Transcript File - Riske Science

Lesson 1: Pharmaceutical
Products and Drug Action
D.1 Monday, March 7th
Understandings
• In animal studies, the therapeutic index is the lethal dose of a drug
for 50% of the population (LD50) divided by the minimum effective
dose for 50% of the population (ED50).
• In humans, the therapeutic index is the toxic dose of a drug for 50%
of the population (TD50) divided by the minimum effective dose for
50% of the population (ED50).
• For ethical and economic reasons, animal and human tests of drugs
(for LD50/ED50 and TD50/ED50 respectively) should be kept to a
minimum.
• The therapeutic window is the range of dosages between the
minimum amount of the drug that produce the desired effect and a
medically unacceptable adverse effect.
• Dosage, tolerance, addiction, and side-effects are considerations of
drug administration.
• Bioavailability is the fraction of the administered dosage that
reaches the target part of the human body.
• The main steps in the development of synthetic drugs include
identifying the need and structure, synthesis, yield, and extraction.
• Drug–receptor interactions are based on the structure of the drug
and the site of activity.
Applications and Skills
• Discussion of experimental foundations for
therapeutic index and therapeutic window
through both animal and human studies.
• Discussion of drug administration methods.
• Comparison of how functional groups,
polarity, and medicinal administration can
affect bioavailability.
Your Body – Natural Defenses
• Metabolism is the sum of all your body’s natural
processes
• Your body has a number of ways to maintain
homeostasis and ward off illness and infection,
recover from injury, and staying in working order.
However, sometimes these systems are not
enough.
• Medicinal chemistry is a study into how we
supplement our bodies natural defenses when
things go wrong
Terms
• We consider microorganisms that can cause us
illness as invaders and our body’s immune
defenses as lines of defense
• Often, what we consider sickness is really a
by-product of our body’s line of defense (i.e. a
fever is a way to kill off invaders whose
proteins change and denature at higher
temperatures)
Drugs
A drug is any substance that, when applied to or
introduced into a living organism, brings about
a change in biological function through its
chemical action.
The change in biological function may be for the
better – in the treatment of diseases – or for
the worse – poisons that cause toxicity.
Drug Action
• A drug produces an effect on the body by
interacting with a particular target molecule.
This target molecule is usually a protein such
as an enzyme or receptor, but may be another
molecule such as DNA or a lipid in a cell
membrane.
Drugs
Drugs can be:
• relatively crude preparations, obtained by
extracting plant or animal materials
• pure compounds isolated from natural sources
• semi-synthetic compounds, produced by
chemical modification of pure natural
compounds
• synthetic compounds.
Medicine
• A medicine is something that treats, prevents
or alleviates the symptoms of disease – they
have a therapeutic action.
• Medicine are usually compound preparations,
which means that they contain a number of
ingredients – the active drug itself plus nonactive substances that improve the
preparation in some way such as taste,
consistency or administration of the drug.
Therapeutic Effect
• The therapeutic effect is the beneficial effect
of a medical treatment.
• The placebo effect is a phenomenon where a
patient believing they are being given a
medicine experience the benefits even when
not taking the medicine; this is the reason
when developing new drugs they must be
tested against a placedo
Drug Administration
• Drugs can be administered in a number of way
1. Oral
2. Rectal
3. Injected
a. Intravenous
b. Intramuscular
c. Subcutaneous
4. Pulmonary
5. Topical
Summary of Methods
Injection Methods
Bioavailability of Drugs
• Regardless of how the drug is administered,
not all of the drug will make its way to the
intended target
• Bioavailability is the fraction of the
administered dosage that reaches the
bloodstream.
• Bioavailability is an important consideration
when calculating how much of a drug to
administer, known as the dosage.
Bioavailability
• What does this tell you about IV vs. oral?
Oral Bioavailability
• Various factors affect the fraction of a drug
dose that survives to reach the general
circulation – for instance, the formulation of
the tablets, their solubility, how easily it is
absorbed through the intestinal wall, and the
susceptibility to being broken down by
enzymes in the gut and liver all affect
bioavailability.
First Pass Effect
• The relatively low bioavailability of a drug taken
orally is known as the first-pass effect, and
means that as little as 20–40% of an orally
ingested drug may reach the bloodstream.
• This is because after swallowing, these drugs pass
into the digestive system where biological
catalysts known as enzymes may alter them
chemically. Once absorbed from the digestive
system, they are passed in the blood to the liver
where further metabolic breakdown reactions
occur.
Oral Administration
• So in general an oral dose of a drug needs
to be about four times higher than the
dosage of the same drug administered
intravenously.
Exam Tip
• When asked to define bioavailability in the
exam you should define it according to the
syllabus definition: the fraction of the
administered dosage that reaches the target
part of the human body.
Solubility
• Water solubility is important for circulation in the aqueous
solution in the blood, but lipid solubility helps in the
passage of the drug through membranes during absorption.
• Only individual molecules of a drug can pass through the
wall of the intestine, therefore it is essential that a drug is
soluble in water – the medium of the gastrointestinal tract.
• Several factors relating to the structure of drug molecules
affect solubility – the presence of polar groups (e.g lots of
OH groups) and/or functional groups that can undergo
ionization (e.g. COOH and NH2).
Functional Groups
• Functional groups in the drug can also in
influence bioavailability, particularly acid–base
groups.
• The pKa and pKb values of these groups in the
molecule will determine the charges carried
on the drug at different pH values, and
therefore its reactivity and solubility in
different parts of the body.
Drug-Receptor Interactions
• A drug can act in various ways on receptors, for
example:
– it can bind to a cell-membrane protein receptor, mimicking
the effect of the normal molecule that binds and cause a
series of reactions in a cell – i.e. it turns a particular
process in the cell on/off; in this case the drug is called a
receptor agonist
– it can bind to a cell-membrane protein receptor so that the
normal messenger molecule can’t – it prevents a particular
response from a cell; in this case the drug is called a
receptor antagonist.
• A drug, wherever possible, should be specific and bind
to only one particular type of receptor
Drug-Receptor Interactions
• Drug–receptor interactions depend on a ‘chemical
fit’ between the drug and receptor – in general
the better the t, the greater the activity of the
drug.
• The binding of drug and receptor usually involves
different types of non-covalent bonding, such as
ionic bonds, hydrogen bonds, van der Waals’
forces, and hydrophobic interactions.
Side Effects
• Side-effects are defined as physiological effects which
are not intended, and they vary greatly from one drug
to another, and with the same drug in different people.
• Sometimes side-effects may be beneficial, such as the
fact that aspirin, taken for pain relief, helps protect
against heart disease. Other times the side-effects may
be relatively benign, such as causing drowsiness,
nausea, or constipation. But of greater concern are
side-effects which are much more adverse, such as
causing damage to organs.
Side Effects
Tolerance and Addiction
• When a person is given repeated doses of a
drug, tolerance can develop, which means a
reduced response to the drug for the same
dose. So higher doses are needed to produce
the same effect, and this increases the
chances of toxic side-effects.
Addiction
• A related but different condition is dependence
or addiction. This occurs when a patient becomes
dependent on the drug in order to feel normal,
and suffers from withdrawal symptoms if the
drug is not taken.
• Symptoms can be mild, such as headaches
suffered on withdrawal from dependence on
caffeine, or serious if the drug is toxic or shows
tolerance, such as opiates, alcohol, and
barbiturates.
Drug Development
Tuesday, March 8
Drug Dosing Regimes
• The dosing regime for a drug refers to the specific quantity of drug
to be taken at
one time, and the frequency of administration.
• Calculations of dosage must take bioavailability into account, as
well as possible side-effects and potential problems of tolerance
and addiction.
• Determining appropriate dosage is usually quite dif cult as there are
so many variables involved – for example the age, sex, and weight
of the patient, as well as factors such as diet and environment.
Interactions with other drugs must also be considered.
• Ideally the dosage should result in constant levels of the drug in the
blood, but this is almost impossible to achieve other than by a
continuous, intravenous drip.
Therapeutic Window
• Since the levels of a
drug in the
bloodstream will
not be constant,
dosing has to try to
get the amount into
an acceptable range
• This target range is
known as the
therapeutic
window.
Therapeutic Index
• The therapeutic window can be quanti ed as the
therapeutic index (TI). This is the ratio of the dose that
produces toxicity to the dose that produces a clinically
effective response in a population. The relevant terms
in the equation are:
1. The minimum effective dose, ED50, is the dose that
produces the therapeutic effect in 50% of the
population.
2. The lethal dose, LD50, is the dose that is lethal to
50% of the population. This is used in animal trials.
3. The toxic dose, TD50, is the dose that is toxic to 50%
of the population. This is used in human studies.
Animal vs. Human Studies
• In animal studies lethal doses are determined;
however, in human trials the upper limit is the
toxic dose.
• Measuring an LD50 can result in the deaths of a
large number of animals – many countries have
phased out this test in favor of others in which
few or no animal deaths result.
• Both have benefits and drawbacks. The situation
is way more complicated than this simple
formula!
What does TI mean?
• If a drug has a high (or wide) therapeutic index,
this means that there is a large difference
between the dose of the drug that causes a
therapeutic effect compared with the dose that
causes a toxic effect.
• For example, if a TI is 100 then TD50 is 100 times
larger than ED50, so it would require a 100-fold
increase in the therapeutic dose to cause a toxic
effect in 50% of the population; a high
therapeutic index is therefore a desirable
property of a drug.
Penicillin vs. Warfarin
Drug Development
• Extremely expensive
• Industry is very selective about which
diseases/conditions to go after; want to make
money off of investment
• Downside to universal healthcare?
• The average time for development of a drug
from its first identification to the market is
about 10–12 years.
– Patent issues
Rational Drug Design
• Knowledge of drug–receptor interactions has
revolutionized the process by which new drugs are
developed.
• Most research now focuses on identifying a suitable
molecular target in the body and designing a drug to
interact with it.
• This approach, known as rational drug design, is very
different from the time when pharmaceutical
companies worked mostly on a ‘trial and error’ basis,
starting with a natural remedy and trying to improve
on nature with no real insight into the mechanism of
the action of the drug at the molecular level.
Lead Compounds
• Once a target molecule has been identified,
the next step is to find a lead compound
– one that shows the desired pharmaceutical
activity which will be used as a start for the
drug design and development process.
• The effectiveness of the lead compound is
optimized by synthesizing and testing many
chemically related compounds known as
analogues. A process called combinatorial
chemistry enables the production and testing
of vast numbers of candidate medicines in a
very short time.
Compound Libraries
• Electronic databases that contain
molecules which have been isolated or
synthesized and tested by pharmaceutical
companies for possible pharmaceutical
properties
• Pharmaceutical companies use such
libraries to identify ‘lead’ compound for a
particular ‘target’ molecule such as an
enzyme, DNA or a receptor.
Combinatorial Chemistry
• https://www.youtube.com/watch?v=MVgsX7P
M4F4
Combinatorial Chemistry
• Involves simultaneous chemical synthesis
• A large number of different but structurally
related compounds (all possible
combinations) from a small number of
reactant molecules which are reacted with a
variety of reactants,
• Uses “mix-and-split” technique and resin
beads
• Screen each product for its biological activity,
resulting in a “combinatorial library”.
• All is automated and uses computers/robots
Solid-Phase Chemistry
• A technique used in combinatorial
chemistry
• Synthesizes large volume of compounds
• Reactions take place on the surface of
resin beads
• Each type of reactant molecule is bonded
covalently onto a very small resin bead
• Uses mix and split process
Advantage Of Solid Phase
• When synthesis reactions are complete, the
products are removed easily from the beads
by filtering off the beads and washing them.
• After that the products are tested “in vitro”
and “in vivo” to find out their biological
activity.
Parallel Chemistry
• Parallel chemistry or parallel synthesis involves the
synthesis of a smaller but selected group of
compounds with a different compound in each
reaction vessels.
• In most combinatorial techniques the compounds
are mixed and need to be separated; not
necessary in parallel synthesis as multiple
experiments run in parallel.
Parallel synthesis
Differences
Combinatorial Synthesis
Parallel Synthesis
•Generates large, more
diverse libraries “combinatorial library”.
•Produces a ‘mixture’ of
compounds in same
reaction vessel.
•Small focused libraries
•Reactions performed in
different reaction vessels
•Produces a ‘single’ product
in each reaction vessel.
Next Steps – Clinical Testing
• Next, the pharmaceutical company must test
their drugs to determine safety, efficacy, and
dosing regimens
• To do this, they must start clinical trials
Drug Development
• https://www.youtube.com/watch?v=wvDvAE
mq-cM
• https://www.youtube.com/watch?v=vYBtlItAT
3c
Phase I
• The first phase (known as Phase I) is carried
out on a small number of healthy volunteers
(usually fewer than 100) and its purpose is to
nd the dose range of the drug that gives a
therapeutic effect and also to identify any
side effects.
Phase II
• If the drug passes Phase I, it then enters Phase
II clinical trials where it is tested on a small
number of volunteer patients who have the
disease or condition on which the drug acts.
Phase II establishes whether or not the drug is
effective in these patients and also identifies
any side e ects. If deemed safe and effective,
the drug then enters Phase III.
Phase III
• In Phase III clinical trials, the drug is tested on
a much larger group of volunteer patients.
This phase confirms the effectiveness of the
drug in the larger group and compares its
activity with existing drug treatments or
placebos.
Thalidomide
• https://www.youtube.com/watch?v=41n3mD
oVbvk
Questions
Answers