Non-narcotic analgesics and antipyretics. Non-narcotic analgesics, non-steroidal anti-inflammatory and antipyretic drugs Dosages used, drug selection algorithm
1. (Analgesics – antipyretics)
Key Features:
Analgesic activity manifests itself in certain types of pain: mainly in neuralgic, muscle, joint pain, headaches and toothaches. For severe pain associated with injuries, abdominal surgeries are ineffective.
The antipyretic effect, which manifests itself during febrile conditions, and the anti-inflammatory effect are expressed to varying degrees in different drugs.
No depressant effect on breathing and cough centers.
The absence of euphoria and phenomena of mental and physical dependence when using them.
Main representatives:
Salicylic acid derivatives - salicylates - sodium salicylate, acetylsalicylic acid, salicylamide.
Pyrazolone derivatives – antipyrine, amidopyrine, analgin.
Derivatives of n-aminophenol or aniline - phenacetin, paracetamol.
According to pharmaceutical action are divided into 2 groups.
1. Non-narcotic analgesics are used in everyday practice; they are widely used for headaches, neuralgia, rheumatoid pain, and inflammatory processes. Because they usually not only relieve pain but also reduce body temperature, they are often called analgesic-antiperetics. Until recently, amidopyrine (pyramidon), phenacetin, aspirin, etc. were widely used for this purpose;
In recent years, as a result of serious research, the possibility of a carcinogenic effect of these drugs has been discovered. Experiments on animals revealed the possibility of a carcinogenic effect of amidopyrine with long-term use, as well as its damaging effect on the hematopoietic system.
Phenacetin may have nephrotoxic effects. In this regard, the use of these drugs has become limited, and a number of finished medicinal products containing these drugs are excluded from the range of drugs (solutions and granules of amidopyrine, amidopyrine with phenacetin, etc.). Novomigrofen, amidopyrine with butadione, etc. are still used. Paracetamol is widely used.
2. Non-steroidal anti-inflammatory drugs.
These drugs have, along with a clearly expressed analgesic effect and anti-inflammatory activity. The anti-inflammatory effect of these drugs is close in strength to the anti-inflammatory effect of steroid hormonal drugs. At the same time, they do not have a steroid structure. These are preparations of a number of phenylpropionic and phenylacetic acids (ibuprofen, ortofen, etc.), compounds containing an indole group (indomethacin).
The first representative of non-steroidal anti-inflammatory drugs was aspirin (1889), which today is one of the most common anti-inflammatory, analgesic and antipyretic drugs.
Nonsteroidal drugs are widely used in the treatment of rheumatoid arthritis, ankylosing spondylitis and various inflammatory diseases.
There is no strict distinction between these groups of drugs, since both have significant antihyperemic, decongestant, analgesic and antipyretic effects, that is, they affect all signs of inflammation.
Analgesics-antipyretics pyrozolone derivatives:
p-aminophenol derivatives:
3. Method for producing antipyrine, amidopyrine and analgin
The structure, properties, and biological activity of these drugs have much in common. In the methods of obtaining too. Amidopyrine is obtained from antipyrine, analgin from an intermediate product of amidopyrine synthesis - aminoantipyrine.
The synthesis can start from phenylhydrazine and acetoacetic ester. However, this method is not used. On an industrial scale, a method for producing this group of compounds is used starting from 1-phenyl-5-methylpyrazolone-5, which is a large-tonnage product.
Antipyrine.
Extensive study of pyrosolone compounds and the discovery of their valuable pharmacological actions are associated with synthetic research in the field of quinine.
In an effort to obtain tetrahydroquinoline compounds that have the antipyretic properties of quinine, Knorr in 1883 carried out the condensation of acetoacetic ester with phenylhydrosine, which exhibits a weak antipyretic effect and is poorly soluble in water; its methylation led to the production of a highly active and highly soluble drug 1-phenyl-2,3-dimethylpyrosolone (antipyrine).
Considering the presence of keto-enol tautomerism of the AC ester, as well as tautomerism in the pyrazolone core, when considering the reaction between phenylhydrazine and the AC ester, one can assume the formation of several isomeric forms of 1-phenyl-3-methylpyrazolone.
However, 1-phenyl-3-methylpyrazolone is known only in 1 form. B/c crystals, suppression temperature – 127 oC, boiling point – 191 oC.
The process of methylation of phenylmethylpyrazolone can be represented through the intermediate formation of a quaternary salt, which, under the action of alkali, is rearranged into antipyrine.
The structure of antipyrine was confirmed by counter synthesis during the condensation of the enol form of acetoacetic ester or halide ester with methylphenylhydrazine, since the position of both methyl groups is determined by the starting products.
It is not used as a production method due to the low yield and inaccessible synthesis products.
The reaction is carried out in a neutral environment. If the reaction is carried out in an acidic environment, then at temperature it is not the alcohol that is eliminated, but the second water molecule, and 1-phenyl-3-methyl-5-ethoxypyrazole is formed.
To obtain 1-phenyl-3-methylpyrazolone, which is the most important intermediate in the synthesis of pyrazolone drugs, a method has also been developed that uses diketone
The properties of antipyrine - high solubility in water, reactions with methyl iodide, POCl3, etc. - are explained by the fact that it has the structure of an internal quaternary base.
In the industrial synthesis of antipyrine, in addition to the importance of the conditions for the main condensation between the AC ester and phenylhydrazine (choice of medium, neutral reaction, slight excess of FG, etc.), the choice of methylating agent plays a certain role:
Diazomethane is not suitable, since it leads to an o-methyl ether quaternary salt, which is partially formed during methylation with methyl iodide.
It is better for these purposes to use methyl chloride or bromide, dimethyl sulfate or, better, benzenesulfonic acid methyl ester, since in this case there is no need for absorbing autoclaves (CH3Br - 18 atm.; CH3Cl - 65 atm.).
Purification of the resulting antipyrine is usually carried out by 2-3 fold recrystallization from water; Vacuum distillation can be used (200-205 °C at 4-5 mm, 141-142 °C in cathode glow vacuum).
Antipyrine - crystals of a slightly bitter taste, odorless, soluble in water (1:1), in alcohol (1:1), in chloroform (1:15), worse in ether (1:75). Gives all characteristic qualitative reactions to alkaloids. With FeCl3 it gives an intense red color. A qualitative reaction to antipyrine is the emerald color of nitrosoantipyrine.
Antipyretic, analgesic, as a local hemostatic agent.
A wide variety of antipyrine derivatives have been studied.
Of all the derivatives, only amidopyrine and analgin turned out to be valuable analgesics, superior in properties to antipyrine.
4. Technology of antipyrine synthesis Description of the main stages of the process.
Phenylmethylpyrazolone is loaded into an enameled, oil-heated reactor and dried in a vacuum at 100 °C until moisture is completely removed. Then the temperature is increased to 127-130 oC and benzosulfonic acid methyl ester is added to the phenylmethylpyrazolone solution. The reaction temperature is not higher than 135-140 oC. At the end of the process, the reaction mass is pressed into a crystallizer, where a small amount of water is loaded and cooled to 10 °C. The precipitated antipyrine benzosulfonate is squeezed out and washed in a centrifuge. To isolate antipyrine, this salt is treated with an aqueous solution of NaOH, the resulting antipyrine is separated from the salt solution and reprecipitated in isopropyl alcohol, and the antipyrine is purified by recrystallization from isopropyl alcohol. Available in powders and tablets of 0.25 g.
Amidopyrine.
If antipyrine was discovered during the study of the alkaloid quinine, then the transition from antipyrine to amidopyrine is associated with the study of morphine.
The establishment of an N-methyl group in the structure of morphine gave reason to believe that the analgesic effect of antipyrine can be enhanced by the introduction of another tertiary amino group into the nucleus.
In 1893, 4-dimethylaminoantipyrine was synthesized - amidopyrine, which is 3-4 times stronger than antipyrine. In recent years, it has been used only in combination with other drugs, due to undesirable effects: allergies, suppression of hematopoiesis.
1-Phenyl-2,3-dimethyl-4-dimethylaminopyrazolone-5 (in water 1:11).
Qualitative reaction with FeCl3 – blue-violet color. Preparation of amidopyrine.
A large number of methods have been developed for carrying out the processes of restoration and methylation. In production conditions, preference is given to the following:
1. Use of antipyrine in the form of benzenesulfonic acid:
The nitrous acid necessary for nitration is formed in this case by the interaction of NaNO2 with benzenesulfonic acid associated with antipyrine.
The reduction of nitrosoantipyrine to aminoantipyrine (light yellow crystals with a melting point of 109°) is carried out in high yields using a sulfite-bisulfite mixture in an aqueous medium:
Reaction mechanism.
There are developed methods for the reduction of nitrosoantipyrine with hydrogen sulfide, zinc (dust), in CH3COOH, etc.
Purification of aminoantipyrine and its isolation from various solutions is carried out through a benzylidene derivative (light yellow, shiny crystals, melting point 172-173 oC), easily formed by the interaction of aminoantipyrine with benzaldehyde:
benzylideneaminoantipyrine is the starting product in the synthesis of analgin.
Methylation of aminoantipyrine is most economically achieved using a mixture of CH2O - HCOOH.
Mechanism of methylation reaction:
With this method of methylation, the formation of quaternary ammonium compounds formed when using halogenated dimethyl sulfonate as a methylating agent is avoided.
When using haloamine, the resulting quaternary compound can be converted in an autoclave.
To isolate and purify amidopyrine, repeated recrystallization from isopropyl or ethyl alcohol is used.
5. Antipyrine synthesis technology
Chemistry of the process
Description of the main stages of the process.
An aqueous suspension of antipyrine salt is pressed into the neutralizer, cooled to 20 °C and a 20% NaNO2 solution is gradually added. The reaction temperature should not exceed 4-5 °C. The resulting suspension of emerald green nitrosoantipyrine crystals is washed with cold water. The crystals are loaded into a reactor, where a bisulfite-sulfate mixture is added. The mixture is first kept for 3 hours at 22-285°C, then 2-2.5 hours at 80°C. The sodium salt solution is pressed into the hydrolyzer. Aminoantipyrine hydrolyzate is obtained, which is subjected to methylation in a reactor with a mixture of formaldehyde and formic acid. Amidopyrine is isolated from formic acid salt by treating the salt solution at 50 °C with a soda solution. After neutralization, amidopyrine floats as an oil. The oil layer is separated and transferred to a neutralizer, where it is recrystallized from isopropyl alcohol.
Analgin.
Structural formula of analgin
1-Phenyl-2,3-dimethylpyrazolone-5-4-methylaminomethylene sulphate.
Empirical formula – C13H16O4N3SNa · H2O – white, slightly yellowish crystalline powder, easily soluble in water (1:1.5), difficult in alcohol. The aqueous solution is transparent and neutral to litmus. When standing, it turns yellow without losing activity.
Analgin is the best drug among pyrazolone compounds. Superior to all pyrazolone analgesics. Low toxic. Analgin is included in many drugs
Its highest single dose is 1 g, daily dose is 3 g.
The industrial synthesis of analgin is based on two chemical schemes.
2). Production method for production from benzylidene aminoantipyrine.
Empirical formula – C13H16O4N3SNa · H2O – white, slightly yellowish crystalline powder, easily soluble in water (1:15), difficult in alcohol. The aqueous solution is transparent and neutral to litmus.
Analgin is the best drug among pyrazolone compounds. Superior to all pyrazolone analgesics. Low toxic.
Description of the technological process.
Phenylmethylpyrazolone is loaded into an enameled, oil-heated reactor and dried in a vacuum at 100 °C until moisture is completely removed. The temperature is raised to 127-130 oC and benzosulfonic acid methyl ester is added to the FMP solution. Reaction temperature 135-140 oC. At the end of the process, the reaction mass is pressed into a crystallizer, where a small amount of water is loaded and cooled to 10 °C. The precipitated antipyrine benzene sulfonate is washed on a filter and fed into the next reactor to carry out the nitrosation reaction. There the mixture is cooled to 20 °C and a 20% NaNO2 solution is gradually added. Reaction temperature 4-5 oC. The resulting suspension of emerald green crystals is filtered using a vacuum filter and washed with cold water. The crystals are loaded into a reactor, where a bisulfite-sulfate mixture is added, which is first kept for 3 hours at 22-25 oC, then another 2-2.5 hours at 80 oC. The resulting salt is pressed into a saponification reactor, where it is treated with a NaOH solution, resulting in the formation of disodium salt of sulfoaminoantipyrine.
The resulting salt is pressed into a reactor for methylation with dimethyl sulfate. DMS is fed into the reactor from the measuring tank. The reaction occurs at 107-110 °C for 5 hours. At the end of the reaction, the reaction product is separated from Na2SO4 on filter 15. The sodium salt solution is pressed into the reactor and hydrolyzed with sulfuric acid at 85 oC for 3 hours. After the reaction is complete, NaOH is added to the reaction mixture to neutralize the acid. The reaction temperature should not exceed 58-62 °C. The resulting monomethylaminoantipyrine is separated from Na2SO4 on a filter and transferred to the methylation reactor. Methylation is carried out with a mixture of formaldehyde and sodium bisulfite at 68-70 oC. The reaction results in analgin, which is then purified.
The solution is evaporated. Analgin is recrystallized from water, washed with alcohol and dried.
Method II – through benzylideneaminoantipyrine..
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Prochko Denis Vladimirovich. Narcotic analgesics. Abstract. CONTENTS Introduction. 3 Mechanisms of action of narcotic analgesics. 5 Alkaloids – derivatives of phenanthrene isoquinoline and their synthetic analogues. 9
The adrenal glands are small paired internal secretion organs. Morpho-functional structure of the adrenal cortex. Catabolic transformations in the liver of corticosteroids up to 17 - CS. Objectives, progress, procedures of study 17 – CS in urine, conclusions, purification of ethanol.
Preferanskaya Nina Germanovna
Associate Professor, Department of Pharmacology, Educational Department, Institute of Pharmacy and Translational Medicine, Multidisciplinary Center for Clinical and Medical Research, International School "Medicine of the Future" of the First Moscow State Medical University. THEM. Sechenov (Sechenov University), Ph.D.
Pain, as an unpleasant sensory and emotional experience, is usually associated with tissue damage or an inflammatory process. The sensation of pain forms a whole complex of universal protective reactions aimed at eliminating this damage. Excessive severe and prolonged pain entails a breakdown of compensatory and protective mechanisms and becomes a source of suffering, and in some cases, a cause of disability. Correct and timely treatment of the disease in most cases can eliminate pain, alleviate suffering and improve the patient’s quality of life.
At the same time, a symptomatic therapy option is possible, in which a significant reduction in pain is achieved, but the cause of its occurrence is not excluded. Means of local and resorptive action, the main effect of which is the selective reduction or elimination of pain sensitivity (analgesia, from the gr. translated as anesthetized, absence of pain), are called analgesics.
In therapeutic doses, analgesics do not cause loss of consciousness, do not inhibit other types of sensitivity (temperature, tactile, etc.) and do not impair motor functions. In this they differ from anesthesia, which eliminates the sensation of pain, but at the same time turns off consciousness and other types of sensitivity, as well as from local anesthetics, which indiscriminately suppress all types of sensitivity. Thus, analgesics have greater selectivity of analgesic action compared to anesthetics and local anesthetics.
Based on the mechanism and localization of action, analgesics are divided into the following groups:
- Narcotic (opioid) analgesics of central action.
- Non-narcotic (non-opioid) peripheral analgesics:
2.1. Analgesics-antipyretics.
2.2. Nonsteroidal anti-inflammatory drugs (NSAIDs).
2.2.1. Non-steroidal anti-inflammatory drugs of systemic action.
2.2.2. Local agents with analgesic and anti-inflammatory effects.
Let's talk only about non-narcotic analgesics and antipyretics. Non-narcotic (non-opioid) analgesics, unlike narcotic ones, do not cause euphoria, drug dependence, addiction and do not depress the respiratory center. They have significant analgesic, antipyretic effects and a weak anti-inflammatory effect.
Non-narcotic analgesics are widely used for primary headaches, pain of vascular origin (migraine, hypertension), neuralgia, postoperative pain of moderate intensity, mild and moderate pain in muscles (myalgia), joints, soft tissue injuries and bone fractures.
They are effective for toothache and pain associated with inflammation, visceral pain (pain coming from internal organs due to ulcers, scars, spasms, sprains, radiculitis, etc.), as well as for reducing elevated temperature and fever. The effect usually appears within 15-20 minutes. and its duration ranges from 3 to 6-8 hours.
Important! Non-narcotic analgesics are ineffective for the treatment of severe pain; they are not used during surgical operations or for premedication (neuroleptanalgesia); they do not relieve pain in severe injuries and are not taken for pain resulting from myocardial infarction or malignant tumors.
Products of destroyed cells, bacteria, proteins of microorganisms and other pyrogens formed in our body, in the process of triggering the synthesis of prostaglandins (Pg), cause fever. Prostaglandins act on the thermoregulation center located in the hypothalamus, excite it and cause a rapid rise in body temperature.
Non-opioid analgesics-antipyretics provide antipyretic effect due to suppression of the synthesis of prostaglandins (PgE 2) in the cells of the thermoregulatory center activated by pyrogens. At the same time, skin vessels dilate, heat transfer increases, evaporation increases and sweating increases. All these processes are externally significantly hidden, as a result of muscle trembling thermogenesis (chills). The effect of lowering body temperature appears only against the background of fever (at high body temperature). The drugs do not affect normal body temperature - 36.6°C. Fever is one of the elements of the body’s adaptation to pathological changes in the body and against its background the immune response increases, phagocytosis and other protective reactions of the body intensify. Therefore, not every increase in temperature requires the use of antipyretics. As a rule, it is only necessary to reduce high body temperature, equal to 38°C or more, because it can lead to functional overstrain of the cardiovascular, nervous, renal and other systems, and this, in turn, can lead to various complications.
√ Analgesic(painkiller) effect non-narcotic analgesics is explained by the cessation of the occurrence of pain impulses in the endings of sensory nerves.
In inflammatory processes, pain occurs as a result of the formation and accumulation in tissues of biologically active substances, the so-called mediators (transmitters) of inflammation: prostaglandins, bradykinin, histamine and some others that irritate nerve endings and cause pain impulses. Analgesics suppress activity cyclooxygenase(COX) in the central nervous system and reduce production PgE 2 And PgF2α, increasing the sensitivity of nociceptors, both during inflammation and tissue damage. BAS increase the sensitivity of nociceptive receptors to mechanical and chemical stimulation. Their peripheral action is associated with an anti-exudative effect, in which the formation and accumulation of mediators is reduced, which prevents the occurrence of pain.
√ Anti-inflammatoryaction non-narcotic analgesics are associated with inhibition of the activity of the enzyme cyclooxygenase, which is key for the synthesis of inflammatory mediators. Inflammation is a protective reaction of the body and is manifested by a number of specific signs - redness, swelling, pain, increased body temperature, etc. Blockade of prostaglandin synthesis leads to a decrease in the manifestations of inflammation caused by them.
Analgesics-antipyretics have a pronounced analgesic and antipyretic effect.
Classification depending on the chemical structure into derivatives:
- aminophenol: Paracetamol and its combinations;
- pyrazolone: Metamizole sodium and its combinations;
- salicylic acid: Acetylsalicylic acid and its combinations;
- pyrrolysinecarboxylic acid: Ketorolac.
PARACETAMOL IN COMBINED DRUGS
Paracetamol- non-narcotic analgesic, derivative para-aminophenol, the active metabolite of phenacetin, which is one of the most widely used drugs in the world. This substance is included in more than one hundred pharmaceutical preparations.
In therapeutic doses, the drug rarely causes side effects. However, the toxic dose of paracetamol is only 3 times higher than the therapeutic dose. A decrease in body temperature is observed against the background of fever, accompanied by dilation of the peripheral blood vessels of the skin and increased heat transfer. Unlike salicylates, it does not irritate the stomach and intestines (no ulcerogenic effect) and does not affect platelet aggregation.
Important! Overdose is possible with long-term use and can lead to serious damage to the liver and kidneys, as well as allergic reactions (skin rash, itching). In case of overdose, the drug causes necrosis of liver cells, which is associated with depletion of glutathione reserves and the formation of a toxic metabolite of paracetamol - N-acetyl-ρ-benzoquinoneimine. The latter binds to hepatocyte proteins and causes a lack of glutathione, which can inactivate this dangerous metabolite. In order to prevent the development of toxic effects, N-acetylcysteine or methionine, which contain a sulfhydryl group in the same way as glutathione, is administered during the first 12 hours after poisoning. Despite causing severe hepatotoxicity or liver failure in overdose, paracetamol is widely used and is considered a relatively safe substitute for drugs such as metamizole and aspirin, especially in childhood to reduce high fever.
Combination drugs containing paracetamol are:
√ Paracetamol + Ascorbic acid (Grippostad, portion, 5 g; Paracetamol EXTRA for children, por. 120 mg + 10 mg; Paracetamol EXTRA, por. 500 mg + 150 mg; Paracetamol Extratab, por. and table 500 mg + 150 mg; Efferalgan with vit. WITH, table effervescent) is intended specifically for the treatment of headaches associated with colds. Ascorbic acid (Vitamin C) is necessary for the normal functioning of the immune system, activates a number of enzymes involved in redox processes, activates the functions of the adrenal glands and takes part in the formation of corticosteroids that have an anti-inflammatory effect.
√ Paracetamol + Caffeine (Solpadeine Fast, table, Migrenol, table No. 8, Migraine, table 65 mg + 500 mg) - good for treating headaches associated with low blood pressure. Caffeine has psychostimulating and analeptic properties, reduces the feeling of fatigue, and increases mental and physical performance.
Important! The drug is contraindicated for hypertension, insomnia and increased excitability.
√ Paracetamol + Diphenhydramine hydrochloride(Migrenol PM) has analgesic, antihistamine, antiallergic and hypnotic effects, therefore it is indicated for those who have difficulty falling asleep due to pain.
√ Paracetamol + Metamizole sodium + Codeine + Caffeine + Phenobarbital (Pentalgin-ICN, Sedalgin-Neo, Sedal-M, table) - the drug contains two analgesics-antipyretics, codeine and caffeine, to enhance the analgesic effect, while codeine also has an antitussive effect. It is used as a powerful analgesic for the treatment of various types of acute and chronic pain of moderate intensity, with a dry and painful cough.
Important! It has a number of side effects, so it is contraindicated for use for more than 5 days.
Summary
Non-opioid analgesics (analgesics-antipyretics) are widely used in pediatric practice. When choosing drugs from this group for use in children, it is especially important to focus on highly effective drugs with the lowest risk of adverse reactions. Today only paracetamol and ibuprofen fully meet these requirements. They are officially recommended by WHO as antipyretics for use in pediatrics. The possibilities of using these drugs in the practice of a general pediatrician (with the exception of pediatric rheumatology) are being considered. The results of a study demonstrating the high antipyretic and analgesic effectiveness of the drug Nurofen for children (ibuprofen) in patients with acute infectious and inflammatory diseases of the respiratory tract and ENT organs are presented. In addition, the high safety of taking Nurofen was noted. It is emphasized that against the background of etiotropic and pathogenetic treatment, timely and adequate therapy with analgesics and antipyretics brings relief to a sick child, improves his well-being and accelerates recovery.
Non-opioid analgesics (analgesics-antipyretics) are among the most widely used drugs (medicines) in pediatric practice. They are distinguished by a unique combination of antipyretic, anti-inflammatory, analgesic and antithrombotic mechanisms of action, which makes it possible to use these drugs to relieve the symptoms of many diseases.
Currently, there are several pharmacological groups of non-opioid analgesics, which are divided into non-steroidal anti-inflammatory drugs (NSAIDs) and simple analgesics (paracetamol). Paracetamol (acetaminophen) is not included in the group of NSAIDs, since it has virtually no anti-inflammatory effect.
Mechanisms of action of non-opioid analgesics and features of their use in children
The main mechanism of action of analgesic-antipyretics, which determines their effectiveness, is the suppression of the activity of cyclooxygenase (COX), an enzyme that regulates the conversion of arachidonic acid (AA) into prostaglandins (PG), prostacyclin and thromboxane. It has been established that there are 2 COX isoenzymes.
COX-1 directs the metabolic processes of AA to the implementation of physiological functions - the formation of PGs, which have a cytoprotective effect on the gastric mucosa, regulating platelet function, microcirculation processes, etc. COX-2 is formed only during inflammatory processes under the influence of cytokines. During inflammation, AA metabolism is significantly activated, the synthesis of PGs and leukotrienes increases, the release of biogenic amines, free radicals, and NO increases, which determines the development of the early stage of the inflammatory process. Blockade of COX in the central nervous system by analgesics-antipyretics leads to an antipyretic and analgesic effect (central action), and a decrease in PG content in the inflammatory zone leads to an anti-inflammatory effect and, due to a decrease in pain reception, to an analgesic effect (peripheral effect).
It is assumed that inhibition of COX-2 is one of the important mechanisms of the clinical effectiveness of analgesics, and suppression of COX-1 determines their toxicity (primarily in relation to the gastrointestinal tract). In this regard, along with standard (non-selective) NSAIDs, which equally suppress the activity of both COX isoforms, selective COX-2 inhibitors have been created. However, these drugs were not without side effects.
The analgesic, anti-inflammatory and antipyretic activity of non-opioid analgesics has been demonstrated in numerous controlled trials that meet the standards of evidence-based medicine (level A). Worldwide, more than 300 million people use NSAIDs annually. They are widely used for feverish conditions, acute and chronic pain, rheumatic diseases and in many other cases. It is noteworthy that most patients use over-the-counter dosage forms of these drugs.
Despite the high effectiveness of analgesics and antipyretics, their use in children is not always safe. So in the 70s. last century, convincing evidence emerged that the use of acetylsalicylic acid (aspirin) for viral infections in children may be accompanied by Reye syndrome, characterized by toxic encephalopathy and fatty degeneration of internal organs, mainly the liver and brain. Restrictions imposed in the United States on the use of acetylsalicylic acid in children led to a significant decrease in the incidence of Reye's syndrome from 555 in 1980 to 36 in 1987 and 2 in 1997. In addition, acetylsalicylic acid increases the risk of developing inflammatory changes in the gastrointestinal tract, disrupts blood clotting, increases vascular fragility, and in newborns it can displace bilirubin from its connection with albumin and thereby contribute to the development of bilirubin encephalopathy. WHO experts do not recommend the use of acetylsalicylic acid as an antipyretic in children under 12 years of age, which is reflected in the Russian National Formulary (2000). By order of the Pharmacological Committee of the Ministry of Health of the Russian Federation dated March 25, 1999, the prescription of acetylsalicylic acid for acute viral infections is permitted from the age of 15. However, under the supervision of a physician, acetylsalicylic acid can be used in children for rheumatic diseases.
At the same time, data on side effects of other analgesics and antipyretics were accumulated. Thus, amidopyrine, due to its high toxicity, was excluded from the drug nomenclature. Analgin (metamizole) can inhibit hematopoiesis, up to the development of fatal agranulocytosis, which contributed to a sharp limitation in its use in many countries of the world (International Agranulocytosis and Aplastic Anaemi Study Group, 1986). However, in such urgent situations as hyperthermic syndrome, acute pain in the postoperative period, etc., which are not amenable to other therapy, parenteral use of analgin and metamizole-containing drugs is acceptable.
Thus, when choosing analgesics-antipyretics for children, it is especially important to focus on highly effective drugs with the lowest risk of adverse reactions. Currently, only paracetamol and ibuprofen fully meet the criteria of high efficiency and safety and are officially recommended by the World Health Organization and national programs for use in pediatrics as antipyretics (WHO, 1993; Lesko S.M. et al., 1997; Practical recommendations for doctors of the Russian Association pediatric centers, 2000, etc.). Paracetamol and ibuprofen can be prescribed to children from the first months of life (from 3 months of age). Recommended single doses of paracetamol are 10-15 mg/kg, ibuprofen - 5-10 mg/kg. Re-use of antipyretics is possible no earlier than after 4-5 hours, but no more than 4 times a day.
It should be noted that the mechanism of action of these drugs is somewhat different. Paracetamol has antipyretic, analgesic and very slight anti-inflammatory effects, since it blocks COX mainly in the central nervous system and does not have a peripheral effect. Qualitative changes in the metabolism of paracetamol were noted depending on the age of the child, which were determined by the maturity of the cytochrome P450 system. In addition, a delay in the elimination of the drug and its metabolites may occur in cases of impaired liver and kidney function. A daily dose of 60 mg/kg in children is safe, but if it is increased, a hepatotoxic effect of the drug may be observed. A case of fulminant liver failure with hypoglycemia and coagulopathy is described when parents chronically exceeded the dose of paracetamol (150 mg/kg) for several days. If a child has a deficiency of glucose-6-phosphate dehydrogenase and glutathione reductase, the administration of paracetamol can cause hemolysis of red blood cells, drug-induced hemolytic anemia.
Ibuprofen (Nurofen, Nurofen for children, Ibufen, etc.) has a pronounced antipyretic, analgesic and anti-inflammatory effect. Most studies show that ibuprofen is as effective for fever as paracetamol. Other studies have found that the antipyretic effect of ibuprofen at a dose of 7.5 mg/kg is higher than that of paracetamol at a dose of 10 mg/kg and acetylsalicylic acid at a dose of 10 mg/kg. This was manifested by a pronounced decrease in temperature after 4 hours, which was also observed in a larger number of children. The same data were obtained in a double-blind study in parallel groups of children from 5 months to 13 years of age with repeated doses of ibuprofen at doses of 7 and 10 mg/kg and paracetamol at a dose of 10 mg/kg.
Ibuprofen blocks COX both in the central nervous system and at the site of inflammation, which determines the presence of not only antipyretic, but also anti-inflammatory effects. As a result, phagocytic production of acute phase mediators, including interleukin-1 (IL-1; endogenous pyrogen), decreases. A decrease in IL-1 concentration helps normalize body temperature. Ibuprofen has a dual analgesic effect - peripheral and central. The analgesic effect is already evident at a dose of 5 mg/kg, and it is more pronounced than that of paracetamol. This allows you to effectively use ibuprofen for mild to moderate sore throat, acute otitis media, toothache, teething pain in infants, as well as for the relief of post-vaccination reactions.
Numerous multicenter studies have shown that among all analgesic-antipyretic drugs, ibuprofen and paracetamol are the safest drugs, the frequency of adverse events with their use was comparable, amounting to approximately 8-9%. Side effects when taking non-opioid analgesics are observed mainly in the gastrointestinal tract (abdominal pain, dyspeptic syndrome, NSAID gastropathy), less often in the form of allergic reactions, a tendency to bleeding, and renal dysfunction is extremely rare.
It is known that aspirin and NSAIDs can provoke bronchospasm in persons with aspirin intolerance, since they inhibit the synthesis of PGE 2, prostacyclin and thromboxanes and contribute to an increase in the production of leukotrienes. Paracetamol does not affect the synthesis of these mediators of allergic inflammation, however, bronchoconstriction is possible when taken, which is associated with depletion of the glutathione system in the respiratory tract and a decrease in antioxidant protection. A large international study showed that when using ibuprofen and paracetamol in 1879 children with bronchial asthma, only 18 people were hospitalized (paracetamol - 9, ibuprofen - 9), which indicates the relative safety of these drugs in children with this disease. For bronchiolitis in children during the first 6 months of life, ibuprofen and paracetamol did not have a bronchospastic effect. Aspirin intolerance in children is quite rare; in these cases, the use of NSAIDs is contraindicated.
Thus, ibuprofen and paracetamol are the drugs of choice in children as antipyretics and analgesics (for moderate pain), and ibuprofen is also widely used for anti-inflammatory purposes. Below we present the main prospects for the use of these drugs in the practice of a general pediatrician (with the exception of the use of NSAIDs in pediatric rheumatology).
Mechanisms of fever in children and principles of antipyretic therapy
Increased body temperature is a common and one of the important symptoms of childhood diseases. Fever in children is the most common reason for visiting a doctor, although parents often try to reduce their children’s elevated body temperature on their own by using over-the-counter antipyretic drugs. The issues of the etiopathogenesis of hyperthermia and modern approaches to the treatment of febrile conditions are still pressing problems in pediatrics.
It is known that the ability to maintain body temperature at a constant level regardless of temperature fluctuations in the external environment (homeothermicity) allows the body to maintain a high metabolic rate and biological activity. Homeothermicity in humans is primarily due to the presence of physiological mechanisms of thermoregulation, i.e., regulation of heat production and heat transfer. Control over the balancing of the processes of heat production and heat transfer is carried out by the thermoregulation center located in the preoptic region of the anterior part of the hypothalamus. Information about the body's temperature balance enters the thermoregulation center, firstly, through its neurons that respond to changes in blood temperature, and secondly, from peripheral thermoreceptors. In addition, endocrine glands, mainly the thyroid gland and adrenal glands, are involved in the hypothalamic regulation of body temperature. Thanks to coordinated changes in heat production and heat transfer, the constancy of thermal homeostasis in the body is maintained.
In response to exposure to various pathogenic stimuli, a restructuring of temperature homeostasis occurs, aimed at increasing body temperature in order to increase the natural reactivity of the body. This increase in temperature is called fever. The biological significance of fever is to increase immunological defense. An increase in body temperature leads to increased phagocytosis, increased synthesis of interferons, activation and differentiation of lymphocytes and stimulation of antibody genesis. Elevated temperature prevents the proliferation of viruses, cocci and other microorganisms.
Fever is fundamentally different from an increase in body temperature due to overheating, which occurs with a significant increase in ambient temperature, active muscle work, etc. In case of overheating, the thermoregulation center is set to normalize the temperature, while in case of fever, this center purposefully rearranges the “set point” to a higher level.
Since fever is a nonspecific protective-adaptive reaction of the body, the reasons that cause it are very diverse. Fever most often occurs in infectious diseases, among which acute respiratory diseases of the upper and lower respiratory tract dominate. Fever of infectious origin develops in response to exposure to viruses, bacteria and their decay products. An increase in body temperature of a non-infectious nature can have different origins: central (hemorrhage, tumor, trauma, cerebral edema), psychogenic (neurosis, mental disorders, emotional stress), reflex (pain syndrome with urolithiasis), endocrine (hyperthyroidism, pheochromacytoma), resorptive (bruise, necrosis, aseptic inflammation, hemolysis), and also occurs in response to the administration of certain medications (ephedrine, xanthine derivatives, antibiotics, etc.).
Each of the fever variants has both general development mechanisms and specific features. It has been established that an integral component of the pathogenesis of fever is the reaction of peripheral blood phagocytes and/or tissue macrophages to infectious invasion or a non-infectious inflammatory process. Primary pyrogens, both infectious and non-infectious, only initiate the development of fever, stimulating body cells to synthesize secondary mediators-pyrogens. The source of secondary pyrogens is predominantly phagocytic mononuclear cells. Secondary pyrogens are a heterogeneous group of proinflammatory cytokines: IL-1, IL-6, tumor necrosis factor α, etc. However, IL-1 plays the leading, initiating role in the pathogenesis of fever.
IL-1 is the main mediator of intercellular interaction in the acute phase of inflammation. Its biological effects are extremely varied. Under the influence of IL-1, the activation and proliferation of T-lymphocytes is initiated, the production of IL-2 is enhanced, and the expression of cellular receptors increases. IL-1 promotes the proliferation of B cells and the synthesis of immunoglobulins, stimulates the synthesis of proteins of the acute phase of inflammation (C-reactive protein, complement, etc.), PG and precursors of hematopoiesis in the bone marrow. IL-1 has a direct toxic effect on cells infected with the virus.
IL-1 is also the main mediator in the mechanism of development of fever, which is why in the literature it is often referred to as an endogenous or leukocyte pyrogen. Under normal conditions, IL-1 does not penetrate the blood-brain barrier. However, in the presence of inflammation (infectious or non-infectious), IL-1 reaches the preoptic region of the anterior part of the hypothalamus and interacts with the receptors of neurons in the thermoregulatory center. In this case, COX is activated, which leads to an increase in the synthesis of PGE 1 and an increase in the intracellular level of cAMP. An increase in the concentration of cAMP promotes the intracellular accumulation of calcium ions, a change in the Na / Ca ratio and a restructuring of the activity of the centers of heat production and heat transfer. An increase in body temperature is achieved by changing the activity of metabolic processes, vascular tone, peripheral blood flow, sweating, synthesis of pancreatic and adrenal hormones, contractile thermogenesis (muscle tremors) and other mechanisms.
It should be especially noted that with the same level of hyperthermia, fever in children can occur differently. So, if heat transfer corresponds to heat production, this indicates an adequate course of fever and is clinically manifested by the child’s relatively normal state of health, pink or moderately hyperemic skin color, moist and warm to the touch (“pink fever”). This type of fever often does not require the use of antipyretics.
In the case when, with increased heat production, heat transfer is inadequate due to impaired peripheral circulation, the course of the fever is prognostically unfavorable. Clinically, severe chills, pale skin, acrocyanosis, cold feet and palms (“pale fever”) are noted. Children with such fever usually require antipyretic drugs in combination with vasodilators and antihistamines (or antipsychotics).
One of the clinical variants of the unfavorable course of fever is a hyperthermic state in young children, in most cases caused by infectious inflammation accompanied by toxicosis. In this case, there is a persistent (6 or more hours) and significant (above 40.0 °C) increase in body temperature, accompanied by impaired microcirculation, metabolic disorders and progressively increasing dysfunction of vital organs and systems. The development of fever against the background of acute microcirculatory metabolic disorders underlying toxicosis leads to decompensation of thermoregulation with a sharp increase in heat production and inadequately reduced heat transfer. All this is associated with a high risk of developing metabolic disorders and cerebral edema and requires urgent use of complex emergency therapy.
In accordance with the WHO recommendations “Treatment of fever in acute respiratory infections in children” (WHO, 1993) and domestic recommendations, antipyretic drugs should be prescribed when the child’s temperature exceeds 39.0 °C when measured rectally. The exceptions are children at risk of developing febrile seizures or severe disease of the pulmonary or cardiovascular systems and children in the first 3 months of life. In the national scientific and practical program “Acute respiratory diseases in children: treatment and prevention” (2002), antipyretics are recommended to be prescribed in the following cases:
- previously healthy children - with a body temperature above 39.0 ° C and/or with muscle aches and headaches;
- children with a history of febrile convulsions - at a body temperature above 38.0-38.5 ° C;
- children with severe heart and lung diseases - with a body temperature above 38.5 ° C;
- children in the first 3 months of life - at a body temperature above 38.0 °C.
As stated above, only paracetamol and ibuprofen are recommended by the World Health Organization and national programs as antipyretics in children.
Antipyretic therapy in children with allergic reactions and diseases
Allergic diseases in children are currently widespread, and their frequency is constantly increasing. Allergy, as a premorbid background, in this group of patients often determines the characteristics of the course of conditions occurring with fever and, in addition, increases the risk of hypersensitivity reactions to the medications used.
The course of fever in children with allergic diseases has its own characteristics. Firstly, these patients have a tendency to have a pronounced and protracted course of fever, which is due to the high level of IL-1 in patients with atopy and, therefore, a closed pathological circle of its synthesis, especially during the acute period of an allergic reaction. Secondly, children predisposed to atopy have a high likelihood of developing fever of drug origin (the so-called allergic fever). Thirdly, it is necessary to take into account that against the background of exacerbation of allergies, an increase in temperature of a non-infectious nature may be observed. The prescription of antipyretic drugs (analgesics-antipyretics) to children with allergic diseases and reactions requires strict medical supervision. It is advisable to include antihistamines along with antipyretics in the complex treatment of febrile conditions in children with allergic diseases.
Some aspects of acute pain therapy in pediatric practice
A general pediatrician encounters the problem of treating acute pain of moderate intensity quite often. Pain in children often accompanies some infectious and inflammatory diseases (acute otitis media, tonsillitis, pharyngitis, acute respiratory infections) and occurs along with fever in the early post-vaccination period. Pain occurs in infants when teething, and in older children after tooth extraction. Pain syndrome, even of slight intensity, not only worsens the child’s well-being and mood, but also slows down reparative processes and, as a result, recovery. It is necessary to emphasize the absolute main role of etiotropic and pathogenetic approaches in the treatment of diseases accompanied by pain. However, the result of therapy will be more successful if, along with pathogenetic methods of treating the disease, adequate pain relief is used.
The mechanism of pain formation is quite complex, but the most important role in it is played by substances of the prostaglandin and kinin series, which are direct neurochemical mediators of pain. Inflammatory swelling, as a rule, increases pain. A decrease in the production of pain mediators and/or a decrease in receptor sensitivity (for example, due to blockade of pain receptors) determines the analgesic effects of therapy.
In the practice of a general pediatrician, the main drugs for the relief of acute pain of moderate intensity are non-opioid analgesics. Blockade of COX in the central nervous system with their help leads to an analgesic effect of central origin, and a decrease in the PG content in the area of inflammation leads to an anti-inflammatory effect and an analgesic peripheral effect due to a decrease in pain reception.
Clinical studies suggest that ibupophen and, to a lesser extent, paracetamol are the drugs of choice for the treatment of acute pain of moderate intensity in children. Timely and adequate accompanying pain therapy brings relief to a sick child, improves his well-being and promotes a faster recovery.
Prevention and treatment of post-vaccination reactions in children
Post-vaccination reactions are expected conditions indicated in the vaccine instructions. They occur quite often and should not be confused with vaccination complications, the development of which is most often unpredictable and reflects the child’s individual reaction or a violation of the vaccination technique. A well-known post-vaccination reaction in children is post-immunization hyperthermia. In addition, moderate pain, hyperemia, and swelling may appear at the site of vaccine administration, which is also sometimes accompanied by fever, malaise and headache. Hyperthermia and local reactions after immunization are considered indications for ibuprofen. Since post-vaccination reactions are predictable, when performing DPT vaccination, it is appropriate to recommend prophylactic use of ibuprofen or paracetamol in a child for 1-2 days after vaccination.
Experience of using Nurofen in children
In order to study the clinical effectiveness of ibuprofen in children with infectious and inflammatory diseases accompanied by fever and/or pain, we conducted an open, uncontrolled study in which the drug Nurofen for children (Boots Healthcare International, UK) was used in 67 children with ARVI and in 10 children with sore throat aged from 3 months to 15 years. In 20 patients, ARVI occurred against the background of mild to moderate bronchial asthma without indications of aspirin intolerance, in 17 - with broncho-obstructive syndrome, in 12 - with manifestations of acute otitis media, in 14 - accompanied by severe headache and/or muscle aches. In 53 children, the disease was accompanied by high fever requiring antipyretic therapy; 24 patients with low-grade fever were prescribed Nurofen only for analgesic purposes. Nurofen suspension for children was used in a standard single dosage of 5 to 10 mg/kg 3-4 times a day, which is usually from 2.5 to 5 ml of suspension per dose (measuring spoons were used). The duration of Nurofen administration ranged from 1 to 3 days.
The study of the clinical condition of patients included assessment of the antipyretic and analgesic effects of Nurofen, registration of adverse events.
In 48 children, a good antipyretic effect was obtained after taking the first dose of the drug. Most children were prescribed Nurofen for no more than 2 days. In 4 patients, the antipyretic effect was minimal and short-lived. Two of them were prescribed diclofenac, the other 2 were treated with parenteral lytic mixture.
A decrease in pain intensity after the initial dose of Nurofen was observed after 30-60 minutes, the maximum effect was observed after 1.5-2 hours. The duration of the analgesic effect ranged from 4 to 8 hours (group average 4.9 ± 2.6 hours).
Adequate analgesic effect of Nurofen was noted in the vast majority of patients. After the first dose of the drug, an excellent or good analgesic effect was achieved in more than half of the children, satisfactory in 28%, and only in 16.6% of patients no analgesic effect was observed. A day after the start of therapy, a good or excellent analgesic effect was noted by 75% of patients, satisfactory relief of pain was recorded in 25% of cases. On the 3rd day of observation, the children had virtually no complaints of pain.
It should be noted that Nurofen for children has good taste and is well tolerated by children of all ages. There were no side effects from the digestive system, the development of allergic reactions, or increased or provocative bronchospasm. None of the patients discontinued Nurofen due to adverse events.
Conclusion
Today, ibuprofen and paracetamol are among the most popular drugs in pediatric practice. They are the first choice drugs for children with fever and moderate pain, and ibuprofen is also widely used as an anti-inflammatory drug. However, when prescribing any analgesic-antipyretic, it is important to carefully determine the required dose and take into account all possible risk factors. The use of combination drugs containing more than one antipyretic agent should be avoided. Course use of antipyretics is unacceptable without specifying the causes of fever.
Our study showed that the drug Nurofen for children containing ibuprofen has a pronounced and rapid antipyretic and analgesic effect in patients with acute infectious and inflammatory diseases of the respiratory tract and ENT organs. The use of the drug was effective and safe. Our experience shows that, along with etiotropic and pathogenetic therapy of the disease, it is advisable to carry out rational accompanying therapy using analgesics and antipyretics. When administered in a timely and adequate manner, such therapy brings relief to a sick child, improves his well-being and promotes a faster recovery.
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CLINICAL PHARMACOLOGY OF THE MOST COMMONLY USED ANTIPECHYMIC DRUGSWhen choosing medications for children, it is especially important to focus on drugs with the lowest risk of severe side effects. This is especially relevant due to the fact that most children with acute viral diseases are at home and parents often prescribe antipyretics on their own before the doctor arrives. At the same time, there is a significant difference in what medications parents should use before the pediatrician arrives and which ones should be prescribed under the supervision of a doctor.
Currently, it is customary to distinguish two groups among analgesics-antipyretics:
- non-steroidal anti-inflammatory drugs (NSAIDs - acetylsalicylic acid, ibuprofen, etc.);
- paracetamol (Fig. 1).
At doses recommended for over-the-counter use, NSAIDs and paracetamol have similar antipyretic and analgesic effects, although paracetamol does not have a clinically significant anti-inflammatory effect. The key difference between paracetamol and NSAIDs is safety, which is directly related to their mechanism of action.
Figure 1. Classification of non-narcotic analgesics and antipyretics allowed for sale without a prescription in the Russian Federation.
It is generally accepted that the mechanism of action of all antipyretics is to block the synthesis of prostaglandins along the cyclooxygenase pathway in the hypothalamus. At the same time, the anti-inflammatory effect of NSAIDs is associated with blocking the synthesis of prostaglandins not only in the hypothalamus, but also in other organs and systems. Along with the anti-inflammatory effect, NSAIDs block the synthesis of protective prostaglandins, which can lead to serious complications: gastrointestinal bleeding, asthma, acute renal failure, etc. The antipyretic and analgesic effect of paracetamol, unlike NSAIDs, is central in nature (pain and thermoregulation centers in central nervous system) and does not suppress the synthesis of protective prostaglandins in other organs and systems, which determines its greater safety profile compared to NSAIDs.
A key safety issue for analgesic-antipyretic drugs is the high risk of gastrointestinal bleeding due to NSAID use. It has been established that more than 50% of all acute gastrointestinal bleeding is associated with the use of NSAIDs, and 84% of them are caused by over-the-counter NSAIDs. As is known, mortality from gastrointestinal bleeding reaches 10%.
Aspirin-induced asthma is another dangerous complication of NSAID use, especially against the backdrop of a steady increase in the incidence of childhood bronchial asthma (from 10% to 15-20%).
Along with gastrointestinal bleeding and bronchial obstruction, NSAIDs can cause:
- severe changes in bone marrow hematopoiesis, including fatal agranulocytosis (metamizole);
- acute renal failure (indomethacin, ibuprofen);
- thrombocytopathy with hemorrhagic syndrome (ASC);
- anaphylactic shock (metamizole);
- Reye's syndrome (RS);
- hepatitis (aspirin);
- and many other complications.
Paracetamol is as effective as NSAIDs such as acetylsalicylic acid and ibuprofen, but it does not cause many of the severe side effects common to all NSAIDs.
Acetylsalicylic acid, paracetamol, metamizole sodium and ibuprofen lead among all analgesics-antipyretics in terms of the number of uses among Russian citizens. The task of a pharmacist or pharmacist is to pay attention to contraindications for use and side effects, some of which can result in serious health problems.
Paracetamol, ibuprofen, metamizole sodium (Analgin) and acetylsalicylic acid (Aspirin) are included in the pharmacological group of non-steroidal anti-inflammatory drugs. For many years they have been the most popular analgesics and antipyretics on the Russian pharmacological market.
From the beginning of the 20th century, unconditional primacy over the next 100 years belonged to acetylsalicylic acid, and only in the late 90s of the last century did paracetamol-based drugs become more popular.
As of the beginning of 2017, over 400 paracetamol preparations, more than 200 preparations based on acetylsalicylic acid and more than one and a half hundred preparations based on metamizole sodium and ibuprofen were registered in Russia.
Taking analgesics-antipyretics: differences in properties and potential dangers
All analgesics-antipyretics, which will be discussed in this article, differ from each other in painkillers.
Thus, the anti-inflammatory effect of ibuprofen and paracetamol significantly exceeds that of acetylsalicylic acid and metamizole sodium, while metamizole sodium and ibuprofen are superior to other drugs in their analgesic effect. The ability to reduce elevated body temperature is approximately the same for all four drugs.
These medications can be easily purchased at any pharmacy without a doctor's prescription, which creates a false impression of their safety. Almost every Russian family has them in the medicine cabinet, but few people realize that each of them has an impressive list of contraindications and side effects.
