Intestinal Permeability Is Increased In Bronchial Asthma

Airway congestion

Accumulation in airways of mucus, inadequate expulsion by cough

A. Drugs used in common cold

Allergic Disorders

IgE-mediated allergic reactions (p. 72) involve mast cell release of histamine (p. 114) and production of other mediators (such as leukotrienes, p. 196). Resultant responses include: relaxation of vascular smooth muscle, as evidenced locally by vasodilation (e.g., conjunctival congestion) or systemically by hypotension (as in anaphylactic shock); enhanced capillary permeability with transudation of fluid into tissues— swelling of conjunctiva and mucous membranes of the upper airways ("hay fever"), cutaneous wheal formation; contraction of bronchial smooth muscle— bronchial asthma; stimulation of intestinal smooth muscle—diarrhea.

1. Stabilization of mast cells. Cromolyn prevents IgE-mediated release of mediators, although only after chronic treatment. Moreover, by interfering with the actions of mediator substances on inflammatory cells, it causes a more general inhibition of allergic inflammation. It is applied locally to: conjunctiva, nasal mucosa, bronchial tree (inhalation), intestinal mucosa (absorption almost nil with oral intake). Indications: prophylaxis of hay fever, allergic asthma, and food allergies.

2. Blockade of histamine receptors. Allergic reactions are predominantly mediated by Hi receptors. H¡ antihistamines (p. 114) are mostly used orally. Their therapeutic effect is often disappointing. Indications: allergic rhinitis (hay fever).

3. Functional antagonists of mediators of allergy. a) ^Sympathomimetics, such as naphazoline, oxymeta-zoline, and tetrahydrozoline, are applied topically to the conjunctival and nasal mucosa to produce local vasoconstriction, and decongestion and to dry up secretions (p. 90), e.g., in hay fever. Since they may cause mucosal damage, their use should be short-term.

b) Epinephrine, given i.v., is the most important drug in the management of anaphylactic shock: it constricts blood vessels, reduces capillary permeability, and dilates bronchi.

c) ß2-Sympathomimetics, such as terbutaline, fenoterol, and albuterol, are employed in bronchial asthma, mostly by inhalation, and parenterally in emergencies. Even after inhalation, effective amounts can reach the systemic circulation and cause side effects (e.g., palpitations, tremulousness, restlessness, hy-pokalemia). During chronic administration, the sensitivity of bronchial musculature is likely to decline.

d) Theophylline belongs to the methylxanthines. Whereas caffeine (1,3,7-trimethylxanthine) predominantly stimulates the CNS and constricts cerebral blood vessels, theophylline (1,3-dimethylxanthine) possesses additional marked bronchodilator, cardiostimulant, vasorelaxant, and diuretic actions. These effects are attributed to both inhibition of phosphodiesterase (^ c AMP elevation, p. 66) and antagonism at adenosine receptors. In bronchial asthma, theophylline can be given orally for prophylaxis or parenterally to control the attack. Manifestations of overdosage include tonic-clonic seizures and cardiac arrhythmias as early signs.

e) Ipratropium (p. 104) can be inhaled to induce bronchodilation; however, it often lacks sufficient effectiveness in allergic bronchospasm.

f) Glucocorticoids (p. 248) have significant anti-allergic activity and probably interfere with different stages of the allergic response. Indications: hay fever, bronchial asthma (preferably local application of analogues with high pre-systemic elimination, e.g., beclometha-sone, budesonide); anaphylactic shock (i.v. in high dosage)—a probably nonge-nomic action of immediate onset.

Pathophysiology Tonic Clonic Seizures

Bronchial Asthma

Definition: a recurrent, episodic shortness of breath caused by bronchocon-striction arising from airway inflammation and hyperreactivity.

Asthma patients tend to underestimate the true severity of their disease. Therefore, self-monitoring by the use of home peak expiratory flow meters is an essential part of the therapeutic program. With proper education, the patient can detect early signs of deterioration and can adjust medication within the framework of a physician-directed therapeutic regimen.

Pathophysiology. One of the main pathogenetic factors is an allergic inflammation of the bronchial mucosa. For instance, leukotrienes that are formed during an IgE-mediated immune response (p. 326) exert a chemo-tactic effect on inflammatory cells. As the inflammation develops, bronchi become hypersensitive to spasmogenic stimuli. Thus, stimuli other than the original antigen(s) can act as triggers (A); e.g., breathing of cold air is an important trigger in exercise-induced asthma. Cyclooxygenase inhibitors (p. 196) exemplify drugs acting as asthma triggers.

Management. Avoidance of asthma triggers is an important prophylactic measure, though not always feasible. Drugs that inhibit allergic inflammma-tory mechanisms or reduce bronchial hyperreactivity, viz., glucocorticoids, "mast-cell stabilizers," and leukotriene antagonists, attack crucial pathogenetic links. Bronchodilators, such as f¡2-sym-pathomimetics, theophylline, and ipratropium, provide symptomatic relief.

The step scheme (B) illustrates successive levels of pharmacotherapeutic management at increasing degrees of disease severity.

First treatment of choice for the acute attack are short-acting, aerosolized p2-sympathomimetics, e.g., salbutamol, albuterol, terbutaline, fenoterol, and others. Their action occurs within minutes and lasts for 4 to 6 h.

If p2-mimetics have to be used more frequently than three times a week, more severe disease is present. At this stage, management includes anti-inflammatory drugs, such as "mast-cell stabilizers" (in children or juvenile patients) or else glucocorticoids. Inhala-tional treatment must be administered regularly, improvement being evident only after several weeks. With proper use of glucocorticoids undergoing high presystemic elimination, concern about systemic adverse effects is unwarranted. Possible local adverse effects are: oropharyngeal candidiasis and dyspho-nia. To minimize the risk of candidiasis, drug administration should occur before morning or evening meals, or be followed by rinsing of the oropharynx. Anti-inflammatory therapy is the more successful the less use is made of as-needed p2-mimetic medication.

Severe cases may, however, require an intensified bronchodilator treatment with systemic p2-mimetics or theophylline (systemic use only; low therapeutic index; monitoring of plasma levels needed). Salmeterol is a long-acting in-halative p2-mimetic (duration: 12 h; onset ~20 min) that offers the advantage of a lower systemic exposure. It is used prophylactically at bedtime for nocturnal asthma.

Zafirlukast is a long-acting, selective, and potent leukotriene receptor (LTD4, LTE4) antagonist with anti-inflammatory/antiallergic activity and efficacy in the maintenance therapy of chronic asthma. It is given both orally and by inhalation. The onset of action is slow (3 to 14 d). Protective effects against inhaled LTD4 last up to 12 to 24 h.

Ipratropium may be effective in some patients as an adjunct anti-asthmatic, but has greater utility in preventing bronchospastic episodes in chronic bronchitis.

Theophylline Asthma

A. Bronchial asthma, pathophysiology and therapeutic approach

Modified after

International Consensus Report 1992

A. Bronchial asthma, pathophysiology and therapeutic approach

Modified after

International Consensus Report 1992

Glucocorticoids systemic

Maintained bronchodilation Theophylline p.o./ß2-mimetics p.o. orbnghacting ß2-mimetics inhalative "or" "or/and"

Parasympatholytics

Antiinflammatory treatment, inhalative, chronically

"Mast cell-stabilizer" or glucocorticoids

Glucocorticoids Glucocorticoids or leukotriene antagonists

Bronchodilation as needed: short-acting inhalative ß2-mimetics

<3 x /week

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