Pulmonary Pharmacology

- dilate constricted bronchi and improve breathing
- reduce the inflammatory response by blocking the inflammatory cascade

- sympathomimetics: Beta-2 adrenergic receptor agonists
- antimuscarinic agents
- non-selective phosphodiesterase (PDE) inhibitors

- corticosteroids
- Mast cell degranulation inhibitors
- leukotriene pathway inhibitors
- anti-IgE

- relax airway smooth muscle by increasing intracellular cAMP levels, thus leading to activation of PKA and resulting in decreased IC calcium

albeuterol
levalbuterol
pirbuterol

1-5 mins

2-6 hr

rapid relief of acute symptoms

- - skeletal muscle tremor
- hyperglycemia
- hypokalemia
- hypomagnesemia
- increased HR
- cardiac arrhythmias

- Salmeterol
- formoterol

15-30in

12 hours

desensitation of Beta-2 adrenergic receptor desensitation

- not as a monotherapy but combined with inhaled corticosteroids for long term control and prevetion of symptoms in moderte to sever asthma

- decreases total dose of corticosteroid while maintaining control of disease by enhancing the action of corticosteroids

- methylzanthines and prototypic drug is theophylline

- relaxes airway smooth muscle by inhibiting PDE-mediated metabolism of cAMP leading to decreased IC calcium levels
- competitively blocks adenossine receptor activation mediated bronchial smooth muscle constriction and histamine release
- promotes apoptosis of eospinophils and neutrophils
- reduces release of inflammatory mediators and increases release of anti-inflamatory cytokines

oral

- 1-2 hours

- CYP1A2

- serum concentration

- alternative but not preferred adjuctive therapy with ICS treatment for moderate persistent asthma.
- potentitates the anti-inflammatory action of corticosteroids

- headache
- nausea
- vomiting
- High conc - arrhythmias and seizures

- caffeine - can be metabolized to theophylline
- drugs affecting CYP1A2

- block M3 muscarinic receptors, decreasing intracellular IP2 levels leading to reduced intracellular Ca2+, thus producing dose related bronchodilationa dn reduction of mucus secretion

inhalation

15-30 min

30-60 min after inhalation

6-8 hours

unchanged

ipratropium bromide

tiotropium bromide

inhilation

24hours

30 mins

3-4 hours

- pts intolerant of inhaled beta-2 agonists
- SAMA administered in multiple doses with SABA in moderate or sever asthma exacerbations to provide additive benefit

- anticholinergic reaction
- allergic type reactions

- dry mouth
- constipation
- mydriasis
- blurred vision
- urinary retention

- interact with trascription factors of growth factor and cytokines thus regulate their gene transcription and protein expression and result in anti-growth, anti-inflammatory, and immunosuppressing effects

- bind to their receptors, corticosteroids interact with

- reduce the number of inflammatory cells at site by promoting eosinophil apoptosis and inhibiting the recuritment of inflammatory cells such as leukocytes
- supress synthesis of inflammatory proteins
- increase synthesis of several anti-inflammatoyr proteins
- decrease mucous secreation
- lessen airway hyperresponsiveness to allergiens

increase expression of B2 adrenergic receptors and preventing the Beta 2 receptor down regulation and uncoupling in response to beta 2 receptor aganists to cause smooth muscle relaxation

-- oral or inhaler

- 7-14 days full action for 6-8 weeks

increase dose of ICS or add LABA

- oral candidiasis
- Dysphonia
- decreased bone mineral density

- Beclomethasone dipropinate
- triamcinolone acetonide
- flunisolide
- budesonide
- fluticasone propinate

- prednisone
prednisolone

- cromolyn
- nedocromil

- Mast cells - inhibit mass cell degranulation causing reduction in release of mediators and blocked chloride channels
- eosinophils - inhibit response of eosinophils to inhaled allergens

- inhalation

unchanged form in urne and bile

1-2 hours

- 3 hours

- 15 mins to peak

preventive treatment before exercise or unavoidable exposure to known allergens
- alternative but not prefered agent for mild persistant asthma

- children of all ages due to lack of toxicity

- children greater than 5 years of age

- zafirlukast
- montelukast

- ziluten

- orally administered with dose 4x a day

- alternative but not prefered for mild persistent asthma
- alternative with ICS to reduce frequency of asthma exacerbation
- asprin induced asthma

inhibition of COX by application of asprin shifts arachidonic acid metabolism from synthesis of prostaglandin to leukotriene leading to asthmatic responses

- possible liver issues monitor LFTs

- increases the half-life of warfarin by inhibition of CYP2C9

- Omalizumab

- IgE monoclonal antibody binds to IgE to prevent the interaction of IgE to the receptors on mast cells and basohils, leading to reduced release of inflammatory mediators and suppressed allergic reaction cascade at a very early stage

- subq every 2-4 weeks
- cleared from blood without deposition in kidney or joints

- used as an adjunctive therapy for pts with sever persistent asthma that can't be controlled by high dose of ICS+LABA
- reduces the freq and severity of asthma

- rare uticaria and anaphylactic rxn
- injection site pain and brusing

long-term exposure to lung irritants causes activation of epithelial cells and macrophages leading to release of inflammatory mediators that attracts inflammatory cells, fibrogenic factors leading to fibroblast proliferation resultin in small airway fibroses, and protease resulting in alveolar wall destruction and mucus hypersecrtation

- sympathomimetics - B2 adrenergic receptor agonists
- Anti muscarinic agents
- Non-selective phosphodiesterase inhibitors

corticosterioids
selevtive PDE4 inhibitor

- acute relief as needed

- SAMA

- LAMA or alone

- inhaled corticosteroids

- indacaterol

- 24h

maintencance treatmetn of airflow obstruction in pt with COPD
- improve lung function in pt with moderate to severe COPD

- drugs that inhibit CYP3A4 and P-glycoprotein transporter

- theophylline

alternative bronchodilator,
when combined with a LABA proudces addictive benefit in pt with COPD

- antimuscarinics are effective or superior due to resting tone maintained by vagal activity and vagal tone is the only reversible element in COPD

- ipatroprium

- alone or combined with saba as a rescue therapy

- tioptropium

- bronchodilator of choice for longterm symptom control in pt with COPD

1) LABA
2) LAMA
3) LABA+ LAMA

- do reduce exacerbations but not mortality
- less effective in treating COPD than asthma
- long term use not recommended

- Roflumilast
- anti-inflammatory agent

- selectively inhibit PDE4 resulting in accumulation of IC cAMP and subsequentially lead to a decrease in inflammatory activity

- oral
- metabolized by CYP3A4 and CYP1A2
- plasma protein binding greater than 90%
- half life 17 for roflumilast and 40 for roflumilast N-oxide
- 70% urine excretion

- prevent COPD exacerbations in pt with sever COPD assoc with chronic bronchitis and hx of exacerbations

- - GI
- Psych changes
- weight loss
- back pain

- pt with moderate to severe liver impairment

- LABA - alone for long term control
- LAMA - Effective or superiro to LABA
- LABA+LAMA -> additive benefits
- LABA+ICS, LAMA+ ICS, ICS+ LAMA+LABA --> severe COPD and frequent exacerbations
- Indacterol - maintence therapy
- nonselective PDE inhibitor - theophylline - alternative therapy
- Selective PDE4 inhibitor - prevention of exacerbation of severe COPD related to chronic bronchitis and a hx of exacerbation