PHARMACOL

OGY PHL 313

Chapter 1
Introduction to Pharmacology
Definition
• Pharmacology: is the study of • Medical pharmacology: is the
substances that interact with living science of substances used
systems through chemical to prevent, diagnose, and

s processes, especially by binding to

regulatory molecules and activating
or inhibiting normal body
treat disease.

processes.
• Toxicology: is the branch of
pharmacology that deals with
the undesirable effects of
• These substances are chemicals
chemicals on living systems from
administered to achieve: individual cells to humans to
 Beneficial therapeutic effect on complex ecosystems.
some process within the body
 Toxic effects on regulatory
processes in parasites infecting the
body
Medical vs.
Pharmacology
Environmental and
toxicology
FIGURE 1–1 (Page 2)
Source: KATZUNG, B. G., MASTERS,
S. B., & TREVOR, A. J. (2012). Basic &
clinical pharmacology. New York,
McGraw-Hill Medical.
 • A drug: is any substance that brings about a change in biologic

General
function through its chemical actions.

• Drug molecule: interacts as an agonist (activator) or

principles of antagonist (inhibitor) with a specific molecule in the biological
system that plays a regulatory role. This molecule is called a

pharmacolog receptor.
• Drugs may be synthesized within the body (e.g. hormones), so

y they are called endogenous

• or may be chemicals not synthesized in the body (i.e.
xenobiotics, from the Greek xenos, meaning “stranger”) or can
be called exogenous.
• Poisons are drugs that have almost exclusively harmful effects
• Toxins are usually defined as poisons of biological origin, i.e.
synthesized by plants or animals
• In contrast to inorganic poisons such as lead and arsenic
Agonist

Binding
site

Receptor
 • A drug molecule must have the appropriate
size, electrical charge, shape, and atomic
composition to be able to interact chemically
with its receptor

The nature of • Drug is often administered at a location distant

from its intended site of action, (example: a pill
drugs given orally to relieve a headache)

• Therefore, a useful drug must have the necessary

properties to be transported from its site of
administration to its site of action.
 • Solid at room temperature (e.g. aspirin, atropine)
• Liquid (e.g. nicotine, ethanol)
The • Gaseous (e.g. nitrous oxide)
nature of drugs
physical  These factors often determine the best route of
administration
 • The molecular size of drugs varies
 very small (e.g. lithium ion, MWt 7 g/mol
 very large (e.g. alteplase , a protein of MWt 59,042 g/mol.

• Most drugs have molecular weights between 100 and 1000.

Drug • To have a good “fit” to only one type of receptor, a drug

size molecule must be sufficiently unique in shape, charge, and

other properties, to prevent its binding to other receptors
(specificity)

• To achieve such selective binding, it appears that a molecule

should in most cases be at least 100 MW units in size.
 • The upper limit in molecular weight is determined primarily by
the requirement that drugs must be able to move within the
body (e.g., from the site of administration to the site of action)

• Drugs much larger than MWt 1000 do not diffuse readily

between compartments of the body

Drug • Therefore, very large drugs (usually proteins) must often be

size administered directly into the compartment where they have

their effect.

• In the case of alteplase, a clot-dissolving enzyme, the drug is

administered directly into the vascular compartment by
intravenous or intra-arterial infusion.
Drug Drugs interact with
There are three major
types:
and drug-
reactivity
receptors by means of
chemical forces or
• Covalent
• Electrostatic
receptor bonds bonds. • Hydrophobic
 • Covalent bonds are very strong and, in many cases, not
reversible under biologic conditions.

Drug • For example, covalent bond formed between the acetyl

group of acetylsalicylic acid (aspirin) and cyclooxygenase, its

and drug-
reactivity
enzyme target in platelets, is not readily broken.

receptor bonds • The platelet aggregation-blocking effect of aspirin lasts long

after free acetylsalicylic acid has disappeared from the
bloodstream (about 15 minutes) and is reversed only by the
synthesis of new enzyme in new platelets, a process that
takes several days.
 Electrostatic bonding is much more common than
covalent bonding in drug-receptor interactions.

Drug Electrostatic bonds vary from

and drug-
reactivity strong linkages between very weak induced dipole

receptor bonds
permanently charged ionic weaker hydrogen bonds interactions such as van der
molecules Waals
forces

Electrostatic bonds are weaker than covalent bonds

 • Hydrophobic bonds are usually quite weak and
Drug are probably important in the interactions of

and drug-
reactivity
highly lipid-soluble drugs with the lipids of cell
membranes and perhaps in the interaction of
receptor bonds drugs with the internal walls of receptor
“pockets.”
 • Determines receptor binding, complementing as key-lock

• The phenomenon of chirality (stereoisomerism) is so common

in biology that more than half of all useful drugs are chiral
molecules; that is, they can exist as enantiomeric pairs.

Drug • In most cases, one of these enantiomers is much more potent

than its mirror image enantiomer, reflecting a better fit to the

shape receptor molecule.

• If one imagines the receptor site to be like a glove into which

the drug molecule must fit to bring about its effect, it is clear
why a “left-oriented” drug is more effective in binding to a left-
hand receptor than its “right-oriented” enantiomer.
Drug
shape • For example, carvedilol, a drug that interacts with adrenoceptors,
has a single chiral center and thus two enantiomers.

• One of these enantiomers, the (S)(−) isomer, is a potent β-receptor

blocker. The (R)(+) isomer is 100-fold weaker at the β receptor.
 • Just as select enantiomers are often more
selective for one receptor, a single enantiomer is
more susceptible to metabolizing enzymes
• One enantiomer’s duration of action, or
elimination half-life may vary dramatically from
the other
• Selectively synthesizing one enantiomer may be
Racemic difficult, for cost-purposes, most drugs are still
used in racemic form
mixture • Most clinical trials are done with racemic mixtures
 Very few drugs on the market are active isomers
only
 Patients are taking 50% of dose that is ineffective
at best, toxic and harmful at worst
 The interactions between a drug and the body are
conveniently divided into two classes:

Pharmacodynamic (PD) processes are the actions of

the drug on the body, Hypertensive, Hyperglycemic…
etc.
Drug- Pharmacokinetic (PK) processes are the actions of
interactions
body the body on the drug. (ADME)
• Absorption
• Distribution
• Metabolism
• Excretion
 Drugs (generally) bind to receptors → some effect
Often not direct bind → effect, may be intermediate steps

Drug (D) + Receptor (R) → D+R complex → effect

Pharmacodynami D + R → D+R complex → effector molecule → effect

c principles
D + R → D+R complex → activation of coupling
mechanism → effector molecule → effect

Effector molecules will be discussed more in Chapter 2

Agonist
Antagonis
and
• Agonist: is any drug that binds to a receptor and
t activates the receptor
• Antagonist: is any drug that binds to a receptor,
compete with and prevent binding of other
molecules.
Agonist
Antagonis
and
t • What happened when the agonist leave the
receptor:
• Either the receptor gets deactivated
• Or permanently activated
 • If the D + R complex exists, the drug
will be efficacious
• Dissociation may be enough to
How long will abrogate drug activity
• More often, duration of action is
drug
the have an longer, especially if a coupling
effect? mechanism or effector molecule is
involved
• If a drug binds covalently, receptor will
need to be resynthesized
 • Some drugs bind to the same receptor molecule
but do not prevent binding of the agonist are said
to act allosterically and may enhance or inhibit the
action of the agonist molecule.
• Allosteric inhibition is not overcome by increasing
Allosteri the dose of agonist.

acctivator
or
inhibitor
 The receptor is postulated to exist in the inactive form (Ri),
and in the activated form (Ra).
Receptors will exist in each form -> basal constitutive activity
Ra <-> Ri
Agonist Agonist
Full agonist shift all Receptors to active form
Ra 99% <-> Ri 1%
and PARTIAL Agonist only shift some receptors to active form
Ra 95% <-> Ri 5%

Antagonist
Antagonist
Neutral antagonist Fix the fractions of Ra and Ri
Ra 90% <-> Ri 10% (basal activity), Doesn’t displace
It is more endogenous agonist from Ra, prevents binding to Ri.

complicate
Inverse Agonist Drug with higher affinity for the active site
than the endogenous ligand may displace the agonist and
decrease basal activity
d Ra 80% <-> Ri 20%
THIS IS CALLED THE TWO STATE RECEPTOR
MODEL
Agonist
and
Antagonist
It is more
complicate
d
 Drug permeation proceeds by several
mechanisms:
• Passive diffusion in an aqueous or lipid
Permeation medium is common

of • Active processes (play a role in the

drugs movement of many drugs, especially
those whose molecules are too large to
diffuse readily)
 Permeation of drugs
Drugs with the Very impermeant drugs may also bind
appropriate to cell surface receptors (dark binding
characteristics may be sites), be engulfed by the cell
Drugs may diffuse passively through transported by carriers membrane (endocytosis),
aqueous channels in the intercellular into or out of cells (C). and then released inside the cell or
expelled via the membrane-limited
junctions (eg, tight junctions, A or
vesicles out of the cell into the
through lipid cell membranes, B) extracellular space (exocytosis) (D).
 1. Aqueous diffusion
• Occurs within the larger aqueous compartments of
the body (interstitial space, cytosol, etc) and
across epithelial membrane tight junctions and the
endothelial lining of blood vessels through
Permeation aqueous pores that—in some tissues—permit the
passage of molecules as large as MW 20,000–
of 30,000.
• Aqueous diffusion of drug molecules is usually
drugs driven by the concentration gradient of the
permeating drug, a downhill movement described
by Fick’s law
 2. Lipid diffusion

The most important limiting factor for drug

permeation because of the large number of
lipid barriers that separate the compartments of
the body.
Permeation
of • Lipid/aqueous (oil/water) partition coefficient
(amphiphilicity) determines how readily drug moves

drugs between compartments

• Varies with pH (shifts to hydrophilic) for weak
acid/base
• Governed by Henderson-Hasselbalch
Equation
(described later)
 3. Special carrier

Special carrier molecules exist for many substances that are

important for cell function and too large or too insoluble
in lipid to diffuse passively through membranes, eg,
peptides, amino acids, and glucose.

Permeation
of Many cells also contain less selective membrane carriers that
are specialized for expelling foreign molecules.

drugs • ATP required family: ABC (ATP-Binding Cassette)

transporters P-glycoprotein (P-gp, MDR1), MRP, BCRP and
more
• Non-ATP required family transporters such as solute
carrier
(SLC) family
 Examples of common drug transporters in the body

Permeation
of
drugs
 4. Endocytosis and exocytosis

A few substances are so large or impermeant that they can

enter cells only by endocytosis, the process by which the

Permeation substance is bound at a cell-surface receptor, engulfed by

the cell membrane, and carried into the cell by pinching

of off of the newly formed vesicle inside the membrane.

The substance can then be released inside the cytosol by
drugs breakdown of the vesicle membrane.

Examples: vitamin B 12 and iron

 The electrostatic charge of an ionized molecule attracts water dipoles and
results in a polar, relatively water-soluble, and lipid-insoluble complex.

Because lipid diffusion depends on relatively high lipid solubility, ionization

of drugs may markedly reduce their ability to permeate membranes.

Acid
• A very large percentage of the drugs in use are weak acids or weak bases
base role
and • They change their polarity in a pH-dependent manner

in
PK/P Weak acid: neutral molecule, can reversibly dissociate into anion and

D
proton
C8H7O2COOH (neutral aspirin) -> C8H7O2COO- + H+
Weak Base: neutral molecule, can reversibly form cation by combining with
a proton
C12H11CIN3NH3+ (pyrimethamine cation) -> C12H11CIN3NH2+ + H+
 pH: the negative logarithm of the hydrogen ion concentration
[H+]
a measure of the degree to which a solution is acidic or
alkaline.
• An acid is a substance that can give up a hydrogen ion (H+)
• A base is a substance that can accept hydrogen ion (H+)
Acid
base role
and
Ka: An acid dissociation constant, it is also known as acidity
constant, or acid-ionization constant.
a quantitative measure of the strength of an acid in solution.
in
PK/P • It is the equilibrium constant for a chemical reaction known
as dissociation in the context of acid-base reactions.
D • For many practical purposes it is more convenient to discuss
the logarithmic constant, pKa
pKa = -log10 (Ka)
 The Henderson-Hasselbalch equation relates the ratio of protonated to
unprotonated weak acid or weak base to the molecule’s pKa and the pH of
the medium as follows
Log ( protonated/ unprotonated ) = pKa – pH

The or
pKa-pH = log [HA]/[A-]

Henderson- This equation applies to both acidic and basic drugs

Hasselbalc Inspection confirms that the lower the pH relative to the pKa , the greater
Equation
h will be the fraction of drug in the protonated form.

The uncharged form is the more lipid-soluble, more of a weak acid will be
in the lipid-soluble form at acid pH, whereas more of a basic drug will be in
the lipid-soluble form at alkaline pH
 Example: aspirin acetylsalicylic acid pKa = 3
C8H7O2COOHC8H7O2COO- + H+

Applicatio pKa-pH = log [HA]/[A-]

 In the urine with pH = 6

n of The 3-6 = log [HA]/[A-] -> -3 = log [HA]/[A-] -> Take the anti log ->
0.001 = [HA]/[A-]

Henderson- This means 1 [HA] for every 1000 [A-]

The majority are ionized means -> Not absorbed

Hasselbalc  In the stomach with pH = 1.92

3-1.92 = log [HA]/[A-] -> 1.08 = log [HA]/[A-] -> Take the anti log ->
h Equation 12 = [HA]/[A]
This means 12 [HA] for every 1 [A-]
The majority are Unionized means -> Absorbed
 pH varies within the body
 Gut; depends on presence of food: 1-4
 Systemic circulation: 7.4
 Bile: 7.5-8.8
Applicatio  Urine: 5-8; normal 6-7

n of The Different fluids can varyingly “trap” drugs by ionizing

Urine Acidification and Alkalinization

Henderson-  Ion trapping is based on the principle that ionized

substances do not cross renal tubular membranes easily
and are not well reabsorbed

Hasselbalc  Alkaline urine favors the ionization of acidic compounds,

and acidic urine favors the ionization of alkaline
compounds.
h Equation Ammonium chloride can be used to promote urinary
acidification.
Urine alkalinization can be performed with use of sodium
bicarbonate
Expected Questions:
• Define the followings: Pharmacology, Toxicology, Xenobiotic substance, Endogenous substance?
• Name four different types of receptors and specify their different mechanisms in performing their function:
• What are the types of bonds that regulate the binding between ligands and receptors?
• Talk briefly about racemic mixture and their importance in pharmacology?
• Explain the difference between agonist and antagonist based on the old receptor theory?
• Explain the difference between agonist and antagonist based on the new receptor theory?
• In pharmacology, what is allosteric activator and allosteric inhibitor?
• List the permeation methods used in the body for drug permeation with brief explanation?
• What is the pH and the pKa and what is the difference between them, and why they are essential to know
in
pharmacology? Explain
• How different body fluids can trap drugs by ionization, with examples?