Scribd
Upload
14 views9 pages

UNIT 3.docx

Uploaded by

L-iminate
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
14 views9 pages

UNIT 3.docx

Uploaded by

L-iminate
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
You are on page 1/ 9

Partition Coefficient

Th e hydrophobic character of a drug can be measured experimentally by testing the drug’s


relative distribution in an n -octanol/water mixture.
Hydrophobic molecules will prefer to dissolve in the n-octanol layer of this two phase
system, whereas hydrophilic molecules will prefer the aqueous layer. The relative distribution
is known as the partition coefficient (P) and is obtained from the following equation:
P = Concentration of drug in octanol
Concentration of drug in aqueous solution
Hydrophobic compounds have a high P value, whereas hydrophilic compounds have a low P
value.
P > 1 – Hydrophobic or Lipophilic
P < 1 - Hydrophilic
Many drugs can exist as an equilibrium between an ionized and an un-ionized form.
However, log P measures only the relative distribution of the un-ionized species between
water and octanol.
Importance:
● Helps to know the nature of drug (Lipophilic or
Hydrophilic).
● Affect drug absorption and distribution.
● Generally used in combination with the pKa to predict
the “distribution of drug” in biological system.
● Since, biological membranes are “Lipophilic” in
nature. So, the rate of drug transfer is directly related to the “Lipophilicity of the
molecules”.

Drug Dissolution
The pharmaceutical phase includes the disintegration of a pill or capsule in the
gastrointestinal tract, the release of the drug contained within, and its dissolution. This is
followed by the pharmacokinetic and pharmacodynamic phases.
The process of solubilisation of drug is drug dissolution.
Drugs are normally taken orally as tablets or capsules. A tablet is usually a compressed
preparation that contains 5–10% of the drug, 80% of fillers, disintegrants, lubricants, glidants,
and binders, and 10% of compounds which ensure easy disintegration, disaggregation, and
dissolution of the tablet in the stomach or the intestine—a process which is defined as the
pharmaceutical phase of drug action.
The drug itself needs to dissolve in aqueous solution at a controlled rate. Such factors as
particle size and crystal form can significantly affect dissolution. Fast dissolution is not
always ideal. For example, slow dissolution rates can prolong the duration of action or avoid
initially high plasma levels.
Acid-Base Properties

Diagram illustrating the key properties that are influenced by the acid/base character of drugs.
Each node highlights an important facet of drug discovery and development.

Acidic and basic characteristics, in combination with whole molecule lipophilicity, affect
drug behaviour in a number of broad areas:
● Molecular interactions with the target macromolecule
● Passage across cells [permeability, absorption and distribution]
● Toxicity [e.g., hERG channel blockade, phospholipidosis]
● Pharmacokinetics [clearance, plasma and tissue binding, metabolism]
● Formulation [dissolution within the GI tract, stability], and
● Environmental impact
Acid-Base Properties
A large number of drugs exhibit typical colloidal behaviour in aqueous solution in that they
accumulate at interfaces, i.e., they are surface active.
Thus, these molecules lower the surface tension of water and form aggregates at sufficiently
high concentrations, resembling micelles that are produced with surfactants.
Typical examples of drugs that produce such surface activity and association are the
antihistamines, e.g., diphenylmethane derivatives (such as diphenhydramine), chlorcyclizine,
chlor-promazine, and tricyclic antidepressants (such as amitriptyline).
Surface active drugs of quite different chemical structure are reported to self-associate and
bind to membranes, causing disruption and solubilization, in a detergent-like manner.
The aggregation of surface-active drugs follows the same principles as classical detergents.
While some drugs display the ability to self-associate forming closed, micelle-like structures,
others aggregate by continuous stacking. When micelles are formed, their aggregation
number usually is small. Drug self-association is also temperature, ionic strength, and pH
dependent.

Bioavailability
Bioavailability refers to how quickly and how much of a particular drug reaches the blood
supply once all the problems associated with absorption, distribution, metabolism, and
excretion have been taken into account. Oral bioavailability (F) is the fraction of the
ingested dose that survives to reach the blood supply.
This is an important property when it comes to designing new drugs and should be
considered alongside the pharmacodynamics of the drug (i.e., how effectively the drug
interacts with its target).

Stereochemical aspect of drug action


Changing the stereochemistry of even one asymmetric centre can result in a drastic change of
shape that could affect how the molecule binds to its target binding site.
For example, epimerization of the asymmetric centre at position 14 results in a stereoisomer
that has only 10% the activity of morphine.

Electronic structures (Hammett Correlations)


The electronic effects of various substituents will clearly 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 interact with a binding site. It is, therefore, useful to
measure the electronic effect of a substituent.
As far as substituents on an aromatic ring are concerned, the measure used is known as the
Hammett substituent constant (σ). This is a measure of the electron withdrawing or
electron-donating ability of a substituent, and has been determined by measuring the
dissociation of a series of substituted benzoic acids compared with the dissociation of benzoic
acid itself.

Subscript H signifies that there are no


substituents on the aromatic ring.
Subscript X represents the substituent on the aromatic ring.
Determining Relationship Between Chemical and Biological Data
(Hansch Equation)
Th e biological activity of most drugs, however, is related to a combination of
physicochemical properties. In such cases, simple equations involving only one parameter are
relevant only if the other parameters are kept constant. In reality, this is not easy to achieve
and equations which relate biological activity to a number of different parameters are more
common.
These equations are known as Hansch equations and they usually relate biological activity to
the most commonly used physicochemical properties (log P, π, σ, and
a steric factor). If the range of hydrophobicity values is limited to a
small range, then the equation will be linear, as follows:

If the log P values are spread over a large range, then the equation will
be parabolic:

The reciprocal of the concentration (1/ C) is used, as more active


drugs will achieve a defined biological activity at lower concentration.

When carrying out a Hansch analysis, it is important to choose the substituents carefully to
ensure that the change in biological activity can be attributed to a particular parameter.

Kinetic analysis of ligand receptor interactions using Scatchard Plot


Scatchard plot - A plot used to measure the affinity of a drug for its binding site.

[L] and [LR] can be found by measuring the


radioactivity of unbound ligand and bound ligand,
respectively, after correction for any background
radiation. However, it is not possible to measure [R], so we have to carry out some
mathematical manipulations to remove [R] from the equation. The total number of receptors
present must equal the number of receptors occupied by the ligand ([LR]) and those that are
unoccupied ([R]), i.e.:

Substituting this into the first equation and rearranging leads to the Scatchard equation, where
both [LR] and [L] are measurable:
A Scatchard plot is drawn which compares the ratio [LR]/[L] versus [LR]. This gives a
straight line; the point where it meets the x-axis represents the total number of receptors
available (Rtot) (line A). Th e slope is a measure of the radioligand's affinity for the receptor
and allows Kd to be determined.

Double Reciprocal Plot (Lineweaver-Burk plot)

A problem related to Michaelis-Menton kinetics is the fact that there may not be sufficient
data points to determine whether the curve of the Michaelis-Menton plot has reached a
maximum value or not. Th is means that values for the maximum rate and KM are likely to be
inaccurate.
More accurate values for these properties can be obtained by plotting the reciprocals of the
rate and the substrate concentration to give a Lineweaver-Burk plot.
The maximum rate can then be obtained from the intersect of the line with the y-axis, while
KM can be obtained from the slope of the line or the intersect with the x-axis.

Used to determine whether the inhibitor of an enzyme-catalysed reaction is competitive,


uncompetitive, or non-competitive. The reciprocals of the reaction rate and the substrate
concentration are plotted, with and without an inhibitor being present.
Hill Plot
Forces Involved

Relationship between Dose and Effect (Graded and Quantal Response)


Graded dose-response relationships:
A Graded dose-response relationship describes a drug effect which increases in proportion to
increasing drug dose.
A graded response to a drug is seen in an individual, and increases with dose.
Graded dose-response graphs plot the response to a drug against its concentration.
(Responses like Blood Pressure, Pain intensity, etc)

Quantal dose-response relationships:


A Quantal dose-response relationship describes a drug effect which is binary (either present
or absent).
A quantal response to a drug is observed in a population, and is either present or absent in
any single individual.
Quantal dose-response graphs plot the rate of an outcome occurrence in a population against
the drug dose.
(% Responders like Loss of Pain, Loss of seizures, etc)

You might also like