PHARMACOLOGY ofRESPIRATORY DRUGS :

PHARMACOLOGY ofRESPIRATORY DRUGS

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0 1 2 3 4 5 6 7 Alveolar Ventilation (Basal Rate = 1) Normal Range Control of Ventilation Arterial Act on Respiratory Center in CNS Act on Chemoreceptors in peripheral (large) arteries

Control of Bronchial Tone :

Control of Bronchial Tone Autonomic Innervation Adrenergic stimulation a: constriction, b: dilation Cholinergic (muscarinic): constriction Autocoids: released in asthmatic attack (Leukotrienes and Adenosine) produce bronchoconstriction increase vascular permeability in bronchi and cause mucosal edema

Drugs acting on Respiratory Center :

Drugs acting on Respiratory Center CNS Stimulants: xanthines(theophylline, caffeine), doxapram CNS depressents a. Opioids: decreases sensitivity of respiratory center to pCO2 b. Sedatives (Benzodiazepines, ethanol): small effect when used alone, severe depression when combined

ASTHMA :
ASTHMA Is characterized by bronchial hyper-reactivity and bronchospasm (reversible airway obstruction) in response to a variety of stimuli that do not affect normal individuals. The immediate reaction to allergens is followed by recurrence of symptoms 4-10 hours after allergen exposure, called late phase. Asthmatic patients also have airway inflammation involving mucosal edema, mucus production and increased vascular permeability.

Airway Basics :
Airway Basics

Airway Basics :
Acute Fatal Asthma Normal Chronic Severe Asthma Airway Basics

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Arterial Blood Gases in Acute ASTHMA Mild pH PaO2 PaCO2 HCO3- Moderate pH PaO2 PaCO2 HCO3- Severe* pH PaO2 PaCO2 HCO3- * Beware the following: Speechless patient PEFR <50% Resp Rate >25 Tachycardia >2 agonist)110 (pre

Treatment Goals :
Treatment Goals To reverse acute episodes To control recurrent episodes To reduce bronchial inflammation

Drugs Used in Asthma :

Drugs Used in Asthma These drugs effect the different aspects of the disease Bronchodilators Beta-adrenergic agonists relax brochial smooth muscle and decrease microvascular permeabilty Muscarinic antagonists inhibit the effects of endenous ACh Theophylline reduce the frequency of recurrent bronchospasm

Drugs Used in Asthma (cont.) :

Drugs Used in Asthma (cont.) Non-bronchodilators (for chronic use) Corticosteroids control mucus production and edema Cromolyn controls mediator release Leucotriene modulators antagonize mediator receptors or decrease their synthesis

-ADRENERGIC AGONISTS PHARMACOLOGY of :

-ADRENERGIC AGONISTSPHARMACOLOGY of Given by inhalation to avoid systemic effects are most effective bronchodilators increase cyclic AMP in smooth muscle cells and decrease tone Various drugs differ in their duration of action & receptor selectivity Shortacting (3-6 hr) & b2 selective Albuterol (Proventil, Ventolin) Short acting & non-selective: Isoproterenol Long-acting (>12 hr) & b2 selective Salmeterol (Serevent)

-ADRENERGIC AGONISTS, cont. PHARMACOLOGY of :

-ADRENERGIC AGONISTS, cont.PHARMACOLOGY of Useful in prevention of exercise-induced asthma. Albuterol like drugs are useful in acute episodes of asthma Prolonged acting Salmeterol used in maintenance treatment (prevent nocturnal attacks of asthma) Salmeterol has a slow onset of action & is not recommended for acute episodes of asthma.

-ADRENERGIC AGONISTS, cont. PHARMACOLOGY of :

-ADRENERGIC AGONISTS, cont.PHARMACOLOGY of -adrenergic agonists have no anti-inflammatory activity. 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

PHARMACOLOGY of IPRATROPIUM (Atrovent) :

PHARMACOLOGY of IPRATROPIUM (Atrovent) a muscarinic receptor antagonist (a synthetic analog of atropine) is a weak bronchodilator given by inhalation, has negligible systemic effects has a longer duration of action than adrenergic agonists. Used in COPD to decrease cholinergic tone Used in asthma in combination with b-adrenergic agonists Combination more effective & less toxic than either drug alone Has no anti-inflammatory activity

PHARMACOLOGY of METHYLXANTHINESTheophylline (Theo-Dur) :

PHARMACOLOGY of METHYLXANTHINESTheophylline (Theo-Dur) stimulate respiratory center (CNS), increases sensitivity of respiratory center to pCO2 relaxes smooth muscles of the bronchi, especially if bronchi has been constricted by a spasmogen as in asthma. ineffective by aerosol, must be given orally less effective bronchodilator & has slower onset of action than inhaled b2-adren. agonists proposed mechanisms: adenosine receptor blockade; phosphodiesterase inhibition in high concentration Used in chronic asthma

PHARMACOLOGY of METHYLXANTHINESTheophylline, cont. :

PHARMACOLOGY of METHYLXANTHINESTheophylline, cont. because of its clearance variability (in patients) & its narrow safety index (10-20 ug/ml), its plasma concentration are to be monitored Due to its high risk/benefit ratio, it is used as an second line or additional therapy Clearance is influenced by smoking, and other drugs metabolized by liver. Toxicity is dependent on plasma concentration Mild (30 mg/L): nausea, vomiting, headache, insomnia, and nervousness Potentially serious (40 mg/L): sinus tachycardia Severe (45 mg/L): cardiac arrhythmias, seizures

) INHALED CORTICOSTEROIDSFluticasone (Flovent :

)INHALED CORTICOSTEROIDSFluticasone (Flovent decrease inflammation & edema in respiratory tract inhibit phospholipase A2 through synthesis of lipocortin, block release of arachidonic acid and its metabolites (leukotrienes) also inhibit production pro-inflammatory cytokines 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

SYSTEMIC CORTICOSTEROIDS (Prednisone) :

SYSTEMIC CORTICOSTEROIDS (Prednisone) Oral (or injected) steroids are most effective drugs for asthma, unresponsive to bronchodilators and inhaled steroids. After recovery from severe exacerbation, oral corticosteroids are continued for 8 to 10 days Alternate-day use decreases adverse effects Potential adverse effects: glucose intolerance, sodium and water retention, increased BP, peptic ulcer, osteoporosis, cataract, immunosuppression, ACTH-suppression

CROMOLYN SODIUM (Intal) :

CROMOLYN SODIUM (Intal) 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

Leukotriene Modulators :
Leukotriene Modulators Two types: 1. LT receptor (LTD4) antagonists: Montelukast (Singulair, Zafirlukast) 2. Inhibitors of LT synthesis: inhibit 5-lipoxygenase, prevent conversion of arachidonic acid to leukotrienes: Zileuton (Zyflo) Are not bronchodilators & not useful in acute episodes of asthma Reduce frequency of acute episodes

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Phospholipid (from cell membrane) Corticosteroids Phospholipase A2 - Arachidonic acid 5Lipoxyenase Leukotrienes Cyclooxygenase PGH2 PGE2 Prostacyclin (PGI2)PGF2

Leukotriene Modulators (contd) :

Leukotriene Modulators (contd) Less effective antiinflammatory agents than corticosteroids Used orally, useful in children in chronic treatment of mid 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.

Anti-IgE :
Anti-IgE Recombinant humanized monoclonal antibody to treat persons over 12 years with moderate to severe asthma Omalizumab - Xolair Inhibits binding of IgE to receptors on mast cells and basophils Prevents the release of mediators of allergic response that cause bronchospasm Given subcutaneously q 2-4 weeks, very expensive but effective in reducing hospital visits and steroid use.