Drugs used in and COPD

Objective : 1. Different types of drugs used for treatment of asthma 2. Differentiate between treatment and prophylactic therapy for asthma 3. Recognize the different types of regarding pharmacokinetics, pharmacodynamics, uses and side effects. 4. Identify the different anti-inflammatory drugs for asthma in respect to kinetics, dynamics, uses and side effects. § Addional Notes § Important § Explanaon –Extra-

For any correcon, suggeson or any useful informaon do not hesitate to contact us: [email protected] Bronchial Asthma

It is a chronic inflammatory disorder of bronchial airways that result in airway obstruction in response to external stimuli (as pollen grains, cold air and tobacco smoke).

• Asthma produces recurrent episodic attack of : Acute , Shortness of breath, Chest tightness, Wheezing, Rapid , Cough. Symptoms • Symptoms can happen each time the airways are irritated by inhaled irritants or allergens.

• Infection, Stress, Exercise (cold air), Pets, Seasonal changes, Emotional conditions, Some drugs as aspirin, β- blockers. Causes

• Airway hyper-reactivity: abnormal sensitivity of the airways to any external stimuli. • Inflammation:↑ edema, swelling +↑ Thick production. Characters • Bronchospasm (constriction of the bronchial smooth muscles). of airways

Irritant receptors in upper airways. We want to enhance the Afferent nerves sympathetic or (sensory) inhibit the C-fiber receptors in lower airways. parasympathetic in this case. Airways Innervations Parasympathetic supply M3 receptors in smooth muscles and glands: Bronchoconstriction and Increase mucus secretion. Efferent nerves (motor nerves) No sympathetic supply but β2 receptors in smooth Afferent nerves (sensory) are stimulated by: muscles and glands: Bronchodilatation, Decrease mucus

- Exogenous chemicals or irritants secretion. - Physical stimuli (cold air) - Endogenous inflammatory mediators e.g. histamine Anti-Asthmatic drugs

of 2 ATP cAMP β 3,5,AMP Adenyl cyclase cyclase frequency agonists. 2 Phosphodiesterase

β ). i.v. ( Bronchodilatation. Bronchodilatation. →

agonists (Increase) agonists (Increase) - asthmaticus Bronchodilaon β cAMP

↑

⎯→ Methylxanthines (inhibit)

which prevents contraction and cause Bronchodilatation. and cause Bronchodilatation. contraction which prevents Bronchodilators used to rapid relieve acute episodic episodic acute relieve rapid to used Bronchodilators

Anti-inflammatory drugs used to reduce the drugs used to reduce Anti-inflammatory stimulate adenyl cyclase stimulate adenyl ⎯→ (this substance has effects like coffee and tea “caffeine “) “) and tea “caffeine coffee like effects has (this substance

______-Given as prophylactic medications, used alone or combined with medications, used -Given as prophylactic -Systemic corticosteroids are reserved for: Status reserved are -Systemic corticosteroids stimulation 2-agonists 2-agonists 2

ß2-agonists β β reduce inflammation of airways reduce the spasm of airways reduce bronchial hyper-reactivity. hyper-reactivity. bronchial

Direct Direct ciliary activity). by (increasing mucus clearance Increase mast cell membrane. Stabilization of ↓ ↓ ↓

- - - Mechanism of Action: of Action: Mechanism Long acting Leukotriene's antagonists Leukotriene's antagonists Anti-IgE monoclonal antibody Mast cell stabilizers. Corticosteroids: Corticosteroids: Anti-muscarinic Anti-muscarinic preparations Xanthine Short acting acting Short agonists three times/week , symptomatic three times/ week or more; or waking one night/week. times/ week or more; three times/week , symptomatic agonists three

When cAMP increase in the cell.. Ca+ levels decrease the cell.. Ca+ levels decrease in When cAMP increase

• • What do they do ? • • • : using inhaled with any of the following features children for adults, should be considered Inhaled steroids -Effective in allergic, exercise, antigen and irritant-induced asthma. exercise, in allergic, -Effective • • •

attacks, and nocturnal awakenings (attacks at night). 2. Control therapy (prophylactic drugs): therapy (prophylactic 2. Control

attacks of asthma. of attacks 1. Quick relief medications (Bronchodilators): (Bronchodilators): medications relief Quick 1. Bronchodilators These drugs can produce rapid relief of bronchoconstriction - β2 adrenoreceptor –agonists (Sympathomimetics)

Classification Non selective β agonists Selective β2 – agonists (Preferable) Salbutamol of β agonists epinephrine isoprenaline Terbutaline Salmeterol Formeterol (albuterol) -combined with inhaled corticosteroids to control asthma. Potent - (decreases the number and severity of asthma attacks). - Rapid action (maximum effect within 15 Short acting ß2 agonists Long acting ß2 agonists min) – different than onset of action - Have rapid onset of action Duration of 12 hours Bronchodilators due to where it works in 5 minutes - (15-30 min). action high lipid solubility (creates depot - Has short duration of action (60-90 min) - short duration of action (4-6 effect). – because it’s natural - hr) , Inhalation, Inhalation Administration Given subcutaneously, S.C. orally, s.c. orally, i.v. -is the preferable way in asthma-.

- not used to relieve acute episodes of asthma –because the onset of Drug of choice for acute anaphylaxis used for acute episodic attack Uses action is delayed - (hypersensitivity reactions). of asthma (drugs of choice). الربو) used for nocturnal asthma - .(drugs of choice) ( الليلي Non selective = many side effects - Not effective orally - will be broken -Skeletal muscle tremors. down by COMT and MAO. - Nervousness Dis- - Hyperglycemia, Skeletal muscle tremor. - Tolerance (β-receptors down regulation) – decrease number of advantages CVS side effects: tachycardia, arrhythmia, receptors à No response - hypertension. - Overdose may produce tachycardia due to β stimulation . - Not suitable for asthmatic patients with 1 hypertension or heart failure. Contra- CVS patients, diabetic patients - indications Minimal CVS side effects and suitable for asthmatic patients with CV Advantages - disorders as hypertension or heart failure. Bronchodilators Con. Anti-muscarinics Xanthine preparations (Methylxanthines) - Are phosphodesterase inhibitor → increases cAMP → (Muscarinic antagonists) Bronchodilatation. –this is the main mechanism- Mechanism of Act by blocking muscarinic receptors - Universal Adenosine receptors (A1) antagonists → prevent Action (Inhibit bronchoconstriction and mucus bronchoconstriction. secretion) - Increase diaphragmatic contraction. - Stabilization of mast cell membrane. Classification of β agonists Ipratropium Tiotropium Theophylline aminophylline

Administration given by aerosol inhalation à local given orally . is given as slow infusion .

-Main choice in chronic obstructive pulmonary diseases (COPD). Second line drug in asthma. For status asthmatics -it is not used in Saudi Arabia and (aminophylline, is given as Uses -In acute severe asthma combined with β it’s very cheap-. slow infusion). 2 agonists & corticosteroids. -metabolized by Cyt P450 enzymes in liver -has short -T ½= 8 hours Pharmaco- duration of kinetics & -has longer -has many drug interactions. action 3-5 hr duration of action -Enzyme inducers: as phenobarbitone and rifampicin → ↑metabolism of Duration of (Have delayed (24 h) theophylline → ↓ ½T . action onset of action) Enzyme inhibitors: as erythromycin→ ↓ metabolism of theophylline → ↑½T. Quaternary derivatives of atropine - Bronchial muscle relaxation (polar) -↑contraction of diaphragm → improve ventilation CVS: ↑ heart rate, ↑ force of contraction Pharmacological -Does not diffuse into the blood GIT: ↑ gastric acid secretions Effects & -Do not enter CNS Kidney: ↑renal blood flow, weak diuretic action characterized by β -Less effective than 2-agonists. CNS stimulation: -No anti-inflammatory action only - stimulant effect on . bronchodilator - decrease fatigue & elevate mood. -Low therapeutic index (narrow safety margin) monitoring of theophylline blood level is necessary. They have slow onset of action - β2 -CVS effects: hypotension- may lead to reflex tachycardia-, Disadvantages blockers are better arrhythmia. -GIT effects: nausea & vomiting -CNS side effects: tremors, nervousness, insomnia, convulsion Advantages Have minimal systemic side effects - Mast cell Leukotriene's Anti-IgE monoclonal stabilizers antagonists antibody Corticosteroids zafirlukast Cromoglycate montelukast Omalizumab Nedocromil pranlukast - Inhibition of phospholipase A2 - Not bronchodilators -↓ prostaglandin and - Not effective in acute Leukotriene B4: chemotaxis leukotrienes attack of asthma. of neutrophils. Any drug ends with -↓ Number of inflammatory - Prophylactic anti- suffix (-mab) means cells in airways. inflammatory drug Cysteinyl leukotrienes C4, that it deals with Me- -Mast cell stabilization →↓ - Reduce bronchial hyper- D4 & E4: antibodies.. So it’s a chanism histamine release. reactivity. - Bronchoconstriction protein, and it can’t be of Action -↓ capillary permeability and - Effective in exercise, - increase bronchial hyper- taken orally because mucosal edema. antigen and irritant-induced reactivity proteins will be broken -Inhibition of antigen-antibody asthma. - ↑ mucosal edema. by stomach gastric. reaction. - Children respond better ↑ β - mucus secretion. Upregulate 2 receptors (have than adults additive effect to B2 agonists). (Pharmacodynamics) -Anti-inflammatory actions, Immunosuppressant effects, Metabolic effects, Hyperglycemia. -are selective, reversible antagonists of cysteinyl -↑ protein catabolism, ↓ protein -is a monoclonal leuko Taken orallytriene anabolism antibody directed receptors (CysLT receptors). -Stimulation of lipolysis - fat 1 against human IgE -Are bronchodilators Pharm- redistribution -prevents IgE binding acolo- Mineralocorticoid effects: -Have anti-inflammatory - with its receptors on gical -sodium/fluid retention, Increase action mast cells & actions potassium excretion (hypokalemia), -Less effective than inhaled basophiles. Increase blood volume corticosteroids -↓ release of allergic (hypertension), Behavioral -Have glucocorticoids changes: depression, Bone loss mediators. sparing effect (potentiate (osteoporosis) due to Inhibit bone formation, ↓ calcium absorption corticosteroid actions). from GIT. Inhalation: e.g. Budesonide & Fluticasone, - given by inhalation beclometasone Adminis (aerosol, nebulizer). given by injection -Given by inhalation (metered-dose - tration - Have poor oral (s.c.) inhaler). absorption (10%) - Have first pass metabolism -Best choice in asthma, less Orally: Prednisone, methyl side prednisolone - - - effects Injection: Hydrocortisone,

dexamethasone -Have delayed onset of action (effect Duration usually attained after 2-4 weeks). - - - of action -Maximum action at 9-12 months. -Treatment of inflammatory disorders -Not effective in acute attack of asthma. -Prophylactic therapy -used for treatment of (asthma, rheumatoid arthritis). -Prophylaxis of mild to moderate asthma. in asthma especially moderate to severe -Treatment of autoimmune disorders -Aspirin-induced asthma in children. allergic asthma which uses (ulcerative colitis, psoriasis) and after -Antigen and exercise-induced asthma -Allergic rhinitis. does not respond to organ or bone marrow -Can be combined with glucocorticoids -Conjunctivitis. high doses transplantation. (additive effects, low dose of of corticosteroids -Antiemetic's in cancer chemotherapy glucocorticoids can be used). -Adrenal suppression , Growth -Bitter taste retardation in children, Susceptibility -minor upper Side to infections, Osteoporosis, Fluid Elevation of liver enzymes, headache, - effects retention, weight gain, hypertension, irritation (burning dyspepsia Hyperglycemia, Fat distribution, sensation, nasal Cataract, Psychosis congestion) Drugs used in chronic obstructive pulmonary disease (COPD) : -COPD is a chronic irreversible airflow obstruction, damage and inflammation of the air sacs (alveoli). -Smoking is a high risk factor but air pollution and genetic factors can contribute. Treatment: Inhaled bronchodilators, Inhaled glucocorticoids, Oxygen therapy, Antibiotics specifically macrolides such as: azithromycin to reduce the number of exacerbations, Lung transplantation. Inhaled bronchodilators in COPD: 1-Inhaled antimuscarinics : pratropium & tiotropium .are superior to β2 agonists in COPD 2-β2 agonists: these drugs can be used either alone or combined: salbutamol + ipratropium Or salmeterol + Tiotropium (long acting-less dose frequency). ­Summary 1. Quick relief medications (Bronchodilators): Drugs B2 agonists – Short acting ↑Adenyl cyclase Salbutamol, terbutaline – main choice in acute attack of asthma – Inhalation ↑ cAMP Salmeterol, formoterol Long acting, Prophylaxis Nocturnal asthma Antimuscarinics Main drugs For COPD Blocks M Ipratropium (Short) Inhalation receprtors Tiotropium (long) Inhalation Xanthine derivatives Inhibits Theophylline (orally) phosphodiesteras e Aminophylline (parenterally) ↑ cAMP

2. Control therapy (prophylactic drugs):

Corticosteroids Inhalation (Inhibits phospholipase A2) Dexamethasone, Fluticasone, budesonide prednisolone Orally Hydrocortisone parenterally Mast stabilizers Inhalation, prophylaxis in children Cromoglycate (Cromolyn), Nedocromil Cysteinyl antagonists (CyLT1 antagoist) Zafirlukast orally Omalizumab (Anti IgE antibody) Injection, SC ­MCQs

1. Drug of choice for acute anaphylaxis? 4. One of main drugs for COPD? A) Terbutaline A) Theophylline B) Epinephrine B) Formoterol C) Salbutamol C) Nedocromil D) Formoterol D) Ipratropium

2. Which are mainly given by inhalaon? 5. Increase of cAMP results in? A) Selecve β agonists A) Bronchoconstricon B) Selecve β2 agonists B) Bronchodilaon C) Non selecve β agonists C) Stabilizaon of mast cell membrane

D) Non selecve β2 agonists D) Increase mucus clearance

3. Which is not used to relieve acute aack 6. Which has addive effect to β2 agonists? of asthma? A) Anmuscarinics

A) Salbutamol B) Methylxanthines

B) Terbutaline C) Glucocorcoids 6- C

5- B

C) Salmeterol D) β2 agonists 4- D

3- C

D) Albuterol 2- B

1- B Answers: Good luck!

Done by Pharmacology team 434

Moneera Al draihem Maha Al-Rabiah Lama Al walaan Lamia Althwadi Rasha Bassas Nuha AlGwaiz

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