PHARMACOLOGY I

(BASIC PRINCIPLES OF PHARMACOLOGY AND

PHARMACODYNAMICS)
 Pharmacology I

•Essential Outcomes
•To learn the basic concepts of pharmacology
•To introduce the students in the concepts of
pharmacodynamics
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PHARMACOLOGY
- the study of substances that interact with living
systems through chemical processes.
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MEDICAL PHARMACOLOGY

- the science of substances used to

prevent, diagnose, and treat disease
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TOXICOLOGY
- is the branch of
pharmacology that deals
with the undesirable effects
of chemicals on living
systems, from individual
cells to humans to complex
ecosystems
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HISTORY OF PHARMACOLOGY

Prehistoric people undoubtedly recognized the

beneficial or toxic effects of many plant and animal
materials.
•Early written records list remedies of many types, including a
few that are still recognized as useful drugs today.
• Most, however, were worthless or actually harmful.
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MATERIA MEDICA
- the science of drug preparation and the medical uses of drugs
- began to develop as the precursor to pharmacology
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François Magendie and his student Claude Bernard

• began to develop the methods of experimental physiology
and pharmacology.
• Advances in chemistry and the further development of physiology in
the 18th, 19th, and early 20th centuries laid the foundation needed for
understanding how drugs work at the organ and tissue levels.
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DRUG RECEPTORS
- around the 1940s and 1950s, a major expansion
of research efforts in all areas of biology began.
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PHARMACOGENOMICS
- the relation of the individual’s genetic makeup to his or her response
to specific drugs
- is becoming an important part of therapeutics
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PHARMACOGENOMICS

- Discovery that small segments of RNA can interfere with protein

synthesis with extreme selectivity has led to investigation of small
interfering RNAs (siRNAs) and micro-RNAs (miRNAs) as therapeutic
agents.
- short nucleotide chains called antisense oligonucleotides (ANOs),
synthesized to be complementary to natural RNA or DNA, can interfere
with the readout of genes and the transcription of RNA.
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GENERAL PRINCIPLES THAT THE STUDENTS SHOULD

REMEMBER:
1. That all substances can under
certain circumstances be toxic.
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GENERAL PRINCIPLES THAT THE STUENTS SHOULD

REMEMBER:
2. that the chemicals in botanicals (herbs and plant
extracts, “nutraceuticals”) are no different from
chemicals in manufactured drugs except for the
much greater proportion of impurities in botanicals
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GENERAL PRINCIPLES THAT THE STUENTS SHOULD

REMEMBER:
3. that all dietary supplements and all therapies
promoted as health-enhancing should meet the same
standards of efficacy and safety as conventional drugs
and medical therapies. That is, there should be no
artificial separation between scientific medicine and
“alternative” or “complementary” medicine.
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GENERAL PRINCIPLES OF
PHARMACOLOGY
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DRUG
- any substance that brings about a change in
biologic function through its chemical actions

RECEPTORS
- target molecule

AGONIST - activator
ANTAGONIST - inhibitor
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DRUG

XENOBIOTIC
- chemicals that are NOT synthesized in the body

POISONS
- drugs that have almost exclusively harmful effects.

TOXINS
- usually defined as poisons of biologic origin, ie, synthesized by plants
or animals, in contrast to inorganic poisons such as lead and arsenic
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NATURE OF DRUGS
SIZE AND MOLECULAR WEIGHT

• vary from MW 7 (lithium) to over 50,000 (alteplase, thrombolytic enzymes)

• majority: MW 100-1000
• <100 - rarely sufficiently selective with their action
• >1000 - poorly absorbed and poorly distributed
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NATURE OF DRUGS
DRUG-RECEPTOR BONDS

• Arranged according to decreasing order of strength

• Covalent bonds
• Electrostatic bonds – ionic bonds, hydrogen bonds, van der waals
• Hydrophobic bonds

• Strength of bonds determine the reversibility of the effect

EX.
Pralidoxime cannot reverse insecticide poisoning if the bonds formed by the poison have aged
and become covalent
PHARMACODYNAMIC
PRINCIPLES
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RECEPTORS
•specific molecules in a biologic system with which drugs
interact to produce changes in the function of the
system
•must be selective in their ligand-binding characteristics
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RECEPTORS
•Must be modified when they bind an agonist to bring
about functional change
•Most proteins
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RECEPTOR SITES OR RECOGNITION SITES

•Specific binding region of the macromolecule
•High and selective affinity for the drug molecule
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EFFECTORS
•Translate the drug-receptor interaction into a change in
cellular activity
•Some receptors are also effectors
•A single molecule may incorporate both the drug binding
site and the effector mechanism
•Example: tyrosine kinase receptor in insulin receptor
molecule, Na/K channel in nicotinic Ach receptor, adenylyl
cyclase.
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GRADED DOSE-RESPONSE RELATIONSHIP

•DOSE-RESPONSE CURVE
• Response of a particular receptor-effector system measured against
increasing drug concentrations
• Yields sigmoid curve if plotted on a semilogarithmic axis
• Efficacy (Emax) and potency are derived from this curve
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BINDING AFFINITY
•Fraction of receptors bound by a drug plotted against the log of the
drug concentration
•Kd is the concentration required to bind 50% of the receptors
• The smaller the , the greater the affinity of a drug for its receptor.
d
K
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Emax
• Maximal effect achievable with increasing concentration of a drug

EC50
• Concentration of the drug wherein half of the maximal effect is achieved
Bmax
• Maximum percentage of receptors with increasing concentration of a
drug/maximal number of receptors bound.
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Kd
• Concentration wherein 50% of receptors is occupied.
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GRADED DOSE-RESPONSE RELATIONSHIP

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QUANTAL DOSE-RESPONSE RELATIONSHIP

•Minimum dose required to produce a specified response is
determined in each member of a population

•QUANTAL DOSE-RESPONSE CURVE

• Fraction of the population that responds at each dose against the log of
the dose administered
• Median effective (ED50), median toxic (TD50), and median lethal (LD50)
doses are derived
• No attempt is made to determine maximal effect
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QUANTAL DOSE-RESPONSE CURVES

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THERAPEUTIC INDEX
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EFFICACY
•Maximal efficacy or Emax
•Maximal effect an agonist can produce if the dose is taken to very
high levels
•Determined mainly by the nature of receptor and its associated
effector system
•Measured with graded-dose response curves NOT with quantal
dose response curves
•Partial agonists have lower maximal efficacy than full agonists
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POTENCY
•Denotes the amount of drug needed to produce a given effect
•Determined mainly by the affinity of the receptor to the drug
•Measurement
• In graded dose-response curve, it is the dose required to produce 50% of the maximal
effect
• In quantal dose-response curve, three potency variables are measurable
• ED50
• TD50
• LD50
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POTENCY
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SPARE RECEPTORS
•Are receptors that do not bind drug when the drug concentration is
sufficient to produce maximal effect
•They are present when Kd50 > EC50
•Increase sensitivity to agonist because the likelihood of
drug-receptor interaction increases directly proportional to the
number of receptors available.
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FACTORS AFFECTING DOSE-RESPONSE CURVES

FULL AGONISTS
•Capable of fully activating the effector system when it binds
to the receptor
• High affinity for the activated receptor conformation
•Sufficiently high concentrations result in all the receptors
achieving the activated state
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FACTORS AFFECTING DOSE-RESPONSE CURVES

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FACTORS AFFECTING DOSE-RESPONSE CURVES

PARTIAL AGONIST
•Produces less than the full effect, even when it has saturated
the receptors
•In the presence of an agonist, a partial agonist acts as an
inhibitor/antagonist
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FACTORS AFFECTING DOSE-RESPONSE CURVES

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FACTORS AFFECTING DOSE-RESPONSE CURVES

INVERSE AGONIST
•If a drug gas a much stronger affinity for the Ri conformation
than the Ra state and stabilizes a large fraction in the Ri-D
complex
•The drug will reduce any constitutive activity thus resulting
in effects opposite of the effects produced by the full agonist
•Example
•GABA receptor-effectors
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FACTORS AFFECTING DOSE-RESPONSE CURVES

ANTAGONIST
•Do not provoke a biological response by themselves upon
binding to a receptor
•Blocks or dampens drug response in the presence of an
agonist
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FACTORS AFFECTING DOSE-RESPONSE CURVES

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FACTORS AFFECTING DOSE-RESPONSE CURVES

ANTAGONIST
• CLASSIFICATION
•Competitive (reversible)
•Non-competitive (irreversible)
•Physiologic
•Chemical
•Allosteric
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FACTORS AFFECTING DOSE-RESPONSE CURVES

ANTAGONIST
• COMPETITIVE OR REVERSIBLE ANTAGONIST
• Binds to receptors in a reversible way without activating the
effector system
• Shifts the dose response curve (DRC) to the right (increased ED50)
but same maximal effect is reached
• Effects overcome by adding more agonist (surmountable)
• Example:
• Beta-blockers (Propranolol) and Beta-
antagonist (Isoproterenol)
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FACTORS AFFECTING DOSE-RESPONSE CURVES

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FACTORS AFFECTING DOSE-RESPONSE CURVES

ANTAGONIST
• NON-COMPETITIVE OR IRREVERSIBLE ANTAGONIST
• Causes downward shift of the DRC
• No horizontal shift of DRC (ED50 unchanged) unless spare
receptors are present
• Not overcome by adding more agonist (insurmountable)
• Example:
• Norepinephrine and phenoxybenzamine
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FACTORS AFFECTING DOSE-RESPONSE CURVES

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FACTORS AFFECTING DOSE-RESPONSE CURVES

ANTAGONIST
• PHYSIOLOGIC ANTAGONIST
• Binds to a different receptor, producing an effect opposite to that
produced by the drug it is antagonizing
• Example
• Histamine and epinephrine
• Propranolol and thyroid hormone
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FACTORS AFFECTING DOSE-RESPONSE CURVES

ANTAGONIST
• CHEMICAL ANTAGONIST
• Interact directly with the drug being antagonized to remove it or
to prevent it from reaching its target
• Does not depend on interaction with agonist receptors
• Example:
• Dimercaprol for lead poisoning
• Pralidoxime for organophosphate poisoning
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FACTORS AFFECTING DOSE-RESPONSE CURVES

ANTAGONIST
• ALLOSTERIC ANTAGONIST
• Binds to a different binding sites that forms a conformational
change in the receptor preventing the agonist to bind.
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SIGNALING MECHANISMS AND DRUG ACTIONS

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SIGNALING MECHANISMS AND DRUG ACTIONS

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SIGNALING MECHANISMS AND DRUG ACTIONS

1. INTRACELLULAR RECEPTOR
•Crosses the plasma membrane and acts on the
intracellular receptor
• Enzyme
• Regulator of gene transcriptor
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SIGNALING MECHANISMS AND DRUG ACTIONS

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SIGNALING MECHANISMS AND DRUG ACTIONS

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SIGNALING MECHANISMS AND DRUG ACTIONS

2. TRANSMEMBRANE RECEPTOR
•The signal binds to the extracellular domain of a
transmembrane protein, thereby activating the
enzymatic activity of its cytoplasmic domain
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SIGNALING MECHANISMS AND DRUG ACTIONS

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SIGNALING MECHANISMS AND DRUG ACTIONS

3. ENZYME-LINKED RECEPTORS
•Have extracellular binding sites where ligand or typically
hormone or growth factor can attach and thus activate
enzymatic activity inside the cell
•Most enzyme-linked receptors are of tyrosine kinase
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SIGNALING MECHANISMS AND DRUG ACTIONS

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SIGNALING MECHANISMS AND DRUG ACTIONS

4. LIGAND-GATED ION CHANNEL
•Signal binds to and directly regulated the opening of an
ion channel
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SIGNALING MECHANISMS AND DRUG ACTIONS

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SIGNALING MECHANISMS AND DRUG ACTIONS

5. G-PROTEIN COUPLED RECEPTORS
•The signal binds to a cell-surface receptor linked to an
effector enzyme by a G protein
•Also called as 7-transmembrane
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SIGNALING MECHANISMS AND DRUG ACTIONS

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SIGNALING MECHANISMS AND DRUG ACTIONS

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SIGNALING MECHANISMS AND DRUG ACTIONS

THREE TYPES OF G-PROTEIN
b) Gs
- is a stimulative G protein that
activates the enzyme called ADENYLYL CYCLASE
* adenylyl cyclase then produces
cyclic AMP which is a very important secondary
messenger.
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SIGNALING MECHANISMS AND DRUG ACTIONS

THREE TYPES OF G-PROTEIN
a) Gi
- is an inhibitory G protein that inhibits ADENYLYL CYCLASE thus
lowers the level of cAMP in the cell
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SIGNALING MECHANISMS AND DRUG ACTIONS

THREE TYPES OF G-PROTEIN
a) Gq
- activates a class of enzyme called phospholipases C (PLC)
- PLC produces two secondary messengers called diacylglycerol
(DAG) and inositol triphosphate (IP3)
- DAG : just like cAMP leads to different responses through
activation of protein kinases
- IP3 : produces various responses by mediating intracellular
release of calcium
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SIGNALING MECHANISMS AND DRUG ACTIONS

* G-protein coupled receptors as well as enzyme-linked receptors
have the ability to amplify signals that they receive
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SIGNALING MECHANISMS AND DRUG ACTIONS

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VARIATIONS IN DRUG RESPONSE

TOLERANCE
- continuous activation may lead to depletion of essential substrates
- reversed by repletion of missing substrates

EXAMPLE:
depletion of thiol cofactors in nitroglycerin tolerance, reversible with
administration of glutathione.
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DOWNREGULATION
- long term reduction in receptor number due to
continuous exposure to agonist
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UPREGULATION
- occurs when receptor activation is blocked for
prolonged
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TACHYPHYLAXIS
- responsiveness diminishes rapidly after administration
of a drug
- frequent or continuous exposure to agonists often
results in short-term diminution of the receptor response.

e.g. Theophylline, Salbutamol, Nitrates, Dobutamine

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TACHYPHYLAXIS
- what drugs display tachyphylaxis?

Metoclopramide Nitroglycerin
Ephedrine Nicotine
Dobutamine Hydralazine
LSD Desmopressin
Calcitonin
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IDIOSYNCRATIC DRUG RESPONSE

- one that is infrequently observed in most patients

Example:
aplastic anemia with chloramphenicol
cataracts with allopurinol
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REFERENCE/S:

•Katzung, B. G. (2018). Basic & clinical pharmacology.

New York: McGraw-Hill Education.
•https://www.youtube.com/watch?v=tobx537kFaI&list=PL
UVRN4iMdIhz4B_MKABlrURCsP6kn_yGe&index=2