Pharmacology Notes – Chapter 1 Introduction
Pharmacology
 Study of substances that interact with living systems through
chemical processes; binding to regulatory molecules and
activating/ inactivating normal body processes
o Achieve beneficial therapeutic effect or toxic effects on
regulatory processes in parasites
 Medical pharmacology – science of substances used to
prevent, diagnose, treat disease
 Toxicology – branch of pharmacology specializing in
undesirable effects of chemicals on living systems
History of Pharmacology
 Early use of medicines in China, Egypt, India
 Sporadic attempts to introduce rational methods into
medicine, none were successful due to philosophies that
explain biology and disease without need for experimentation
and observation
 End of 17th century
o Reliance on observation and experimentation replaced
theorizing in medicines
o Methods were applied on traditional drugs
o Materia medica
 Science of drug preparation and medicinal use of
drugs
 Precursor to pharmacology
o Mechanisms of action were not understood due to
absence of methods to purify active ingredients from
crude materials, lack of methods to test hypotheses
 Late 18th and 19th centuries
o Francois Magendie and student Claude Bernard
developed experimental physiology and pharmacology
o Needed for understanding how drugs work at organ and
tissue levels
o Real advances in basic pharmacology accompanied by
outburst of unscientific claims by manufacturers
o Controlled clinical trials reintroduced into medicine, 60
years ago to accurately evaluate therapeutic drugs
 Major expansion of research in all areas of biology
o Information about drug action and receptors
o New drug groups and new members of old groups
introduced
o Molecular mechanisms identified, numerous receptors
isolated, structurally characterized, and cloned
o Discover of orphan receptors – receptors with no known
ligand and hypothesized function
o Receptors and effectors strongly influenced by
companion regulatory proteins
 Pharmacogenomics – relation of individual’s genetic make up
to his or her response to specific drugs
o Recognition of unsuspected relationships between
receptor families and way receptor proteins have evolved
 Alternative health care industry
o Irrational use of innumerable, expensive, ineffective,
sometimes harmful remedies
o Medication-consuming public exposed to inaccurate,
incomplete, unscientific information regarding
pharmacological effects
 All substances can be toxic, chemicals in botanicals are no
different that chemicals in manufactured drugs except for
proportion of impurities
 All dietary supplements and health-enhancing therapies
should meet same standards of efficacy and safety as
conventional drugs and medical therapies
 No artificial separation between scientific medicine and
alternative/ complementary medicine
Pharmacology and Pharmaceutical Industry
 Big pharma – multibillion dollar corporations that specialize in
drug discovery and development
o Exploiting discoveries from academic and governmental
laboratories and translating findings into commercially
successful therapeutic breakthroughs
 Escalating costs of drugs is significant contributor to
inflationary increase in cost of health care
o Drug development is expensive; companies pay costs of
drug development and marketing and return profit to
shareholders
o Costs of development and marketing grossly inflated by
marketing procedures
o Profit margins have exceed all other industries
 Pricing schedules vary dramatically from countries and within
countries
Nature of Drugs
 Drug – any substance that brings about a change in biologic
function through chemical actions
o Agonist – activator
o Antagonist – inhibitor
o Specific to a receptor
 Chemical antagonists – interact directly with drugs
o Osmotic agents – interact with water
 Drugs synthesized in body – hormones
o Not synthesized in body – xenobiotics
 Poisons – drugs with almost exclusively harmful effects
o Paracelsus – the dose makes the poison
o Any substance is harmful if taken in wrong dosage
o Toxins – poisons of biologic origin, synthesized by plants
or animals
o Inorganic poisons – lead, arsenic, heavy metals
 To interact with receptor, drug must have appropriate size,
charge, shape, atomic composition
 Must have necessary properties to be transported from site of
admin to site of action
 Should be inactivated or excreted so that actions will be of
appropriate duration
Drug Characteristics
1. Physical nature
a. Solid, liquid, gaseous
b. Often determine best route of administration
c. Inorganic elements or organic drugs (weakly acidic/ basic)
d. pH differences in body may alter degree of ionization
2. Drug size
a. Molecular size from very small (Lithium, MW 7 to
alteplase MW 59,050)
b. Most drugs between MW 100-1000
c. Lower limit is set by requirements for specificity of action
i. To be good fit to one receptor – must be sufficiently
unique in shape, charge, and other properties to
prevent binding to other receptors
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 d. Upper limit determined by ability to move within the
body
i. Large MW of 1000 do not diffuse readily
ii. Very large drugs (proteins) administrated directly
into compartment to have effect
iii. Alteplase directly into vascular compartment via IV
or intra-arterial infusion
3. Drug reactivity and drug-receptor bonds
a. Covalent bonds
i. Strong, not reversible under biological conditions
ii. Ex. Bond between ASA and cyclooxgenase in
platelets
1. Platelet aggregation blocking effect lasts long
after free ASA has disappeared from blood,
reversed only through synthesis of new enzyme
in new platelets
iii. Ex. DNA-alkylating agents in cancer chemotherapy to
disrupt cell division in tumor
b. Electrostatic bonds
i. More common, form relatively strong linkages,
weaker than covalent
ii. Bonds between permanently charged ionic
molecules, weak hydrogen bonds, very weak
induced dipole interactions (Van der Waals forces)
c. Hydrophobic bonds
i. Quite weak
ii. Important in interactions of highly lipid-soluble
drugs with lipids in cell membranes and interaction
with internal walls of receptor pockets
d. Drugs that bind through weak bonds are generally more
selective than those that bind with strong bonds
i. Weak bonds require very precise fit; only few
receptor types provide such a precise fit
ii. To make highly selective short-acting drug, avoid
highly reactive molecules that form covalent bonds
e. Few substances are almost completely inert
i. May still have significant pharmacologic effects
ii. Xenon – inert gas, anesthetic effects at high
pressures
4. Drug shapes
a. Shape must permit binding to its receptor site via bonds
b. Shape must be complementary to that of the receptor
c. Chirality – stereoisomerism
i. More than half of all useful drugs exist in
enantiomeric pairs
ii. Most cases only one enantiomer is more potent
than the other, better fit to receptor
d. More active enantiomer at one type of receptor may not
be more active at another receptor, type may be
responsible for some other effect
i. Ex. Carvedilol – interacts with adrenoreceptors, one
chiral center
ii. S-isomer is potent β-receptor blocker
iii. R-isomer is 100 fold weaker at the β-receptor
e. Some isomers are approximately equipotent as α-
receptor blockers
i. Ketamine, IV anesthetic
ii. R-isomer more potent anesthetic and less toxic than
S-isomer
iii. Still used as racemic mixture
f. Enzymes are usually steroselective, one enantiomer more
susceptible than other to metabolism
i. Duration of action of one enantiomer differs than
other
ii. Drug transporters may also be steroselective
g. Most studies of clinical efficacy done with racemic
mixtures rather than with separate enantiomers
i. Small percentage of chiral drugs used are marketed
as the active isomer, others only available as
racemic mixtures
ii. Many patients receive drug which is only 50% or
more is less active, inactive, or actively toxic
h. Administration of pure, active enantiomer decreases
adverse effects relative to racemic mixture not firmly
supported
i. More chiral drugs available as active enantiomers
through scientific and regulatory levels
5. Rational drug design
a. Ability to predict appropriate molecular structure on
basis of information of biological receptor
b. Drugs developed through random testing of chemicals or
modification of drugs know to have some effect
c. Few drugs developed through molecular design based on
knowledge of 3D structure of receptor
6. Receptor nomenclature
a. Newer, more efficient ways to identify and characterize
receptors resulted in different naming systems
b. International Union of Pharmacology committee on
Receptor Nomenclature and Drug Classification
Drug-body Interactions
 Pharmacodynamic processes – actions of drug on the body
o Determine group which drug is classified, play major role
in deciding whether the group is appropriate therapy
 Pharmacokinetic processes – actions of body on drug
o Absorption, distribution, metabolism
Pharmacodynamic Principles
 Drugs must bind to receptor to bring an effect, series of
complicated steps
o D+R-> D-R complex -> effect
o D+R-> D-R complex -> effector molecule -> effect
o D+R-> D-R complex -> activation of coupling molecule ->
effector molecule -> effect
o Inhibition of metabolism of endogenous activator ->
increased activator -> increased effect
 Final change in function through effector mechanism
o May be part of receptor or separate molecule
 Large number of receptor communicate with effectors
through coupling molecules
Pharmacodynamics
1. Types of drug-receptor interactions
a. Agonists – bind to and activate the receptor to directly or
indirectly bring an effect
i. Activation results in change in conformation
ii. Some receptors have effector machinery so that
drug binding brings about effect directly
iii. Can be linked through coupling molecules to a
separate effector molecule
b. Pharmacological antagonist drugs – bind to receptor,
compete and prevent binding by other molecules
i. Acetylcholine receptor blockers – atropine, prevent
access of acetylcholine and cholinergic drugs to
acetylcholine receptor and stabilize receptor in its
inactive state
ii. Reduce effects of acetylcholine, action overcome by
increasing dosage of agonist
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 iii. Some bind so tightly to receptor that irreversible or
pseudoirreversiblly and cannot be displaced
c. Allosteric inhibition – drugs that bind to receptor
molecule but do not prevent binding of agonist
i. Can enhance or inhibit agonist molecule
ii. Not overcome by increasing dose of agonist
2. Agonists that inhibit binding molecules
a. Inhibit molecules responsible for terminating action of
endogenous agonist
b. Acetylcholinesterase inhibitors – slow destruction of
endogenous acetylcholine cause cholinomimetic effects
resembling actions of cholinoceptor agonist although
cholinesterase inhibitors do not bind or only incidentally
bind to cholinoreceptors
c. Amplify effects of physiologically released agonist ligands
d. Effects can be more selective, less toxic than exogenous
agonists
3. Agonists, partial agonists, inverse agonists
a. Receptor can exist in inactive, nonfunctional form and
activated form
b. Constitutive activity In the absence of any agonist,
receptor pool must exist in Ra form and may produce
same physiologic effect as agonist-induced activity
i. Constitutive activity depends on receptor density,
concentration of coupling molecules, number of
effectors
c. Agonists – have higher affinity for Ra configuration and
stabilize it, large percentage resides in Ra-D form and
produces large effect
d. Full agonists – activate receptor-effector systems to
maximum extent, shift almost all of pool to Ra-D form
e. Partial agonists – bind to receptors and activate them but
do not evoke great response, no matter how high the
concentration
i. Do not fully stabilize Ra configuration as full
agonists, significant fraction exists in Ri-D form; have
low intrinsic efficacy
i. Pindolol - β-adrenoreceptor partial agonist; may act
as agonist if no full agonist is present or antagonist if
full agonist is present
ii. Independent of affinity to receptor
c. Conventional antagonist action by fixing Ri and Ra
fractions in same amounts so that no change will be
observed
d. Neutral antagonism – presence of antagonist at receptor
will block access of agonist to receptor and prevent
agonistic effect
e. Inverse agonists – drugs that have stronger affinity for Ri
state and stabilizes pool as Ri-D, reduce constitutive
activity, opposite of effects produce by conventional
agonists
i. γ-aminobutyric acid receptor-effector
ii. Activated by endogenous transmitter GABA,
inhibition of postsynaptic cells
iii. Exogenous agonists – benzodiazepins, facilitate
receptor-effector system to cause GABA-like
inhibition with sedation as therapeutic result
iv. Inhibition blocked by conventional neutral
antagonists – flumazenil
v. Also found that cause anxiety and agitation, inverse
of sedation
vi. Found for β-receptors, H1 and H2 receptors, etc
4. Duration of action
a. Effect lasts only as long as drug occupies receptor,
disassociation terminates effect
b. Action may persist after dug as dissociated, coupling
molecule still present in activated form
c. Drug may be covalently bonded, effect persists until D-R
complex is destroyed and new receptors/ enzymes are
produced
d. Incorporate desensitization mechanisms for preventing
excessive activation when agonists are present for long
periods of time
5. Receptors and inert binding sites
a. Endogenous molecule must be selective in choosing
ligands to bind
i. Selectivity required to avoid constant activation of
receptor by excessive binding of different ligands
b. Change function upon binding
i. Necessary if ligand is to cause pharmacologic effect
c. Not all endogenous molecules are regulatory
i. Inert binding site – binding to nonregulatory
molecule will result in no detectable change
ii. Binding will affect distribution of drug in body and
determines amount of free drug is in circulation
Pharmacokinetic Principles
 Drug should reach site of action after admin
 Must be sufficiently lipid soluble and stable
 Prodrug – inactive precursor chemical converted to active
drug through metabolic processes
 Most situations require drug to be administered into another
compartment, must move to its site of action
o Must be absorbed in blood, distributed to site of action,
permeate through barriers, eliminated at reasonable rate
by metabolic inactivation or excretion
Pharmacokinetics
1. Permeation
a. Passive diffusion – common in aqueous/ lipid medium,
active processes for most drugs
b. Aqueous diffusion
i. Occurs within larger aqueous compartments, across
epithelial membrane tight junctions
ii. Some tissues permit passage of large molecules of
MW 20-30K
iii. Driven by concentration gradient described by Fick’s
Law
iv. Drugs bound to plasma proteins do not permeate
v. Flux of charged drugs influenced by electrical fields
(membrane/ transtubular potential)
c. Lipid diffusion
i. Most important limiting factor for drug permeation
ii. Lipid/water coefficient determines how readily drug
moves between the phases
iii. Weak acids/ bases’ movement dependent on pH of
medium, charged molecules attract water
1. Henderson-Hasselbalch equation
d. Special carriers
i. For molecules too large or too insoluble in lipid to
diffuse profusely (peptides, amino acids, glucose)
ii. Through active transport or facilitated diffusion
iii. Mechanisms are selective, saturable, inhibitable
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 iv. ATP-binding cassette family g. pH differences from blood pH may cause trapping or
1. P-glycoprotein/ multidrug-resistance type 1 reabsorption
transporter found in brain, testes, drug- h. Overdose of methamphetamine (weak base) countered
resistant neoplastic cells with admin of ammonium chloride to acidify the urine to
2. Multidrug resistance-associated protein rapidly eliminate drug
transporters excrete some drugs, metabolites i. Most drugs are weak bases containing amines
into urine and bile i. Primary, secondary, tertiary – reversible
v. Some drugs do not bind ATP but use ion gradients protonation, vary lipid solubility on pH
for transport energy ii. Quaternary – permanently charged, always poorly
1. Solute carrier family – uptake of soluble
neurotransmitters across nerve-ending
membranes Drug Groups
e. Endo/exocytosis  Drugs currently available arranged into about 70 groups
i. For substances very large, substance is bound at cell  Drugs within each group are similar in pharmacodynamic
surface receptor, engulfed by cell membrane, actions and pharmacokinetic properties
carried into cell by formation of a vesicle then  Prototype drugs identified to typify most important
released in cytosol characteristics
1. Transport of cyanocobalamin complexed with
intrinsic factor
2. Iron transported into hemoglobin-synthesizing
RBC precursors with transferring
ii. Exocytosis responsible for secretion of
neurotransmitters
1. Stored in vesicles in nerve endings to protect
from metabolic destruction
2. Activation of nerve ending causes fusion of
storage vesicle with cell membrane and
expulsion of contents
2. Fick’s Law of Diffusion
a. Fick’s Law – describes passive flux of molecules down
concentration gradient
i. Permeability coefficient – measure of mobility of
drug molecules in medium of diffusion path
ii. Thickness of diffusion path
b. Lipid diffusion – lipid/ water coefficient is major
determinant of drug mobility
3. Ionization of Weak Acids/ Bases
a. Electrostatic charge of ionized molecule attracts water
dipoles -> polar, relatively water soluble and lipid-soluble
complex
i. Ionization reduces ability to permeate membranes
b. Weak acid – neutral molecule that reversibly dissociates
into a conjugate base and proton
i. Protonated form is neutral, lipid soluble
c. Weak base – neutral molecule that forms conjugate acid
by combining with a proton
i. Unprotonated form is neutral, lipid soluble
d. Reactions move left in an acid environment and to the
right in alkaline environment
e. Henderson-Hasselbalch equation relates ratio of
protonated to unprotonated weak acid/base to
molecule’s pKa and pH of the medium
i. Lower pH relative to pka, greater fraction in
protonated form
ii. Weak acid will be lipid soluble at acid pH, weak base
at alkaline pH
f. All drugs filtered at glomerulus
i. Lipid soluble form will be reabsorbed by passive
diffusion
ii. Accelerate excretion by converting to ionized form
to prevent reabsorption by adjusting urine pH
iii. Weak acids excreted faster in alkaline urine, weak
bases in acidic

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