metabolism
Excretion
Route of Administration
Local activity only
Intramuscular or
Subcutaneous
Injection
Oral
Gastrointestinal
tract
Tissue Depots
DRUG
DRUG
DRUG
DRUG
Topical
Administration
Intravenous
Injection
DRUG
Systemic circulation
Drug
Serum Albumin
+
First
Pass
Effect
Lipid
Membranes
Drug Metabolites
Drug Metabolites
Enterohepatic
Recirculation
Primarily the Liver
produces Drug
Metabolites
Route of
Metabolism
Bile
Duct
Intestinal
Tract
Kidney
Feces
Urine: Drug &
Drug Metabolite
Receptors
for desired
effects
Receptors
for undesired
effects
Pharmacology
Route of Elimination
•Routes of administration:
1- Parentral route:
In case of IV, intra-arterial or intraspinal routes there are no
absorption barriers; while in case of IM, SC, intradermal or
intraperitoneal routes, the drug has to pass some membrane
barriers till it reaches the circulation.
2- GIT route:
The drug has first to come into solution before it can be absorbed
from the GIT. This is affected by the pH of the part of GIT from
which the drug is absorbed (stomach pH 1-3.5, duodenum pH 6-7,
lower ileum pH 8), and the dissociation rate (pKa) of the drug at
that pH.
i) Particle size:
The smaller the particle size of the drug powder, the greater will
be the surface area exposed to the fluids of the GIT and the
faster will be the dissolution.
Spironolactone and griseofulvin are drugs that were reformulated
in ‘micronized’ forms to improve their bioavailability.
ii) The pH of the medium:
Weakly acidic drugs are better dissolved in the alkaline regions
of the GIT and the opposite holds true for weakly basic drugs.
Drug absorption
a) Active transport or carrier mediated transport where energy is
required because transport of the drug occurs against concentration
gradient. Also, there should be some structural similarity between the
drug and the substrate normally carried across the membrane.
b) Passive diffusion where the movement of the drug occurs following
concentration gradient
i.e. from high concentration to low concentration.
The rate of diffusion is proportional to the drug concentration on the other
side of the membrane.
Where –dC/dt is the rate of diffusion
and C1 is the concentration of the drug at the site of absorption
and K is proportionality constant depending on the area and thickness of
the membrane,
and the partition coefficient of the drug.
c) Convective absorption where small molecules of molecular radius less
than 4Ǻ
pass through water filled pores in the biological membrane.
Conjugate Acid - Base
 For an acid (ex. R-COOH)
 HA
Conjugate Acid
R-COOH
H+ + A-
Conjugate base
R-COO-
 For a base (ex. R-NH2)

BH+
Conjugate Acid
R-NH3+
H+ + B
Conjugate base
R-NH2
Effect of dissociation constant (pKa) and partition coefficient (logP) on drug absorption
i) Dissociation constant (pKa):
For acids: RCOOH = RCOO- + H+
If pKa > pH unionized acid has the greater concentration e.g. pKa=3; pH=1
i.e. unionized =99% and ionized =1%
i.e. unionized =90% and ionized =10%
If pKa < pH ionized acid will prevail. e.g. pKa=1; pH=7
i.e. unionized =0.0001% and ionized =99.9999%
Drug Transfer – Acidic Drugs
Acidic Drug "A" - Primary absorption in the stomach
Blood
HA
pH = 7.4
H2O + A-
Lipid Membrane
pH = 1-2
HA
Stomach
H3O+ + A-
Example: Aspirin - Acetylsalicylic acid
CO2H
CO2Water
O
O
+ H3O+
O
CH3
O
CH3
pKa = 3.5------The pH at which you have 50% unionized
and 50% ionized forms of the molecule.
Drug Transfer – Acidic Drugs
Acidic Drug "A" - Little absorption in the small intestine
Blood
HA
pH = 7.4
H 2O + A-
Lipid Membrane
pH = 8-9
HA
Small
intestine
H 2O + A-
Example: Aspirin - Acetylsalicylic acid
CO2H
CO2Water
O
O
+ H3O+
O
CH3
O
CH3
pKa = 3.5---------@ pH = 4.5 - 90.0% in ionized form
@ pH = 5.5 - 99.0% in ionized form
For bases: RNH3+ = RNH2 + H+
If pKa > pH ionized base will prevail.
i.e. ionized=99% and unionized=1%
If we know that the unionized form of the drug is the lipid soluble form
and therefore is the absorbable form, then we can conclude that weak
acids will exist in the stomach mostly in the unionized form so they are
mainly absorbed from the stomach. So are weak bases which exist in
the small intestine in unionized form they will be absorbed mainly from
the intestine.
In fact, there is always equilibrium between the unionized and ionized
forms of the drug. When part of the unionized species is absorbed,
some of the ionized forms get converted into the unionized forms to
restore equilibrium. The latter will in turn be absorbed and the process
continues.
Drug Transfer – Basic Drugs
Basic Drug "B" - Little absorption in the stomach
Blood
BH+
pH = 7.4
H2O + B
Lipid Membrane
pH = 1-2
BH+
Stomach
H3O+ + B
Example: Pseudoephedrine HCl
HO
Cl+
NH2CH3
H
CH3
H
HO
Water
H
NHCH3
H
+ HCl
CH3
Pseudoephedrine HCl
pKa = 9.9------The pH at which you have 50% unionized
and 50% ionized forms of the molecule.
Drug Transfer – Basic Drugs
Basic Drug "B" - Primary absorption in the small intestine
Blood
BH+
pH = 7.4
H 2O + B
Lipid Membrane
pH = 8-9
BH+
Small
intestine
H 2O + B
Example: Pseudoephedrine HCl
HO
Cl+
NH2CH3
H
CH3
H
HO
Water
H
NHCH3
H
+ HCl
CH3
Pseudoephedrine HCl
pKa = 9.9---------@ pH = 8.9 - 90.0% in ionized form
@ pH = 7.9 - 99.0% in ionized form
% Ionized vs. pH
 For HA acids:
% ionization = 100/(1 + 10(pKa – pH))
 For BH+ acids:
% ionization = 100/(1 + 10(pH – pKa))
Example: Percentage ionized pseudoephedrine HCl
(pKa 9.9) in the small intestine at pH 8.0?
% ionization = 100/(1 + 10(8.0– 9.9))
% ionization = 100/(1 + 0.0126)
% ionization = 100/1.0126
% ionization = 98.76%
pH Effects on Absorption
Acids
5-nitrosalicylic acid
Salicylic acid
Thiopental
Bases
Quinine
Dextromethorphan
pKa
%
absorbed
at pH1
%
absorbed
at pH8
2.3
3.0
7.6
52
61
46
16
13
34
8.4
9.2
0
0
18
16
ii) Partition coefficient (logP):
Where, Co is the concentration of drug in organic phase (n-octanol) ,
and Cw is its concentration in aqueous phase (water).
The presence of the drug in the unionized form does not guarantee that it
will be absorbed from the GIT. The lipid solubility of the unionized form is
also a ruling factor. This is because of the composition of biological
membranes which is mainly lipid in nature; therefore solubilization of the
drug in the membrane is a must for absorption to occur.
Barbital and secobarbital which have similar pKa values, 7.8 and 7.9,
respectively have partition coefficients 0.7 and 23.3, respectively. So it can
be expected that secobarbital is better absorbed than barbital although
both drugs have the same percentage of unionized form under the same
condition.
Accordingly, one can modify a drug to improve its lipid solubility through
the introduction of hydrophobic groups. The hydrophobicity constants (π)
of various chemical groups are available in tables so that one can select
the proper group according to its π value and estimate the partition
coefficient of the modified drug.
Ph
C2H5
O
HN
NH
O
C2H5
O
H13C6
O
HN
NH
C2H5
O
O
HN
NH
O
O
S
Phenobarbital
Hexethal
Thiopental
On the contrary, it might be useful to decrease the lipophilicity of a drug so
as to prevent its absorption from the GIT and therefore localize its effect in
the GIT as in the case of intestinal sulfonamides (sulfaguanidine and
succinyl sulfathiazole)
NHCOCH2CH2COOH
NH2
N
NH
SO2NH
SO2NH
NH2
Sulfaguanidine
S
Succinyl sulfathiazole
•Sites of loss:
1- Protein binding:
Binding of drugs to plasma protein depends mainly on the chemical
structure of the drug. The bound drug is a large complex incapable of
performing any biological process (no metabolism, no excretion, no
interaction with receptors..etc.). So, the plasma protein binding can be
regarded as storage site for the drug from which the drug is gradually
released according to the equilibrium existing between the free and
bound drug. This, in some cases, contributes to the long duration of
action of some drugs. Also, protein binding protects the drug, to some
extent, from rapid metabolism and excretion.
2- Neutral fat:
Deposition of drugs into the adipose tissue depends largely on the
partition coefficient and pKa of the drug, so that lipophylic
unionized drugs are expected to partition rapidly into neutral fat.
Drugs stored in the adipose tissue will eventually be released into
the circulation to exert their action.
3- Excretion:
Drugs of suitable size to pass the glomerular membranes and that are
soluble enough in aqueous medium at the pH of urine are expected to
be excreted in the urine.
4- Metabolism:
this is discussed in a separate part.
Quantitative Structure Activity Relationship (QSAR)
The relation of one physicochemical parameter with biological activity can
be quantified; and this holds true for other parameters so that a generalized
equation can be developed to correlate activity to the physicochemical
properties of a given drug. In QSAR, an additive mathematical model is
developed in which it is assumed that a certain substituent in a specific position
contributes additively to the biological activity of the molecule.
Substituent hydrophobicity effect
Substituent electronic effect
Steric factors
1- Partition coefficient and Hansch substituent hydrophobicity constant (π):
Increase in PC result in improvement in pharmacokinetics and distribution of
the drug.
log 1/C
12
log 1/C
12
10
10
8
8
6
6
X
4
2
√
4
2
0
0
0
5
10
log P
0
10
20
log P
The reasons for this behaviour are:
a) The drug may be too hydrophobic to be soluble in aqueous body fluids.
b) The drug may be trapped in the fat depot and not reach the site of action.
c) Hydrophobic drugs are more susceptible to metabolism and loss.
Hydrophobicity of a given molecule is a sum of the hydrophobicity
constants (π) of the chemical groups that constitute the molecule. This
quantitative approach helps to theoretically predict the PC of a given
molecule and thereby chemical modifications by replacement of some
functional groups will be selected on the basis of the (π) constants of the
new chemical groups.

substituent
O
O
NH
O
N
H
O
NH
-1.35
O
N
H
O
Amobarbital
2.30
1.00
log P=sum of 
How to measure π constant of a given substituent?
π constant of –COOH can be calculated by the difference between PC of
benzene and benzoic acid.
π Cl = log P chlorobenzene – log P benzene
Positive π values increase PC and negative values decrease PC.
2- Electronic effects and Hammett sigma (σ) constant:
The sigma σ constant is a measure of the electronic contribution of
substituents relative to hydrogen. It affects the electron density on
particular regions in the molecule and thereby affects drug-receptor
interactions.
How to measure the δ constant of a particular group?
δ = pKa of benzoic acid- pKa of substituted benzoic acid
σ is positive for electron withdrawing groups e.g. CN, Cl, COOH, NO2, CF3,
and negative for electron donating groups e.g. OH, OCH3, NH2, CH3.
Hammett’s equation:
σ is electronic Hammett constant,
ρ is characteristic of the reaction considered and its selectivity to the substitution
in parent compounds,
K and Ko refer to the rate constants for the derivative and the parent compound.
In aromatic systems, the position of substituent whether meta,
ortho or para to a given group (R) will affect its electronic effect on
that group. In the meta position, the effect of the substituent on (R)
will be only inductive; while in the para position it will be due to
both inductive and resonance effects.
O
OH
N
O
INDUCTIVE EFFECT
R
R
O
O
N
R
R
O
O
N
OH
OH
R
R
R
INDUCTIVE AND RESONANCE EFFECTS