ANTIASTHMATICS

Asthma Recurrent bouts of shortness of breath, chest tightness and wheezing often associated with coughing. Reversible narrowing of the bronchial airways Marked increase in bronchial responsiveness to inhaled stimuli Mast cell activation by allergens and physical stimuli releases bronchoconstriction mediators such as histamine, leukotriene D 4 which cause bronchoconstriction, micro vascular leakage and plasma exudation.

Most effective treatment for asthma is identifying triggers & limiting/eliminating exposure to them Such as o Pets o Aspirin If trigger avoidance is insufficient, medical treatment is available

Pathogenesis  Contraction of airway smooth muscle  Inspissation of viscid mucus plugs in the airway lumen  Thickening of the bronchial mucosa from edema, cellular infiltration and hyperplasia of secretory, vascular and smooth muscle cells.  IgE antibodies are involved  Histamines, tryptase, leukotrienes C 4 and D 4.

CLASSIFICATION

1- BRONCHODILATORS: a- Sympathomimetics: i.  &  adrenoceptor Agonists:  Adrenaline  Ephedrine ii.  - adrenoceptor Agonists:  Isoprenaline  Orciprenaline iii.  2 - adrenoceptor Agonists:  Albuterol (Salbutamol)  Terbutaline

 Metaproterenol  Pirbuterol  Salmeterol  Formoterol b- Methylxanthines:  Aminophylline  Theophylline  Theobromine  caffeine c- Muscarinic Antagonists: Ipratropium Bromide

II. CORTICOSTEROIDS:  Hydrocortisone Sodium Succinate  Methyl Prednisolone  Betamethasone  Beclomethasone  Budesonide  Ciclesonide  Fluticasone  Flunisolide  Mometasone  Triamcinolone

III. MAST CELL STABILIZERS:  Na Cromoglycate (Cromolyn)  Nedocromil  Ketotifen (H1 Blocker)

IV.LEUKOTRIENE PATHWAY INHIBITORS: a- Leukotriene Receptor Antagonist:  Montelukast  Zafirlukast b- 5-lipooxygenase inhihitor (synthesis inhibitor} Zileuton V- NEWER APPROACHES:  Anti IgE monoclonal antibodies: Omalizumab  Calcium channel blockers: Verapamil Nifedipine

Forms of treatment include:  Desensitization – currently the only known "cure" to the disease  Relief medication  Preventive medication  Long-acting β2-agonists  Emergency treatment Desensitization is a method to reduce/eliminate an organism's negative reaction to a substance or stimulus

BRONCHODILATORS

Bronchodilator is a substance that dilates bronchi & bronchioles increasing airflow They may be:  Short-acting: Provide quick or "rescue" relief from acute bronchoconstriction eg; o Anticholinergics o β 2 -agonists  Long-acting: Control/prevent symptoms eg; o β 2 -agonists o Theophylline

β 2 -AGONISTS: Mechanism Of Action:  2 receptors in airway smooth muscles  Stimulate adenylyl cyclase   cAMP in airway tissue  Relaxation of smooth muscle  Bronchodilation

o Mediator release – prevented o Microvascular leakage is prevented o  Mucociliary transport

 Short-acting β 2- agonists:  Quick-relief or "rescue" medications  Provide fast, temporary relief from symptoms/flare-ups  Usually take effect within 20 minutes or less  Effect last from 4 – 6 hours  Inhaled medications are best for treating Sudden Severe

Taken 15 – 20 minutes ahead of time – can also prevent asthma symptoms triggered by exercise/exposure to cold air Drugs include: o Salbutamol/albuterol o Levalbuterol o Terbutaline o Pirbuterol o Procaterol o Metaproterenol o Fenoterol o Bitolterol mesylate

 Long-acting β 2 -agonists:  Long-term medications taken routinely  Control/prevent bronchoconstriction  Not intended for fast relief  Take longer to begin working  Particularly effective at night  Relieve airway constriction for up to 12 hours

Adverse effects: o Increased heart rate. o Hyperactivity o Feeling nervous/shaky/over-excited o Upset stomach o Difficulty in sleeping

Drugs include: o Salmeterol o Formoterol o Bambuterol o Clenbuterol

SALBUTAMOL

 Salbutamol sulfate /albuterol – is a short-acting β2- adrenergic receptor agonist Used for relief of bronchospasm in o Asthma o COPD Given by  Inhaled route – direct effect on bronchial smooth muscles Through o MDI o Nebuliser

Maximal effect – take place within 5 – 20 minutes of dosing Some relief is immediately seen  Orally  Intravenously  Metabolism: Hepatic  T1/2: 1.6 hrs  Excretion: Renal

 CLINICAL USES: 1)Acute asthma 2)Maintenance therapy of asthma 3)COPD 4)Protection against exercise-induced asthma 5)Hyperkalaemia eg; renal failure 6)Aerosolized with a nebulizer in cystic fibrosis along with ipratropium bromide

7) Intravenously as tocolytic – relax uterine smooth muscle – delay premature labour  ADVERSE EFFECTS: Well-tolerated when compared with theophylline Common adverse effects: o Tremors o Palpitations o Low BP o Headache

Infrequent adverse effects: o Muscle cramps o Agitation o Hypokalaemia o Tinnitus o Hyperactivity in children o Insomnia

SALMETEROL & FORMOTEROL Long acting Dose: o Inhalation MDI – 12 hrs Bronchodilatation – maximum by 30 Min

METHYL XANTHINES

o Theophylline o Theobromine o Caffeine

THEOPHYLLINE

MECHANISM OF ACTION  Phosphodiestrase Inhibition  Increased intracellular cAMP  Smooth muscle relaxation Decreases Histamine release

 Adenosine cell surface receptors Inhibition  Decreased mediator release  Bronchodilatation

PHARMACOKINETICS Orally – Well absorbed from GIT Rectal suppositories – absorption is unreliable Types of preparations: o Microcrystalline – Complete & rapid absorption o Sustained Release – Therapeutic levels for 12 hrs

Long-acting bronchodilator – prevents asthma episodes Available in oral/injectable form Prescribed in o Severe cases of asthma o Difficult to control asthma Blood tests are required to o Monitor therapy o Dosage adjustment

Pharmacodynamics of Methylxanthines CNS effects (mild cortical arousal to nervousness and insomnia) Cardiovascular effects ( positive chronotropic and inotropic effects, inhibition of presynaptic adenosine receptors in sympathetic nerves increasing catecholamine release)

GIT stimulate secretion of both gastric acid and digestive enzymes. Renal system Mild diuretics Effects on Skeletal Muscle strengthen the contractions of isolated skeletal muscle. Improve contractility and reverse fatigue of the diaphragm in COPD.

 Adverse effects 1) Nausea 2) Vomiting 3) Anorexia 4) Gastritis 5) Headache 6) Rapid/irregular heart beat 7) Muscle cramps 8) Hyperactivity 9) Promotes GERD – relaxing lower esophageal sphincter muscle

ANTICHOLINERGICS

Ipratropium bromide Tiotropium bromide

IPRATROPIUM BROMIDE Quaternary ammonium derivative of atropine

 Relief/rescue medication  Relieves acute asthma  Often paired with a short-acting β2-agonist  Only available as an inhalant

MECHANISM OF ACTION: o Blocks muscarinic receptors in lung o Inhibits bronchoconstriction & mucus secretion o Does not diffuse into the blood – prevents systemic side effects o Does not cross BBB – prevents central side effects

 CLINICAL USES:  Asthma Inhaled  2 agonists Intolerance Acute severe asthma  COPD

Side-effects: o Dry throat – most common o Blurred vision – gets in contact with eyes Onset of action: o minutes Duration of action: o Several hours Excretion: o Kidneys o Bile

TIOTROPIUM

Long-acting – 24 hour Used in o Bronchial asthma o COPD

 Mode of delivery Capsule from the blister pack – manually pierced – places it into piercing chamber of inhalation – medication is inhaled through mouthpiece Repeated x to ensure all medication is drawn from capsule Bioavailability: 19.5% Metabolism: Hepatic 25% Half life: 5–6 days Excretion: Renal

CORTICOSTEROIDS

Cortisone

Dexamethasone

 Mechanism of action: Inhibit multiple cell types involved in asthmatic response e.g. o Mast cells o Eosinophils o Basophils o Lymphocytes o Macrophages o Neutrophils

Mediate secretion of o Histamine o Eicosanoids o Leukotrienes o Cytokines Action on cells requires several days – used for preventive and maintenance therapy  Bronchial Hyper-reactivity  air way caliber  asthmatic attacks

FLUTICASONE

 Synthetic corticosteroid  Bioavailability: 0.51% (Intranasal)  Protein binding: 91%  Metabolism: Hepatic  Half life: 10 hours  Excretion: Renal

Routes: o Intranasal o Inhaled o Topical Cream/Ointment

 Clinical Use :- Asthma o Oral/Parenteral – only given as urgent treatment o Mild disease aerosol is used  Adverse effects : o Osteoporosis o Growth retardation o Oral candidiasis o Cataract o Immunosuppression o Hyperglycemia - "steroid diabetes“

o Increased skin fragility o Easy bruising o Weight gain o Adrenal insufficiency o Proteolysis o Cushing's syndrome

MAST CELL STABILIZERS

o Disodium cromoglycate (Cromolyn sodium) o Nedocromil

Mechanism of action Alteration in function of delayed chloride channels in cell membrane inhibiting cell activation. Inhibition of cough On mast cells to inhibit early response to an antigen challenge Eosinophils inhibition of the inflammatory response to inhalation of allergens.

SODIUM CROMOGLICATE / CROMOLYN

Cromoglicate

 Clinical Uses: Allergic Rhinitis – Nasal spray Asthma – Inhaler o Exercise induced o Aspirin induced o Industrial agents Allergic conjunctivitis – Eye drops

Oral form – o Mastocytosis o Dermatographic urticaria o Ulcerative colitis o Food allergies Effective only when given via inhalation Poorly absorbed from GIT

 Adverse effects: Minimal – at the site of deposition 1) Throat irritation 2) Dry mouth 3) Cough 4) Chest tightness 5) Wheezing Rare: 1) Dermatitis 2) Myositis 3) Gastroenteritis

NEDOCROMIL SODIUM

Nedocromil

Not given below 12 years Prophylaxis of Br. Asthma due to: o Exercise o Aspirin o Occupational allergens – wood dust o Other unavoidable allergens Allergic rhinitis Hay fever Systemic Mastocytosis

LEUKOTRINE PATHWAY INHIBITORS

Montelukast Zafirlukast Zileuton

SYNTHESIS 5- Lipooxygenase  Arachidonic acid → Leukotrienes Synthesized from o Eosinophils o Mast cells o Macrophages o Basophils

 Effects: LTB4 – powerful neutrophil chemoattractant LTC4 & LTD4 – o Bronchoconstriction o ↑ bronchial activity o Mucous hypersecretion → Mucosal oedema

 2 main approaches to block actions of leukotrienes 1- Inhibition of 5-lipoxygenase pathway: o Zileuton – Block 5-lipoxygenase → inhibiting synthetic pathway of LT metabolism 2- Antagonism of cysteinyl-leukotriene type 1 receptors: o Montelukast o Zafirlukast – Block actions of cysteinyl leukotrienes at CysLT1 receptor on target cells such as bronchial smooth muscle

 Clinical Effects: Improve asthma symptoms  asthma exacerbations Limit markers of inflammation such as eosinophil counts in o Peripheral blood o Bronchoalveolar lavage fluid

MONTELUKAST

Leukotriene receptor antagonist (LTRA) Used for o Maintenance treatment of asthma o Relieve symptoms of seasonal allergies Not useful for treatment of acute asthma attacks Blocks action of LTD4 on CysLT1 in lungs/bronchial tubes by binding to it Does not interact with other asthma medications such as theophylline

Administered orally o Oral tablets o Chewable tablets o Oral granules Side effects: o GI disturbances o Hypersensitivity reactions o Sleep disorders o ↑ bleeding tendency

Bioavailability: 63% - 73% Protein binding: 99% Metabolism: Hepatic Half life: hours Excretion: Biliary

ZAFIRLUKAST

Oral LTRA Maintenance treatment of asthma Used in conjunction with an inhaled steroid / long-acting bronchodilator Available as a tablet – Usually dosed twice daily

Bioavailability: Unknown Protein binding: 99% Metabolism: Hepatic Half life: 10 hours Excretion: Biliary

ZILEUTON

Inhibits 5-lipoxygenase – an enzyme of eicosanoid synthesis pathway Bioavailability: Not yet established Protein binding: 93% Metabolism: Hepatic Half life: 2.5 hours Excretion: Renal Least prescribed due to liver toxicity

OMALIZUMAB

Recombinant DNA – derived monoclonal antibody Selectively binds to IgE →  binding to IgE receptors on surface of mast cells/basophils → inhibit degranulation High cost Useful in o Moderate – severe asthma not responding to conventional therapy