Asthma treatment drugs can be divided into two major categories: control drugs and relief drugs, which are described below.
Asthma control drugs: They are drugs that achieve clinical control of asthma mainly through anti-inflammatory effects and require long-term and daily use. They mainly include inhaled glucocorticoids, leukotriene modulators, long-acting inhaled β2 agonists, theophylline, chromogranin, long-acting oral β2-agonists, systemic glucocorticoids and oral anti-allergic drugs.
(A) Inhaled glucocorticoids
1. Glucocorticoids have powerful anti-inflammatory and immunosuppressive effects, and are currently the most effective drugs for asthma control. The efficacy of glucocorticoids on asthma is mainly to reduce the inflammatory response of bronchial mucosa, which is manifested in inhibiting the activation of inflammatory cells, recruitment and release of cytokines and inflammatory mediators, improving the inflammatory edema of the airway mucosa, and delaying the process of airway remodeling in patients with bronchial asthma. In addition, glucocorticoids have an upregulatory effect on airway smooth muscle β2-adrenoceptors.
2.Commonly used ICS
Long-term inhalation of ICS can relieve asthma symptoms, improve quality of life, improve lung function, reduce the number of asthma attacks, prevent irreversible airway changes, and ultimately reduce mortality in asthma patients. The main commonly used ICS are beclomethasone dipropionate (Bicodone, BDP), budesonide (Pramipexole, BUD), and fluticasone propionate (Co-codone FP). In addition to the different pharmacological properties such as lipophilicity and glucocorticoid receptor binding affinity, their inhalation devices are also different, which directly affect the therapeutic effect of ICS.
3.The main side effects of inhaled glucocorticoids
(1) Local side effects: mainly include Candida infection in the oropharynx and hoarseness.
(2) Systemic side effects: mainly include suppression of adrenocortical function, reduction of bone density, cataract and glaucoma, etc. Budesonide and fluticasone are less likely to cause side effects at therapeutic doses and do not produce systemic side effects at doses below 400ug of budesonide or its equivalent per day. There is no evidence from current studies that ICS increases the risk of pulmonary infections, including tuberculosis infections, and active tuberculosis is not a contraindication to ICS therapy.
(ii) Leukotriene modulators
Leukotriene modulators are the only new class of anti-inflammatory mediators that have been successfully developed in studies from 1989 to the present. 2006 GINA recommended leukotriene modulators as an alternative to low-dose ICS for the first-line treatment of mild persistent asthma. However, single mediator modulators are much less effective than β2-agonists and glucocorticoids in clinically calming asthma. There are 2 types of leukotriene modulators commonly used in clinical practice.
1. Zallust (Zileuton, trade name Encore): adults and children over 12 years old (including 12 years old), starting dose 20mg twice daily.
2. Montelukast (trade name Sunelukast): Adults and children over 15 years old (including 15 years old), 1 tablet (10mg) daily, children 6 to 14 years old, 1 tablet (4mg) daily.
(C) Long-acting inhaled β2 agonists (LABA)
1. β2-receptor is a glycoprotein, consisting of a 413 amino acid polypeptide with a molecular weight of about 46,500 Da (Daltons). β2-receptor is a type of G protein-coupled receptor with common features of G protein-coupled receptors. β2-receptor has a wide distribution in the respiratory system (airway smooth muscle, airway epithelium, blood vessels and their endothelium, alveolar type II cells, cholinergic nerves in lung tissue, sensory nerves, etc.). The distribution density of β2-receptors in the airway increases with the grading of the airway, being more densely distributed in small airways than in larger airways and highest in the alveolar region. This characteristic determines that β2-agonists can exert their pharmacological effects through systemic and local administration. β2-agonists bind to β2-agonists and produce major effects (such as relaxation of bronchial smooth muscle, enhancement of cilia movement and mucus clearance, reduction of exudation, reduction of airway edema, inhibition of inflammatory cell mediators, etc.) that are conducive to the relief and elimination of wheezing, with strong and rapid effects and reliable efficacy. The effect is strong and rapid, with reliable efficacy.
2.Classification
According to the pharmacological properties and clinical applications of β2-agonists are divided into four categories.
The first category has rapid onset and long duration of action (>12h), such as inhaled formoterol;
The second category has a slow onset and long duration of action, such as inhaled salmeterol and oral bambuterol;
The third category has a slow onset and short duration of action, such as oral terbutaline and salbutamol;
The fourth category has rapid onset of action but short duration of action, such as inhaled terbutaline or salbutamol.
3.Characteristics of LABA
(1) Not recommended for use alone, cannot reduce airway inflammation in asthma, can be used to prevent exercise-induced bronchospasm, and has a longer duration of prevention than rapid-acting inhaled β2 agonists (SABA).
(2) Combination with ICS is more effective: when asthma control cannot be achieved with moderate doses of ICS alone, combination with LABA is the best treatment to improve symptom scores, reduce nocturnal asthma attacks, improve lung function, reduce SABA dosage and reduce the number of acute attacks.
(3) Most patients achieve control faster than ICS alone when combined with low-dose ICS.
(4) The combined dosage form of formoterol and budesonide can be used as both emergency and maintenance medication, and the on-demand administration plays a role in preventing acute attacks, and the lower dose can improve the control of asthma.
4.Commonly used LABA
(1)Salmeterol: It is a lipophilic long-acting β2 agonist, not advocated to be applied alone, combined with inhaled corticosteroids, inhaled dose: 50ug each time, 2-4 times a day.
(2) Formoterol: a fast-acting long-acting β2 agonist, inhalation dose: at least 12ug, the maximum dose of 54ug a day, can be applied as needed. The minimum oral dose is 80ug.
5.Side effects
β2 agonists appear side effects related to the dose, is due to too much β2 agonist stimulated by, mainly in oral and intravenous medication, inhalation treatment required dose reduction, systemic effects significantly reduced.
(1) Muscle tremor: the most common, caused by stimulation of β2 receptors on skeletal muscle.
(2) Tachycardia and palpitations: peripheral vascular bed β2 receptors are affected by drug action resulting in peripheral vasodilation, producing secondary reflex cardiac excitation, and also direct stimulation of atrial β2 receptors, and possibly excitation from myocardial β1 receptors.
(3) Metabolic effects: Increase in free fat, insulin, glucose, pyruvate, and lactate may occur after systemic high dose use.
(4) Hypokalemia: especially when used intravenously, beta receptors are stimulated to allow potassium to enter skeletal muscle and redistribute potassium.
(4) Theophylline
1. The basic structure of theophylline is methylxanthine, which has a direct relaxing effect on airway smooth muscle. The possible mechanism is related to the fact that theophylline has the ability to inhibit phosphodiesterase, increase intracellular cAMP and cGMP levels, and activate proteinase A and G, respectively, thereby diastaging large airway smooth muscle. Other possible molecular mechanisms include.
(1) Promoting the release of endogenous epinephrine and norepinephrine, causing smooth muscle relaxation;
(2) Inhibition of calcium inward flow and promotion of calcium outward flow, reducing intracellular free calcium levels and relaxing smooth muscle;
(3) Protect mast cell membrane and inhibit the release of inflammatory mediators;
(4) act as an adenosine receptor antagonist, antagonizing the bronchoconstrictive effect of adenosine. Experimental studies have shown that theophylline also has anti-inflammatory effects, promoting airway cilia movement, immunomodulatory effects on lymphocytes, as well as cardiac, diuretic, coronary artery dilation, respiratory center and respiratory muscle excitation effects.
2.Therapeutic effects
(1) Bronchodilator, anti-inflammatory effect when applied in small doses, as additional treatment, theophylline is not as effective as long-acting inhaled β2 agonists.
(2) There is a lack of data on the effectiveness of theophylline as a long-term controller drug, and the data suggest that extended-release theophylline has a limited role as a first-line controller drug.
(3) Patients who fail to achieve control with ICS therapy alone may benefit as additional therapy, and these asthma patients become poorly controlled and are associated with withdrawal of extended-release theophylline.
3.Commonly used theophylline drugs
According to the different preparations, they are divided into three categories: common theophylline, theophylline extended-release and theophylline controlled-release.
Common theophylline mainly has aminophylline, doxorubicin, dihydroxypropyl theophylline (asthma, glycerol theophylline) and theophylline compound preparations.
Theophylline extended-release agents include theophylline (Theovent, Schering-Plough, USA), 250-500mg, 1/day, Shuvumet (Guangzhou Xinghua Pharmaceutical), 100-200mg, 1/day.
Theophylline controlled-release agent Protheo (Shanghai Schering-Plough), adults and over 17 years old, 400-800mg/day; 9-16 years old, 200mg/day.
4.Side effects
Mainly caffeine-like reactions (e.g. mild neutralization and nervous system irritation), related to blood concentration. Mild reactions such as nausea, stomach upset. More serious and persistent adverse reactions, usually seen in blood concentration >20mg/L, include nausea, vomiting, headache, diarrhea, irritability and insomnia; >35mg/L can appear hyperglycemia, hypotension, arrhythmia, convulsions and brain damage.
(E) Chromogranin
Including sodium cromoglycate and sodium nedolomide two types, the most commonly used clinically is sodium cromoglycate. The clinical effect on asthma is mainly manifested in the two aspects of airway anti-inflammation, prevention and control of bronchospasm. Long-term regular inhalation of sodium cromoglycate can reduce the inhaled dose of glucocorticoids and can partially replace the anti-inflammatory effect of glucocorticoids. In clinical application, it is mainly effective for mild persistent asthma and exercise-induced bronchospasm, but not as effective as low-dose ICS.
(vi) Long-acting oral β2-agonists
Applied only in a few cases such as when additional bronchodilator effects are needed, treatment alone may be harmful and must be combined with ICS. The two main drugs commonly used are the following.
(1) Bambuterol (Bambec, help prepare): It is a terbutaline precursor and a long-acting oral β2-receptor agonist. Oral: Adults, 10-20mg per dose, 1 time per day.
(2) Procaterol (Meprobamate): It is a medium to long-acting oral β2 agonist. Oral: adults, 50ug each time, 1 to 2 times daily; children over 6 years old, 25ug each time, 1 to 2 times daily; children under 6 years old, 1.25ug/Kg each time, 1 to 2 times daily.
Oral long-acting β2-agonists have more side effects than the inhaled type, mainly including cardiovascular stimulation (tachycardia), anxiety and skeletal muscle tremor, etc. They are not used in children aged 5 years and younger.
(vii) Systemic glucocorticoids
Although ICS and ICS combined with LABA and other asthma drugs can control the symptoms of most asthma patients, there are still some “refractory” patients who cannot achieve clinical control with ICS and other treatments. The 5th step of treatment recommended by GINA 2006 is to have oral hormones to control asthma symptoms. However, because of the side effects of long-term application of systemic glucocorticosteroids, when long-term application is necessary, care must be taken to minimize systemic side effects, and oral preparations are preferred over parenteral (intramuscular or intravenous) administration for long-term application.
Commonly used drugs mainly include cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, etc. Major side effects include osteoporosis, arterial hypertension, diabetes mellitus, hypothalamic pituitary adrenal axis suppression, obesity, cataracts, glaucoma, skin thinning resulting in skin streaks and easy subcutaneous bleeding, and muscle weakness. When acute exacerbation of asthma occurs, oral prednisone 40-50mg can be given daily for 5-10 days depending on the severity of the disease. When asthma reaches control, hormones can be discontinued or gradually reduced and ICS substitution therapy can be used.
(H) Oral anti-allergic drugs
The main drugs include Trinostat, Rebifast, Tazalest, Peromis, Ozagrel, CEIATRODAST, Amlodipine and Isobutide. The main mechanism of action of these drugs is to inhibit the activation of mast cells, block the synthesis of allergic inflammatory mediators, or act as antagonists of inflammatory mediators. The relative effectiveness of these drugs needs to be further investigated before they can be recommended for long-term asthma control, and their therapeutic effects are limited and appear to have only a limited calming effect. The most common side effect is sedation, and other adverse effects have not been reported.
Second, asthma relief drugs: are used on demand and can quickly relieve bronchial smooth muscle spasm and clinical symptoms. They include five types of fast-acting inhaled β2-agonists (SABA), systemic glucocorticoids, anticholinergic drugs, theophylline and short-acting oral β2-agonists.
(A) Fast-acting inhaled β2-agonists (SABA)
It is mainly used to relieve bronchospasm and prevent exercise-induced bronchoconstriction during acute exacerbation of asthma, and should be administered as needed at the minimum dose and the minimum number of uses. In patients with acute exacerbations, the need for short-term oral glucocorticoids may be indicated for those who do not respond rapidly enough to β2-agonists and do not maintain them for long enough.
Commonly used drugs include salbutamol, terbutaline and formoterol.
(1) Salbutamol: aerosol inhalation: adults, 0.1-0.2 mg each time, applied as needed; nebulized solution inhalation: adults, 2.0 ml each time, applied as needed, mostly for severe attacks.
(2) Terbutaline: Adults: 0.25-0.50mg per dose, applied as needed.
(3) Formoterol: fast-acting, as a symptom reliever, used only in combination with conventional control therapy for ICS patients. The common inhaled dose is at least 12ug, and the maximum dose of 1 day can be 54ug.
(ii) Systemic glucocorticoids
They are usually not considered as relieving drugs, but play an important role in the treatment of acute asthma exacerbations, preventing the development of asthma exacerbations, reducing the number of emergency visits and hospitalizations, preventing early relapses, and reducing mortality. Depending on the severity of the acute attack, oral prednisone 40-50mg/d (or the corresponding dose of methylprednisolone) can be given for 5-10 days, depending on the severity of the disease.
(C) anticholinergic drugs
M1 cholinergic receptor blockers can inhibit parasympathetic ganglion neurotransmission and relax the airway, but the strength of the effect is weak. M2 cholinergic receptors inhibit the release of acetylcholine from postganglionic fibers and norepinephrine from sympathetic fibers.
M3 cholinergic receptors, when agitated, cause airway smooth muscle contraction, airway caliber reduction, promote mucus secretion, and vasodilation. Selective M3 cholinergic receptor blocking drugs can relax airway smooth muscle, reduce mucosal secretion and vascular exudation, etc., and can have significant asthma calming effects. The bronchodilator effect of anticholinergic drugs is weaker than that of fast-acting β2-agonists.
2, commonly used anticholinergic drugs ipratropium bromide (Atrovent, Atrovent) is atropine N-isopropyl substituted derivative, water-soluble, lipid-soluble, difficult to penetrate the biological barrier, on M1, M2, M3 choline receptors can be blocked, due to blocking M2 choline receptors, cancel the inhibitory feedback regulation of the receptor, can make cholinergic postganglionic fibers release excessive acetylcholine The blockade of M3 choline receptors is partially antagonized by the blockade of M3 choline receptors. Isoproterenol is not readily absorbed orally and is currently available in four inhalation dosage forms.
①Metered dose inhaler (MDI), 20ug or 40ug per spray, 200 sprays per bottle;
②Ipratropium bromide nebulizer solution, 20ml per bottle, 25ug per ml of ipratropium bromide;
③Combivent quantitative aerosol, 10ml, 200 syringes. Each syringe contains 21ug of ipratropium bromide and 120ug of salbutamol sulfate, 1~2 syringes each time, 3~6 times a day.
④Corbet nebulizer solution, 2.5ml per bottle (containing ipratropium bromide 0.5mg and salbutamol 2.5mg), 1~2.5ml each time, 2~4 times a day.
3. Side effects: rare. A few patients may experience dry mouth and bitterness, occasionally dry cough and throat discomfort. Atropine allergy is prohibited; early pregnancy use with caution; glaucoma patients nebulized inhalation operation should be cautious.
(iv) Theophylline
Theophylline is mainly a short-acting theophylline used to relieve asthma symptoms. It may have no bronchodilatory effect on acute asthma attacks in which appropriate doses of SABA have been applied, but may be beneficial in improving respiratory drive. Short-acting theophylline should not be reapplied in patients with long-term application of extended-release theophylline.
The most commonly used drugs are aminophylline (Aminophylin) and doxofylline (Doxofylline).
(E) Short-acting oral β2-agonists
Because of the high incidence of side effects, less frequently used, mainly for a small number of people who can not apply inhaled drugs. Commonly used drugs include.
(1) Salbutamol (Salbutamol): adults: 2-4mg per dose, 3-4 times a day; children: 0.1-0.15mg/kg per dose, 2-3 times a day.
(2) Terbutaline: Adults: 1.25-2.5mg, 2-3 times a day.