Respiratory Agents Flashcards by Maggie McDonell

How do the SNS and PNS affect the pulmonary system?

SNS:
- B2 adrenoceptors cause relaxation/dilation of smooth muscles in blood vessels, bronchi, the uterus, bladder, and other organs
- done by increasing cAMP
PNS
- stimulation of the vagus nerve leads to bronchoconstriction and increase in mucus secretion
- M3 receptors are most important pharmacologically
  - found on bronchial smooth muscle
  - mediate bronchoconstriction by activating IP3 which increases intracellular Ca
  - mediates mucus secretion

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How do non adrenergic, non cholinergic nerves affect the pulmonary system?

relax airway smooth muscle by releasing NO and vasoactive intestinal peptide (VIP)

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What different parts of the asthma disease process do the drugs effect? (flow chart)

B2 agonists

glucocorticoids

B2- reverse the bronchospasm caused by the histamines and prostaglandins released
glucocorticoids- inhibit the chronic airway inflammation and hyperactivity
**It is important to address both the inflammation and bronchoconstrictive aspects of the disease

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What are the advantages of inhalation drug therapy?

What are the different delivery methods (3)?

Advantages:
- high local concentration of the drug in the bronchial tree, where it is needed
  - enhanced pulmonary effects
  - minimized systemic effects
  - drug onset is rapid, useful for acute attacks
delivery methods:
- MDI- only 10% makes it into lungs
- dry powder inhalers (DPIs)
- Nebulizers

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What are the anti-inflammatory drugs used to treat asthma?

how often are they taken?

which one is most effective?

Taken daily for long-term control
- inhaled corticosteroids (glucocorticoids)
  - most effective preventative treatment for asthma
- Cromolyns
- leukotriene inhibitors
- Anti- IgE antibodies

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Glucocorticoids

MOA?

target?

what effect does it have?

MOA- suppress inflammation by altering genetic transcription
target: glucocorticoid receptor alpha in cytoplasm of airway epithelial cells
- increases transcriptions of genes for B2 receptors and responsiveness
- increases trans of genes for anti-inflammatory proteins
- decreases trans of genes for pro-inflammatory proteins
- induces apoptosis in inflammatory cells (eosinophils, TH2, lymphocytes)
- indirect inhibition of mast cells over time
- reverses bronchial hyperreactivity
- used as suppressive therapy, does not change the progression of the disease NOT A CURE

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What are the different corticosteroids that may be used to help with asthma?

inhaled

Inhaled:
- Budesonide (MDI, neb, or DPI)
- Beclomethasone
- Triamcinolone
- Fluticasone
IV (status asthmaticus)
- Hydrocortisone
- Methylprednisolone
PO (acute exacerbation, but limit time course)
- Prednisone
- Prednisolone
*These patients may need stress dose steroids, but NOT if the steroids they use are inhaled

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How much of any MDI reaches the airway?

10-20%

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What are some side effects of inhaled corticosteroids?

Adrenal suppression (mild compared with IV/PO routes)
oropharyngeal candidiasis
Hoarseness
Delayed growth in children
Osteopenia/osteoporosis
- encourage vit D, Ca, and weight bearing exercise

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What are side effects of IV/PO systemic corticosteroids?

Minor when taken acutely (<10 days), can be severe if used long-term
- myopathy/weakness
- adrenal suppression (taper, do not stop suddenly)
- increased infection risk
- suppression of growth and development
- PUD- increased risk with NSAIDS
- weight gain, edema, hypokalemia
- hyperglycemia- may need to increase insulin dose in DM

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Cromolyn

MOA?

Principle use?

administration?

MOA: Stabilizes pulmonary mast cells
- inhibits antigen-induced release of histamine and the release of inflammatory mediators from eosinophils, neutrophils, monocytes, etc…
- inhibits immediate allergic response to an antigen but not the allergic response once it has been activated
Principle use: Prophylactic therapy of bronchial asthma
- can help prevent exercise induced bronchospasm
- does not releive an allergic response after initiation- not a rescue inhaler
Administration via inhalation- 8-10% enters systemic circulation, poor oral absorption
- taken 4 times daily

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What are the SE of Cromolyn?

Route?

Side effects are rare and it is the safest of all anti-asthma medications
- cough and/or bronchospasm
- Laryngeal edema
- angioedema
- urticaria
- anaphylaxis
route: Inhaled
- MDI or neb

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What are Leukotrienes?

Leukotrienes are made from Arachidonic Acid (AA) when inflammatory cells are activated
C₄, D₄, and E₄ promote bronchoconstriction, eosinophil infiltration, mucus production, and airway edema
Inhibitors reduce these effects

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What are the Leukotriene inhibitors?

How effective are they?

Zileuton (Zyflo)
Zafirlukast (Accolate)
Montelukast (Singulair)
efficacy:
- Less effective than inhaled glucocorticoids
- not effective in treatement of acute attacks

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Zileuton

MOA?

pharmacokinetics?

What do you have to monitor?

SE?

MOA- lipoxygenase inhibitor which blocks the biosynthesis of leukotrienes from AA
- produces bronchodilation, improves asthma symptoms, shows long-term improvement in PFT
Pharmacokinetics:
- low bioavailability, low potency
- Hepatotoxic- monitor LFTs once/month early in tx
SE:
- neuropsychiatric issues- depression, anxiety, agitation, hallucinations, suicidal thinking and behavior
- CYP450 interactions

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Montelukast (Singulair)

MOA?

Uses?

effects?

PB?

Metab?

MOA- Leukotriene receptor antagonist that blocks the mechanism of bronchoconstriction and smooth muscle effects
- prevents leukotrienes from binding to leukotriene-1 receptor
Uses
- used to treat asthma in pts <1 year
- prevents exercise induced bronchospasm >15 years old
- treats allergic rhinitis
Effects:
- improve bronchial tone, pulmonary function, and asthma symptoms
- SE similar to placebo
99% PB
Undergoes extensive metabolism by CYP450
- minimal drug interactions

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Omalizumab

Class?

target/MOA?

When is it used?

Anti-IgE antibody- Humanized mouse monoclonal antibody
Target: Prominence of IgE mediated allergenic responses in asthma
- binds to IgE in the blood inactivating it (IgE levels decrease for a year)
- decreased amt of circulating IgE prevents binding of IgE to mast cells
- Down regulation of receptors d/t less circulating IgE
Only administered to pts who fail all other treatments because there are SO many SEs

Omalizumab

Cost?

SE?

$10,000 per year
SQ, pt must be monitored at hospital, can’t be given at home
1/2 life of 26 days
SE:
- injection site reactions
- viral infection
- URI and sinusitis
- pharyngitis
- H/A
- CV complications- get an EKG
- possible increased risk of cancer
May trigger anaphylaxis
- monitor for 2 hours after 1st 3 doses
- monitor for 30 minutes after all later doses

How do bronchodilators treat asthma?

What are the bronchodilators used?

Provide symptomatic relief but do not alter the underlying disease process (inflammation)
- usually a pt requiring a bronchodilator will also be on glucocorticoid treatment for inflammation
Bronchodilators:
- beta- adrenergic agonists (most effective in asthma)
- anticholinergics
- methylxanthines

Beta Adrenergic receptors:

MOA?

What is the primary effect?

Beta adrenergic receptors are coupled to G-proteins
they activate adenlyl cyclase which increases the production of cAMP, causing bronchodilation
Decreases intracellular Calcium and increases membrane K conductance
Primary effect: dilate the bronchi by a direct action on the B2 adrenoreceptors
- results in smooth muscle relaxation and bronchodilation
- inhibits mediator release from mast cells
- increases mucous action of cilia

What are the Beta adrenergic agonists selective to?

What are the short acting agents?

What are the long acting agents?

Selective to B2
- 200-400x more strongly than to B1
Short acting
- albuterol
- levalbuterol- even less B1 binding, but more expensive
Long acting
- Salmeterol
- terbutaline- IV/PO

Beta adrenergic agonists

onset

use

administration route

Onset 15-30 minutes
Good for use as a rescue inhaler
administered via:
- inhalation or aerosol
- powder or nebulized
- orally or injected (SC)
Short or long acting

What are the side effects of Beta adrenergic agonists?

*SE are minimized by inhalation delivery
tremor
increased HR
vasodilation
metabolic changes
- hyperglycemia
- hypokalemia (increased K conductance into cell)
- hypomagnesemia
With high doses of oral drugs:
- angina, tachydysrhythmias

What is the preferred Beta adrenergic agonist?

How is it administered?

doses?

DOA?

Albuterol
administered via MDI
- 2 puffs, q 4-6 hrs
- 100 mcg/puff
Nebulizer 2.5-5.0 mg in 5 ml of saline
DOA_ 4-8 hours

What are the other Beta adrenergic (Beta2 selective) agonists used to treat asthma?

* Metaproterenol-Alupent * beta2 agonist * MDI * not to exceed 16 puffs/day * longer lasting than albuterol * Bitolterol * longer asting * CV side effects are rare * Daily metered dose is 16-20 puffs/day * each dose is 270 mcg

Terbutaline class use administration/dose

* Beta 2 selective adrenergic agonist * Used to treat asthma * administration: * SC peds: 0.01 mg/kg; adult: 0.25 mg q 15 min * MDI 16-20 puffs/day- 200 mcg/puff

**Salmeterol** or Formoterol Class? what makes it last longer? DOA? What is it used for? Warning?

* Long acting B-agonist * Has a lipophillic side chain that resists degradation and binds to receptor tightly * DOA is 12-24 hours * Good for prevention NOT acute flare * BLACK BOX WARNING: may increase risk of fatal asthma attack * should always be given with a steroid as well

What are the long acting beta agonist/steroid combo drugs? Indications? Warnings?

* Available combination drugs: * Fluticasone/Salmeterol (advair) * Budesonide/Formoterol (symbicort) * Indicated for long-term maintenance in adults and children * convenient, but limited flexibility with dose * reduces symptoms, reduces the risk of exacerbation, and helps reduce steroid dose * Not recommended for initial treatments- many pts only need a glucocorticoid * BLACK BOX WARNING: increased risk of asthma related death

Methylxanthines class? MOA? Effect? Clinical applications? Examples?

* Class: phosphodiesterase inhibitors * MOA: unclear; possible inhibition of phosphodiesterase isoenzymes (Type III and IV) which prevents cAMP degradation in airway smooth muscle as well as in inflammatory cells * possible adenosine receptor blockade at A₁ and A₂ receptors * may also have anti-inflammatory effect * Drug effect: airway relaxation and bronchodilation * Clinical applications: * COPD * asthma * Theophylline (prototype), Aminophylline

What are the problems with Methylxanthines? metabolization?

* Multiple side effects and a narrow therapeutic index * TI plasma level of 10-20 mg/ml * Toxic \>20 mg/ml * wide 1/2 life variation; smokers metabolize 50% faster * Susceptible to drug-drug interactions (CYP450) * Cimetidine, Cipro, and antifungals (CYP450 inhibitors) increase plasma levels * phenobarb and phytoin can decrease levels * **Caffeine** is also a methylxanthine and can increase levels and promote CNS and CV toxicity * Metabolized in liver and excreted in kidney * Sustained release only

What are the SE of methylxanthines?

* Almost always at toxic levels * Cardiac arrhythmias * N/V * irritability * insomnia * sz * brain damage * hyperglycemia * hypokalemia * hypotension * death from CV collapse

Anticholinergic bronchodilators MOA? Uses?

* MOA: competative antagonists at muscarinic acetylcholine receptors * promote smooth muscle relaxation and decreased mucus gland secretion by antagonizing endogenous Ach * **M3 is most important** * Uses * treatment of COPD * second line treatment of asthma

Atropine Class? dose?

* Naturally occurring alkaloid * formally considered 1st line treatment for asthma * 1-2 mg diluted in 3-5 ml of saline via nebulizer * Highly absorbed across respiratory epithelium, causing systemic anticholinergic effects * tachycardia, nausea, dry mouth, GI upset

Ipratroprium bromide (atrovent) structure? MOA? dose? onset? DOA?

* Quanternary ammonium salt derivative of atropine * does not easily absorb across pulmonary epithelium compared to atropine * MOA: antagonizes the effect of endogenous acetylcholine at M3 receptor subtypes * MDI 40-80 mcg in 2-4 puffs * Onset: 30-90 minutes * DOA: 4-6 hours

Tiotropium structure? class? use?

* Quaternary ammonium salt * Long acting anticholinergic * Not significantly absorbed across the resp. epithelium * FDA approved for COPD

How is initial treatment of asthma determined? Goals of asthma treatment? How can this be achieved chronically?

* Stepwise therapy * step chosen for initial therapy is based on pre-treatment classification of asthma severity * moving up or down a step is based on ongoing assessment of asthma control * Goals: to reduce impairment and risk * reduce exposure to allergens and triggers (dust mites, pets, mold, cockroaches) * other factors: tobacco smoke, wood smoke, household sprays

What should you do for acute exacerbation in the OR?

* This requires immediate attention * Goal is to relieve airway obstruction and hypoxemia and normalize lung function as quickly as possible * initial therapy: * oxygen * systemic glucocorticoid to reduce inflammation * nebulized high dose SABA * nebulized ipratroprium * Try ketamine before epi

Are steroids very helpful in COPD?

* Not really, sometimes a trial will be done, but they arent usually very useful * Bronchodilators might work better, but only show modest improvement

What drugs are usually used to treat COPD?

* Usually started on one agent and then will add another if one is not enough * Long acting inhaled beta 2 agonist (salmeterol) * long acting anticholinergic (tiotropium) * Inhaled glucocorticoid (budesonide) is last choice * If using two agents, usually LABA and steroid

What is the new drug used to treat COPD? MOA? SE?

* Roflumilast (Daliresp)- a selective phosphodiesterase type 4 inhibitor that appears to reduce exacerbations * MOA: increases cAMP levels resulting in reduced cough, inflammation, and mucus * SE: diarrhea, weight loss, loss of appetite, nausea, HA, back pain, depression