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Pulmonary Week 3 > ICL 2.9: Pharmacotherapy for Asthma, COPD and Smoking Cessation > Flashcards

ICL 2.9: Pharmacotherapy for Asthma, COPD and Smoking Cessation Flashcards

1
Q

what is the general pathophysiology of asthma?

A

allergen causes inflammation subsequent and broncochonstriction from the cytokine storm

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2
Q

what is the general pathophysiology of COPD?

A

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

end result is fibrosis, alveolar wall destruction and mucus hypersecretion

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3
Q

how are most asthma medications administered?

A

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

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4
Q

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

A

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

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5
Q

how are oral drugs metabolized?

A

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

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6
Q

what is the complication with giving inhaled drugs?

A

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

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7
Q

what are the 4 types of inhaled delivery devices?

A
  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
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8
Q

which drug classes cause bronchoconstriction?

A
  1. ACh
  2. adenosine
  3. leukotrienes
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9
Q

what drug classes cause bronchodilation?

A

B agonists that activating cAMP that bronchodilates directly

you can also inhibit bronchoconstriction drugs

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10
Q

which drugs are B agonists used for the lungs?

A
  1. albuterol

2. salmeterol

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11
Q

what is the MOA of B agonists in asthma?

A
  1. Gs-coupled GPCR activation on bronchial smooth muscle causes relaxation (bronchodilation
  2. B2 activation on mast cells reduces histamine release = anti-inflammatory effect
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12
Q

where are B2 receptors located and what do they do?

A
  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
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13
Q

what are the most characteristic side effects of B2 agonists?

A
  1. skeletal muscle tremors and excitement
  2. hypokalemia from PKA-mediated effects on membrane-bound Na/K ATPase
  3. arrhythmia
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14
Q

what are B2 agonists used for in the lungs?

A
  1. all types of asthma

2. COPD

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15
Q

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

A
  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
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16
Q

what do you need to be careful of with LABAs?

A

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

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17
Q

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

A

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**

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18
Q

which drugs are long-acting antimuscarinics?

A

LAMAs

  1. tiotropium
  2. ipratropium

they are both inhaled!

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19
Q

what is the MOA of long-acting antimuscarinics?

A

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)

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20
Q

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

A
  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
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21
Q

what are the side effects of long-acting antimuscarinics?

A

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

  1. somewhat variable efficacy between patients, due to differences in parasympathetic tone
  2. major side effect is dry mouth, a local effect at the site of administration
  3. these drugs have a quaternary amine structure
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22
Q

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

A

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

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

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23
Q

which drug classes are anti-inflammatory drugs?

A
  1. glucocorticoids
  2. methylxanthines
  3. mast cell stabilizers
  4. leukotriene modifiers
  5. anti-IgE MCA
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24
Q

which drugs are glucocorticoids?

A
  1. fluticasone

2. budesonide

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25
Q

what is the MOA of glucocorticoids in asthma/COPD?

A

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

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26
Q

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

A

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

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27
Q

which drugs are systemic corticosteroids?

A
  1. prednisone
  2. prednisolone

given orally

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28
Q

what are systemic corticosteroids used for in the lungs?

A

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

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29
Q

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

A
  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
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30
Q

what are the features of Cushing’s syndrome?

A
  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
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31
Q

which drugs are inhaled corticosteroids?

A
  1. fluticasone

2. budesonide

32
Q

what are the uses of inhaled corticosteroids?

A

they’re first-line maintenance therapy for mild-severe persistent asthma

onset takes days to weeks

33
Q

what are the side effects of inhaled corticosteroids?

A
  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

34
Q

which drugs are anti-IgE monoclonal antibodies?

A

omalizumab

given via SC injection

35
Q

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

A

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

36
Q

what is the dosing for anti-IgE monoclonal antibodies?

A

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!

37
Q

what is the MOA of anti-IgE monoclonal antibodies?

A

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)

38
Q

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

A

rare anaphylaxis but no overdose toxicity

slightly increased malignancy rate

39
Q

which drugs are mast cell stabilizers?

A

cromolyn

given inhaled

40
Q

what is the MOA of mast cell stabilizers?

A

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

41
Q

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

A

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!

42
Q

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

A

no

if you’re having an exacerbation those mast cells have already released their granules and the cytokines are already out

43
Q

which drugs are leukotriene modifiers?

A
  1. montelukast
  2. zafirlukast
  3. zileuton

all taken PO!

44
Q

what are the uses of leukotriene modifiers?

A

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

45
Q

what is the MOA of leukotriene modifiers?

A
  1. blocking the enzyme (5-LO) that synthesizes LTs from arachidonic acid (zileuton)
  2. antagonist activity at LTD4 receptors (montelukast, zafirlukast)
46
Q

why are leukotrienes bad in someone with asthma?

A
  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

47
Q

how does aspirin induce asthma?

A

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

48
Q

what is the onset of action in leukotriene modifiers?

A

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

49
Q

what are the side effects of leukotriene modifiers?

A
  1. headache, nausea diarrhea but otherwise well-tolerated
  2. liver toxicity
  3. increased risk of infection
  4. neuropsychiatric events
50
Q

which drugs are methylxanthines?

A

theophylline

orally

51
Q

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

A

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

52
Q

what are the side effects of methylxanthines?

A
  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
53
Q

what are methylxanthines used for in the lungs?

A

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

54
Q

what is the overdose treatment for methylxanthines?

A
  1. charcoal
  2. hemodialysis
  3. anti seizure medications
55
Q

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

A

roflumilast

given PO and used in COPD prophylaxis treatment

56
Q

what is the MOA of phosphodiesterase-4 inhibitors?

A

inhibits PDE4 which is the enzyme responsible for breakdown of cAMP

this results in cAMP accumulation which:
1. relaxes airway smooth muscle cells (bronchodilation)

  1. suppresses cytokine release and neutrophil lung infiltration
  2. reduces pulmonary remodeling
57
Q

what are the side effects of phosphodiesterase-4 inhibitors?

A
  1. contraindicated in hepatic impairment
  2. rare neuropsychiatric effects, weight loss
  3. CYP3A4 interactions
58
Q

how do you manage asthma?

A
  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

59
Q

how is asthma severity classified?

A

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

60
Q

what is the preferred treatment for all persistent asthma?

A

inhaled glucocorticosteroids

61
Q

what are GOLD guidelines?

A

they outline the management strategies for COPD

emphasis on:
1. demonstrating and checking ability to use inhaled medications

  1. continuous follow-up review of efficacy and side effects to allow adjustments to therapy

smoking cessation has greatest impact on natural history of COPD

62
Q

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

A

A = bronchodilator

B = LAMA or LABA

C = LAMA

D = LAMA or LAMA+LABA or ICS+LABA

63
Q

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

A
  1. nicotine replacement therapy
  2. varenicline
  3. bupropion
64
Q

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

A

nicotine replacement therapy

can be a patch, gum, inhaler or nasal spray

65
Q

what is the MOA of nicotine replacement therapy?

A

full agonist at nicotinic ACh receptors

it reduces withdrawal symptoms associated with cessation of smoking

it does not replicate pleasurable effects of smoking

66
Q

what is the MOA of varenicline?

A

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!

67
Q

what are the side effects of varenicline?

A
  1. nausea
  2. headache
  3. insomnia
  4. vivid dreams
68
Q

what are the uses of bupropion?

A
  1. smoking cessation
  2. antidepressant
  3. ADHD
69
Q

what is the MOA of bupropion?

A
  1. increases DA and NE levels in the synapse by inhibiting reuptake transporters
  2. non-competitive nAChR antagonist

slow onset of action (weeks)

70
Q

what are the side effects of bupropion?

A
  1. nausea
  2. insomnia
  3. vivid dreams
  4. CNS stimulation
  5. increased suicide risk
71
Q

what are the contraindications against the use of bupropion?

A
  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
72
Q

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

A

use varenicline > NRT > bupropion

bupropion most likely to exacerbate severe mental illness

73
Q

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

A

varenicline and NRT are safe

bupropion is contraindicated

74
Q

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

A

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

75
Q

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

A

benefits of quitting with pharmacotherapy likely outweigh risks of continued smoking

use low doses, and if possible, delay until 2nd trimester (after organogenesis)

Pulmonary Week 3 (8 decks)

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