Pharmacology of respiratory drugs Flashcards
Learning outcomes
- Review physiological mechanisms that influence airway smooth muscle tone and the pathophysiological processes that occur in asthmatic airways
- Classify anti-asthmatic drugs into symptomatic control, prophylactic and anti-inflammatory treatment
- Relate the pharmacodynamic and pharmacokinetic properties of shortand long acting beta-selective adrenoceptor agonists to their beneficial and toxic effects
- Describe the proposed mechanisms of action of anti-muscarinic drugs, corticosteroids, leukotriene antagonists (and xanthines) in the airways
- Apply the national asthma stepped treatment algorithm to appropriately escalate or reduce therapy
- Discuss personalized asthma action plans (PAAP)
Airway smooth muscle tone
•The parasympathetic input (cholinergic/muscarinic receptors): heart rate, BP, bladder, bowels, lung airflow and secretions
-Sympathetic- fight, flight or fright
•The inhibitory influence of circulating adrenaline (adrenergic)
–The NANC (Non-adrenergic, non-cholinergic) inhibitory nerves- not drug target at present
Asthma
•Characterised by airway inflammation and episodic, reversible bronchospasm
•Immediate bronchoconstriction mediated by several mediators
•Cytokines / enzymes produce inflammation that leads to bronchial hyper-reactivity to various stimuli
- Hypersecretion in mucous glands- mucous plugs
Oedema causes white cells to enter lung parenchyma, inflammation and epithelial shedding: nerve endings exposed, hypersensitive and can trigger smooth muscle contraction/ asthma attack
Steps to an asthma flare up
Exposure to antigen (dust, pollen, etc): AVOIDANCE >
Antigen and lgE on mast cells (Leukotriene receptor antagonists(LTRAs)>Mediators (leukotrienes, cytokines, etc)
(Beta 2 agonists, muscarinicantagonist, theophylline,leukotrienereceptor antagonists (LRTAs))
1.Early response:bronchoconstriction >Acute symptoms
2. Late response: inflammation> Bronchial hyper-reactivity
Classification of anti-asthma drugs
Symptomatic (bronchodilators)
•β2Adrenoceptor agonists (short-acting e.g. Salbutamol; long-acting e.g. Salmeterol, formoterol, indacaterol) •Anticholinergics(e.g. Ipratropiumbromide)•Xanthines (e.g. Theophylline)
Prophylactic (prevent inflammation)
•Inhaled corticosteroids (e.g. Beclometasone, Fluticasone and Budesonide)–Xanthines(e.g. Theophylline) - debatable effect
Anti-inflammatory (resolve inflammation)
•Inhaled corticosteroids (e.g. Beclometasone, Fluticasone and Budesonide)
Airway smooth muscle
ASM (+ beta-2-agonist) > G protein coupled receptor in CSM > ATP (adenylyl cyclase)> inc cAMP > 5-AMP (catalysed by phosphodiesterase) OR
dec cAMP> activation of protein kinsa A (PKA) >
Phosphorylation of > myosin light chain kinsae and Ca2+ dependent K+ channels»_space; bronchodilation
4 receptor superfamilies
- Ligand-gated ion channels (ionotropic receptors)
-time scale: milliseconds
e.g Nicontinic ACh receptor - G-protein-coupled receptors (metabotropic)
seconds
Muscarinic ACh receptor - Kinase- linked receptors
Hours
Cytokine receptors - Nuclear receptors
Hours
Oestrogen receptor
Mode of action- salbutamol
Target: B2 adrenoceptors in bronchial smooth muscle
Action: agonist
Effect: activation of B2 adrenoceptors stimulates adenylate cyclase enzymes to increase production of cAMP
Overall effect: bronchial smooth muscle relaxation- bronchodilatation
Beta- adrenoceptor agonists
Short acting beta 2 agonist (SABA) e.g. salbutamol, terbutaline (3-4hr) long acting beta 2 agonist (LABA) e.g. Salmeterol, formoterol, indacaterol, vilanterol(12hr)
- β2selective →bronchodilatation
- Stimulate adenylyl cyclase →↑cAMP in smooth muscle →sm muscle relaxation (bronchodilatation)
- Short acting beta 2 agonist(SABA) – ACUTE USE (reliever)
- Long Acting beta 2 agonist(LABA) - PROPHYLACTIC USE (preventer)
- Drugs of choice
- Inhalation -↓systemic dose while retaining effectiveness
Beta-adrenoceptor agonists- adverse effects
- TREMOR
- Beta-2 selectivity dose dependent – tachycardia at high dose (palpitations)
- Arrhythmias
- Hypokalaemia
- Loss of responsiveness from excessive use
Muscarinic antagonists
•Short acting muscarinic antagonist (SAMA) – Ipratropium
•Long acting muscarinic antagonist (LAMA) –Tiotropium
Newer LAMAs: Umeclidinium, Aclidiniumand Glycopyrronium
•Block receptors, antagonise bronchospasm and ↓mucus secretion*
•Better for irritant induced asthma – does not work in all asthma patients
•Better in COPD with episodes of bronchospasm
•Inhaled; bronchodilation in 30 mins to 5 hours
•No tremor or arrhythmias but cause dry mouth
Examples of drugs targeting receptors coupled to phospholipase C-Beta by G proteins
- α1 adrenoceptors – Gq-↑IP3 /DAG (blood vessels)–agonists are vasoconstrictors (norepinephrine, phenylephrine)–antagonists are vasodilators (prazosin, doxazosin)
- α1A adrenoceptors – Gq-↑IP3 /DAG (non-vascular smooth muscle in neck of bladder, prostate)–agonists are muscle constrictors (norepinephrine)–antagonists are muscle relaxants (tamsulosin)
- Μ3 muscarinic cholinoceptors Gq-↑IP3 /DAG (airway smooth muscle)–agonists are bronchoconstrictors (acetylcholine)–antagonists are bronchodilators (ipratropium, tiotropium)
Xanthines/ theophyllines
Theophylline e.g. Neulin SA, Uniphyllin continus
•Inhibit phosphodiesterase (cAMP/cGMP), block adenosine receptors, prevent diaphragmatic fatigue
•Oral – slow release formulations•narrow therapeutic window – need to monitor drug levels
•P450 liver metabolism (age, smoking, drug interactions)
•Used in difficult to control asthma
•Causes: - nausea, arrhythmias and convulsions
Serum theophylline levels
Serum theophylline levels increased by: •OCP •Erythromycin •Calcium channel blockers •Cimetidine
Serum theophylline levels decreased by: Liver enzyme inducers
•Phenytoin
•Carbamazepine
•Rifampicin
Corticosteroids
- Inhaled preferred and oral preparations
- Inhibit phospholipase A2and COX-2, increase β2 responsiveness*
- Prophylactic therapy
- Oropharyngeal candidiasis, use spacing device and/or rinse mouth after use; growth retardation in children etc.
