Flashcards in * Pharmaology 3 (Lecture 2) Deck (73):
Is airflow obstruction reversible in COPD?
Little or no reversibility (compared to reversible airway obstruction in asthma)
What is the pathogenesis of COPD?
Cigarette smoke and other noxious chemicals stimulate resident alveolar macrophages (possibly also influenced by CD8+ lymphocytes)
This causes the release of neutrophilic chemotactic factor, IL-8, LTB4 and O2 radicals
These cause the activation of neutrophils, and more macrophages and CD8 T cells
These release proteases (matrix metalloproteinases) and free radicals
This leads to chronic bronchitis and emphysema
What do matrix metalloprotineases cause in terms of bronchitis? (symptoms of chronic bronchitis)
They causes inflammation of bronchi and bronchioles, cough, clear mucoid sputum, infections with purulent sputum
What do matrix metalloprotineases cause in terms of emphysema? (symptoms of emphysema)
Distension and damage to alveolar
Destruction of acinial pouching in alveolar sacs
What 3 different types of muscarinic acetylcholine receptors do human airways contain?
M1, m2, m3
What nerve is the preganglionic neurone that supplies the bronchial smooth muscle?
Vagus nerve (No sympathetic innervation_
What receptors are located in the ganglia of the parasympathetic branch which is supplying the airways? (2)
nAChR (nicotinic receptors)
M1 receptors (mediate a slow excitatory post synaptic potential that increases action potential frequency resulting from nicotinic receptor stimulation)
Where is M2 located and what does it do (in terms of parasympathetic supply to airways)?
Located on the postganglionic neurone terminals (acts as inhibitory auto receptors reaching release of ACh)
Where is M3 located and what does it do (in terms of parasympathetic supply to smooth muscle)?
Present on smooth muscle and mucus-secreting cells
mediates contraction and increased secretion
Apart from the drugs in the guidelines, what do drug do doctors sometimes prescribe patients who have difficult to control asthma?
What happens when ACh activates M3 muscarinic receptors on airway smooth muscle cells?
Through Gq, PLC (phosopholipase C) is activated which converts PIP2 to IP3
IP3 binds to the IP3 receptor on the sacroplasmic reticulum (basically a ligand gated ion channel)
This causes calcium to diffuse into the cytoplasm leading to contraction
How do muscarcinic acetylcholine receptor antagonists work?
They are block the M3 muscarinic receptor, meaning ACh cannot bind leading to contraction of the smooth muscle (bronchoconstriction)
Are muscarcinic acetylcholine receptor antagonists currently used competitive or non-competitive?
What are the 2 categories of competitive muscarinic receptor antagonists current licensed?
Short acting muscarinic antagonists (SAMAs)
Long active muscarinic antagonists (LAMAs)
What are the 2 SAMAs currently licensed?
What are the 2 LAMAs currently licensed?
How are all the muscarcinic receptor antagonists given?
What feature of muscarinic receptor antagonists reduces absorption and system exposure avoiding multiple potential adverse effects?
Quaternary ammonium group
How long is the onset of action of muscarinic ACh receptor antagonists roughly?
Delayed (grater than 30 mins)
What effect do using macaroni ACh receptor antagonists have? (3)
Relax bronchospasm caused by irritant stimuli (irritants initiate a vagal reflex that liberates ACh)
Also block Ach-mediated basal tone
Decrease mucus secretion
Do muscarinic ACh receptor antagonists have any effect on the development of COPD?
Only have a little effect - their effect is mainly palliative
Why do muscarinic ACh recepto antagonists have few adverse effects?
Due to the possession of a quaternary ammonium grou
What is the main disadvantage of ipratropium?
It is a non-selective blocker of M1, M2 and M3 receptors
Why is Tiotropium functionally selective for M2 muscarinic receptors?
It has a greatly longer half life at the M3 muscarinic receptor - Aclidinium works in the sam way
Why is block of M2 by muscarinic antagonists not desirable?
Release of ACh from parasympathetic post-ganglionic neurones is increased (M2 acts as a pre junctional inhibitory auto receptor - activaiton by ACh inhibits further ACh release)
Are b2-adrenoceptor agonists used to treat COPD?
Yes - they provide some bronchodilation although have no effect on underlying inflammation (both LABAs and SABAs)
What is indaceterol?
A recently licensed "ultra-LABA" that has rapid onset of action (unlike salmeterol)
What is superior to using either a LABA or a LAMA along?
A combination of a LABA and a LAMA (e.g. salmeterol/ tiotropium) - superior to either drug separately in increasing FEV1 - recommended for moderate COPD
What are MABAs?
Advantage of these?
Muscarinic antagonist B2-agonists
LABA/ LAMA combinations are likely to be most effective when both drugs are deposited in the same location in the airways - MABAs are a novel approach that are attempting to develop ligands that possess both LABA and LAMA activity within the same molecule
What is the prominent phosphodiesterase found in neutrophils, T cells and macrophages?
What does this do?
cAMP degenerating enzyme that therefore reduces the amount if PKA activation and therefore bronchodilation
(therefore by inhibiting it, we can inhibit inflammatory and immune cells
What is the name of a selective PDE4 inhibitor?
What does this do?
What is it approved for treatment of?
Suppresses inflammation and emphysema in animal models of COPD
Approved as an oral treatment for severe COPD accompanied by chronic bronchitis
Has limiting adverse effects on GI system
What are B2-adrenoceptor agonists co-administered with?
Glucocorticoids in combination inhalers - benefit of the routine inclusion of a glucocorticoid in most COPD patients has been debated, since even high dose glucocorticoids alone do not suppress inflammation
What is glucocorticoid unresponsiveness in COPD patients thought to be due to possibly?
Oxidative/ nitrative stress (associated with chronic inhalation of tobacco smoke)
What is in the "triple inhaler"?
What types of medications are used to treat COPD?
Muscarinic ACh receptor antagonists (SABAs and LABAs)
B2-adrenoceptor agonists (LAMA works better when given along with a LABA - B2-agonists are routinely given along with glucocorticoids but with a questionable benefit)
Glucocorticoids are beneficial in patients with frequent and severe exacerbations
PDE4 inhibitor (Rofumilast) is used in patients with severe COPD
*triple inhaler is available with LABA, LAMA and glucocorticoid
What is rhinitis?
A common and often debilitating disease involving acute, or chronic, inflammation of the nasal mucosa which is characterised by rhinorrhoea, sneezing, itching, nasal congestion and obstruction
What is the scientific name for runny nose?
What is swelling of nasal mucosa largely due to?
Dilated blood vessels - particularly in cavernous sinusoids
What are the 3 different types of rhinitis?
What are the 3 different types of allergic rhinitis?
Perennial (present all year)
In allergic rhinitis, what does inhalation of the allergen cause?
Increases specific IgE levels
This causes IgE to bind to receptors on mast cells and basophils
Re-exposure to allergen causes mast cell and basophil degranulation
This causes the release of mediators inclusion histamine, cysts, tryptasae, prostaglandins, causing acute itching, sneezing, rhonorrhoea and nasal congestion
Delayed response caused by recruitment of lymphocytes and eosinophils to nasal mucosa contributes to congestion and obstruction
(very similar to asthma)
What is non-allergic rhinitis?
Any rhinitis, acute or chronic, that does not involve IgE dependent events
What are some examples of causes of non-allergic asthma? (5)
Infectious rhinitis (largely viral)
Vasomotor rhinitis (cause unknown)
Non-allergic rhinitis with eosinophilia syndrome (NARES)
Drug induced rhinitis
Is occupational rhinitis allergic or non-allergic?
May involve both allergic and non-allergic componenets
What types of targets are used in the drug treatment of rhinitis and rhinorrhoea?
Mediator receptor blockade
Nasal blood flow
What anti-inflammatory drugs are used for rhinitis?
What mediator receptor blockade drugs are used for rhinitis? (2)
H1 receptor antagonists
CysLT1 receptor antaonists
What rhinitis medications affecting nasal blood flow is used for rhinitis?
What anti-allergic drugs are used for rhinitis?
What is the mainstay therapy for seasonal allergic rhinitis and perennial allergic rhinitis and of value in NARES and vasomotor rhinitis?
How are glucocorticoids for rhinitis applied?
Topically as a spray to the nasal mucosa (usually once daily)
Given orally (short term) in very severe intractable cases
What can glucocorticoids be combined with in moderate-to-severe rhinitis?
Specific examples of glucocorticoids for rhinitis?
What is the more common name of H1 receptor antagonists?
How do anti-histamines (H1 receptor antagonists) work?
Competitive antagonists of H1 receptors reduce effects of mass cell derived histamine that include vasodilation and increased capillary permeability, activation of sensory nerves, mucus secretion from submucosal glands
What types of rhinitis are anti-histamines effective in?
Allergic rhinitis (less so for non-allergic rhinitis)
How are anti-histamines administered?
Orally or as an intranasal spray (azelastine)
Why are second generation anti-histamines preferred over first generation anti-histamines?
Reduced sedation as they do not cross the blood brain barrier and lack of anti-cholinergic effects
Examples of anti-histamines for allergic rhinitis?
Cetrizine (also has mild anti-inflammatory action)
What causes the watery secretions that contribute to rhinorrhoea?
ACh released from post-ganglionic parasympathetic fibres which activates muscarinic receptors on nasal glands - blocked by muscarinic antagonists
What symptom are anti-cholinergic drugs (muscarinic receptor antagonists) effective in treating?
Reducing rhinnorhoea in PAR and SAR - have no influence upon itching, sneezing and congestion
How are muscarinic receptor antagonists for rhinnorhoea always administered?
Via the nasal route
What is the adverse effect of muscarinic receptor antagonists?
Dryness of nasal membranes
What is the only muscarinic receptor antagonist used for rhinitis?
what is sodium cromoglicate thought to do?
Stabilise mast cells
What is sodium cromoglicate used for in terms of rhinitis?
Onset of action?
Maintenance treatment of allergic rhinitis
4 to 7 days
How is sodium cromoglicate for allergic rhinitis administered?
Nasal administraiton - less effective than nasal corticosteroids
What are cysteinyl leukotriene receptor antagonists used to treat in terms of rhinitis?
PAR and SAR (are equi-effecitve with H1 receptor antagonists in treating these, with which their effect may be additive)
*should be considered in patients with asthma also
How are Cysteinyl leukotriene receptor antagonists administered?
What is the only cysteinyl leukotriene receptor antagonist used to treat Rhinitis?
How do vasoconstrictors produce vasoconstriction (rhinitis)?
Act as direct, or indirect, sympathomimetics to mimic the effect of noradrenaline (produce vasoconstriction via activation of alpha 1 adrenoceptors to decrease swelling in vascular mucosa)
What is a selective alpha1-adrenoceptor agonist which is effective, short term, in reducing congestion in allergic rhinitis?
How is this given?