Pharmacology Ofrespiratory Drugs

7/30/2019 Pharmacology Ofrespiratory Drugs

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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- ModeratepH PaO2 PaCO2 HCO3- Severe* pH PaO2 PaCO2 HCO3- * Bewarethe following: Speechless patient PEFR 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 microvascularpermeabilty 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 AGONISTSPHARMACOLOGY of :-ADRENERGIC AGONISTSPHARMACOLOGY of Given by inhalation to avoid systemiceffects are most effective bronchodilators increase cyclic AMP in smooth muscle cells and

decrease tone Various drugs differ in their duration of action & receptor selectivity Short-

acting (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 ofexercise-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 :


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-ADRENERGIC AGONISTS, cont.PHARMACOLOGY of -adrenergic agonists have noanti-inflammatory activity. Their continuous use may result in desensitization of adrenergicreceptors 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 inrespiratory 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) :


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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, immuno-

suppression, 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 5-Lipoxyenase 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.

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Pharmacology Ofrespiratory Drugs