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Introduction
Classification
Bronchodilators
Sympathomimetic Methylxanthines Antimuscarinic
Agents
agents
Non-bronchodilator Corticosteroids
M Rabbani Ph.D. Department of Pharmacology Isfahan University of Medical Sciences
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M.Rabbani
Cromolyn
Drug pictures
M.Rabbani
Asthma is characterized by:
Increased responsiveness of the bronchi
Contraction of airway smooth muscle
Mucosal thickening
Viscid plugs of mucus
General signs and symptoms
Mediators and cells involved in asthma
The most easily reversed pathology
& nedocromil Pathway Inhibitors
Leukotriene
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Asthma may be treated by different drugs.
Drugs that reduce the amount of IgE bound to mast cells Anti-IgE antibody Prevent mast cell degranulation
Cromolyn, Nedocromil Block the action of the products released
Inhibit acetylcholine released from vagus nerve Antihistamines & Muscarinic antagonists Relax smooth muscle Leukotriene antagonists
Sympathomimetics, Methylxanthines
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Sympathomimetic Agents
Xanthine drugs
Muscarinic antagonists
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Along with corticosteroids, are the most widely used drugs for asthma.
Most effective bronchodilators
Given by inhalation to avoid systemic effects
Increase cAMP in smooth muscle cells and decrease tone
They cause tachycardia and tremor
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Their continuous use may result in desensitization of adrenergic receptors that can be prevented or reversed by corticosteroids
In high doses these drugs can produce tachycardia, palpitations, and tremor
Immediately report: Difficulty breathing, palpitations, tremors, vomiting, nervousness, or vision changes Use carefully: Limited use in children < 6
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β2 selective drugs are classified into 4 class:
They are usually used with other drugs (eg: inhaled corticosteroids)
Bronchodilation is maximal within 15-30 min. and persists for 3-4 hr. All can be diluted in saline for administration from a nebulizer.
Relax bronchial smooth muscle and decrease microvascular permeability
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Contraindicated: MI or dysrhythmia, Breastfeeding
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Xanthine structure
Methylxanthines:
Theophylline (tea)
Caffeine (coffee)
Theobromine (cocoa)
Reduce the frequency of recurrent bronchospasm
They Inhibit phosphodiesterase (PDE) and increase cAMP.
Stimulate secretion of both gastric acid and digestive enzymes.
Even decaffeinated coffee has a potent stimulant effect on GI secretion.
Decrease blood viscosity and may improve blood flow.
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Most selective in its smooth muscle effects.
Not an ideal drug, but has a low cost.
Because of its clearance variability & its narrow safety index, its plasma concentration are to be monitored
Aminophylline is an injectable derivative of theophylline. Improves contractility and reverses fatigue of the diaphragm in COPD.
Due to its high risk/benefit ratio, it is used as an second line or additional therapy
Rifampicin, phenobarbital, phyenytoin, carbamazepine & cigraette smokers increase theophylline metabolism
Pentoxifylline is used for treating intermittent claudication in patients to reduce pain, cramping, numbness, or weakness in the arms or legs.
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Can diminish dyspnea even in patients with irreversible airflow obstruction.
Rate of metabolism: Children > adults > neonates and young infants
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Toxicity is dependent on plasma concentration
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Mild: nausea, vomiting, headache, insomnia, and nervousness Potentially serious: sinus tachycardia Severe: cardiac arrhythmias, seizures
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Caffeine has the most marked CNS effects.
Caffeine causes mild arousal with increased alertness and deferral of fatigue.
Very high doses cause convulsions and even death.
Caffeine has positive chronotropic and inotropic effects on the heart.
In very sensitive individuals, consumption of a few cups of coffee may result in arrhythmias.
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• Atropine • Ipratropium bromide • MOA Use: • Not as useful as ß2 agonist aerosols • Useful in copd
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Effective bronchodilator
Synthetic analog of atropine
Too many side effects
A weak bronchodilator
Not used today in treatment of asthma
Given by inhalation, has negligible systemic effects
Has a longer duration of action than adrenergic agonists.
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Used in COPD to decrease cholinergic tone
Used in asthma in combination with b-adrenergic agonists
Corticosteroids control mucus production and edema
Cromolyn controls mediator release
Leucotriene modulators antagonize mediator receptors or decrease their synthesis
for chronic use
Combination more effective & less toxic than either drug alone
Has no anti-inflammatory activity
Poorly absorbed & does not readily cross BBB
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Inhaled corticosteroids:
Oral corticosteroids for severe asthma:
Beclomethasone, Budesonide, Fflunisolide, Fluticasone
Prednisone, Prednisolone
Injected corticosteroids: Methylprednisolone, Dexamethasone
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Inhibition phospholipas A2
Anti-inflammatory
Inhibition of the lymphocytic, eosinophilic airway mucosal inflammation of asthmatic airways
Inhibition of production of inflammatory cytokines
Potentiating the effects of b-agonists
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Used in chronic asthma, lowers the frequency of acute episodes Are not bronchodilators & are not useful acute attacks May cause dysphonia and/or esophageal candidiasis Symbicort contains a combination of budesonide and formoterol. Advair Diskus contains Fluticasone and Salmeterol
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Oral (or injected) steroids are most effective drugs for asthma, unresponsive to bronchodilators and inhaled steroids.
Alternate-day use decreases adverse effects
Potential adverse effects: glucose intolerance, sodium and water retention, increased BP, peptic ulcer, osteoporosis, cataract, immunosuppression, ACTH-suppression
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Stabilizes mast cells & decreases airway responsiveness to spasmogens Useful for prophylaxis only Not effective in all patients More effective in children and adolescents than in older patients May take up to 4-6 weeks of its treatment to be effective in chronic asthma Has no bronchodilating activity Has virtually no toxicity
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Two types:
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A 4 weeks trial determines whether a patient will respond.
Cromolyn solution is also useful for allergic rhinoconjunctivitis.
Because the drugs are so poorly absorbed, adverse effects are minor and are.
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1. LT receptor (LTD4) antagonists: Montelukast , Zafirlukast
Less effective anti-inflammatory agents than corticosteroids
2. Inhibitors of LT synthesis: inhibit 5-lipoxygenase, prevent conversion of arachidonic acid to leukotrienes: Zileuton
Used orally, useful in children in chronic treatment of mild to moderate asthma
Generally well tolerated
Zileuton can elevate liver enzymes
Zileuton increase plasma concentrations of theophylline and warfarin because it inhibits cytochrome P450 enzymes in the liver.
Are not bronchodilators & not useful in acute episodes of asthma Reduce frequency of acute episodes
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Metered dose inhaler
Inhaler
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nebulizer
nebulizer
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