PHARMACOLOGY

AND THERAPEUTICS

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
 GENERAL PRINCIPLES OF
PHARMACOLOGY

PHARMACOLOGY

Body of knowledge concerned with the

action of chemicals on biologic systems,
especially by binding to regulatory
molecules (receptors) and activating or
inhibiting normal body processes
 GENERAL PRINCIPLES OF
PHARMACOLOGY

MEDICAL PHARMACOLOGY
Area of pharmacology concerned with the
use of chemicals in the prevention,
diagnosis,
and treatment of disease, especially in
humans
 GENERAL PRINCIPLES OF
PHARMACOLOGY

TOXICOLOGY
Area of pharmacology concerned with the
undesirable effects of chemicals on
biologic systems
 GENERAL PRINCIPLES OF
PHARMACOLOGY

PHARMACOGENOMICS

Finds the exact mechanism of action of

drugs
Identifies the receptors
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG

Any substance that brings about a change

in biologic function through chemical
actions
 GENERAL PRINCIPLES OF
PHARMACOLOGY

RECEPTOR

Specific molecule in the biologic system

that plays a regulatory role
 GENERAL PRINCIPLES OF
PHARMACOLOGY

THE NATURE OF DRUGS

Inorganic ions, nonpeptide organic

molecules, small peptides and proteins,
nucleic acids, lipids, and carbohydrates
Found in plants or animals, many are
partially or completely synthetic
 Hormones
 Xenobiotics
 GENERAL PRINCIPLES OF
PHARMACOLOGY

PHYSICAL NATURE OF DRUGS

Solid
Liquid
Gas
Drugs are given at a site distant from the
intended site of action
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG SIZE AND MOLECULAR

WEIGHT
(MW)
Vary in size
 MW 7 (lithium)
 MW 50,000 (thrombolytic agents)

Majority have MW between 100 and

1000
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG SIZE AND MOLECULAR

WEIGHT
(MW)
100 MW
 For selective binding
1000 MW
 For traversing to different barriers of the body
>1000 MW
 Cannot move within the body
 Given directly at the site of action
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG SHAPE
CHIRALITY
 Stereoisomerism
 Exist as enantiomeric pairs
Carvedilol
(S)(-) isomer, potent beta receptor blocker
(R)(+) isomer weak beta receptor blocker
Ketamine
(+) more potent anesthetic and less toxic
than the (-)
Racemic mixture
 DRUG SHAPE

 Lock and key mechanism

 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG RECEPTOR BONDS

 Chemical forces or bonds through which

the drug interacts with the receptors
 Weaker bonds are more selective bonds
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG RECEPTOR BONDS

COVALENT BONDS
 Strongest
 Irreversible
GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG RECEPTOR BONDS

ELECTROSTATIC BONDS
 More common
 Weaker
 Eg, between cation and an anion
GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG RECEPTOR BONDS

HYDROPHOBIC BONDS
 Weakest
 Highly lipid soluble drugs
GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG-BODY INTERACTIONS

PHARMACODYNAMICS
PHARMAKOKINETICS
 PHARMACODYNAMIC PRINCIPLES

 Drug (D) + receptor-ef fector (R) → drug-receptor-ef fector

complex → ef fect

 D + R → drug-receptor complex → ef fector molecule → ef fect

 D + R → D-R complex → activation of coupling molecule →

ef fector molecule → ef fect

 Inhibition of metabolism of endogenous activator → increased

activator action on an ef fector molecule → increased ef fect
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG-BODY INTERACTIONS
 PHARMACODYNAMICS
Constitutive activity
Some of the receptor pool must exist in
Ra form
May produce same physiologic effect as
agonist-induced activity
Occurs in the absence of the agonist
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG-BODY INTERACTIONS
PHARMACODYNAMICS
 Agonist-binds to and activate the receptor
Full agonist
Activates receptor-effector system to the
maximum extent (Ra-D pool){activated form}
Partial agonist
Binds to the same receptors and activate them
in the same way but do not evoke as great a
response
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG-BODY INTERACTIONS
 PHARMACODYNAMICS
 Allosteric modulators
 Binds to a site on the receptor molecule separate
from the agonist binding site
 Modifies receptor activity without blocking
agonist activity
 May increase or decrease response to agonist
 Noncompetitive
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG-BODY INTERACTIONS
 PHARMACODYNAMICS
Inverse agonist
Drug has a stronger affinity for the Ri
pool (nonfunctional form)
Reduces constitutive activity
Results in effects that are opposite of
the effects produced by conventional
agonists
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG-BODY INTERACTIONS

 PHARMACODYNAMICS

 Antagonist
 Binds to a receptor, compete with and
prevent binding by other molecules
A model of drug-receptor interaction. The receptor is able to assume two conformations. In the Ri conformation, it is inactive and produces no effect, even
when combined with a drug molecule. In the Ra conformation, the receptor can activate downstream mechanisms that produce a small observable effect,
even in the absence of drug (constitutive activity). In the absence of drugs, the two isoforms are in equilibrium, and the Ri form is favored. Conventional full
agonist drugs have a much higher affinity for the Ra conformation, and mass action thus favors the formation of the Ra–D complex with a much larger
observed effect. Partial agonists have an intermediate affinity for both Ri and Ra forms. Conventional antagonists, according to this hypothesis, have equal
affinity for both receptor forms and maintain the same level of constitutive activity. Inverse agonists, on the other hand, have a much higher affinity for the
Source: Introduction: The Nature of Drugs & Drug Development & Regulation, Basic & Clinical Pharmacology, 13e
Ri form, reduce constitutive activity, and may produce a contrasting physiologic result.
Citation: Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 13e; 2015 Available at:
http://accesspharmacy.mhmedical.com/content.aspx?bookid=1193&sectionid=69103583 Accessed: January 24, 2017
Copyright © 2017 McGraw-Hill Education. All rights reserved
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG-BODY INTERACTIONS
 PHARMACOKINETICS
 Prodrug
 Inactive precursor
 Must be administered and converted to the
active drug by biologic process inside the
body
 GENERAL PRINCIPLES OF
PHARMACOLOGY

DRUG-BODY INTERACTIONS

PHARMACOKINETICS
Absorption
Distribution
Metabolism
Elimination
 GENERAL PRINCIPLES OF
PHARMACOLOGY

THE MOVEMENT OF DRUGS IN THE

BODY
To reach its receptors and bring about
biologic effect
 A drug molecule (eg, sedative) must
travel from the site of administration
(eg, gastrointestinal tract) to the site
of action (eg, brain)
 GENERAL PRINCIPLES OF
PHARMACOLOGY

A. PERMEATION

 Movement of drug molecules into and

within the biologic environment
 GENERAL PRINCIPLES OF
PHARMACOLOGY

A. PERMEATION

1. AQUEOUS DIFFUSION
 Movement of molecules through the watery
extracellular and intracellular spaces
 Membranes of capillaries with small water-
filled pores
 Passive process
 Governed by Fick’s law
 GENERAL PRINCIPLES OF
PHARMACOLOGY
A. PERMEATION

2. LIPID DIFFUSION
 Movement of molecules through
membranes
and other lipid structures
 Most important factor for drug permeation
 Large lipid barriers that separate the
compartments of the body
 Passive process
 Governed by Fick’s law
 GENERAL PRINCIPLES OF
PHARMACOLOGY

A. PERMEATION

3. TRANSPORT BY SPECIAL CARRIERS

 Drugs transported across barriers by
mechanisms that carry similar
endogenous
substances
 Amino acid, peptides, glucose
 Capacity limited
 Not governed by Fick’s law
 GENERAL PRINCIPLES OF
PHARMACOLOGY

A. PERMEATION

3. TRANSPORT BY SPECIAL CARRIERS

ACTIVE TRANSPORT
 Needs energy
 Against a concentration gradient
FACILITATED DIFFUSION
 No energy required
 Downhill
 GENERAL PRINCIPLES OF
PHARMACOLOGY

A. PERMEATION

4. ENDOCYTOSIS
 Binding to specialized components
(receptors) on cell membranes
 Internalization by infolding of the area
of
the membrane and contents of the
vesicle
are subsequently released into the
cytoplasm
 GENERAL PRINCIPLES OF
PHARMACOLOGY

A. PERMEATION

4. ENDOCYTOSIS
 Permits very large or very lipid-
insoluble
chemicals to enter the cell
 B 12 with intrinsic factor
 Iron with transferrin
 GENERAL PRINCIPLES OF
PHARMACOLOGY

A. PERMEATION

5. EXOCYTOSIS
 Reverse process
 Expulsion of membrane-encapsulated
material from the cell
 Neurotransmitters
Mechanisms of drug permeation. Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg, tight junctions, A), or through
lipid cell membranes (B). Drugs with the appropriate characteristics may be transported by carriers into or out of cells (C). Very impermeant drugs may
also bind to cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis), and then released inside the cell or expelled via
the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D).

Source: Introduction: The Nature of Drugs & Drug Development & Regulation, Basic & Clinical Pharmacology, 13e
Citation: Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 13e; 2015 Available at:
http://accesspharmacy.mhmedical.com/content.aspx?bookid=1193&sectionid=69103583 Accessed: January 24, 2017
Copyright © 2017 McGraw-Hill Education. All rights reserved
 GENERAL PRINCIPLES OF
PHARMACOLOGY

B. FICK’S LAW OF DIFFUSION

 Predicts the movement of molecules

across a barrier
 Drug absorption is faster in organs with
larger surface areas (eg, small intestine)
than from organs with smaller absorbing
areas (eg, stomach)
 PHARMACOKINETIC PRINCIPLES

 Fick’s Law of Dif fusion

 GENERAL PRINCIPLES OF
PHARMACOLOGY

B. FICK’S LAW OF DIFFUSION

 Drug absorption is faster from organs

with
thin membrane barriers (eg, lungs) than
those with thick barriers (eg, skin)
 GENERAL PRINCIPLES OF
PHARMACOLOGY

THE HENDERSON-HASSELBACH
EQUATION

(protonated)
log ___________ = pka - pH
(unprotonated)

Protonated means associated with a proton

(a hydrogen ion)
 GENERAL PRINCIPLES OF
PHARMACOLOGY

C. WATER AND LIPID SOLUBILITY

OF DRUGS
3. Ionization of Weak Acids and Weak
Bases
WEAK BASE
 Neutral molecule that can form a cation
(+ charged) by combining with a proton
(hydrogen ion)
 Ionized, more polar, more water soluble
when they are protonated
 GENERAL PRINCIPLES OF
PHARMACOLOGY

C. WATER AND LIPID SOLUBILITY OF

DRUGS
3. Ionization of Weak Acids and Weak Bases
WEAK ACID
 Neutral molecule that can reversibly
dissociate into an anion (- charged) and
a proton ( hydrogen ion)
 Not ionized, less polar, less water soluble
when they are protonated
 GENERAL PRINCIPLES OF
PHARMACOLOGY

RNH 3 + RNH 2 + H+
protonated weak unprotonated weak proton
base (charged, base (uncharged, more

more water-soluble)lipid-soluble)

RCOOH RCOO _ + H+
protonated weak unprotonated weak proton
acid (uncharged, acid (charged, more
more lipid-soluble) water-soluble)
 GENERAL PRINCIPLES OF
PHARMACOLOGY

The Henderson-Hasselbach Equation

 Clinically important when it is necessary

to estimate or alter the partition of drugs
between compartments of different pH
 GENERAL PRINCIPLES OF
PHARMACOLOGY

The Henderson-Hasselbach Equation

When a patient takes an overdose of a
weak acid drug, excretion maybe
accelerated by alkalinizing the urine
Weak acids dissociate to its charged,
polar form in alkaline urine and cannot
readily diffuse back from the renal tubule
back to the blood
 GENERAL PRINCIPLES OF
PHARMACOLOGY

Large number of drugs are weak bases

with amine containing molecules
Nitrogen of a neutral amine has 3 atoms
associated with it plus a pair of unshared
electrons
 GENERAL PRINCIPLES OF
PHARMACOLOGY

Primary Secondary Tertiary

Quaternary

H R R R
.. .. .. . .
R : N: R : N : R : N:
R :N:R
.. .. .. . .
H H R
R