General Pharmacotoxicology

Pharmacotoxicology is a part of pharmacology that studies the side effects

and side effects of drugs.
Adverse reactions are undesirable effects that occur at doses commonly used
in therapy.
They must be distinguished from both pharmacodynamic side effects that are
not harmful to health, e.g. dry mouth caused by atropine, as well as by the
phenomena of acute intoxication, which are harmful manifestations that occur at
very high doses, exceeding those used in therapy.
Chemical poisoning is not a study of pharmacology, but of toxicology.

Research into adverse drug reactions in humans is done through clinical trials
that assess the clinical safety of drugs, understanding by clinical safety studies
clinical trials that assess the risks of exposure of a person to the drug to be
investigated. Predictable adverse reactions from non-clinical pharmacology data or
from previous clinical trials, called expected adverse reactions, may occur during
clinical trials prior to authorization of the medicinal product, but unexpected adverse
reactions may also occur. Due to these aspects in these clinical trials all adverse
events are recorded, even if, apparently, there is no link between the adverse event
and the drug studied.
In general, following all these studies, it is possible to decide which adverse
events really represent adverse reactions, which allows to establish the benefit / risk
ratio called clinical efficacy of the drug.
After the drug is introduced into therapy, its monitoring continues throughout
the life of the drug through a system called pharmacovigilance. Within it, each doctor
has the obligation to report any adverse reaction found in his medical practice.
 Depending on the mechanisms of production, there are 3 categories of
side effects: toxic side effects, idiosyncratic side effects and allergic side effects.

Toxic side effects are dose-dependent reactions. They are all the more
frequent and the more severe the higher the doses. These side effects can be detected
before the introduction of drugs into therapy, some even in the non-clinical research
phase.
To assess acute toxicity after a single dose, determine the dose that kills half
of the laboratory animals called the lethal dose 50 LD50. LD50 is considered a
parameter that determines the toxicity of a substance. The lower the LD50 value of
a substance, the more toxic that substance is.
Much more important is the comparison of the LD50 parameter with the ED50
parameter, the dose that is effective in 50% of subjects or that produces half of the
maximum effect. The LD50 value must always be much higher than the ED50 value
in order to be able to use a drug safely. Starting from the 2 values, a parameter called
therapeutic index is calculated, which is the ratio between LD50 and ED50.
There are also situations when LD50 cannot be determined, the substance
being so non-toxic that a sufficiently large amount cannot be administered to kill
laboratory animals. In such situations, other parameters are determined, depending
on the possibilities, such as the minimum lethal dose (LD1) or the maximum
tolerated dose (MTD), ie the maximum dose that could be administered and did not
kill any laboratory animal.
Of great importance for research into the safety of a drug is also the
determination of chronic toxicity after repeated doses. For this, the toxic effects of
the test substance in case of chronic administration to laboratory animals are studied.
In practice, the test substance is administered daily for a certain period of time which,
in general, should be longer than the time allowed for treatment with that substance
in humans. If human treatment is expected to be indefinite, the toxicity of that
substance will be studied for at least two years (104 weeks). The experiments are
performed on at least 2 species of animals, one of which must be non-rodent.

There are several mechanisms by which these toxic side effects can occur.
 Sometimes it is an exaggeration of the therapeutic effect, following the
action of the drug, by the same mechanism and on the same receptors as in the case
of the therapeutic effect, receptors located right in the organ whose disease is being
treated. For example, medications that lower heart rate may be helpful in treating
tachycardia, but at high doses they can cause excessive bradycardia as an adverse
reaction. Another example is drugs that lower blood pressure, useful for the
treatment of high blood pressure, but which, in high doses and under certain
conditions, can cause hypotension as an adverse reaction.
Sometimes side effects occur by acting on the same pharmacological
receptors as in the case of the therapeutic effect, but these are receptors located
in organs other than those whose condition is being treated. For example, drugs
that stimulate adrenergic receptors produce bronchodilation by stimulating
adrenergic receptors in the bronchi and are useful in the treatment of asthma, but
they can also act on adrenergic receptors in the heart, increasing heart activity and
myocardial oxygen consumption thus, aggravating an ischemic heart disease.
There are situations of drugs that produce side effects through a mechanism
other than the one through which the therapeutic effect occurs. For example,
aminoglycosides, drugs whose therapeutic effect consists in the specific destruction
of certain microbes, may be toxic to the kidneys and to the acoustic-vestibular
apparatus by a mechanism other than that by which they specifically kill microbes
sensitive to these antibiotics.
There are several situations that may explain the occurrence of toxic side
effects, even if the drugs are administered at therapeutic doses.
Sometimes it is about people who are more sensitive to drugs, who have
toxic phenomena at high therapeutic doses. Sometimes it is an increased sensitivity
of certain organs.
At other times, there may be a need to increase the dose to achieve a more
intense effect.
Pharmacokinetic problems may also occur that increase the plasma levels
of the drug. Sometimes we can encounter phenomena that lead to the prevention of
the elimination of a drug from the body. Thus, the administration of a drug to a
patient affected by the organ involved in the elimination of that drug, can lead to an
increase in the serum level of the drug and thus the toxicity.
 In other cases, there is an increase in the concentration of the free form of
the drug, unrelated to plasma proteins. Thus, a decrease in plasma proteins, as
may be found in nephrotic syndrome or liver failure, may increase the free form of
drugs that bind to these proteins, thus increasing their toxicity. There may also be
phenomena of displacement of a drug from the plasma proteins by another drug, thus
increasing the concentration of the free form of the drug displaced from the plasma
proteins and thus the toxicity.
A toxic reaction is treated, and the treatment is the same as the treatment of
intoxication with the drug.
Also in the category of toxic side effects are included some particular side
effects such as dysmorphogenicity and teratogenicity, mutagenicity and
carcinogenicity.

Idiosyncratic side effects usually occur at low doses, but only in certain
people who have an increased sensitivity (responsiveness) to certain substances.
This sensitivity is usually genetically determined. Depending on the genetic
deficiency, these side effects may occur as a drug intoxication, even though low
doses have been given, or may occur completely differently from the usual effects
of the drug.
Those that manifest as intoxication are usually due to a genetic deficiency in
the enzyme that is involved in the metabolism of the drug.
Sometimes there are enzymatic defects responsible for side effects with
completely unusual manifestations compared to the usual effects of the drug. Thus,
there are people who are deficient in glucose-6-phosphate dehydrogenase, an
enzyme involved in maintaining the shape of the red blood cell. In such people many
drugs can cause hemolytic anemia.

Allergic side effects are harmful effects due to the intervention of immune
mechanisms. They occur at very low doses of the drug, if the person has been
previously sensitized to that drug. These reactions involve an antigen-antibody
immune mechanism.
The allergic reaction does not occur at the first contact with the medicine, but
at this first contact an antibody-generating sensitization occurs. At a new contact,
usually after a latency of 7-14 days, if the antibodies are in excess, an allergic
reaction occurs. The allergy lasts for long periods of time, most often the person's
entire life.
Drug allergy is cross-linked to chemical groups of drugs, a person allergic to
a drug being often allergic to several products structurally related to that drug. Thus
a person allergic to a penicillin may be allergic to all penicillins, and a person allergic
to a sulfamide may be allergic to all sulfamides, not only antibacterial sulfamides
but also antidiabetic sulfamides or some diuretics with sulfamide structure.
All 4 immunological mechanisms for producing an allergy can be involved in
the production of allergic reactions.

Drug allergies often occur through the type I, or anaphylactic,

mechanism, which involves the formation of immunoglobulin E-type
antibodies.

Sometimes allergies can be caused by a type II or cytotoxic

mechanism, in which the drug binds to certain proteins on the cell
surface, modifies them structurally and turns them into antigens. This
results in the synthesis of immunoglobulin G-type antibodies directed
against the respective cells.

There are also situations in which allergic reactions occur through a

type III mechanism that involves the formation of circulating antigen
(drug) -antibody immune complexes, which are deposited in small
vessels in the kidneys, joints, etc.

Finally, a type IV mechanism may occur, which consists in sensitizing

T-type lymphocytes, producing delayed-type adverse reactions. The
manifestations are usually cutaneous, the most characteristic being the
contact dermatitis, caused for example by antibiotics with local
application such as neomycin, gentamicin and others.