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FROM EARLY EXPERIENCES WITH PLANTS • X-ray crystallography-detailed structural

TO MODERN CHEMISTRY info;
• Nuclear Magnetic Resonance (NMR)
• The human fascination – and sometimes
Spectroscopy – protein target not larger
infatuation – with chemicals that alter
than 35-40 kDa;
biological function is ancient and results
• The approach: roll all chemicals over the
from long experience with and
protein of interest to human proteins to
dependence on plants.
discard compounds that have unwanted
• The collaboration of pharmacology with
interactions;
chemistry on the one hand and with
• Predict structural & functional
clinical medicine on the other has been
consequences of a drug binding to its
a major contributor to the effective
target & pharmacokinetic properties;
treatment of disease, especially since
• LARGE MOLECULES: uncommon
the middle of the 20th century.
before recombinant DNA technology;
SOURCES OF DRUGS • Designed, customized, & optimized
using genetic engineering techniques:
• SMALL MOLECULES: The usual ✓ Hormones
approach to invention of a small- ✓ Growth Factors
molecule drug is to screen a collection ✓ Cytokines
of chemicals (“library”) for compounds ✓ Monoclonal Antibodies
with the desired features;
• An alternative is to synthesize and focus • Protein therapeutics are administered
on close chemical relatives of a parenterally, & their receptors or targets
substance known to participate in a must be accessible extracellularly.
biological reaction of interest;
TARGETS OF DRUG ACTION
• DRUGABILITY: ease with wc the
function of a target can be altered in the
Crucial questions arise:
desired fashion by a small organic
molecule; • Can one find a drug that will have the
DESIRED EFFECT AGAINST ITS
• Initial “hits” have modest affinity for the
TARGET?
target & lack the desired SPECIFICITY &
PHARMACOLOGICAL PROPERTIES of a • Does MODULATION OF THE TARGET
successful pharmaceutical; PROTEIN affect the course of the
DISEASE?
• Medicinal chemists synthesize
DERIVATIVES OF HITS; • Does this PROJECT make sense
ECONOMICALLY?
• Thereby defining the structure-activity
relationship and optimizing parameters; •
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Is the Target Drugable?
• The DRUGABILITY of a target with a low
molecular-weight organic molecule
relies on the presence of a binding site
for the drug that exhibits considerable
AFFINITY and SELECTIVITY.

Has the Target Been Validated?

• Biological systems frequently contain
redundant elements or can alter
expression of drug-regulated elements
to compensate for the effect of the drug;
• The question of whether the target has
been validated is obviously a critical
one.
Is This Drug Invention Effort Economically
Viable?
• Drug invention and development is
expensive (see Table 1-1), and
economic realities influence the
direction of pharmaceutical research.
• Affinity and selectivity for the interaction
with the target;
• Pharmacokinetic properties (absorption,
distribution, excretion, metabolism);
• Issues regarding large-scale synthesis or
purification from natural source;
• Pharmaceutical properties (stability,
solubility, questions of formulation)
• Safety

Criticisms
• Those who treat drugs as
entitlements & those who view drugs
as high-tech products of a capitalistic
society;
• Investor-owned pharmaceutical
companies who have no profit
motive & an obligation to
stakeholders;
• Intellectual property & patents
• Drug promotion
• Exploitation or “medical imperialism”
• Product liability
• “me-too drug” is a term used to
describe a pharmaceutical that is
usually structurally similar to a drug
already on the market

What is TOXICOLOGY?

The study of poisons and poisoning
Poison:
• any substance, including any drug,
that has the capacity to harm a living
organism
• all things are poison and nothing is
without poison; solely the dose
determines that a thing is not a
poison
Poisoning:
• implies that damaging physiological
effects result from exposure to
pharmaceuticals, illicit drugs, or
chemicals
Conventional dose response curves:
• Individual: There is a graded dose-
response relationship; Result to a
greater magnitude of response as the
dose increases
• Population: There is a quantal dose
response relationship; Result in an
increase in the percentage of
population affected as the dose
increases; The effect is judged to be
either present or absent in a given
individual; May be used to
determine:
A. LD50
Median lethal dose; the
concentration of a drug at
which 50% of the population
will die
B. ED50
Median effective dose; the
concentration of a drug at
which 50% of the population
will have the desired response
Therapeutic Index (TI)
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• Quantifies the relative safety of the
drug;
• Identifies the range of the drug’s
safety;
• A comparison of the amount of the
therapeutic effect to the amount
that causes cytotoxicity
TI = LD50/ED50
Margin of Safety
• A better safety index than LD50 for
materials that have both desirable
and undesirable effects;
• Factors in the end of the spectrum
where doses may be necessary to
produce a response in one person
but can, in the same dose, be lethal
in another;
• ED99 (for therapeutic effect) is
compared to the LD1 (for lethality
or toxic effect)
• Margin of safety = LD1/ED99
The higher the ratio, the safer the drug.
• Drugs with low TI: must be
administered with caution (e.g.,
digoxin, cancer therapeutic agents)
• Drugs with very high TI: extremely
safe in the absence of known allergic
response in a patient (e.g.,
penicillin)
Drugs with narrow therapeutic index:
• Carbamazepine
• Cyclosporine
• Digoxin
• Ethosuximide
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• Levothyroxine sodium
• Lithium
• Phenytoin
• Procainamide
• Theophylline
• Warfarin sodium
• Tacrolimus

POISONING? When confronted with

potential poisoning, two questions should
be foremost in the clinician’s mind:
• How long does an asymptomatic
patient need to be monitored (drug
absorption & dynamics)?
• How long will it take an intoxicated
patient to get better (drug elimination &
dynamics)?
TYPES OF THERAPEUTIC DRUG TOXICITY
• In therapeutics, a drug typically
produces numerous effects, but
usually only one is sought as the
primary goal of treatment.
• Side effects:
- undesirable effects for a
therapeutic indication
- bothersome but not deleterious
• Toxic effects:
- refer to other undesirable
effects of a drug
- may be classified
pharmacological, pathological,
of genotoxic
1. DOSE-DEPENDENT REACTIONS: the
incidence and seriousness of the
toxicity is proportionately related to
the concentration of the drug in the
body and the duration of the
exposure.
A. Pharmacological Toxicity
B. Pathological Toxicity
C. Genotoxic Toxicity
2. ALLERGIC REACTIONS: an adverse
reaction that results fr previous
sensitization to a particular chemical or
to one that is structurally similar;
mediated by the immune system; four
(4) general categories based on the
mechanism of immunological
involvement:
as
A. Type I: Anaphylactic Rxns
➢ IgE Fc portion bind to
receptors on basophils &
mast cells
➢ GI, skin, respi, vasculature
B. Type II: Cytolytic Rxns

➢ IgG & IgM activate the
complement system
➢ Circulatory system cells
C. Type III: Arthrus Rxns
➢ IgG
➢ Ag-Ab complexes that fix
complement
D. Type IV: Delayed Hypersensitivity
Rxns
➢ Sensitized T-lymphocytes &
macrophage
➢ Lymphokines, neutrophils, &
macrophages
3. IDIOSYNCRATIC REACTIONS:
abnormal reactivity to a chemical that is
peculiar to a given individual; extreme
sensitivity to low doses or extreme
insensitivity to high doses of drugs;
genetic polymorphisms that cause
individual differences in drug
pharmacokinetics.
4. DRUG-DRUG INTERACTIONS: may
lead to altered rates of absorption,
protein binding or different rates of
biotransformation or excretion of one or
both interacting compounds; additive
when the combined effect of 2 drugs
equals the sum of the effect of each
agent given alone;
➢ SYNERGISTIC – when the
combined effects exceed the
sum of the effects of each drug
given alone;
➢ POTENTIATION – describes the
creation of a toxic effect from one
drug to the presence of another
drug;
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➢ ANTAGONISM – interference of
one drug with the action of
another (e.g. antidote)
1. Functional or Physiological
Antagonisms: when 2 chemicals
produce opposite effects on the same
physiological function
2. Chemical Antagonism or Inactivation:
reaction between 2 chemicals to
neutralize their effects (e.g. chelation)
3. Dispositional Antagonism: alteration of
the disposition of a substance
(absorption, biotransformation,
distribution, or excretion) so that less of
the agent reaches the target organ is
reduced
4. Receptor Antagonism: entails the
blockade of the effect of a drug with
another drug that competes at receptor
site
TOXICITY TESTING
• Those effects of chemical produced in
lab animals, when properly qualified,
apply to human toxicity;
• When calculated on the basis of dose
per unit of body surface, toxic effects in
human beings usually are encountered
in the same range of concentrations as
those in experimental animals;
• Exposure of experimental animals to
toxic agents in high doses in a necessary
and valid method to discover possible
hazards to human beings who are
exposed to much lower doses (quantal
dose-response concept)
➢ PHASE I: predictable toxicities
detected; research centers by clinical
pharmacologists
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➢ PHASE II: special clinic centers or • Topical preparations
university hospitals; highest rates of
• Cold & cough medication
drug failures, only around 25% move on
to Phase III • Antidepressants
➢ PHASE III: designed to minimize errors POISONS ASSOCIATED WITH THE LARGEST
caused by placebo effects, variable NUMBER OF HUMAN FATALITIES
course of the disease, etc.; in settings • Sedatives/hypnotics/antipsychotics
similar to those anticipated for the
• Acetaminophen
ultimate use of the drug; expensive
phase; formulation as intended for the • Opioids
market; investigators are specialists in • Antidepressants
the disease being treated
• Cardiovascular drugs
POTENTIAL SCENARIOS FOR THE
OCCURRENCE OF POISONING • Stimulants and street drugs
• Alcohols
• Therapeutic drug toxicity
*Medication errors are 50-100x more common
• Exploratory exposure by young children
than adverse drug error
• Environmental exposure
*Mandatory & redundant checkpoints
• Occupational exposure
5 RIGHTS OF SAFE MEDICATION
• Recreational abuse ADMINISTRATION
• Medication error 1. RIGHT DRUG
o Prescribing error 2. RIGHT PATIENT
o Dispensing error 3. RIGHT DOSE
o Administration error 4. RIGHT ROUTE
• Purposeful administration for self-harm 5. RIGHT TIME
• Purposeful administration to harm ABCDE: Initial Treatment Approach for Acute
another Poisoning
SUBSTANCES MOST FREQUENTLY • Airway
INVOLVED IN HUMAN POISONING
• Breathing
EXPOSURE
• Circulation
• Analgesics
• Disability
• Personal care products
• Exposure
• Cleaning substances
• Sedatives/hypnotics/antipsychotics
• Foreign bodies
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