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Introduction to Pharmacology
Written by: Nikolas Dietis from Leicester University,
Contents:
1. Introducing Pharmacology
What is pharmacology?
A Brief history of development
2. Importance of Pharmacology in Medical Sciences
Pharmacology & related sciences
Subdivisions of Pharmacology
Pharmacokinetics & pharmacodynamics: the heart and soul of pharmacology!
Why should a Medic master pharmacology?
3. Drugs
Definition of drugs & classification
Routes of administration & drug preparations
4. Therapeutic activity Vs Side-effects
Selectivity and Specificity of drugs: an out-of-date outopia
Therapeutic window & side-effects
1. Introducing Pharmacology
1A. What is pharmacology?
The definition of pharmacology arises from its literal meaning. Most words in medical sciences
have roots in ancient Greek language, and pharmacology is no exception:
pharmacon ( poison) and logos (os talking). And since for ancient Greek
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philosophers the verb to talk was also used for to know about, the latinized word of
pharmacology literally means to know about drugs.
In modern context, pharmacology is defined as the study of drugs mainly in terms of their
mechanism of action and their therapeutic or adverse effects, rather than their chemical
structure (medicinal chemistry), dispensing (pharmacy) or prescribing suitability with regards to a
particular diagnosis (medicine). A pharmacologist is the scientist that studies what a drug does
in a particular system, model or molecular pathway, how the body reacts to it and determinesits functional or physicochemical properties.
1B. A Brief history of development
Pharmacology as a discipline is relatively new (about 150 years old), since the science of
pharmacology has sprung from the research of 19th-century chemists, biologists and medics.
Due to its vital role in the development of drugs and the successful treatment of diseases, it
was soon characterized as a separate scientific discipline.
Ancient civ iliz ations like the Greeks, Egyptians, Chinese, Persians and Romans had extensive
knowledge about the use of different medicines and where they could be found in nature.However, since the efficient study of drugs is vastly dependent on sufficient knowledge in other
fields (i.e. successful extraction or synthesis, efficient purification methods, knowledge of its
chemical structure, knowledge on the physiology of a particular disease state), pharmacology
has developed only after advances in these fields (or simultaneously at best).
Since the early 18th century, the development of pharmacology mostly follows a specific
pattern:
Successful isolation (or synthesis) of a drug depends on efficient purification.
Once the substance is purified, the focus is put on identifying its target in the body.
Identification of the target (usually a receptor) initiates research for identifying its
endogenous ligand (the compound that the body uses to react with its natural target).Identification of the endogenous ligand springs research in various neighboring fields.
These include: 1) analysis of its chemical structure and comparison with that of the
isolated drug, providing knowledge of how can we synthesize an improved version of the
drug, 2) study of the diseased states produced by irregularities of the target or the
production of the endogenous compound, providing knowledge on pathophysiology, 3)
study of the molecular pathways linked to the target and how the endogenous ligand or
the drug affects them, providing knowledge on the mechanisms responsible for the drugs
action.
The general goal of pharmacology is to understand the underlying molecular mechanismsresponsible for the biological activity of drugs in order to enable their rational use and enhance
their improvement. Recently, swift advances in a variety of scientific fields (molecular biology,
genetics, chemical modeling, electrophysiology, physics, computing) have provided a platform
for future pharmacological innovations. During the last decade, these scientific fields have
developed sophisticated tools that are being used in modern pharmacology for greater advances
in the prognosis, diagnosis and treatment of medical disorders.
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2. Importance of Pharmacology in Medical Sciences
2A. Pharmacology & related sciences
In the biomedical world, there are a number of different disciplines that can overlap or even
combine with others to structure their identity. There are six major disciplines that can be
regarded as discrete sciences and combine together to produce more generalsciences/professions, like pharmacy (preparation, storage and dispensing of drugs), medicine
(diagnosis, treatment and prevention of diseases) and pharmaceutics (formulation and physical
properties of pharmaceutical products).
The Major-Six disciplines are:
biochemistry (study of chemical processes in living organisms),
biophysics (study of matter and energy in biological systems),
molecular biology (study of molecular processes of biological activity),
medicinal chemistry (study of design and synthesis of drugs),
genetics (study of structure and function of genes)and
pharmacology (study of drug activity).
Of course, in modern biomedicine the rational study of any of the Major-Six premises
substantial knowledge in all of them in order to make the most of its capabilities and
applications (e.g. study of pharmacology presupposes some knowledge of biochemistry,
molecular biology and genetics).
DID YOU KNOW: ..that in the US and the EU the Pharmacology University-degrees
are considered to be the fastest-developed and most-grown degrees within Biomedical
Sciences during the last decade?
2B. Subdivisions of Pharmacology
Another consequence of the rapid advance in most of the Major-Six is the development of
subdivisions in order to focus their training and research in discrete topics. For example, in
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pharmacology, some of the subdivisions that can be often found as discrete degrees or
research areas are:
Neuropharmacology = Looking at the molecular mechanisms of drug action for PNS &
CNS diseases, like Alzheimers, Parkinsons, neuropathic pain, dementia, memory loss,
etc.
Psychopharmacology = Looking at the effects of drugs on the psychological state and
mental health for neural diseases like mania, phsychosis, anxiety, depression, addiction,
drug abuse, panic, phobias etc.
Neuropsychopharmacology = A connecting division between the two above, looking atthe molecular mechanisms of drug action for disease that affect the psychological state
and mental health.
Pharmacogenetics = Looking at drugs that interact with the genetic material or affectin
its behaviour.
Pharmacoepidimiology = Researching drugs implicated in epidimeology, virology etc.
Pharmacognosy = Focusing on natural drugs extracted from different plants.
Clinical pharmacology = The study of drugs' clinical use, in a strict clinical setting.
Behavioural pharmacology = Focusing on drugs that affect the mood and behaviour,
utilizing observational means of reserch (i.e. observing how an organism reacts under
different conditions with and without a drug).
Environmental pharmacology = Looking at drugs affecting the ecosytem by their
toxicity through the human or veterian use.
Toxicology = Study of toxic effects of drugs and poisons in humans (e.g. venoms,
pesticides, carcinogenics).
For obvious reasons, the boundaries between these rapidly-developed areas of research are not
evident and refined. Their scope of study and research objectives should be viewed as a
continuous and overlapping research across the spectrum of pharmacology, such as the colours
overlap across the light spectrum. Also, their major differences are not based on the diseases
they implicate, but rather on the angle of research they use to approach a specific disease (e.g.
molecular, pathological, psychological, behavioural, genetic).
2C. Pharmacokinetics & pharmacodynamics: the heart and soul of pharmacology!
From the time that a drug enters the body to the point of its excretion, pharmacology looks at
every aspect of the relationship drug-body:
how the body handles the drug (pharmacokinetics) and
how the drug affects the body (pharmacodynamics).
Pharmacokinetics involve the administration of the drug in the body (and the various barriers of
the latter to its diffusion i.e. the blood brain barrier), absorption of the drug from the tissues,
metabolism of drug by the body (as a defense mechanism for an external unknown substance),
distribution of the drug to the tissues (and its site of action) and excretion of the drug (removal
from the body i.e. sweat, urine, feces). You can see that all the aspects of pharmacokinetics
involve actions of the body to the drug.
Pharmacodynamics involve the soul of pharmacology, what the drug does to the body once it
reaches its target, what biological effects does the drug produce and how these effects change
the body from a diseased state to a healthy one. Using a useful metaphor for pharmacokinetics
and pharmacodynamics, it can be seen as the missions to the moon: the launch of the rocket,
the travel in space, the landing to the moon, the later departure from the moon and the landing
on earth they all represent pharmacokinetics. What the landing spacecraft does in the moon
once it arrives there represents pharmacodynamics.
On Fastbleep you can find analytical texts that explain in detail these two main parts of
pharmacology.
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2D. Why should a Medic master pharmacology?
All the aspects of medicinal science have their own importance to the therapeutic outcome:
accurate diagnosis, correct prescribing, effective treatment and a thorough follow-up are all part
of the job of a good doctor. However, deep knowledge of pharmacology marks the difference
between a good doctor and an excellent doctor.
Mastering pharmacology means that you know the major differences in various similar drugs,
you are aware of the contraindications which are vital for tailoring a prescription to each
patients own needs, you acknowledge all the drug-drug interactions between a patients
simultaneous treatments, you are able to identify a drugs side-effect and choose a different
drug therapy for the same disease, etc.
In order for a doctor to be capable and skillful for completing the above, he/she has to master
the knowledge of where it acts, how it acts and what are its disadvantages and advantages
compared to another similar drug.
3. Drugs
3A. Definition of drugs & classification
Drug can be defined as ANY substance that causes a biological effect, either therapeutic or
toxic. The classification of drugs exists in different forms.
Major classifications include two:
1. according to their effect (e.g. antiepileptics, antihypertensives, hypnotics) and
2. according to their mechanism of action (e.g. beta-blockers, alpha2-agonists).
"Indications" are a minor classification of drugs (e.g. for epilepsy there are barbiturates and
benzodiazepines, for asthma there are bronchodilators, corticosteroids, cromolyns and
leukotriene-receptor antagonists).
3B. Routes of administration & drug preparations
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It has been mentioned above that drug administration is part of pharmacokinetics. There are a
number of different routes of administration that a drug can enter the body.
To classify the different routes we divide into two main sections: topical (the drug acts at the
site of application and might enter the systemic circulation) and systemic (the drug is delivered
on purpose into the general blood circulation).
Also, there can be a number of different preparations for the same drug so that, either to make
use of different physicochemical advantages (i.e. for the oral route tablets, capsules and
syrups, have different physicochemical characteristics) or to make use of a different route of
administration (i.e. morphine exists in tablets, capsules, solutions, suppositories, injections
and transdermal patches) - See table below.
Choosing a particular preparation of a drug is based on the acknowledgment of the advantages
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& disadvantages of each one related to the disease to be treated and the particular needs of
the patient.
It is known that the body has a number of defense mechanisms in order to protect itself from
harmful substances. These mainly are the metabolism of drugs by the liver (the first-pass
effect) - where the blood is screened by the liver for unknown substances - and the blood
brain barrier (BBB) which protects the brain from active substances reaching the brain.
Depending on factors such as the physicochemical properties of the drug (molecular weight,
lipophilicity, ionization constant, molecular stability etc) and its pharmacological properties, the
doctor decides which particular preparation of a drug is appropriate.
Example: Why is insulin administered only by injection and not by a tablet?
Answer: The reason is that insulin is not effective when taken by mouth because it is
degraded in the stomach by its high acidity. Therefore, the physicochemical properties of
insulin underline the reasons for its parental preparation.
When a tablet is given, the drug must overcome a number of barriers before reaching its
target:
It has to withstand stomachs acidic environment (pH 1-3) and be dissolved in
solution in order to be absorbed (usually in the intestine) into the bloodstream [most
small proteins cannot be given into oral form because they break down into amino acids
in the stomach]
The absorption of the drug from the intestinal walls and across membranes into the
bloodstream will depend on the drugs lipophilicity, its size and its molecular weight,
All blood from the gut passes through the liver via the portal system and drugs
undergo extended metabolism (chemical changes) that can alter the drugs biological
activity or render it inactive [bypassing this first pass effect can be achieved by
different routes of administration]
Drugs that enter the circulation may bind to serum proteins and thus reduce the
percentage of the free drug in the blood that can reach the target,
Free drug in the blood must cross membranes in order to reach its target [some drugs
are deposited in the adipose tissue - fat - because of their high lipophilicity and thereforenot enough of the drug reaches other tissues],
Drugs that target the brain have to pass through the blood brain barrier, which consists
of tightly packed membranes with gates that control which substances pass through.
Examples: Benzyl penicillin, insulin and lincomycin are examples of drugs destroyed
in the stomach. Lignocaine is metabolized in the liver so that not enough of the active
drug reaches the target.
In some cases, a drug is given in an inactive or less active form (called a pro-drug) and it ismetabolized by the liver into an active form, thus using the first pass effect to our advantage.
Examples: Valaciclovir is an antiviral pro-drug that converts into the active acyclovir. Heroin is
an opiate pro-drug that is converted to morphine by the liver. Prednisone is a cortico-steroid that
is activated by the liver to prednisolone.
If you think about it, for a drug to be effective it must in one way or another be delivered
unchanged or in a form and concentration that is effective to a target. The target might be a
metabolic system, a cell, an enzyme or a specific tissue, or a bacterium. How the drug is
delivered to its target depends on the chemical characteristics of the drug and the available
product formulations (as discussed earlier in the article). Where a drug can be formulated for a
range of routes of administration, it is up to the doctor to decide which form will be most
effective and convenient for the patient (e.g. some elderly patients find it difficult to swallowand therefore large tablets should be excluded if possible when prescribing).
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4. Therapeutic activity Vs Side-effects
4A. Selectivity and Specificity of drugs: an out-of-date outopia
When a drug has a therapeutic effect through its activity on a particular tissue or molecular
target, it is only logical that any other "secondary" activity of the drug will produce a biological
effect that is not intented. This effect is called a side-effect (or adverse reaction).
A general notion among pharmacologists was that side-effec ts were produced solely because of
the non-specificity of a drug's action and so the main aim of the pharmaceutical industry and
the pharmacological science should be to produce and develop drugs that are more selective on
the desired target or tissue.
Remember: Selective is a drug that acts on a particular target and not another.
Specific is a drug that has a particular effect and not another. A selective drug does NOT
mean that is specific and vice versa. For example, a drug binds on a particular receptor-
target (so its selective), but that target may be expressed in different tissues and thus
may exert different biological effects (so no-specific). In that sense, it is very rare (close
to impossible) to find a drug that is specific and selective at the same time. This is whyselectivity/specificity has been the holy grail of pharmacologists in previous generations.
Nevertheless, new ideas have promoted "multi-functionality" in drug development, a strategy
that takes advantage of the variability of the targets and their expression in different tissues
and keeps away from selectivity and specificity. "Multiple Receptor Selectivity" is a new term
that has been introduced to distinguish the intentional design of drugs to be multi-selectivity,
with the unintentional non-selective drugs existed.
An example of multiple-receptor selectivity is found in opioid receptors (types: MOP,
DOP and KOP) where the old notion was that a strong opioid analgesic should be highly
selective to the MOP receptor to have maximum analgesia. Recent advances in opioid
pharmacology has shown that when activating the MOP receptor and blocking the DOP
receptor, there is strong analgesia with reduced opioid side-effects (tolerance,
dependance, constipation). Intentional design of new drugs that will do both these two
actions are considered an example of multiple-receptor selectivity.
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Important: The concept of selectivity should not be regarded as outdated or without scientific
essence in terms of pursuing it in research. The development of side-effects due to the activity
of drugs in "secondary" targets is quite real indeed. Equally, it has to be acknowledged that the
complexity of biological systems and the relationship between 'therapy-target-drug' is constantly
changing in a dynamic manner. Appreciating this concept of constant change brings forward
new strategies that seek to explore and take advantage of this variability in drug targets and
drug structures so that a therapeutic effect and a reduction in side-effects is achieved by
creating multifunctional drugs.
4B. Therapeutic window & side-effects
To understand the meaning of the "therapeutic window", one has to realise that ALL substances
in the universe may cause side-effects (or toxic effects) if their DOSE is adjusted accordingly.
Additionally , if the DOSE of any drug is too low, there will be no therapeutic effec t. This dose-
effect relationship of drugs is the main study of Pharmacodynamics.
The logarithmic sigmoidal relationship of a drug's action (see picture below) shows that there is
only a particular "dosing window" that can produce a therapeutic effect when gradually
increasing the dose of a drug (below that window there is no effect, above that window there are
toxic effects).
Example 1: Administration of oral broad-spectrum antibiotics may alter the microflora
in the gastrointestinal tract and produce symptoms of diarrhoea or thrush. This is
because these antibiotics will be active against a wide range of microorganisms, including
the symbiotic ones in the gut. organism (i.e. tetracyclins).
Example 2: Aspirin is an antiinflammatory analgesic (inhibiting cyclooxy genase) and
also a preventive of strokes due to its anticoaggulant activity on platelets (inhibiting
thromboxane which binds platelets to form clots). However, its inhibition of the protective
cyclooxygenase-2 (which produces prostaglandins for the protection of the stomach wallsfrom its acid) may cause ulcers.
Illustration of an example of therapeutic window of a drug
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Side-effects are not only part of a standard practical & theoretical approach. Apart from
variations in the dose of drug and its non-selective "unwanted" effects, there are other issues
that may produce a side-effect which is not expected. These issues are similar to those
responsible for drug variability among a population:
Pharmacokinetics can differ (based on weight, metabolism, body structure. This is why
medics subscribe higher doses to super-overweight patients).
Pharmacodynamics can differ (based on variation of expression of targets in some
humans, i.e. some people do not produce specific enzymes)
Age (differences in organ efficiency , system maturation etc)
Gender (differences in expression of targets)
Pregnancy or breast feeding
Concurrent drugs (drug-drug interactions can affect the activity/metabolism of drugs)
Concurrent diseases (a disease state may affect the activity of a drug for another
disorder, i.e. renal disfunction may affect excretion of drugs for Alzheimer's)
Genetics (polymorphism and genetic variability can affect target expression)
Allergies/ hypersensit ivities/intolerance (people have allergies and hypersensit ivit ies to
different substances, some people are intolerant to even low doses of a particular drug)
PrinciplesCommon InteractionsFY1 EssentialsIntroduction to PharmacodynamicsIntroduction to PharmacokineticsIntroduction to PharmacologyMedicines
AnalgesicsAnti-arrhythmi csAnti-emeticsAntibiot icsAntic oagulantsFluid BalanceHypnotics
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