• Pain is associated with many pathological
conditions. They not only cause painful
experiences, but also worsen the underlying
disease. Generally recognized the leading role
of the factor of pain in the etiology and
pathogenesis of traumatic shock, which in
some cases can cause death. All this shows the
great importance for practical medicine
painkillers.
Pain is perceived by specific receptors, which
are called 'nociceptors'. They represent the
end of the tree-like branched afferent fibers
located in the skin, muscles, joint capsules,
periosteum, internal organs, etc. are damaged
(nociceptive) stimuli may be mechanical,
thermal and chemical effects.
Title
• Pain is often a cause pathological process
(e.g., inflammation). Known endogenous
substances which, acting on nociceptors, can
cause pain (e.g., bradykinin, histamine,
serotonin, potassium ions etc.).
• Prostaglandins (for example, group E2)
increase the sensitivity of nociceptors to
chemical (and thermal) irritation.
Pain caused by irritation of pulses propagate
along the C and 'Aδ-fibers and come back in
the horn of the spinal cord. Here is the first
switch from afferent fibers in the neurons of.
Hence the excitement extends to the
following paths.
• One - ascending afferent tracts. They
spend excitement to the upstream
departments - the reticular formation,
thalamus, hypothalamus, to basal ganglia,
the limbic system and the cerebral cortex.
The combined interaction of these
structures leads to the perception of pain
assessment and the relevant behavioral
and autonomic responses. The second way
- to send pulses to the motor neurons of
the spinal cord, which is manifested motor
reflex. The third way is through the
excitation of neurons in the lateral horn,
which is activated as a result of the
adrenergic (sympathetic) innervation.
• The functioning of the neurons of spinal cord
dorsal horn is regulated by supraspinal
antinociceptive system. The last is a complex of
structures, it turns descending inhibitory effect
on the transmission of pain stimuli in primary
afferent neurons of fibers. For example, it is
shown that electrical stimulation of the
periaqueductal gray or reticular nucleus or
microinjection of enkephalins in them causes a
reduction in pain sensitivity. Carried downward
through the inhibition of serotonergic,
noradrenergic, and neurons.
It should also consider the presence of a large
number of various endogenous peptides
including analgesic activity (enkephalins, βendorphin, dynorphin, etc.), as well as
nociceptive properties (e.g., substance P).
• In the brain tissues are formed and many
other biologically active substances which
may be involved not only as mediators and
modulators but nociceptive stimulation. As
the last act, and some neurohormones.
Peptides with analgesic activity (opioids)
interact with a specifical opiate receptors,
which are found in most formations accepting
part in the conduct and perception of pain.
Identified different types of opioid receptors,
which differ in their sensitivity to endogenous
and synthetic opioids.
• Thus, in the body there is a complex
neurohormonal antinociceptive system. In the
event of failure (with over-expressed or longterm damaging effects) pain must be
repressed with the help of painkillers.
Depending on the origin, nature and intensity,
and duration of pain use certain painkillers
mediaproperties.
Analgesics - drugs that selectively inhibit pain
sensitivity. They do not turn off the mind and
does not inhibit other types of sensitivity.
Based on the pharmacodynamics of the
drugs, they are divided on narcotic and nonnarcotic analgesics power industry.
Pharmacological effects of narcotic analgesics and their
antagonists anta due to the interaction with opioid
receptors are found in the central nervous system and in
peripheral tissues.
Based on the principle of interaction of these
substances with opiate receptors, they can be
represented by the following groups:
Agonists:
Morphine Fentanyl Promedol
Agonist-antagonists (partial agonists):
Pentazosin Nalorfin
Antagonists
Naloxone
• Narcotic analgesics mainly relate to the first
group of substances. However, this can be used
as a partial agonist and if they predominate
agonist properties (e.g. pentazocine).
Narcotic analgesics have a marked inhibitory
effect on the central nervous system. It appears
analgesic-sky, sleeping pills, antitussive effect. In
addition, most of these changes the mood
(euphoria occurs) and causes drug dependence
(physical and mental).
The group of opioids include a number of
products derived from plant material as well as
synthetically.
• The most widely used in medical practice has
received alkaloid morphine. Set it apart from
opium, which is frozen PWM latex heads of opium
poppy (Papaver somniferum). In opium for medical
purposes, shall not be less than 10% of morphine.
Total Opium contains more than 20 alkaloids.
According to the chemical structure of some opium
alkaloids are derivatives phenanthrene, and others to derivatives of isoquinoline.
For phenanthrene derivatives (morphine, codeine,
etc.) character thorn in the main inhibitory effect
on the central nervous system (analgesic,
antitussive), and for a number of isoquinoline
alkaloids (papaverine, etc.) - a direct antispasmodic
effect on smooth muscle.
• Of opium alkaloids morphine only be
considered as a typical representative of
narcotic analgesics.
The important thing for the analgesic effect of
morphine is. Morphine has a fairly pronounced
selective analgesic effect. Other types of
sensitivity (tactile, temperature sensitivity,
hearing, vision) at therapeutic doses, it is not at
suppresses.
The mechanism of analgesic effect of morphine
is not fully elucidated.
• Nevertheless, there is every reason to believe
that it is composed of two main components:
• 1) the inhibition of the process interneural
transmission of pain impulses in the central part
of the afferent paths and
• 2) violation of the subjective-emotional
perception of pain assessment and response to
it.
The mechanism of analgesic effect of morphine
due to its interaction with opiate receptors. This
is manifested by activation of endogene
antinociceptive system and a violation
interneural transmission of painful stimuli at
different levels of the central nervous system.
• The experiment showed that administration of
morphine in some of these nuclei (eg in the
periaqueductal gray in the reticular nucleus and
giant paragigantokletochnoe) causes analgesia.
The importance of top-down system is also
proved by the fact that the destruction of a
large raphe nucleus significantly reduces the
analgesic effect of morphine.
Of considerable importance is also a direct
inhibitory effect of morphine on spinal neurons.
Thus there is a violation of interneural excitation
transfer at the posterior horns of the spinal
cord.
• Thus, the inhibitory effect of morphine on the
transmission of pain impulses in the spinal cord
from primary afferent fibers neurons consists of
strengthening the descending inhibitory
influences and direct inhibitory action on the
formation of synaptic spinal cord. These types
of activities are located both on the
postsynaptic membrane of neurons, and the
level of presynaptic terminals. Violation of
morphine interneural transmission in the spinal
cord reduces the intensity of the impulses
coming into the ascending afferent pathways,
and reduces motor and autonomic responses.
• Under the influence of morphine is also the
oppression of the transmission of pain stimuli in
ascending afferent paths of the brain,
particularly in the area of ​the thalamus. At that
disrupts the function of associative and not ¬
specific thalamic nuclei and their relationship to
the cerebral cortex. One ¬ temporarily blocked
the transmission of nerve impulses to the
collaterals of specific pathways in the reticular
formation of the brain stem. When pain
stimulation of the transmission of nerve
stimulation on specific ¬ cal afferent pathways
under the influence of morphine at therapeutic
doses does not change.
• Changing the perception of pain is due,
apparently, not only with de ¬ sheniem receipt
of pain impulses to the upstream departments,
but also with the soothing effects of morphine.
The latter, obviously, affects the assessment of
pain and its emotional coloring, which is
important for motor and autonomic
manifestations of pain. The role of mental
health for evaluation of pain is very great.
Suffice it to note that the positive effect of the
"placebo" with some pain reaches 35-40%.
• The calming effect of morphine may be due to its effect
on neurons of the cerebral cortex, the activating upward
reticular formation of the brain stem, as well as the
limbic system and hypothalamus. For example, it is
known that morphine inhibits activation reaction cortex
(EEG desynchronization suppresses external stimuli),
and the reaction limbic system and hypothalamus,
thalamus to afferent impulses.
Sedation may be accompanied by improvement in
mood, feeling ¬ tion of peace of mind, a positive
perception of the situation and prospects in life
regardless of the actual real. This condition is called
euphoria. Especially it is expressed with repeated use of
morphine. However, some people celebrated the
opposite phenomenon: poor health, negative emotions
(disfORHIA).
• At therapeutic doses of morphine causes drowsiness,
and when the good environment conducive to the
development of sleep. Dream Caused by the Phin,
usually superficial and easily interrupted by external
stimuli residents.
One of the manifestations of the central action of
morphine is a decrease in body temperature associated
with inhibition of thermoregulation center, located in
the hypothalamus. However, a clear hypothermia is
observed only at high doses of morphine. However,
morphine may have a stimulating effect on certain
centers of the hypothalamus. In particular, this leads to
higher release of antidiuretic hormone (vasopressin)
and reducing diuresis.
One of the effects of morphine is decreased appetite.
• Observed with morphine (especially in toxic doses),
constriction of the pupils (miosis) also has a central
origin and is associated with the excitation of the
centers of the oculomotor nerve. The latter is
apparently, secondary and results from exposure to
morphine overlying parts of the central nervous system.
This conclusion is based on the fact that dogs
dekortitsirovannyh morphine does not cause miosis.
Significant place in the pharmacodynamics of morphine
is its effect on the medulla oblongata and the first on
the respiratory center. Morphine (from therapeutic
doses) inhibits the respiratory center, reducing its
excitability to carbon dioxide and reflex actions. First
comes a decrease in the frequency of breaths, offset by
an increase in their amplitude. At higher doses to subtoxic respiratory rate is reduced even more, decreases
the amplitude of single breaths and minute volume.
• At therapeutic doses of morphine causes drowsiness,
and when the good environment conducive to the
development of sleep. Dream Caused by the Phin,
usually superficial and easily interrupted by external
stimuli residents.
One of the manifestations of the central action of
morphine is a decrease in body temperature associated
with inhibition of thermoregulation center, located in
the hypothalamus. However, a clear hypothermia is
observed only at high doses of morphine. However,
morphine may have a stimulating effect on certain
centers of the hypothalamus. In particular, this leads to
higher release of antidiuretic hormone (vasopressin)
and reducing diuresis.
One of the effects of morphine is decreased appetite.
• Often there is an abnormal respiratory rate,
possibly periodic breathing (at toxic doses of
the substance). When morphine poisoning
death occurs from paralysis of the respiratory
center.
Morphine depresses the central units of the
cough reflex and has potent antitussive activity.
On the vomiting center morphine, as a rule, is
depressing. However, in some cases it can cause
nausea and vomiting. Attribute this to the
stimulating effect of morphine on the
chemoreceptors trigger zone (trigger zone),
located at the bottom of the IV ventricle and
activating center of vomiting.
• Morphine increases the tone and contractile
activity of the ureters. It also tones up the sphincter
of the bladder, making it difficult mochebtdelenie.
Under the influence of morphine, the tone of the
bronchial muscles, which may be due to the direct
action of miotropnym, and with having mastered ¬
bozhdeniem histamine.
Directly on the blood vessels morphine has virtually
no effect. In therapy, ¬ vticheskih doses are usually
not alter blood pressure levels. At higher
concentrations, can cause a small hypotension,
which has been attributed to a slight inhibition of
the vasomotor center, as well - the release of
histamine. Against the background of the action of
morphine may develop orthostatic hypotension.
• Another representative of piperidine derivatives fentanyl (sentonil) - has a very high analgesic activity.
According to the experimental data obtained by
different methods of investigation, it is superior to
morphine activity 100-400 times. A distinctive feature is
the short duration of fentanyl caused them pain relief
(20-30 min). The effect is 1-3 minutes. Fenty ¬ nile
causes marked, but short depression of respiratory
center of ¬ (until you stop breathing).
To the piperidine derivative is also piritramide
(dipidolor). He actively morphine and operates more
lasting. The effect comes quickly. Addiction and drug
dependency develop to a lesser extent than morphine.
Intramuscularly and subcutaneously.
Funds are also fenadona group, which includes fenadon
(methadone hydrochloride, Amidon) and
dextromoramide (Palffy).
• Fentanyl is primarily used in combination with a
neuroleptic droperidol (both substances are included in
the drug Talamonal; synonym: innovar) for
neyroleptanalgesia.
Widely used narcotic analgesics for sedation prior to
surgery. Administered morphine and under local
anesthesia, as it increases the effects of anesthetics.
• In the application of narcotic analgesics (eg, promedola)
for labor analgesia should be aware that they cross the
placental barrier and cause respiratory depression of
the center of the fruit. If, despite precautions, there was
a newborn asphyxia, umbilical vein naloxone or
nalorphine - antagonist drugs ¬ cal analgesics.
When the pain caused by spasms of the bile duct or
ureter, as well as in gastric ulcer and duodenal ulcer,
intestinal colic shows the use of a promedola and
omnopona, since they are smaller than morphine,
increase the tone of smooth muscles.
• When toxic effects using antagonists of narcotic
analgesics - nalorfin (antorfin) or naloxone (Narcan).
According to the chemical structure and
pharmacological properties nalorfin, which is a partial
agonist, similar to morphine. It has analgesic activity
(similar to morphine), several respiratory depression,
reduces the heart rate, constricts the pupils. Does not
cause constipation. Drug dependence is not produced
to it. However, the independent value as an analgesic
due nalorfin has significant side effects (depression of
the higher nervous activity, action, breach of focusing
islands of vision, nausea, vomiting).
Applied nalorphine as active antagonist opioids
(excluding pentazocine). Nalorfin eliminates the
oppression caused by the last center of breath,
bradycardia, vomiting, spasms sphynters of the
gastrointestinal tract, etc.
• Non-narcotic analgesics
Most of the drugs in this group is characterized by
three main types of actions: analgesic, antiinflammatory and antipyretic. In contrast to the
narcotic analgesics, they do not have the sedative
action and soporific effects, euphoria, addiction and
drug dependence in their application does not arise.
For non-narcotic include synthetic drugs.
Derivatives of salicylic acid (salicylate):
• Acetylsalicylic acid
• Methyl salicylate
Pyrazolone derivatives
• Amidopyrine
• Analginum Phenylbutazone
• Aniline derivatives
• Phenacetin Paracetamol
• The analgesic effect of narcotic analgesics,
apparently mainly consists of peripheral and to
a lesser extent from the central effects.
The mechanism of analgesic action of nonnarcotic analgesics related to their inhibitory
effect on prostaglandin synthesis (by inhibiting
the enzyme cyclooxygenase). As known,
prostaglandins induce hyperalgesia - sensitize
nociceptors to mechanical and chemical stimuli.
Therefore, inhibition of the synthesis of
prostaglandins (PGE2, PGR2a, PGI2) prevents
the development of hyperalgesia. The threshold
of sensitivity to painful stimuli thus increased.
• A central component in the analgesic effect of
non-narcotic analgesics can not be excluded. Its
presence is confirmed in Example dryer and
paracetamol, in which the peripheral
component (antiinflammatory properties), and
that the analgesic effect is expressed
sufficiently. Apparently, non-narcotic analgesics
are only violated conduct pain stimuli in the
afferent pathways without affecting the
psychological component of pain and its
assessment. It is possible that in this case has a
value of inhibition of prostaglandin synthesis,
which are way in the central nervous system.
Distinct sedative effect of these substances is
not detected. Non-narcotic analgesics are
characterized antipyretic action.
• In the appointment of therapeutic doses of
salicylates in violation of the acid-base balance
is limited compensated alkalosis, since the
kidneys are rapidly released basic compounds
(as well as K + and Na +) and the pH to normal.
However, the buffering capacity of tissue fluids
is lowered. On the cardiovascular system
salicylates affect small. Only in high doses to ¬
they have a direct vasodilator effect.
Salicylates may affect on the liver, increasing the
separation of bile. Separating renal function
salicylates generally do not break.
• Appointment of salicylates to reduce body temperature
is only suitable for very high temperature, which is
called adversely on the state of the body.
Side effects associated with the appointment of
salicylates appear as dyspeptic symptoms. So, are
frequent nausea and vomiting. They are explained in
the main central influence of substances (on
chemoreceptors trigger zone of the vomiting center)
and partly irritated mucosa of the stomach.
Due to the violation of prostaglandin synthesis in the
gastric mucosa irritation and salicylates cause damage
to the mucous membrane of the stomach. There
ulceration, hemorrhage. At regular reception
acetylsalicylic acid, these phenomena occur in a
significant percentage of cases.
• Chronic poisoning (salitsilizm) is usually
observed in long use of salicylates and is
associated with some of their overdose. In
general, symptoms are similar to that noted for
acute poisoning, but the severity of its
correspondingly less. Furthermore, there may
be skin irritation, hemorrhage (due to
gipoprotrombinemiey). Treatment of chronic
poisoning to cease the administration of
salicylates. In the presence of hemorrhage
appropriate to prescribe vitamin K1. Basically
salitsilizma symptomatic treatment and
depends on the specific ¬ governmental
manifestations of toxic effects of salicylates.
• Of pyrazolone derivatives widely used in
medical practical got amidopirin
(aminophenazone, headache tablets), analgin,
algokalmin, metapirin) and phenylbutazone
(Phenylbutazone, butazolidin). This group is
antipyrine (Phenazone), but he rarely be
applicable.
Pyrazolone derivatives possess analgesic,
antiinflammatory and antipyretic properties.
The analgesic effect of pain above expressed in
amidopirina and dipyrone, anti butadione. Last
significantly increases the excretion of uric acid
by the kidneys (due to inhibition of its reabsorption), in connection with what has been
applied for gout.
• Phenylbutazone is used primarily due to its antiinflammatory activity in nonspecific infectious
arthritis, and acute gout.
The adverse effects are observed when using
butadiona very often (about 50% of cases).
Phenylbutazone can cause dyspepsia ¬ sical
disorders (nausea, vomiting, diarrhea, stomach
bleeding), swelling (due to increased
reabsorption in the renal tubules of sodium and
chloride), allergic reactions (skin reactions,
arthritis). Severe complications from the blood
(agranulocytosis, aplastic anemia), and liver.
• From the gastro-intestinal tract aniline
derivatives are absorbed well. The maximum
plasma concentration of phenacetin noted ¬ is
denoted by 1-2 h, paracetamol is required even
less time - 30 minutes - 1 hour in a part of the
blood substances (1/4- ⅓) bound to plasma
proteins. Approximately 5 hours phenacetin
plasma hardly detported, as it is metabolized in
the n-acetaminophenol (paracetamoles).
Reduction in the plasma by 50% paracetamol is
quite rapidly (within 2 hours). Kidneys secrete
substances, mainly in the form of conjugates.
• Apply phenacetin and paracetamol as a non-narcotic
analgesics for pain of low intensity. Furthermore, they
can be used to reduce the temperature of fever.
Both drugs were well tolerated. At therapeutic doses
does not violate the circulatory, respiratory, liver, blood,
oxygen leaf itself-base status, do not irritate the gastric
mucosa.
With prolonged use, especially in overdose fenatsetina
can form small concentrations of methemoglobin and
sulfgemoglobina. It is believed that the appointment of
paracetamol side effects occur less frequently. The
possibility of a negative impact of phenacetine on the
kidneys (called "fenacetine ​jade"). In this regard,
individuals with kidney disease should not be given
phenacetin. Toxical action of phenacetin may be
accompanied by hemolytic anemia