GENERAL PHARMACOLOGY
* Pharmacology - the science of the interaction of chemical
compounds from living organisms. In general pharmacology
studies drugs used to treat and prevent various diseases and
pathological conditions. One of the major problems of
pharmacology is to find new drugs.
* The search for new drugs developed in the following areas.
* The chemical synthesis of drugs
* II. Receipt of drugs from medicinal plants and the selection of
individual substances:
* 1) animal origin;
* 2) vegetable origin;
* 3) mineral.
* III. Isolation of drugs, which are products of vital activity of
fungi and microorganisms.
* As a biomedical science, pharmacology closely
related to the different areas of experimental
and practical medicine. Thus, pharmacology
has a great influence on the development of
many other biomedical sciences, especially
physiology and biochemistry. For example,
using Wegetotropona substances could reveal
subtle mechanisms of synaptic transmission is
carried out with the participation of
neurotransmitters acetylcholine and
norepinephrine.
* Many complex functions of the central nervous
system have become available for the study due to
psychotropic drugs: the discovery of hallucinogenic
drugs has led to the creation of animal models of
psychosis. For experimenters core value of
pharmacological agents is that they represent a
great deal of control many biochemical and
physiological processes.
Very large value of Pharmacology for practical
medicine. As a result, creating a large range of
high-performance products pharmacotherapy has
become a universal treatment for many diseases.
* Broader meaning in medicine have received funds, depressing
and stimulating the central and peripheral nervous system,
raising and lowering blood pressure, stimulates heart activity,
breathing, regulating blood, metabolism, etc. The important
role played by antimicrobial and anti-parasitic drugs used for
the treatment and prevention of infectious diseases.
Progress pharmacology inevitably affects the development of
clinical disciplines. Thus, the emergence of tools for
anesthesia, anesthetics, curariform funds ganglioblokatorov
and other drugs contributed to the success of surgery. A
qualitatively new stage in the development of mental health
associated with the discovery of psychotropic substances.
Isolation and synthesis of hormonal methods have significantly
changed the results of treatment of patients with endocrine
diseases.
* General pharmacology is the study of the common patterns of
drugs pharmacokinetics and pharmacodynamics.
Pharmacokinetics (from the Greek. pharmacon - medicine,
kineo - move) - this section pharmacology of absorption,
distribution in the body, depositing, metabolism and
excretion of substances. The main content of the
pharmacodynamics (from the Greek. pharmacon - medicine,
dynamis - force) - the biological effects of substances, as well
as localization and mechanism of action.
* Drug administration routes. Existing ways of bringing in is
usually divided into enteral (through the digestive tract) and
parenteral (bypassing the digestive tract).
* For enteral routes include introduction through the mouth
under the tongue, buccally, the duodenum, rectum (rectal).
* For parenteral introduction of routes include subcutaneous,
intramuscular, intravenous, intra-arterial, intrasternalny,
intraperitoneal, inhalation, subarachnoid, sub occipital and
some other.
* Effective treatment of bacterial infections has
become possible only after receiving antibiotics and
sulfa drugs. Organ transplant managed to carry out
mainly in connection with the creation of
immunosuppressive agents. Such examples are
many. All of them indicate the paramount role of
pharmacology in medicine today.
Progress pharmacology characterized by a
continuous search for and creation of new and
better drugs. Drug development begins with
research chemists and pharmacologists, creative
community that is absolutely necessary for "design"
of new drugs.
* The search for new drugs developed in the following areas.
1. Chemical synthesis of drugs
A. The direct synthesis:
1) reproduction of nutrients;
2) creation of anti-metabolites;
3) the modification of the molecules of compounds with known
biological activity;
4) a combination of structures of two compounds with the desired
properties;
5) synthesis based on the study of chemical transformations of the
body.
B. empirical way:
1) random findings;
2) "screening".
II. Getting drugs from medicinal plants and isolation of individual
substances:
1) of animal origin;
2) of plant origin;
3) of the minerals.
* This is the most convenient and simple way of introduction.
Sterile preparation in this case not needed. Absorption
(absorption) of a number of substances (for example,
acetylsalicylic acid, barbiturates, and other weak electrolytes
that are acidic in nature) is part of the stomach (in the acidic
environment of the stomach, these compounds are found
mainly in the non-ionized (lipophilic) form and are absorbed
by diffusion). However, the vast majority of drug is absorbed
mainly in the small intestine. This favorable large suction
surface of the intestinal mucosa (approx. 200 m2) and its
intense perfusion.
Known basic mechanisms of absorption:
* 1. Passive diffusion across the cell membrane. Determined by the
gradient of concentration of substances. In this way easily
absorbed lipophilic (mostly nonpolar) substance. The more
lipophilic substances, they are more easily penetrate through the
cell membrane (so-called isolated facilitated diffusion. It involves
transport system functioning without energy loss).
2. Filtration through membrane pores. The pore diameter of the
membrane of the intestinal epithelium is small (about 0.4 nm).
Therefore, water diffuses therethrough, some ions and small
hydrophilic molecules (e.g., urea).
3. Active transport (involved in this process of cell membrane
transport systems) is characterized by selectivity for certain
compounds, the possibility of competition between two substances
in a single transport mechanism saturability (at high
concentrations), the possibility of transport against a
concentration gradient and energy expenditure (metabolic poisons
inhibit active transport) . Active transport provides hydrophilic
absorption of polar molecules, some inorganic ions, sugars, amino
acids, pyrimidines.
* 4. When pinocytosis cell membrane invagination occurs with the
consequent formation of the bubble (vacuoles). Last full of liquid with
entrained large molecules of substances. Bubble migrates through the
cytoplasm to the opposite side of the cell, wherein the contents by
exocytosis bubble is expelled.
These mechanisms of passage of substances through the membrane are
universal in nature and are not only important for the absorption of
substances, but also for their distribution in the body and excretion.
The main mechanism of drug absorption in the small intestine is passive
diffusion. Minor role played by active transport. Filtration through a
cellular membrane pores virtually irrelevant. Absorption of certain
proteins and complex cyanocobalamin (vitamin B12) to biermerin is
apparently by pinocytosis.
Absorption from the small intestine is relatively slow. It depends on the
functional state of the intestinal mucosa and its motility and pH, the
quantity and quality characteristics of the intestinal contents. It is
important to bear in mind that the substance from the small intestine to
the liver (where part of inactivated or excreted in bile) and only then - in
general circulation. Note that some substances inside ineffective when
assigning as degraded by the enzymes of the gastrointestinal tract (e.g.,
insulin), as well as the particular reaction medium, especially in acidic
environment of the stomach (e.g., penicillin).
* If the drug is destroyed by stomach acid or is irritating to the
mucous membrane of the stomach, it is prescribed in special
dosage forms (capsules, pills) that are soluble only in the
small intestine.
Absorption of substances regulated as a special membrane
transporter - P-glycoprotein. It promotes the excretion of
substances into the lumen of the intestine and prevents their
absorption.
P-glycoprotein pump is also blood-brain barrier, kidney, liver,
placenta and other tissues. Therefore, this transportation
system affects many processes: absorption, distribution,
elimination.
Known inhibitors of P-glycoprotein - cyclosporin A, quinidine,
verapamil, itraconazole, and many others. There is evidence
that rifampin, an inducer of this transporter.
* Due to the fact that the substance developing a systemic effect only
after getting into the bloodstream, where it enters the tissue is
provided, the term "bioavailability". It reflects the amount of
unchanged substance has reached the blood plasma, relative to the
initial dose. In this case the bioavailability of enterally value
determined lossy substance at its absorption from the digestive
tract and first-pass hepatic barrier. To assess the bioavailability
usually measure the area under the curve, which reflects the
relationship between the concentration of the substance in the
blood plasma and the time since the rate is directly proportional to
the number of substances introduced into the systemic circulation.
Also determine the maximum concentration of free (active) of the
substance in the blood plasma and the time required to achieve it.
Biodostupnost substance when administered intravenously as 100%.
On bioavailability can be judged by the release of the drug in the
urine, provided it is not subject to biotransformation. In some
cases, the criterion may be the amount bioavailability
pharmacological effect if applicable its precise quantitative
measurement.
* With the introduction of the substance under the tongue - sublingual
(tablets, granules, drops) - suction starts pretty quickly. In this case,
the drugs have general action, bypassing the first hepatic passage
barrier and contact with enzymes and the environment of the
gastrointestinal tract. Sublingual designate certain substances with
high activity (single hormonal agents, nitroglycerin) where the dose is
low.
Sometimes drugs are administered by gavage to the duodenum (e.g.,
magnesium sulfate as a choleretic), which allows to quickly create a
high concentration of gut connection.
*
When administered into the rectum (per rectum) substantial part of the substance (about 50%) goes
into the bloodstream, bypassing the liver. Moreover, in this way the introduction substance is not
exposed to enzymes of the digestive tract. Absorption from the rectum occurs by simple diffusion.
Rectally administered drugs into suppositories or enemas drug (volume 50 ml). If the substance is
irritating effect, they are combined with mucus.
Medicinal substances having the structure of proteins, fat and polysaccharides in the colon are not
absorbed.
Rectal use of substance and for local effects.
For parenteral routes of administration include subcutaneous, intramuscular, intravenous,
intraarterial, intrasternal, intraperitoneal, inhalation, subarachnoid, suboccipital and others.
Parenteral routes of the most common is the introduction of substances under the skin, into the
muscle and veins. Effect occurs especially quickly when administered intravenously, is somewhat
slower - intramuscular and subcutaneous administration. In order to prolong the effect of
pharmacotherapeutic drugs injected into a muscle in the form of poorly soluble (suspension) in oil
or other grounds, delaying absorption of substances from the site of administration.
Intramuscular and subcutaneous should not introduce substances which have a pronounced irritant
effect, as this can cause inflammatory reactions and even necrosis infiltrates.
*
Intravenously administered drugs are usually slow. Possible single, fractional, and a drip infusion.
Should not be administered intravenously insoluble compounds, oil solutions (possibility of embolism),
funds with a strong irritant (could lead to the development of thrombosis, thrombophlebitis), drugs
that cause blood clotting or hemolysis.
Negative aspects of these three routes of administration are their relative complexity and morbidity,
the need for sterile preparations and participation of medical personnel.
Intra-arterial injection can create in the area of the artery that supply blood to high concentrations of
the substance. In this way, sometimes introducing an antineoplastic. In order to reduce their overall
toxicity blood flow may be artificially difficult (by compression of veins). Also administered intraradiopaque agents that can accurately determine the location of the tumor, blood clot, constriction of
blood vessels, the aneurysm.
Intrasternal injection path (in the sternum) is usually used in technical impossibility intravenous
(children, elderly people).
Intraperitoneal formulations administered infrequently (for example, antibiotics during celiac
operations).
Sometimes the medicines prescribed intrapleural (the pleural cavity).
For gaseous and volatile compounds is a major inhalation route of administration. In the same way, and
some are administered aerosols. Light - a vast absorption band (90-100 m2), receives abundant blood
supply, so the absorption of substances from inhalation is rapid. The severity of the effect is easily
controlled by changing the concentration of substances in the breathing air.
* Deposition
After absorption of the substance into the blood and then to various organs and tissues.
Most drugs are unevenly distributed and only a small part - relatively evenly (for example,
some funds for inhalation anesthesia). Significant impact on the distribution of substances
have biological barriers, which are found in the way of their distribution: the capillary
wall, cell (plasma) membrane, the blood-brain and placental barriers.
Through the wall of the capillaries, which has the character of a porous membrane (pore
size in a person's average is 2 nm), the majority of drugs takes place quite easily.
Exception of plasma proteins and their complexes with drugs. Hydrophilic compounds are
readily soluble in water, pass through pores of the capillary walls and fall into the
interstitial space. A protein-phospholipid cell membranes they practically do not diffuse
(inside the cells can enter only if participation transport systems). Lipophilic compounds
pass through the fine capillary endothelium and the cell membrane.
* Difficult passage of many substances through the blood-brain barrier. This
is due to the structure of the capillaries of the brain. Prezhde of their
endothelium has pores through which the capillaries extend to many
common materials. In the capillaries of the brain is practically no
pinocytosis. Have a certain value and glial elements (astroglia) lining the
outer surface of the endothelium and, obviously, playing the role of an
additional lipid membrane. After the blood-brain barrier poorly polar
compounds tested. Lipophilic molecules penetrate into the brain tissue
easily. Basically substances pass through the blood-brain barrier by
diffusion, and some compounds - by active transport. There are some
small parts of the brain (the region epiphysis, posterior pituitary, and
others) in which the blood-brain barrier is practically ineffective. It
should also be borne in mind that in some pathological conditions (e.g.
inflammation of the meninges) increased permeability of the blood-brain
barrier.
* Some drugs (in particular, quinacrine), especially in large quantities in the cell
detected depot. Binding of the cells possibly due to protein, nucleoprotein and
phospholipids.
Fat depots are of particular interest because they may be retained lipophilic
compound (in particular, some means for anesthesia).
Deposited drugs, usually at the expense of convertible bonds. Length of stay in the
tissue depots varies widely. Thus, some sulfonamides (sulfadimethoxine, etc.) form
stable complexes with plasma proteins, with which a considerable part of the length
of their associated actions. Very long trapped in the body of heavy metals ions.
Note that the distribution of substances not usually characterizes the direction of
their action. The latter depends on the sensitivity of tissues to them, i.e. the
affinity of the drug to those biological substrates, which determine the specificity of
their action.
In clinical pharmacology often use the-apparent volume of distribution - Vd. It
reflects the hypothetical volume of liquid in which material is distributed (arbitrarily
assumed that the concentration in plasma and other body fluids the same).
The volume of distribution gives an indication of the fraction of a substance in the
blood plasma. For lipophilic compounds easily penetrate tissue barriers and having a
broad distribution (plasma, interstitial fluid, intracellular fluid in) are characterized
by high value Vd. If a substance mainly circulates in blood, Vd has low values. This
parameter is important for efficient dispensing of substances, as well as to
determine the elimination rate constant (Ke | jm) and "half-life" of a substance (t1 /
2).
*
Chemical conversions (biotransformation, metabolism) of drugs in the
body
Most drugs undergoes biotransformation in the body. Unchanged for
vysokogidrofilnyh mostly ionized compounds. Of lipophilic substances,
with the exception of funds for inhalation anesthesia, most of them in the
chemical reactions in the body does not enter. These light output in the
same form in which have been introduced. In the biotransformation of
drugs involved many enzymes, of which the most important role is played
by the liver microsomal enzymes (located in the endoplasmic reticulum).
They are foreign to the body metabolize lipophilic compounds (different
structure), making them more hydrophilic. Substrate specificity they do
not. Are essential and different localization nemikrosomalnye enzymes
(liver, intestine and other tissues and plasma), especially in the case of
hydrophilic substances biotransformation.
Allocate two main types of drugs conversion: 1) metabolic transformation,
and 2) the conjugation. Metabolic transformation - is the transformation
of substances due to oxidation, reduction and hydrolysis. Thus, oxidation
are imipramine, ephedrine, chlorpromazine, histamine, codeine.
Oxidation occurs mainly due to the microsomal mixed oxidase activity
with the participation is necessary, oxygen, and cytochrome P-450.
* Conjugation - is a biosynthetic process, accompanied by
adherence to the drug substance or its metabolites or
grupirovok number of chemical molecules endogenous
compounds. For example, methylation may be substances
(histamine, catecholamines) or acetylation (sulfanilamidy)
interaction with glucuronic acid (morphine, oxazepam),
sulfates (chloramphenicol, phenol), glutathione
(paracetamol), etc.
In the process of conjugation involves many enzymes:
glyukuroniltransferazy, sulfotransferase, transatsilaza,
methyl transferase, glutathione-5-transferase, etc.
Conjugation may be the only way of transformation of
substances or she follows its predecessor metabolic
transformation.
*
When metabolic transformation and conjugation agents pass more polar and more
soluble metabolites and conjugates. It is conducive to their further chemical
transformations, if they are needed, and promotes their excretion from the body. It is
known that the kidneys are derived hydrophilic compounds, whereas the lipophilic
highly exposed to the renal tubular reabsorption of (reabsorption)
As a result of metabolic transformation, and conjugation of drugs usually lose their
biological activity. Thus, this process is limited in time action substances. In the
pathology of the liver, accompanied by decreased activity of microsomal enzymes, the
duration of action of a number of substances increases. Known inhibitors and various
enzymes such as microsomal (chloramphenicol, phenylbutazone) and nemikrosomalnyh
(anticholinesterase agents, MAO inhibitors, etc.). They prolong the effects of drugs
which are inactivated by these enzymes. However, a compound (e.g., phenobarbital)
that increase (induce) the synthesis rate of microsomal enzymes.
In some cases, chemical reactions of drugs in the body may lead to increased activity
of the compound (imipramine <desipramine), increased toxicity (phenacetin
<phenetidine), change mode of action (one of the metabolites is iprazida
antidepressant isoniazid having antitubercular activity), as well as conversion of one
other active compound (partially converted codeine to morphine).
Ways elimination of drugs from the body