Drugs used for bronchial obstruction
Drugs used for bronchial obstruction
(bronchial asthma - BA, chronic obstructive pulmonary disease - COPD)
- Adrenomimetics (adrenergic agonists)
- М-cholinoblockers (cholinergic antagonists)
- Theophylline drugs – methylxantines
- Mast cell membrane stabilizers
- Leukotrienes inhibitors
Bronchoobstructive syndromeBronchial obstruction – a syndrome of disturbance of bronchial permeability caused by the edema of bronchial mucous tunic (chronic bronchitis, allergic reactions) and bronchospasm. Rarely in case of peribronchial fibrosis, pulmonary emphysema.
In the norm the tone of bronchial muscles is supported by cholinergic innervation. There's no sympathetic innervation for bronchi. However, in bronchi there are non-innervated beta2-adrenoreceptors, interacting with catecholamines and adenotropic mediums circulating in blood. The stimulation of beta2-adrenoreceptors induces bronchodilation.
Hyperreactivity of bronchi to various stimuli – allergens, infection, chemical substances, inhalation of cold air, stress – leads to bronchospasm.
Inflammatory reaction. The base of hyperreactivity of bronchi is conditioned by mediators of inflammation. They are formed in the epithelial cells of bronchi, in mast cells, macrophages of alveoli, in neutrophils, eosinophils, monocytes.
Mediators of inflammation: histamine, adenosine, hematotoxic factors for neutrophils and eosinophils are formed in the mast cells. Like leukotrienes, prostaglandins, thromboxan, they cause bronchospasm, infiltration, edema of the mucous tunic, hypersecretion of mucin.
Classification
1. Drugs dilating bronchi (broncholytics):
A) stimulators of beta2-adrenoreceptors (salbutamol, fenoterol, terbutaline, isadrin, orciprenaline sulfate, adrenaline hydrochloride).
B) M-cholinoblockers (atropine sulfate, platyphyline, methacin, ipratropium bromide, tiotropium bromide).
C) spasmolytics of myotropic action: Theophyllin, Euphyllin.
2. Antiinflammatory and broncholytic drugs.
A) steroid antiinflammatory drugs (Hydrocortisone, Dexamethasone, Beclosone diopropionate, Fluticasone propionate, Budesonide);
B) antiallergic drugs: Cromolyn sodium, Ketotifen).
C) drugs affecting the system of leukotrienes - inhibitors of leukotrienes biosynthesis (inhibitors of 5-lipoozygenase); Zileuton; - blockers of leukotriene receptors (Zafirlukast, Montelukast).
β2-adrenomimetics
β2-AM are found on the membranes of the effector cells outside the synapses (non-innervated AR). They are activated by circulating adrenalin out of the adrenal medulla. Besides, β2- AR are located on the presynaptic membrane of adrenergic fibers. At the activation of β2- AR the excretion of noradrenalin is being increased.
β2-AM activate adenylate cyclase, increases the production of CAMP that intensifies the transport of Са2+ out of myofibrils into endoplasmatic reticulum what slows down the interaction of actin and myosin in bronchial smooth muscles leading to its relaxation and dilation.
β2- АM (extrasynaptic):- Stimulation of cardiac activity;
- Vasodilation (in skeletal muscles);
- Relaxation of bronchial smooth muscles;
- Decrease of tone and contractile activity of myometrium;
- Contraction of skeletal muscles;
- Stimulation of glycogenolysis.
Short action β2- agonists
Salbutamol (Salbutamolum). Ventolin, Saltos, Salgim, Salamol Eco. Short action β2- АМ do not increase AP, do not induce tachycardia. They are used to relieve the attacks of BA, treat COPD and at the threat of preterm delivery. The duration of action – 4-6 hours. Interval – 4 h. Dosage forms: metered-dose inhaler 0,025 and 0,1mg/dose. Powder for inhalation in capsules, rotadisks, cyclohalers. Tablets of 0,002;0,004; extended-release tablets (retard) - 0,004;0,008g. 0,1% 5ml ampoules for injections.Prescription: Inhalation – 0,1-0,2mg, by nebulizer: 2,5-5mg. Orally – 1 tab. 3-4 times a day; extended-release tablets - 1-2 times a day. Injections: s/c, i/m - 0,5mg 6 times a day.; i/v - 0,25mg 1-2 times a day. Contraindications: myocarditis, CHD, arrythmia, hepatic and renal failure, diabetes, hyperthyroidism, pheochromocytoma.
Fenoterol. Berotec, Berotec N. The onset of action occurs in the first minutes, maximum in 45 minutes. The duration of action – 5-6 h. Dosage forms: metered-dose inhaler – 0,1 and 0,2 mg/dose. Powder for inhalations in capsules – 0,2mg; 01% solution in vials-instillators.Prescription: inhalations – 0,2mg (1-2 inhales). Contraindications: valvular defects, arrhythmia, CHD, thyrotoxicosis, glaucoma, status asthmaticus.Terbutalin. Onset of action is in the first minutes, maximum in 45 min. Duration of action – 5-6 h. It is used 3-4 times a day.
Long action β2-agonists
Salmoterol. Salmeter, Serevent. Onset of action – 30 min, duration of action – 12 h. One dose contains 50 microgram per day. Dosage forms: metered-dose inhaler – 25 microgram in a dose; powder for inhalations in rotadisks – 50 microgram in a dose. Prescription: inhalations – 0,05-0,1mg 2-4 times a day. Side effects: tachycardia, headache, tremor, nervousness, dyspepsia, hypokalemia, rhinitis, laryngitis, skin itch. Contraindications: pregnancy, lactation, age under 12. With caution - thyrotoxicosis, serious BA, hypoxia.
Formoterol. Oxis Turbuhaler, Foradil – the onset of action is 6 min., the duration of action – up to 8-10 hours. It is used for BA, COPD, if there’s a threat of preterm delivery. Dosage forms: Powder for inhalations in 0,012 mg capsules and turbuhaler with 4,5 and 9 µg per a dose. Prescription: Inhalations of 0,012-0,024mg 2 times a day. Side effects: tachycardia, hypotension, headache, dizziness, sweatiness, tremor, nausea, vomiting, tachyphylaxis.Contraindications: CHD, arrhythmia, vulvular disease, liver cirrhosis, thyrotoxicosis, glaucoma.
The block of М1-ChR, located in ganglia, ganglionic transmission is inhibited, bronchospasm is reduced.
The block of М3- ChR eliminates the muscle spasm in bronchioles, mucus secretion by bronchial glands is inhibited.
Stimulation of М3- ChR activates guanylcyclase with the formation of cGMP out of GTP, leads to the arrival of Са2+ into a cell, activates protein kinase, phosphorylates proteins, develops bronchospasm.
Ipratropium bromide (Atrovent). Quaternary ammonium compound (polar). If administered in the form of inhalations, it affects bronchi, gets absorbed into blood insignificantly, does not exert a systemic action. It blocks М1, М2, М3-ChR. Bronchodilating effect is associated with the block of М3-ChR, but the block of the presynaptic М2- ChR promotes the release of ACH and reduces the effect of ipratropium.
Bronchodilating effect starts within 10 min and reaches its peak in 1 hour, lasts for 6-8 hours. For the prevention of bronchospasm attacks it is used 3-4 times a day.Dosage forms: metered-dose spray in bottles – 0,02 mg in a dose; 0,025% solution for inhalations. Prescription: spray inhalations – 0.02 mg x 2-4 times a day; solution for inhalations – 0,1-0,5 mg x 3-4 times a day. Side effects: dry mouth, increased viscosity of sputum. Contraindications: closed-angle glaucoma, pregnancy. Used with caution in case of prostatic hypertrophy.
Tiotropium bromide (Spiriva) quaternary ammonium compound. Similar to Ipratropium, but it blocks М1, М3 – ChR for a longer time and М2- ChR insignificantly. That is why it does not increase the formation of acetylcholine in cholinergic synapses of bronchi and is more effective than Ipratropium. Peak effect is reached in 1.5-2 hours. Pharmacokinetics. Bioavailibility is around 20%, Т1/2 - 5-6 days, metabolism is in liver, excretion through kidneys.Prescription: 18 µg in the form of inhalation powder, once a day with the help of a handihaler. Side effects: dryness of the oral mucous. Rarely – urine retention, constipation. Contraindications: I trimester of pregnancy, age under 18.
Methylxanthines
Pharmacodynamics. Inhibitors of phosphodiesterase in smooth muscle cells of bronchi increase the intracellular level of CAMP, decrease the concentration of Са2+, lead to bronchodilation. They block adenosine (purine) receptors.
Theophylline- Relaxes smooth muscles of bronchi, blood vessels of brain, heart, lungs and other organs, smooth muscles of intestines, bile-excreting ducts;
- Stimulates CNS; activates the respiratory center, increases its sensitivity to carbonic acid;
- Inhibits the release of inflammatory mediators out of mast cells, monocytes, neutrophils, activates and relocates neutrophils, decreases the number of eosinophils, their degranulation in respiratory tracts. It decreases the production of cytokines IL-1β, IL-4, IL-5, tumor necrosis factor α (TNF-α ), increases the production of antiinflammatory IL-10, IgE.
Pharmacokinetics. Effective and safe concentration of Theophylline in blood – 10-15 mg/l, at the insignificant overdose, dysfunctions of GIT are possible, as well as convulsions, arrhythmias. Bioavailability for the regular one – 90-100%, for the prolonged ones – lower. Сmax in blood in blood is in 2 hours, for the extended-release – in 6 hours. Biotransformation – in liver. 10% of the unchanged drug is excreted with urine. Indications: COPD (reversible bronchial obstruction); BA: for the prevention of night suffocation attacks and night apnoe.Contraindications: thyrotoxicosis, myocardial infarction, extrasystole, subaortic stenosis, epilepsy, pregnancy. Use with caution in case of ulcer.
Aminophylline (Aminophillinum). Euphylline. A compound of Theophylline (80%) and Ethylendiamine (20%). Indications: relief of bronchoobstruction attacks – i/v, bolus dosing or drop-by-drop introduction. Disturbances of cerebral blood circulation. The duration of action is about 4 hours. Dosage forms: 1, 5, 10ml ampoules – 2,4%; 0,15 g tab. Prescription: i/v 10-20ml 2,4% mixed with 10-20ml of physiological (salt) solution (slowly!). I/m – 1ml 2,4%. Orally – 0,15-0,3g 3-4 times a day.Side effects: agitation, sleep disorder, fast heart beat, arrhythmia. Administered i/v, it may cause pains in the region of heart, AP fall.
Theophyllines of prolonged action Prolonged theophyllines reduce the repetition of intakes, increase the precision of dosing, possess a stable therapeutic action, are used to prevent night- and day-time suffocation attacks, the attacks cause by exercising, are better tolerated, cause less side effects.
Theopec. Theopecum
- Administration: Orally – 0,15-0,3 g 2 times a day.
- Dosage form: Tab. – 0,1, 0,2, 0,3 g.
Theobiolongum
- Administration: Orally – 0,1-0,3 g 2 times a day.
- Dosage form: Tab. – 0,1 g.
- Theotard – 1 extended-release tab contains 200, 350, 500mg of theophylline. Bioavailability – 100%. It is prescribed 2 times a day, in case of night attacks – once a day before sleep.
- Retaphyl – tab. – 200 and 300mg. Bioavailiability – 90-92%. It is prescribed 2 times a day. The therapeutic effect is reached on the 3-5 day.
- Euphylong – capsules – 250, 350, 500mg, once a day.
Inhalation glucocorticoids
IGC inhibit all the phases of inflammation in bronchi by blocking phospholipase А2, activity of COX, formation of prostaglandins and leukotrienes, cytokines (IL-1β,2-6,8.12,13 TNF-α etc.), decrease the number of mast cells, macrophages, eosinophils, T-lymphocytes, development of an allergic inflammation (they decrease the penetrability of the vessels, production of secretion, activate β2-receptors).
Pharmacokinetics. The systemic activity of IGC is conditioned by their fraction in the blood stream. It is summed by the portions from mouth, swallowed, absorbed in the intestines and arrived into blood out of the lungs. Indications: BA of moderate and severe scale.- All-year and seasonal allergic rhinitis.
- Sarcoidosis of respiratory organs.
- COPD.
Side effects. Local: oropharyngeal candidiasis, dysphonia, paradoxic bronchospasm, cough, nasal bleeding and dry mouth.Systemic: depression of HPA-system (hypothalamic-pituitary-adrenal system), symptoms of hypercorticism, changes in hemogram.
Beclometasone. Альдецид, Arumet, Beclazone, Beclat, Beclojet, Becotide, Becloforte.Administration: Spray inhalations – 0,2mg 2 times a day or 0,1mg 3-4 times a day. No more than 1 mg. Dosage form. Metered-dose inhalation spray – 0,05, 0,1, 0,2 and 0,25mg/dose. Powder for inhalations – in 0,1, 0,2, 0,4mg capsules together with diskhaler or cyclohaler; spray for intranasal administration – 0,05mg/dose.Flunisolide (Inhacort) is provided with a special spacer device. It is prescribed for the inhalations 2mg/day (8 inhalations with each dose being 250 µg/dose).Budesonide (Benacort, Pulmicort) – 200µg 2 times a day.Indications:- Severe course of BA hardly treated by all the other methods;
- Hormone-dependent BA;
- Status asthmaticus;
- Exacerbation of COPD.
Systemic glucocorticoids
Hydrocortisone hemisuccinate (Hydrocortisonum Hemisuccinate) – Sopolcort N. Administration: I/v, i/m – 0,1-0,5g 3-4 times a day. The dose is adjusted.Dosage form: Frozen-dried powder in amp. – 0,025 and 0,1 g.
Prednisolone (Prednisolonum): Декортин, PrednisolAdministration: Orally in tab. – 0,02-0,04 g/day.Dosage form: Tab. – 0,001 and 0,005 g.
Prednisolone hemisuccinate (Prednisolonum Hemisuccinate)Administration: for status asthmaticus: 0,5-1,2g/day.Dosage form: Frozen-dried powder in amp – 0,025
Mast cell membranes stabilizers
Cromoglicic acid (cromoglicic acid, Sodium cromoglicate, Intal, Lomudal, Cramolin).Pharmacodynamics: it depresses the release of the primary and secondary mediators; inhibits the activity of eosinophils, macrophages, neutrophils, thrombocytes; decreases the sensitivity of afferent nerves. Therapeutic effect is reached within 10-14 days. It can be used for more than 3-4 months.Pharmacokinetics: used in the form of a spray, inhalation powders. It is easily absorbed, but is badly absorbed in GIT. Short Т1/2 (90min). It is not cumulated and eliminated by kidneys and partly with bile.It is used for the prevention of BA attacks.Administration: inhalation spray – 0,01g 4 times a day, if necessary – 6-8 times a day. Inhalation powder – 0,02 g 4 times a day, in the severe course – up to 8 times a day. Inhalations with a nebulizer – 0,02g 4 times a day, in case of severe course – 6 times a day.Dosage forms: metered-dose inhalation spray (balloons – 0,001 and 0,005 g); inhalation powder in capsules – 0,02 g.
Ketotifen (Ketotifenum), Zaditen.Pharmacodynamics. In inhibits the release of histamine, leukotriens out of basophils and neutrophils, decreases the accumulation of eosinophils in the respiratory tracts and the reaction to histamine. It prevents the development of bronchospasm, inhibits phosphodiesterase, increases the amount of CAMP, possesses a moderate Н1-histamineblocking activity. Pharmacokinetics. It is well-absorbed, bioavailibility – around 50% (liver “first pass” effect). The time needed for the peak concentration is – 2-4 h, binding with plasma proteins – 75%. Metabolized in liver, excreted by kidneys in the form of metabolites.
They are used for the prevention of BA attacks in case of hay fever, rhinitis, hives.Prescription: 1mg х 2 times a day orally during the meal. Therapeutic effect is noticeable in 3-4 weeks. Adverse reaction from the site of the nervous system: sleepiness, dizziness, delayed reactions (absent within several day of therapy), sedative effect, feeling of tiredness; rarely - agitation, sleep disorders, nervousness (especially in children). From the site of the digestive system: dry mouth, better appetite, nausea, vomiting, gastralgia, constipation. From the site of urinary system: dysuria, cystitis.Others: thrombocytopenia, gaining of weight, allergic skin reactions.Dosage form: 1 mg tab.
Nedocromil sodium (nedocromil, Tilade)Pharmacodynamics: compared to Intal - 10 times greater anti-inflammatory activity. It is quite effective in the treatment of allergic and non-allergic BA. Peak acticity – on the 5th – 7th days. It reduces considerably the need for inhalation GC.Pharmacokynetics: systemic bioavailability is not considerable (7-17%). Binding with proteins is up to 89%. Т1/2 – 1,5 – 3,3 h. It is not metabolized, excreted with urine in an unchanged form.
Administration: inhalation spray – 0,004 g (2 inhales) 4 times a day, if necessary – 6-8 times a day.Dosage form: metered-dose inhalation spray – 0,002 g per a dose. Tilade Mint metered-dose inhalation spray: balloons with synchronizer – 0,002 g in a dose.
Zafirlukast (Accolate).Pharmacodynamics. It selectively blocks leukotriene receptors (LTD4, LTE4). The anti-inflammatory action is associated with the decrease in penetrability of vessels, reduction of edema of bronchial mucous tunic, inhibition of sputum secretion, simultaneous bronchodilation. Pharmacokinetics. In the form of injections and inhalations. Peak concentration – in 3 hours. Food reduces the absorption down to 40%. Binding with plasma proteins – 99%. It is actively metabolized, excreted by intestines (90%) and kidneys (10%). It inhibits microsomal enzymes.Used as an additional drug to β-АМ, GC.Side effects: headache, gastritis, pharyngitis, myalgia, arthralgia etc. Administration: orally – 0,02 g 2 times a day. No meal.Dosage form: Tab. – 0,02 and 0,04 g.
5-lipoxygenase inhibitors
Zileuton (zyflo, lentrol) – a selective and reversible 5-lipoxygenase inhibitor which decreases the formation of sulfidopeptide leukotrienes (LT) and LTB4. It is confirmed that this drug exerts a bronchodilating effect (its onset of action is within 2 hours, duration of action – 5 hours after the intake) and prevents the development of bronchospasm caused by aspirin and cold air. Pharmacokinetics. When injected it is quickly absorbed. Presystemic metabolism. Peak concentration – in 1,8-2,5 hours. Binding with proteins – 93%. t1/2 - 1-2,3 h.Dosage forms: in tab. – 0,3 and 0,6 g. 4-fold intake a day. Adverse reactions. When used for a long time, the level of hepatic enzymes must be monitored.
Leukotriene receptor antagonists
Montelukast (Singulair)Pharmacodynamics. Selective antagonist of leukotriene LTD4. The mechanism of action is similar to Zafirlukast. It does not inhibit the microsomal hepatic enzymes and does not influence the action of other substances. Pharmacokinetics. It is injected, quickly absorbed. Food does not affect the absorption. T1|2 – 2,7-5,5 h. It is metabolised intensively, excreted by intestines. Indications: prevention and long treatment of BA. Side effects: headache, dizziness, dyspepsia, skin rash.
Bronchial obstruction – a syndrome of disturbance of bronchial permeability caused by the edema of bronchial mucous tunic (chronic bronchitis, allergic reactions) and bronchospasm. Rarely in case of peribronchial fibrosis, pulmonary emphysema.
In the norm the tone of bronchial muscles is supported by cholinergic innervation. There's no sympathetic innervation for bronchi. However, in bronchi there are non-innervated beta2-adrenoreceptors, interacting with catecholamines and adenotropic mediums circulating in blood. The stimulation of beta2-adrenoreceptors induces bronchodilation.
Hyperreactivity of bronchi to various stimuli – allergens, infection, chemical substances, inhalation of cold air, stress – leads to bronchospasm.
Inflammatory reaction. The base of hyperreactivity of bronchi is conditioned by mediators of inflammation. They are formed in the epithelial cells of bronchi, in mast cells, macrophages of alveoli, in neutrophils, eosinophils, monocytes.
Mediators of inflammation: histamine, adenosine, hematotoxic factors for neutrophils and eosinophils are formed in the mast cells. Like leukotrienes, prostaglandins, thromboxan, they cause bronchospasm, infiltration, edema of the mucous tunic, hypersecretion of mucin.
Classification
1. Drugs dilating bronchi (broncholytics):
A) stimulators of beta2-adrenoreceptors (salbutamol, fenoterol, terbutaline, isadrin, orciprenaline sulfate, adrenaline hydrochloride).
B) M-cholinoblockers (atropine sulfate, platyphyline, methacin, ipratropium bromide, tiotropium bromide).
C) spasmolytics of myotropic action: Theophyllin, Euphyllin.
2. Antiinflammatory and broncholytic drugs.
A) steroid antiinflammatory drugs (Hydrocortisone, Dexamethasone, Beclosone diopropionate, Fluticasone propionate, Budesonide);
B) antiallergic drugs: Cromolyn sodium, Ketotifen).
C) drugs affecting the system of leukotrienes - inhibitors of leukotrienes biosynthesis (inhibitors of 5-lipoozygenase); Zileuton; - blockers of leukotriene receptors (Zafirlukast, Montelukast).
β2-adrenomimetics
β2-AM are found on the membranes of the effector cells outside the synapses (non-innervated AR). They are activated by circulating adrenalin out of the adrenal medulla. Besides, β2- AR are located on the presynaptic membrane of adrenergic fibers. At the activation of β2- AR the excretion of noradrenalin is being increased.
β2-AM activate adenylate cyclase, increases the production of
CAMP that intensifies the transport of Са2+ out of myofibrils into endoplasmatic reticulum what slows down the interaction of actin and myosin in bronchial smooth muscles leading to its relaxation and dilation.
β2- АM (extrasynaptic):
- Stimulation of cardiac activity;
- Vasodilation (in skeletal muscles);
- Relaxation of bronchial smooth muscles;
- Decrease of tone and contractile activity of myometrium;
- Contraction of skeletal muscles;
- Stimulation of glycogenolysis.
Short action β2- agonists
Salbutamol (Salbutamolum). Ventolin, Saltos, Salgim, Salamol Eco. Short action β2- АМ do not increase AP, do not induce tachycardia. They are used to relieve the attacks of BA, treat COPD and at the threat of preterm delivery. The duration of action – 4-6 hours. Interval – 4 h.
Dosage forms: metered-dose inhaler 0,025 and 0,1mg/dose. Powder for inhalation in capsules, rotadisks, cyclohalers. Tablets of 0,002;0,004; extended-release tablets (retard) - 0,004;0,008g. 0,1% 5ml ampoules for injections.
Prescription: Inhalation – 0,1-0,2mg, by nebulizer: 2,5-5mg. Orally – 1 tab. 3-4 times a day; extended-release tablets - 1-2 times a day. Injections: s/c, i/m - 0,5mg 6 times a day.; i/v - 0,25mg 1-2 times a day.
Contraindications: myocarditis, CHD, arrythmia, hepatic and renal failure, diabetes, hyperthyroidism, pheochromocytoma.
Fenoterol. Berotec, Berotec N. The onset of action occurs in the first minutes, maximum in 45 minutes. The duration of action – 5-6 h.
Dosage forms: metered-dose inhaler – 0,1 and 0,2 mg/dose. Powder for inhalations in capsules – 0,2mg; 01% solution in vials-instillators.
Prescription: inhalations – 0,2mg (1-2 inhales).
Contraindications: valvular defects, arrhythmia, CHD, thyrotoxicosis, glaucoma, status asthmaticus.
Terbutalin. Onset of action is in the first minutes, maximum in 45 min. Duration of action – 5-6 h. It is used 3-4 times a day.
Long action β2-agonists
Salmoterol. Salmeter, Serevent. Onset of action – 30 min, duration of action – 12 h. One dose contains 50 microgram per day.
Dosage forms: metered-dose inhaler – 25 microgram in a dose; powder for inhalations in rotadisks – 50 microgram in a dose.
Prescription: inhalations – 0,05-0,1mg 2-4 times a day.
Side effects: tachycardia, headache, tremor, nervousness, dyspepsia, hypokalemia, rhinitis, laryngitis, skin itch.
Contraindications: pregnancy, lactation, age under 12. With caution - thyrotoxicosis, serious BA, hypoxia.
Formoterol. Oxis Turbuhaler, Foradil – the onset of action is 6 min., the duration of action – up to 8-10 hours. It is used for BA, COPD, if there’s a threat of preterm delivery.
Dosage forms: Powder for inhalations in 0,012 mg capsules and turbuhaler with 4,5 and 9 µg per a dose.
Prescription: Inhalations of 0,012-0,024mg 2 times a day.
Side effects: tachycardia, hypotension, headache, dizziness, sweatiness, tremor, nausea, vomiting, tachyphylaxis.
Contraindications: CHD, arrhythmia, vulvular disease, liver cirrhosis, thyrotoxicosis, glaucoma.
The block of М1-ChR, located in ganglia, ganglionic transmission is inhibited, bronchospasm is reduced.
The block of М3- ChR eliminates the muscle spasm in bronchioles, mucus secretion by bronchial glands is inhibited.
Stimulation of М3- ChR activates guanylcyclase with the formation of cGMP out of GTP, leads to the arrival of Са2+ into a cell, activates protein kinase, phosphorylates proteins, develops bronchospasm.
Ipratropium bromide (Atrovent).
Quaternary ammonium compound (polar). If administered in the form of inhalations, it affects bronchi, gets absorbed into blood insignificantly, does not exert a systemic action. It blocks М1, М2, М3-ChR. Bronchodilating effect is associated with the block of М3-ChR, but the block of the presynaptic М2- ChR promotes the release of ACH and reduces the effect of ipratropium.
Bronchodilating effect starts within 10 min and reaches its peak in 1 hour, lasts for 6-8 hours. For the prevention of bronchospasm attacks it is used 3-4 times a day.
Dosage forms: metered-dose spray in bottles – 0,02 mg in a dose; 0,025% solution for inhalations.
Prescription: spray inhalations – 0.02 mg x 2-4 times a day; solution for inhalations – 0,1-0,5 mg x 3-4 times a day.
Side effects: dry mouth, increased viscosity of sputum.
Contraindications: closed-angle glaucoma, pregnancy. Used with caution in case of prostatic hypertrophy.
Tiotropium bromide (Spiriva)
quaternary ammonium compound. Similar to Ipratropium, but it blocks М1, М3 – ChR for a longer time and М2- ChR insignificantly. That is why it does not increase the formation of acetylcholine in cholinergic synapses of bronchi and is more effective than Ipratropium. Peak effect is reached in 1.5-2 hours.
Pharmacokinetics. Bioavailibility is around 20%, Т1/2 - 5-6 days, metabolism is in liver, excretion through kidneys.
Prescription: 18 µg in the form of inhalation powder, once a day with the help of a handihaler.
Side effects: dryness of the oral mucous. Rarely – urine retention, constipation.
Contraindications: I trimester of pregnancy, age under 18.
Methylxanthines
Pharmacodynamics. Inhibitors of phosphodiesterase in smooth muscle cells of bronchi increase the intracellular level of CAMP, decrease the concentration of Са2+, lead to bronchodilation. They block adenosine (purine) receptors.
Theophylline
- Relaxes smooth muscles of bronchi, blood vessels of brain, heart, lungs and other organs, smooth muscles of intestines, bile-excreting ducts;
- Stimulates CNS; activates the respiratory center, increases its sensitivity to carbonic acid;
- Inhibits the release of inflammatory mediators out of mast cells, monocytes, neutrophils, activates and relocates neutrophils, decreases the number of eosinophils, their degranulation in respiratory tracts. It decreases the production of cytokines IL-1β, IL-4, IL-5, tumor necrosis factor α (TNF-α ), increases the production of antiinflammatory IL-10, IgE.
Pharmacokinetics. Effective and safe concentration of Theophylline in blood – 10-15 mg/l, at the insignificant overdose, dysfunctions of GIT are possible, as well as convulsions, arrhythmias. Bioavailability for the regular one – 90-100%, for the prolonged ones – lower. Сmax in blood in blood is in 2 hours, for the extended-release – in 6 hours. Biotransformation – in liver. 10% of the unchanged drug is excreted with urine.
Indications: COPD (reversible bronchial obstruction); BA: for the prevention of night suffocation attacks and night apnoe.
Contraindications: thyrotoxicosis, myocardial infarction,
extrasystole, subaortic stenosis, epilepsy,
pregnancy. Use with caution in case of ulcer.
Aminophylline (Aminophillinum). Euphylline.
A compound of Theophylline (80%) and Ethylendiamine (20%).
Indications: relief of bronchoobstruction attacks – i/v, bolus dosing or drop-by-drop introduction. Disturbances of cerebral blood circulation. The duration of action is about 4 hours.
Dosage forms: 1, 5, 10ml ampoules – 2,4%; 0,15 g tab.
Prescription: i/v 10-20ml 2,4% mixed with 10-20ml of physiological (salt) solution (slowly!). I/m – 1ml 2,4%. Orally – 0,15-0,3g 3-4 times a day.
Side effects: agitation, sleep disorder, fast heart beat, arrhythmia. Administered i/v, it may cause pains in the region of heart, AP fall.
Theophyllines of prolonged action
Prolonged theophyllines reduce the repetition of intakes, increase the precision of dosing, possess a stable therapeutic action, are used to prevent night- and day-time suffocation attacks, the attacks cause by exercising, are better tolerated, cause less side effects.
Theopec. Theopecum
- Administration: Orally – 0,15-0,3 g 2 times a day.
- Dosage form: Tab. – 0,1, 0,2, 0,3 g.
- Administration: Orally – 0,1-0,3 g 2 times a day.
- Dosage form: Tab. – 0,1 g.
- Theotard – 1 extended-release tab contains 200, 350, 500mg of theophylline. Bioavailability – 100%. It is prescribed 2 times a day, in case of night attacks – once a day before sleep.
- Retaphyl – tab. – 200 and 300mg. Bioavailiability – 90-92%. It is prescribed 2 times a day. The therapeutic effect is reached on the 3-5 day.
- Euphylong – capsules – 250, 350, 500mg, once a day.
Inhalation glucocorticoids
IGC inhibit all the phases of inflammation in bronchi by blocking phospholipase А2, activity of COX, formation of prostaglandins and leukotrienes, cytokines (IL-1β,2-6,8.12,13 TNF-α etc.), decrease the number of mast cells, macrophages, eosinophils, T-lymphocytes, development of an allergic inflammation (they decrease the penetrability of the vessels, production of secretion, activate β2-receptors).
Pharmacokinetics. The systemic activity of IGC is conditioned by their fraction in the blood stream. It is summed by the portions from mouth, swallowed, absorbed in the intestines and arrived into blood out of the lungs.
Indications: BA of moderate and severe scale.
- All-year and seasonal allergic rhinitis.
- Sarcoidosis of respiratory organs.
- COPD.
Side effects. Local: oropharyngeal candidiasis, dysphonia, paradoxic bronchospasm, cough, nasal bleeding and dry mouth.
Systemic: depression of HPA-system (hypothalamic-pituitary-adrenal system), symptoms of hypercorticism, changes in hemogram.
Beclometasone. Альдецид, Arumet,
Beclazone, Beclat, Beclojet, Becotide, Becloforte.
Administration: Spray inhalations – 0,2mg 2 times a day or 0,1mg 3-4 times a day. No more than 1 mg.
Dosage form. Metered-dose inhalation spray – 0,05, 0,1, 0,2 and 0,25mg/dose. Powder for inhalations – in 0,1, 0,2, 0,4mg capsules together with diskhaler or cyclohaler; spray for intranasal administration – 0,05mg/dose.
Flunisolide (Inhacort) is provided with a special spacer device. It is prescribed for the inhalations 2mg/day (8 inhalations with each dose being 250 µg/dose).
Budesonide (Benacort, Pulmicort) – 200µg 2 times a day.
Indications:
- Severe course of BA hardly treated by all the other methods;
- Hormone-dependent BA;
- Status asthmaticus;
- Exacerbation of COPD.
Systemic glucocorticoids
Hydrocortisone hemisuccinate (Hydrocortisonum Hemisuccinate) – Sopolcort N.
Administration: I/v, i/m – 0,1-0,5g 3-4 times a day. The dose is adjusted.
Dosage form: Frozen-dried powder in amp. – 0,025 and 0,1 g.
Prednisolone (Prednisolonum): Декортин, Prednisol
Administration: Orally in tab. – 0,02-0,04 g/day.
Dosage form: Tab. – 0,001 and 0,005 g.
Prednisolone hemisuccinate (Prednisolonum Hemisuccinate)
Administration: for status asthmaticus: 0,5-1,2g/day.
Dosage form: Frozen-dried powder in amp – 0,025
Mast cell membranes stabilizers
Cromoglicic acid
(cromoglicic acid, Sodium cromoglicate, Intal, Lomudal, Cramolin).
Pharmacodynamics: it depresses the release of the primary and secondary mediators; inhibits the activity of eosinophils, macrophages, neutrophils, thrombocytes; decreases the sensitivity of afferent nerves. Therapeutic effect is reached within 10-14 days. It can be used for more than 3-4 months.
Pharmacokinetics: used in the form of a spray, inhalation powders. It is easily absorbed, but is badly absorbed in GIT. Short Т1/2 (90min). It is not cumulated and eliminated by kidneys and partly with bile.
It is used for the prevention of BA attacks.
Administration: inhalation spray – 0,01g 4 times a day, if necessary – 6-8 times a day. Inhalation powder – 0,02 g 4 times a day, in the severe course – up to 8 times a day. Inhalations with a nebulizer – 0,02g 4 times a day, in case of severe course – 6 times a day.
Dosage forms: metered-dose inhalation spray (balloons – 0,001 and 0,005 g); inhalation powder in capsules – 0,02 g.
Ketotifen (Ketotifenum), Zaditen.
Pharmacodynamics. In inhibits the release of histamine, leukotriens out of basophils and neutrophils, decreases the accumulation of eosinophils in the respiratory tracts and the reaction to histamine. It prevents the development of bronchospasm, inhibits phosphodiesterase, increases the amount of CAMP, possesses a moderate Н1-histamineblocking activity.
Pharmacokinetics. It is well-absorbed, bioavailibility – around 50% (liver “first pass” effect). The time needed for the peak concentration is – 2-4 h, binding with plasma proteins – 75%. Metabolized in liver, excreted by kidneys in the form of metabolites.
They are used for the prevention of BA attacks in case of hay fever, rhinitis, hives.
Prescription: 1mg х 2 times a day orally during the meal. Therapeutic effect is noticeable in 3-4 weeks.
Adverse reaction from the site of the nervous system: sleepiness, dizziness, delayed reactions (absent within several day of therapy), sedative effect, feeling of tiredness; rarely - agitation, sleep disorders, nervousness (especially in children). From the site of the digestive system: dry mouth, better appetite, nausea, vomiting, gastralgia, constipation. From the site of urinary system: dysuria, cystitis.
Others: thrombocytopenia, gaining of weight, allergic skin reactions.
Dosage form: 1 mg tab.
Nedocromil sodium (nedocromil, Tilade)
Pharmacodynamics: compared to Intal - 10 times greater anti-inflammatory activity. It is quite effective in the treatment of allergic and non-allergic BA. Peak acticity – on the 5th – 7th days. It reduces considerably the need for inhalation GC.
Pharmacokynetics: systemic bioavailability is not considerable (7-17%). Binding with proteins is up to 89%. Т1/2 – 1,5 – 3,3 h. It is not metabolized, excreted with urine in an unchanged form.
Administration: inhalation spray – 0,004 g (2 inhales) 4 times a day, if necessary – 6-8 times a day.
Dosage form: metered-dose inhalation spray – 0,002 g per a dose. Tilade Mint metered-dose inhalation spray: balloons with synchronizer – 0,002 g in a dose.
Zafirlukast (Accolate).
Pharmacodynamics. It selectively blocks leukotriene receptors (LTD4, LTE4). The anti-inflammatory action is associated with the decrease in penetrability of vessels, reduction of edema of bronchial mucous tunic, inhibition of sputum secretion, simultaneous bronchodilation.
Pharmacokinetics. In the form of injections and inhalations. Peak concentration – in 3 hours. Food reduces the absorption down to 40%. Binding with plasma proteins – 99%. It is actively metabolized, excreted by intestines (90%) and kidneys (10%). It inhibits microsomal enzymes.
Used as an additional drug to β-АМ, GC.
Side effects: headache, gastritis, pharyngitis, myalgia, arthralgia etc.
Administration: orally – 0,02 g 2 times a day.
No meal.
Dosage form: Tab. – 0,02 and 0,04 g.
5-lipoxygenase inhibitors
Zileuton (zyflo, lentrol) –
a selective and reversible 5-lipoxygenase inhibitor which decreases the formation of sulfidopeptide leukotrienes (LT) and LTB4. It is confirmed that this drug exerts a bronchodilating effect (its onset of action is within 2 hours, duration of action – 5 hours after the intake) and prevents the development of bronchospasm caused by aspirin and cold air.
Pharmacokinetics. When injected it is quickly absorbed. Presystemic metabolism. Peak concentration – in 1,8-2,5 hours. Binding with proteins – 93%. t1/2 - 1-2,3 h.
Dosage forms: in tab. – 0,3 and 0,6 g. 4-fold intake a day.
Adverse reactions. When used for a long time, the level of hepatic enzymes must be monitored.
Leukotriene receptor antagonists
Montelukast (Singulair)
Pharmacodynamics. Selective antagonist of leukotriene LTD4. The mechanism of action is similar to Zafirlukast. It does not inhibit the microsomal hepatic enzymes and does not influence the action of other substances.
Pharmacokinetics. It is injected, quickly absorbed. Food does not affect the absorption. T1|2 – 2,7-5,5 h. It is metabolised intensively, excreted by intestines.
Indications: prevention and long treatment of BA.
Side effects: headache, dizziness, dyspepsia, skin rash.
