PH2113 - Asthma 2 Flashcards
What is reliever medication?
Opens up airways
- cause bronchodilation
Oppose inflammation-mediated bronchoconstriction
- provide relief
Give examples of reliever medications (bronchodilators)
- beta-2-adrenoceptor agonists
- xanthines
- muscarinic receptor antagonists
- leukotriene receptor antagonists
- histamine receptor antatonists
Give two examples of beta-2-adrenoceptors agonists
SABA - short acting beta-2-adrenoceptor e.g Salbutamol or terbutaline LABA - long acting beta-2-adrenoceptor e.g Salmeterol, Fomoterol, oladaterol
What class of medication is salbutamol when used as a reliever for asthma?
SABA
- short acting beta-2-adrenoceptor
How do muscarinic receptor antagonists work?
Parasympatholytics (opposite of PS effect), bind to muscarinic receptors and prevent ACh from exerting its effect - competitive antagonists
Muscarinic receptor antagonists block the parasympathetic tone generating bronchoconstriction in the lungs. The only autonomic neuronal input into the lung is parasympathetic.
Acetylcholine is released from post-ganglionic nerves that activates muscarinic M3 receptors located on the smooth muscle of the airway to generate bronchoconstriction, narrowing the airway and reducing airflow. This typically occurs in response to noxious stimuli such as cold dry, air
When do muscarinic antagonists tend to be used more ?
Muscarinic antagonists tend to be used more in COPD as the lungs of COPD patients have greater parasympathetic tone than the lungs of asthmatic patients.
How do leukotriene receptor antagonists work?
Leukotriene receptor antagonists work by blocking the CysLT1 receptor on airway smooth muscle. Leukotrienes are high affinity agonists of this receptor and contribute to inflammation-induced bronchoconstriction.
therefore Leukotriene receptor antagonists cause bronchodilation
What is the drawback with using histamine receptor antagonists as a reliever medication?
Not effective at relieving bronchoconstriction
When may histamine receptor antagonists get used ?
when controlling allergy generally reducing the progression of mild inflammatory reactions onto more serious ones such as asthma.
What is the general function of reliever medication in asthma?
All reduce cytosolic calcium concentrations which causes bronchodilation
Give two mechanisms in which Bronchodilation can occur using reliever medication
Activation of adenyl cyclase to generate cAMP from ATP is a very important second messenger system for reducing free Ca2+ levels in smooth muscle cells. Activation of 2-adrenoceptors generates bronchodilation by this method. Levels of intracellular cAMP are regulated by an enzyme called phosphodiesterase. One of the proposed mechanisms by which xanthines, such as theophylline generate bronchodilation is to block PDE increasing the level of cAMP in the cell.
Bronchodilation can also be generated by blocking receptors that generate bronchoconstriction. This is the mechanism by which muscarinic antagonists work. Xanthines are also known to be able to block adenosine receptors. In asthmatic, stimulation of adenosine receptors causes bronchoconstriction. Interestingly, in non-asthmatics, adenosine receptor stimulation causes bronchodilation!
Describe short acting beta-2-adrenoceptor agonists (SABAs)
- hydrophilic
- short duration of action
Describe long acting beta-2-adrenoceptor agonists (LABAs)
- lipophilic
- leech out of membrane prolonging duration of action (> 12 hours)
- MUST NOT BE GIVEN WITHOUT A CORTICOSTEROID
How do beta-2-adrenoceptors agonists work?
- beta-2 agonist activates G-protein which activates adenyl cyclase
- the G-proteins also activate the calcium activated K+ channel
- K+ channel efflux increases which causes hyperpolarisation which inhibits Ca channel
- reduced Ca2+ influx
- reduced contraction = bronchodilation
- adenyl cyclase converts ATP into cyclic AMP which activates protein kinase A (PKA)
- decreases PI/Ca2+ = bronchodilation
- decreases myosin light chain kinase (MLCK) = broncodilation
- increases Na+/K+ATPase - polarisation of smooth muscle
- increased concentration gradient across membrane = bronchodilation
Describe the properties of xanthines?
Quite insoluble
- hydrophobic
Narrow therapeutic index (the difference between an effective dose and a toxic dose)
- limits clinical use
Many drug-drug interactions (CYP450)
- substrate for CYP450 which is used for other drugs
- smoking upregulates CYP450 so needs higher doses - overdose if quit smoking!
