Ministry of Education and Science of Ukraine
Ministry of Public Health of Ukraine
Sumy State University
DRUGS INFLUENCING
THE FUNCTIONS OF INTERNAL
ORGANS
Course of Lectures on Pharmacology
for the students of speciality 7.110101 "Medical science"
of the full-time course of studies
Part 2
Approved
by the session of biophysics,
biochemistry, pharmacology,
and biomolecular engineering
department
as a course of lectures
on Pharmacology.
Minutes №25 of 13.05.2013
Sumy
Sumy State University
2014
Drugs influencing the functions of internal organs : course of
lectures on Pharmacology. Part 2 / compilers : I. Yu. Vysotsky,
R. A. Chramova, A. A. Kachanova, L. F. Sukhodub, V. L. Vigunov. Sumy : Sumy State University, 2014. - 93 p.
Biophysics, biochemistry, pharmacology, and biomolecular
engineering department.
DRUGS INFLUENCING DIGESTIVE SYSTEM
Drugs Influencing Appetite
Appetite is an emotional feeling about human desire to eat
certain foods. Appetite is realized by neurohumoral way. Nervous
system has the predominant role in this regulation. Appetite is under
control of hunger centre (lateral nuclei of the hypothalamus) and
saturation centre (ventromedial nuclei of the hypothalamus). These
centres receive impulses from the gustatory, visual, and olfactory
systems. An appetite largely depends on the state of cortex and
limbic system.
The primary importance in the regulation of appetite belongs to
such mediators as noradrenaline, serotonin, and dopamene influecing
the appropriate receptors (β1- and β2-adrenergic receptors, α1adrenergic receptors, 5-HT1B and 5-HT2C-serotoninergic receptors,
D1-dopaminergic receptors). Besides, specific neuropeptides
regulating appetite and energetic balance are in hypothalamus.
Appetite-increasing substances (orexigens) are neuropeptide Y,
orexigens A and B, ghrelin (stomach peptide which after absorption
in the blood stimulates growth hormone production by
hypothalamus), hormone stimulating the growth hormone secretion,
GABA, etc.
There are substances which reduce appetite (anorexigenous
substances). They are leptin (hormone of fatty cells which penetrates
into the brain and stimulates production of anorectic substances by
hypothalamus and simultaneously inhibits the secretion of orexigenic
substances),
α-melanocyte-stimulating
hormone,
hormones
stimulating release of thyrotropin, neurotensin, serotonin,
cholecystokinin, glucagon-like compounds, etc.
Drugs Increasing Appetite
Appetite is stimulated by means of taste and extractive
substances of pepper, cinnamon, cloves, bay leaf, garlic, onion,
horseradish, dill, mustard, etc. Broth, vegetable broths, juices,
mineral water, dry wine also have stimulating influence upon
appetite.
Medicines used for stimulation of appetite include bitters:
tinctures of wormwood, centaury ordinary, water shamrock, rhizome
of calamus, etc. These drugs are taken 15 minutes before meals.
Mechanism of drugs action is the following. Bitters stimulate
receptors of oral cavity that results in increase of reflex excitability
of hunger centre. Owing to this, first (complex-reflex) phase of
gastric secretion is enhanced.
Drugs increasing appetite also include insulin, aminazinum,
amitriptyline, lithium carbonate, clophelinum, and anabolic steroids.
Drugs Decreasing Appetite
(Anorexic or Anorexigenic Drugs)
Anorexigenic drugs are used for treatment of alimentary obesity.
This disease is accompanied by disturbances of metabolism, which
result in increased hazard of diabetus mellitus, cardio-vascular
diseases, etc.
The main method of obesity treatment is the decrease of amount
of food with high energy value and the increase of physical activity.
Drugs which decrease the appetite and are used for treatment of
obesity are called anorexigenic drugs or appetite suppressants.
According to mechanism of action these drugs are classified into the
following groups:
1. Drugs stimulating catecholaminergic system of brain:
amphetamine, phepranone, desopimone, mazindole.
2. Drugs stimulating cerotoninergic system of brain:
fenfluramine, dexfenfluramine.
3. Drug stimulating both catecholaminergic and serotoninergic
systems of brain: sibutramine.
4. Inhibitor of gastrointestinal lipases: orlistat.
Active anorexigenic drug is amphetamine (phenaminum). It
is a derivative of phenylalkylamine. Drug has central and peripheral
adrenomimetic action. Phenaminum increases the release of
noradrenaline and dopamine by neurine endings and supresses
reuptake of these neurotransmitters. It results in excitation of central
adrenergic and dopaminergic neurons and reduction of feeling of
hunger. Simultaneously drug excites other central and peripheral
neurines which results in number of undesirable effects: insomnia,
agitation, tachycardia, increase of blood pressure. The use of
phenaminum can result in physical and psychical dependence. In
connection with the above-mentioned, phenaminum is not used as
anorexigenic drug.
Phepranone is a derivative of phenylalkylamine. Drug has
identical mechanism of action with phenaminum. But phepranone
less stimulates central and peripheral nervous systems. Phepranone is
prescribed 30–60 minutes before meal. Because drug can cause
insomnia, it should be taken in the first half of the day. Possible side
effects are agitation, insomnia, tachycardia, increase of blood
pressure. In case of chronic use of phepranone, the tolerance and
drug dependence can develop.
.
Fenfluramine selectively acts in the area of serotoninergic
receptors and inhibits neuronal reuptake of serotonin. Drug inhibits
central nervous system and increases blood pressure.
Sibutramine simultaneously inhibits neuronal reuptake of
adrenaline, serotonin, and dopamine. Drug decreases the level of uric
acid and lipid in the blood. During treatment with sibutramine such
side effects can be observed: tachycardia, sleep disturbances,
headache, and increased excitability of central nervous system.
One of the ways of treating obesity is decrease of intestinal
absorption of lipids. It is achieved by inhibition of lipase activity
(enzyme which is necessary for lipid absorption). This mechanism of
action is typical for orlistat. Drug inhibits lipase in stomach and
intestine that results in reduction of hydrolysis of dietary
triglycerides. In result, the absorption of lipids is decreased by 30%.
Orlistat also inhibits the absorption of lipid-soluble vitamins.
Approximately 83% of absorbed drug dose is excreted through
intestine in unchanged state. Full elimination of orlistat occurs during
3–5 days. Side effects depend on triglycerides level in food. The
urging to stool, abdominal pain, diarrhoea, nausea, and vomiting are
possible.
Restriction use of sugar or use of sweetener (saccharin, etc.) is
also recomemded for decrease of calorie food.
Recently, hormon of fat cells leptin is recommended for
reduction of appetite. Its administration promotes the lowering of
body weight in patient with obesity. But drug is effective only in
patients with deficiency of endogenous leptin.
Melanocortin also inhibits an appetite owing to interaction
with specific MC4-receptors. Other agonists of these receptors also
have anorexigenic effect.
Cholecystokinin is also noteworthy. Besides the regulation of
functions of digestive system, this hormon also acts as saturation
factor. Series of compounds activating the cholecystokinin system
are now being studied.
But it is necessary to undestand, that pharmacotherapy of obesity
has auxiliary character and the base of obesity treatment is
combination of low-calorie diet with additional physical activity.
Drugs Influencing Function of Salivary Glands
Salivary glands secretion is under control of both
parasympathetic and sympathetic nervous systems. The tone of
parasympathetic nervous system is predominante; therefore
stimulation of M-cholinoceptors, located in salivary glands,
determines the degree of salivation.
Drugs with M-cholinomimetic activity (proserinum,
carbacholine, pilocarpine, aceclidine, etc.) increase
salivation. Cholinoblocking drugs (atropine, scopolamine, etc.)
inhibit salivation. Drugs with blocking activity are used practically
more commonly for reduction of hypersalivation in patients with
Parkinson disease, helminth infestation, and poisoning with heavy
metals.
Drugs Used in Hyposecretion of Stomach
Mucosa of stomach secretes several enzymes, the main of which
is pepsinogen. The acidic environment is necessary for
transformation of it to active pepsin. Necessary acidity is achieved
owing to secretory activity of parietal cell producing hydrochloric
acid (precisely, ions of hydrogen).
Hypofunction of gastric glands occurs in 10–15 % of practically
healthy people. Sometimes, it is only insufficient secretion of
hydrochloric acid, but quite often it combines with hyposecretion of
pepsinogen. Hyposecretion can cause inflammation with
development of hypoacid gastritis.
Vagus nerve and several gastrointestinal hormones regulate the
stomach secretion. It is known, that the increase of vagal tone and the
release of gastrin and histamine result in the elevation of gastric
secretion. In turn, reduction of cholinergic influence and supression
of gastrin or histamine release cause the decrease of gastric juice
secretion. Endogenous substances supressing gastric secretion are
secretin, cholecystokinin, prostaglandins, vasoactive intestinal
peptide, peptide inhibiting gastric secretion, etc.
Administration of gastrin, histamine or extractive substances can
significantly increase gastric secretion in patients with hypoacid
gastritis which is caused by functional disorders. But administration
of these substances does not result in secretion increase in patients
with organic lesions of the gastric mucosa. Thereby, these substances
may be used for diagnostic aim.
Pentagastrin is a synthetic analogue of histamine. Drug
stimulates gastric secretion. Pharmaceutical industry produces
0.025% ampular solution of pentagastrin. Drug is administered
subcutaneously for diagnosis of secretory activity of the stomach. Its
administration gives possibility to estimate the secretory ability of
stomach and to determinate the character of stomach damages. In the
patients with functional insufficiency of gastric mucosa pentagastrin
increases the secretion. But in patietns with organic diseases of the
stomach the secretion is not increased.
Attempts to increase secretion have low efficiency or are
completely ineffective in patients with hypoacid gastritis which is
accompanied by atrophic process. Therefore, treatment of patients
with such pathological states needs the drugs of substitutive therapy.
For this aim, such drugs as natural gastric juice , pepsin,
diluted hydrochloric acid, acidin-pepsin, and abomin are
used.
The most physiological drug is natural gastric juice, which
is obtained from animals. It is taken during meal in dose 1 table
spoon. Artificial gastric juice (obtained by insisting of stomach
mucosa of pigs in 0.2–0.5 % solution of hydrochloric acid) has less
activity. It is taken also during meal in dose 1–2 table spoons.
Abomin is tableted drug obtained from gastric mucosa of calves
and lambs. It is taken during meal in dose 1–2 tablets. Course of
treatment is 1–3 months. Abomin contains several of proteolitic
gastric enzymes. The treatment with this drug needs simultaneous
intake of hydrochloric acid.
Pepsin is obtained from gastric mucosa of pigs. Mixture of
pepsin and hydrochloric acid is used during meal in dose 1 table
spoon.
Hydrochloric acid is used in hypoacid gastritis without
deficiency of pepsin. Diluted standard solution of hydrochloric acid
is taken during meal in dose 10–15 drops with ½ glass of water. This
solution in recommended to take through tubule for prevention of
tooth enamel destruction. Organic acids (malic, citric, or acetic) are
also used in hypoacid gastritis. These acids realease hydrogen ions in
stomach and undergo absorption and energy metabolism in body.
The use of acidic foods, such as sauerkraut, fruits, etc. also is
recommended.
Acidin-pepsin is used in patients with hypoacid gastritis. One
tablet of drug is dissolved in ½ glass of watet and is taken during or
immediately after eating.
Drugs Used in Hypersecretion of Gastric Glands and
in Disturbances of Trophism or
Regeneration of Gastric Mucosa
These drugs are used in patients with hyperacid gastritis, ulcer
disease of stomach and duodenum. According to studies,
approximately 10% of 30–55-year-old males and 6% of females
under 55 years suffer from ulcer disease. Ulcer disease lasts for years
and is characterized by periods of exacerbation and remission.
According to modern ideas, ulcer disease is a result of imbalance
between protective and agressive factors influecing upon the stomach
mucus.
Acid-peptide (predominant role of hydrochloric acid) and
bacterial (Helicobacter pylori) factors play a key role between
agressive factors. Other agressive factors are bile components, such
drugs as nonsteroid anti-inflammatory agents and glucocorticoids,
thermal and mechanical lesions of the mucous membrane, frequent
stressful situations, etc.
Protective factors include such factors as mucosal barrier,
microcirculation, regenerative ability of mucous membrane of
stomach and duodenum, bicarbonate secretion, etc.
Considering the above factors, the main aims of ulcer disease
therapy are:
- decrease of acid-peptide aggression;
- antibacterial therapy against Helicobacter pylori;
- increase of protective abolity of mucous membrane of stomach
and duodenum;
- stimulation of regeneration on the ulcer surface.
Drugs Decreasing Secretory Activity of Gastric Glands
This group occupies the central position in treatment of ulcer
disease of stomach and duodenum, hyperacid gastritis, esophagitis,
and Zollinger-Ellison syndrome. It is necessary to consider the
mechanisms of secretion regulation at the cellular level to understand
the mechanisms of drugs action.
Secretion of gastric juice occurs continuously throughout the day
(nearly 2–3 L a day) and sharply increases during digestion. Mucous
membrane of stomach contains 3 types of cells: сhief cells (secreting
pepsinogen), parietal cells (secreting hydrogen ions), and mucous
cells (secreting mucin and bicarbonate). In membranes of parietal
cells such receptors are located as M2-cholinergic, H2-histaminergic,
and gastrinergic. Stimulation of these receptors causes an increase of
proton pump activity. In turn, proton pump secretes hydrogen ions
into the stomach. An increase of acidity of gastric juice promotes
transformation of pepsinogen to pepsin. Acetylcholine, gastrin, and
histamine also increase the secretion of сhief cells. M-cholinolytics,
blockers of H2-histamine receptors, and proton pump inhibitors are
used for decrease of secretion of these cells. Especially pronounced
therapeutic effect of these drugs is observed in patients with ulcer
disease of duodenum, in which acid-peptic factor is greater.
Drugs which decrease the gastric secretion are devided into the
following groups:
1. M-cholinoceptor antagonists:
- drugs of nonselective action: atropine, platyphyllin ,
methacin;
- drugs which inhibit predominantly M1-cholinoceptors:
pirenzepine, telenzepine.
2. H2-histaminergic
receptor
antagonists:
cimetidine,
ranitidine, famotidine, nizatidine, roksatidine.
3. Proton pump inhibitors: omeprazole, pantoprazole,
lansoprazole, rabeprazole, esomeprazole.
4. Prostaglandins and their synthetic analogues: misoprostol.
5. Gastrin receptor antagonists: proglumide.
M-Cholinoceptor Antagonists
This group includes atropine, platyphyllin, methacin,
pirenzepine, and telenzepine. Depending on the affinity of the
different types of M-cholinoceptors these drug are devided into
selective (which block only M1-cholinoceptors) and nonselective
(which block all types of M-cholinoceptors) M-cholinergic
antagonists. Nonselective drugs (atropine, platyphyllin,
methacinium) are the first agents which were used for treatment of
ulcer disease and hyperacid gastritis. Mechanism of these drugs
action is associated with blockage of M2-cholinergic receptors which
are located in membranes of the cells of mucous membrane of
stomach and in the cells of smooth muscles of gastrointestinal tract.
Drugs eliminate vagal influence predominantly upon basal and
nocturnal secretion. These drugs have less influence upon stimulated
secretion. Drugs influence results in the decrease of volume of
gastric juice as well as concentration of hydrochloric acid in it.
However, drugs at the same time reduce the tone of stomach and
intestine and increase the time of gastric emptying. These effects
result in activation of gastric secretion owing to gastric distension.
Clinically significant antisecretory effect of M-cholinergic
antagonists develops in case of high degree of blockage of
M-cholinergic receptors. As a rule, such degree of blockage is
accompanied by side effects (constipation, dry mouth, disturbances
of accomodation, tachycardia, etc.). Therapeutic effect of
M-cholinergic antagonists quickly reduces owing to tolerance.
Practically, such nonselective drugs are used as tincture and
extract of Belladonna; tablets and injections of atropine, platyphilin,
methacinium, etc. Combination drugs are used: “Bekarbon”,
“Bellastezin”, “Bellalgin”, etc. Non-selective drugs are used for
reduction of hypertonus of pyloric section with delayed food
evacuation and cramping (spasmodic pains).
Pirenzepine and telenzepine, selective M1-cholinergic
antagonists, are mainly used presently. These drugs are characterised
by higher affinity to M1-cholinergic receptors of parasympathetic
ganglia of stomach. It results in low probability of side effects.
Moreover, there is evidence that selective M-cholinergic antagonists
increase the mucosal resistance to damaging factors.
Pirenzepine is administered parenterally and prescribed orally.
Drug bioavailability in gastrointestinal tract is 20–30%. Maximal
concentration in blood is achived in 2 hours after drug intake. In
blood, pirenzepine binds in insignificant degree with plasma
proteins. Drug is excreted predominantly with bile in unmodified
form. Pirenzepine is prescribed two times a day for 15–20 minutes
prior to meal. Prolonged drug use can cause side effects which is
typical for nonselective M-cholinergic antagonists: dry mouth,
tachycardia, etc.
Telenzepine has 25 times more activity than pirenzepine. Drug
significantly suppresses secretion of not only gastric glands, but also
salivary. The use of telenzepine is restricted.
H2-Histaminergic Antagonists
H2-histaminergic antagonists are divided into 5 generations:
I generation: cimetidine.
II generation: ranitidine (Zantac).
III generation: famotidine (Quamatel).
IV generation: nizatidine (Axid).
V generation: roxatidine (Roxane).
This classification is based on different pharmacological activity
of drugs, differences in pharmacokinetics, and side effects.
These drugs block H2-histaminergic receptors at competitive
type. Degree of drugs affinity to H2-receptors is significantly higher
in drugs of II–V generation. This makes it possible to prescribe drugs
in significantly less doses. H2-histaminergic antagonists inhibit basal
and nocturnal secretion, as well as secretion stimulated by food,
gastric distension, histamine, etc. Drugs increase the production of
prostaglandin E2 by the mucosal membrane of stomach and
duodenum. It results in gastroprotective effect, owing to which drugs
promote the ulcer healing.
It must be borne in mind, that discontinuation of drug intake
(except for nizatidine and roxatidine) can result in rebound
syndrome. The causes of this phenomenon include hypergastrinemia
which is developed owing to decrease of gastric juice acidity, and
increase of density of H2-histaminergic receptors and its affinity to
histamine. Therefore, discontinuation of therapy with these drugs
should be gradual. Doctor should gradually decrease prescribed dose
and prescribe simultaneously other agents with antisecretory activity.
H2-histaminergic antagonists are used intravenously and orally.
Their bioavailability from gastrointestinal tract varies from 50 to
90%. Degree of binding with plasma proteins is 15–20 %. Drugs
easily penetrate placenta and can be secreted with breast milk.
Cimetidine also easily penetrates through blood brain barrier.
Duration of cimetidine effect is 6 hours, ranitidine – 8–12 hours,
famotidine – 12–24 hours, nizatidine and roxatidine – more than 24
hours. Cimetidine is prescribed 4 times a day (3 times after meal and
once at night), ranitidine – 2 times a day (in the morning 30 minutes
before meals and at night), famotidine and other drugs – once a day
at night. Course of treatment lasts from 4 to 6 weeks.
50% of administered dose of cimetidine undergoes
biotransformation. Ranitidine is metabolized in less degree.
Famotidine and other drugs are not metabolized practically. The
main route of excretion from the body is kidneys. Cimetidine is lowactive, short-acting, and rather toxic drug.
Combined drug ranitidine bismuth citrate (Pilorid) blocks
H2-histaminergic receptors and also has high bactericidal activity
against Helicobacter pylori.
Indications for clinical use of H2-histamenergic antagonists are
the following:
1. Ulcer disease of stomach and duodenum.
2. Hyperacid gastritis.
3. Duodenitis, esophagitis, and other diseases which are
accompanied by increasing secretion of hydrochloric acid.
4. Prevention of ulcers and erosions in patients with
craniocerebral traumas, sepsis significant burns, etc.
5. Emergency in bleeding ucers of stomach, duodenum, and
esophagus.
Side effects of H2-histaminergic drugs are diarrhoea,
constipation, skin rash, headache, myalgia, and dizziness. These
effects are more common in case of cimetidine use. Besides,
cimetidine blocks androgen receptors that can results in impotetion
and disturbances of spermatogenesis. If drug is prescribed to
pregnant woman, adrenogenital syndrome can develop in newborn.
Cimetidine decreases secretion of honadotropic hormones and
increases prolactin level. It can be the cause of gynecomastia,
galactorrhoea, and macromastia. II–V generations of drugs do not
have antiandrogenic activity.
In result of binding with H2-histaminergic receptors of blood
cells, drugs can cause leukopenia, thrombocytopenia, haemolytic
anaemia. Aggrevations of bronchial asthma, cutaneous
manifestations of lupus erythematosus, etc. are possible owing to
blockage of H2-histaminergic receptors in the membranes of tissue
basophils.
It is necessary to notice, that prolonged artificial decrease of
gastric acidity promotes cancerogenesis.
Proton Pump Inhibitors
Proton pump inhibitors include omeprazole, pantoprazole ,
lansoprazole, rabepr azole, and esomeprazole.
Independently of mode of stimulation (acetylcholine, histamine,
gastrin, etc.), the single way of hydrochloric acid secretion exists. It
is reliased on the level of membranes of parietal cells by means of
energy-dependent exchange of potassium ions and hydrogen ions.
Specific H+,K+-ATPase exists in these membranes and provides
production of hydrochloric acid in stomach and entry of potassium
ions into the blood.
Based on these data, drugs blocking the activity of H+,K+ATPase were established. All of them are prodrugs. In acidic
environment near parietal cells, these drugs are transformed to active
metabolites – sulfenamides, which interact with sulfhydryl groups of
H+,K+-ATPase. Proton pump inhibitors markedly decrease basal,
nocturnal, and stimulated secretion of hydrochloric acid. These drugs
are also effective in cases which are resistive to the use of
M-cholinergic and H2-histaminergic antagonists. It should be noted,
that these drugs also suppress the activity of H+,K+-ATPase of
Helicobacter pylori that results in bacteriostatic effect.
A use of proton pump inhibitors causes the increase of gastrin
concentration in the blood. Therefore, sudden cessation of drug
intake can cause the rebound-syndrome. In this regard, cessation of
proton pump inhibitor intake should be fulfiled in patients receiving
antacid drugs.
Proton pump inhibitors are administered intravenously or taken
orally prior breakfast. Drugs are poorly absorbed in acidic
enviroment; therefore its intake should be together with intake of
sodium hydrocarbonate. Enteric-soluble granules of drugs are
protected by means of gelatin capsules from hydrochloric acid.
Therefore, it is impossible to chew them. Bioavailability of drugs is
35–50 %. The degree of drugs binding with plasma proteins is nearly
95%. Proton pump inhibitors undergo the hepatic biotransformation.
Maximum effect develops in 1–2 hours after drugs intake. Because
proton pump inhibitors are weak base, they fastly undergo absorption
and accumulation in acidic environment of parietal cells. Drugs of
this group are prescribed once a day. Effect of drugs persists during
24 hours (sometimes up to 3–4 days). Such long-time effect is due to
irreversible inhibition of proton pump. Thereby, a new synthesized
enzyme is needed for restoration of secretion.
The indications for use for proton pump inhibitors are identical
with indications for H2-histaminergic antagonists.
During treatment with proton pump inhibitors the following side
effects are possible: headache, drowsiness, dizziness, diarrhoea or
constipation, and abdominal pain. These phenomena arise owing to
the first drug intake and disappear in 1–2 days. Cases of vission and
hearing loss are discribed in case of intravenous drug administration.
Long-time administration of proton pump inhibitors is accompanied
by risk of mucous membrane hyperplasia with formation of
carcinoids in submucosal layer of stomach.
Prostaglandins and Their Synthetic Analogues
Drugs of this group exhibit two dose-dependent effects. Low
doses of drugs cause gastroprotective effect owing to the increase of
secretion of bicarbonates and mucus and microcirculation improving.
Large doses of drugs cause blockage of hydrochloric acid secretion.
Representative of this group is misoprostol (synthetic analogue of
prostaglandin E1). Drug blocks both basal and stimulated secretion of
hydrochloric acid and exhibits gastroprotective effect. Misoprostol is
used in treatment of erosions and ulcer disease of stomach and
duodenum. Drug is taken in tablets 3–4 times a day (during meal and
at night). Course of treatment lasts 3–8 weeks. Side effects of
misoprostol are abdominal pain, meteorism, diarrhoea, allergic
reactions, decrease of blood pressure, etc.
Blockers of Gastrin Receptors
Representative of this group is proglumide. Agent inhibits
gastrointestinal motility and reduces gastric secretions.
Despite years of searching of inhibitors of gastrin receptors and
creation of several agents with this type of action, clinical use of
these drugs is not widely spread. Non-selective blocker of gastrin
receptors proglumide blocks both subtypes of gastrin receptors –
CCKA and CCKB. Antisecretory activity of proglumide is equivalent
to the first generation of H2-histaminergic antagonists. But
proglumide has fewer side effects. Selective antagonists of gastrin
receptors lorglumide and devazipid are not used in clinical practice.
Gastroprotective Drugs
This group includes drugs with different chemical structure and
mechanisms of action, which provide protection of gastric mucosa
from aggressive influence. Also, gastroprotectors create conditions
for ulcers healing or stimulate it. Basically, gastroprotectors are used
for treatment of ulcer disease of stomach and duodenum.
Gastroprotectors are devided into two subgroups:
1. Drugs creating mechanical protection of gastric mucosa:
sucralfate, De-nol, bismuth subsalicylate.
2. Drugs increasing protective properties of mucous barrier and
the stability of gastric mucosa: carbenoxolone, misoprostol.
Sucralfate (Venter) is sulfated disaccharide in complex with
aluminum hydroxide. Agent is polymerized in acid enviroment of
stomach. Polymerized molecules have significant negative charge,
owing to which drug binds with positively charged protein radicals
of the damaged surface. The sucralfate concentration within the ulcer
area is 5–7 times more than on the healthy areas of mucosa.
Protective pellicle is held on the ulcer surface of stomach up to
8 hours and on the duodenal ulcer – up to 4 hours. Sucralfate is taken
4 times a day: 3 times 30 minutes prior the meal and once at night.
Duration of treatment is 4–6 weeks.
Sucralfate does not decrease the secretion of hydrochloric acid
and pepsin, but these substances can be absorbed on the surface of
drug.
Sucralfate intake can result in the following side effects:
discomfort in the epigastrium, dry mouth, itching and redness of the
skin. Sucralfate can decrese the intestinal absorption of phosphate
and fluoride.
Drug is contraindicated in pregnant women, children up to
4 years of age, and nursing mothers.
De-nol is colloidal bismuth subcitrate, which forms complex
with proteins in acid environment. Most of the drug is concentrated
in erosive area. Furthermore, the gastroprotective activity of de-nol is
connected with its ability to increase the local synthesis of
prostaglandin E2 by mucosa of gastric antral and duodenum. De-nol
also improves the microcirculation and stimulates the secretion of
hydrocarbonate. Drug has bactericidal effect against Helicobacter
pylori. Bacteria disappear from the mucosal surface in 30–90
minutes after de-nol intake. Pathogen completly is not detected after
3 weeks of treatment, but cessation of de-nol can be accompanied by
recolonization of Helicobacter pylori. Therefore, combination of denol with antibacterial drugs is most appropriate.
De-nol is taken in 30 minutes prior meal and at night. Course of
treatment lasts 4–6 weeks.
Side effects of de-nol are nausea, vomiting, diarrhoea, headache,
dizziness. Bismuth sulfide (formed in the intestines) stains tongue
and feces black.
Carbenoxolone is glyceric acid of licorice root. Drug
stimulates mucus secretion and increases its viscosity. Furthermore,
carbenoxolone inhibits enzymes which participate in prostaglandin
inactivation. Carbenoxolone has some mineralocorticoid activity and
antiinflammatory properties. Drug inhibits the transformation of
pepsinogen to pepsin.
Absorbtion of carbenoxolone occurs in intestines. The degree of
binding with plasma proteins is 80–90%. Elimination of
carbenoxolone from the body is performed by the kidneys (60%) and
by the liver. It should be noted, that drug undergoes enterohepatic
recycling.
Carbenoxolone is taken 30 minutes prior meal and at night. The
main indication is treatment of ulcer disease in patient with high
secretory rate. Sometimes drug is used in treatment of duodenal
ulcers.
Side effects of carbenoxolone are the result of its
mineralocorticoid activity. They are oedemas, increase of body
weight, hypertension, muscular weakness, etc.
Misoprostol is a synthetic analogue of prostaglandin E1. It is
known, that gastric mucosa synthesizes prostaglandins, which
stimulate secretion of mucus and bicarbonate. Prostaglandins also
inhibit secretion of hydrogen ions by parietal cells, expand the
vessels of deep layers of mucosa, increase the resistance of vessels
wall to aggressive factors, and create the necessary conditions for
healing of erosions and ulcers.
Especially marked gastroprotective effect of misoprostol is
observed in treatment of ulcers, which are developed owing to the
use of steroidal and nonsteroidal anti-inflammatory drugs (these
agents inhibit the prostaglandin synthesis). Misoprostol is taken
during meal 3–4 times a day. Effect develops in 30 minutes and lasts
up
to
3 hours. Duration of treatment is 4–8 weeks. Misoprostol is not used
as drug for monotherapy due to frequent side effects which include
abdominal pain, nausea, vomiting, rash, uterine bleeding during
menstruation. Drug is predominantly recommended for prevention of
ulcers in patient treated by anti-inflammatory drugs.
Antacids
This group includes the following drugs: sodium
hydrocarbonate , calcium carbonate, magnesium oxide ,
aluminium hydroxide, Almagel, Phosphalugel, Maalox,
Gastal, etc.
These drugs are weak bases which inactivate the hydrochloric
acid in result of direct chemical interaction.
Depending on the ability to be absorbed from gastrointestinal
tract, antacids are divided into drugs of resorptive action and drugs of
pre-resorptive action.
Drugs of resorptive action are sodium hydrocarbonate and
calcium carbonate.
Sodium hydrocarbona te has high solubility in water. After
intake, drug is readily distributed in stomach. Sodium
hydrocarbonate shows almost lightning, but short antacid effect.
Duration of effect is 15–20 minutes. Interaction of sodium
hydrocarbonate with hydrochloric acid results in release of carbone
dioxide which expands the stomach. It results in belching gas and the
feeling of heaviness in epigastrium. Rebound syndrome is typical
for sodium hydrocarbonate, in which gastric distension results in the
secondary increase of secretion of hydrochloric acid and pepsin. It is
the cause of fast resumption of pain.
Chronic intake of sodium hydrocarbonate can result in the
systemic alkalosis owing to absorption of bicarbonate ion. The risk
of this complication increases in patients with impaired renal
function. The symptoms of systemic alkalosis include poor appetite,
nausea, vomiting, weakness, abdominal pain, muscular spasms, and
convulsions. Long-term use of sodium hydrocarbonate is
accompanied by accumulation of sodium ion, increase of blood
pressure, development of oedemas.
Calcium carbonate is poorly soluble in gastric contents. The
action is slow and absorption is less than absorption of sodium
hydrocaronate. Drug neutralizes hydrochloric acid with the release of
carbone dioxide. Calcium carbonate causes the strongest rebound
syndrome. Chronic drug intake together with milk diet (typical diet
for patients with ulcer disease) is commonly accompanied by
development of “milk alkali syndrome”. Symptoms of this syndrome
include nausea, vomiting, hydruria, hypercalcemia, calcification of
vessels and kidneys, kidney stones, azotemia, psychical disorders.
Pre-resorptive antacids are magnesium oxide, aluminium
hydroxide, Almagel and other drugs.
Magnesium oxide interacts with hydrochloric acid without the
release of carbone dioxide. Therefore, drug intake is not
accompanied by rebound syndrome. Synthesized in reaction of
neutralization magnesium chloride is poorly absorbed from intestines
and has weak laxative effect. Laxative effect is result of the increase
of osmotic pressure into the intestines and stimulation of
cholecystokinin secretion, which stimulates peristalsis. Magnesium
oxide does not influence acid-base balance. Antacid effect of drug
develops slowly.
Aluminium hydroxide is characterised by both antacid and
absorptive activity. Drug interacts with hydrochloric acid without the
release of carbone dioxide. Systemic alkalosis does not develop
owing to chronic drug intake. Regular use of drug can be
accompanied by slowdown of intestinal motility which promotes
constipation. A part of administered dose, which does not interact
with hydrochloric acid, turns into phosphate and carbonate. These
aluminium sults is poorly absorbable in the intestines. Therefore,
chronic aluminium hydroxide intake reduces absorption of
phosphates and can cause hypophosphatemia and hypophosphaturia.
Deficiency of phosphates is manifested by fatiguability, muscular
weakness, thinking disturbances, anorexia, etc. Prolonged phosphate
deficiency is accompanied by bone lesions (osteoporosis,
osteomalacia), impaired healing of wound, and increased risk of
infections. Aluminium also binds fluoride ions into intestines that
results in damage to dental enamel.
Combined antacid drugs are widely used in medicine for
decrease of develompment of side effects and for increase of efficacy
of antacids. These drugs include Almagel, Posphalugel,
Maalox, Gastal, etc.
Almagel consists of aluminium hydroxide gel, magnesium
oxide, and sorbitol. Magnesium oxide has laxative effect and
sorbitol – cholagogic effect. Gel form promotes the uniform
distribution of drug over the surface of stomach.
Almagel A contains additionally anaesthsinum which causes
local anaesthesia and inhibits gastrin secretion.
Phosphalugel contains aluminium phosphate in form of
hydrophilic colloidal micelles, pectin gel, and agar-agar. Drug has
antacid and absorptive activity. Micelles of aluminium hydroxide
bind bacteria, viruses, toxines, and gases and eliminate them from
intestines. Drug does not influence upon acid-base balance and
phosphates absorption. Pectin and agar-agar promote the formation
of mucoid protective layer in gastrointestinal tract.
As a rule, all antacids are prescribed in 1 hour after meal (in
connection with decrease of buffering effect of food in period of maximal
secretion) or in 3 hours after meal (for restoration of antacid action after
food evacuation). Also, antacids are prescribed before going to bed for
protection of mucous membrane during nocturnal secretion. In
acute period of disease, the course of treatment with antacids lasts 2–
4 weeks. In cases when pain arises during meals, antacids are
prescribed in 30–40 minutes prior meal.
Indications for antacids use are ulcer disease of stomach and
duodenum with hyperacid syndrome, hyperacid gastritis, hiatal
hernia, esophagitis, and reflux esophagitis.
Drugs Used in Hypofunction of Pancreas
During day, pancreas produces 1.5–2 L of juice which contains
more than 10 enzymes. Pancreatic juice also contains significant
amount of bicarbonate and has alkaline reaction. It promotes the
neutralization of hydrochloric acid and the normal activity of
pancreatic enzymes, which are involved in the digestion of peptides,
lipids, and carbohydrates.
Trypsin, chemotrypsin, carboxypeptidase A and carboxypeptidase B, and elastase complete proteolysis of proteins which are
initiated by pepsin. Amylase promotes the hydrolysis of
polysaccharides. Lipase and phospholipase hydrolyze fatty acids and
phospholipids. Bile is also necessary for hydrolysis of lipids, because
it promotes their emulsification. Additionally, bile participates in
absorption of amino acids.
Pancreatic insufficiency is developed owing to transferred acute
and chronic pancreatitis; in patients with chronic gastritis, ulcer
disease, cholangitis, etc.
Drugs of pancreatic enzymes often contain also pepsin or bile
components. Such combination increases functional integration of
digestive system and is the most effective in patients with chronic
digestive disturbances and in old patients.
Pancreatic enzymes are obtained from gland of livestock for
slaughter, some enzymes – from microorganisms and even plants.
Pancreatin (powder of the dry pancreas of livestock for
slaughter) contains predominantly two enzymes – trypsin and
amylase. It is used in patients with pancreatic insufficiency. The
following combined drugs are commonly used in medicine: Mezym
Forte (pancreatin contaning amylase, lipase, and protease),
Panzinorm (drug contains pancreatin, extract of gastric mucosa,
bile ecstract, amino acids), Digestal (consists of pancreatin, bile
extract, hemicellulose), Festal, Enzystal, Licrease, Kreon, etc.
All drugs act in alkaline environment and are inactivated in acids.
Therefore, drugs are manufactured in intestinal-soluble dragee or
capsules. Course of treatment with pancreatic enzymes lasts from
2 up to 4–6 weeks. Regular drug intake results in reduction of
bloating, diarrhoea, and improves general condition of the patient.
Indications for drugs use are chronic pancreatitis, achylia,
chronic hypoacid gastritis, hepatitis, cholecystitis, etc.
Drugs are well tolerated by patients. It is necessary to notice,
that these drugs contain significant amounts of purines and can cause
exacerbation of gout and formation of urate kidney stones.
Drugs Inhibiting Pancreatic Secretion
Drugs inhibiting pancreatic secretion are used for treatment of
acute pancreatitis.
Normally, inactive trypsinogen is synthesized in pancreas. In
duodenum by means of enterokinase, it is activated to trypsin. In
acute pancreatitis, transformation of trypsinogen to trypsin occurs
directly in pancreas owing to action of cytokinase. In turn, trypsin
activates other proteolytic enzymes in pancreas. These processes
result in autolysis and necrosis of pancreas. Simultaneously
sinthesized bradykinin causes vasodilation and hypotension.
The aim in treatment of acute pancreatitis is reduction of
secretion and activation of protelytic pancreatic enzymes – trypsin
and kallikrein. The following drugs are used for this aim:
1. M-choliceptor antagonists: atropine, platyphyllin, etc.;
2. Inhibitors of proteolytic enzymes: contrical, trasilol,
gordox, aminocapronic acid, etc.
Contrical is used most commonly. This drug is obtained from
lung tissues of livestock for slaughter. Contrical inhibits the
proteolytic enzymes and prevents or reduces the autolysis and
necrosis of pancreas. Contrical is dosed with units of action and
administered intravenously drop by drop.
Treatment of acute pancreatitis also includes administration of
analgesics, antibiotics, antacids, plasma expanders, and electrolytes.
Drugs Improving Functions of Liver
(Hepatotropic Drugs)
Hepatotropic drugs are devided into bile-expelling drugs,
gepatoprotectors, and drugs for dissolution of gallstones.
Hepatocytes produce bile continuously. Bile is deposited in large
bile-ducts and in gallbladder, in which bile is concentrated.
Sphincters are located in the common bile duct, gallbladder, and in
the output in the duodenum. Parasympathetic nervous system plays
an important role in the process of bile evacuation. Increase of tone
of parasympathetic nervous system results in sphincters relaxation
and contraction of gallbladder.
Bile ejection occurs during digestion. It is stimulated by
cholecystokinin, which is synthesized by duodenal epitelium owing
to food intake. Daily volume of produced bile is about 1 L.
Process of digestion requires the bile acids which participate in
emulsification of fats and activation of lipase. Bile acids also
promote absorption of fat-soluble vitamins (A, D, E, K, F).
Furthermore, bile increases activity of pancreatic proteases and
amylase, has bacteriostatic action against putrefactive intestinal
microflora.
Bile-expelling drugs are devided into two groups:
1. Drugs stimulating bile production (cholosecretics).
2. Drugs promoting bile excretion (cholokinetics).
Drugs Stimulating Bile Secretion
These drugs are devided into 3 groups:
1. Drugs containing bile and bile acids: “Allohol”,
“Cholenzymum”, lіobіlum, chenodeoxycholic acid .
2. Drugs of plant origin: “Cholaflux”, holagol, flamіn,
berberine sulfate, holosas, syrup of wild rose, decoctions
from flowers of Helichrusum arenarium , oats seeds,
Stigmatum maydis.
3. Synthetic
drugs:
oxaphenamіdum ,
cycvalonum,
nіkodinum, odeston.
Bile-contaning drugs stimulate bile formation in hepatocytes and
simultaneously perform the function of drugs for substitutive therapy.
“Allochol” consists of bile, garlic and nettle extracts, and
activated carbon. Drug is taken orally 3 times a day after meal. Dose
is 1–2 tablets. Course of treatment is 3–4 weeks.
Tablets “Cholenzymum” consist of dry bile, chopped dried
pancreas, and dried mucous membrane of the small intestines of
slaughter cattle. Drug is taken orally, in dose 1 tablet three times a
day after meal.
Liobilum is manufactured in tablets containing 0,2 g of freezedried bovine bile. Drug is taken orally, in dose 1–3 tablets at the end
of meals 3 times a day. The course of treatment is 1–2 months.
Drugs of plant origin are widely used in the form of infusions,
decoctions, and extracts. Cholesecretory activity is typical for
flavonoids and essential oils of everlasting flower, corn silk,
barberry, dandelion root, fruits of mountain ash and wild rose, etc.
Pharmaceutical industry produces extracts of these plants in different
medicinal forms: drops for oral intake “Cholagol”, tablets
“Flaminum”, tablets of berberine sulfate, sirup “Cholosas”.
“Cholagol” consists of pigments of turmeric root,
frangulaemodin, magnesium salicylate, peppermint oil, and
eucalyptus oil. Drug has choleretic, moderate antispasmodic, antiinflammatory, disinfectant, and laxative effects. “Cholagol” is taken
in dose 5–10 drops on a piece of sugar 3 times a day 30 minutes prior
meals.
“Flaminum” contains dry extract Helichrysum arenarium. Drug
is taken in dose 1 tablet 3 times a day 20 minutes priot meals (tablet
is dissolved in 1/2 cup warm water).
“Cholosas” contains extractum of wild rose. “Cholosas” has
choleretic and hepatoprotective effects. Drug restores and maintains
normal function of hepatocytes, restore the flow of bile, normalizes
the immune system. Also, “Cholosas” has anti-inflammatory and
diuretic effects, increases intestinal motility. Due to the presence of
vitamin C and other bioactive natural products, drug improves
immunity. “Cholosas” is taken in dose 1 tea-spoon 2–3 times a day
30 minutes prior meals.
Synthetic
drugs
(oxaphenamіdum,
cycvalonum,
nіkodinum, odeston) increase bile production and promote its
excretion. These drugs have more prominent choleretic effect than
bile-containing drugs and drugs of plant origin.
Synthetic drugs (except nikodinum) increase the tone of
gallbladder and relax the smooth muscles of bile ducts. In addition,
some of them (for example, nikodinum) have antimicrobial effect
that is clinicaly useful in treatment of inflammatory diseases of liver,
bile ducts, and gallbladder. These drugs are prescribed 3 times a day
prior meals.
Drugs Stimulating Bile Discharge
Cholokinetics causes the contraction of gallbladder and
relaxation of Oddi sphincter. It results in bile release into the
duodenum. Mechanism of action of most of them is due to irritation
of duodenal mucosa owing to which cholecystokinin is released into
the blood. Namely cholecystokinin causes the release of bile.
Cholecystokinin is a duodenal hormone, molecules of which
consist of 33 residues of aminoacids. This drug is derived from
duodenal mucosa of pigs. Drug promotes the contraction of
gallbladder and activates hydrochloric acid secretion in stomach.
Cholecystokinin is used for diagnostics of gallbladder contractility
and its content.
Magnesium sulfate is administered in a warm solution (25–10%
of 50–200 ml respectively by means of duodenal probe once in srveral
days) or perorally (as 25% solution in dose 1 table-spoon 3–4 times a
day during 2–3 weeks). Drug also may be used for tubage. In this case,
patient lying on his right side drinks during 30 minutes
100 ml of 10–20% solution of magnesium sulfate. After this, patient
should lie during 1.5–2 hours with hotty over the liver area.
As cholokinetics also the following drugs may be used:
sorbitol (50–70 ml of 10% solution, 2–3 times a day prior meal),
sunflower or olive oil (1–2 table-spoons, it is possible with lemon
juice), plants containing bitters (dandelion, ya rrow, wormwood,
etc.), essential oils of coriander and cumin, extracts and
fruit juice of cranberries, cowberry , etc.
Indications for use of cholokinetics are dyskinesia, chronic
hepatitis, hypoacid gastritis which is accompanied by gallbladder
atony with cholestasis. Drugs are contraindicated in acute period of
liver diseases, in cholelithiasis, in exacerbation of hyperacid gastritis
and ulcer disease.
Myotropic antispasmodics, such as No-spa, papaverine,
euphillinum, atropine, platyphyllin, are used for reduction of
spasticity of bile ducts. These drugs reduce the pain which occurs in
pathology of bile ducts. Myotropic antispasmodics are effective in
moderate pain and well combined with other hepatotropic drugs.
These drugs should be administered parenterally together with
analgesics in case of intensive pain in attack of cholelithiasis.
Hepatoprotectors
Hepatoprotectors are drugs which increase the resistance of liver
to unfavourable factors and decrease the damage and destruction of
hepatocytes.
Hepatoprotective effect is due to the normalization of
hepatocytes metabolism, the increase of microsomal enzymes
activity, and restoration of damaged cell membranes. Drugs are used
in acute and chronic hepatitis, liver dystrophy, cirrhosis, and toxic
liver damage (including alcoholism and hepatic coma).
Hepatoprotectors derived from thistle (Silybum marianum) and
other plants richest on flavonoids are used most widely in medicine.
They are Legalon, Carsil, Hepabene, Hepatofalk Planta ,
LIV-52, etc.
Flavonoids are phenolic compounds – derivative of chromone.
Together with ascorbic acid, flavonoids paticipate in redox
processes. Flavonoids also belong to antioxidant system of cells.
Flavonoids have anti-inflammatory, bile-expelling, antiviral,
analgesic, and immunomodulatory effects. These agents stabilize the
vascular wall, imrove the hemophoresis, reduce vascular spasm,
increase level of calcium and glucocorticoids into the blood, and
reduce cholesterol level. Flavonoids are widely used for prevention
of stomach, liver, and cardiovascular diseases. Antioxidative activity
of flavonoids is higher than activity of vitamin E. Flavonoids are
easily absorbed in gastrointestinal tract and accumulated in the liver
and kidneys. Flavonoids of Silybum marianum have high
hepatotropic properties which are the base for their efficacy in liver
diseases. These drugs stimulate protein synthesis, normalize
phospholipids metabolism, and increase the glutathione reserve in
liver.
Legalon is an extract of the fruit of Silybum marianum. It
contains mixture of flavonoids with hepatoprotective activity –
silibinin, silimarin, etc. Mechanism of legalon action is associated
with stabilization of hepatocytes membranes, antioxidative
properties, and ability to stimulate protein synthesis and increase the
gluthatione reserve in the liver. Drug is used orally in capsules,
dragee, and emulsion. Drug has low toxicity. Sometimes, diarrhea is
possible.
Presently, monodrag of flavonoid silibinin is established –
silibinin dihydrosuccinate sodium salt . This agent is
administered intravenously in poisoning by death cup.
Another group of hepatoprotectors is presented by drugs which
are involved in the building of cellular membranes – unsaturated
fatty acids, choline, phospholipids, essential amino acids, etc. As a
rule, these drugs also contain vitamins which paticipate in
detoxifying function of liver and in restoration of cellular
membranes. These drugs are essentiale,
ademethionine, lipoic acid, etc.
thiotriazoline,
Essentiale contains fatty acids in the form of phospholipids,
vitamins of group B, and tocoferol. Drug is administered
intravenously in emergency (hepatic coma, acute poisoning with
hepatic dysfunction, etc.). In other cases, essentiale is usually used
orally in dose 2–3 capsules 3 times a day before meals. Essentiale is
prescribed in chronic hepatitis, liver cirrhosis, hepatic dysfunction in
patients with diabetes mellitus, for revention of reccurance of
cholelithiasis, in pre- and postoperative periods, etc.
Thiotriazoline is synthetic agent with anti-ischemic,
antioxidative, membrane stabilizing, and immunomodulatory effects.
Drug prevents hepatocytes destruction, inhibits fatty infiltration and
necrosis of liver. Thiotriazoline normalizes peptide, carbohydrate,
and pigmentary metabolism in liver. Under influence of
thiotriazoline, both synthesis and discharge of bile increase.
Aditionally, thiotriazoline reduces the ischemia of myocardium,
reduces the necrotic zones after myocardial infarction, activates
fibrinolytic properties of blood. Drug is administered intravenously
and intramuscularly in hepatitis, hepatic cirrhosis, ischemic heart
disease, myocardial infarction, cardiosclerosis, and arrhythmias.
Ademethionine (Heptral) contains the methyl groups which
are involved in synthesis of membrane phospholipids. Also, methyl
groups paticipate in synthesis of cysteine, glutathione, sulfate, and
taurine. All these substances are essential for detoxifying function of
liver. Additionally, ademethionine has antidepressive, analgesic, and
anti-inflammatory action. Drug is taken orally and administered
intravenously or intramuscularly. Indications for ademethionine use
are intrahepatic cholestasis; toxic, viral, alcoholic, and drug-induced
liver damage; cirrhosis, encephalopathy, including those in hepatic
failure; depressive and abstinence syndrome.
Lipoic acid stimulates detoxifying function of liver, exhibits
an antioxidant activity, paticipates in lipid and carbohydrate
metabolism. The agent is prescribed in infective hepatitis, chronic
hepatitis, cirrhosis, intoxications, coronary atherosklerosis, and
diabetic polyneuropathy.
Drugs Used to Dissolve Gallstones
It is proved, that certain derivatives of deoxycholic acid, such as
ursodeoxycholic acid (ursofalk) and chenodeoxycholi c
acid (chenofalk) promote the dissolution of cholesterol stones in
gallbladder. These drugs use results in reduction of cholesterol
concentration in bile. Chenodeoxycholic acid inhibits the synthesis of
cholesterol in hepatocytes. Ursodeoxycholic acid decreases the
intestinal absorption of cholesterol and oppresses its synthesis.
Reduction of cholesterol in bile results in a decrease of an ability of
stones formation in gallbladder. The change in ratio of cholesterol
and bile acids in favor of the latter promotes gradual dissolution of
cholesterol-containing gallstones. These drugs are taken orally for a
long time (during 1 year and more). Side effects are diarrhea, itching,
and increase of aminotransferase level. Ursofalk is also used for
treatment of biliary cirrhosis.
Drugs Influencing Gastric Motility
These drugs are divided into agents which increase gastric
motility (prokinetics) and those which inhibit gastric motility.
Prokinetics are: metoclopramide, cisapride, domperidone
(motilium), etc. Prokinetics are used in case of delayed gastric
emptying and in reflux esophagitis. Metoclopramide blocks
peripheral and central D2-dopaminergic receptors and activates
5HT3-serotoninergic receptors. Cisapride acts as 5HT3-serotoninergic receptor agonist and indirectly excites cholinergic
receptors of intramural ganglia. Domperidone blocks peripheral
D2-dopaminergic receptors.
M-cholinoblocking
drugs
(atropine,
platyphyllin,
methacinum), ganglion blocking drugs (benzohexonium,
pirilene), agents which block both M- and N-cholinoceptors of
ganglia (buscopane, probanthine), and myotropic spasmolytics
(papaverine, No-Spa, etc.) are used for reduction of gastric
motility.
Emetic Drugs
Emetic drugs are agents which cause vomiting. They are:
apomorphine, herb of thermopsis, root of ipecacuanha ,
copper sulfate, and zinc sulfate.
Vomiting is complex reflex act with protective value which
develops due to activation of vomiting (emetic) centre. Stimulants of
vomiting centre convey impulses from the mucous membrane of
stomach, intestine, and other internal organs; impulses from
vestibular apparatus and the cortex (psychogenic vomiting), from
visual, scents and taste analyzers, etc. But chemoreceptors of trigger
zone are of principal importance in stimulation of vomiting. Trigger
zone is located on the base of the fourth ventricle of cerebrum. Its
neuronal membranes contain D2-dopaminergic, 5-HT3-serotoninergic, and M1-cholinergic receptors. Excitation of these
receptors results in stimulation of vomiting centre.
Certain chemical substances which are synthesized in disturbed
metabolism in renal and hepatic failure or in toxemia of pregnancy,
as well as number of drugs (opioid analgesics, digitalis, antitumoral
agents) also are stimulants of chemoreceptors of trigger zone.
Apomorphine is an emetic drug with central action. It is a
specific agonist of D2-receptors. The drug is used for elimination of
poisoning, caused by gastric contents, in cases when gastric lavage is
impossible (for example, poisoning by mushrooms or by other foods,
which do not pass through a tube), in case of suicide, etc.
Apomorphine is administered subcutaneously or intramuscularly.
Emetic effect develops in 2–15 minutes.
Inducing vomiting is contraindicated for unconscious patients,
pregnants, in childhood and advanced age, as well as in poisoning by
gasoline, kerosene, turpentine, acids, alkalis, and other substances,
affecting mucous membranes. In such cases, the gastric lavage with
absorbents and the following saline laxatives is preferable.
Thermopsis herb and ipecacuanha root are agents which
excite emetic centre reflexively. If these drugs are taken orally in
high doses, they excite stomach receptors and stimulate vomiting by
reflex. It should be noted, that alkaloids of thermopsis and
ipecacuanha after absorption into the blood can directly stimulate the
chemoreceptors of trigger zone.
Copper sulfate and zinc sulfate also have the peripheral
mechanism of emetic action which is associated with irritation of
mucous membrane of stomach.
It should be noted, that the use of emetic drugs in medical
practice is significantly restricted.
Antiemetic Drugs
Antiemetic drugs are devided into two main groups:
1. Agents which are effective in vomiting of central origin:
- antagonists of D2-dopaminergic receptors: metoclopramide,
thiethylperazine, aminazine (chlorpromazine), aethaperazine, triftazinum, etc.;
- blockers of 5-HT3-serotoninergic receptors: ondansetron ,
tropisetron, granisetron.
2. Agents which are effective in vomiting caused by violation of
vestibular apparatus:
- M-cholinoblockering drugs: scopolamine, “Aeron”;
- antagonists of H1-histaminergic receptors: dimedrolum,
diprazinum.
In kinetosis (seasickness and airsickness) vomiting occurs in the
result of overexcitation of vestibular apparatus. Vestibular apparatus
carries out impulses to the cerebellum, which, in turn, transmits
impulses to the vomiting centre. As M-cholinergic and H1-histaminergic receptors of cerebellum paticipate in this transduction of
impulses, the following drugs are used to prevent vomiting of
vestibular origin: tablets “Aeron” (contain M-cholinoblocking
agents scopolamine and hyoscyamine), scopolamine in tablets or
as a patch (Scopoderm TTS), and H1-histaminoblocking agents –
dimedrolum and diprazinum. Efficacy of these drugs in kinetosis
develops due to blockage of M-cholinergic and H1-histaminergic
receptors in cerebellum. But it is possible, that a direct inhibitory
influence upon vomiting centre also participates in antiemetic effect
of these agents. Side effects of these drugs include drowsiness, dry
mouth, and blurred vision.
Metoclopramide (cerucal, reglan) is one of the most often
used antiemetic agents. Mechanism of its action is associated with
the blockage of D2-receptors in neurones of trigger zone. The agent
used in high doses can also block 5-HT3-serotoninergic receptors.
Indications for use of metoclapramide include stomach and
duodenum ulcer, meteorism, dyskinesia, oncological diseases of
gastrointestinal tract, radiation sickness, uraemia, delayed gastric
emptying, and reflux esophagitis. The drug is taken orally or
administered parenterally (intramuscularly or intravenously). The
effect develops quickly and lasts 6-8 hours. Side effects of
metoclapramide include drowsiness, sonitus, dry mouth, and
extrapyramidal disorders.
Certain neurileptics – phenothiszine
derivatives, such as
thiethylperazine, chlorpromazine (aminazine), aethaperazine,
and triftazinum are also used as antiemetic agents. Mechanism of
their action is associated with blockage of D2-receptors of trigger
zone. Thiethylpirazine also directly oppresses vomiting centre. These
drugs are also characterized by marked sedative and antipsychotic
effects. Neurileptics are effective in vomiting of central origin.
Ondansetron (zofran), tropisetron, and granisetron are
antagonists of 5-HT3-serotoninergic receptors. Drugs are
characterized by high efficacy in vomiting following chemotherapy
of cancer, in postoperative period, and in radiation sickness. Drugs
are prescribed to take once a day orally or parenterally. Side effects
are: headache, dizziness, and constipation.
Antiemetic drugs are not used in unconscious patients, in
patietns with gastrointestinal bleeding, with perforated ulcer, and
ileus.
Drugs Influenc ing Intestinal Motility
Drugs stimulating intestinal motility
This group includes drugs that elimanate the intestinal atony.
Agents are classified into the following subgroups:
1. Drugs stimulating M-cholinergic receptors: aceclidine.
2. Cholinesterase inhibitors: proserinum, pyridostigmine ,
distigmine.
3. Agonists of 5-HT4-serotoninergic receptors: cisapride.
4. Agonists
of
motilin
receptors:
erythromycin,
oleandomycin.
Aceclidine interacts and excites M-cholinergic receptors of
smooth muscles of gastrointestinal tract.
Cholinesterase inhibitors (proserinum, etc.) suppress the activity of cholinesterase and increase the level of acetylcholine in
cholinergic synapses.
Motilin receptors are located in antrum of the stomach and in
duodenum. These receptors are excited by motilin. It is
gastrointestinal polypeptide hormone which stimulates smooth
muscle contractions in the stomach and small intestine. Antibiotics
erythromycin and oleandomycin excite motilin receptors and
stimulate intestinal motility.
Moreover, such drugs as hormonal agent vasopressin and
laxative drugs also stimulate intestinal smooth muscles.
Drugs Inhibiting Intestinal Motility and
Reducing Intestinal Spasms
Following groups of drugs are used in intestinal spasticity:
1.
M-cholinoblockers:
atropine,
platyphyllin e,
methacinum.
2. Ganglion
blockering
drugs:
benzohexonium
(hexamethonium), pirilenum.
3. Myotropic spasmolytics: papaverine, drotaverine (No-spa).
4. Agonist of peripheral opiod receptors: loperamide.
Pharmacology of M-cholinoblockering and ganglion blockering
drugs is presented in relevant sections. Myotropic spasmolytics or
myotropic
antispasmodic
agents
inhibit
the
enzyme
phosphodiesterase that leads to accumulation of cAMP and decrease
of smooth muscles’ tone and motility.
Loperamide (imodium ) is a phenylpiperidine derivative
which stimulates μ-opioid receptors in the intestine and inhibits
peristalsis.
Drugs which inhibit intestinal motility are used in spastic colitis
and for symptomatic treatment of acute and chronic diarrhoea.
Laxative Drugs
Laxative agents are divided into the following groups:
1. Saline laxatives: magnesium
sulphate,
sodium
sulphate.
2. Organic laxatives.
2.1. Drugs of plant origin:
- vegetable oils: castor oil;
- drugs contaning anthraquinone glycosides: extract of
buckthorn (Rhamnus cathartica ) cortex, rhubarb (Rheum)
root, senna leaves.
2.2. Synthetic drugs: isaphenine,
phenolphthalein,
guttalax, bisacodyl.
Saline Laxatives
Magnesium sulphate and sodium sulphate are used for
purification both small and large intestine. These drugs create high
osmotic pressure in intestine that causes the retention of water in
lumen of intestine. An increase of intestinal content volume results in
distension of bowel and irritation of intestinal mechanoreceptors that
increases peristalsis. Drugs act throughout small and large intestine.
Saline laxatives are taken orally in dose 15–30 g with 1–2 glasses of
water. The effect develops in 2–3 hours and lasts up to 6 hours.
Drugs are used in acute poisoning and to prevent the absorption of
toxins into the blood.
Vegetable Oils
Castor oil is extracted from castor seeds. In duodenum, castor
oil is hydrolysed under influence of pancreatic lipases with release of
glycerin and castor acid. Castor acid irritates receptors and stimulates
the peristalsis throughout small and large intestine. Moreover, castor
acid affects the absorption of ions and water from the intestine.
The agent is taken orally in dose 15–30 g during 30 minutes. The
effect develops in 2–6 hours.
Castor oil is used in acute constipations, in preparation of a
patient to roentgenologic examinations or to surgery on the
abdominal organs. Castor oil stimulates the uterine contractions.
Drugs Containing Anthraquinone Glycosides
These drugs increase the peristalsis and facilitate the excretion
of feces. The extracts of buckthourn cortex, rhubarb root, and
senna leaves are most commonly used drugs. Vegetable
anthraquinone glycosides lack laxative effect. Under the influence of
intestinal bacteries, these substances are hydrolyzed into
anthraquinone derivatives, which irritate the intestinal receptors and
stimulate peristalsis. These drugs act only in large intestine.
Drugs are taken orally once in 2–3 days, as a rule at night or in
the morning before breakfast. Laxative effect develops in 8–10
hours.
Anthraquinone glycosides accumulate in the mucous membrane
and smooth muscles of the bowels and can cause the atrophy of its
smooth muscle layer. In this case constipation becomes chronic and
insensitive to therapy with laxative drugs. Prolonged drugs intake
can also cause the disturbances in the liver function.
Synthetic Laxative Drugs
Phenolphthalein is absorbed into the small intestine and
secreted into the large one, where it irritates receptors and decreases
the absorption of ions and water. Laxative effect develops in
6–8 hours after the drug intake. Phenolphthalein can cumulate in the
body and affect the kidneys function. Side effects of the drug include
the allergic reactions, intestinal colics, tachycardia, and collapse.
Isaphenine is hydrolyzed into the intestine with release of
dioxiphenylisatine. This substance irritates the receptors and
increases the peristalsis of large intestine. Laxative effect develops in
8–12 hours after isaphenine intake. Isaphenine has fewer side effects
than phenolphthalein.
Guttalax and bisacodyl under the influence of intestinal
bacteries release the active radicals stimulating intestinal receptors
and increasing peristalsis. The drugs are used in chronic
constipations. The onset of laxative effect is observed in 6–10 hours
after drugs intake.
Table 1 – Drugs for prescription
Drug name
1
Desopimonum
Succus gastricus
naturalis
Pepsinum
Acidum
chidrochloricum
dilutum
Pirenzepinum
Ranitidinum
Omeprazolum
Magnesii oxydum
Almagelum
Single dose and mode of
administration
2
0.025 g 2 times per day orally
15-30 ml during meal orally
Drug product
3
Tablet 0.025 g
Bottle 100 ml
0.2-0.5 g during meal orally
10-15 drops during meal orally
Powder
Bottle 50 ml
0.05 g 2 times per day orally;
Tablet 0.025 or 0.05 g;
0.01 g 2 times per day ampoule 2 ml of
intravenously or intramuscularly
0.5% solution
0.15 g 2-3 times per day orally
Tablet 0.15 g
0.02 g once per day orally
Capsule 0.02 g
0.25-1.0 g 4 times per day orally
Powder;
tablet 0.5 g
1 tea-spoon 4 times per day orally
Bottle 150 ml
Table 1 continuation
1
De-nolum
Sucralfat
Apomorphini
hydrochloridum
Metoclopramidum
Aethaperazinum
Cholenzymum
Cholosasum
Papaverini
hydrochloridum
Nospanum
Oxaphenamidum
Pancreatinum
Magnesii sulfas
Oleum Ricini
Isapheninum
Contrical
2
0.12 g 4 times per day orally
Orally 0.5-1.0 g 4 times per day
0.002-0.005 g subcutaneously
3
Capsule 0.12 g
Tablets 0.5 or 1.0 g
Ampoule 1 ml of 1%
solution
0.01-0.02 g 2-3 times per day orally;
Tablet 0.01 g;
0.01 g 1-3 times per day ampoule 2 ml of
intramuscularly or intravenously
0.5% solution
0.004-0.006 g 3-4 times per day Tablet 0.004 or 0.006 g
orally
1 tablet 1-3 times per day after meal Tablet
orally
1 tea-spoon 2-3 times per day after Bottle 50 or 300 ml
meal orally
0.04-0.06 g 3-4 times per day orally; Tablet 0.04 g;
0.02-0.04
g
subcutaneously, ampoule 2 ml of 2%
intramuscularly or intravenously
solution
0.04-0.08 g 2-3 times per day orally; Tablet 0.04 g;
0.04-0.08 g
subcutaneously, ampoule 2 ml of 2%
intramuscularly or intravenously
solution
0.25-0.5 g 3 times per day after Tablet 0.25 g
meal orally
0.25 or 0.5 g tablets 3 times per day Tablet 0.25 or 0.5 g
during or after meal orally
10-30 g in 1 glass of water per day Powder
orally
15-30 g per day orally
Capsule 1.0 g
0.005-0.01 g 1-2 times per day orally Tablet 0.01 g
10000-50000
IU
per
day Bottle 10000, 30000
intravenously drop-by-drop
or 50000 IU of dry
substance
DIURETIC AGENTS
Diuretic agents are drugs which increase the excretion of salts
and water from the organism. They are also called “saluretics”
because for mechanism of action of these drugs is based on the
increase of sodium and chlorine ions excretion. Diuretics are widely
used in medicine, including the emergency treatment. Various
diseases of kidneys, cardiovascular system, lever patology, etc. are
accompanied by retention of salts and water that results to the
increase of tissues hydratation, development of edemas, and
accumulation of fluids in body cavities.
Mechanism of diuretics action can be understood on the basis of
the modern ideas about process of diuresis. Nearly 150–200 L of
fluid and 25,000 milliequivalents of sodium are filtrated in human
kidneys during 24 hours. But up to 99 % of initial urine undergoes
reabsorption and only 2 L of fluid and 100 milliequivalents of
sodium are excreted from organism with urine. Initially, reabsorption
of sodium from the renal tubules occurs through apical membrane.
Sodium is transported through apical membrane via special carrier
protein which is synthesized under control of aldosterone. After
moving through apical membrane into the cells of renal tubules,
sodium ions are absorbed through basal membrane into the
intersticium and capillaries. Sodium transporting through basal
membrane is an active process that occurs by means of special
pumps. These pumps transport sodium ions against concentration
gradient with energy consumption. One pump transports sodium ions
in exchange for potassium ions; another pump transports sodium ions
together with chlorine or hydrocarbonate ions independently of
potassium. Reabsorption of water is a passive process which depends
on sodium reabsorption.
Reabsorption of sodium, chlorine, potassium, calcium,
magnesium, and equivalent amount of water occurs in proximal
convoluted tubules. Hydrocarbonate ions also undergo reabsorption
under the control of carbonic anhydrase. Approximately 70–80 % of
initial urine is reabsorbed in this segment of nephron. The isoosmotic
urine remains after passing through proximal convoluted tubules.
Descending part of the Henle’s loop is easily permeable for
water, but not for ions. Owing to this, after passing through this part
of Henle’s loop urine becomes hyperosmotic.
Thick ascending limb of the Henle’s loop is poorly permeable
for water. Ions of chlorine and sodium are reabsorbed by means of
active transporting in this segment of nephron. In result of passing
through this segment, urine becomes hyposmotic. But interstitial
fluid in kidneys medulla becomes hyperosmotic. It promotes the
reabsorption of water in descending part of Henle’s loop.
Reabsorption of sodium and chlorine ions continues in the initial
part of distal convoluted tubules that increases the hyposmoticity of
urine. But water reabsorption occurs in the finite part of distal
convoluted tubules under control of vasopressin. Urine becomes
isosmotic. The passive secretion of potassium ions occurs in distal
convoluted tubules.
Uropoiesis is completed in collecting ducts. In this part of
nephron, the aldosterone-dependent reabsorption of sodium and
secretion of potassium ions occur. Water reabsorption controlled by
vasopressin is also typical for collecting ducts.
Based on the characteristics of the process of urine formation, it
is evident that diuretics can either directly influence uropoiesis, or
change hormonal regulation of this process.
There are numerous classifications of diuretics. Classification
based on the action mechanism of diuretics and localization of the
action is given below.
1. Diuretics acting on the level of epitelial cells of renal tubules
1.1. Diuretics acting on the level of basal membrane:
a) derivatives of antranilic and benzoic acids: furosemide,
torsemide, bumethanide (bufenox);
b) non-thiazide sulfonamides: oxodolinum, clopamide,
indapamide;
c) thiazides: dichlothiazidum (hydrochlorothiazide),
cyclomethiazide , polythiazide;
d) derivatives of dichlorophenoxyacetic acid: ethacrynic a cid;
e) carbonic anhydrase inhibitors: diacarb.
1.2. Diuretics acting on the level of apical membrane – drugs
inhibiting proteins which transfer sodium: triamterene,
amiloride.
2. Aldosterone antagonists: spironolactone.
3. Osmotic diuretics: mannitol.
4. Drugs increasing kidneys blood flow: euphyllinum.
5. Diuretics of plant origin: horsetail herb , bearberry
leaves, birch buds, etc.
Depending on the efficacy of diuretic activity, all drugs may be
classified into the following groups:
1. Most effective diuretics: furosemide, ethacrynic acid,
clopamide, mannitol.
2. Diuretics with moderate activity: dichlothiazidum,
cyclomethiazide , polythiazide, oxodolinum.
3. Diuretics
with
weak
activity:
spironolactone,
triamterene, amiloride, euphyllinum , drugs of plant
origin.
Depending on speed of effect development, diuretics are
classified into:
1. Diuretics with fast development of the effect (within
30–40 minutes): furosemide, ethacrynic acid , mannitol,
bumethanide, torsemide.
2. Drugs with a moderate speed of the effect development (onset
of action is within 1–4 hours after drug administration, and duration
of the action is 9–24 hours): dichlothiazidum, diacarb,
euphyllinum, cyclomethiazide, clopamide, oxodolinum,
triamterene, indopamide.
3. Diuretics with slow development of the effect (onset of action
is within 2–5 days after drug intake, and duration of action is
5–7 days): spironolactone.
Diuretics Acting on the Level of Epitelial Cells
of Renal Tubules
Loop Diuretics
Furosemide, torsemide, bumethanide (bufenox) inhibit
hexokinase, malate dehydrogenase, succinate dehydrogenase, and
Na+/K+-ATPase. This results in deterioretion of sodium/potassium
pump. Besides, these drugs separate energy production and its input
to the pump. These changes cause the reduction of sodium current
through basal membrane into intersticium. Diuretics of this group
increase the synthesis of prostaglandins and kinines that relax renal
vessels and increase sodium excretion.
A principal place of these drugs action is a thick ascending limb
of the Henle’s loop, therefore, these drugs are called “loop diuretics”.
To a certain degree anthranilic acid derivatives inhibit sodium
reabsorption in proximal tubules.
All agents of this group increase potassium excretion that is
undesirable. An elevation of potassium excretion is result of the
increase of permeability of luminal membrane of distal tubules for
sodium ions. It causes the increase of inside potencial of tubules and
enhances passive potassium secretion into the tubules’ lumen.
Furosemide (Lasix) was introduced in medical practice in
1963. The drug has marked a diuretic effect both in parenteral and
enteral administration. In case of oral intake, the effect develops in
30–60 minutes and lasts 6–8 hours. In case of intravenous
administration, the effect develops in 5–10 minutes and lasts
2–4 hours.
Furosemide is easily absorbed in gastrointestinal tract. After
absorption, the drug binds with plasma proteins. Furosemide
undergoes hepatic metabolism through hydrolysis and conjugation
with glucuronic acid. Metabolites are excreted by the kidneys.
Furosemide is a low toxic agent with dosage range of therapeutic
action from 0.002 g to 2.0 g.
Therapeutic indications for furosemide are chronic oedemas of
cardiac, renal, and hepatic origin; acute heart failure, pulmonary
oedema, brain oedema, acute and chronic renal failure, forced
diuresis, treatment of hypertensive disease, and interruption of
hypertensive crisis.
Hypotensive effect of furosemide mainly results from the
decrease of sodium level in the walls of arterioles, and only partially
results from the decrease of blood volume. Reduction of sodium
concentration in the walls of vessels results in the decrease of
vascular sensitivity to vasoconstrictive influence of catecholamines.
Side effects of furosemide are hypokalemia, hypokalemic
metabolic alkalosis, hyperglycemia (furosemide reduces the secretion
of insulin by pancreas), hyperuricemia, hypomagnesemia, increase of
renin activity, ototoxicity (in case of intravenous administration of
high doses of furosemide).
Torasemide acts longer than furosemide. It is presribed once a
day.
Bumethanide (bufenox ) acts faster than furosemide. Diuretic
bufenox is 20–50 times more effective than furosemide. Duration of
action is 4–6 hours. Bumethanide is administered parenterally or
taken orally. Indications for use and side effects are similar to
furosemide. Bufenox causes hypokalemia less than furosemide.
Pharmacological properties of clopamide are similar to
furosemide. The drug is taken orally. Onset of action of the diuretic
is 1–3 hours. Duration of action is 8–20 hours. Indications for use are
oedemas in chronic heart failure, nephrosis, postthrombotic oedema,
cirrhosis, ascites, pregnancy, premenstrual syndrome, and
hypertensive disease. Side effects of clopamide use are nausea,
vomiting, arrhythmias, decreased blood pressure, hypercalcemia,
hypokalemia, hyperglycemia, hyperuricemia, flushing of the skin,
and allergic reactions.
Indopamide has diuretic and hypotensive effects. The drug is
taken orally once a day in the morning. Indopamide is used
predominantly for treatment of hypertensive disease.
Thiazides
Hydrochlor othiazide (dichlothiazidum ) is a drug with
moderate diuretic activity. The agent inhibits the reabsorption of
sodium and chlorine ions mainly in initial part of distal convoluted
tubules and, in a certain degree – in proximal convoluted tubules.
Hydrochlorothiazide is effective both in orall and parenteral
administration, but is practically used mainly for orall intake. Onset
of action of diuretic is 30–60 minutes after drug intake. Duration of
action is 8–12 hours. Nearly 60% of the administered dose binds to
plasma proteins. Hydrochlorothiazide is excreted through kidneys.
Tolerance to dichlothiazidum practically does not develope.
Therapeutic indications are: hypertensive disease; oedemas of heart,
hepatic and nephrotic origin; diabetes insipidus, and nephrolithiasis.
Mechanism of dichlothiazidum action in diabetes insipidus is the
following. The drug inhibits phosphodiesterase in cells of kidneys
medulla that results in accumulation of intracellular cAMP. Owing to
this, the water reabsorption through epithelium of collecting ducts is
increased. Volume of urina is reduced. That is, dichlothiazidum
potentiates or restores the effect of vasopressin in patients with
diabetes insipidus.
Most common side effects of hydrochlorothiazide are
hypokalemia and alkalosis. Hypomagnesemia, hypercalcemia (due to
increase of parathyroid hormone activity in kidneys), hyperuricemia,
and hyperglycemia are also possible.
Polythiazide and cyclomethiazide have properties and
therapeutic indications similar to dichlothiazidum. But diuretic
activity of these agents is higher than activity of dichlothiazidum:
polythiazide –50 times, cyclomethiazide –100 times.
Oxodolinum has properties similar to thiazides. This drug is
characterized by long duration of action. After oral intake onset of
action of diuretic ranges 2–4 hours, duration of effect is nearly 3 days.
Derivatives of Dichlorophenoxyacetic Acid
Ethacrynic acid is a derivative of dichlorophenoxyacetic acid.
According to mechanism of action, this drug is a loop diuretic. The
agent oppresses the reabsorption of sodium and chlorine ions on the
level of basal membrane of epithelial cells in the thick ascending
limb of the Henle’s loop. Diuretic effect of ethacrinic acid is high.
Ethacrinic acid is administered parenterally and orally. In case of oral
use, the effect develops in 30–60 minutes after drug intake and lasts
up to 8 hours. In intravenous administration, the effect develops in
20–40 minutes after injection and lasts 3–4 hours.
Therapeutic indications for ethacrinic acid are chronic oedemas
of cardiac, renal, and hepatic origin; acute heart failure; pulmonary
oedema; brain oedema; acute and chronic renal failure; forced
diuresis; treatment of hypertensive disease and interruption of
hypertensive crisis.
Treatment with ethacrinic acid is accompanied by the following
side effects: hypokalemia, hyponatriemia, hypomagnesemia,
alkalosis, hypocalcemia, hearing impairment, weakness, dizziness,
diarrhea, etc. Intravenous administration of ethacrinic acid is painful
and can causes phlebitis.
Carbonic Anhydrase Inhibitors
Diacarb is a weak diuretic which inhibits carbonic anhydrase
in epithelial cells of proximal convoluted tubules. This enzyme
catalizes the synthesis of carbonic acid from water and carbon
dioxide. Carbonic acid dissociates to hydrogen ions and
hydrocarbonate ions. Kidneys secrete the hydrogen ions into urine
with reabsorption of the hydrocarbonate ions. This process provides
support of an acid-based balance in organism. Owing to the action of
diacarb, the reabsorption of the hydrocarbonate ions is reduced and
pH of urine increases. In this case, alkaline reserve of the blood
decreases. Retention of hydrogen ions is accompanied by
compensatory secretion of potassium ions. Treatment with diacarb
quickly results in acidosis owing to hyperchloremia.
Diacarb is a diuretic for oral administration. Therapeutic
indications are: alkalosis, exacerbation of glaucoma, glaucomatous
crisis, intracranial hypertension, epilepsy, and poisoning by
barbituric acid derivatives (increase of pH of urine promotes the
excretion of barbiturates by kidneys).
Main side effects of diacarb are acidosis and hypokalemia. In
addition, such side effects as paresthesia, and allergic reactions
(erythema sulfa) can develop. Fever, leukopenia, hemolytic anemia,
and bone marrow damage are also possible.
Diuretics Acting on the Level of Apical Membrane
Drugs Inhibiting Proteins which Transfer Sodium
Triamterene and amiloride are weak diuretics. These drugs
inhibit the passive transport of sodium ions through apical membrane
of epithelial cells into the distal convoluted tubules and collecting
ducts. The agents interact both with sodium transport proteins and
sodium channels. Triamterene and amiloride inhibit the potassium
secretion in nephrons and are called “potassium-sparing diuretics”.
Both drugs are taken orally. Effect develops in 15–20 minutes after
drug intake and lasts up to 6–8 hours.
These drugs are used in long-term maintenance therapy of
chronic cardiovascular failure of various origins, in treatment of
hypertensive disease, and cirrhosis. Potassium-sparing diuretics are
widely used in combination with thiazides or loop diuretics to
prevent hypokalaemia.
Side effects of potassium-sparing diuretics are hyperkalaemia,
nausea, vomiting, headache, convulsions of muscles of the lower
extremities.
Aldosterone Antagonists
Spironolactone (Aldactone, verospiron ) has chemical
structure similar to aldosterone.
Spironolactone binds with
intracellular cytoplasmic receptors of aldosterone and prevents the
aldosterone interaction with nuclear chromatin. It results in the
decrease of synthesis of sodium transporting proteins – permease.
Owing to such mechanism spironolactone decreases the aldosteronedependent sodium reabsorption and potassium secretion in collecting
ducts of nephron. Therefore, spironolactone is a potassium-sparing
diuretic.
Diuretic effect of spironolactone develops in 2–5 days after start
taking of the drug and lasts up to 2–3 days after completing the drug
administration.
Therapeutic indications of spironolactone are oedemas in
patients with chronic heart failure, liver cirrhosis, nephrotic
syndrome, essential hypertension in adults, ascites, diagnostics and
treatment of primary hyperaldosteronism (Conn's syndrome),
prevention of hypokalaemia in treatment with diuretics and in
patients receiving cardiac glycosides.
Side effects of spironolactone include dizziness, drowsiness,
headache, ataxia, nausea, vomiting, diarrhea, abnormal liver function,
gynecomastia, menstrual disorders, urticaria, hyperkalemia, etc.
Osmotic Diuretics
Mannitol has a pronounced diuretic action and weak saluretic
effect. The drug is easily filtered in renal glomerulus but is not
reabsorbed from the primery urine. Thereby mannitol creates high
osmotic pressure in tubular lumen and significantly decreases the
water reabsorption. Reduction of sodium concentration in the tubular
lumen creates concentration gradient of sodium between the
intersticium and tubular lumen. According to this concentration
gradient, sodium ions move through intercellular spaces into the
tubular lumen.
Mannitol increases the osmotic pressure of the blood that
promotes water movement into the blood vessels and the increase of
the circulating blood volume. Hypervolemia results in the release
increase of atrial natriuretic peptide which stimulates natriuresis.
Mannitol is used as a dehydrating agent in acute oedemas of
brain and lungs, in glaucoma, for forced diuresis in poisoned
patients, in acute renal failure, and in shock states with decrease of
blood pressure.
The drug is administered slowly intravenously. Diuretic effect
develops in 10–15 minutes and lasts 4–6 hours.
We should remember that the performance of dehydrating
therapy is dangerous in patients with heart failure. The raise of blood
osmotic pressure results in hypervolemia, particularly in patients
with concomitant renal failure. The increase of pulmonary circulation
pressure and systemic blood pressure can cause the overload of the
left ventricle and development of pulmonary oedema.
Therapy with mannitol can be aggravated by dehydration,
hyponatremia, impaired consciousness, nausea, vomiting, dizziness,
and chest pain. The drug is not reccommended for treatment of
children under 1 year.
Drugs Increasing the Renal Blood Supply
Aminophylline
(euphyllinum),
theophylline ,
and
theobromine increase diuresis due to the increase of renal blood
perfusion and glomerular filtration. Simultaneously drugs reduce, to
some extent, sodium reabsorbtion in proximal convoluted tubules. It
happens due to the ability of methylxanthines to stimulate purine
(adenosine) receptors and to inhibit the phosphodiesterase activity. It
results in accumulation of cAMP and decrease of vasopressin
activity.
Methylxanthines are weak diuretics. These drugs are prescribed
to elderly patients for reduction of insignifacant oedemas caused by
chronic diseases.
It should be noticed, that children are especially sensitive to
methylxanthines. Intravenous administration of the drugs can cause
them serious poisoning. Therefore, methylxanthines are
contraindicated to children under 2 years.
Diuretics of Vegetable Origin
Herbal diuretics occupy a special position among diuretics.
These agents are used in the form of infusions and broths. The
following herbal agents are used as diuretics: leaves of
bearberry, leaves of orthosiphon stamineus, leaves and
buds of birch, horsetail herb , flowers of cornflower , etc.
These drugs have low diuretic activity. Herbal diuretics are
prescribed to children and elderly patients with oedemas caused by
cardiovascular, hepatic, and inflamatory renal diseases. These drugs
are taken 3–4 times a day. Therapy with herbal diuretics does not
result in disturbances of electrolyte balance.
Lespenefril is a drug which is derived from leaves and stems
of Lespedeza capitata and anise fruit. The drug increases diuresis,
excretion of nitrogenous compounds, and excretion of sodium and
potassium ions. The drug is used for reduction of azotemia.
Therapeutic ndications for lespenefril are acute and chronic nephritis
with azotemia. The agent is also used for reduction of extrarenal
azotemia. Lespenefril is taken orally in a dose of 1–2 teaspoons a day.
In severe cases a dose may be increased up to 6 teaspoons a day.
A similar drug is lespeflan. The drug is taken in a dose of
1 teaspoon or 1 tablespoon 3–4 times a day. Duration of course of
treatment is 3–4 weeks. Lespeflan is contraindicated in pregnancy.
Principles of Combined Use of Diuretics
Diuretics are usually combined with each other as well as with
agents of other groups. Such combinations are used for treatment of
chronic heart failure, renal failure, hypertensive disease, etc.
To inchance the excretion of sodium and water from the
organism, diuretics with different mechanisms of action are
commonly combined. For example, osmotic diuretic (mannitol) is
combined with loop diuretics (furosemide, ethacrynic acid). This
combination is used in emergencies: for forced diuresis in poisoning,
in patients with acute brain or lung oedema.
Combination of diuretics acting on the level of basal membrane
(furosemide, hydrochlorothiazide, etc.) with diuretics acting on the
level of apical membrane (spironolactone, triamterene, etc.) is often
used in practice. Such combination increases the efficacy of diuretics
and prevents the hypokalemia. Phrmaceutical industry manufactures
ready-to-use combined drugs, such as “Triampur Compositum ”
(triamterene and hydrochlorothiazide), “Moduretic” (amiloride and
hydrochlorothiazide), etc.
Combination of diuretics with hypotensive agents is also widely
used in treatment of hypertensive disease. There are the following
ready-to-use combined drugs like: “Tenoric” (β-adrenergic
antagonist atenolol and diuretic oxodolinum), “Enap-H”
(angiotensin-converting
enzyme
inhibitor
enalapril
and
hydrochlorothiazide), “Adelphane” (sympatholytic reserpine and
arterial vasodilator dihydralazine), “Crystepin” (sympatholytic
reserpine, clopamide, and α-adreno-blocker dihydroergocristine), etc.
Potassium-sparing diuretics (spironolactone, triamterene) are
used together with cardiac glycosides for prevention of hypokalemia.
Diuretics can potentiate the effects of many antitumoral agents.
But it should be noticed, that certain diuretics can enchance
toxicity of other drugs. For example, furosemide and ethacrynic acid
increase ototoxicity of some antibiotics (gentamycin, etc.).
DRUGS INFLUENCING MYOMETRIUM
Uterus is a smooth muscle organ which is under control of
certain hymoral and nervous factors. Myometrium contains
M-cholinergic, α- and β-adrenergic receptors. M-cholinergic and
α-adrenergic receptors stimulate contractile activity of uterus, while
β2-adrenergic receptors inhibit it. Expressed stimulating influence
upon uterus is characteristic of estrogens, posterior pituitary hormone
oxytocin, and prostaglandins E2 and F2α. Progestins (progesterone)
inhibits the contractile activity of myometrium.
Drugs influencing upon uterus are classified into the following
groups:
1. Drugs stimulating contractile activity of uterus.
1.1. Drugs of oxytocin group: oxytocin, demoxytocin
(sandopart), methyloxytocin (mesotocin), pituitrinum .
1.2. Drugs
of
prostaglandin
group:
dinoprost
(prostaglandin F 2 α ), methyldinoprost, dinoprostone
(prostaglandin E 2 ).
1.3. Estrogens: estrone, estradiol, synoestrolum.
1.4. β-adrenoblockers: propranolol (anaprilinum).
1.5. Miscellaneous drugs: proserinum, pachycarpine,
castor oil, vitamins C and B 1 .
2. Drugs inhibiting uterine tone and contractile activity
(tocolytics).
2.1. Drugs stimulating β2-adrenergic receptors: fenoterol
(partusisten ), salbutamol , terbutaline.
2.2. General anaesthetics: sodium oxybutirate.
2.3. Hormonal drugs: progesterone.
2.4. Miscellaneous drugs: magnesium sulfate, tocopherol.
3. Drugs increasing uterine tone.
3.1. Ergot alkaloids: ergotal, ergotamine, ergometrine ,
methylergometrine, ergot extract.
3.2. Synthetic drugs: cotarnine.
4. Drugs decreasing uterine tone: atropine, dinoprost,
dinoprostone.
Drugs Stimulating Contractile Activity of Uterus
Drugs of Oxytocin Group
Oxytocin and prostaglandins are physiological stimulants of
uterine contractions. The membranes of smooth muscle cells in
uterus contain the receptors which are sensitive to these substances.
Excitation of these receptors causes the intrance of sodium and
calcium into the cells with depolarization and contraction of smooth
muscle cells.
Oxytocin is a polypeptide hormone of posterior pituitary which
consists of 8 amino acids. The drug in doses 3–5 UA causes the
rhythmic contraction of myometrium that promotes labor. Sensitivity
of pregnant uterus to oxytocin is higher than that of non-pregnant
uterus. High doses of hormone (up to 10 UA) cause more frequent
and stronger uterus contractions and promote the increase of
intrauterus pressure that can result in disturbances of blood supply to
placenta.
Oxytocin is destroyed when taken orally; therefore drug is
administered intravenously drop-by-drop. The effect of the drug
develops in 0.5–2 minutes. Oxytocin undergoes fast
biotransformation in the liver and kidneys. For arresting of uterus
bleeding, oxytocin may be administered intramuscularly.
Desamino-oxytocin is a synthetic analogue of oxytocin with
higher activity. The drug is used sublingually in the form of buccal
tablets. Therapeutic indications for desamino-oxytocin are
acceleration of uterine involution and stimulation of lactation.
Pituitrinum contains the mixture of hormones of posterior
pituitary – oxytocin and vasopressin. Therefore, this drug not only
stimulates the uterine contraction, but also increases the blood
pressure. The drug is administered subcutaneously or
intramuscularly. Therapeutic indications are the same as for
oxytocin.
Drugs of Prostaglandin Group
Small quantities of prostaglandins are permanently synthesized
in the uterus. Prostaglandins relax the uterus vessels, improve the
blood supply of placenta, and have cytoprotective effect.
Concenrtation of prostaglandins significantly increase in labor.
Prostaglandins E2 and F2α are used in medicine.
Dinoprost (prostaglandin F 2 α ) inhibits the function of
corpus luteum, blocks synthesis of progesteron, and increases the
level of estrogens. The drug sensitizes myometrium to oxytocin.
Dinoprost causes rhythmical contraction, increases the tone of both
pregnancy and non-pregnancy uterus, and relaxes the neck of uterus.
Prostaglandin F2α increases the bronchial tone, stimulates cardiac
rhithm and force of cardiac contraction, increases the motility of
gastrointestinal tract, increases the tone of pulmonary vessels, and
increases the vessels permeability.
Methyldinoprost is more active and long-acting dinoprost
analogue.
Dinoproston (prostaglandin E 2 ) causes the rhythmic
uterine contraction and relaxes the neck of uterus. Dinoproston
causes the degeneration of corpus luteum (luteolysis). The agent
reduces peripheral vascular resistance, relaxes pulmonary vessels and
bronchi, increases the capillar permeability, stimulates the motility of
gastrointestinal tract, and inhibits the gastric secretion.
Prostaglandins administration can cause excessive uterine
contraction with disturbances of uterus and placenta blood supply.
Duration of prostaglandins action is longer than that of oxytocin.
Most common side effects include nausea, diarrhea, headache, and
elevation of body temperature. Intravenous administration of
prostaglandins can cause phlebitis. Due to such side effects,
prostaglandins are seldom used for stimulation of labor. Drugs may
be used for abortions.
Administration of oxytocin and prostaglandins are admissible
only in clinic.
Estrogens
Such estrogens as estrone, estradiol, or synoestrolum are
commonly used for stimulation of labor. The drugs inhibit
oxycitonase patisipating in degradation of oxytocin and due to this
stabilize the level of oxytocin. In addition, estrogens sensitize the
receptors to oxytocin. For induction of labor, estrogens are
administered parenterally.
Β-Adrenoblockers
Anaprilinum (propranolol) decreases tocolytic effect of
catecholamines, which are released through β2-adrenergic receptors.
For induction of labor, anaprilinum is administered intravenously
drop-by-drop. The agent is contraindicated in parturient women with
heart failure, hypotension, bronchial asthama, and conduction blocks.
Miscellaneous Drugs
The following drugs may also be used for stimulation of labor:
proserinum, serotonin, pachycarpine, castor oil, calcium
chloride, ascorbic acid, and vitamin B 1 .
Proserinum inhibits the acetylcholinesterase activity and
promotes accumulation of acetylcholine near M-cholinergic
receptors of uterus. Excitation of M-cholinergic receptors increases
the uterine contraction.
Serotonin stimulates the intensivity of mitochondrial
respiratory function in myofibrils, interacts with ATP, actomyosin,
and calcium. The drug improves membrane permeability for calcium
ions that results in increase of uterine contraction. Serotonin is
administered intravenously drop-by-drop.
Pachycarpine is a ganglion blocker. The drug inhibits
Nn-cholinergic receptors of mesenteric ganglion. In addition,
pachycarpine stimulates the release of oxytocin by posterior pituitary
and sensitizes myometrium to action of estron and oxytocin.
Castor oil increases the cholinergic influence upon the uterus
and, therefore, stimulates contraction of myometrium.
Such vitamins as ascorbic acid and thiamin induce labor.
Vitamin C stimulates synthesis of estrogens, which stimulate the
uterine contraction. Thiamin stimulates synthesis of acetylcholine
and inhibits the activity of acetylcholinesterase. These effects result
in stimulation of labor.
Drugs Decreasing Uterine Tone and
Contractile Activity (Tocolytics)
β2-adrenergic receptors inhibit contractile activity and relax the
uterus. Quantity of β2-adrenergic receptors changes in different
periods of pregnancy. The highest density of β2-adrenergic receptors
in the uterus is observed during the last tremester of pregnancy that
provides the rest of the uterine muscle and child-bearing. Before and
during labor the density of β2-adrenergic receptors decreases that is
accompanied by the increase of uterus sencitivity to oxytocin and
estrogens.
Β2-adrenergic agonists are reliable drugs for reduction of tone
and contractile activity of myometrium. These drugs are widely used
in obstetric practice. The drugs have few side effects well tolerated
by pregnant women, and do not influence upon the fetus and
newborn negatively. The following β2-adrenergic agonists are used
as tocolytics: partusisten (fenoterol), salbutamol (salbupart),
and terbutaline (bricanyl). The drugs are prescribed orally,
intramuscularly, and intravenously drop-by-drop. Maximal tocolytic
effect develops in 2 hours after drug intake orally, in 30 minutes after
intramuscular administration, and in 5–10 minutes after intravenous
administration. Administration of β2-adrenominetics can cause
tachycardia (both in mother and fetus), constipations, nausea,
anxiety, decrease of diastolic blood pressure, and hyperglycemia.
Therapeutic indicatons for β2-adrenomimetics are the folliwng:
- prevention of premature labors;
- high tone of the uterine neck at onset of labor;
- excessive fast delivery with strong and fast uterine contraction
which create a threat of uterine rupture;
- fetus hypoxia because of delivery abnormalities, the need for
intrauterine fetal resuscitation;
- performance of intrauterine fetal rotation, especially in case of
twins;
- preparation to operation during delivery (cesarean section).
Substitutive therapy by progesterone or synthetic progestin
turinal is used in cases of threat of abortion in early period of
pregnancy (under 4 months) and in recurrent abortions owing to
insufficient production of progesterone. Also, in these cases
vitamin E (tocopherol) is used.
Magnesium sulfate is an antagonist of calcium. For
relaxation of uterus this agent is administered intravenously in dose
5–10 ml of 25% solution.
Recently nifedipine calcium channel antagonist is used as a
tocolytic.
Sodium oxybutyrate is a general anaesthetic. The agent
sometimes is used for decrease of excessive uterine contraction
during delivery.
Drugs Increasing Tone of Myometrium and
Involution of Uterus in the Postpartum Period
Postpartum uterine atony and delayed involution are
accompanied by bleeding which can cause the gemorrhagic anemia.
Most effective agents for elimination of uterine atony are drugs
containing ergot alkaloids: ergotamine,
ergometrine,
methylergometrine, ergotal, and ergot extract. A synthetic
drug cotarnine is also used in this case. Oral intake or
intramuscular administration of these drugs is accompanied by stable
contraction of myometrium. It results in mechanical compression of
blood vessels and bleeding cessation. Similar effect is also typical for
oxytocin in postpartum period.
Therapeutic indications for the use of drugs increasing
myometrium tone are the following:
- postpartum bleeding, uterine atony, delayed involution of
uterus, bleeding after manual placenta separation;
- dysfunctional uterine bleeding in woman with uterine fibroids;
- bleeding owing to inflammation;
- ergometrine is also used in migraine.
Treatment by ergot alkaloids can be accompanied by the
following side effects: nausea, vomiting, diarrhea, and headache.
Overdose of ergot alkaloids causes the acute poisoning with the
following symptoms: excitement, convulsions, nausea, vomiting,
epigastric pain, tachycardia, and disturbances of sensitivity.
Prolonged drugs use can cause chronic poisoning – ergotism which
exists in two clinical forms: gangrenous and convulsive. Gangrenous
form develops owing to spasm of peripheral vessels and following
necrosis of the extremities. Convulsive form is caused by the drug
influence upon central nervous system.
Drugs Decreasing the Uterine Neck Tone
This group includes atropine, No-spa, dinoprost, and
dinoprostone. The drugs that relax uterine neck and promote labor.
Lidasum is also used in case of cervix rigidity. The drug contains
enzyme hyaluronidase which destroys hyaluronic acid.
DRUGS USED FOR GOUT TREATMENT
Gout is the disease which develops due to disorders of purine
metabolisim. In this disease the concentration of urates is increased
that causes formation of urolithes and development of inflammation.
Classification of drugs which are used for gout treatment:
1. Drugs decreasing the uric acid concentration in blood:
- drugs increasing the excretion of uric acid by kidneys:
aethamidum, probenecid, urodanum;
- drugs reducing the synthesis of uric acid: allopurinol.
2.
Antiinflammatory
drugs:
colchicine,
steroid
antiinflammatory drugs (prednisolone, dexamethazone),
nonsteroid antiinflammatory drugs (indomethacin, diclofenac
sodium, phenylbutazone).
Aethamidum and probenecid inhibit the reabsorbtion of uric
acid in proximal convoluted tubules of nephron. The drugs are used
for treatment of chronic gout. Urodanum increases the solubility of
salt of uric acid in the water that results in an increase of its excretion
with urine.
Allopurinol is the inhibitor of xanthine oxidase (enzyme which
catalizes the transformation of hypoxantine and xanthine into the uric
acid). The drug suppresses the synthesis of uric acid. The effect of
allopurinol develops slowly. The concentration of uric acid in the
blood is normalized in 7–10 days from the start of treatment; the
elimination of urates from tissues is observed in several months.
Antiinflammatory drugs are used for interruption of acute
attacks of gout. Colchicine inhibits proliferation of granulocytes
and their migration into the inflammatory arreas. The drug, also,
reduces the concentration of glycoprotein and lactate and suppresses
the accumulation of crystals of uric acid in tissues. Colchicine stops
the attack of gout in several hours. Side effects of colchicine are
inhibition of hemopoiesis, nausea, vomiting, abdominal pain, etc.
Pharmacological characteristic of steroid and nonsterois
antiinflammatory drugs are given in related topics.
Table 2 – Drugs for prescription
Drug name
1
Dichlothiazidum
Oxodolinum
Triamterenum
Furosemidum
Acidum
etacrinicum
Spironolactonum
Mannitum
Single dose and mode of
administration
2
0.025-0.05 g 1-2 times per day orally
0.025-0.1 g once in 2 or 3 days
orally
0.05-0.1 g 2 times per day orally
0.04 g once a day in the morning orally;
0.02 g 1-2 times per day
intramuscularly or intravenously
0.05-0.1 g 1 time a day or once in
2 days orally;
0.05 g once a day intravenously
0.025-0.05 g once a day orally
0.5-1,5 g/kg intravenously
Drug product
3
Tablet 0.025 or 0.1 g
Tablet 0.05 g
Capsule 0.05 g
Tablet 0.04 g;
ampoule 2 ml of 1%
solution
Tablet 0.05 g;
ampoule 0.05 g of dry
substance (dissolved
before administration)
Tablet 0.025 g
Bottle 30.0 g of dry
substance (dissolved
and used as 10-15%
solution);
ampoule 200, 400 or
500 ml of 15% solution
Table 2 continuation
1
2
Ergometrini
0.0002-0.0004 g 2-3 times per day
maleas
orally;
0.0001-0.0002 g 2-3 times per day
intramuscularly or intravenously
Oxytocinum
Drop-be-drop 5 UA in 500 ml of
5% glucose solution intravenously;
0.2-2 UA intramuscularly
Aethamidum
0.35 g 4 times per day orally
Allopurinolum
0.1-0.2 g once per day orally
Fenoterolum
0.005 g 4-6 times per day orally;
drop-be-drop 0.0005 g in isotonic
solution of NaCl or glucose
intravenously
3
Tablet 0.0002 g;
ampoule 0.02% - 1 ml
Ampoule 1 ml (5 UA)
Tablet 0.35 g
Tablet 0.1 g
Tablet 0.005 g;
ampoule 10 ml of
0.005% solution
DRUGS INFLUENCING HEMOPOIESIS
These drugs are devided into the following groups:
I. Drugs influencing erythropoiesis.
1. Drugs stimulating erythropoiesis.
1.1. Drugs which are used for treatment of hypochromic (irondeficiency) anemias:
- iron-containing mono-drugs: ferrous sulfate , ferrous
lactate, Ferrum-Lek;
- iron-containing combined drugs: Fercoven (iron and cobalt
salts with carbohydrate solution), Ferroplex (iron lactate with
ascorbic acid), Ferramidum (complex compound of iron with
nicotinamide), Tardyferon (iron lactate, ascorbic acid, and
mucoprotease), Haemostimulinum (iron lactate and copper
sulfate);
- cobalt-containing drugs: Coamidum;
- recombinant human erythropoietins: epoetin alfa, epoetin
beta.
1.2. Drugs which are used for treatment of hyperchromic
anemias: cyanocobalamin, folic acid.
2. Drugs inhibiting erythropoiesis: sodium phosphate with
radioactive isotope 3 2 P.
II. Drugs influencing leukopoiesis.
1. Drugs stimulating leukopoiesis:
- non-specific drugs which stimulate the synthesis of nucleic
acid: sodium nucleinate, pentoxylum, methyluracilum ,
leukogenum;
- myeloid growth factors: lenograstim, molgrastim,
filgrastim.
2. Drugs inhibiting leukopoiesis:
2.1. Drugs inhibiting leukocytes in interphase:
- alkylating
drugs:
cyclophosphanum
(cyclophosphamide),
thiophosphamidum
(thiotepa),
myelosanum;
- antimetabolites: methotrexate, mercaptopurine;
- cytotoxic antibiotics: rubomycinum;
- glucocorticoids: prednisolone, dexamethazone;
- enzyme agents: L-asparaginase;
- cytokines: interferon α.
2.2. Drugs which inhibit mitosis of leukocytes:
- cytotoxic drugs of plant origin: vinblastine, vincristine.
Drugs Influencing Erythropoiesis
Iron ions, cyanocobalamin, and folic acid are primarily
necessary for normal erythropoiesis. Their deficiency is accompanied
by development of anemia. Erythropoietin stimulates erythropoiesis.
This hormone is synthesized by peritubular intersticial renal cells
(about 90%) and in the liver (10%). Erythropoietin stimulates
proliferation and differentiation of erythrocytes.
Drugs Stimulating Erythropoiesis
Drugs which are Used for Treatment of Hypochromic
Anemias
Main cause of hypochromic anemia is insufficient production of
hemoglobin by erythroblasts of bone marrow over iron deficiency.
Iron deficiency most commonly develops due to iron deficit in food,
disturbances of absorption, bleeding, during pregnancy, lactation,
etc.
Iron-containing drugs are the main agents which are used for
treatment of hypochromic anemias. Daily demand of iron for adults
is about 0.2 mg/kg (considering that only 10% of taken iron is
absorbed into gastrointestinal tract). Distribution of iron in organism
is the following: about 70% of iron (3–4 g) is included in
hemoglobin, 10–20% is deposited in the forms of ferritin and
hemosiderin, 10% is included in muscular protein myoglobin, and
about 10% is in structure of respiratory and other enzymes.
Only ionized iron (better in form of divalent ion) is absorbed in
gastrointestinal tract. Hydrochloric acid transforms a molecular iron
into an ionized form. Ascorbic acid restores trivalent iron to divalent
one. Therefore, hydrochloric acid and ascorbic acid are necessary for
normal absorption of iron in gastrointestinal tract. Iron absorption
occurs mainly due to active transport. Apoferritin of intestinal
mucosa binds to iron ions with formation of ferritin. After entering
blood circulation, iron ions interact with β1-globulin transferrin. This
transport system delivers iron to various tissues, including bone
marrow, where iron is being released and included to structure of
hemoglobin. The excess of iron is deposited in forms of ferritin or
hemosiderin. Iron is eliminated from the body through intestine,
kidneys, and sweat glands.
In case of hypochromic anemias, iron-containing drugs are
prescribed mainly orally. For prevention of contact of iron with
mucous membrane of oral cavity, iron-cntaining drugs are used in
form of tablets with special coating or in capsules. Because of iron
ability to bind with hydrogen sulfide, coloring teeth black, iron
sulfide is being formed. Due to formation of iron sulfide, intake of
iron-containing drugs also can cause constipation.
Iron-containing drugs are taken 1.5 hours prior meal or 2 hours
after meal.
Recently, combined iron- and vitamin-containing drugs are used
in medicine for treatment of hypochromic anemias. They are:
Ferroplex,
Sorbifer,
Ascofer,
Globiron,
etc.
Ferrogradumet is a representative of combined drugs with
prolonged action.
Treatment of hypochromic anemia lasts 3–6 months. First
improvement of hemopoiesis is observed in 5–7 days after starting
drug intake. In case of therapeutic effect failing, parenteral
administration of iron-containing drugs is started. Parenteral
administration of iron-containing drugs is possible only for inpatients, because it is commonly accompanied by side effects:
redness of the face and neck, lower back pain and joint pain,
tightness in the chest, tachycardia, nausea, vomiting, allergic
reactions, etc. These side effects are eliminated by administration of
analgesics and atropine.
Coamide is a cobalt-containing drug which is used for
treatment of hypochromic anemias. It is compound of cobalt and
amide of nicotinic acid. Cobalt stimulates erythropoiesis and
promotes absorption of iron in gastrointestinal tract. Coamide is
administered subcutaneously.
Recently, recombinant human erythropoietins are used in
medicine. Epoetin alfa and epoetin beta are such drugs. They
are used for treatment of anemias in chronic renal deseases,
rheumatoid arthritis, aplastic anemia, malignant diseases of bone
marrow, AIDS, etc. The drugs are administered subcutaneously or
intramuscularly 3 times a week. Side effects are headache,
hyperkalemia, arthralgias, etc. Therapeutic effect develops within
2 weeks, and normalization on hemopoiesis is observed in
8–12 weeks.
Drugs Used for Treatment of Hyperchromic Anemias
Megaloblastic anemia develops due to deficiency of vitamin B12
(cyanocobalamin). Lack of vitamin B12 results in disturbances of
DNA synthesis and patological changes in erythropoiesis.
Disturbances of erythropoiesis may be caused by anemia of
megaloblastic type. The large erythrocytes with high RNA/DNA
ratio are produced in megaloblastic anemia. Red blood cells are oversaturated with hemoglobin. Color index is usually more than 1.1–1.3.
However, the total hemoglobin in the blood is reduced considerably
due to the significant decrease in the number of red blood cells.
Megaloblastic anemia occurs due to the loss of Castle’s intrinsic
factor. This glycoprotein of gastric mucosa is necessary for
absorption of vitamin B12. Deficiency of Castle’s intrinsic factor
develops in Addison Biermer anemia (primary loss of Castle’s
intrinsic factor), total gastrectomy, atrophy of mucous membrane of
stomach and duodenum, invasion by broad tapeworm, and
exclusively vegetable diet. Deficiency of Castle’s intrinsic factor
results in reducrion of vitamin B12 absorption and disturbances of
neucleic acid synthesis. Beside erythropoiesis, peripheral nervous
system is also affected in megaloblastic anemia. This is a result of
reduction of myelin synthesis in which cyanocobalamin participates
as a cofactor. Therefore, along with megaloblastic anemia there is a
damage to the nervous system.
In megaloblastic anemia, cyanocobalamin is administered
intramuscularly once a day or every other day. Normalization of
erythropoiesis, functions of gastrointestinal tract and nervous system
is observed in 1–2 month.
Folic acid (vitamin B c ) participates in synthesis of proteins,
nucleic acids, and macroergic compounds. Deficiency of folic acid
results in disturbances of erythropoiesis with development of
macrocytic anemia. In this case, erythroblast turns into hyperchromic
macronormoblast with following transformation into macrocyte.
Folic acid is prescribed for treatment of alimentary and druginduced macrocytic anemia, celiac sprue, and anemias of pregnancy.
Drug-induced anemia can develop owing to therapy with
dipheninum, phenobarbital, isoniazide, hormonal drugs, etc.
The alone use of folic acid in patients with megaloblastic anemia
normalizes erythropoiesis but does not reduce pathological changes
of nervous system and gastrointestinal tract. Therefore, folic acid
may be used for treatment of megaloblastic anemia only with
cyanocobalamin.
Folic acid is taken orally. Sometimes, the drug may cause
allergic reactions.
Herbal Drugs Used for Treatment of Anemias
Herbal drugs are widely used for treatment of anemias because
these drugs contain a variety of microelements, vitamins,
antioxidants, and other bioactive substances stimulating
erythropoiesis. These drugs increase the resistance to unfovarable
factors, imrove health, stimulate immunity and hemopoiesis.
Herbal drugs for treatment of anemia include strawberry
fruit, black currant, rowan, rose, etc.
Drugs Inhibiting Erythropoiesis
Drugs inhibiting erythropoiesis are used for treatment of
polycythemia (hyperglobulia). Solution of sodium phosphate
with radioactive isotope 3 2 P is one of these drugs. Use of this
agent reduces the number of erythrocytes and platelets. Drug is
administered intravenously or taken orally.
Drugs Influencing Leukopoiesis
Drugs Stimulating Leukopoiesis
Various poisons, radioactive radiation, certain medicines, etc.
can damage leukopoiesis. It results in leukopenia and
agranulocytosis. The following drugs are used for correction of these
disturbances of leukopoiesis: sodium nucleinate, pentoxylum,
methyluracilum, leucogenum , molgramostim, filgrastim,
etc.
Sodium nucleinate is sodium sult of nucleic acid which is
obtained from yeast. For stimulation of leukopoiesis, drug is
administered intramuscularly or taken orally.
Pentoxylum is a synthetic agent – a derivative of pyrimidine.
Pentoxylum stimulates leukopoiesis, accelerates wounds healing, and
has anti-inflammatory effect. The drug is taken orally 3–4 times a
day.
Methyluracilum is a synthetic agent stimulating synthesis of
pyrimidine nucleotides, increasing leukopoiesis, accelerating wound
healing, and stimulating immunity (antibody synthesis and interferon
production). Also, the drug has anti-inflammatory action.
Methyluracilum is taken orally and applied topically in ointments.
Indications for use are leukopenia, agranulocytosis, gastro-duodenal
ulcers, wounds, burns, bone fractures, and chronic pancreatitis.
Leukogenum is prescribed for treatment of leukopenia and
agranulocytosis. The drug potentiates the effects of other
leukopoiesis stimulators. Leukogenum is taken orally.
Recently, regulating leukopoiesis growth factors are introduced
in medical practice. Molgrastim and filgrastim are among them.
Human
recombinant
granulocyte-macrophage
colony
stimulating factor is created by genetic engineering. Appropriate
drug is called molgramostim. This glycoprotein stimulates the
proliferation, differentiation, and activity of granulocytes and
monocytes. These cells carry out phagocytosis, stimulate immunity,
and produce biologically active substances regulating cytokines
production. The drug increases the protective properties of the
organism against bacteria, fungi, and tumors. Molgramostim is
administered intravenously in cases of inhibition of leukopoiesis due
to cancer chemotherapy, after bone marrow transplantation, in
aplastic anemia, and in AIDS. Side effects of molgramostim are
nausea, vomiting, diarrhea, hypertermia, muscular pain, and allergic
reactions.
Filgrastim is a recombinant human granulocyte colony
stimulating factor. It is also glycoprotein. The agent stimulates
proliferation and differentiation of granulocytic progenitor cells and
increases the activity of mature granulocytes. Therapeutic indications
for filgrastim are the same as for molgramostim. Filgrastim is
administered intravenously or subcutaneously. Side effects are
seldom and include arthralgias, allergic reactions, disturbances of
hepatic function, etc.
Pharmacokinetics and pharmacodynamics of drugs inhibiting
leukopoiesis will be considered in the chapter “Antitumoral drugs”.
Table 3 – Drugs for prescription
Drug name
1
Ferri lactas
Fercovenum
Coamidum
Single dose and mode of
Drug product
administration
2
3
1.0 g 3–5 times daily orally
Capsule 1.0 g
2–5 ml once a day intravenously Ampoule 5 ml
Chlorbutinum
0.01 g once a day
subcutaneously
2 ml 1–2 times per day
intramuscularly;
2–5 ml once a day
intravenously
0.0001–0.0005 g once a day
subcutaneously, intramuscularly or intravenously
0.005 g once a day orally
0.2–0.3 g 3 times per day orally
0.000005 g/1 kg once a day
intravenously or
subcutaneously
0.2–0.4 g once a day orally,
intravenously or
intramuscularly
0.002–0.01 g once a day orally
Myelosanum
0.002–0.006 g once a day orally Tablet 0.002 g
Ferrum Lek
Cyanocobalaminum
Acidum folicum
Penthoxylum
Filgrastimum
Cyclophosphanum
Ampoule 1 ml of 1%
solution
Ampoule 2 (for
intramuscular
introduction) or 5 ml (for
intravenous introduction)
Ampoule 1 ml of 0.003%,
0.01%, 0.02% or 0.05%
solution
Tablet 0.001 g
Coated tablet 0.2 g
Bottle with 0.0003 g or
0.00048 g of dry
substance
Coated tablet 0.05 g;
ampoule with 0.1 g or
0.2 g of dry substance
Tablet 0.002 g or 0.005 g
Table 3 continuation
1
Methotrexatum
Mercaptopurinum
Vinblastinum
(Rosevinum)
2
0.03 g 2 times per week or
0.05 g once per 5 days orally,
intramuscularly or
intravenously
0.001–0.00125 g / 1 kg once a
day orally
0.00015–0.0003 g/kg once per
week intravenously
3
Coated tablet 0.0025 g;
ampoules with 0.005,
0.05 or 0.1 g of dry
substance
Tablet 0.05 g
Ampoule with 0.005g or
0.01 g of dry substance
DRUGS INFLUENCING BLOOD
COAGULATION
Two systems exsist in organism in dynamic equilibrium: one of
them promotes blood clotting and another system prevents it. The
system promoting blood coagulation consists of platelets and plastic
clotting factors which are contained in them, as well as plasma
proteins sinthesized in liver (prothrombin, kappa factor, fibrinogen,
etc.). The system preventing blood clotting consists of proteolytic
enzyme fibrinolysin (plasmin), its predecessor profibrinolysin
(plasminogen), plasma proteins inhibiting thrombin formation
(antithrombin III, etc.), as well as substances which are produced or
fixed on the vascular endothelium (prostacyclin, heparin, etc.).
Disequilibrium between these two systems causes either
angiostasis or thrombosis. Sometimes, unification of both
phenomena develops – syndrome of disseminated intravascular
coagulation. These pathological states require the pharmacological
correction.
Drugs influencing blood coagulation are classified into the
following groups.
I. Drugs which are used for prevention and treatment of
thrombosis.
1. Drugs decreasing blood coagulation (anticoagulants):
1.1. Directly acting anticoagulants.
1.2. Indirectly acting anticoagulants.
2. Drugs which activate fibrinolysis (fibrinolytics).
3. Drugs decreasing platelets aggregation (antiaggregants).
II. Drugs which promote blood coagulation (hemostatics).
1. Drugs increasing blood clotting (procoagulants).
2. Drugs inhibiting fibrinolysis (antifibrinolytics).
3. Drugs promoting platelets agregation.
Drugs for Prevention and Treatment of Thrombosis
Drugs Decreasing Blood Coagulation (Anticoagulants)
Blood clotting is ordered system of enzymatic reactions with
partisipation of numerous factors of coagulation. Final result of these
reactions is formation of thrombin which influences fibrinogen
convertion into insoluble fibers of fibrin.
According to mechanism of action, drugs decreasing blood
coagulation are divided into the following groups:
1. Directly acting anticoagulants (agents which inactivate
clotting factors directly in blood): heparin, fraxiparin,
enoxaparin, dalteparin, nadroparin, hirudin, sodium
hydrocitrate.
2. Indirectly acting anticoagulants (agents which inhibit the
synthesis of clotting factors in the liver): neodicumarinum,
syncumarum, warfarin, phenindione.
Directly Acting Anticoagulants
Heparin is a natural anticoagulant which is synthesized by
mast cells and basophils. Especially high concentration of heparin is
contained in liver and lungs. Heparin is an acidic
mucopolysaccharide with molecular weight 15,000–20,000 daltons.
Molecules of heparin contain residues of sulfuric acid. Due to that,
they have expressed acidity and negative charge. Heparin is obtained
from lungs and liver of cattle.
Negatively charged sites of heparin interact with positively
charged amino groups of antithrombin III. The activated
antithrombin III neutralizes the IIa, IXa, Xa, XIa, XIIa, XIIIa clotting
factors and suppresses the prothrombin transformation into thrombin.
Moreover, heparin increases the activity of fibrinolytic system
owing to formation of complex with antifibrinolysin (factor VII,
proconvertin, serum prothrombin conversion accelerator).
Also, heparin inhibits the adhesion and aggregation of platelets
because heparin molecules fix on the surface of endotheliocytes and
blood cells that creates negative charge of endothelial surface and
surface of platelets. Thus, heparin is an anticoagulant with
antiaggregatory and fibrinolytic activity. Heparin is active both in
vivo and in vitro.
Heparin has also antiallergic effect. The agent suppresses
cooperation of T- and B-lymphocytes and synthesis of
immunoglobulines, and activates histaminase.
Heparin increases pulmonary ventilation and coronary blood
circulation, inhibits complement system and excessive synthesis of
aldosterone, activates lipoprotein lipase and decreases blood level of
cholesterol and β-lipoproteins.
Heparin is administered intravenously, intramuscularly,
subcutaneously, in inhalations, and by electrophoresis. The agent
may be also used topically in ointments and cremes. In intravenous
administration, the heparin effect develops immediately and lasts up
to 4–6 hours. In case of subcutaneous administration, onset of the
effect is in 40–60 minutes and duration is up to 12 hours. The
maximum effect of inhaled heparin occurs in 18–20 hours and lasts
up to 2 weeks. An average therapeutic dose of intravenously
administered heparin in urgent cases (for example, acute myocardial
infarction) is 15,000–20,000 UA. In critical case (pulmonary arterial
thromboembolism) the dose is increased up to 40,000–60,000 UA
with following intramuscular or subcutaneous administration of
heparin (5,000–10,000 UA) every 4 hours. Discontinuaton of heparin
administration should be gradual because a sudden stop of heparin
therapy can result in hypercoagulation.
Therapeutic indications for heparin are the following:
- thrmbosis of coronary vessels in myocardial infarction;
- thromboembolism of pulmonary and cerebral vessels;
- thrombophlebitis;
- prevention of thromboembolism during surgery and in
postsergical period in patients with embolism in anamnesis;
- lengthy orthopedic surgery and sugery of heart and vessels;
- prevention of blood clotting in a ventricular assist device;
- thrombophlebitis of superficial veins of lower extremities
(commonly in form of ointments and cremes);
- diseases with increased risk of thrombosis: atrial fibrillation,
endarteritis, acute nephritis);
- treatment of bronchial asthma and rheumatism.
High-molecular-weight heparin does not cross through placenta
and is not excreted in breast milk. Therefore, this heparin is the drug
of choice in case of need to prescribe a direct anticoagulant to
pregnants and breast-feeding mothers.
Heparin therapy can cause the following complications:
1. Main complication of heparin therapy is bleeding due to
overdose. In this case, antagonist of heparin is administered –
protamine sulfate. The agent is administered intravenously slowly.
1 mg of protamine neutralizes 85–100 UA of heparin. Duration of
action of protamine sulfate is 2 hours.
2. Thrombocytopenia, which may be of two different types.
Moderate thrombocytopenia, which develops within 2–4 days from
starting heparin treatment; it is transient and is eliminated in
following treatment.
Life-threatening is thrombocytopenia which develops after
6–12 days of treatment. Its mechanism is related to antibodies
formation (immunoglobulins G and M) which causes platelets
aggregation. Owing to this, heparin-induced thrombosis (white clot
syndrome), which can cause embolia, is developed.
3. Dispeptic disorders.
4. Allergic reactions.
5. Osteoporosis and calcification of soft tissues. This
complication is developed in long-term use of heparin. It is caused
by binding of calcium with heparin and fatty acids, which are formed
due to the increase of activity of lipoprotein lipase and parathormone.
6. Alopecia.
7. Rethrombosis in case of sudden cessation of heparin therapy.
For prevention of rethrombosis, cessation of heparin therapy should
be gradual and with use of indirect anticoagulants.
Recently, the new group of anticoagulants is introduced in
medicine
–
low-molecular-weight
heparins:
logiparin,
dalteparin, fraxiparin, nadroparin. Molecular weight of these
heparins is 2,500–8,000. These drugs are obtained by method of
enzymatic depolymerization of heparin by bacterial heparinase. Lowmolecular-weight heparins do not change the time of blood
coagulation, because these drugs do not inhibit factor IIa (thrombin).
Mechanism of these drugs action is associated with the increase of
action of antithrombin III upon factor Xa of blood clotting which is
required for transformation of prothrombin into thrombin. Main
influence of low-molecular-weight heparins is directed to the
decrease of adhesion and aggregation of thrombocytes.
Bioavailability of these drugs is three times more than bioavailability
of heparin. Duration of these drugs action is longer. Therefore, drugs
are administered subcutaneously 1–2 times a day. Low-molecularweight heparins seldom cause hemorrhages and thrombocytopenia.
Antagonist of low-molecular weight heparins is protamine sulfate.
Hirudin is an anticoagulant, which is contained in salivary
glands of leech. It is a polypeptide which consists of 65 residues of
amino acids. Hirudin inactivates thrombin. Lepirudin is recombinant
analog of hirudin which is used in medicine. The drug is
administered intravenously. Lepirudin has short duration of action:
half-life is 1.3 hours. The agent can cause hemorrhages. The
antagonist for lepirudin does not exist.
Recently, there were synthesized derivatives of hirudin:
bivalirudin and low molecular weight agents melagatran and
ximelagatran. Bivalirudin is administered intravenously for
anticoagulant therapy during percutaneous transluminal coronary
angioplasty. Melagatran is administered subcutaneously for
prevention of venous thromboembolism in patients undergoing hip or
knee elective surgery. Ximelagatran is taken orally. Its indications
are similar to melagatran.
Sodium citrate is also a directly acting anticoagulant. The
agent interacts with calcium ions which participate in transformation
of prothrombin into thrombin. 4–5% solution of sodium citrate is
used for preservation of donor blood.
Indirectly Acting Anticoagulants
Group of indirectly acting anticoagulants consists of synthetic
agents which inhibit the biosynthesis of vitamin K-dependent
clotting factors in liver. This group includes neodicumarinum,
syncumarum, warfarin, and phenindione.
A chemical structure of neodicumarinum is similar to
structure of vitamin K that results in structural antagonism between
neodicumarinum and vitamin K. Neodicumarinum inhibits enzyme
epoxide reductase catalyzing transformation of vitamin K epoxide
form into the hydroquinone form. Namely the hydroquinone form of
vitamin K is active and participates in the synthesis of prothrombin
(factor II), prothrombin conversion factor (factor VII),
antihemophilic globulin B (factor IX), and thromboplastin (factor X).
Because neodicumarinum inhibits the synthesis of clotting factors in
liver, the agent is active only in vivo.
Neodicumarinum also inhibits the activity of the factor
supporting the elastisity of vessels walls. Therefore, the prolonged
intake of neodicumarinum increases the fragility and permeability of
capillaries.
Neodicumarinum is taken orally 3–4 times a day. The drug is
characterized by high degree of gastrointestinal absorption.
Anticoagulant effect develops in 2–3 hours and reaches the
maximum in 12–24 hours. The duration of the latent period is
affected by the synthesized clotting factors in blood. After cessation
of drug intake, anticoagulant effect lasts 1.5–2 days.
Neodicumarinum can easily penetrate through placenta. The drug
accumulates in the body.
Therapeutic indications for neodicumarinum are the following:
1. Prevention and treatment of venous thrombosis,
thrombophlebitis, myocardial infarction, ischemic stroke.
2. Prevention of thrombosis in postoperative period.
3. Prevention of thrombosis and thromboembolia in patients with
rheumatic heart damages.
4. Prevention of thrombosis after angioplasty, prosthetic heart
valves.
5. Prevention of thrombosis after cessation by therapy with
directly acting anticoagulants.
Therapy with neodicumarinum can be aggravated by the
following side effects:
1. Hemorrhages due to excessive inhibition of blood clotting and
increase of vessels permeability. In this case it is necessary to stop
neodicumarinum intake and prescribe vitamin K or vicasolum
(menadione), vitamins C and P. Blood transfusion is also possible.
2. Coumarin-induced necrosis of soft tissues (buttocks, breasts,
cheeks, etc.) due to thrombosis of capillaries and small venules. This
complication develops in 4–10 days after start of drug intake.
Coumarin-induced thrombosis more frequently develops in women.
A cause of coumarin necrosis is low levels of protein C, a serine
protease with anticoagulant and fibrinolytic activity. In the presence
of indirectly-acting anticoagulants, the levels of protein C is
decreased more rapidly than the levels of procoagulant factors IX, X
and prothrombin. Therefore, when indirect anticoagulant is given to a
patient with low levels of protein C, a transient hypercoagulable state
can develop that result in local thrombosis.
3. Dispepsia.
4. Allergic reactions.
5. Toxic damage of liver and kidneys.
6. Drug intake by pregnant woman can cause malformations of
the skeleton in the first part of pregnancy and hemorrhage in fetus in
late pregnancy.
7. Sudden stop of neodicumarinum intake can cause thrombosis.
Warfarin, syncumarum, and phenindione mechanism of
action, effects, and indications for use are similar to
neodicumarinum. Main difference of these drugs is a longer latent
period (anticoagulant effect develops in 24–72 hours) and longer
duration of action – up to 2–4 days.
Antagonists of indirectly acting anticoagulants are vitamin K
and its synthetic analog – vicasolum.
Drugs Activating Fibrinolysis (Fibrinolytic Drugs)
The fibrinolytic system is involved in restricting clot
propagation in blood and in the fibrin removal as wounds healing.
Treatment of patients with fibrinolytic drugs is not a substitute for
the anticoagulant drugs. Because the purpose of thrombolytic therapy
is a rapid lysis of already formed clots, while the aim of
anticoagulant therapy is a prevention of the new clotting formation.
Fibrinolysis is initiated due to the transformation of
profibrinolysin (plasminogen) of clots and plasma into fibrinolysin
(plasmin). Fibrinolysin is a proteolytic enzyme which normally does
not exist in blood. Fibrinolysin catalyzes the degradation of fibrin.
Plasminogen activators (tissue plasminogen activator and a singlechain urokinase-type plasminogen activator) are necessary for
transformation of profibrinolysin into fibrinolysin. Plasminogen
activators are synthesized in vascular endothelium and released into
the blood.
Fibrinolytic drugs cause lysis of formed clots in both arteries and
veins and reestablish tissue perfusion.
Fibrinolytic drugs are devided into 2 groups.
1. Directly acting fibrinolytics: fibrinolysin.
2. Indirectly acting fibrinolytics: streptokinase, streptodecase,
anistreplase, urokinase, and alteplase.
Fibrinolysin is a proteolytic enzyme which is formed in the
result of activation of profibrinolysin by trypsin. Fibrinolysin causes
only superficial lysis of thrombus (predominantly in veins) because
fibrinolysin is quickly neutralized by antiplasmin. Fibrinolysin is
active both in vivo and in vitro. The drug is administered
intravenoulsy drop-by-drop. Immediately prior to administration, dry
fibrinolysin is dissolved in sterile isotonic sodium chloride solution
or isotonic glucose solution at the rate of 100–160 UA of fibrinolysin
in 1 ml of solution. Heparin should be added to this solution at the
rate 1 UA of heparin for 2 UA of fibrinolysin. Course of treatment
with fibrinolysin can last 10–14 days.
Therapeutic indications for fibrinolysin use are thrombosis of
peripheral arteries, myocardial infarction, ischemic stroke, and
thrombosis of peripheral veins. It should be noticed, that in case of
arterial trombosis, fibrinolysin is effective during the first day (initial
6 hours after thrombosis); while, in case of venous thrombosis, the
drug is effective during 5–7 days.
Therapy with fibrinolysin can be accompanied by hemorrhages.
In this case, aminocapronic acid is given. Because fibrinolysin is the
drug of peptide origin, its administration may be accompanied by
allergic reactions.
Streptokinase is an enzymatic agent which is obtained from
culture of β-hemolytic streptococcus. This is a fibrinolytic drug with
indirect action. Streptokinase forms a complex with plasminogen
which results in a conformational change and exposure of an active
site that can convert additional plasminogen into plasmin. Unlike
fibrinolysin, streptokinase is capable to penetrate inside thrombus
where it activates fibrinolysis. The drug is administered
intravenously or intra-arterially drop-by-drop during 16–18 hours.
Onset of action starts in 30–60 minutes. The course of treatment lasts
4–6 weeks.
Therapeutic indications for streptokinase are the following:
1. Embolism of pulmonary artery and its branches.
2. Acute thrombosis and ambolism of peripheral arteries.
3. Acute thrombosis of superficial and deep veins.
4. Acute myocardial infarction (during first 8 hours).
5. Acute thrombosis of retinal thrombosis.
Side effects include hemorrhages, hemolysis, nephrotoxicity,
and allergic and anaphylactic reactions.
Streptodecase is a prolonged form of streptokinase which is
applied to the water-soluble polysaccharide matrix. Duration of
streptodecase action lasts 48–72 hours. Drug is administered
intravenously.
Recently, another drug containing strepkinase was created –
anistreplase – the complex of streptokinase with modified
plasminogen. The drug is administered intravenously in coronary
thrombosis. Elimination half-life is 70–120 minutes. Side effects of
anistreplase are hemorrhages, allergic reactions, bradycardia,
transient hypotension, etc.
Urokinase is a plasminogen activator which consists of two
polypeptide chains. The plasma half-life of urokinase is 10–20
minutes. Drug is administered intravenously in acute arterial and
venous thrombosis of different localization. Urokinase is not
antigenic because it is derived from human cells. Nowadays
urokinase is derived by genic engineering.
Alteplase (aktilyse) is a tissue-type plasminogen activator.
The agent is derived by genic engineering. Alteplase has a high
affinity with fibrin. Owing to this, alteplase causes the fibrinselective activation of plasminogen. The drug causes insignificant
activation of plasminogen in plasma. Alteplase is administered
intravenously or intra-arterialy. A plasma half-life of the drug is
5 minutes. Fibrinolytic efficacy of alteplase is higher than the eficacy
of streptokinase. Administration of alteplase can cause bleeding
because its selectivity in activation of plasminogen of thrombus is
not absolute.
Recently, tenecteplase (metalyse) was created. It is a
recombinant genetically-modified activator of tissue plasminogen.
Tenecteplase binds to the fibrin component of the thrombus and
selectively catalyzes the transformation of associated with thrombus
plasminogen into plasmin, which breaks down fibrin of clot. A
plasma half-life of tenecteplase is nearly 20–25 minutes. The drug is
administered intravenously to patients with acute myocardial
infarction. Most common possible side effect is hemorrhage.
Drugs Inhibiting Thrombocyte Aggregation
(Antiaggregants)
Platelet aggregation is significantly regulated by ratio of
thromboxane A2 and prostacycline (PGI2). The release of ADP from
the platelet granules causes the activation of platelet phospholipase
A2. This enzyme, cyclooxygenase-1, and thromboxane synthetase
consequentially convert arachidonic acid into cyclic endoperoxides
and thromboxane A2 (TXA2). In contrast to endothelial cells,
platelets lack PGI2 synthetase. Several endogenous substances
promote the platelet aggregation. These are such drugs, as serotonin,
epinephrine, thrombin, collagen of vessels walls, and platelet
activating factor. But certain substances that carry out the opposite
function are present in the organism. Prostacyclin is the most
important among them. Prostacyclin is the result of metabolic
transformation of arachidonic acid by the endothelial cells of vessels.
In these cells the prostacyclin synthetase transforms the cyclic
endoperoxides into prostacyclin. Besides prostacyclin, such
substances as PGE1, heparin, cAMP, adenosine, and NO prevent the
platelets aggregation. If the equilibrium between these two groups of
substances is broken for the benefit of TXA2, the platelet aggregation
increases. It can cause the myocardial infarction, ischemic stroke,
etc.
Antiaggregants are drugs which are used for prevention of
platelet aggregates formation. According to mechanism of action
these drugs are divided into the following groups:
1. Agents which decrease the activity of thromboxane system:
acetylsalicylic acid (aspirin), dasoxiben.
2. Drugs which increase the activity of prostacyclin system:
epoprostenol (prostacyclin ), carbacycline.
3. Drugs which inhibit the binding of fibrin with thrombocyte
receptors: ticlopidine, clopidogrel, and abciximab.
4. Miscellaneous agents: dipyridamole, trental.
Drugs Decreasing the Activity of Thromboxane System
Acetylsalicylic acid (aspirin) irreversibly inhibits
cyclooxygenase by acetylation of it. This process develops both in
platelets, preventing the formation of TXA2, and in endothelial cells,
inhibiting the synthesis of PGI2. Endothelial cells can synthesize a
new cyclooxygenase while platelets can not, because platelets have
no nucleus. Therefore, ratio between TXA2 and PGI2 changes in
favor of the last. The aim of therapy with acetylsalicylic acid is the
selective inhibition of TXA2 synthesis in the platelets that results in
the decrease of platelet aggregation. This is achieved by drug intake
in dose from 75 mg to 325 mg per day. The action of acetylsalicylic
acid is dose-dependent: by increasing drug concentration in blood,
initially the antiaggregant effect appeares, which is followed by
antipyretic, analgetic, and anti-inflammatory effects.
During last years the nitroaspirin has been synthesized. In the
human organism this drug releases nitric oxide (NO) which decreases
the tone of vessels and oppresses the platelets aggregation.
Dasoxiben is a selective inhibitor of thromboxane synthase.
But monotherapy with dasoxiben is ineffective due to accumulation
of cyclic endoperoxides – substances with proaggregative activity.
Therefore, dasoxiben is used in combination with acetylsalicylic
acid.
Drugs Increasing the Activity of Prostacyclin System
Epoprostenol (prostacyclin) dilates blood vessels and
inhibits platelets aggregation. Because the drug has a very short
duration of action, epoprostenol is administered intraarterially dropby-drop. The drug is used for treatment of patients with vascular
diseases of lower extremities. Epoprostenol improves blood
circulation in skeletal muscules, decreases the ischemic pain, and
promotes the healing of trophic ulcers. The agent is also used during
hemodialysis and hemosorption (for prevention of thrombocytes
adhesion to dialysis membranes), and in apparatus of extracorporeal
circulation.
Carbacycline is the synthetic derivative of prostacyclin which
also has short duration of action. The drug acts up to 10 minutes.
Therapeutic indications for carbacycline are the same.
Drugs Inhibiting the Binding of Fibrin with
Thrombocyte Receptors
Abciximab (ReoPro) prevents the interaction of fibrinogen
with platelet glicoprotein receptors (GP IIb/IIIa) in result of
irreversible blockade of these receptors. This drug is administered
intravenously. Abciximab is administered intravenously during
angioplasty and in complex therapy of myocardial infarction and
severe angina pectoris. Duration of its action is nearly 24 hours. Most
common side effect of abciximab is hemorrhages. Patients who
received abciximab before may produce the immune response after
the second administration.
Ticlopidine (ticlid) and clopidogrel (plavix) are drugs that
irreversibly inhibit platelet aggregation due to blockage of
P2-purinergic receptors for ADP on the platelet membrane. This
action inhibits ADP-induced binding of fibrinogen with glicoprotein
receptors of platelets. Antiaggregative effect develops gradually
within several days. Ticlopidine is taken orally while eating 2 times a
day. Indications for use are myocardial infarction, unstable angina
pectoris, ischemic stroke, and angioplasty. The drug is prescribed to
patients who cannot tolerate aspirin. Ticlopidine is well absorbed,
binds to plasma proteins, and is metabolized by liver. Side effects are
gastrointestinal disturbances, neutropenia, agranulocytosis, and
allergic reactions. Clopidogrel is taken orally once a day. This agent
produces fewer side effects than ticlopidine.
Miscellaneous Agents
Dipyridamole is a coronary vasodilator with anti-aggregation
activity. It is a phosphodiesterase inhibitor which increases platelet
cyclic adenosine monophosphate (cAMP) concentrations. The drug
also blocks enzyme adenosine deaminase and prevents destruction of
adenosine. Adenosine inhibits the platelets aggregation and causes
vasodilation. Dipyridamole is also useful in combination with aspirin
(Aggrenox). Side effects of dipyridamole include headache,
dispepsy, hypotension, allergic reactions, and steal syndrome.
Pentoxifylline (trental) is the derivative of xanthine. The
agent inhibits phosphodiesterase and promotes accumulation of
cAMP in platelets. This results in decrease of platelets aggregation.
Hereby, the elastisity of erythrocytes increases that creates the
comfortable conditions for capillary blood flow. Pentoxifylline
increases the release of plasminogen activator, reduces the level of
fibrinogen in blood, and decreases blood viscosity. The agent has a
moderate vasodilative activity. Under the influence of trental, the
reological properties of blood are improved. Marked therapeutic
effect of trental develops in 2–4 weeks after the start of treatment.
Indications for use are Raynaud's disease, diabetic angiopathy,
disturbances of cerebral and coronary blood circulation, and shock.
Side effects of trental include decrease of appetite, diarrhea, nausea,
dizziness, hypotension, and facial flushing.
Drugs Promoting Blood Coagulation
(Hemostatics)
Drugs, which promote hemostasis, are used for prevention and
treatment of acute and chronic hemorrhages. Disorders of blood
coagulation can develop due to genetically based deficiency of
clotting factors (haemophilia), sharp activation of fibrinolysis,
inhibition of adhesion and aggregation of thrombocytes, surgery
(especially on the lungs and pelvic organs), hepatic diseases, protein
deficiency, radiation sickness, intoxications, etc. For interruption of
hemorrhages, the following groups of drugs are used: drugs
increasing blood clotting (procoagulants), antifibrinolytics, and drugs
promoting platelets agregation.
Drugs Increasing Blood Clotting (Procoagulants)
Procoagulants promote the blood clotting. These drugs are
divided into two subgroups:
1. Drugs for the local use: thrombin, hemostatic sponge ,
and beriplast.
2. Drugs for systemic action: vicasolum, phytomenadione,
fibrinogen, calcium chloride, calcium gluconate, gelatin,
etamsylate.
Thrombin is an active key factor (IIa) of blood coagulation
which converts the fibrinogen to fibrin. The drug is derived from
donated blood. This drug is used locally in surgery on
parenchymatous organs (most commonly on the liver), in
hemorrhages from osteal tissues, and gingiva. The parenteral
introduction of thrombin is inadmissible, because the drug rapidly
causes the generalized thrombosis.
Beriplast and hemostatic sponge are received from blood. Both
drugs contain thrombin. They are used only locally for arresting of
capillary bleeding.
Vitamin K exists in two forms: K1 (phytonadione) and K2
(menaquinone). Phytonadione is a vitamin of plant origin.
Menaquinone is synthesized by intestinal bacterial flora and is
contained in animal liver. Vitamin K participates in hepatic synthesis
of K-dependent factors of blood coagulation: prothrombin, VII
(proconvertin), IX (Christmas factor), and X (Stuart-Prower factor).
Phytomenadione and vicasolum are synthetic analogues of
vitamin K. Phytomenadione is taken orally 30 minutes before meals
or administered parenterally – subcutaneously, intramuscularly, and
intravenously. Vicasolum is taken orally or administered
intramuscularly 2–3 times a day. In liver, vicasolum transforms into
vitamin K1. The response to vitamin K drugs is slow and requires
about 24 hours. These drugs also have the antihypoxic activity. They
are used for treatment and prevention of hemorrhages before and
after surgery, in bleeding caused by ulcer disease, radial
illness, uterus bleeding, hemorrhagic disease of newborn, in
hypoprothrombinemia.
Fibrinogen is the drug, which is derived from donor blood. The
drug is introduced drip intravenously through the system with special
filter during 2–4 hours once daily. The direct indication for its
administration is hypofibrinogenemia. This phenomenon develops in
several diseases of liver, in case of overdosage of fibrinolitics, and in
proteins starvation. Also, fibrinogen is preventively used before
surgery on organs, which are rich on tissue activators of fibrinolysis
(lung, pancreas, prostates, and thyroid glands).
Calcium-containing drugs (calcium chloride and calcium
gluconate) stimulate the formation of thromboplastin, conversion
of prothrombin to thrombin, and polimerization of fibrin.
Additionally, calcium ions decrease the permeability of vessel walls.
Drugs are used in cases of internal bleeding due to thrombocytopenia
and increased permeability of vessel walls. Calcium-containing drugs
are also administered to recipients during transfusion of citrated
blood.
Gelatin contains high quantity of calcium ions, and due to that,
increases the blood coagulation. Also, gelatin increases blood
viscosity and thromboplastin release. 10% gelatin solution is
administered intravenously.
Etamsylate stimulates the formation of thromboplastin. Also
the drug inhibits hyaluronidase that results in stabilization of vessel
walls. Etamsylate is used for prevention and interruption of capillary
bleeding in patients with diabetic angiopathy and during various
surgeries. The drug is taken orally or administered parenterally.
Drugs Inhibiting Fibrinolysis ( Antifibrinolytic Drugs )
The activity of fibrinolytic system may be increased due to
overdose of fibrinolytic drugs, sepsis, serious traumas of internal
organs, etc. In such cases of hemorrhages, administration of
procoagulants is ineffective while administration of antifibrinolytic
drugs is necessary.
Antifibrinolytic drugs are divided into two groups:
1. Direct fibrinolysin inhibitors: сontrical, trasylol , gordox
(the active substance of these drugs is aprotinin).
2. Inhibitors of factors, which promote profibrinolysin
activation: aminocapronic acid (Amicar), tranexamic acid
(сyclokapron).
Aprotinin is the inhibitor of proteases. The agent directly
inhibits the active fibrinolysin. This agent also oppresses other
proteolytic enzymes. Aprotinin also inhibits the activity of trypsin,
chemotrypsin, and kallikrein. This ensures the use of this agent in
acute pancreatitis. Aprotinin-contained drugs are: contrical, trasylol,
and gordox. Drugs are administered intravenously slowly or drop-bydrop.
Aminocapronic acid is a synthetic agent – the derivative of
amino acid lysine. The drug interacts with activator of
profibrinolysin and prevents the transformation of profibrinolysin
into fibrinolysin. Besides, aminocapronic acid interacts with active
centres of profibrinolysin and fibrinolysin, and oppresses their
activity. The drug is introduced orally or drop-by-drop intravenously.
The duration of action is 6 hours; therefore, frequency of
introduction is 4 times daily. Therapy with aminocapronic acid may
be accompanied by allergic reactions and dispeptic disorders.
Intravenous drug administration can result in decrease of blood
pressure, thrombosis, embolism, etc.
Tranexamic acid (сyclokapron ) is the drug with higher
activity and longer duration of action than aminocapronic acid.
Cyclocapron is taken orally or administered intravenously. The
drug’s half-life in intravenous administration is 2 hours.
The indications for clinical application of fibrinolytic inhibitors are:
- overdose of fibrinolytics;
- surgery and traumas of organs, which are rich in proteolytic
enzymes;
- hemorrhagic insult;
- intrauterine death of fetus.
Drugs Promoting Platelets Agregation
This group includes such drugs, as calcium chloride,
calcium gluconate, serotonin, adroxonum, and etamsylate.
Serotonin is the endogenous amine. It activates S1- and
S2-serotinin receptors on the surface of platelets and thus promotes
the platelets aggregation. Besides, serotonin causes vasospasm. The
drug is introduced intravenously or intramuscularly in hemorrhages,
hypo- and aplastic anemias. Adverse effects are bronchospasm,
intestinal spasms and pain.
Adroxonum is the derivative of adrenaline, which is unable to
stimulate the adrenoceptors of smooth muscles and heart. The drug
excites α-adrenoceptors on the platelet surface. This results in the rise
of phospholipase C activity and in the increase of the aggregation of
platelets. Adroxonum is used orally, subcutaneously, intramuscularly
or as a local agent in hemorrhages.
Calcium chloride and calcium gluconate increase the
aggregation of platelets, activate the formation of thrombin, and
decrease permeability of vessel walls. Calcium gluconat e is
introduced intramuscularly, intravenously or taken orally before
meal. Calcium chloride is introduced only intravenously or taken
orally after meal. The frequency of administration of calciumcontaining drugs is 3–4 times a day. These drugs are used in
hypocalcemia, thrombocytopenia, fragility of vessels, hemorrhages
in ulcer diseases, lung diseases, uterus hemorrhages, etc.
Etamsylate blocks the effects of prostacyclin. At present it is
the most effective drug of this group. Etamsylate also increases
polymerization of hyaluronic acid and hence the density of basal
membrane of capillaries. Etamsylate is used in parenchymatous and
capillary hemorrhages and in thrombocytopenia. The drug is
introduced intravenously, intramuscularly, or orally 3–4 times a day.
Table 4 – Drugs for prescription
Drug name
Acidum
acetylsalicylicum
Dipyridamolum
Heparinum
Calcii chloridum
Neodicumarinum
Syncumarum
Streptokinasum
Acidum
aminocapronicum
Contricalum
Fibrinogenum
Vikasolum
Single dose and mode of
administration
0.075–0.325 g once a day
orally
0.025–0.05 g 3 times per day
orally
5000–20000 IU 4 times per
day intravenously
0.5–1.0 g 1-2 times daily
intravenously slowly
0.05–0.1 g 3 times per day
orally
0.001–0.006 g 1–2 times per
day orally
250000–500000 IU (250000
IU is dissolved in 50 ml of
isotonic NaCl) intravenously
drop-by-drop
2–3 g 4 times daily orally;
5.0 g once a day intravenously
drop-by-drop
10000–50000 IU daily 4–6
times per day intravenously
drop-by-drop
1.0–2.0 g (1g is dissoled in
250 ml of water for injections)
intravenously drop-be-drop
0.015 g 2–3 times per day
orally;
0.01 g once a day
intramuscularly
Drug product
Tablet 0.075 or 0.325 g
Tablet 0.025 or 0.075 g
Bottle 5 ml (1 ml – 5000,
10000, or 20000 IU)
Ampoule 5 or 10 ml of
10% solution
Tablet 0.05 or 0.1 g
Tablet 0.002 or 0.004 g
Ampoule 250000 or
500000 IU of dry
substance
Powder for internal use;
bottles 100 ml of 5%
solution
Bottle containing 10000,
30000 or 50000 IU of
dry substance
Bottle containing 1.0 or
2.0 g of dry substances
Tablet 0.015 g;
ampoule 1ml of 1%
solution
INDEX
A
Abciximab 77, 79
Abomin 8
Aceclidine 6, 34
Acetylsalicylic acid 77, 78
Acidin-pepsin 8
Adelphane 50
Ademethionine 29
Adroxonum 84
Aeron 32
Aethamidum 57
Aethaperazine 32, 33
Aktilyse q.v. Alteplase
Aldactone q.v. Spironolactone
Allochol 25
Allohol 24
Allopurinol 57, 58
Almagel 19, 20, 21
Alteplase 74, 76
Aluminium hydroxide 19, 20, 21
Amicar q.v. Aminocapronic acid
Amiloride 41, 46, 50
Aminazine 32, 33
Aminocapronic acid 23, 75, 83
Aminophylline q.v. Euphillinum
Amphetamine 4
Anaprilinum 54
Anistreplase 74, 76
Apomorphine 31
Aprotinin 83
Artificial gastric juice 8
Ascofer 62
Ascorbic acid 28, 54, 59, 61
Asparaginase 60
Aspirin q.v. Acetylsalicylic acid
Atropine 6, 10, 11, 23, 27, 30, 34, 51, 57,
62
Axid q.v. Nizatidine
B
Bearberry leaves 41
Bekarbon 11
Bellalgin 11
Bellastezin 11
Benzohexonium 30, 34
Berberine sulfate 24, 25
Beriplast 81
Birch buds 41
Bisacodyl 35, 37
Bismuth citrate 13
Bismuth subsalicylate 17
Black currant 64
Bufenox q.v. Bumethanide
Bumethanide 40, 41, 42
Buscopane 31
C
Calcium carbonate 19, 20
Calcium chloride 54, 81, 82, 84
Calcium gluconate 81, 82, 84
Carbacholine 6
Carbacycline 77, 79
Carbenoxolone 17, 18
Carsil 28
Castor oil 35, 36, 51, 54
Chenodeoxycholic acid 24, 30
Chlorpromazine q.v. Aminazine
Cholaflux 24
Cholecystokinin 6, 26
Cholenzymum 24, 25, 38
Сimetidine 10, 12, 13, 14
Cisapride 30, 34
Clopamide 40, 41, 43, 50
Clopidogrel 77, 79
Coamide 62
Coamidum 59, 66
Colchicine 57, 58
Contrical 23, 83
Copper sulfate 31, 32
Cotarnine 51, 56
Crystepin 50
Cyanocobalamin 59, 60, 63
Cyclokapron q.v. Tranexamic acid
Cyclomethiazide 40, 41, 44
Cyclophosphamide q.v.
Cyclophosphanum
Cyclophosphanum 60
Cycvalonum 25, 26
D
Dalteparin 68, 71
Dasoxiben 77, 78
De-nol 17, 18
Desaminooxytocin 52
Desopimone 4
Dexamethazone 57, 60
Dexfenfluramine 4
Diakarb 40, 41, 45
Dichlothiazidum 40, 41, 44
Diclofenac sodium 57
Digestal 23
Diluted hydrochloric acid 8
Dimedrolum 32, 33
Dinoprost 51, 53, 57
Dinoprostone 51, 57
Diprazinum 32, 33
Dipyridamole 77, 79, 80
Distigmine 34
Domperidone 30
Drotaverine q.v. No-spa
E
Enap-H 50
Enoxaparin 68
Enzystal 23
Epoetin alfa 59, 62
Epoetin beta 59, 62
Epoprostenol 77, 78
Ergometrine 51, 56
Ergot extract 51, 56
Ergotal 51, 56
Ergotamine 51, 56
Erythromycin 34
Esomeprazole 10, 14
Essentiale 29
Estradiol 51, 53
Estrone 51, 53
Etamsylate 81, 82, 84
Ethacrynic acid 40, 41, 45, 49, 50
Euphillinum 27
Euphyllinum 41
Extract of buckthorn (Rhamnus) cortex
35
F
Famotidine 10, 12, 13
Fenfluramine 4
Fenoterol 51, 55
Fercoven 59
Ferramidum 59
Ferrogradumet 62
Ferroplex 59, 62
Ferrous lactate 59
Ferrous sulfate 59
Ferrum-Lek 59
Festal 23
Fibrinogen 67, 68, 79, 80, 81, 82
Fibrinolysin 67, 74, 75, 83
Filgrastim 60, 65, 66
Flamіn 24
Folic acid 59, 60, 63, 64
Fraxiparin 68, 71
Furosemide 40, 41, 42, 43, 49, 50
G
Gastal 19, 21
Gastrin 7, 10, 14, 15, 16, 21
Gelatin 15, 81, 82
Globiron 62
Gordox 23, 83
Granisetron 32, 33
Guttalax 35, 37
H
Haemostimulinum 59
Helichrusum arenarium 25
Hemostatic sponge 81
Hepabene 28
Heparin 67, 68, 69, 70, 71, 75, 77
Hepatofalk Planta 28
Heptral q.v. Ademethionine
Herb of thermopsis 31
Hexamethonium q.v. Benzohexonium
Hirudin 68, 71
Histamine 7, 10, 12, 13, 14
Holagol 24
Holosas 24
Horsetail herb 41, 49
Hydrochlorthiazide q.v. Dichlothiazidum
I
Imodium q.v. Loperamide
Indomethacin 57
Indopamide 40, 41
Interferon α 60
Ipecacuanha root q.v. Root of
Ipecacuanha
Isaphenine 35, 37
K
Melanocortin 6
Menaquinone q.v. Vitamin K
Mercaptopurine 60
Metalyse q.v. Tenecteplase
Methacin 10, 11
Methacinium 11, 30, 34
Methotrexate 60
Methyldinoprost 53
Methylergometrine 51, 56
Methyluracilum 60, 65
Metoclopramide 30, 32
Mezym Forte 23
Misoprostol 10, 16, 17, 18, 19
Moduretic 50
Molgramostim 65, 66
Molgrastim 60, 65
Motilium q.v. Domperidone
Myelosanum 60
N
Kreon 23
L
Lansoprazole 10, 14
Legalon 28
Lenograstim 60
Leptin 3, 6
Lespeflan 49
Lespenefril 49
Leucogenum 65
Leukogenum 60, 65
Licrease 23
Liobilum 25
Lipoic acid 29
LIV-52 28
Logiparin 71
Loperamide 34
Lіobіlum 24
M
Maalox 19, 21
Magnesium oxide 19, 20, 21
Magnesium sulfate 26, 27, 51, 56
Magnesium sulphate 35
Mannitol 41, 47, 48, 49
Mazindole 4
Nadroparin 68, 71
Natural gastric juice 8
Neodicumarinum 68, 72, 73, 74
Nitroaspirin 78
Nizatidine 10, 12, 13
No-spa 27, 31, 34
Nіkodinum 25, 26
O
Oats seeds 25
Odeston 25, 26
Oleandomycin 34
Omeprazole 10, 14
Ondansetron 32, 33
Orlistat 4, 5
Oxaphenamіdum 25, 26
Oxodolinum 40, 41, 44, 50, 58
Oxytocin 51, 52
P
Pachycarpine 51, 54
Pancreatin 22
Pantoprazole 10, 14
Panzinorm 23
Papaverine 27, 31, 34
Partusisten q.v. Fenoterol
Pentagastrin 7
Pentoxifylline 80
Pentoxylum 60, 64, 65
Pepsin 7, 8, 9, 10, 17, 18, 20, 22
Phenaminum q.v. Amphetamine
Phenindione 68, 72, 73
Phenolphthalein 35, 37
Phenylbutazone 57
Phepranone 4, 5
Phosphalugel 19, 21
Phytomenadione 81
Phytonadione q.v. Vitamin K
Pilocarpine 6
Pilorid q.v. Bismuth citrate
Pirenzepine 10, 11, 12
Pirenzepine 11, 12
Pirilene 30
Pirilenum 34
Pituitrinum 52
Platyphyllin 10, 11, 23, 27, 30, 34
Polythiazide 40, 41, 44
Prednisolone 57, 60
Probanthine 31
Probenecid 57
Progesterone 50, 51, 55, 56
Proglumide 10, 16
Propranolol q.v. Anaprilinum
Proserinum 6, 34, 51, 54
Prostacyclin 67, 77, 78, 79, 84
Prostaglandin E2 q.v. Dinoproston
Prostaglandin F2α q.v. Dinoprost
Pyridostigmine 34
Q
Quamatel q.v. Famotidine
R
Rabeprozole 10, 14
Ranitidine 10, 12, 13
ReoPro q.v. Abciximab
Rhubarb (Rheum) root 35
Roksatidine 10
Root of ipecacuanha 31
Rose 25, 26, 64
Rowan 64
Roxane q.v. Roxatidine
Rubomycinum 60
S
Salbutamol 51, 55
Scopolamine 6, 32
Senna leaves 35, 36
Serotonin 3, 5, 54, 77, 84
Sibutramine 4, 5
Silibinine dihydrosuccinate sodium salt
28
Sodium hydrocarbonate 15, 19, 20
Sodium hydrocitrate 68
Sodium nucleinate 60, 64, 65
Sodium oxybutirate 51
Sodium oxybutyrate 56
Sodium phosphate with radioactive
isotope 32P 60, 64
Sodium sulphate 35
Sorbifer 62
Sorbitol 21, 27
Spironolactone 41, 46, 47, 50
Stigmatum maydis 25
Strawberry fruit 64
Streptodecase 74, 76
Streptokinase 74, 75, 76
Sucralfate 17
Syncumarum 68, 72, 73
Synoestrolum 51, 53
Syrup of wild rose 24
T
Tardyferon 59
Telenzepine 10, 11, 12
Tenecteplase 76
Tenoric 50
Terbutaline 51, 55
Theobromine 48
Theophylline 48
Thermopsis herb q.v. Herb of thermopsis
Thiamin q.v. Vitamin B1
Thiethylperazine 32, 33
Thiophosphamidum 60
Thiotepa q.v. Thiophosphamidum
Thiotriazoline 29
Thrombin 67, 68, 69, 71, 72, 77, 81, 82,
84
Ticlopidine 77, 79
Tocopherol 51, 56
Torasemide 43
Torsemide 40, 41, 42
Tranexamic acid 83
Trasilol 23
Trasylol 83
Trental 77, 80
Triampur Compositum 50
Triamterene 41, 46, 50
Triftazinum 32, 33
Tropisetron 32, 33
U
Urodanum 57
Urokinase 74, 76
Ursodeoxycholic acid 30
Ursofalk q.v. Ursodeoxycholic acid
V
Venter q.v. Sucralfate
Verospiron q.v. Spironolactone
Vicasolum 73, 74, 81
Vinblastine 60
Vincristine 60
Vitamin B1 54
Vitamin B12 q.v. Cyanocobalamin
Vitamin Bc q.v. Folic acid
Vitamin E q.v. Tocopherol
Vitamin K 81
W
Warfarin 68, 72, 73
Z
Zantac q.v. Ranitidine
Zinc sulfate 31, 32
Zofran q.v. Ondansetron
REFERENCES
1. Bertram G. K. Basic and clinical pharmacology : textbook /
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384 p.
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CONTENTS
P.
DRUGS INFLUENCING DIGESTIVE SYSTEM…..............….........…...3
Drugs Influencing Appetite...................................................................... ........3
Drugs Increasing Appetite.................................................................... ........3
Drugs Decreasing Appetite (Anorexic or Anorexigenic Drugs).......... ........4
Drugs Influencing Function of Salivary Glands...................................... ........6
Drugs Used in Hyposecretion of Stomach............................................... ........7
Drugs Used in Hypersecretion of Gastric Glands and in Disturbances
of Trophism or Regeneration of Gastric Mucosa.............................................9
Drugs Decreasing Secretory Activity of Gastric Glands...................... ......10
M-cholinoceptor Antagonists......................................................................11
H2-Histaminergic Antagonists.............................................................. ......12
Proton Pump Inhibitors........................................................................ ......14
Prostaglandins and Their Synthetic Analogues.................................... ......16
Blockers of Gastrin Receptors.............................................................. ......16
Gastroprotective Drugs.......................................................................... ......17
Antacids................................................................................................ ......19
Drugs Used in Hypofunction of Pancreas................................................ ......22
Drugs Inhibiting Pancreatic Secretion..................................................... ......23
Drugs Improving Functions of Liver (Hepatotropic Drugs).................... ......24
Drugs Stimulating Bile Secretion.......................................................... ......24
Drugs Stimulating Bile Discharge......................................................... ......26
Hepatoprotectors..........................................................................................27
Drugs Used to Dissolve Gallstones....................................................... ......30
Drugs Influencing Gastric Motility.......................................................... ......30
Emetic Drugs..................................................................................................31
Antiemetic Drugs..................................................................................... ......32
Drugs Influencing Intestinal Motility...................................................... ......34
Drugs Stimulating Intestinal Motility.................................................... ......34
Drugs Inhibiting Intestinal Motility and Reducing Intestinal Spasms.. ......34
Laxative Drugs...................................................................................... ......35
Saline Laxatives..................................................................................... ......35
Vegetable Oils....................................................................................... ......36
Drugs Containing Anthraquinone Glucosides...................................... ......36
Synthetic Laxative Drugs....................................................................... ......37
DIURETIC AGENTS............................................................................ ......39
Diuretics Acting on the Level of Epithelial Cells of Renal Tubules..............42
Loop Diuretics...................................................................................... ......42
Thiazides............................................................................................... ......44
Derivatives of Dichlorophenoxyacetic Acid...............................................45
Carbonic Anhydrase Inhibitors............................................................. ......45
Diuretics Acting on the Level of Apical Membrane................................ ......46
Drugs Inhibiting Proteins which Transfer Sodium................................ ......46
Aldosterone Antagonists..............................................................................46
Osmotic Diuretics...........................................................................................47
Drugs Increasing the Renal Blood Supply.......................................................48
Diuretics of Vegetable Origin.........................................................................49
Principles of Combined Use of Diuretics.......................................................49
DRUGS INFLUENCING MYOMETRIUM..............................................50
Drugs Stimulating Contractile Activity of Uterus..........................................51
Drugs of Oxytocin Group............................................................................51
Drugs of Prostaglandin Group.....................................................................52
Estrogens............................................................................................... ......53
β-Adrenoblockers........................................................................................54
Miscellaneous Drugs....................................................................................54
Drugs Decreasing Uterine Tone and Contractile Activity (Tocolytics).........55
Drugs Increasing Tone of Myometrium and Involution of Uterus in the
Postpartum Period...........................................................................................56
Drugs Decreasing the Utering Neck Tone......................................................57
DRUGS USED FOR GOUT TREATMENT....................................... ......57
DRUGS INFLUENCING HEMOPOIESIS......................................... ......59
Drugs Influencing Erythropoiesis...................................................................60
Drugs Stimulating Erythropoiesis................................................................61
Drugs Used for Treatment of Hypochromic Anemias.................................61
Drugs Used for Treatment of Hyperchromic Anemias................................63
Herbal Drugs Used for Treatment of Anemias............................................64
Drugs Inhibiting Erythropoiesis...................................................................64
Drugs Influencing Leukopoiesis.....................................................................64
Drugs Stimulating Leukopoiesis..................................................................64
DRUGS INFLUENCING BLOOD COAGULATION...............................67
Drugs for Prevention and Treatment of Thrombosis......................................68
Drugs Decreasing Blood Coagulation (Anticoagulants)..............................68
Directly Acting Anticoagulants...................................................................68
Indirectly Acting Anticoagulants.................................................................72
Drugs Activating Fibrinolysis (Fibrinolytic Drugs)......................................74
Drugs Inhibiting Thrombocytes Aggregation (Antiaggregants)...................77
Drugs Decreasing the Activity of Thromboxane System..............................78
Drugs Increasing the Activity of Prostacyclin System.................................78
Drugs Inhibiting the Binding of Fibrin with Thrombocyte Receptors.. ......79
Miscellaneous Agents..................................................................................79
Drugs Promoting Blood Coagulation (Hemostatics)......................................80
Drugs Increasing Blood Clotting (Procoagulants).......................................81
Drugs Inhibiting Fibrinolysis (Antifibrinolytic Drugs).................................82
Drugs Promoting Platelets Agregation.........................................................84
INDEX........................................................................................................86
REFERENCES..........................................................................................91