1. Permits drugs delivery directly to the target tissue
2. Most asthmatic patients can be managed by aerosol treatments alone (assuming they can use an inhaler) 

Drug deposition:

1. Particle size (> 10 um deposit in the mouth and oropharynx;< 0.5 um are inhaled and then exhaled; particles 1-5um are deposited in the small airways and are really effective 
2. How much patient can hold their breath 

Primary route of absorption:

• Only 2-10% od drug is deposited in the lungs; the remainder is usually swallowed.  So to avoid SE, need a drug that is either poorly absorbed in the GI tract or quickly inactivated by the liver 

• Metered-dose inhalers (MDI):  Pressurized canisters that deliver the drug w/hydrofluoroalkane (HFA), co-solvents, and/or surfactants.  Dose is controlled by meter valve
• Nebulizer:  Administered w/face mask.  Used for severe asthma attacks
• Dry powder inhaler:  Require high airflow to suspend powder, can be irritating when inhaled

• Young children (< 5 yrs of age):  Who cannot manipulate the metered dose inhalers and have occasional wheezing w/upper respiratory tract infections. Use oral albuterol or metaproterenol syrups 
• Individuals where aerosol, nebulizer, or MDI is irritating and causing a worsening of cough and bronchospasm:  Such as in the setting of severe asthma exacerbation.  Oral administration of albuterol or terbutaline 

Albuterol (rapid acting) 

Salmeterol (slow acting)

Epinephrine 

This is important in emergencies in which it is administered systemically 

• Preferred therapy for bronchoconstriction.  They are the ONLY agents that have been shown to be effective IMMEDIATELY
• Inhalation of Beta-2 agonists usually produce an excellent bronchodilation and used for short-term protection against respiratory challenge 

Albuterol 

• SABA = short acting beta-2 agonists are rapidly acting 
• Used as "rescue inhalers" 
• Used as needed for treatment of acute bronchospasm 
• May be used as prophylactic treatment for exercise induced bronchospasm 

Salmeterol 

• LABA = Long-acting beta-2 adrenergic agonists 
• Much longer onset of action
• Used in combination w/corticosteroids in prophylaxis of asthma

• These might be associated w/worsening asthma control + increase risk of asthma-induced death 
• Discontinue use of LABA after asthma has been brought under control 
• There is a black-box warning "Long-acting beta-2 adrenergic agonists may increase the risk of asthma-related death."  
• They should ONLY be used for patients that are NOT adequately controlled by inhaled corticosteroids alone 

• Beta-adrenergic agonists stimulate adenylyl cyclase → causes increase in intracellular cAMP → causes decrease in intracellular calcium → causes bronchial smooth muscle relaxation and inhibits mediator relase from mast cells 

SABA 

Example

Onset 

Duration

ROA

• Example:  Albuterol 
• Onset:  < 15 minutes
• Duration:  6-8 hours
• ROA:  Metered dose inhalers; solution for nebulizer; powder inhaler; syrup; tablet; extended release tablets 

Non-selective beta agonists

Example

Use 

ROA 

Effects 

• Example:  Epinephrine
• Use:  Given to patients that are unable to take aerosolized B2-agonists b/c age or asthma severity.  It is the DOC for emergency treatment of anaphylactic reactions in general.  
• ROA:  Subcutaneous Injection (normally); can also be given IM or IV 
• Effects:  Vasoconstriction that limits edema and swelling in the upper airways and bronchodilation and inhibits mediator release by mast cells 

LABA 

Examples

• Examples:  Salmeterol and Formoterol 

Salmeterol 

MOA

Onset

Duration

Use 

• MOA:  LABA
• Onset:  Slow onset so it is NOT suitable for acute bronchospasm 
• Duration:  It is long acting (12 hours) 
• Use:  Prophylactic treatment of asthma.  Used to prevent nighttime asthma attacks 

Formoterol/Arformoterol

MOA

Use

ROA

• MOA:  LABA
• Use:  For maintenace therapy of asthma or prevention of bronchospasm in COPD and exercise induced asthma.  
• ROA:  Dry powder and recently approved for solution in nebulization 
• Note:  Arformoterol is an isomer of formoterol and used for treatment of COPD as nebuilizer 

Indacaterol 

MOA

Use 

ROA

• MOA:  LABA
• Use:  Maintenance treatment for COPD
• ROA:  Powder inhaled once/day

• CNS stimulation:  Restlessness/apprehension/anxiety/tremors.  Muscle tremors are the most common SE
• CVS stimulation:  Tachycardia due to beta-1 stimulation or reflex stimulation after beta-2 vasodilation.  Dysrhythmia especially in patients taking MOA inhibitor or tricyclic anti-depressant.  Hyper or hypo-tension 
• Hypokalemia:  Especially when patients are taking non-potassium sparring diuretic or systemic corticosteroids.  This is because beta-1 agonists cause release of renin and cause increased Na reabsorption and loss of K
• Hyperglycemia:  B1 is going to cause decreased levels of insulin and so diabetics will require more insulin 

Aclidinium bromide

Ipratropium bromide

Tiotropium 

"ium" drugs 

"ium" drugs

• Muscarinic receptor antagonists 
• Drugs target parasympathetic-mediated bronchospasm 

• Symptoms of cold
• Diarrhea

"ium drugs"

• Principal use is for COPD.  
• Sometimes used for asthma, mainly in patients that are tolerant to beta-2 agonists or who must take a beta-blocker

Anti-Cholingerics 

ROA and why

Downside of anti-ACh vs beta-agonist 

• ROA:  All three are inhaled.  This produces little or no change in HR, BP, bladder fucntion, intraocular pressure, pupillary diameter b/c poor absorption from lung or GI-tract
• Anti-ACh vs beta agonist:  Bronchodilation w/ipratropium more slowly and is less intense than by beta-agonists

Anti-ACh combination

When do you use it?

Ipratropium + Albuterol 

• Results in greater and prolonged bronchodilation than either therapy alone. 
• Use when there is severe asthma exacerbation 

• PS-tone + degree of reflex activation of cholinergic pthwy differs from patient to patient 
• PS-mediated bronchospasm may be a component of pathophysiology of individuals w/asthma or COPD patients 

Theophylline 

Remember that methylxanthines are bronchodilators 

Theophylline is a methylxanthine 

• Methylxanthines include adenosine receptor ANTAGONISM and inhibition of cyclic nucleotide phosphodiesterases (cyclic-AMP and cyclic-GMP).  Aka anti-PDE.  Leads to an increase in cAMP and cGMP 

Theopylline = methylxanthine 

• CNS stimulation 
• Cardiac stimulation 
• Peripheral vasodilation 
• Increased skeletal muscle contractility
• Thiazide-like diuresis 

Methylxanthine use

Examples of methylxanthine drugs (both of them) 

Methylxanthine drugs = theophylline + aminophylline 

Methylxanthine drugs = "line" drugs

• Theophylline:  Formerly DOC for asthma.  Still some use in the trtmnt of nocturnal asthma.  However, it is less prominent because: 

1. Less effective than newer drugs
2. Narrow therapeutic window 
3. Considerable variation in absorption + elimination b/t patients 
4. Plasma drug levels need to be monitored (therapeutic concentration = 5-10; 15 some individuals have anorexia/nausea/vomiting; > 20 is toxic and lead to seziure + arrhythmias) 

• Corticosteroids
• Cromolyn compounds 
• Leukotriene inhibitors 

Beclomethasone

Dipropionate 

Budesonide

Fluticasone 

Mometasone 

Prednisone 

Methylprednisolone

• Glucocorticoid receptors (GRs) are activated by TF ligands bindings.  They are part of nuclear receptor superfamily.  Another member of this family is thyroid hormone receptor (TR).  
• Glucocorticoid binds to INTRACELLULAR receptor in the cytoplasm → GRs bound to ligand translocates to the nucleus → causes positive gene transcription if bound to specific-DNA-response elements or negative regulation of gene transcription if bound to other transcription factors 
• Glucocorticoids can also alter membrane potentials known as enrichment
• For asthma, cause down-regulation of many genes involved in inflammatory response such as interleukins 

• Glucocorticoid receptors are distributed throughout the body and so they can cause a variety of SE. HOWEVER the dose via inhalation is small and so the PRIMARY side-effect in inhaled glucocorticoids is mainly local called oral candidiasis 

***Enrichment is caused by glucocorticoids***

There were 3 discoveries that allowed for the the formation of glucocorticoids with tissue specificity and thus allowed for the identification of new therapeutic targets of glucocorticoids:

1. Discovery that co-regulators are necessary for GR transcriptional effects 
2. Discovery that co-regulators mediate changes in chromatin structure and contribute to epigenetic changes 
3. Solution of nuclear receptor crystal structures 

• Studies have shown that asthmatic patients on inhaled corticoids have an improvement of symptoms and lowered requirements for "rescue" w/beta-adrengeric agonists.  This improvement is seen w/in 1 week and can continue for up to 2 years or longer 
• Reduction in dose over time is often possible 

• Asthmatic patients who require beta-adrenergic agonists 2+ times/week 

ROA for glucocorticoids 

Benefit and downside of each 

When would you use said method

• Aerosol:  Equivalent in efficacy and with equivalent SE.  However, the amount of drug that is inhaled varies considerably based on the patient.  Therefore, steroid dose must be determined empirically for each patient.  
• Systemic: In the most severe asthmatic attacks such as those requiring hospitalization. Prednisone or methylprednisolone is given via IV and followed by gradual tapering of oral doses.  In less severe cases, oral prednisone is given for 1-2 weeks.  Longer treatment requires gradual tapering b/c hypothalamic-pituitary-adrenal axis becomes suppressed.  

Beclomethasone 

Dosing 

Triamcinolone 

Dosing 

Flunisolide 

Dosing 

Used twice daily 

• Historically:  Inhibition of mast cell granule release (questionable)
• Currently:  Suppress activating affects of chemo-atractant peptides on eosinophils, neutrophils, and monocytes 

**Use has diminished considerably b/c of inhaled corticosteroids**

• Used prophylactically. When inhaled several times a day, can inhibit BOTH the immediate + late asthmatic reponses to antigenic challenge or exercise.  Less effective than corticosteroids but are used as alternative to inhaled corticosteroids in children
• Nedocromil is more effective than cromlyn and has been approved for asthmatic patients > 6 years of age 
• Useful in mild-moderate asthma and are added to therapeutic regiment or used as alternatives for beta-agonists or methylxanthines.  They are less effective than inhaled corticosteroids. 
• With long-term use, bronchial hyperreactivity to allergins/histamine/exercise may become diminished 

***Montelukast***

Zafirlukast 

Zileuton 

• Leukotrine (LT) are mediators of inflammation and anaphylaxis.  They are derived from arachidonic acid in the 5-lipoxogenase pathway.  They are made by eosinophils + mast cells + macrophages + basophils 
• LT-B4 = neutrophil chemoattractant
• LT-C4 + LT-D4 = bronchoconstriction + increased bronchial reactivity + mucosal edema + mucus hypersecretion 

Montelukast

MOA

ROA

Absorbtion 

Metabolization 

1/2 Life 

• MOA:  Selective inhibition of LT-D4 receptor
• ROA:  Oral
• Absorbtion:  Rapid w/peak concetration in 1-3 hours
• Metabolization:  Metabolized by the liver and excreted in the urine 
• 1/2 life:  2.5 hours, so needs to be dosed often 

Inhibition of 5-lipoxigenase 

So it is an inhibitor of leukotriene synthesis 

• Dyspepsia (m/c SE)
• Liver toxicity (contraindicated in patients with Ab liver function)

• Especially useful in patients w/aspirin-induced asthma attacks.  This is b/c aspirin in these patients causes arachidonic acid to be shifted from producing prostaglandin to leukotriene production 
• Modestly effective for maintenance therapy 
• No as effective as steroids 
• NOT recommended for acute asthma attacks

MOA of omalizuab 

Elimination 

Half-life 

ROA

Omalizuab = monoclonal Ab against IgE

• MOA:  Binds to human IgE w/high-affinity at the Fc receptor.  Prevents IgE binding to cells that are associated with the allergic reponse 
• Elimination:  Slowly eliminated 
• Half-life:  22 +/- 9 days
• ROA:  SC

• Anaphylaxis 
• Costs 6K-24K a year!!!

• Moderate-severe allergic asthma which is refractory to trt w/inhaled corticosteroids