Lecture 26 - 3rd Asessment - Respiratory Drugs Additional

Drugs Affecting the Respiratory System Non-Asthma Drugs: • Cough Suppressants (antitussives) • Nasal Decongestants Asthma Drugs: • Bronchodilators • Anti-inflammatory drugs • Others

COUGH SUPPRESSANTS (ANTITUSSIVES) • Codeine (narcotic with little addicting property) • Dextromethorphan (non-addicting narcotic derivative) I. Indicated in painful, unproductive and intolerable cough (e.g., bronchial carcinoma). II. Suppresses cough Centre in CNS.

Advantages of Dextromethorphan over codeine • No inhibition of ciliary activity and bronchial secretions. • No constipation • No liability to addiction

NASAL DECONGESTANTS • Alpha-1 agonists (e.g., phenylephrine). • Anti-histamines (e.g., chlorpheniramine) Mechanisms of Action • Vasoconstriction (α1 receptor activation) • Block of vascular permeability (H1 antagonism). Disadvantages of Nasal Decongestants • Tachyphylaxis • Rebound congestion

ASTHMA • Inflammatory lung disease characterised by reversible bronchoconstriction, wheezing and difficulty in breathing (dyspnoea). • May be intrinsic or extrinsic • Major medical problem in Kuwait • Incidence is increasing world-wide (pollution?).

ANTIGEN-INDUCED DEGRANULATION OF MAST CELL AND THE RELEASE OF ALLERGIC MEDIATORS allergen IgE antibody Mast cell

Mediator release -histamine -PAF -leukotrienes -PGD2 Degranulating mast cell

FcєRI

Mast Cell

MEDIATORS OF ASTHMA Acute asthma Symptom:Bronchoconstriction Mediators: Histamine, Leukotrienes (C4& D4), etc. Chronic Asthma Symptoms: Bronchoconstriction, inflammation, hyperreactivity. Mediators: Cytokines (eg, LTB4, IL-5, TNFα, GM-CSF).

BRONCHODILATORS There are 4 main Groups • β-2 Receptor Agonists (eg, salbutamol) • Xanthine Derivatives (eg, theophylline) • Muscarinic receptor antagonists (eg, ipratropium) • Anti-leukotriene drugs

MECHANISM OF ACTION OF β 2 AGONISTS 1. Activation of β2 receptors on br. smooth muscles 2. Activation of adenylate cyclase 3. Adenylate cyclase converts ATP to cAMP 4. Activation of cAMP-dependent protein kinase 5. Phosphorylation and inhibition of myosin light-chain kinase 6. Muscle Relaxation

Mechanism of Action ofβ 2-agonists and PDE Inhibitors β 2-receptor

PDE Inhibitors

G-protein Adenylate cyclase ATP

cAMP

PDE

cAMP-dep protein kinase Myosin LC kinase-P MUSCLE REAXATION

AMP-’5

CLINICAL USE OF β2 AGONISTS • Most widely-used anti-asthma drugs • Drugs of choice in acute asthma attack • Salbutamol and Terbutaline most widely used • Given by inhalation, but also orally. • Effect starts instantly, lasts 3-5 h (12h for some) • Also used in chronic bronchitis Adverse Effects: • Skeletal muscle tremor • β1-mediated tachycardia at high dose • May mask asthma deterioration

XANTHINE DERIVATIVES • Theophylline (aminophylline) mainly used. • Relax bronchial smooth muscles • Have some anti-inflammatory effects Mechanism of action: • Inhibition of phosphodiesterase enzymes Adverse Effects: • Nausea, nervousness, tremor & seizure • Rapid i.v injection contraindicated

MUSCARINIC RECEPTOR ANTAGONISTS • Ipratropium bromide mainly used

• Blocks muscarinic receptors on bronchial smooth muscles to produce relaxation. • More effective in reflex asthma • Often used in conjunction with other bronchodilators. • Given only by aerosol (not absorbed orally) • Safe and well tolerated

ANTI-LEUKOTRIENE DRUGS Leukotriene synthesis inhibitors • Inhibits enzymes 5-LO or FLAP in LT synthesis • Affects synthesis of Cyst-LT and LTB4 • Have both bronchodilating and anti-inflammatory effects. • Example - Zileutin

Cyst-LT receptor antagonists (Block Cyst.-LT receptor (common for LTC4 and LTD4 • .Bronchodilating effect slightly less than for salbutamol • ,Example - zafirlukast •

STEROIDS IN ASTHMA • Powerful anti-inflammatory effect • Drugs of last resort in asthma • No bronchodilator effect • Effect takes 6h to start • Members include: - Budesonide (aerosol) - Prednisolone (systemic, oral) - Hydrocortisone (systemic, i.v. injection) • Mechanism of action: - Inhibits synthesis and release of mediators - Inhibits migration of inflammatory cells

CLINICAL USE OF STEROIDS IN ASTHMA • Inhalational route preferred (less side effects) • Often combined with bronchodilators • Given I.V. in acute severe asthma • First line drug in asthma prophylaxis • Caution in children Adverse Effects: Aerosol : Oropharyngeal candidiasis, dysphonia Systemic: Adrenal insufficiency, osteoporosis, Low resistance to infection, Cushing’s syndrome, Hyperglycemia.

DISODIUM CROMOGLYCATE • Good prophylactic anti-asthma drug • No bronchodilator effect • Affects all forms of asthma • More effective in children • Given only by inhalation (not absorbed orally) •Has some anti-inflammatory effects • Mechanism of action: - stabilizes mast cells to prevent mediator release. May also inhibit neuronal reflex. • No side effects, only cough from particle irritation

Drugs Affecting the Respiratory System Objectives:

• To be able to classify the drugs used to treat cough, and nasal congestion, their mechanisms of action, if known, and the problems or disadvantages of their use. • To be able to classify the drugs used to treat asthma and describe their mechanisms of action. • To understand how anti-asthma drugs are used clinically, and describe their main adverse effects