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Summary Medical Pharmacology
- Instelling
- Vrije Universiteit Amsterdam (VU)
Medical Pharmacology notes directly from the lectures and course material, integration with laboratory practicals and workgroups.
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MEDICAL PHARMACOLOGYIntroduction to Pharmacology - part 1: Pharmacology defined
Pharmacology: it tries to provide explanations of the actions of pharmaceuticals, which are
characterized by the fact that they are biologically active substances (including toxins) in the
human or animal body.
Medicine: a pharmaceutical, a drug, which is applied for therapeutic purposes in disease
state.
Pharmacodynamics PD: how drugs act to change the disease's state or to induce certain
actions in the body.
Pharmacokinetics PK: opposite of PD, what the body does with the drugs.
Pharmacotherapy: applied pharmacology, use of knowledge and insight gained from
pharmacology for the treatment of diseases in humans or animals in a responsible, effective
and safe manner.
History of pharmacology: very old established science, but it started out thousands years
ago as investigation of the application for therapeutic purposes of herbs and potions, which
developed over time into the first commercial application by the pharmacists. They
eventually developed from individual practices to the pharmaceutical industry, which became
prominent, not only using medicines from natural sources, but also synthetic forms. 1600,
scientific revolution, development of chemistry, and biomedical sciences in 1900, important
to identify the chemical structure of the active part of the natural products, these potions or
herbal remedies, and to develop that structure into synthetic chemistry, eventually leading to
the production of synthetic drugs. At the same time, with the biomedical sciences such as
pathology, physiology, biochemistry and molecular biology, they became important for
pharmacology and development of new treatments, because they used their information to
feed pharmacology knowledge, used to explain the action of these pharmaceuticals. The
latest development is the biopharmaceuticals, which combines all these knowledge of
commercial purposes, biomedical sciences to fit into new approaches and compounds, such
as vaccines against COVID, to use them as pharmacol preventing measures.
What is pharmacology: the study of what drugs do and how they do it, so the mechanisms.
A drug is always a chemical, in one way or another, usually used to treat a disease, but also
toxins are included. They tend to have a selective action, because they are applied for
certain purposes, for certain to treat certain symptoms, but unfortunately the ideal situation is
seldom achieved, and this leads to the consequence that there is always a risk of adverse
effects as well as benefit connected with the use of any drug, which have to be weight
against each other before the doctor prescribes drugs or when they evaluate data for studies
to insert one drug to the market. Pharmacology is essential for using drugs effectively and
safely in therapy.
Basis, pharmacological basis to use pharmacotherapy: therapeutic window is established
by following the concentration of drug in the blood plasma (Y axis) in time after the start of
administration (x axis), and it’s the concentration of the drug which at the lower level is
defined by the minimum effective concentration, in other words the concentration of the
drug in the blood plasma after administration above which the aimed at effective therapeutic
action starts, and it is constrained at the top by the minimum toxic concentration, above
which toxic or adverse effects start to occur which interfere with the effectiveness and safety
of the drug. The therapeutic window between them is the concentrations which fluctuate over
time within an acceptable level of benefits versus risks.
Defined by the PD and PK.
,Introduction to pharmacology - part 2: Effects of drugs and drug discovery
Primary effect: effects for which the compound is administered, used by the therapeutic
window.
Side effect: any other observed effect that doesn't belong to the primary one, so adverse or
unwanted.
The distinction between them is determined by the aim for which the medicine is
administered under a given condition, at that particular moment in time, for instance, aspirin
can be used as a painkiller (analgetic) or against blood clotting (anti-coagulant), which came
later and now is the primary effect most often, and when we started to use it as a painkiller
the most popular side effect was the anticoagulant effect, so stomach bleedings happened.
Placebo: a preparation without any pharmacologically active substance, so there’s nothing
inside it with a biological action. This is important for clinical pharmacological research,
either during the times and phases of drug development before introduction to the market or
after, for certain uses and to compare the efficacy in a large population after it is accepted.
Nocebo: placebo with unwanted effect, so the placebo can also have therapeutic/positive
effects, but the nocebo has only unwanted effects, something you don’t thrive for. These
therapeutic effects of the placebo are called placebo effects. These are determined to a
large extent on the expectations of the patients, which determine the strength of the effect,
but also explains why a placebo can become a nocebo, because it all depends on the
expectations of the patient. The contribution of the placebo effect to the overall effect of a
drug is usually investigated in randomized placebo-controlled clinical trials, which are often
performed within a contest of phase III trials, and these are used before the introduction to
the market.
Drug development and discovery: the development is distinguished into two main
preclinical phases: the discovery and the development.
It all starts out, to find out what sort of indication, with discovery chemistry, which is about
synthesizing the synthetic group compounds, and discovery biology, which is to find out
whether these synthetic compounds indeed interact with the target to which they are
intended to bind. During the drug discovery phase, investigation starts with ADME, which is
a pharmacokinetic term, to establish in vitro whether some forms of metabolites are formed.
Then, toxicology screening is started. These information found during the early drug
discovery is fit into the lead optimization and preclinical development, because overall it
starts with many compounds which eventually lead to introduction of one optimized
compound which after a long time can be introduced into the market, so as early as possible,
during the discovery and preclinical development, what is the most likely small numbers or
one number of compound which eventually stands a chance to be accepted, after a lot of
clinical trials. So, during lead optimization and preclinical development, animal models of
the disease you’re interested in need to be introduced and converted into data which are
used to see whether a drug could at all be tested on humans. Pharmacokinetics is
extended, looking into ADME characteristics of the drug in animals. Also toxicology
screening is extended. The data from the preclinical discovery and development need to be
evaluated before one can start further clinical drug development phases, consisting of three
phases. During phase I, ADME is further investigated in humans both healthy and diseased,
depending on what phases the drug is in, and eventually we’ll see the medical effects, which
are evaluated in large scale during phase III, which is prior to a possible registration of the
drug.
This all might take quite long, the combined activity of chemistry and biology discovery can
take 2-5 years on average, the whole issue of identification and optimization of a group just
,before using only one compound for clinical purposes. Often, patent applications are started
because you cannot wait that long so you already start to claim property rights on
compounds. The drug development takes from 5 to 9 years, from preclinical drug
development and the three phases, which culminate in application for approval by
organizations, which have to approve that the drug enters the market, EMA in Europe. This
takes a lot because you have to combine the biological and chemical aspects, with
toxicology, the clinical phases, the manufacturing since you start with little amount but
eventually if you need to try it out in the clinical trials you need large amounts, which start to
be produced in the early phase of drug development. Usually at this time, also a patent
application will be granted.
Then market penetration during a post-approval regulation, called pharmacol vigilance, the
drug is used in large patients under the actual circumstances at home or hospital in phase
IV.
PD 1: introducing pharmacodynamics
Pharmacodynamics describes what the drugs do with the body and how they do that. One
can define this on four levels. First we need to look at a patient or a healthy subject, and we
can establish an effect at a system level, which is to look for multiple effects of the system
function, for example in a drug needed for higher blood pressure we can look at what
happens to blood pressure. The second level, we can look at what the drug does at a tissue
level, so for example look at the contraction frequency at the level of cardiac tissue. Then,
the cellular level, for example inside cardiac muscle cells to look at the ions. Finally, the
molecular level, which is very important for pharmacodynamics in particular because this is
said to be the level of action of a drug which has a direct connection to its mechanism of
action and therefore to what the drug does at a system level. So, the purpose of
pharmacodynamic investigations is to look at the molecular level but the actual aim is to find
out the interactions with molecular targets, which are enzymes, receptors, carrier molecules,
to get a direct link between the action at the molecular level with the ultimately effects at
system level via cellular and tissue levels.
Drugs acting via receptors are divided into agonist, which binds to the receptor but also
changes the conformational shape of the receptor, activating it, and leading to changes in
activity states of the cells on which these receptors are expressed, and antagonist, which
bind to the receptors but don’t cause any effect, not changing the conformation, therefore not
leading to any measurable changes in activity changes, but at the same time, binding of an
antagonist drug to these receptors prevents efficacy of endogenous mediators, which
normally act as agonist at these receptors, so you’ll see that the cell indeed changes its
activity.
Drugs that act via ion channels are called blockers, which will enter the channel when they
are open and block it, so the permeation of sodium or other ions is reduced, and
modulators, which bind to the subunits of the ion channel proteins and either increase or
decrease open probability of ion channel, so the amount of time they stay in the close or
open conformation changes.
Drugs that act via enzymes are called inhibitors, when the drugs bind to the catalytic site of
the enzyme and block its activity, so a normal reaction is inhibited, and false substrate,
when the drug shows up to be a substrate of an enzyme, so the reaction will go on and the
substrate will be transformed into a metabolite but an abnormal one, and the normal reaction
is also inhibited, and also pro-drug, which is used to create an active drug by making it bind
to the catalytic site of an enzyme and promoting a reaction.
, Drugs that act via transporters / carriers are called either inhibitor, when they block the
normal carrying of one substrate from one side of the barrier to the other side by the direct
binding to the protein, and false substrate, in which the transporter will carry an abnormal
substrate leading to the accumulation of the abnormal compound to the other side.
Four main families of drug receptors:
1. Ligand-gated ion channels (ionotropic): this means that the receptors also contain
an ion channel, making different specificity for ions.
Speed: hyperpolarization or depolarization, which creates immediate cellular effects
because of the change of the flux of ions, so this takes milliseconds.
Examples: Nicotinic, ACh receptor.
2. G-protein-coupled receptors (metabotropic receptors): when the receptor is
activated, G proteins will be attracted to the receptors, which can be stimulatory or
inhibitory, so when this receptor is activated there’ll be an intermediate reaction via
the attraction of G proteins.
Speed: because of the intermediate reaction via G protein, the second messengers
will change, changes usually in protein phosphorylation, which takes seconds.
Examples: Muscarinic, ACh receptor.
3. Kinase-linked receptors: they contain a catalytic domain, meaning they are also
enzymes, so their activation leads to a kinase reaction that will take place with the
substrate of these receptors.
Speed: catalytic reactions via kinases, leading to alterations in gene transcription and
protein synthesis, so it takes hours.
Examples: Cytokine receptor, insulin receptor.
4. Nuclear receptors: they are usually expressed inside the cells, and the inactive form
is present in the cytoplasm and only upon activation by its own agonist, this receptor
will be transported inside the nucleus and will bind to the DNA, and they belong to
the transcription factors because they recognize specific DNA-binding domains.
Speed: when moved to the nucleus, they change the gene transcription and protein
synthesis, so it also takes hours.
Example: Estrogen receptor, vitamin A and D receptors.
PD 2: Molecular theory of drug action
This will focus on drugs that act via receptors, meaning that it’s much more diffused.
Exogenous: a drug is an exogenous chemical compound that modifies the functioning of a
physiological system in a selective manner.
Biomolecules: drugs interact (bind) selectively with certain cellular proteins (the four seen
before).
Endogenous: receptor in pharmacology is described as a protein that recognizes an
endogenous chemical compound, causing a cellular effect.
Characteristic selectivity: different receptor proteins recognize only certain endogenous
chemical compounds and drugs, so they’re there to interact with endogenous agonists in a
selective way.
Specific effect: usually a drug does not have a specific effect, in other words a single
molecular mechanism of action, but in fact this depends on the dose, because a drug may
mediate multiple effects via interaction with different types of receptor proteins, so it depends
on the concentration at the receptor site, which will be activated by this drug. So, selectivity
depends on the concentration or dose of the drug administered, so on the binding affinity for
different subtypes of receptor proteins at a specified (usually low) drug concentration.
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