ICL 2.9: Pharmacotherapy for Asthma, COPD and Smoking Cessation

Question 1

what is the general pathophysiology of asthma?

Answer 1

allergen causes inflammation subsequent and broncochonstriction from the cytokine storm

Question 2

what is the general pathophysiology of COPD?

Answer 2

smoking or other insult leads to epithelial cell injury and a cytokine storm

end result is fibrosis, alveolar wall destruction and mucus hypersecretion

Question 3

how are most asthma medications administered?

Answer 3

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

Question 4

what is the difference for giving oral vs. parenteral administration of drugs?

Answer 4

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

Question 5

how are oral drugs metabolized?

Answer 5

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

Question 6

what is the complication with giving inhaled drugs?

Answer 6

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

Question 7

what are the 4 types of inhaled delivery devices?

Answer 7

1. pressurized metered-dose inhalers (pMDIs) – used as a propellant
2. space chambers – reduced velocity to minimize drugs in oropharynx/maximize to lower airways
3. dry powder inhalers – inhalation scatters the fine powder
4. nebulizers – jet driven by gas stream or ultrasonic vibration

Question 8

which drug classes cause bronchoconstriction?

Answer 8

1. ACh
2. adenosine
3. leukotrienes

Question 9

what drug classes cause bronchodilation?

Answer 9

B agonists that activating cAMP that bronchodilates directly

you can also inhibit bronchoconstriction drugs

Question 10

which drugs are B agonists used for the lungs?

Answer 10

1. albuterol

2. salmeterol

Question 11

what is the MOA of B agonists in asthma?

Answer 11

1. Gs-coupled GPCR activation on bronchial smooth muscle causes relaxation (bronchodilation
2. B2 activation on mast cells reduces histamine release = anti-inflammatory effect

Question 12

where are B2 receptors located and what do they do?

Answer 12

1. heart –> increase rate and force
2. lungs –> bronchodilation
3. arterioles
4. eye –> fluid production
5. bladder –> urinary retention
6. liver/pancreas –> increased serum glucose

Question 13

what are the most characteristic side effects of B2 agonists?

Answer 13

1. skeletal muscle tremors and excitement
2. hypokalemia from PKA-mediated effects on membrane-bound Na/K ATPase
3. arrhythmia

Question 14

what are B2 agonists used for in the lungs?

Answer 14

1. all types of asthma

2. COPD

Question 15

what are the 2 classes of B2 agonists used in the lungs?

Answer 15

1. SABAs = short acting beta agonists –> rapid onset of action for acute exacerbations; NOT recommended for daily, chronic use
   ex. albuterol, terbutaline
2. LABAs = long-acting beta agonists –> longer duration of action for prophylaxis
   ex. salmeterol, indacatarol

Question 16

what do you need to be careful of with LABAs?

Answer 16

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

Question 17

what is tachyphylaxis? which lung drug is it associated with?

Answer 17

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**

Question 18

which drugs are long-acting antimuscarinics?

Answer 18

LAMAs

1. tiotropium
2. ipratropium

they are both inhaled!

Question 19

what is the MOA of long-acting antimuscarinics?

Answer 19

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)

Question 20

what are some other clinical uses for antimuscarinic agents outside the lungs?

Answer 20

1. eye –> cycloplegia, mydriasis
2. CNS –> relieves dystonia and motion sickness
3. GI tract –> antispasmodic effects
4. bladder –> treats overactive bladder
5. glands –> reduces salivation, sweating, gastric secretions

Question 21

what are the side effects of long-acting antimuscarinics?

Answer 21

LAMAs:
1. long duration of action related to longer residence time on receptor (tiotropium has longer duration of action, 24 hours)

2. somewhat variable efficacy between patients, due to differences in parasympathetic tone
3. major side effect is dry mouth, a local effect at the site of administration
4. these drugs have a quaternary amine structure

Question 22

what role does quaternary amine play in the use of LAMAs?

Answer 22

it makes them very poorly-absorbed into blood from lungs or GI tract

this is good because it means almost no systemic side effects!

Question 23

which drug classes are anti-inflammatory drugs?

Answer 23

1. glucocorticoids
2. methylxanthines
3. mast cell stabilizers
4. leukotriene modifiers
5. anti-IgE MCA

Question 24

which drugs are glucocorticoids?

Answer 24

1. fluticasone

2. budesonide

Question 25

what is the MOA of glucocorticoids in asthma/COPD?

Answer 25

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: 1. increase synthesis of anti-inflammatory proteins (e.g., IκB which inhibits NFκB) 2. decrease synthesis of inflammatory proteins (e.g., PGs, LTs, cytokines) 3. 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

Question 26

given the MOA, what would you predict about the speed of onset and offset of glucocorticoids effects?

Answer 26

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

Question 27

which drugs are systemic corticosteroids?

Answer 27

1. prednisone 2. prednisolone given orally

Question 28

what are systemic corticosteroids used for in the lungs?

Answer 28

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

Question 29

what are the adverse effects from long term use of systemic corticosteroids?

Answer 29

1. iatrogenic Cushing’s syndrome 2. HPA axis suppression: abrupt withdrawal can cause lethal adrenal insufficiency so you need to taper the dose if you take them off 3. impaired inflammatory/immune response increases risk of infections 4. children: growth retardation

Question 30

what are the features of Cushing's syndrome?

Answer 30

1. psychosis, impaired memory, sleep disturbances, depression, anxiety 2. hypertension, dyslipidemia 3. overweight, facial fat accumulation, abdominal fat accumulation, impaired glucose tolerance, DM 4. muscle and skin atrophy 5. osteoporosis

Question 31

which drugs are inhaled corticosteroids?

Answer 31

1. fluticasone | 2. budesonide

Question 32

what are the uses of inhaled corticosteroids?

Answer 32

they're first-line maintenance therapy for mild-severe persistent asthma onset takes days to weeks

Question 33

what are the side effects of inhaled corticosteroids?

Answer 33

1. oral candidiasis = thrush 2. 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

Question 34

which drugs are anti-IgE monoclonal antibodies?

Answer 34

omalizumab given via SC injection

Question 35

what are the uses of anti-IgE monoclonal antibodies in the lungs?

Answer 35

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

Question 36

what is the dosing for anti-IgE monoclonal antibodies?

Answer 36

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!

Question 37

what is the MOA of anti-IgE monoclonal antibodies?

Answer 37

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)

Question 38

what are the side effects of anti-IgE monoclonal antibodies?

Answer 38

rare anaphylaxis but no overdose toxicity slightly increased malignancy rate

Question 39

which drugs are mast cell stabilizers?

Answer 39

cromolyn given inhaled

Question 40

what is the MOA of mast cell stabilizers?

Answer 40

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

Question 41

how would mast cell stabilizer effects compare to antihistamines or GCs?

Answer 41

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!

Question 42

would mast cell stabilizers help with an exacerbation that has already started?

Answer 42

no if you're having an exacerbation those mast cells have already released their granules and the cytokines are already out

Question 43

which drugs are leukotriene modifiers?

Answer 43

1. montelukast 2. zafirlukast 3. zileuton all taken PO!

Question 44

what are the uses of leukotriene modifiers?

Answer 44

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

Question 45

what is the MOA of leukotriene modifiers?

Answer 45

1. blocking the enzyme (5-LO) that synthesizes LTs from arachidonic acid (zileuton) 2. antagonist activity at LTD4 receptors (montelukast, zafirlukast)

Question 46

why are leukotrienes bad in someone with asthma?

Answer 46

1. ↓ mucociliary clearance 2. ↑mucus secretion 3. attract leukocytes to airways 4. ↑ 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

Question 47

how does aspirin induce asthma?

Answer 47

aspirin inhibits the COX pathway, shunting arachidonic acid through the 5-lipoxygenase pathway to produce more leukotriene B4, C4, D4, and E4

Question 48

what is the onset of action in leukotriene modifiers?

Answer 48

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

Question 49

what are the side effects of leukotriene modifiers?

Answer 49

1. headache, nausea diarrhea but otherwise well-tolerated 2. liver toxicity 3. increased risk of infection 4. neuropsychiatric events

Question 50

which drugs are methylxanthines?

Answer 50

theophylline orally

Question 51

what are the dose-dependent effects of methylxanthines? MOA at different doses?

Answer 51

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

Question 52

what are the side effects of methylxanthines?

Answer 52

1. CNS, CV and GI side effects = restlessness, tremors, vomiting, insomnia, agitation, flushing, hypotension, delirium, convulsions, shock, arrhythmias 2. narrow therapeutic window + highly variable clearance requires monitoring 3. doubling dosing or crushing/chewing slow release formulations can result in toxicity 4. inhibition of PDE3 results in : - hypotension - tachycardia - headache - emesis 5. inhibition of adenosine receptors results in alterations in cerebral blood flow

Question 53

what are methylxanthines used for in the lungs?

Answer 53

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

Question 54

what is the overdose treatment for methylxanthines?

Answer 54

1. charcoal 2. hemodialysis 3. anti seizure medications

Question 55

which drugs are phosphodiesterase-4 inhibitors? what are they used for?

Answer 55

roflumilast given PO and used in COPD prophylaxis treatment

Question 56

what is the MOA of phosphodiesterase-4 inhibitors?

Answer 56

inhibits PDE4 which is the enzyme responsible for breakdown of cAMP this results in cAMP accumulation which: 1. relaxes airway smooth muscle cells (bronchodilation) 2. suppresses cytokine release and neutrophil lung infiltration 3. reduces pulmonary remodeling

Question 57

what are the side effects of phosphodiesterase-4 inhibitors?

Answer 57

1. contraindicated in hepatic impairment 2. rare neuropsychiatric effects, weight loss 3. CYP3A4 interactions

Question 58

how do you manage asthma?

Answer 58

1. diagnose 2. assess severity 3. initiate mediation and demonstrate use 4. develop written asthma action plan 5. 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

Question 59

how is asthma severity classified?

Answer 59

based on symptoms, lung function, risk, age and use of short-term meds

Question 60

what is the preferred treatment for all persistent asthma?

Answer 60

inhaled glucocorticosteroids

Question 61

what are GOLD guidelines?

Answer 61

they outline the management strategies for COPD emphasis on: 1. demonstrating and checking ability to use inhaled medications 2. continuous follow-up review of efficacy and side effects to allow adjustments to therapy smoking cessation has greatest impact on natural history of COPD

Question 62

what is the initial pharmacological treatment for group A-D COPD according to the GOLD guidelines?

Answer 62

A = bronchodilator B = LAMA or LABA C = LAMA D = LAMA or LAMA+LABA or ICS+LABA

Question 63

which 3 drugs are the main types used for smoking cessation?

Answer 63

1. nicotine replacement therapy 2. varenicline 3. bupropion

Question 64

what is the standard of care initial therapy for smoking cessation?

Answer 64

nicotine replacement therapy can be a patch, gum, inhaler or nasal spray

Question 65

what is the MOA of nicotine replacement therapy?

Answer 65

full agonist at nicotinic ACh receptors it reduces withdrawal symptoms associated with cessation of smoking it does not replicate pleasurable effects of smoking

Question 66

what is the MOA of varenicline?

Answer 66

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!

Question 67

what are the side effects of varenicline?

Answer 67

1. nausea 2. headache 3. insomnia 4. vivid dreams

Question 68

what are the uses of bupropion?

Answer 68

1. smoking cessation 2. antidepressant 3. ADHD

Question 69

what is the MOA of bupropion?

Answer 69

1. increases DA and NE levels in the synapse by inhibiting reuptake transporters 2. non-competitive nAChR antagonist slow onset of action (weeks)

Question 70

what are the side effects of bupropion?

Answer 70

1. nausea 2. insomnia 3. vivid dreams 4. CNS stimulation 5. increased suicide risk

Question 71

what are the contraindications against the use of bupropion?

Answer 71

1. seizure disorder or risk for seizures (lowers seizure threshold) 2. history of anorexia/bulimia (structural similarity to appetite suppressants) 3. undergoing abrupt drug withdrawal (ethanol or sedatives) 4. taken an MAOI within 15 days

Question 72

for smoking cessation, what medication should you use for patients with psychiatric illness?

Answer 72

use varenicline > NRT > bupropion bupropion most likely to exacerbate severe mental illness

Question 73

for smoking cessation, what medication should you use for patients with seizures?

Answer 73

varenicline and NRT are safe bupropion is contraindicated

Question 74

for smoking cessation, what medication should you use for hospitalized smokers?

Answer 74

with abrupt cessation of smoking associated with hospitalization, NRT is most often used, due to rapid onset of action

Question 75

for smoking cessation, what medication should you use for pregnant smokers?

Answer 75

benefits of quitting with pharmacotherapy likely outweigh risks of continued smoking use low doses, and if possible, delay until 2nd trimester (after organogenesis)