General Principles of Drug Therapy

Integrated Scientific and

Clinical Pharmacology

Definitions, Basic Principles and

Pharmacodynamics I
Marc Imhotep Cray, M.D.
BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
General Principles of Drug Therapy

Definition- pharmacology
Derived from Greek words pharmakon, meaning drug or
poison, and logos, meaning rational discussion or study
rational discussion or study of drugs and their interactions
with body
body of knowledge concerned with action of chemicals on
biologic systems

Also see Integrated Basic and Clinical Pharmacology Course

Syllabus and Digital Guidebook pgs. 9-13

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Definition- pharmacology (2)

Study of drug action at both molecular and
whole-organism levels
 At molecular level, biologic effect of a drug

 At whole-organism level, therapeutic effects of a

drug and unwanted (i.e., adverse or side) effects

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Scope of Pharmacology
“What is pharmacology?” only partially answered by derivation of the term

Pharmacology is:
a branch of biology as it is concerned with living organisms
it borrows heavily from physiology and biochemistry for
substantive matter and experimental techniques

related to chemistry, because it deals with chemical agents

an essential part of medicine

the cornerstone of modern therapeutics is drugs
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Scope of Pharmacology (cont.)

Pharmacology uses:
mathematics to express its principles in quantitative terms

behavioral sciences, such as psychology, to understand

actions of drugs that lead to changes in mood or emotion
(psychoactive drugs)

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Definition- pharmacology (3)

“Pharmacology is the unified study of the properties of
chemicals and living organisms and all aspects of their
interactions; it is an integrative rather than an autonomous
science, drawing on the techniques and knowledge of many
allied scientific disciplines.”
From: Levine's Pharmacology: Drug Actions and Reactions 7th ed. Walsh C and Schwartz-Bloom RD (Eds.)
New York, Taylor Francis, 2005. Pg. 18

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“WHAT IS PHARMACOLOGY?”
A Summary Statement
…“Medical pharmacology is a bridge between basic science and
clinical medicine. It makes use of all the disciplines that comprise the
scientific foundation of clinical medicine; from anatomy, physiology,
pathophysiology, pathology and immunology to biochemistry, molecular
and cell biology, epidemiology, genetics and genomics. Hence…it is
particularly useful for pre-clinical student to view and engage the
subject as a major horizontal and vertical integrator, as it pulls together
all the different strands of the basic medical science years and
simultaneously introduces one to the cornerstone of modern clinical
therapeutics, ie .drugs”…
From: Integrated Scientific and Clinical Pharmacology: A Course Syllabus and
Digital Guidebook for Medical Students. Cray MI (2015) . Pg.4 7
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“The broad science of pharmacology.”

four main categories (subdivisions)
1. pharmacodynamics,
2. toxicology,
3. pharmacotherapeutics
4. pharmacy

Clinical pharmacology =The principles behind the prescribing process

as opposed to
Pharmacotherapeutics =The process of medical treatment
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Pharmacology categories defined:

Pharmacodynamics the study of the actions and effects of
chemicals at all levels of organization of living material and of the
handling of chemicals by the organism.

Toxicology is the study of the toxic or harmful effects of chemicals

as well as of the mechanisms and conditions of occurrence of these
harmful effects.

Pharmacotherapeutics the application of drugs in the prevention,

treatment or diagnosis of disease and their use in purposeful
alteration of normal functions...

Pharmacy concerned with the preparing, compounding and

dispensing of chemical agents for therapeutic use.
For additional related key terms see: MedPharm Glossary 9
General Principles of Drug Therapy

Two major divisions of medical

pharmacology:
pharmacodynamics (PD) & pharmacokinetics (PK)

Pharmacodynamics study of
1) molecular, biochemical and physiologic effects of
drugs on cellular systems
2) Drug-receptor interactions
3) drug mechanisms of action= therapeutic and toxic
 Operationally, what drug does to body
 Processes that determine variability in drug actions
despite equivalent drug delivery to effector sites
 Drug Concentration-Effect relationship
Dose-Response phenomena 10
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Two major divisions of med pharm (2)

Pharmacokinetics study of ADME
Absorption drug in
Distribution
Metabolism
Excretion drug out = Elimination
Movement of drug molecules through various
physiologic compartments drug deposition
Operationally, what body does to drug
Processes that determine drug delivery to (in)
and removal from (out) molecular targets
Drug Concentration-Time relationship
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Drug deposition
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free

Systemic
circulation

Absorption Free drug Excretion

Bound drug Metabolites

Biotransformation
The summation of these processes will determine plasma
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drug concentrations (Cp) at any point in time
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Third emerging division of medical

pharmacology
Pharmacogenomics study of how genetic
makeup affects PD and PK
affects drug selection and application to
individual patients
“Pharmacogenomics may hold the opportunity of allowing
practitioners to integrate a molecular understanding of the basis of
disease with an individual's genomic makeup to prescribe
personalized, highly effective, and safe therapies.”
From: Roden DM. (2012) Ch. 5 Principles of Clinical Pharmacology. In: Longo DL, Fauci AS,
et al. Harrison's Principles of Internal Medicine,18th Ed., McGraw-Hill 2012, Pg. 33

Learn more: Ritter JM, Lewis LD, Mant TG, Ferro A. Ch.14 Pharmacogenetics. In:
A Textbook of Clinical Pharmacology and Therapeutics 5th-ed. Hodder Arnold,
2008; Pgs. 79-85. 13
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Relationship between PK and PD

Pharmacokinetics Pharmacodynamics

Drug concentration Mechanism and

Dose of drug in target organ magnitude of
over time drug effect
Absorption Receptor binding
Distribution Signal transduction
Biotransformation Physiological effect
Excretion
Redrawn after Brenner GM and Stevens CW. Pharmacology 4th ed. (Sanders, 2014) 14
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Definition-Drug
No precise uniformly accepted definition
 commonly accepted -drug is any exogenous
non-nutritive substance that affects bodily
function
In medicine drug is a chemical agent used in
prevention, diagnosis, treatment or cure of
disease (or affect fertility)

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Drug- cardinal features:

 modify communication system within organism
[humans and (or) animals]
modification should not interfere with fidelity

of biochemical and physiologic signal
 should not activate unwanted compensatory
response
 should selectively target specific cellular
components that Fx in normal signaling process

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Properties of an ideal drug

 Safety
Fewer side effects or lower toxicity

 Effectiveness
Better therapeutic effects

 Selectivity
Target to desired sites or molecules

NB Due to the multiple variations in patient profiles and drug

variables and the interaction between the two, the ideal drug
“Does not exist” 17
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Clinical Pharmacology
A complex interaction between patient and drug
Patient profile Patient profile Drug profile
The patient is a unique individual, Age Name (generic)
with many distinguishing features Weight Class
that need to be taken into account Sex Action
during prescribing. Race Pharmacokinetics
Drug profile Allergies Indications
The drug, likewise, is unique, Smoking history Contraindications/
with its own distinguishing features Alcohol history precautions
Diseases Interactions
Good prescribing involves tailoring Pregnant/lactating Side effects
the drug and dosing regimen to the Current therapy Dosing regimen
unique patient Intelligence Monitoring
Clinical pharmacology provides the Overdose
basis of this
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Drug Nomenclature
Several names refer to the same drug:
 Chemical Name
 Based on a drug's chemical and molecular constituents and structure

 Generic Name (Nonproprietary, Approved)

 Assigned by manufacturer after approval by regulatory body in country of
origin (e.g., United States Adopted Names Council)

 Trade, Brand, or Proprietary Name

 Assigned by manufacturer, copyrighted and therefore can be used
commercially only by originating pharmaceutical company

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Drug Nomenclature (2)

Clinical Connection:
Drugs can have many different names:
For example, a prototypical calcium channel blocker of
dihydropyridine class has
 Chemical name 3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate

 Generic name nifedipine, and is available in U.S.under several

 Trade names including Adalat, Nifedical, and Procardia
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General Principles of Drug Therapy
How drugs work
Drug effects are produced by altering normal functions of cells and
tissues via one of four general mechanisms:
1. Interaction with receptors
Ligand-activated ion channels
G-protein–coupled receptors
 Gαs-coupled receptors
 Gαi (Ginhibitory)-coupled receptors
 Gq (and G11)-coupled receptors
Intracellular nuclear receptors
Receptor-activated tyrosine kinases
2. Nonspecific chemical or
physical interactions
 e.g., antacids
3. Antimetabolite action
 e.g., ChemoTx agents
4. Alteration of the activity
of enzymes
 increasing or decreasing

NB
 Drugs do not produce new function
 No drug has a single action, but have both therapeutic and adverse
actions or have multiple therapeutic effects
 Drug vs poison dose related
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Receptors*
 Specialized proteins that are binding sites for
neurotransmitters and hormones
 Postsynaptic cell membranes (neurotransmitters)
 Cell nucleus (steroid hormones)
 Linked to one of many signal transduction mechanisms
“Receptor” (According to Rang & Dale Pharmacology):
A target or binding protein for a small molecule (ligand), which
acts as an agonist or antagonist.
Rang HP etal. Rang & Dale's Pharmacology, Churchill Livingstone; 7th edition 2011

*“not to be confuse with other drug targets such as enzymes etc.”

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Ligand-Receptor Interactions
 Complementary conformations in 3 dimensions
 Similar to enzyme-substrate interactions
 Physiologic interactions are weak attractions
 H-bonding, van der Waal’s forces
 Drug mechanisms
– Agonists - bind and activate receptors
– Antagonists - bind but DO NOT activate receptors

"Receptor" according to IUPHAR (International Union of Basic and Clinical Pharmacology):

A cellular macromolecule, or an assembly of macromolecules, that is concerned directly and
specifically in chemical signaling between and within cells. Combination of a hormone,
neurotransmitter, drug, or intracellular messenger with its receptor(s) initiates a change in cell
function.
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Steps in Signal Transduction Process

 There are three general classes of signal transducing receptors:
 G-proteins are one and are referred to as serpentine receptors

Binding of the neurotransmitter, hormone or drug

to receptor> signaling of G-protein> enzyme
activation> production of a second-messenger>
protein kinase activation > phosphorylation of
specific proteins (effect)> termination

See: GPCRs-Signal Transduction Toolkit (& Other Receptor Mechanisms)

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GPCR structure & function (simplified)

G-Protein Coupled Receptor Binding of neurotransmitter,
hormone or drug to receptor>
signaling of G-protein> enzyme
activation> production of a second-
messenger> protein kinase
activation >phosphorylation of
specific proteins (effect)>termination
Mechanism of cAMP dependent signaling

The neurohormone epinephrine and its receptor (pink) is used in this example: The
activated receptor releases the Gs alpha protein (tan) from the beta and gamma subunits
(blue and green) in the heterotrimeric G-protein complex. The activated Gs alpha protein
in turn activates adenylyl cyclase (purple) that converts ATP into the second messenger
cAMP 25
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Neal, MJ Medical Pharmacology at a Glance

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Further study:
 eNotes: GP- General Principles of Drug Action

 Drug-Receptor Interactions, Morris ZS, Golan DE and (or)

 Brody’s Human Pharmacology: Ch.1 Pharmacodynamics- Receptors

and Concentration-Response Relationships

 Enzyme kinetics Notes

 MedPharm Wiki| PK and PD, Pgs. 73-88

 Integrated Scientific & Clinical Pharmacology Course Website 28