Respiratory Drugs

• 2 main classes
• 1. Anti-inflammatory Agents: principle drugs are glucocorticoids 
• 2. Brochodilators: principle drugs are beta2 agonists

• allergen or trigger stimulates mast cells which release mediators (histamines, leukotrines, interleukins, prostaglandins). these cause an infiltration of inflammatory cells and they, mainly the eosinophils release mediators ie cytokines that cause inflammation which causes airflow restriction. Mediators themselves from the mast cells can also cause bronchospasm which contributes to airflow constriction as well. 
• common triggers- cold air, exercise, smoke, pollutants can also cause bronchial hyperactivity leading to bronchospasm

smoke/air pollution causes inflammation of the airway epithelium. infiltration of inflammatory cells and release of cytokines (pmns, macs, lymphocytes, leukotrines, interleukins) not only cause systemic effects such as muscle weakness and weight loss but also cause continuous bronchial irritation and inflammation which causes chronic bronchitis with bronchial edema, hypersecretion of mucous and bacterial colonization of airways which can lead to airway obstruction, air trapping, loss of surface area for gas exchange, frequent exacerbations, bronchospasms and infections. these cause things like dyspnea, cough, hypoxemia, hypercapnea, and cor pulmoale

again, smoke/pollution causes inflammation of the airway epithelium. infiltration of inflammatory cells and release of cytokines (pmns, macs, lymphocytes, leukotrines, interleukins) cause inhibition of normal endogenous antiproteases (this could also be caused by alpha1 antitrypsin deficiency) and increased protease activity with breakdown of elastin in lung connective tissue which causes emphysema (destruction of alveolar septa and loss of elastic recoil of bronchial walls) which again causes airway obstruction, air trapping, loss of surface area for gas exchange, frequent exacerbations, infections and bronchospasm which lead to dyspnea, cough, hypoxemia, hypercapnia and cor pulmonale

• inherited
• causes inhibition of normal endogenous antiproteases
• since they are inhibited, protease activity increases and they break down elastases, causing emphysema

• administered on a fixed schedule for asthma
• almost always inhaled
• inhaled: beclomethasone dipropionate (QVAR), Budesonide (PulmicortFlexhaler, Pulmicort Respules, Pulmicort Turbuhaler), Ciclesonide (Alvesco), Flunisolide (Aerospan), Flutaicasone propionate (Flovent HFA, Flovent Diskus), Mometasone furoate (Asmanex Twisthaler)
• Oral: methylprednisolone (A-methapred, depo-medrol, medrol, medrole dose-pak), Prednisolone (Flo-Pred, Milllipred, prelone), Prednisone (Deltasone, Winpred)

• main: glucocorticoids
• leukotriene modifiers
• cromolyn
• IgE antagonists
• Phosphodiesterase-4 inhibiters

• inhalation: therapeutic effects are enhanced by delivering drugs directly to site of action, systemic effects are minimized, relief of acute attacks is rapid
• types: metered dose inhalers, respimats, dry-powder inhalers, and nebulizers

• small, hand-held, pressurized devises that deliver a metered dose of drug with each actuation
• dosing usually done with 1-2 inhalations with 1min between
• begin inhaling before activating the device
• 80% affects oropharynx and is swallowed, 10% goes to lungs and 10% left in device or exhaled
• use a spacer to increase delivery of drug to the lungs and decrease deposition in oropharynx mucosa

• inhalers that deliver drugs as a very fine mist
• activated by the user, however the device does not use propellants unlike MDI
• the extremely small particle size ensures greater delivery of drug to the lungs and less drug falls out of the mist due to partical weight and less in the mouth and pharynx

• DPIs 
• used to deliver drugs in the form of a dry micronized powder directly to lungs
• breath activated, so they dont require hand breath coordination
• easier to use
• deliver more drug to the lungs than MDI (20%)

• a small machine used to convert a drug solution into a mist
• droplets in the mist are much finer than those produced by inhalers, resulting in less drug deposit in oropharynx and increased in the lungs
• can have facemask or mouthpiece
• mist inhaled with each breath, no hand breath coordination
• take several mins to deliver the same amount of drug contained in one inhaler breath, but for some PT its more effective
• usually used at home or in a clinic or hospital, but are portable

• the most effective drugs available for long-term control of airway inflammation
• usually inhaled, but can be IV or oral
• adverse reactions are minor, except if systemic ones (iv) are taken long term

• supress inflammation by: decreasing synthesis and release of inflammatory mediators (leukotrines, histamine, prostaglandins etc), decreasing infiltration and activity of inflammatory cells (like eosinophils), and decreasing edema of the airway mucosa by decreasing vascular permeability)
• by suppressing inflammation, they reduce bronchial hyperreactivity and decrease airway mucous production
• may also increase the number of bronchial beta recepttors and their responsiveness to beta 2 agonists, another med for asthma

• used for prophylaxis (disease prevention) of chronic asthma
• dosing must be done on a fixed schedule
• bc beneficial effects develop slowly, these drugs cannot be used to abort an ongoing attack
• do not alter the natural course of asthma
• inhaled: first line therapy for management of the inflammatory component of asthma. most pts with persistant asthma should take them daily. very effective and safer than systemic glucocorticoids
• oral: may be required in patients with moderate to severe persistant asthma or for acute exacerbations of asthma/COPD. ony prescribed when safer meds cant control symptoms, as they can be toxic. risk of toxicity increases with each use, so stop treatment asap

• even in high doses, chances of severe toxicity is low
• most serious concern: adrenal suppression, may develop with long-term high dose therapy but still low suppression, not that bad
• most common effects: oropharyngeal candidiasis and dysphonia. both result from local deposition of inhaled meds
• can slow growth in children and solescents but dont decrease adult height
• longterm use may promote bone loss, but loss is much lower than oral routes

hoarseness, speaking difficulty

• use spacer, rinse mouth with water and gargle after inhaling to reduce dysphonia and oropharyngeal candidiasis (take antifungals if candidiasis develops)
• use the lowest effective dose and ensure adequate calcium and vitamin d and participate in weight bearing exercise to prevent bone loss

• when used acutely, even in very high doses, no significant adverse effects, but long term use even in smaller doses does
• more severe adrenal suppression
• osteoporosis
• hypoglycemia
• peptic ulcers
• growth suppression (in young pts)

• biggest concern: adrenal suppression- can prevent adrenal cortex from producing its own glucocorticoids. This can be life-threatening if person gets severe stress (surgery, trauma or systemic infection)
• pts must be given more glucocorticoids IV in stress to survive if on these
• several months are required for adrenalcortex function after discontinuation, so its important to decrease dose gradually so you have some glucocorticoids and give supplemental IV ones in stress

compounds that promote smooth muscle constriction, blood vessel permeability, and inflammatory responses through direct action as well as through recruitment of eosinophils and other inflammatory cells

• suppress the effects of leukotrienes
• in patients with asthma, they can decrease bronchoconstriction and inflammatory responses such as edema and mucous secretion

• zileuton
• zafirlukast
• montelukast

• Trade: Zyflo, Zyflo CR
• blocks leukotriene synthesis
• for asthma prevention and maintenance in anyone over 12
• symptom improvement in 1-2 hours after dosing, so cant be used for a current attack
• less effective than an inhaled glucocorticoid alone, and less effective than a long acting inhaled beta 2 agonist in pt who glucocorticoids dont control symptoms

• inhibits 5-lipoxygenase, the enzyme that converts arachidonic acid into leukotrienes
• this decreases the amount of leukotrienes available to induce inflammation

• oral
• absorbed rapidly with or without food
• plasma levels peak 2-3 hours after ingestion
• rapidly metabolized by liver
• excretion: metabolites in urine
• half life: 2.5 hours

• livery injury- hepatitis (reversed after drug withdrawal)
• neuropychiatric effects: depression, anxiety, agitation, abnormal dreams, hallucination, insomnia, restlessness, suicidal thinking/acts
• can slow metabolism of drug substrates metabolized by CYP1A2 isoenzymes and increase concentrations of those drugs if doses not adjusted properly

Alanine Aminotransferase ALT activity monitored- increased levels means liver impaired- monitor once a month for 3 months then every 2-3 months for year 1 then periodically thereafter

• trade: Accolate
• leukotrine receptor antagonist- blocks leukotriene receptors
• oral 
• for ppl over 5

reduces infiltration of inflammatory cells by blocking receptors, resulting in decreased bronchoconstriciton

• absorption: rapid, food reduces it by 40%, so 1hr before meals or 2hrs after
• metabolism: liver
• excretion: feces
• half life: 10hrs, up to 20 in older

• most common: headache and GI disturbances (infrequent)
• arthralgia and myalgia
• same neuropsychiatric effects as zileuton
• rare: clinical signs of liver injury
• inhibits several enzymes of cytochrome P450 so metabolism of drugs that need it may be slower, which can cause toxicity if not dosed accordingly

• trade: Singulair
• a leukotriene receptor blocker
• most commonly used leukotriene modulator
• uesd for prophylaxis and maintenance therapy of asthma in patients over a year, prevention of exercise induced bronchospasm in pt over 15years, and relief of allergic rhinitis
• effects develop within 24hrs of first dose and are maintained with once daily dosing- so not for an active attack
• decreases asthma related nocturnal awakening, improves morning lung function, and decreases need for short acting inhaled beta2 agonists

• has a high affinity for leukotriene receptors in the airway and on proinflammatory cells like eosinophils
• occupies receptors and blocks receptor activation by the bodys leukotrienes

• absorption: rapid after oral. bioavailability 64%. blood levels peak 3-4hrs after ingestion
• drug highly bound (more than 99%) to blood plasma proteins
• metabolism: extensive by hepatic cytochrome p450 enzymes
• excretion: bile
• half-life: 2.7-5.5 hrs

• generally well tollerated
• does not cause liver injury like zileuton and zafirlukast
• possible neuropsychiatric effects, esp mood changes and suicide
• no serious drug interactions, doesnt increase thophylline or warfarin levels like the other 2 bc it doesnt inhibit p450

• an inhalational agent that suppresses bronchial inflammation
• used for prophylaxis, not quick relief in ppl with mild to moderate asthma
• anti-inflammatory effecs are less than with glucocorticoids, so its not preffered unless glucocorticoids cant be used

• suppresses inflammation
• does not cause bronchodilation
• stabilizes the cytoplasmic membrane of mast cells, preventing release of histamine and other mediators
• inhibits eosinophils, macrophages and other inflammatory cells

• administered by nebulizer
• fraction absorbed from lungs is small and rarely produces significant systemic effects
• excreted unchanged in the urine

• chronic aslthma: alternative to glucocorticoids for mild persistant asthma. reduces frequency and intensity of asthma attacks but best effects may take weeks. good for allergy attacks
• exercise induced bronchospasm: can prevent bronchospasm. give 10-15 min before exertion
• allergic rhinitis: intranasally can relieve symptoms

• safest of all antiasthma meds
• cough or bronchospasm occurs in a tiny fraction of ppl

• a monoclonal antibody
• IgE antagonist
• a second line agent indicated only for allergy related asthma when preffered options have failed
• modest benefits with significant drawbacks

• forms complexes with free IgE in the blood and thereby reduces the amount of IgE available to bind mast cell receptors and therefore limits the ability of allergens to trigger histamine and leukotriene and other mediator release
• this prevents brochospasm and airway inflammation related to allergies
• decreases IgE in serum by 96% but needs a year after stopping for it to go back to normal

• only for ppl over 12 with allergic asthma that cannot take a glucocorticoid
• pts should get an allergen test to confirm asthma is allergy related

• route: subQ
• absorption: slow, peak plasma levels in 7 to 8 days
• metabolism: liver, drug is degrated
• half life: 26 days

• most common: injection site rxn, viral infection, URI, sinisitis, headache, pharyngitis
• small risk of cardiovascular problems and cancer
• most serious: anaphylaxis" rare but most likely with first dose. observe for 2 hours after first 3 doses and for 30min after all others

• Decreases release of inflammatory cells
• approved for treatment of severe COPD with a chronic bronchitis component
• NOT for asthma

• a phosphodiesterase type 4 (PDE4) inhibitor. PDE4 is an enzyme that breaks down cyclic adenosine monophosphate (cAMP). the end result of this process is increased release of inflammatory mediators
• by inhibiting the enzyme the med decreases the release of inflammatory products
• prevents inflammation and decreases damage to lung tissue thereby improving pulmonary function

• highly (99%) protein bound
• half life: 17hrs
• metabolism: by CYP3A4 and CYP1A2 enzymes
• excretion: urine

• psychiatric effects are most concerning: anxiety, depression, suicidal behavior
• loss of appetite
• gi complaints (nausea, diarrhea), insomnia, headache
• can cause toxicity of drugs competing for CYP3A4 and CYP1A2 enzymes for metabolism with it

• provide symptomatic releif in patients with asthma and COPD but do not alter the underlying inflammation that is part of the disease process
• usually combined with an inhaled glucocorticoid for this reason
• used alone only for very mild asthma with infrequent attacks

• main: beta2-adrenergic agonists
• methylxantines
• anticholinergic drugs

• inhaled most common, but can be oral
• the most effective drugs available for relieiving acute bronchospasm and preventing exercise induced bronchospasm (EIB)
• nearly all asthma pt have these first line drugs as a component of treatment

• sympathomimetic drugs that activate beta2-adrenergic receptors
• by activating these receptors in smooth muscle of the lungs, they promote bronchodilation and relieve bronchospasm
• have a small role in suppressing histamine release in the lung and increasing ciliary motility

• all oral are long acting
• some inhaled are short acting (Short acting beta2-adrenergic agonists- SABAs) and some are long acting
• short acting inhaled: effects begin immediately, peak in 30-60min and persist for 3-5 hours, so can be used for ongoing attack. taken PRN
• long acting inhaled (LABAs): onset depends on drug. used on a fixed schedule for long term control for those with frequent attacks,

• LABAs preferred over SABAs in patients with stable COPD
• SABAs are the first line therapy in asthmatics
• LABAs must always be combined with a glucocorticoid. alone, they can increase asthmatic death

• used only for longterm control bca onset is too slow
• like LABAs not a first line therapy

• well tollerated
• systemic effectys- tachycardia, angina and tremor can occur but are usually minimal
• overdose can caus tachydysrhymisas and siezures and even death. if patine is using SABA more than twice a week you need to step up therapy

• may increase risk fo severe asthma and asthma death if used alone for long term control
• use with a glucocorticoid

• not super selective for just beta 2 receptors so can activate beta1 receptor sin the heart
• if dosage is excessive, stimulation of cardiac beta 1 receptors can cause angina pectoris and tachydysrhythmias
• often cause tremor by activating beta 2 in skeletal muscle

• CNS excitors and bronchodilators
• main type: theophylline

• the principle methylxanthine employedi n asthma
• benefits come primarily from bronchodilation
• has a narrow therapeutic range so control dose carefuly
• oral, but can be IV

• relaxes bronchi smooth muscle for bronchodilation
• most likely blocks adenosine to do this but not fully known

• used for chronic stable asthma
• appropriate for those with nocturnal asthma attacks because its effects are prolonged
• no longer recommended for COPD, used to be
• use as a last option in COPD
• IV can be used in emergencies, but its no more effective but is more dangerous than b2agonists and glucocortiocids

• absorption: oral can be sustained release or elixir. abs. from SR is slow and can be altered by food
• metaboism: liver, rate varies by individual. half life changes based on many factors