Asthma and COPD drugs Flashcards
what are six drug classes to consider?
Six Classes
i) ß2-selective adrenergic agonists – Albuterol, Pirbuterol,
Terbuterol & Salmeterol (LA)
ii) Adenosine Antagonist + PDE Inhibitor – Theophylline & Aminophylline
iii) Muscarinic Antagonist – Ipratropium & tiotropium
iv) Mast Cell Stabilizer – Cromolyn, Nedocromil, (Omalizumab)
v) Corticosteroids- Beclomethasone, Fluticasone
vi) Leukotriene Synthesis Inhibitor:
Zileuton-(5-Lipoxygenase Inhibitor);
Zafirlukast, Montelukast-Leukotriene-Antagonist- (CysLT1 Antagonist)
what is the clinical background of asthma and COPD?
- Episodic reversible obstruction of the airways
- Bronchial asthma : 10-20% of the population
- Triggers: Allergens (pollens), Autoimmune Disease
- Characterized by airway inflammation & bronchial hyper-responsiveness to stimuli.
- Initial Bronchial Hyperreactivity (BHR), later leads to Asthma (severe bronchoconstriction and airway obstruction). If it persists, due to lung fibrosis it becomes at later stages -Chronic Obstructive Pulmonary Disease (COPD).
- Patients with Asthma and COPD present symptoms of coughing, wheezing, chest tightness, and shortness of breath.
what is the difference between early onset and late onset asthma and what are some trigger factors?
Early and late onset asthma share many features in common, but there is little evidence that there is a strong allergic component in late onset asthma.
Skin test Positive, Family history of allergic disorders –> early onset, extrinsic atopic
Skin test negative, Family history of allergic disorders, not characteristic –> late onset, intrinsic, non-atopic
triggers - Infection Exercise Environment Occupation Drugs Emotion
for early onset ALLERGENS!!!!
what is the pathology of asthma decreased airway?
mucus plug, smooth muscle hypertrophy and hyperplasia, thickened basement membrane, oedematous submucosa with infiltration of granulocytes
what is the connection of ashtma to FEV?
The hyper-reactivity of the bronchioles is shown. Airway obstruction in asthma characteristically reduces aflow in expiration.
Reduced expiratory flow is conveniently measured by the volume of air expired in one second: Forced Expiratory Volume (FEV1).
there is a reduced FEV
what is a good summary?
Early and late onset asthmatics share many common features. An allergic component appears to be associated with early onset asthma but not with the late onset asthma.
Factors that contribute to asthma include mucus plug, edema, bronchoconstriction, and cellular infiltration leading to airway obstruction.
Non specific bronchial hyper-reactivity is a cardinal feature of most asthmatics. This bronchial hyper-reactivity (BHR) appears to be linked to airway inflammation and exaggerated neural reflex response to irritants and mediators of inflammation.
Early onset asthma following exposure to an allergen can be relieved by bronchodilators whereas late onset advanced asthma could be managed by treatment with anti-inflammatory agent like corticosteroid (beclomethasone aerosol) or prophylactically by treatment with cromolyn (sodium cromoglycate) before the onset of an attack.
What are three types of bronchodilators?
A) Bronchodilators
- Beta-adrenergic agonists: beta2 selective agonists,
eg. , Salbutamol, terbutaline, Pirbuterol,Salmeterol (LA), - Phosphodiesterase Inhibitor and an Adenosine antagonist:
eg. , Methylxanthine – Theophylline, aminophylline - M3 Muscarinic antagonist [Cholinergic Antagonist]:
eg. , Ipratropium bromide and tiotropium
what are the goals of anti-asthmatic drugs?
- The goals of drug therapy are both to treat acute attacks and to prevent their occurrence.
- Generally, drugs used to treat acute attacks have bronchodilator properties.
- Whereas drugs used to prevent attacks affect mediator release and hyperreactivity.
- The mechanisms by which commonly used drugs evoke bronchodilatation are depicted in next slide figure.
SHOULD I LOOK AT THE DIAGRAM OF MECHANISM OF ACTION OF BRONCHODILATORS?
YES
What is the target of anti-asthmatic drugs?
- Relaxation of bronchial smooth muscle can be achieved by either elevations in cAMP level or by blocking bronchoconstrictor mechanisms.
- Elevations in cAMP can be evoked by stimulating its formation through activation of adenylate cyclase (e.g. ß-agonists) or by inhibiting its breakdown through inhibition of phosphodiesterase (e.g. theophylline).
- Inhibition of bronchoconstrictor mechanisms may involve antagonists of parasympathetic cholinergic activity (e.g. ipratropium) or of adenosine (e.g. theophylline).
look at the compared responses of salbutamol and isoproterenol
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Drug A is a non-selective ß-agonist with high affinity for both ß1 and ß2 Receptors while Drug B is selective for ß2R.
Elevations in heart rate evoked by ß agonists is due both to their direct action on ß1/ß2 receptors in the heart and to baroreflexively mediated via activation of vascular ß2 R.
Note that mast cells have ß2 receptors so this added effect of ß agonists is thought to result from inhibition of the release of cellular mediators of bronchoconstriction and inflammation from mast cells besides promoting bronchodilatation.
ß2 receptors also have a modest inhibiting effect on the late asthmatic response.
Note: At a dose of 1.0 µg/min dose salbutamol increased FEV1 (upper panel) but not the increase in HR (lower panel).
what can be a problem with the use of beta adrenergic agonists?
Frequent use of ß-agonists is often associated with the development of tolerance.
what is the mechanism of action of theophylline?
Mechanism of Action:
- Theophylline has been used for decades but its importance has diminished somewhat with the advent of other bronchodilators.
- The mechanism of action of theophylline is illustrated in Fig #5. While theophylline is a Phosphodiesterase (PDE) inhibitor, there is doubt that sufficient intracellular concentrations are achieved in vivo to inhibit PDE and increase cAMP level.
- Thus, attention has focused on the ability of theophylline to act as an adenosine antagonist. Anti-inflammatory properties of theophylline and related compounds may also contribute to their beneficial effects in asthma.
Pharmacokinetics and Adverse Effects:
Figure #7 and Figure #8 relate therapeutic and toxic effects to plasma concentrations of Theophylline. Nausea, vomiting, seizures and cardiac arrhythmias are its adverse effects.
what is the bad thing about theophylline?
Note:
A reasonable therapeutic window for theophylline is 5-20 µg/ml.
Anorexia, nausea, vomiting, headache may occur in some patients even at therapeutic concentrations.
Serious adverse effects including life threatening seizures and cardiac arrhythmias have been reported at concentrations > 40 µg/ml.
Thus, it is essential to monitor plasma levels of Theophylline.
Its Therapeutic window, margin of safely is lower.
TI = LD50/ED50 is relatively low. 40µg/20µg = 2
what are antimuscarinic agents: ipratropium like?
[Note: Although sympathetic fibers do not innervate bronchial smooth muscle, there is a sympathetic supply to the parasympathetic ganglia and there are adrenergic receptors (b2 subtype) located on the bronchial smooth muscle.
As well, there are non-adrenergic non-cholinergic (NANC) fibers that evoke bronchodilatation.
Vagal activation promotes bronchoconstriction and mucus secretion.
Ipratropium blocks these effects.
Dry mouth is the undesirable side/adverse effect.
Mechanism of Action:
Afferent and efferent parasympathetic pathways regulating bronchial smooth muscle tone.
