The Nature of Drugs and Drug

Development and Recreation

John Edward T. Unas, MD

 Pharmacology
• study of substances that interact with living
systems through chemical processes
• occur by binding of the substance to
regulatory molecules > activating/ inhibiting
body processes
– Beneficial therapeutic effect
– Toxic effects on parasites
 Pharmacology
• Medical Pharmacology
– science of substances used to prevent, diagnose,
and treat disease
• Toxicology
– branch of pharmacology that deals with the
undesirable effects of chemicals on living systems,
from individual cells to humans to complex
ecosystems
• Pharmacokinetics: absorption, distribution, and
elimination of drugs
• Pharmacodynamics: actions of the chemical on
the organism
• Environmental Toxicology: concerned with the
effects of chemicals on all organisms and their
survival in groups and as species
 Remember:
1. that all substances can under certain
circumstances be toxic
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
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
 Nature of Drugs
• defined as any substance that brings about a
change in biologic function through its
chemical actions
• Molecule that interacts with another target
molecule (receptor) as
– Agonists (activator)
– Antagonists (inhibitor)
 Nature of Drugs
• Chemical antagonists
– Interact directly with other drugs
• Hormones: drugs synthesized within the body
• Xenobiotics: not synthesized in the body
• Poisons: drugs that have almost exclusively
harmful effects,
– “the dose makes the poison”
– Toxins: biologic in origin
 Physical Nature of Drugs
• Interacts w/ a receptor > proper size, electrical
charge, shape, and atomic composition
• Drug administered at a distant site > necessary
properties to be transported from its site of
administration to its site of action
• Practical drug should be inactivated or excreted
from the body at a reasonable rate > appropriate
duration of action
 Physical Nature of Drugs
• Drug Size
– MW 100-1000
– 100 – for specificity, good “fit” to only one type of
receptor, a drug molecule must be sufficiently unique in
shape, charge, and other properties to prevent its
binding to other receptors
– 1000 - >1000 do not diffuse readily between
compartments of the body
 Physical Nature of Drugs
• Drug Reactivity and Drug Receptor Bonds
– Covalent > electrostatic > Hydrophobic
– Drugs with weak bonds to their receptor > more
selective
 Physical Nature of Drugs
• Drug Shape
– shape of a drug molecule must be such as to permit
binding to its receptor site via the bonds
– Lock & key
– Chirality/ Stereoisomerism
• 1 stereoisomer more active
• more active enantiomer at one type of receptor site may not
be more active at another receptor type
• Carvedilol
– (S)(–) isomer, is a potent β-receptor blocker. The (R)(+) isomer is 100-
fold weaker at the β receptor.
– Alpha receptor: same
 Physical Nature of Drugs
• Drug Shape
– shape of a drug molecule must be such as to permit
binding to its receptor site via the bonds
– Lock & key
– Chirality/ Stereoisomerism
• 1 stereoisomer more active
• more active enantiomer at one type of receptor site may not
be more active at another receptor type
• Carvedilol
– (S)(–) isomer, is a potent β-receptor blocker. The (R)(+) isomer is 100-
fold weaker at the β receptor.
– Alpha receptor: same
 Physical Nature of Drugs
• Drug Shape
– Chirality/ Stereoisomerism
• 1 stereoisomer more susceptible to an enzyme
• Drug transporters may also be stereoselective
 Physical Nature of Drugs
• Rational Drug Design
– ability to predict the appropriate molecular structure of
a drug on the basis of information about its biologic
receptor
– drugs now in use were developed through molecular
design based on knowledge of the three- dimensional
structure of the receptor site
 Drug Body Interactions
• Pharmacodynamic processes
– the actions of the chemical on the organism
• Pharmacokinetic processes
– govern the absorption, distribution, and elimination of
drugs
 Pharmacodynamics
• Drugs must bind a receptor > effect

• 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
 Pharmacodynamics
• change in function is accomplished by an effector
mechanism
– Part of the receptor
– Different molecule
 Pharmacodynamics
• Types of Drug-receptor Interaction
– Agonist: bind to and activate the receptor in some
fashion, which directly or indirectly brings about the
effect

– Antagonists: compete with and prevent binding by other

molecules.

– Allosteric: drugs that bind to the same receptor

molecule but do not prevent binding of the agonist
 Pharmacodynamics
• Agonists That Inhibit Their Binding Molecules
– Some drugs mimic agonist drugs by inhibiting the molecules
responsible for terminating the action of an endogenous
agonist
– Sometimes more selective, less toxic
 Pharmacodynamics
• Agonists, Partial Agonists, Inverse Agonists
– Non functional receptor (R1) and functional (Ra)
– Even without agonists, some receptors are in functional
form (Ra) > some physiologic effect (constitutive effect)
– Full agonists: can activate their receptor- effector
systems to the maximum extent of which the system is
capable;
– Partial agonists: bind to the same receptors and acti-vate
them in the same way but do not evoke as great a
response, lower efficacy
 Pharmacodynamics
• Agonists, Partial Agonists, Inverse Agonists
– Neutral antagonism: antagonists block receptors from
agonists
– Inverse agonists: drugs with higher affinity for the R1
state > dec constitutive activity > effects opposite of
agonists
 Duration of Drug Action
• Onset of condition: timing and mechanism
• Pain
• Numbness
• Tingling/ paresthesias
• Weakness
• Discoloration
• Coldness
• Clicking or snapping
• Thing that worsen or improve the condition
 Receptors and Inert Binding Sites
• Receptor
– Selective
– Change its function upon binding > function of
biologic system altered
• Inert Binding Site
– A substance that after binding with a drug would
not elicit a detectable change in the function of
thebiologic system
 Pharmacokinetics
• Drug > target organ
1. Lipid soluble, stable
2. Prodrug: Inactive precursor readily distributed
converted to an active form
• Absorbed
• Distributed
 Permeation
• Movement of drugs through barriers
• Passive: Diffusion
• Active: larger substance
• Drug vehicles
– Facilitates transport/ permeation
 Permeation
• Aqeous 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
– Depends on concentration gradient
– Other factors: charge, bound to other substances
 Permeation
• Lipid diffusion
– most important limiting factor for drug
permeation > large number of lipid barriers
– Lipid barriers separate aqueous environment >
lipid:aqueous partition coefficient
• determines how readily the molecule moves between
aqueous and lipid media
– Weak acid/base easily lose/gain protons > ability
to move dependent on pH
 Special Carriers
• For too large or too insoluble in lipid to diffuse
passively through membranes
• peptides, amino acids, and glucose
• Active transport/ Facilitated diffusion
– selective, saturable, and inhibitable
• Drugs mimic peptides, amino acids or sugars
 Special Carriers
• Less selective carriers > for expelling of foreign
molecules
• ABC (ATP binding cassette)
– P-glycoprotein or multidrug resistance type 1
(MDR1) transporter
– Multidrug resistance-associated protein (MRP)
 Endocytosis/ Exocytosis
• For larger substances
• Endocytosis
– Vit B12 w/ intrinsic factor
– Hemoglobin w/ transferrin
• Exocytosis
– Neurotransmitters
 Fick’s Law of Diffusion

• C1 is the higher concentration

• C2 is the lower concentration
• Area is the cross-sectional area of the diffusion path
• Permeability coefficient: measure of the mobility of the
drug molecules in the medium of the diffusion path
• Thickness is the length of the diffusion path
Ionization of Weak Acids and Weak Bases;
the Henderson-Hasselbalch Equation

• Electrostatic charge > attracts water

– More water soluble, lipid insoluble
• Lipid solubility ~ lipid diffusion
– More charged > less lipid solubility > less lipid
diffusion
Ionization of Weak Acids and Weak Bases;
the Henderson-Hasselbalch Equation

• Weak acid
– a neutral molecule that can reversibly dissociate
into an anion (a negatively charged molecule) and
a proton (a hydrogen ion)
Ionization of Weak Acids and Weak Bases;
the Henderson-Hasselbalch Equation

• Weak base
– a neutral molecule that can form a cation (a
positively charged molecule) by combining with a
proton
• Neutral form > more lipid soluble
• 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
Ionization of Weak Acids and Weak Bases;
the Henderson-Hasselbalch Equation

• 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
Ionization of Weak Acids and Weak Bases;
the Henderson-Hasselbalch Equation

• Kidneys
– drug is in a lipid-soluble form during its passage
down the renal tubule, a significant fraction will
be reabsorbed by simple passive diffusion
– Increased excretion > drug in ionized state
– Increased absorption > drug in neutral state
Ionization of Weak Acids and Weak Bases;
the Henderson-Hasselbalch Equation

• Amines: nitrogen containing bases

• Quaternary amine: permanently charged, no unshared
electrons > permanently poorly lipid soluble
• Primary, secondary, and tertiary amines may undergo
reversible protonation and vary their lipid solubility with pH
 Drug Development and Regulation

• New drug
– Requires discovery of a new target (universities,
research institute)
– Development > industrial laboratories
 Drug discovery
1. Screening for biologic activity of large numbers
of natural products, banks of previously
discovered chemical entities, or large libraries of
peptides, nucleic acids, and other organic
molecules
2. Chemical modification of a known active
molecule, resulting in a “me-too” analog
3. Identification or elucidation of a new drug target
4. Rational design of a new molecule based on an
understanding of biologic mechanisms and drug
receptor structure.
 Pre clinical Safety and Toxicity Testing
• All chemicals are toxic in some individuals at
some dose.
• Goals:
– identifying potential human toxicities
– designing tests to further define the toxic
mechanisms
– predicting the most relevant toxicities to be
monitored in clinical trials
 Pre clinical Safety and Toxicity Testing
• no-effect dose: the maximum dose at which a
specified toxic effect is not seen
• minimum lethal dose—the smallest dose that
is observed to kill any experimental animal
and
• median lethal dose (LD50)—the dose that kills
approximately 50% of the animals in a test
group
 Pre clinical Safety and Toxicity Testing
• Limitations:
1. Toxicity testing is time-consuming and expensive. Two
to 6 years may be required to collect and analyze data
on toxicity before the drug can be considered ready
for testing in humans.
2. Large numbers of animals may be needed to obtain
valid pre- clinical data.
3. Extrapolations of toxicity data from animals to
humans are reasonably predictive for many but not
for all toxicities.
4. For statistical reasons, rare adverse effects are
unlikely to be detected in preclinical testing.