ICL 2.9: Pharmacotherapy for Asthma, COPD and Smoking Cessation Flashcards
what is the general pathophysiology of asthma?
allergen causes inflammation subsequent and broncochonstriction from the cytokine storm
what is the general pathophysiology of COPD?
smoking or other insult leads to epithelial cell injury and a cytokine storm
end result is fibrosis, alveolar wall destruction and mucus hypersecretion
how are most asthma medications administered?
most elements of asthma are localized to lung
local drug delivery maximizes effects while minimizing side effects which is good (relative to systemic delivery)
since some of an inhaled dose may be swallowed, minimal PO absorption / high first-pass loss can help reduce systemic exposure
what is the difference for giving oral vs. parenteral administration of drugs?
oral route: must give much larger doses, increases systemic effects (causes side effects)
parenteral route: for mAB drugs, since they can’t be given orally since they are degraded in GI tract
how are oral drugs metabolized?
oral drugs go directly to the portal vein to the liver which cleans the blood by metabolizing drugs
liver can clean up a lot of the drugs before they even get to the heart or the rest of the body
what is the complication with giving inhaled drugs?
it is one of the most complicated drug therapies for patients to self-administer
you can swallow the medication instead of inhaling it which means it will have systemic effects and most likely cause side effects
to minimize this, use drugs that have a high degree of first pass loss in the liver so that if anything gets swallowed it’ll met metabolized and won’t make it to the systemic circulation
what are the 4 types of inhaled delivery devices?
- pressurized metered-dose inhalers (pMDIs) – used as a propellant
- space chambers – reduced velocity to minimize drugs in oropharynx/maximize to lower airways
- dry powder inhalers – inhalation scatters the fine powder
- nebulizers – jet driven by gas stream or ultrasonic vibration
which drug classes cause bronchoconstriction?
- ACh
- adenosine
- leukotrienes
what drug classes cause bronchodilation?
B agonists that activating cAMP that bronchodilates directly
you can also inhibit bronchoconstriction drugs
which drugs are B agonists used for the lungs?
- albuterol
2. salmeterol
what is the MOA of B agonists in asthma?
- Gs-coupled GPCR activation on bronchial smooth muscle causes relaxation (bronchodilation
- B2 activation on mast cells reduces histamine release = anti-inflammatory effect
where are B2 receptors located and what do they do?
- heart –> increase rate and force
- lungs –> bronchodilation
- arterioles
- eye –> fluid production
- bladder –> urinary retention
- liver/pancreas –> increased serum glucose
what are the most characteristic side effects of B2 agonists?
- skeletal muscle tremors and excitement
- hypokalemia from PKA-mediated effects on membrane-bound Na/K ATPase
- arrhythmia
what are B2 agonists used for in the lungs?
- all types of asthma
2. COPD
what are the 2 classes of B2 agonists used in the lungs?
- SABAs = short acting beta agonists –> rapid onset of action for acute exacerbations; NOT recommended for daily, chronic use
ex. albuterol, terbutaline - LABAs = long-acting beta agonists –> longer duration of action for prophylaxis
ex. salmeterol, indacatarol
what do you need to be careful of with LABAs?
LABAs should NOT be used in monotherapy without an ICS because of safety concerns!
studies found association of chronic LABA use with increased asthma-related mortality
this risk was only observed when a LABA was used alone; LABAs given with an ICS did not increase mortality so the current recommendation is to only use LABAs in combination with an ICS
LABAs are considered “GC-sparing” agents so when given with ICS, they reduce the dose of ICS needed
what is tachyphylaxis? which lung drug is it associated with?
decreased effectiveness associated with frequent use
this can happen when a receptor is stimulated too often it can become phosphorylated and endocytose and removed from the membrane so you have less receptors so there’s down-regulation of receptors
it’s the most pronounced with SABAs**
which drugs are long-acting antimuscarinics?
LAMAs
- tiotropium
- ipratropium
they are both inhaled!
what is the MOA of long-acting antimuscarinics?
antagonist at M3 muscarinic cholinergic receptors
they are found in goblet cells so when you block muscarinic receptors, you decrease mucus secretion
they’re also found in bronchial smooth muscle cells so when you block them you relax smooth muscle by reducing cholinergic tone
note: at clinical doses, they’re only effective against bronchoconstriction caused by ACh stimulation so they’re less useful than B2 agonists and are used as an alternative to LABAs for maintenance treatment of COPD (and sometimes asthma)
what are some other clinical uses for antimuscarinic agents outside the lungs?
- eye –> cycloplegia, mydriasis
- CNS –> relieves dystonia and motion sickness
- GI tract –> antispasmodic effects
- bladder –> treats overactive bladder
- glands –> reduces salivation, sweating, gastric secretions
what are the side effects of long-acting antimuscarinics?
LAMAs:
1. long duration of action related to longer residence time on receptor (tiotropium has longer duration of action, 24 hours)
- somewhat variable efficacy between patients, due to differences in parasympathetic tone
- major side effect is dry mouth, a local effect at the site of administration
- these drugs have a quaternary amine structure
what role does quaternary amine play in the use of LAMAs?
it makes them very poorly-absorbed into blood from lungs or GI tract
this is good because it means almost no systemic side effects!
which drug classes are anti-inflammatory drugs?
- glucocorticoids
- methylxanthines
- mast cell stabilizers
- leukotriene modifiers
- anti-IgE MCA
which drugs are glucocorticoids?
- fluticasone
2. budesonide
what is the MOA of glucocorticoids in asthma/COPD?
they bind to glucocorticoid receptors and get into cells and move into the nucleus to alter the expression of proteins involved in inflammatory response by:
- increase synthesis of anti-inflammatory proteins (e.g., IκB which inhibits NFκB)
- decrease synthesis of inflammatory proteins (e.g., PGs, LTs, cytokines)
- also inhibits down-regulation/promotes up-regulation of β2 receptors in lung
so when GCs bind to their receptors, this complex moves into the nucleus where it can bind to DNA and acts as a transcription factor, or binds to other transcription factors to ↑ or ↓ protein synthesis
given the MOA, what would you predict about the speed of onset and offset of glucocorticoids effects?
they are NOT for acute symptoms!
they alter gene transcription and protein synthesis so they don’t work quickly but they do have long-lasting effects
which drugs are systemic corticosteroids?
- prednisone
- prednisolone
given orally
what are systemic corticosteroids used for in the lungs?
short-term therapy for moderate-severe acute asthma attacks resistant to bronchodilators
this when for like when there’s an asthma attack that isn’t responding to bronchodilators so it’s a last resort
onset of action: 6 hours; given for 3-10 days
what are the adverse effects from long term use of systemic corticosteroids?
- iatrogenic Cushing’s syndrome
- HPA axis suppression: abrupt withdrawal can cause lethal adrenal insufficiency so you need to taper the dose if you take them off
- impaired inflammatory/immune response increases risk of infections
- children: growth retardation
what are the features of Cushing’s syndrome?
- psychosis, impaired memory, sleep disturbances, depression, anxiety
- hypertension, dyslipidemia
- overweight, facial fat accumulation, abdominal fat accumulation, impaired glucose tolerance, DM
- muscle and skin atrophy
- osteoporosis
which drugs are inhaled corticosteroids?
- fluticasone
2. budesonide
what are the uses of inhaled corticosteroids?
they’re first-line maintenance therapy for mild-severe persistent asthma
onset takes days to weeks
what are the side effects of inhaled corticosteroids?
- oral candidiasis = thrush
- hoarseness
way fewer side effects than systemic steroids because it’s given locally so you’re not going to get Cushing’s or HPA axis deviation
which drugs are anti-IgE monoclonal antibodies?
omalizumab
given via SC injection
what are the uses of anti-IgE monoclonal antibodies in the lungs?
severe allergic asthma not adequately controlled with other drugs
so you should only give this to someone who has allergy-mediated asthma and test their blood to see if they have high levels of IgE
what is the dosing for anti-IgE monoclonal antibodies?
they’re injected once every 2-4 weeks; free IgE levels remain reduced for months
dosing based on pre-treatment serum IgE levels, must be tested before starting drug
they’re given injection but not orally because the protein would get denatured in the GI tract!
what is the MOA of anti-IgE monoclonal antibodies?
they bind specifically to circulating IgE and block its binding with the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils
this interferes with the synthesis and release of mediators of the allergic response (e.g., leukotrienes, cytokines, chemokines)
what are the side effects of anti-IgE monoclonal antibodies?
rare anaphylaxis but no overdose toxicity
slightly increased malignancy rate
which drugs are mast cell stabilizers?
cromolyn
given inhaled
what is the MOA of mast cell stabilizers?
inhibits mast cell degranulation which prevents release of inflammatory mediators
they are alternative agent for asthma prophylaxis; so taken long term to reduce frequency of asthma attacks! not taken acutely
how would mast cell stabilizer effects compare to antihistamines or GCs?
antihistamines block receptors so they’re used after the mast cells have degranulated and you’re blocking the histamine form binding
mast cell stabilizers prevent the mast cells from degranulation gin the first place so you don’t have to block receptors!
would mast cell stabilizers help with an exacerbation that has already started?
no
if you’re having an exacerbation those mast cells have already released their granules and the cytokines are already out
which drugs are leukotriene modifiers?
- montelukast
- zafirlukast
- zileuton
all taken PO!
what are the uses of leukotriene modifiers?
preventing exercise induced asthma, aspirin-induced asthma, asthma that doesn’t respond to glucocorticoids
especially useful in children because you can give them orally instead of with an inhaler
what is the MOA of leukotriene modifiers?
- blocking the enzyme (5-LO) that synthesizes LTs from arachidonic acid (zileuton)
- antagonist activity at LTD4 receptors (montelukast, zafirlukast)
why are leukotrienes bad in someone with asthma?
- ↓ mucociliary clearance
- ↑mucus secretion
- attract leukocytes to airways
- ↑ pulmonary vascular permeability
inhaled leukotrienes C4 and D4 are 1,000x more potent than histamine in causing airflow obstruction and have a longer duration of action
how does aspirin induce asthma?
aspirin inhibits the COX pathway, shunting arachidonic acid through the 5-lipoxygenase pathway to produce more leukotriene B4, C4, D4, and E4
what is the onset of action in leukotriene modifiers?
slow onset of action (2-6 weeks) so prophylaxis use only
duration of action longest for montelukast (once-daily)
food interactions; zafirlukast must be taken on empty stomach
what are the side effects of leukotriene modifiers?
- headache, nausea diarrhea but otherwise well-tolerated
- liver toxicity
- increased risk of infection
- neuropsychiatric events
which drugs are methylxanthines?
theophylline
orally
what are the dose-dependent effects of methylxanthines? MOA at different doses?
LOSE DOSE
immunomodulatory, anti-inflammatory, bronchoprotective, reverses GC resistance
MOA: adenosine receptor blockade and histone deacetylase (HDAC) activation
HIGH DOSE
bronchodilator effects
MOA: non-competitive, non-selective inhibition of PDE3 and PDE4 enzymes which increases levels of cAMP and cGMP
what are the side effects of methylxanthines?
- CNS, CV and GI side effects = restlessness, tremors, vomiting, insomnia, agitation, flushing, hypotension, delirium, convulsions, shock, arrhythmias
- narrow therapeutic window + highly variable clearance requires monitoring
- doubling dosing or crushing/chewing slow release formulations can result in toxicity
- inhibition of PDE3 results in :
- hypotension
- tachycardia
- headache
- emesis - inhibition of adenosine receptors results in alterations in cerebral blood flow
what are methylxanthines used for in the lungs?
they’re used as alternative maintenance agent for asthma (less effective than GCs)
they were formerly used (high-dose) for bronchodilation but now used low-dose for anti-inflammatory effects and for reversing GC resistance
what is the overdose treatment for methylxanthines?
- charcoal
- hemodialysis
- anti seizure medications
which drugs are phosphodiesterase-4 inhibitors? what are they used for?
roflumilast
given PO and used in COPD prophylaxis treatment
what is the MOA of phosphodiesterase-4 inhibitors?
inhibits PDE4 which is the enzyme responsible for breakdown of cAMP
this results in cAMP accumulation which:
1. relaxes airway smooth muscle cells (bronchodilation)
- suppresses cytokine release and neutrophil lung infiltration
- reduces pulmonary remodeling
what are the side effects of phosphodiesterase-4 inhibitors?
- contraindicated in hepatic impairment
- rare neuropsychiatric effects, weight loss
- CYP3A4 interactions
how do you manage asthma?
- diagnose
- assess severity
- initiate mediation and demonstrate use
- develop written asthma action plan
- schedule follow up
emphasis on demonstrating and checking ability to use inhaled medications
continuous follow-up review of efficacy and side effects –> adjustments to therapy
how is asthma severity classified?
based on symptoms, lung function, risk, age and use of short-term meds
what is the preferred treatment for all persistent asthma?
inhaled glucocorticosteroids
what are GOLD guidelines?
they outline the management strategies for COPD
emphasis on:
1. demonstrating and checking ability to use inhaled medications
- continuous follow-up review of efficacy and side effects to allow adjustments to therapy
smoking cessation has greatest impact on natural history of COPD
what is the initial pharmacological treatment for group A-D COPD according to the GOLD guidelines?
A = bronchodilator
B = LAMA or LABA
C = LAMA
D = LAMA or LAMA+LABA or ICS+LABA
which 3 drugs are the main types used for smoking cessation?
- nicotine replacement therapy
- varenicline
- bupropion
what is the standard of care initial therapy for smoking cessation?
nicotine replacement therapy
can be a patch, gum, inhaler or nasal spray
what is the MOA of nicotine replacement therapy?
full agonist at nicotinic ACh receptors
it reduces withdrawal symptoms associated with cessation of smoking
it does not replicate pleasurable effects of smoking
what is the MOA of varenicline?
partial agonist at nicotinic ACh receptors
it binds to nAChR with higher affinity than nicotine and occupies the receptor, but with lower maximal degree of activation
it relieves withdrawal symptoms and also blocks full effects of smoking because of high affinity to the receptor
used for smoking cessation and it is more effective than treatment with a single NRT or bupropion!
what are the side effects of varenicline?
- nausea
- headache
- insomnia
- vivid dreams
what are the uses of bupropion?
- smoking cessation
- antidepressant
- ADHD
what is the MOA of bupropion?
- increases DA and NE levels in the synapse by inhibiting reuptake transporters
- non-competitive nAChR antagonist
slow onset of action (weeks)
what are the side effects of bupropion?
- nausea
- insomnia
- vivid dreams
- CNS stimulation
- increased suicide risk
what are the contraindications against the use of bupropion?
- seizure disorder or risk for seizures (lowers seizure threshold)
- history of anorexia/bulimia (structural similarity to appetite suppressants)
- undergoing abrupt drug withdrawal (ethanol or sedatives)
- taken an MAOI within 15 days
for smoking cessation, what medication should you use for patients with psychiatric illness?
use varenicline > NRT > bupropion
bupropion most likely to exacerbate severe mental illness
for smoking cessation, what medication should you use for patients with seizures?
varenicline and NRT are safe
bupropion is contraindicated
for smoking cessation, what medication should you use for hospitalized smokers?
with abrupt cessation of smoking associated with hospitalization, NRT is most often used, due to rapid onset of action
for smoking cessation, what medication should you use for pregnant smokers?
benefits of quitting with pharmacotherapy likely outweigh risks of continued smoking
use low doses, and if possible, delay until 2nd trimester (after organogenesis)
