General principles of Pharmacology,the nature of

the drug.
Pharmacodynamic and Pharmacokinetic principles.

Development of new drugs.

Mariam Chubinidze, MD
• Pharmacology - study of substances that interact with living systems
through chemical processes. These interactions usually occur by
binding of the substance to regulatory molecules and activating or
inhibiting normal body processes.
• Toxicology - branch of pharmacology that deals with the undesirable
effects of chemicals on living systems, from individual cells to humans
to complex ecosystems
 The nature of drugs
A drug may be defined as any substance which change in biologic function through its chemical
actions.

• agonist (activator)

• antagonist (inhibitor)

the drug molecule interacts with a specific target molecule(receptor) that plays a regulatory role in the
biologic system.

chemical antagonists may interact directly with other drugs, whereas a few drugs (osmotic agents)
interact almost exclusively with water molecules.

Drugs may be synthesized within the body (eg, hormones) or may be chemicals not synthesized in
the body (ie, xenobiotics).
• To interact chemically
with its receptor, a
drug molecule must
have the appropriate
size, electrical charge,
shape, and atomic
composition.

Drug size
100 MW - 1000MW
 Drug Reactivity & Drug-Receptor Bonds
• Covalent bonds are very strong and in many cases not reversible
under biologic conditions. Thus, the covalent bond formed between
the acetyl group of acetylsalicylic acid (aspirin) and cyclooxygenase,
its enzyme target in platelets, is not readily broken.

• Electrostatic bonding is much more common than covalent bonding

in drug-receptor interactions. Electrostatic bonds vary from
relatively strong linkages between permanently charged ionic
molecules to weaker hydrogen bonds and very weak induced
dipole interactions such as van der Waals forces and similar
phenomena. Electrostatic bonds are weaker than covalent bonds.

• Hydrophobic bonds are usually quite weak and are probably

important in the interactions of highly lipid-soluble drugs with the
lipids of cell membranes .
 Drug Shape
• The drug’s shape is complementary to that of the receptor site in the
same way that a key is complementary to a lock.
• chirality (stereoisomerism) - more than half of all useful drugs are
chiral molecules; that is, they can exist as enantiomeric pairs. Drugs
with two asymmetric centers have four diastereomers.
DRUG-BODY INTERACTIONS
• Pharmacodynamic processes - the actions
of the drug on the body.
• Pharmacokinetic processes - the action of
the body on the drug.
Pharmacodynamic Principles

• Drug (D) + receptor-effector (R) → drug-receptor-effector complex →

effect

• D + R → drug-receptor complex → effector molecule → effect

• D + R → D-R complex → activation of coupling molecule →effector

molecule → effect

• Inhibition of metabolism of endogenous activator → increased

activator action on an effector molecule → increased effect
Types of Drug-Receptor Interactions

Drugs may interact with receptors in several ways.

Drugs that alter the agonist (A) response may
activate the agonist binding site, compete with
the agonist
(competitive inhibitors,

B), or act at separate (allosteric) sites, increasing

(C) or decreasing

(D) the response to the agonist. Allosteric

activators

(C) may increase the efficacy of the agonist or its

binding affinity. The curve shown reflects an
increase in efficacy; an increase in affinity would
result in a leftward shift of the curve.
• Full agonists - after administered with sufficient concentration
they saturate the receptor pool and can activate their receptor-
effector systems to the maximum extent of which the system is
capable. Full agonist drugs have a much higher affinity for the Ra
conformation, and cause a much larger observed effect.
• Partial agonists - bind to the same receptors and activate them in
the same way but do not evoke as great a response, no matter
how high the concentration. Partial agonists have an intermediate
affinity for both Ri and Ra forms. Such drugs are said to have low
intrinsic efficacy. Because they occupy the receptor, partial
agonists can also prevent access by full agonists. Intrinsic efficacy
is independent of affinity for the receptor.
• Conventional antagonist - fixing the fractions of drug-bound Ri
and Ra in the same relative amounts as in the absence of any drug.
In this situation, no change in activity will be observed, so the drug
will appear to be without effect. However, the presence of the
antagonist at the receptor site will block access of agonists to the
receptor and prevent the usual agonist effect. Such blocking action
can be termed neutral antagonism.
• Inverse agonists has a much stronger affinity for the Ri than for
the Ra state and stabilizes a large fraction in the Ri–D pool. Drug
will reduce any constitutive activity, thus resulting in effects that
are the opposite of the effects produced by conventional agonists
at that receptor.
 Duration of Drug Action

• Termination of drug action can result from several processes. In some cases, the
effect lasts only as long as the drug occupies the receptor, and dissociation of
drug from the receptor automatically terminates the effect. In many cases,
however, the action may persist after the drug has dissociated because, for
example, some coupling molecule is still present in activated form. In the case of
drugs that bind covalently to the receptor site, the effect may persist until the
drug-receptor complex is destroyed and new receptors or enzymes are
synthesized.

Binding of a drug to a nonregulatory molecule such as plasma albumin will result in

no detectable change in the function of the biologic system, so this endogenous
molecule can be called an inert binding site. Such binding is not completely without
significance, however, because it affects the distribution of drug within the body and
determines the amount of free drug in the circulation.
Pharmacokinetic Principles
Prodrug – an inactive precursor
chemical that is readily absorbed and
distributed must be administered and
then converted to the active drug by
biologic processes— inside the body.
Permeation
1. Aqueous diffusion—occurs within the larger aqueous compartments of the body and across epithelial membrane
tight junctions and the endothelial lining of blood vessels through aqueous pores, that permit the passage of
molecules as large as MW 20,000–30,000.
Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the permeating drug, a
downhill movement described by Fick’s law (see below).
Drug molecules that are bound to large plasma proteins (eg, albumin) do not permeate most vascular aqueous
pores. If the drug is charged, its flux is also influenced by electrical fields .

2. Lipid diffusion—Lipid diffusion is the most important limiting factor for drug permeation because of the large number
of lipid barriers that separate the compartments of the body. Because these lipid barriers separate aqueous
compartments, the lipid:aqueous partition coefficient of a drug determines how readily the molecule moves between
aqueous and lipid media.
Fick’s Law
The passive flux of molecules down a concentration gradient

where C1 is the higher concentration, C2 is the lower concentration, area is the cross-sectional
area of the diffusion path, permeability coefficient is a measure of the mobility of the drug
molecules in the medium of the diffusion path, and thickness is the length of the diffusion path.

.
 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:

The pKa is that pH at which the concentrations of the ionized and nonionized forms are equal.

The protonated form of a weak acid is the neutral,more lipid-soluble form, whereas the
unprotonated form of a weak base is the neutral form.

The law of mass action requires that these reactions move to the left in an acid environment (low
pH, excess protons available) and to the right in an alkaline environment.
3. Special carriers molecules - exist for many substances that are too large or too insoluble in lipid to diffuse passively
through membranes, eg, peptides, amino acids, and glucose. These carriers bring about movement by active transport or
facilitated diffusion and, unlike passive diffusion, are selective, saturable, and inhibitable.
Many cells also contain less selective membrane carriers that are specialized for expelling foreign molecules. One large
family of such transporters binds adenosine triphosphate (ATP) and is called the ABC (ATP-binding cassette) family. This
family includes the P-glycoprotein or multidrug resistance type 1 (MDR1) transporter found in the brain, testes, and other
tissues, and in some drug-resistant neoplastic cells.

Several other transporter families have been identified that do not bind ATP but use ion gradients to drive transport. Some
of these (the solute carrier [SLC] family) are particularly important in the uptake of neurotransmitters across nerve-ending
membranes
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 substance is bound at a cell-surface receptor, engulfed by the cell
membrane, and carried into the cell by pinching off of the newly formed vesicle inside the membrane. The
substance can then be released into the cytosol by breakdown of the vesicle membrane.(eg. vitaminB12,
iron).
The reverse process (exocytosis) is responsible for the secretion of many substances from cells.
 Ionization of Weak Acids and Weak Bases
For drugs,a weak acid is best defined as a neutral molecule that can reversibly dissociate into an
anion (a negatively charged molecule) and a proton (a hydrogen ion). For example, aspirin
dissociates as follows:

A weak base can be defined as a neutral molecule that can form a cation (a positively charged
molecule) by combining with a proton. For example, pyrimethamine, an antimalarial drug,
undergoes the following association-dissociation process:
Drugs have double names – generic and brand names.

Generic name (official) is the legal, noncommercial name for a drug.

Brand (trade name ) name is the commercial name for a drug, normally
the property of the drug manufacturer.

Chemical name is the chemical formula for a drug.

Drugs are usually administered by one of the following routes of administration:

• Oral;
• Buccal;
• Sublingual;
• Rectal;
• Topical;
• Intravitreal
• Transdermal;
• Intravenous;
• Intramuscular;
• Intraossal;
• Subcutaneous;
• By inhalation.
Parenteral
Routes of Administration
 Transdermal - This route involves application
to the skin for systemic effect usually via a
transdermal patch.

Absorption usually occurs very slowly, but

the first-pass effect is avoided. This route is
most often used for the sustained delivery of
drugs, such as the

Antianginal drug nitroglycerin

The antiemetic scopolamine
Nicotine transdermal patches, which are
used to facilitate smoking cessation.
Fentanyl patch for pain control