DRUGS FOR BRONCHIAL OBSTRUCTION SYNDROME
Bronchial asthma is a chronic inflammatory disease of the respiratory tract. The key
element is bronchial obstruction (narrowing of the lumen of the bronchi), caused by
specific immunological (sensitization and allergy) or non-specific mechanisms.
Manifested by repeated episodes of wheezing, shortness of breath, chest congestion
and coughing.
Bronchial obstruction is reversible partially or completely, spontaneously or under
the influence of treatment.
Bad complication - asthmatic status.
ETIOLOGY
Risk factors: heredity, occupational factors (influence of biological and mineral dust,
harmful gases), environmental factors (exhaust fumes, smoke, high humidity, harmful
fumes), nutrition (use of animal products that are rich in fats, proteins, refined, easily
digestible carbohydrates), respiratory infections, home allergens (pet dander, dust,
mushrooms, ticks, cockroaches), the use of certain drugs (nonsteroidal anti-inflammatory
drugs, beta-blockers), etc.
PATHOGENESIS
Increased reactivity of the bronchial tree. It is caused by a dysfunction of the
autonomic regulation of smooth muscle tone and the action of inflammatory mediators and
leads to periodic reversible bronchial obstruction.
The role of the autonomic nervous system. Smooth muscle cells has β1, β2 and αadrenoreceptors. Β2-adrenoreceptors prevail (x3).
The tone of the bronchial smooth muscles is regulated mainly by the
parasympathetic fibers of the vagus nerve (block – dilation, stimulation of these fibers
causes bronchospasm).
Biochemical factors. Calcium (Increasing the concentration of calcium inside the cell
leads to a reduction, and a decrease to the relaxation of the smooth muscle muscles).
ROLE OF INFLAMMATORY CELLS
Mast cells. Activation of mast cells occurs during the interaction of allergens with IgE
(Immunoglobulin E). They release the mediators (histamine, cysteinyl leukotrienes,
prostaglandin D2), which cause bronchospasm.
Eosinophils. The number of eosinophils in the airways is increased. These cells
secrete the main proteins that damage the bronchial epithelium, and also release the
growth factors and remodeling of the respiratory tract.
T Lymphocytes. Their number in the airways is also increased. They release specific
cytokines (IL-4, IL-5, IL-9 and IL-13, etc.), affecting the process of eosinophilic inflammation
and the production of Ig E by B-lymphocytes.
Dendritic cells takes allergens from the surface of the bronchial mucosa and bring
them to regional lymph nodes, where interacting with regulatory T-cells stimulate Tlymphocyte differentiation into Th2 cells.
Macrophages. The number of macrophages is increased in the respiratory tract. They
activating when allergens interact with Ig E. Result: the release of inflammatory mediators
and cytokines.
INFLAMMATORY MEDIATORS
1. Histamine and leukotrienes are mediators of the early phase of an immediatetype allergic reaction. Histamine action: fast and short-time bronchospasm. Leukotrienes
cause delayed and longer bronchospasm.
2. The mediators of the late phase of an immediate type of allergic reaction include
chemotaxis factors and platelet activating factor. The bronchospasm caused by them occurs
2-8 hours after the onset of an allergic reaction and can last several days.
BRONCHIAL OBSTRUCTION
Pathological changes leading to bronchial obstruction affect the mucous membrane,
submucous layer and muscular layer of the bronchial tree. From the trachea and large
bronchi to the terminal bronchioles.
The following reasons lead to the narrowing of the bronchi:
1. The formation of mucous plugs. Asthma produces thick, viscous mucus containing
desquamated bronchial epithelium, eosinophils, Charcot-Leiden crystals. The mucus can
partially or completely block the lumen of the bronchi. With the duration and severity of
the attack, due to dehydration, the mucus becomes more viscous.
2. Changes in the wall of the bronchi (the number of cells with ciliated epithelium is
reduced, the quantity of goblet cells secreting mucus increasing, eosinophilic infiltration,
edema and thickening of the basement membrane).
3. Spasm of smooth muscles of the bronchi. The obstruction is intensified on
expiration. Because of the obstruction of the bronchi, part of the air is retained in the
alveoli, which leads to overstretching of the lungs and lengthening of the exhalation.
Excessive airway resistance leads to an increase in the work of breathing, which leads to the
inclusion of auxiliary muscles, shortness of breath.
Noisy, wheezing - a sign of obstruction of the large bronchi, and attacks of shortness
of breath and cough more often occur with obstruction of the small bronchi.
Obstruction leads to an increase in residual volume, a decrease in VC and an increase
in total lung capacity. Due to airway obstruction, their ventilation is reduced.
CLASSIFICATION
Depending on the causes of attacks:
1. Exogenous bronchial asthma - attacks are caused by an allergen from the external
environment (pollen, mold fungi, animal dander, tiny mites in house dust). A special option
is atopic bronchial asthma, caused by a hereditary-conditioned predisposition to allergic
reactions;
2. Endogenous bronchial asthma - an attack caused by factors such as infection,
exercise, cold air, psycho-emotional stress;
3. Bronchial asthma of mixed genesis - attacks can occur both when exposed to the
respiratory tract of the allergen, and when exposed to the factors listed above.
TREATMENT
For the treatment of bronchial asthma using basic therapy drugs (affecting the
mechanism of the disease, by means of which patients control asthma), and symptomatic
drugs (affect only the smooth muscles of the bronchial tree and relieve an attack).
Symptomatic treatment drugs include bronchodilators:
- β2-adrenomimetics
- xanthines
To the drugs of basic therapy include:
- Cromons
- inhalation glucocorticosteroids
- leukotriene receptor antagonists
- monoclonal antibodies
If basic therapy not using, the need for inhalation of bronchodilators (symptomatic
agents) will increase over time.
Cromones
Sodium cromoglycate (Intal), nedocromil sodium (Tayled), ketotifen (Zaditen).
Indicated as a basic therapy for intermittent and mild bronchial asthma.
Cromons has less efficiency than IGCC (inhaled glucocorticosteroids).
Now Cromones are gradually being replaced by more convenient IGCCs (inhaled
glucocorticosteroids).
Glucocorticosteroids
Inhaled glucocorticosteroids (IGCC) do not have the majority of side effects of
systemic steroids (adding in case of ineffectiveness of inhaled corticosteroids).
IGCC - the main group of drugs for the treatment of bronchial asthma.
CLASSIFICATION of inhaled glucocorticosteroids depending on the chemical
structure:
Non-halogenated:
- budesonide (Pulmicort, Benacort)
- ciclesonide (Alvesco)
Chlorinated:
- beclomethasone dipropionate (Bekotid, Beklodzhet, Klenil, Beclason Eco, Beclazon
Eco Light Breath)
- mometasone furoate (Asmonex)
Fluorinated:
- flunisolide (Ingakort)
- triamcenolone acetonide
- azmokort
- fluticasone propionate (flixotide)
The ANTI-INFLAMMATORY EFFECT of inhaled corticosteroids is associated with:
- the suppression of inflammatory cell activity,
- decreased cytokine [ˈsītəˌkīn] production,
- changing the arachidonic acid metabolism and the synthesis of prostaglandins and
leukotrienes,
- reduction of vascular permeability of the microvasculature,
- prevention of direct migration and activation of inflammatory cells,
- increased sensitivity of β-receptors of smooth muscle,
- increased the synthesis of the anti-inflammatory protein lipocortin-1,
- by inhibiting interleukin-5 they increase the apoptosis of eosinophils, reducing their
number, that leading to the stabilization of cell membranes.
Differences from systemic glucocorticosteroids:
- inhaled corticosteroids are lipophilic (due to this accumulating in the airways and
better affecting receptors),
- have a short half-life,
- are quickly inactivated,
- have a local (topical) effect, due to which they have minimal systemic effects.
Until recently, the dominant concept of IGCC administration was «step reception»
(more severe forms of the disease=higher doses)
Equivalent doses of inhaled corticosteroids (mcg):
International name
Low doses Medium doses High doses
Beclomethasone dipropionate
200–500 500–1000 1000
Budesonide
200-400 400-800 800
Flunisolid
500-1000 1000-2000 2000
Fluticasone propionate
100–250 250–500 500
Triamsinolone acetonide
400-1000 1000-2000 2000
This concept effective for treatment before 2 years from the onset of the disease.
Combinations of inhaled corticosteroids and prolonged β2-adrenomimetics
Symbicort
Turbuhaler
According to the global strategy of GINA, fixed combinations are the most effective
means for basic therapy of bronchial asthma (allow to relieve an attack and at the same time
are a therapeutic agent).
The most popular combinations (two):
1. salmeterol + fluticasone (Seretid 25/50, 25/125 and 25/250 mcg / dose, Seretid
Multidisk 50/100, 50/250 and 50/500 mcg / dose)
2. formoterol + budesonide (Symbicort Turbuhaler 4.5 / 80 and 4.5 / 160 mcg / dose)
Seretide. "Multidisk"
The maximum allowable daily dose of salmeterol is 100 mcg (the maximum frequency
of using Seretid is 2 breaths 2 times for the metered-dose inhaler and 1 breath 2 times for
the Multidisk device). Effects after 2 hrs.
This gives Symbicort an advantage (the maximum permissible dose is 24 mcg/day),
possible to inject up to 8 times a day. Effects immediately after inhalation.
GLUCOCORTICOSTEROIDS FOR SYSTEMIC USE
Can be used: - intravenously in small doses for asthma exacerbations,
- orally (short courses),
- orally (long courses in case of ineffectiveness of inhaled
glucocorticosteroids).
- Sometimes Intravenous administration of large doses (pulse therapy).
Side effects: osteoporosis, hypertension, diabetes mellitus, suppression of the
functional activity of the hypothalamic-pituitary-adrenal system, cataracts, glaucoma,
obesity, thinning of the skin with the formation of stretch marks and increased capillary
permeability, muscular weakness, muscular dystrophy.
Since taking this drugs we should begin therapy for the prevention of osteoporosis.
For oral administration: prednisone, prednisolone, methylprednisolone (metipred),
hydrocortisone (have less mineralocorticoid activity than other corticosteroids, an unsharply
pronounced effect on striated musculature and a relatively short half-life.
Long-term use of the triamcinolone (Polkortolon) lead to side effects, such as the
development of, weight loss, weakness, the gastrointestinal tract disfunction.
Dexamethasone is not used for a long time orally due to the suppression of adrenal cortex,
the ability to retain fluids.
ANTI-LEUKOTRIENE DRUGS
- zafirlukast (accol)
- montelukast (Singular)
Effects: quickly reduce the basal tone of the respiratory tract (created by leukotrienes
due to the chronic activation of the 5-lipoxygenase enzyme system).
Due to this, this group widely used in aspirin bronchial asthma, in the pathogenesis of
which there is an increased activation of the 5-lipoxygenase system and an increased
sensitivity of the receptors to leukotrienes.
Using with corticosteroids and prolonged β2-agonists allows quickly improve disease
control and reduce the dose of inhaled corticosteroids.
MONOCLONAL ANTIBODIES
Omalizumab (Xolair) - an concentrate of antibodies to IgE.
Xolar binds free IgE in the blood and preventing degranulation and the release of
biologically active substances that trigger early allergic reactions.
Xolar can be used in persons over 12 years of age with moderate and severe persistent
bronchial asthma, with allergic asthma.
Adding Xolara to inhaled corticosteroids therapy can significantly reduce the IGCC
dose.
LONG ACTING Β2 ADRENOMIMETICS
The long-acting β2-adrenomimetics currently include:
- formoterol (Oxis, Foradil)
- salmeterol (Serevent)
- indacaterol
SHORT-ACTING Β2-ADRENOMIMETICS
The short-acting β2-adrenergic range is represented by the following drugs:
- fenoterol (berotek)
- salbutamol (ventolin)
- terbutaline (bricanil)
They are the most effective bronchodilators, and using for acute asthma symptoms at
any age.
The inhalation route of administration is preferred since it provides a faster effect
with a lower dose and fewer side effects.
Inhalation of a β2-agonist provides pronounced protection against bronchospasm
against the background of physical activity and other provoking factors, for 0.5-2 hours.
XANTHINES
Aminophylline (эуфиллин) (using for asthma attack) and theophylline (long-acting),
taken orally.
These drugs have been used before β2 adrenomimetics and currently used in some
cases.
The theophylline is effective as a monotherapy and combined therapy (with
corticosteroids) for children over 5 years.
Eliminates day and night symptoms, improves lung function, has supportive effect
during physical activity.
Adding theophylline in children with severe asthma can improve control and reduce
the dose of corticosteroids.
At present, therapy with xanthines has secondary importance.
DRUGS OF OTHER GROUPS
Expectorant drugs improve sputum separation. As the main expectorant drugs use
iodine drugs, guaifenesin, N-acetylcysteine, Ambroxol.
When using them through a nebulizer, reduce the viscosity of sputum, contribute to
loosening mucus plugs and slow their formation.
Recommended with this drugs: fluid intake in a volume of 3-4 liters/day, postural
drainage, percussion and vibration massage of the chest.
ALLERGEN-SPECIFIC IMMUNOTHERAPY (ASIT)
Switch of the immune response from Th2-type to Th1-type, inhibits both the early and
late phases of the IgE-mediated allergic reaction, inhibits the cellular picture of allergic
inflammation and nonspecific tissue hyperreactivity.
It is performed for patients from 5 to 50 years old with exogenous bronchial asthma.
At certain intervals, the allergen is injected subcutaneously, gradually increasing the dose
(tree pollen, fungi, ticks). Course duration - at least 3 months. ASIT is most effective with
house tick allergens.
CLINICAL AND PHARMACOLOGICAL CHARACTERISTICS OF ANTIINFLAMMATORY DRUGS (NONSTEROID AND STEROID)
EFFECTS. Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs that
have analgesic, antipyretic and anti-inflammatory effects, reduce pain, fever and
inflammation.
NSAIDs are first-line drugs for the treatment of inflammatory diseases of the musculoskeletal
system (rheumatic diseases, pathological conditions associated with pain, inflammation and
fever).
Even short-term use of these drugs in small doses in some cases can lead to the
development of side effects (occur in about 25% of cases, and in 5% of patients can pose a
serious threat to life).
CLASSIFICATION OF
STRUCTURE
NSAIDS BY ACTIVITY AND CHEMICAL
NSAIDS WITH PRONOUNCED ANTI-INFLAMMATORY ACTIVITY
Acids
Salicylates A) Acetylated:
- Acetylsalicylic Acid (Ask) - (Aspirin);
- Lysine monoacetylsalicylate (Aspizol, Laspal);
B) Non-acetylated:
- Sodium Salicylate;
- Hollinsalicilat (Sahol);
- salicylamide;
- Dolobid (Diflunizal);
- Disalkid;
Pyrazolidines - Azapropazone (Reimox);
- Clophason;
- Phenylbutazone (Butadion);
- Oxyphenylbutazone.
Indole acetic acid derivatives - Indomethacin (Metindol);
- Sulindak (Klinoril);
- Etodalak (Lodin);
Phenylacetic acid derivatives - Diclofenac Sodium (Ortofen, Voltaren);
- Diclofenac Kalia (Voltaren - Rapid);
- Fentiazak (Donorest);
- Lonazalak Calcium (Irriten).
Oxycams -Piroxicam
-Tenksikam
Lornoxicam
-Meloxicam
Propionic acid derivatives - Ibuprofen (Brufen, Nurofen, Solpaflex);
- Naproxen (Naprosyn);
- Sodium Naproxen Salt (Apranax);
- Ketoprofen (Knavon, Profenid, Oruvel);
- Flurbiprofen (Flugalin);
- Fenoprofen (Fenopron);
- Fenbufen (Lederlen);
- Tiaprofenovoy Acid (Surgam).
Non-acidic derivatives
Alcanones - Nabumeton
Sulfonamide derivatives - Nimesulide
-Celecoxib
Rofecoxib
NSAIDS WITH WEAK ANTI-INFLAMMATORY ACTIVITY
Anthranilic acid derivatives - Mefenamic Acid (Pomstal);
- Meklofenamovaya Acid (Meklomet);
- Niflumic Acid (Donalgin, Nifluril);
- Morniflumate (Nifluril);
- Etofenamat;
- Tolfenamic Acid (Clots).
Pyrazolones - Metamizole (Analgin);
- Aminofenazone (Amidopyrine);
- Propifenazone.
Para-aminophenol derivatives - phenacetin;
- Paracetamol.
Heteroaryl Acetic Acid Derivatives - Ketorolac;
- Tolmetin (Tolectin).
CLASSIFICATION OF NSAIDS (BY DURATION)
1. Short action (T1 / 2 = 2-8 hours):
- ibuprofen; - Ketoprofen;
- indomethacin; - Fenoprofen;
- Voltaren; - Fenamata.
- tolmetin;
2. The average duration of action (T1 / 2 = 10-20 hours):
- naproxen;
- sulindak;
- diflunizal.
3. Long-acting (T1 / 2 = 24 hours or more):
- oxicam;
- phenylbutazone.
CLASSIFICATION OF NSAIDS FOR SELECTIVITY FOR VARIOUS
FORMS OF CYCLOOXYGENASE
Selective COX-1 blockers Low doses of acetylsalicylic acid Aspirin, Aspekard, Aspirin
cardio, Cardiomagnyl, etc.
Nonselective COX-1 and COX-2 blockers Ketoprofen, Diclofenac, Ibuprofen,
Indomethacin, etc., Ketonal, Voltaren, Naklofen, Olfen, Diklobrru, Dikloberl, Solpafleks,
Nurofen, etc.
Pre-emptive COX-2 blockers Meloxicam, Movalis, Melox, Revmoksikam, Nimesil,
Neise, Nimegezik, Aponil, Nimesulide
Selective COX-2 blockers Celecoxib, Rofecoxib, Celebrex, Ranselex, Zitzel, Revmoksib,
Flogosib, Rofic, Denebol, Rofnik.
CLASSIFICATION OF NSAIDS ON THE IMPACT ON THE PROCESSES
OF BIOSYNTHESIS IN CARTILAGE TISSUE.
I. Suppressing inflammation and neutral to arthrosis - Piroxicam, diclofenac, sulindac,
solpaflex;
II. Suppressing inflammation and strengthening arthrosis - Acetylsalicylic acid,
indomethacin, fenoprofen, phenylbutazone;
Iii. Suppressing inflammation and normalizing cartilage metabolism - Benoxaprofen,
tiaprofenic acid (surgam), paracetamol.
MECHANISM OF ACTION
The most important mechanism of NSAIDs is associated with the inhibition of the
synthesis of cyclooxygenase (COX) and lipoxygenase (LOG) - the key enzymes of the
arachidonic acid metabolism.
Anti-inflammatory effect may be associated with:
- inhibition of lipid peroxidation,
- stabilization of lysosome membranes (both of these mechanisms prevent damage to
cellular structures),
- a decrease in Adenosine triphosphate (ATP) formation (reduced energy supply of the
inflammatory reaction),
- inhibition of neutrophil aggregation (release of inflammatory mediators from them is
reduced, inhibition of rheumatoid aggregation) in patients with rheumatoid arthritis.
The analgesic effect is associated with blocking a conduction of pain impulses in the
spinal cord (Metamizole).
REQUIREMENTS FOR MODERN NSAIDs
•
•
•
•
Anti-inflammatory effect
Prevailing inhibitory effect on COX-2 [cyclooxygenase]
analgesic effect
Chondroprotective effect or low influence on the cartilage [ˈkärtl-ij] metabolism;
improved synovial fluid composition
•
•
•
•
•
Normalizing Ca++ metabolism in bone tissue
Myotropic antispasmodic action
Immunomodulatory properties
Minimum side effects
The possibility of creating on the basis of the substance dosage forms
(ointments, suppositories, tablets, etc.) that meet the biopharmaceutical
requirements.
MAIN EFFECTS
1. Anti-inflammatory effect. NSAIDs suppress predominantly the exudation phase. The most
powerful drugs - indomethacin, diclofenac, phenylbutazone - also act on the proliferation
phase (reducing collagen synthesis and tissue sclerosis), but weaker than on the exudative
phase.
2. Analgesic effect. It is more effective for pain of weak and medium intensity, which are
localized in muscles, joints, tendons, nerve trunks, as well as headache or toothache.
With severe visceral pain, are less effective (need narcotic analgesics but: inhibit the
respiratory center, cause euphoria and drug dependence, and spasmogenic effect ).
Sufficiently high analgesic activity with colic and postoperative pain has diclofenac,
ketorolac, ketoprofen, metamizol.
3. Antipyretic effect. NSAIDs are act only for fever. They are not affect normal body
temperature.
4. Antiplatelet effect. As a result of inhibition of COX-1 [cyclooxygenase] reducing synthesis
of endogenous thromboxane (proagregant). Aspirin has the strongest and most prolonged
anti-aggregation activity, which irreversibly suppresses the ability of the platelet to aggregate
for the entire duration of its life (7 days). The anti-aggregation effect of other NSAIDs is
weaker and reversible.
Selective COX-2 inhibitors do not affect platelet aggregation.
5. Immunosuppressive effect. It is expressed moderately, it manifests itself with long-time
use and has a "secondary" character: reducing the permeability of capillaries, NSAIDs impede
the contact of immunocompetent cells with the antigen and the contact of antibodies with
the substrate.
PHARMACOKINETICS
Well absorbed in the gastrointestinal tract. Almost completely bound to plasma albumin.
Metabolized in the liver, excreted through the kidneys.
INDICATIONS:
1. Rheumatic diseases: rheumatism (rheumatic fever), rheumatoid arthritis, gouty and
psoriatic arthritis, ankylosing spondylitis (Bechterew's disease), Reiter's syndrome.
2. Non-rheumatic diseases of the musculoskeletal system: osteoarthritis, myositis,
tendovaginitis, trauma (household, sports). Often, in these conditions, it is effective to use
local NSAID dosage forms (ointments, creams, gels).
3. Neurological diseases: neuralgia, radiculitis, sciatica, lumbago.
4. Renal, hepatic colic.
5. Pain syndrome of various etiologies, including headache, toothache, postoperative pain.
6. Fever (usually at body temperature above 38.5 ° C).
7. Prevention of arterial thrombosis.
8. Dysmenorrhea. NSAIDs are used in primary dysmenorrhea to relieve pain associated with
increased uterine tone due to hyperproduction of PG-F2a. In addition to the analgesic action,
NSAIDs reduce blood loss. Especially when using naproxen and its sodium salt, diclofenac,
ibuprofen, ketoprofen. NSAIDs are prescribed at the first appearance of pain on a 3-day
course or on the eve of menstruation. Undesirable reactions, taking into account short-term
reception, are rarely observed.
SIDE EFFECTS:
1. Gastrointestinal tract. Affect any part of the gastrointestinal tract (from the lower third of
the esophagus (in the presence of gastroesophageal reflux) to the distal parts of the large
intestine, enteropathy). But most often in the antrum of the stomach and the duodenal bulb.
Dyspeptic disorders in 30–40% of patients, erosion and ulcers of the stomach and duodenum
in 10–20%, bleeding and perforation in 2–5%. Currently highlighted a specific syndrome NSAID-gastropathy.
The damage of the gastric mucosa has 3 stages:
1) inhibition of prostaglandin synthesis in the mucosa;
2) reduction of protective mucus and bicarbonates production;
3) the appearance of erosions and ulcers, which may be complicated by bleeding or
perforation.
Risk factors for the development of NSAID gastropathy are: age over 60 years, female
gender, smoking, alcohol abuse, gastrointestinal diseases in anamnesis, concomitant use of
glucocorticoids, immunosuppressants, anticoagulants, prolonged therapy with NSAIDs.
Among all NSAIDs, acetylsalicylic acid, indomethacin, piroxicam, ketoprofen, etodolac have
the most pronounced gastrotoxic effect (patients with a history of gastrointestinal diseases,
use of these drugs is strictly contraindicated).
Methods to improve the portability of NSAIDs.
- combination with proton pump inhibitors, H2-histamine blockers or;
- using low doses;
- using of enteric-soluble forms or prodrugs (sulindaka);
- using of parenteral, rectal or local administration of NSAIDs;
- using NSAIDs that selectively block COX-2 [cyclooxygenase] (at therapeutic doses do not
have a significant effect on COX-1) (celecoxib, rofecoxib, meloxicam, etodolac, nabumetone
and nimesulide have a good gastrotoxicity profile). Currently, specific COX-2 inhibitors are
widely used in clinical practice, for example, , which have practically no negative effect on
the gastrointestinal tract.
Synthetic analogue PG-E2 [Prostaglandin E2] – misoprostol can prevent the
development of ulcers, both in the stomach and in the duodenum, has a high efficiency.
Combination products are available that include NSAIDs and misoprostol.
2. Kidneys. Nephrotoxicity is the second largest group of unwanted NSAID reactions.
Two main mechanisms of the negative effect:
I. By blocking the synthesis of PG-E2 [Prostaglandin E2] and prostacyclin in the kidneys,
cause vasoconstriction and disturbances of the renal blood flow (ischemic changes in the
kidneys, reduced glomerular filtration and diuresis). As a result, violations of water and
electrolyte metabolism can occur: water retention, edema, hypernatremia, hyperkalemia, an
increase in serum creatinine levels, an increase in blood pressure.
Indomethacin and phenylbutazone have the most pronounced effect on the renal
blood flow.
II. Can have a direct effect on the kidney parenchyma, causing interstitial nephritis (the
so-called "analgesic nephropathy"). The most dangerous in this regard is phenacetin,
paracetamol. Possible serious damage to the kidneys until the development of severe renal
failure. The development of acute renal failure with the use of NSAIDs as a result of acute
allergic interstitial nephritis is described.
Risk factors for nephrotoxicity: age over 65 years, liver cirrhosis, previous renal
pathology, decreased blood volume, gout, atherosclerosis, long-term NSAID therapy,
concomitant diuretic therapy, congestive heart failure, arterial hypertension.
Paracetamol, indomethacin, phenylbutazone, ibuprofen, fenoprofen, piroxicam
have the highest nephrotoxicity among NSAIDs. These drugs are not recommended for
patients with impaired renal function: chronic renal failure, nephrotic syndrome, etc. In these
cases, it may be recommended to use drugs with moderate nephrotoxicity, for example,
sulindaka, meloxicam, nimesulide.
3. Hepatotoxicity. Changes in the activity of transaminases and other enzymes. In
severe cases - jaundice, hepatitis.
The risk factors for hepatotoxicity: older age, impaired kidney function, alcohol and
other hepatotoxic drugs.
Hepatotoxic effect is most often observed with diclofenac, nimesulide,
phenylbutazone, sulindac, paracetamol, indomethacin, which limits the use of these drugs
in patients with a history of liver disease. For these patients, the use of coxibs, meloxicam,
ketoprofen is rational.
4. Hematotoxicity: manifested by aplastic anemia, thrombocytopenia,
agranulocytosis, methemoglobinemia (paracetamol). The most pronounced inhibitory effect
on the hematopoietic system causes paracetamol, indomethacin, acetylsalicylic acid,
metamizole sodium, fenoprofen.
5. Coagulopathy: manifests as gastrointestinal bleeding (most NSAIDs inhibit platelet
aggregation and decreasing synthesis of prothrombin in the liver).
6. Allergic hypersensitivity reactions: rash, urticaria, erythema, angioedema,
anaphylactic shock, Lyell and Stevens-Johnson syndromes, allergic interstitial nephritis,
which most often occur with the use of acetylsalicylic acid, indomethacin, phenylbutazone,
clofesone. Patients with a clinical triad including vasomotor rhinitis, nasal polyposis and
bronchial asthma are at high risk of developing hypersensitivity reactions to NSAIDs;
7. Bronchospasm: "Aspirin" asthma (or Vidal syndrome) develops most often when
taking acetylsalicylic acid and its derivatives. The causes of bronchospasm: predominant
formation of leukotrienes and thromboxane A2 from arachidonic acid and inhibition of the
PG-E2 synthesis - endogenous bronchodilators.
8. Ototoxicity.
9. Prolongation of pregnancy. Prostaglandins (PG-E2 and PG-F2a) stimulate the
myometrium (mainly non-selective NSAIDs due to the effect on COX-1).
10. Teratogenicity, premature closure of the ductus arteriosus of the fetus. All NSAIDs
are not recommended to be taken during pregnancy; indomethacin, salicylates,
aminophenazone have the greatest teratogenic effect.
11. Retinopathy and keratopathy - as a result of deposition of indomethacin in the
retina and cornea.
12. Possible mutagenicity and carcinogenicity. NSAIDs cross the placenta and can
cause the development of congenital pathological changes in the fetus. If indicated, it is
recommended to use derivatives of propionic (ibuprofen, flurbiprofen) or phenylacetic acid
(diclofenac), which have a short half-life and form inert metabolites.
13. The hypertensive effect of NSAIDs is due to several mechanisms:
- a decrease in natriuresis;
- increased renal resistance;
- increased release of norepinephrine from nerve endings;
- reduction of glomerular filtration and renal blood flow, activation of the reninangiotensin system, damage to the renal parenchyma (“analgesic nephropathy”);
- increased endothelin secretion;
- mineralocorticoid activity of a number of NSAIDs (for example, phenylbutazone).
The risk factors for the hypertensive effect: old age, congestive heart failure,
renovascular hypertension, and liver cirrhosis. Do not use in such patients piroxicam,
phenylbutazone, indomethacin, rofecoksib; The use of ketoprofen, ibuprofen, meloxicam
is recommended.
14. Side reactions caused by the use of COX-2 inhibitors include: arterial
hypertension, myocardial infarction, angina pectoris, cardiac arrhythmias, thromboembolic
events, congestive heart failure, cerebrovascular bleeding and others.
15. Neurological and mental - indomethacin, phenylbutazone can cause headache,
dizziness, attention disorders, hand tremors, depression and even psychosis, therefore they
are not recommended to be prescribed to people whose profession requires increased
attention and quick reactions.
Using ibuprofen, sulindaka, in patients with lupus erythematosus can cause the
aseptic meningitis.
CONTRAINDICATIONS
Erosive and ulcerative conditions of the gastrointestinal tract (especially in the acute
stage), severe dysfunction of liver and kidney, cytopenias, idiosyncrasy, and pregnancy. If
necessary, the safest (but not before childbirth!) Are small doses of aspirin.
Indomethacin and phenylbutazone should not be administered to persons whose
professions require increased attention.
RULES OF APPOINTMENT AND DOSING
Individualization of drug choice
For each patient should choose the most effective drug with the best tolerability.
When using NSAIDs in rheumatology, it is necessary to take into account that the
development of the anti-inflammatory effect takes 10-14 days, analgesic – first hours.
Dosage. Should be prescribed first in the lowest dose. With good tolerance in 2-3 days
increase the daily dose. In some patients, the therapeutic effect is achieved only when using
very high doses of NSAIDs.
Time of reception. With long term course (for example, in rheumatology), taking after
meals. But for a quick analgesic or antipyretic effect, it is 30 minutes before or 2 hours after
eating, with 1/2-1 cup of water.
STEROIDAL ANTI-INFLAMMATORY DRUGS (GLUCOCORTICOSTEROIDS).
Glucocorticosteroids are synthetic drugs (analogs of endogenous hormones produced
by the adrenal cortex) that have anti-inflammatory, desensitizing, immunosuppressive, antishock and anti-toxic effects.
Alclomethasone (Afloderm). Betamethasone (Akriderm, Beloderm, Belosalik,
Belogent, Diprosalik, Diprospan, Garazon, Nasobek, Triderm, Flutsicort, Celeston,
Celestoderm - B). Beclomethasone dipropionate (Aldecine, Bezlazon Eco, Beklodzhet,
Bekotid, Klenil, Rinoklenil). Budesonide (Benocort, Pulmicort, Symbicort Turbuhaler, Tafen
Nazal). Flumethasone (Lorinden C, Seretid). Hydrocortisone (Hydrocortisone, Cortef,
Latikort, Oksikort). Dexamethasone (Ambene, Dex-Gentamicin, Maxidex, Maxitrol,
Polydex, Tobradex). Methylprednisolone (Advantan, Metipred, Solu-Medrol).
Mometasone furoate (Momat, Nasonex, Elokom). Prednisolone (Aurobin, Dermozolon).
Triamcinolone acetonide (Kenalog, Polkortolon, Ftorokort). Fluticasone propionate
(Fliksonaze, Fliksotid). Flukortolon (Ultraprokt).
EFFECTS:
1. The anti-inflammatory effect of corticosteroids (manifested in the form of antiexudative and anti-proliferative effects.
A. Antiexudative effect:
• stabilization of cellular and subcellular membranes (mitochondria and
lysosomes);
• a decrease in the permeability of the vascular wall (in particular, capillaries);
• reducing the release of biologically active amines (histamine, serotonin, kinins
and prostaglandins) from mast cells;
• inhibition of neutrophil and macrophage migration to the inflammatory focus,
disruption of their functional activity (chemotactic and phagocytic), peripheral
leukocytosis;
• induction of lipomodulin synthesis(blocks cell membrane phospholipase A,
disrupts the release of phospholipid-bound arachidonic acid and the formation
of pro-inflammatory prostaglandins, leukotrienes and thromboxane A2);
• suppression of the synthesis of proinflammatory cytokines and blockade of the
synthesis of cytokine receptor protein in tissues.
• vasoconstriction at the site of inflammation;
• decrease in the intensity of energy formation processes in the inflammation
focus;
• suppressing the migration of monocytes (slowing the release of mature
monocytes from the bone marrow and reducing their functional activity);
• inhibition of leukotriene formation (leukotriene B4 reduces leukocyte
chemotaxis, and leukotrienes C4 and D4 (slow-reacting substance) reduce the
contractile ability of smooth muscles, vascular permeability and secretion of
mucus in the airways);
B. Antiproliferative effect:
• Block fibrocytes differentiation from fibroblasts;
• suppression of nucleic acid synthesis;
• decreasing the functional activity of fibroblasts
2. Immunosuppressive effect:
• a decrease in the number of lymphocytes in the peripheral blood (lymphopenia),
due to the transfer of circulating lymphocytes (mainly T-cells) to the lymphoid
tissue, and possibly their accumulation in the bone marrow;
• increased apoptosis of T- and B-lymphocytes;
• suppression of T-cell proliferation;
• reduced function of T-helper cells, T-suppressors, cytotoxic T-lymphocytes;
• inhibition of the complement system activity;
• inhibition of the fixed immune complexes formation;
• decreasing level of immunoglobulins (high doses of glucocorticoids);
• inhibition of the delayed-type hypersensitivity reaction (type IV allergic
reactions), in particular tuberculin test;
• violation of cooperation between T - and B - lymphocytes;
• violation of the synthesis of immunoglobulins and antibodies, including
autoantibodies;
• decreasing the number of monocytes in the bloodstream.
3. Antiallergic action
4. Metabolic action
Carbohydrate metabolism:
• stimulation of glyconeogenesis;
• violation of the glucose utilization rate by tissues;
• transient hyperglycemia and glycosuria;
• depletion of the insular apparatus of the pancreas.
Protein metabolism:
• increased protein breakdown;
• increasing the content of free amino acids and products of nitrogen metabolism
in the blood plasma;
• stimulation of the synthesis of albumin in the liver and free amino acids of the
plasma.
Fat metabolism:
• lipolytic effect in the subcutaneous tissue of the hands;
• lipogenetic action with predominant deposition of fat in the anterior abdominal
wall, interscapular region, on the face and neck;
• increasing cholesterol and lipoproteins levels in the blood plasma;
• increasing the conversion of carbohydrates into fats.
Water and mineral metabolism:
• suppression of the antidiuretic hormone secretion;
• increasing the glomerular filtration rate, stimulation of the sodium and water
excretion of from the body (with short courses);
• stimulation of aldosterone synthesis and sodium and fluid retention, increase in
edema syndrome (with long-time use);
• increasing the content of potassium calcium in the blood plasma,
hypokaligistiya;
• hypercalciuria;
• increasing the content of urea, uric acid in the blood.
PHARMACOKINETICS OF GLUCOCORTICOSTEROIDS
Absorbed mainly in the small intestine. Absorption occurs in the proximal (75%) and distal
(25%) parts of the small intestine.
The adrenal cortex of a healthy adult under the influence of corticotropin produces daily 1560 mg of cortisol and 1-4 mg of corticosterone. More than 95% of plasma cortisol forms
complexes with plasma proteins, mainly with corticosteroid-binding alpha globulin
(transcortin). The hormone affinity for transcortin is very high, however, the binding ability
of transcortin is small and with an increase in plasma cortisol concentration above 20 μg /
100 ml is completely exhausted. In this case, the transfer of the drug is carried out by plasma
albumin (from 40 to 90% of the corticosteroids in the blood plasma are in a state associated
with albumin). At the same time, only the unbound (free) fraction of corticosteroids is
physiologically active, which exerts its pharmacological action on target cells. Side effects in
patients receiving corticosteroids, are determined by the amount of the free fraction of
corticosteroids. However, there is no correlation between the half-life and the duration of
the physiological action of a particular GCS drug.
GCS is classified into drugs of short, intermediate and long-acting depending on the duration
of inhibition of ACTH after a single dose. At the same time, the half-elimination period of GCS
is much shorter: from 30 minutes for cortisone and 60 minutes for prednisolone to 300
minutes for dexamethasone.
Interestingly, the maximum pharmacological activity of GCS falls on that period of time when
their peak blood concentrations are already behind. Thus, according to pharmacokinetic
studies, the peak concentration of prednisolone in plasma is reached in 1–3 hours, the halflife is 2–3.5 hours, and the maximum biological effect develops in about 6 hours. This
suggests that the effects of corticosteroids are more dependent on their induction of
enzymatic activity inside the cell than on the direct action. The period of anti-inflammatory
activity of corticosteroids is approximately equal to the duration of their suppression of the
hypothalamic-pituitary-adrenal axis - GGN (from 4 to 8 days).
Normally, cortisol levels begin to increase at 2 am with a peak at 8 am and return to the basal
level by 12 am. Symptoms of RA (stiffness, inflammatory activity) usually decrease after a few
hours after awakening at the peak of cortisol synthesis. Until recently, it was believed that
taking GCS in the morning hours to a lesser extent inhibits the synthesis of ACTH and cortisol
than at night and evening. Recently, there was evidence that a circadian increase in the level
of IL-6 may also be associated with an increase in RA activity in the morning. Daily fluctuations
of IL-6 are observed in normal and in patients with RA. Normally, the peak concentration of
IL-6 occurs a little earlier than ACTH and cortisol between 1 - 4 am. However, in case of RA,
the peak of IL-6 is late and occurs between 2–7 am and the concentration of IL-6 is
significantly higher than normal. Therefore, the appointment of GCS (5-7.5 mg) at night (at
about 2 am) is more preferable from the point of view of suppressing the secretion of IL-6
and is associated with a significantly more pronounced decrease in the duration of morning
stiffness, joint pain, Lansbury index, Richie index.
In untreated patients with active RA, a weakening of the basal and corticotropin-stimulated
cortisol synthesis is also noted. Moreover, approximately 10% of RA patients show signs of
adrenal insufficiency. It is obvious that in these patients we can expect a higher efficacy of
low doses of GCS than in patients without a defect in the HGN axis.
Different activity of corticosteroids is also determined by different degrees of binding to
plasma proteins. Thus, most of the natural cortisol is in a bound state, whereas only 3% of
methylprednisolone and less than 0.1% of dexamethasone bind to the corticosteroid-binding
globulin.
Liver microsomal enzymes metabolize GCS to inactive compounds, which are then excreted
by the kidneys. Metabolites are excreted in the urine in the form of glucuronides, sulfates
and unconjugated compounds. Conjugation reactions occur mainly in the liver and, to a lesser
extent, in the kidneys. Metabolism in the liver increases with hyperthyroidism and is induced
by phenobarbital and ephedrine. Hypothyroidism, cirrhosis, concomitant treatment with
erythromycin leads to a decrease in hepatic clearance of GCS. In patients with hepatocellular
insufficiency and low serum albumin in plasma, the concentration of the prednisolone free
fraction increases, which contributes to more rapid development of side effects. In
pregnancy, by contrast, the proportion of its free fraction decreases.
Drug
Plasma half-life, h
Tissues half-life, h
Hydrocortisone
0.5-1.5
8-12
Cortisone
0.7-2
8-12
Prednisolone
2-4
18-36
Methylprednisolone
2-4
18-36
Fludrocortisone
3.5
18-36
Dexamethasone
5
36-54
CLASSIFICATION OF GLUCOCORTICOSTEROIDS
Depending on the duration of inhibition of ACTH [Adrenocorticotropic hormone]
after a single dose of GCS:
a) into short-acting GCS - they suppress ACTH activity for 24-36 hours,
b) GCS of average duration - up to 48 hours
c) long-acting GCS - over 48 hours.
I. NATURAL - Cortisol, Cortisone (Hydrocortisone), Cortisone Acetate - inhibit the
activity of ACTH for 24-36 hours.
II. SEMISYNTHETIC
1. Short-acting drugs - Prednisolone, Prednisone, Methylprednisolone (Urbazon,
Metipred) - inhibit the activity of AGTG for 24-36 hours.
2. Average duration of action - Triamcinolone (Polcortolone) - inhibits ACTH for up to
48 hours.
3. Long-acting drugs - Betamethasone, dexamethasone - inhibit ACTH for more than
48 hours.
USING
GCS are used as anti-inflammatory, antiallergic and immunosuppressive agents and as
replacement therapy for adrenal insufficiency.
Types GK-therapy:
1. Systemic:
• average therapeutic doses
• alternating therapy (GCS of short action without pronounced mineralocorticoid
activity once in the morning every 48 hours. Therapeutic efficacy and the
severity of side effects decreases. The positive only with long-time treatment.
Not used in the short-term, in the initial stage of treatment or during the acute
phase of the disease.)
• pulse therapy (rapid (within 30-60 minutes) intravenous administration of large
doses of GCS (1000 mg in terms of methylprednisolone (MP)) once a day for 3
days.)
• “mini-pulse” therapy
• combined (primarily with cytotoxicants)
2. Local (intra-articular, inhalation, rectal administration, etc.);
3. Local (ointment, drops, aerosol).
Systemic therapy of GCS is one of the most effective methods of treating a number of
diseases. The use of steroids can significantly improve the prognosis and increase the life
expectancy of patients.
PHASES in the treatment of corticosteroids:
• Induction: apply short-acting GCS (prednisone or methylprednisolone) in a dose
approximately corresponding to 1 mg / kg of body weight per day with an 8-hour
interval.
• Consolidation: switching to a full dose of GCS in the morning once a day.
• Reduction: the rate of reduction depends on the dose. OR transition to
alternating therapy is possible.
• Supportive treatment: the use of the minimum effective dose of drugs.
• Prevention of complications of GCS therapy: starting with the induction phase.
GCS therapy should be started only in case strict indications and as early as possible, without
trying to apply softer treatment methods first.
In this case, hormone therapy should be used together with usual therapy.
Rational therapy: it using of short-acting corticosteroids in the optimal dose during
activity of pathological process and only under doctor monitoring.
INDICATIONS:
1. Rheumatic diseases:
•
•
•
•
•
•
rheumatism 2-3 tbsp. activity of the process in the presence of rheumatic carditis, especially in
combination with polyarthritis and polyserositis - medium therapeutic doses of GCS;
systemic lupus erythematosus in the period of exacerbation (pulse therapy), in chronic forms medication doses of GCS or as maintenance therapy;
systemic dermatomyositis during the period of exacerbation - pulse therapy of GCS or as maintenance
therapy;
periarteritis nodosa in the period of exacerbation - pulse therapy GCS or as maintenance therapy;
rheumatoid arthritis when combined with viscerite (febrile syndrome, carditis, nephritis, serositis);
with rapidly progressive articular forms of rheumatoid arthritis and a high titre of rheumatoid factor pulse therapy, then, often, supportive therapy; the ineffectiveness of previous NSAID therapy and
basic therapy — medically therapeutic doses of GCS; in monoarthritis — intra-articular administration
of GCS;
juvenile rheumatoid arthritis.
2. Systemic vasculitis - systemic treatment of SCS.
3. Carditis (infectious-allergic myocarditis, Abramov-Fidler's myocarditis, subacute
septic endocarditis - the immunological phase) - systemic therapy of corticosteroids.
4. Diseases of the musculoskeletal system:
a. post-traumatic osteoarthritis - for short-term use in the acute period or for intraarticular GCS;
b. ankylosing spondylitis (ankylosing spondylitis);
c. subacute gouty arthritis - for short-term use in the acute period or for intra-articular
GCS;
d. acute and subacute bursitis;
e. acute non-specific tendosynovitis;
f. psoriatic arthritis.
5. Kidney diseases (chronic nephritis with nephrotic syndrome - the most indicated is
the administration of corticosteroids with membranous and membranous proliferative
variants; with lupus nephritis) - systemic therapy of corticosteroids.
6. Diseases of the gastrointestinal tract (ulcerative colitis, Crohn's disease, SPRU) systemic therapy of the SCS.
7. Liver diseases (autoimmune hepatitis) - systemic therapy of corticosteroids.
8. Diseases of the bronchopulmonary system (obstructive bronchitis, allergic
bronchial asthma, sarcoidosis - systemic therapy and inhaled GCS).
9. Hematological diseases: acquired (autoimmune) hemolytic anemia,
thrombocytopenic purpura - systemic therapy of GCS.
10. Allergic states. Control of allergic conditions with the ineffectiveness of
conventional remedies: seasonal or chronic allergic rhinitis, nasal polyps, bronchial asthma
(including an asthmatic condition), contact dermatitis, atopic dermatitis (neurodermatitis),
drug susceptibility and serum sickness (anaphylactic shock, Quincke edema, syndrome Lyell,
Stephen-Johnson, medicinal or food agranulocytosis, thrombocytopenia, giant urticaria).
11. Eye diseases: severe acute and chronic allergic reactions and inflammatory
processes in the eyes and surrounding structures, such as allergic conjunctivitis, keratitis,
allergic corneal ulcer, corneal herpes, iritis and iridocyclitis, chorioretinitis, anterior segment
inflammation, diffuse posterior area, , retrobulbar neuritis, sympathetic ophthalmia.
12. Skin diseases: eczema (chronic dermatitis), in the treatment of keloids and
localized hypertrophic infiltrating inflammations (administration of GCS to the lesion site),
lichen planus, psoriasis, ring-shaped granuloma, simple chronic lichen (neurodermatitis),
discoid lupus erythematosus, necrotizus necrosis, ringworm (neurodermatitis), discoid lupus
erythematosus, lipoid necrobiosis, diabetes mellitus (neurodermatitis), discoid lupus lupus
erythematosus, necrotizing necrosis diabetes mellitus, neurodermatitis, discoid lupus
erythematosus, lipoid necrobiosis, psoriasis, neurodermatitis, discoid lupus erythematosus,
lipoid necrobiosis, lichen edema, neurodermatitis, discoid lupus erythema , nestingal
alopecia, psoriasis, erythema nodosum, and others - local GCS therapy.
13. Tumor diseases: palliative treatment of leukemia and lymphomas in adults, acute
pediatric leukemia.
14. Endocrine disorders: primary or secondary adrenal insufficiency, acute adrenal
insufficiency, bilateral adrenectomy, congenital adrenal hyperplasia, acute thyroiditis and
thyrotoxic crisis, hypercalcemia associated with cancer.
15. Shock conditions: hemodynamic, traumatic, endotoxic, cardiogenic (infarction).
16. Brain edema (increased intracranial pressure) - GCS is needed as an aid in reducing
the intensity or preventing brain edema associated with surgical or other brain injury, stroke,
primary or metastatic malignant brain tumors. The use of glucocorticosteroids should not be
considered as a substitute for neurosurgical treatment.
17. Prevention of renal allograft rejection. The drug is used in combination with
commonly used immunosuppressants.
Indications for the use of intranasal glucocorticoids.
• Seasonal (intermittent) allergic rhinitis.
• Year-round (persistent) allergic rhinitis.
• Polyposis of the nose.
• Non-allergic rhinitis with eosinophilia.
• Idiopathic (vasomotor) rhinitis.
Inhaled glucocorticosteroids are used for: bronchial asthma, chronic obstructive
pulmonary disease.
CONTRAINDICATIONS
• Glucocorticosteroids are prescribed with caution in the following clinical
situations:
• Itsenko-Cushing disease.
• Diabetes.
• Peptic ulcer of the stomach or duodenum.
• Thromboembolism.
• Hypertension.
• Severe renal failure.
• Mental diseases with productive symptoms.
• Systemic mycoses.
• Herpetic infection.
• Tuberculosis (active form).
• Syphilis.
• Vaccination period.
• Purulent infections.
• Viral or fungal diseases of the eye.
• Corneal diseases combined with epithelium defects.
• Glaucoma.
• Lactation period.
Intranasal glucocorticoid administration is contraindicated in the following cases:
• Hypersensitivity.
• Hemorrhagic diathesis.
• Repeated nasal bleedings in the anamnesis.
• Side effects
SYSTEMIC SIDE EFFECTS:
Central nervous system: • Increased nervous irritability.• Insomnia.• Euphoria.•
Depression.• Psychoses.
Cardiovascular system: • Myocardial dystrophy.• Increased blood pressure.
• Deep vein thrombosis.• Thromboembolism.
Digestive system:
• Steroid ulcers of the stomach and intestines.
• Bleeding from the gastrointestinal tract.
• Pancreatitis.
• Fatty degeneration of the liver.
Sense organs:
• Posterior subcapsular cataract.
• Glaucoma.
Sndocrine system:
• Inhibition of function and atrophy of the adrenal cortex.• Diabetes.• Obesity.
• Cushing's syndrome.
Skin:
• Thinning of the skin.
• Striae.
• Alopecia.
Musculoskeletal system:
• Osteoporosis.• Fractures and aseptic necrosis of bones.• Stunted growth in children.
• Myopathy.• Muscle hypotrophy.
Reproductive system:
• Violations of the menstrual cycle.
• Sexual dysfunction.
• Delayed sexual development.
• Hirsutism.
Laboratory tests:
• Hypokalemia.• Hyperglycemia.• Hyperlipidemia.• Hypercholesterolemia.
• Neutrophilic leukocytosis.
Other:
• Sodium and water retention.
• Edema.
• Exacerbations of chronic infectious and inflammatory processes.
LOCAL SIDE EFFECTS:
Inhaled glucocorticosteroids:
• Candidiasis of the mouth and pharynx.
• Dysphonia.
• Cough.
Intranasal glucocorticosteroids:
• Itching nose.
• Sneezing.
• Dryness and burning of the mucous membrane of the nose and throat.
• Nosebleeds.
• Perforation of the nasal septum.