Respiratory pharmacology Flashcards
Asthma
A reversible obstructive lung disease, characterized by bronchoconstriction due to hyperresponsiveness of the airways to physical, chemical and pharmacological stimuli
It is a chronic inflammatatory condition with acute exacerbations
Asthma can be life threatening if not propertly managed
COPD
An obstructive lung disease that overtime makes it hard to breathe
Involves inflammation and thickening of the airways
It also involves destruction of the tissue of the lung where O2 is exchanged
Sometimes referred to as either chronic bronchitis or emphysema
3rd leading cause of death in US
Allergic response of asthma
Ag triggeres peripheral lymphoid tissue to release IgE, a sensitized mast cell and the IgE interact, leading to release of :
-histamine, tryptase, LTC4, D4, PGD2
Acute response: in minutes, degranulation-> histamine, leukotrienes, cytokines, proteases–> bronchoconstriction (immediate early reaction)–> mediators-> trigger mediators
In hours-> secretion –> cytokines and chemokines–> late phase reactions and inflammation
Treatment groups of asthma
Quick relievers: meds to quickly reverse the symptoms of asthma (short acting bronchodilators-albuterol)
Exacerbation of Asthma: short causes of oral steroids (antii inflammatory- prednisone)
Long-term controllers: include meds to prevent airway narrowing over time, inhaled corticosteroids (fluticasone), Long acting bronchodilators (LABAs- never used alone, salmetorol), and Leukotriene modifiers (montelukasts
Airway narrowing
causes the symptoms of asthma, due to smooth muscle hypertrophy and constriction, mucous gland hypertrophy and hypersecretion
Vascular engorgement and leakage causing airway wall edema, and subepithelial basement membrane thickening and fibrosis
Omalizumab
Anti- IgE receptor therapy
Ige and allergen activates high affininty receptors (FCErI) in mast cells and and low ffinity receptors (FceR2, CD23) on other inflammatory cells
OMALIZUMAB binds free iGE, prevents mast cell degranulation and the resulting inflammation
Therapeutic use: pts with severe asthma who remain poorly controlled despite high doses of inhaled steroids combined with long-acting bronchodilators
Bronchodilator drugs
3 main classes
SABA (short acting beta agonists)- albutorol, immediate reversal of airway obstruction
SandLABAS: salmetorol, formoterol- prevent bronchoconstriction, LABA- never used alone in asthma
RELAX constricted airway smooth muscle
Albuterol and Salmetorol/formoterol
Albuterol (SABA), bronchodilator
Salmetorol and Formoterol (LABA): bronchodilator treatment of choice in asthma, have minical side effects when used correctly
LABA-neverused alone in asthma
SABA- 3-6 hours
LABA- >12 hours
Directly stimulate B2 receptors in airway smooth muscle
Rapid bronchodilator action is attributable to a direct effect on airway smooth muscle
SE of B2 selective agonists
dose related, CV disease, administer by inhalation to avoid other rists
Has tolerance (desensitization, subsensitivity)- down regulation of the receptor
AS more and more saba is used you need more
LABA is never used alone
Theophylline
Methylxanthines, non selective phosphodiesterase (PDE) inhibitor and adenosine receptor antagonism,
SE: headache, tachycardia, cardiac arrhythmias and seizures
Steroids
Oral corticosteroids (prednisone) for a short period of time, 3 to 10 days is the only treatment for asthma axacerbations
ICS are considered as first line therapy in Moderate to severe asthma (not mild)
MOA of Corticosteroids in asthma
iinflammatory stimuli (IL1 TNF a) acticivates NFkB–> histone acetyltransferase (HAT)–> acetylation of core histones, increased expression of genes encoding multiple inflammatory proteins
Cytosolic glucocorticoid receptors bind corticosteroids – inhibit HAT activity, reverses histone acetylation–> suppression of activated inflammatory genes
Steroids dont directly affect contractile response of airway, inhibit late response and hyper responsiveness
Steroid effect on B2 adrenergic responsiveness
steroids increase transcription of B2 receptor (prevent down regulation)
B2 agonists enhance glucocorticoid recepotr
B2 agonists and corticosteroids enhance eachothers beneficial effects in asthma therapy
Chronic use of LABA
should not be done in monotherapy, could make things worse
Systemic/oral steroids
Prednisone most common, takes a few days to kick in
short courses are indicated for exacerbations of asthma
Be careful when taking off after long term use
Clinical use inhaled corticosteroids
1st line therapy for all pts w/ persistent astham, started in any pt who needs to use a B2 agonists inhaler more than 2x weekly, effectivel in mild, moderate and severe asthma in kids and adults
Leukotriene modifiers
Montelukast, indicated as an add on therapy
Aspirin induced asthma
aspirin hypersensitivity,
Anti interleukin 5 therapy
IL5 is a pro eosinophilic cytokine mediator of eosinophilic hematopoiesis and contributes to eosinophilic inflammation in the airways, Mepolizumab
> 150 ul of eosinophil is indicated
COPD and treatment
Progressive small airway narrowing and fibrosis (chronic obstructive bronchiolitis)
Destruction of the alveolar walls (emphysema)
Pharmacological treatment of stable COPD:
Short acting bronchodilators: Beta2 agonists (abuterol), Anticholinergics (ipratropium), combination therapy
Long acting bronchodilators: Beta 2 agonists (salmetorol, formoterol) can be used as monotherapy unlike asthma, anticholinergics (tiotropium), combination therapy
Inhaled steroids (fluticasone, budesonide), Bronchodilators + ICS
Anticholinergics
Ipratropium bromide- short acting
Tiotrpium- long acting
RElaxes airway smooth muscle, decreases mucus secretion, Ach released onto the airway smooth muscle causes bronchoconstriction via M3 muscarinic receptors and mucus secretion via the M1 and M3 muscarinic receptors
Adverse effects and contraindications are of less concern with anticholinergics administered by inhalation
Effect is greates in affected airways
Corticosteroids in COPD
dont work well
Cystic fibrosis
AR disorder caused by mutation of chloride channel, prduction of abnormal mucus which depresses lung function
Treatments
CF has no cure, Ab to treat lung infections, anti inflammatory, inhaled bronchodilation, rhDNAase, ivacaftor
Dornase alpha inhaled
infiltrating PMNs release DNA which has a high viscosisty
DNAse breases in up , allows for sputus clearance, imporoves lung function, decreases frequency of infection
Ifacaftor
binds to defective protein at the cell surface, opens up the chloride channel and restores the proper flow of fluids and sodium
Luma-ivacaftor- caution in pts with advanced liver disease
F508del mutation
improper folding of CFTR protein during synthesis, most common mutation–> Cf (50 % are homozygous, 40 % heterozygous)
Class 2 mutation when the protein doesnt make it to the cell surface
