Lecture 25 - 3rd Asessment - Respiratory Drugs I & Ii

RESPIRATORY DRUGS Part 1

(NON-ASTHMA DRUGS)

a. Respiratory stimulants (analeptics) b. Respiratory depressant c. Cough suppressant (antitussives) d. Nasal decongestants

RESPIRATORY DRUGS (cont’d) Part 2

(ASTHMA DRUGS)

a. Bronchodilators b. Anti-inflammatory drugs c. Others

RESPIRATORY STIMULANTS (ANALEPTICS)  Stimulates respiration by increasing activity of carotid chemoreceptors (PO2) or respiratory centre (PCO2) or both  No longer in popular use. Only occasionally used, in ventilatory failure due to chronic obstructive disease, but not in ventilatory failure due to severe asthma or overdose of CNS depressants  Largely replaced by mechanical ventilation

RESPIRATORY STIMULANTS (ANALEPTICS)  Doxapram (main member used)  Stimulates both the carotid chemoreceptor and respiratory centre  Serious side effects restricts use (tremor, dizziness, convulsion, hypertension)

ANTITUSSIVES (COUGH SUPPRESSANTS)  Codeine (opiate with little addiction)  Dextromethorphan (non-opiate codeine analogue)  Indicated in painful, unproductive and intolerable cough (eg. bronchial carcinoma)  Suppress cough centre in CNS (diff. receptors)

ANTITUSSIVES (cont’d) (COUGH SUPPRESSANTS)  Advantages of Dextromethorphan over codeine a. No inhibition of ciliary activity b. of secretions c. No Noinhibition constipation d. No liability to addiction  Not used in cough of asthma and chronic bronchitis-sputum thickening/retention

NASAL DECONGESTANTS :Nasal Congestion • Results from oedema of nasal mucosa • Occurs mainly in - Flu (URTI) - Rhinitis (allergic or non-allergic)

RHINITIS (The inside story)

NASAL DECONGESTANTS Mechanisms of Action Vasoconstriction (α 1(receptor activation • .)e.g., phenylephrine(

Block of vascular permeability (anti-histamines • or H 1blockers); ))e.g., chlorpheniramine -Inhibition of release of mediators (by anti • allergic drugs) ))e.g., inhaled steroids Disadvantages of Nasal Decongestants • Tachyphylaxis • Rebound congestion

ASTHMA Inflammatory lung condition manifesting as • .recurrent reversible bronchoconstriction .May be extrinsic or intrinsic • .Major medical problem in Kuwait • (?Incidence on increase world-wide (pollution •

CONTROL OF AIRWAY CALIBRE

Bronchoconstriction Histamine Leukotrienes

Bronchodilation Adrenaline PGE2

Acetylcholine

EpDRF

PGD2

NO

Neuropeptides Adenosine Etc

CONTROL OF AIRWAY CALIBRE Bronchoconstriction

Bronchodilation



Ach ***



Catecholamines *** (adrenaline)



PGF2α PGD



NANC (VIP? NO?)



Substance P?



PGE2



Neurokinins?

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 Phase

Symptoms

Acute Attack Bronchoconstriction (phase I)

Mediator Extrinsic asthma Histamine (stored) Leukotrienes C4, D4, E4 Prostanoids (PGF2α, PGD) PAF Kinins Etc. Neuronal (reflex) Ach Neurokinin A Substance P Etc.

MEDIATORS OF ASTHMA (cont’d) Phase Delayed or chronic (phase II)

Symptoms

Mediator

Bronchoconstriction LTB4 PAF, Bronchial inflammation Interlukins Hyper-reactivity of (eg IL-2, IL-3, IL-5), bronchial tissues TNF, GM-CSF etc

CHARACTERISTICS OF ASTHMA  Bronchoconstriction  Bronchial hyper-reactivity  Blood and bronchial eosinophilia  Increase in mucus secretion  Bronchial inflammation (oedema & cell influx)  Dual phase

THE TWO PHASES OF ASTHMA AND THE EFFECT OF ANTIASTHMA DRUGS

Learning Objectives Understand the limited use and adverse effects .analeptics

the .1

List the advantages of dextromethorphan over .2 .codeine as an antitussive Describe, with examples, the various ways by which .3 .nasal decongestants may act, and the limitations in their use Understand how airway calibre is controlled .4 and whyβ.-blockers are contra-indicated in asthma Understand the pathophysiology of asthma and the .5 basis for the effects of drugs in the two phases of asthma

ANTI-ASTHMA DRUGS Bronchodilators Anti-inflammatory Agents Corticosteroids Anti-rheumatics Immunosupressors Others -

DSCG, Nedocromil, etc.

BRONCHODILATORS 4 Groups a.β 2( Agonists (eg. Salbutamol (b. Xanthine Derivatives (eg, Theophylline (c. Muscarinic receptor antagonists (Ipratropium d. Anti-Leukotriene Drugs • Cyst-LT receptor antagonists (eg, Zafirlukast) • LT synthesis inhibitors (eg, Zileutin)

BETA ADRENOCEPTOR AGONISTS Drugs

Receptor Specificity

ß 1,

ß2

Adrenaline Nor-adrenaline

α, +++ +++

+++ +

+++ +

-

+++ + + + + +

+++ +++ +++ +++ +++ +++

Isoprenaline Salbutamol Terbutaline Remiterol Fenoterol Salmeterol Longformoterol acting

Mechanism of Action ofβ 2-receptor agonists β 2-receptor G-protein Adenylate cyclase ATP

cAMP

AMP-’5

cAMP-dep protein kinase Myosin LC kinase

Myosin LC kinase-P

MUSCLE REAXATION

CLINICAL USE OF ß2 AGONISTS  Most widely used antiasthma drugs  Drug of choice for acute attack  Salbutamol and terbutaline most used  Given by inhalation, but also orally  Instant effect (lasts 3-5h; 12h for some)  Also used in chronic bronchitis

ADVERSE EFFECTS OF ß2 AGONISTS  Muscle tremor  ß1 -mediated tachycardia  May mask deterioration of asthma

XANTHINE DERIVATIVES  Theophylline (aminophylline)-prototype  Enprofylline  Proxifylline

Actions of Xanthine Derivatives  Bronchodilators  Stimulate heart & CNS (use is beverage)  Has anti-inflammatory effect Mechanisms of Action  Inhibition of phosphodiesterases?  Antagonism of adenosine receptors?  Release of adrenaline?

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

PDE Inhibitors

G-protein Adenylate cyclase ATP

cAMP

PDE

AMP-’5

cAMP-dep protein kinase Myosin LC kinase Myosin-P

Myosin LC kinase-P

Myosin MUSCLE REAXATION

MUSCLE CONTRACTION

CLINICAL USE OF XANTHINE DERIVATIVES IN ASTHMA

 Theophylline most widely used  Given orally or by slow I.V. infusion  Theophylline metabolized by liver, caution in liver disease, Enprofylline preferred  Caution in heart disease (stimulates heart)  Used in moderate to severe asthma  Narrow therapeutic range, blood level to be monitored

Adverse Effects of Theophylline  Nausea and vomiting (at therapeutic dose)  Anorexia  Tremor  Cardiac arrest (rapid I.V. injection)  Drug interaction  Nervousness  Seizure (children) • Enprofylline has less side effects-does not stimulate CNS

MUSCARINIC RECEPTOR ANTAGONISTS IN ASTHMA  Ipratropium bromide is mainly used  Blocks muscarinic receptors on bronchial smooth muscle to produce relaxation  More effective in reflex asthma  Often used in conjunction with other bronchodilators  Given by aerosol, not absorbed orally  Safe and well tolerated

LEUKOTRIENE ANTAGONISTS Cyst-LT receptor antagonists (Block Cyst.-LT receptor (common for LTC4, LTD4 and LTE4 • .Bronchodilating effect slightly less than for salbutamol • .Examples - zafirlukast, montelukast etc •

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 •

Anti-inflammatory Agents - Corticosteroids - Immunosupressors - Others

STEROIDS (GLUCOCORTICOIDS) IN ASTHMA  Powerful anti-inflammatory and immunosuppressive actions  Drugs of last resort in chronic asthma  No bronchodilator effect  Effect takes up to 6h to start

STEROIDS IN ASTHMA

 Members most frequently used are -

Beclomethasone (aerosol) Budesonide (aerosol) Prednisolone (systemic, oral) Hyrocortisone (systemic, IV)

Mechanism of Action of Steroids in Asthma  Inhibit the synthesis and/or release of inflammatory mediators  Induce synthesis and release of anti-inflammatory mediators. May blocks the ability of inflammatory cells to respond to chemotactic and other stimuli

Mechanism of action of Steroids Steroid

Steroid -receptor complex inhibition

GENE

induction

Cytokine s(IL-1, TNFa, IL-5, IL-4, GM-CSF)

Annexins (lipocortins)

Adhesion molecules (ICAM-1,VCAM-1)

PLA2

Enzymes (COX2, cPLA2, iNOS)

CLINICAL USE OF STEROIDS IN ASTHMA  Inhalation is preferred route of adm. (less side effects); oral in severe chronic asthma.  Often combined with bronchodilators  Given I.V. in acute severe asthma  Very useful as prophylaxis (first line drug)  Caution in children

ADVERSE EFFECTS OF STEROIDS Aerosol:  Oropharyngeal candidiasis  Dysphonia Systemic:  Adrenal insufficiency (if withdrawn rapidly)  Osteoporosis  Lowered resistance to infection  Cushing’s syndrome  Hyperglycemia

DISODIUM CROMOGLYCATE IN ASTHMA  Prophylactic anti-asthma drug  No bronchodilator effect  Affects all forms of asthma  More effective in children than adults  Drug of choice in children  Effective against both early & late phases

DISODIUM CROMOGLYCATE IN ASTHMA (cont’d)  Poorly absorbed, given by inhalation  Has some anti-inflammatory effect  May also act by inhibiting neuronal reflex and stabilization of mast cells  No side effects except cough by particle irritation

OTHER ANTI-ASTHMA DRUGS KETOTIFENHT antagonist. • Effect due mainly to anti-inflammatory action. • Effective orally. • Effect develops after 2-3 weeks NEDOCROMIL SODIUM • Similar to DSCG in many respects. METHOTHREXATE/CYCLOSPORIN-A MONOCLONAL ANTI-IGE (Omalizumab) OXYGEN

Learning Objectives Classify bronchodilators and describe the mechanism of .1 .action of each group Understand the central role of cAMP as second messenger .2 in bronchodilation by bothβ.2-agonists and PDE inhibitors -Describe the precautions, adverse effects and contra .3 .indications of theophylline in asthma Describe the mechanism of action of steroids and the .4 .adverse effects associated with its use in asthma .Understand the pharmacology of disodium cromoglycate .5 Appreciate the therapeutic options in steroid resistant .6 .asthma and in status asthmaticus

MECHANISM OF ACTION OF ß2 AGONISTS IN ASTHMA Activation of ß2 receptors on bronchial smooth muscles G-protein mediated activation of adenylyl cyclase Conversion of ATP to cAMP Activation of cAMP-dependent protein kinases Phosphorylation/inhibition of myosin light chain kinase Muscle relaxation (Similar mechanism on mast cells inhibit mediator release)