Asthma 2015

Asthma is characterized clinically by recurrent bouts of coughing, shortness of breath, chest tightness, and wheezing; physiologically by widespread, reversible narrowing of the bronchial airways and a marked increase in bronchial responsiveness to inhaled stimuli; pathologically by lymphocytic, eosinophilic inflammation of the bronchial mucosa. – includes also remodeling of the bronchial mucosa, with deposition of collagen beneath the epithelium's lamina reticularis – hyperplasia of the cells of all structural elements - vessels, smooth muscle, and secretory glands and goblet cells.

Submucosa Mucosa Infiltration of inflammatory cells, (mononuclear cells, eosinophils etc.) Hypertrophied smooth muscle Mononuclear cell Oedema Mast cell Mucus plug with eosinophils and desquamated epithelial cells Thickened basement membrane Epithelium Eosinophil Dilated blood vessels Schematic diagram of a cross-section of a bronchiole showing the changes that can occur with severe chronic asthma.

Antiasthmatic agents are often used by : inhalation Inhalation methods are: metered dose Inhaler-aerosol, aerosol administered via a nebulizer, and a dry powder administered by Rotahaler or Diskhaler. orally i.v.

DRUGS FOR ACUTE USE: quick relief quick relief DRUGS USED FOR PROPHYLAXIS

DRUGS FOR ACUTE USE: quick relief quick reliefBRONCHODILATORSGLUCOCORTICOIDS

DRUGS FOR ACUTE USE: quick relief quick reliefBRONCHODILATORS 1. Methylxanthines 2. Sympathomimetic agents 3. Muscarinic antagonists 4. New bronchodilatorsGLUCOCORTICOIDS

DRUGS FOR ACUTE USE: quick relief 1. Methylxanthines Theophylline, theobromine, and caffeine (alkaloids from tea, cocoa, and coffee, respectively). Pharmacodynamics of methylxanthines Central nervous system effects Cardiovascular effects Effects on the GIT Effects on kidney Effects on smooth muscle

DRUGS FOR ACUTE USE: quick relief Pharmacodynamics of methylxanthines Central nervous system effects increased alertness, tremor and nervousness, stimulant effects on respiration Cardiovascular effects stimulation of the heart (positive chronotropic and inotropic actions) Effects on the GIT spasmolytic action, increase in HCL secretion Effects on kidney weak diuretic effect, involving both increased GF and reduced reabsorption in the tubules Effects on smooth muscle vasodilation, bronchodilation

DRUGS FOR ACUTE USE: quick relief Clinical use of methylxanthines Theophylline is used as a theophylline salt - aminophylline, which contains 86% theophylline by weight and ethylenediamine. Improvements in theophylline preparations: anhydrous theophylline in a microcrystalline form in which the increased surface area facilitates solubilization for complete and rapid absorption after oral administration.

DRUGS FOR ACUTE USE: quick relief Theophylline blood level should be m o n i t o r e d. Therapeutic and toxic effect of theophylline are related to the plasma concentrations of the drug. Improvement in pulmonary function is well correlated with plasma concentration in the range of 5-20 mg/L. Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety begin to occur at concentrations of 15 mg/L in some patients and become common at concentrations greated than 20 mg/L. Higher levels (> 40 mg/L) may cause seizures or arrhythmias, these may not be preceded by gastrointestinal or neurologic warning symptoms.

Rational administration of theophylline, therefore, requires knowledge of its pharmacokinetics. plasma clearance and factors with impact on it: (adults, the mean plasma clearance is 0.69 mL/kg/min - 0,041 L/kg/h).  : changes in hepatic function (cirrhosis or decrease in hepatic blood flow caused by heart failure may decrease plasma clearance, viral infection).  :induction of hepatic enzymes by cigarette smoking may increase plasma clearance and cause inadequate concentrations of drug (the dose is usually increased by 30%) Age: children appear to clear theophylline faster than adults (1-1.5 mL/kg/min: L/kg/h). Neonates and young infants have the slowest clearance.

DRUGS FOR ACUTE USE: quick relief 2. Sympathomimetic agents Nonselective Adrenaline is an effective, rapidly acting bronchodilator when injected subcutaneously (1:1000 solution) or inhaled as a microaerosol. Maximal bronchodilation is achieved 15 minutes after inhalation and lasts for minutes. Adverse effects: tachycardia, arrhythmias, worsening of angina pectoris

Beta 2 -selective agonist drugs are the most widely used sympathomimetics for the treatment of asthma at the present time. Salbutamol (albuterol), terbutaline, fenoterol are available as metered-dose inhalers. Bronchodilation begins in 5 minutes, is maximal by minutes and persists for 2 hours. Bronchial deposition depends on the particle size. Even with particles in the optimal size range of 2-5  m, 70-50% of the total dose is deposited in the mouth or pharynx. Particles under 1-2  m in size remain suspended and may be exhaled. Terbutaline is also prepared in tablet form. One tablet 3 times daily is the usual regimen.

DRUGS FOR ACUTE USE: quick relief DRUGS FOR ACUTE USE: quick relief Adverse effects of beta agonists. Cardiac arrhythmias from β1-adrenoceptor stimulation, hypoxemia - angina muscle tremor headache and insomnia flushing hypokalemia

DRUGS FOR ACUTE USE: quick relief 3. Muscarinic antagonists Muscarinic antagonists competitively inhibit the effect of acetylcholine at muscarinic receptors. More selective quaternary ammonium derivative of atropine, ipratropium bromide, short-acting drug is used for patients with heart disease or thyreotoxicosis in whom beta agonists are unsuitable.

DRUGS FOR ACUTE USE: quick relief 4. New bronchodilators Cysteinyl leukotriene-receptor antagonists. Montelucast prevents antigen-induced and exercise- induced asthma. It relaxes the airways in mild asthma, its effects are additive with  2 adrenoceptors agonists. 5-lipoxygenase inhibitors- zileuton

DRUGS FOR PROPHYLAXIS BRONCHODILATORS GLUCOCORTICOIDS

BRONCHODILATORS 1.beta 2 -selective agonists 2. aminophylline and theophylline 3. corticosteroids 4. cromolyn and nedocromil

DRUGS USED FOR PROPHYLAXIS 1. Newer beta 2 -selective agonists developed for an increased duration of action (12 hours or more) compared with the older beta 2 agonists (4-6 hours) include: f o r m o t e r o l, s a l m e t e r o l (for inhalation) c l e n b u t e r o l, p r o c a t e r o l (per os) They appear to achieve their long duration of action as a result of high lipid solubility. Their high lipid solubility permits them to dissolve in the smooth muscle cell membrane and reach high concentration "slow release depot" that provides the drug available to beta receptors over a long period.

DRUGS USED FOR PROPHYLAXIS 2. In addition, several sustained-release preparations with aminophylline and theophylline (Theo-Dur) are available and can produce therapeutic blood levels of theophylline for up to 12 or 24 hours. These preparations offer the advantages of - less frequent drug administration, - less fluctuation of theophylline blood levels, - and, in many cases, more effective treatment of nocturnal bronchospasm.

DRUGS USED FOR PROPHYLAXIS 3. Corticosteroids work by inhibiting or otherwise modifying the inflammatory response in airways

DRUGS USED FOR PROPHYLAXIS Corticosteroids administered orally or i.v. Because of severe adverse effects when given chronically, oral corticosteroids (or i.v.) are generally reserved for patients: who do not improve adequately with bronchodilators or who experience worsening symptoms despite maintenance bronchodilator therapy Treatment: oral dose of mg of prednisone per day. In most patients, corticosteroid therapy can be discontinued in a week or 10 days, but in other patients symptoms may worsen as the dose is decreased to lower levels.

DRUGS USED FOR PROPHYLAXIS Systemic adverse effects of glucocorticoids administered orally or i.v. gluconeogenesis (hyperglycemia) hypertension immunosuppresion adrenal suppresion osteoporosis growth decelaration in children cataract glaucoma

DRUGS USED FOR PROPHYLAXIS Corticosteroids administered by inhalation. The most effective method of decreasing systemic adverse effects due to corticosteroid therapy is to administer the drug as an aerosol or powder by inhalation.

DRUGS USED FOR PROPHYLAXIS Inhaled corticosteroids (ICS) are currently the most effective long-term preventive medications early diagnosis and treatment are important prevention of airway remodelling long-term treatment with minimal daily doses of ICS

symptoms pulmonary function bronchial hyperreactivity months RESPONSES TO INHALED CORTICOSTEROIDS Responses (%)

DOSE - RELATED RESPONSES OF ASTHMATICS TO INHALED CORTICOSTEROIDS (ICS) Doses (  g/day) resistence to ICS severe asthma moderate asthma mild asthma supersensitivity to ICS

DRUGS USED FOR PROPHYLAXIS lipid-soluble corticosteroids for inhalations are: beclomethasone, budesonide, and fluticasone with minimal systemic absorption and reduced adverse effects. An average daily dose ranges from  g/day inhalation according to asthma severity. Systemic steroid effects are still negligible if compared with those of the oral prednisone : oropharyngeal candidiasis- mouthwashes can alleviate this problem

DRUGS USED FOR PROPHYLAXIS ICS and the growth in children Long-term and retrospective studies proved that treatment with ICS (BUD  g/day) does not lead to the shorter definitive stature. Noncontrolled asthma itself leads to the growth deceleration but also to the shorter definitive stature.

DRUGS USED FOR PROPHYLAXIS Chronic use of inhaled corticosteroids:  - effectively reduces symptoms and  - improves pulmonary function in patients  - reduces bronchial hyperreactivity (unlike beta- stimulant agents and theophylline),  - the maximal reduction may not be achieved until the ninth to twelfth months of therapy.