Advanced Pharmacology: Respiratory Drugs

chronic inflammatory disorder of the airway leading to recurrent but reversible episodes of airway limitations and hyperresponsiveness, wheezing, breathlessness, and coughing

Asthma pathophysiology: early
IgE binds to receptors on most cells with allergen exposure causing degranulation and release of histamine, proteolytic, enzymes, cytokines, leukotrienes, and prostaglandin resulting in bronchoconstriction, vasodilation, and airway inflammation

Asthma pathophysiology: late
Activated TH2 lymphocytes release cytokines that recruit more inflammatory cells (eosinophils, mast cells, IgE producing B cells), leads to airway hyperresponsiveness, edema, mucous production, fibrosis (scarring), and airway remodeling

Airway remodeling
chronic inflammation that replaces healthy tissue with scar tissue. Weakens lung function and growth. IRREVERSIBLE

Asthma triggers
allergens, exercise, cold air, environmental pollutants, or stress

Chronic inflammatory reactions
lead to airway remodeling and damage

Pulmonary Function Tests
Spirometry, PEF, FVC, FEV1

forced expiratory volume in 1 second (less than 25% of predicted value indicates disease)

forced vital capacity- maximum act one can forcibly exhale with full inspiration

peak expiratory flow (maximum speed of inspiration)

most common PFT, detects 2 abnormal patterns-obstructive (asthma) or restrictive

Reduced ratio of FEV1:FVC suggests
obstruction, indicative of asthma

Asthma classifications
Intermittent or persistent-mild, moderate, severe

Treatment goals
minimal or no symptoms, infrequent episodes, no ED visits, minimal need for reliever medication (SABA), no limitations on activity (including exercise), normal PEF, minimal adverse effects

Treatment approach
“stepped therapy”, as few meds as possible

short acting Beta2 antagonist, Albuterol or Xopenex, used for quick relief

Inhaled Cortocisteroid- QVAR, Pulmicort, Flovent, Asmanex, used for maintenence

Long acting Beta-adrenoceptor agonist. Should not be used without ICS. Servant, Foradil

Combination Products
Fluticasone/Solmeterol (Advair), Budesonimide/formoterol (Symbicort)

Persistent asthma med progression
1) SABA prn 2) low dose ICS, SABA 3) Med dose ICS, or low dose ICS, LABA and SABA 4) Med Dose ICS, LABA and SABA 5) High dose ICS, LABA, SABA (omidizumab?) 6) High dose ICS, LABA, SABA, oral corticosteroid (omidizumab?)

Histamine and asthma
Asthmatics’ bronchial smooth muscle may be 1000x more sensitive to histamine induced bronchoconstriction than non asthmatics

Why don’t we use histamines with asthma?
although they may block histamine release, they do no reverse bronchoconstriction. Can be used in allergic reactions

Beta 2 Agonist Adverse Effects: Common
tremor, nervousness, headache, nausea, tachycardia

Beta 2 Agonist Adverse Effects: Long term use
Tolerance (receptor desensitization, increases asthma exacerbation, decreases bronchoprotection)

Causes of tolerance of Beta 2 Agonists
receptor down regulation, genetic polymorphisms or beta receptor, isomer effects (can use levalbuterol or Xopenex- same chemical compound).

Corticosteroids MOA
Enter cellular membranes, bind to glucocorticoid receptors, activate receptor complexes (travel to nucleus where they act as gene transcription factors to increase the production of anti-inflammatory mediators and decrease production of pro inflammatory mediators OR travel within the cytoplasm where they bind to and increase the activity of 2 rapidly acting pro inflammatory transcription factors- nuclear factor KB and activating protein 1)

Corticosteroid effects are noticeable at
1-2 weeks

Corticosteroids are in full effect at
4-8 weeks

When combined with Beta 2 agonists
the rate at which the glucocorticoid receptor translocates to the nucleus increases

substance that forms a complex with a biomolecule to serve a biological purpose

Adverse effects: ICS
Local: oral candidiasis Systemic: adrenal suppression, bone loss, growth suppression

Interactions between steroids and beta agonists
synergistic effect, beta 2 receptor gene has steroid sites-offsets one of the mechanisms for desensitization

Steroids and long acting Beta agonists
promote translocation of glucocorticoid receptor into the nucleus without a ligand present, accelerate the rate of translocation when a ligand is present

combination ICS and LABA

Asthma Pharmacotherapy additional drug classes
Leyukotrine receptor antagonists (Singular), Leukotrine synthesis inhibitors (Zyflo), Anti-antibody (omalizumab-Xolair)

Leukotriene synthesis
lipoxygenase enzymes catalize arachidonic acid metabolism leading to the formation of leukotrienes. They bind to cysteinyl leyukotrine receptors. Upon binding they stimulate asthma- airway edema, smooth muscle contraction, and induce allergic inflammatory cells

a class of lipid inflammatory mediators

cysteinyl leyukotrine receptors
located in airway smooth muscle cells, produced in mast cells, eosinophils and airway macrophages

If cysteinyl leyukotrine binding is blocked,
many symptoms of asthma can be successfully treated

Leukotriene Receptor Inhibitor example and indication
Monteluask (Singulair), asthma, seasonal allergic rhinitis

Leukotriene Receptor Inhibitor MOA
Competitive antagonist of cysteinyl leyukotrine receptors

Leyukotrine Formation Inhibitor example and indication
Zileuton (Zyflo), prophylaxis and chronic treatment of asthma

Leukotreine Formation inhibitor MOA
inhibits 5-lipoxygense

the enzyme that facilitates arachidonic acid metabolism

Leukotriene Formation Inhibitor Adverse effects
can case liver problems, monitor LFTs closely

IgE antibody receptors are located on
mast cells

IgE binding to mast cells produces
an inflammatory cascade

Inflammatory cascade causes
smooth muscle contraction, vascular leakage, secretion of mucous, all of which impair breathing

Anti IgE: Omalizumab (Xolair) MOA
Binds to Fc, a fragment of the IgE receptor and inhibits IgE receptor binding. Decreases IgE by 99%, decreases IgE mediated inflammation.

Why does Anti IgE work?
If the Fc fragment is occupied, IgE cannot bind to its receptor on mast cells and then degranulation cannot occur. Only free IgE not bound by IgEis affected by the drug.

Anti IgE Indication
for adults and adolescents with moderate to severe persistent asthma who have a positive skin or in vitro reactivity to a perineal aeroallergen who’s symptoms are inadequately controlled with ICS.

Anti IgE Adverse Effects
Nasopharyngitis, URI, Headache, 0.1% anaphylaxis can occur in 2-24 hours after administration

Asthma Exacerbation
Episodes of progressive increase in SOB, Cough, wheezing, or chest tightness, and decreased expiratory airflow. Potentially life threatening and requires close supervision.

How do you identify a severe asthma patient?
Obtain a good history

What components need to be addressed with obtaining a patient’s history?
Recent events, interruptions in sleep, recent ER visits or hospitalizations, ICU admissions, intubations, status asthmatics. Increase in use of SABA?

Long term treatment of asthma exacerbation must include
2 types of meds: bronchodilators and controllers of inflammation

Pocket peak flow meter
measure pre and post bronchodilator

Normal peak flow is

good response to bronchodilator is
Doubling PEF

Symptoms of acute asthma episode
cough wheezing, chest tightness

Treatment of acute asthma episode
O2- full face reservoir, SABA, epinephrine 0.3mg SQ q 20 min x 3 if no other meds available and if pt is having severe dyspnea with accessory muscle use. Measure PEF to stage severity, activate EMS

If PEF is less than 100L/min
Pt needs hospitalization

preventable and treatable disease with some significant extra pulmonary effects, leading to progressive, irreversible airflow limitation in response to noxious particles or gases.

COPD symptoms
dyspnea, chronic cough, chronic sputum production

Asthma Differential Diagnosis
onset early in life, symptoms vary daily, symptoms early in am and at night, allergy, rhinitis, and/or eczema also present, family history of asthma, largely reversible airflow limitation

COPD Differential diagnosis
onset mid life, symptoms slowly progress, dyspnea with exercise, long smoking history or working around noxious gases, largely irreversible airflow limitation

Airflow limitation staging is determined by a patient’s
FEV1, ratio of FEV1:FVC <70%

How is COPD classified?
A,B,C, or D. Takes into account airflow limitation by staging, exacerbation history, and symptom scoring

COPD class A therapy
prn short acting anticholinergic or PRN SABA

COPD class B therapy
Long acting anticholinergic or LABA

COPD class C therapy
ICS + long acting anticholinergic or LABA

COPD class D therapy
ICS + long acting anticholinergic or LABA

Long acting anticholinergics with LABA
provide better maintenance control than ICS, ICS are added after long acting anticholinergics (Spiriva)

Physiology of airway smooth muscle contraction
SNS-beta 2 adrenergic receptors are activated relaxing smooth muscle, PNS- muscarinic receptors are activated contracting smooth muscles

COPD treatment- bronchodilators
Beta 2 Agonists and Anticholinergics

Beta 2 Agonists (COPD tx)
Stimulate smooth muscle relaxation, Albuterol or Xopenex- short acting, Solmeterol (Serevent) long acting

Inhibit bronchoconstriction. Short acting- Ipratropium (Atrovent), Long acting- Tiotropium (Spiriva). Combination- Albuterol/Atrovent

Anticholinergic MOA
Competitively antagonize acetylcholine (prevents bronchoconstriction) @ M3 receptors in the lung

Anticholinergic half-life
Short acting- 0.3 hours, Long acting- 35 hours (may be dosed daily)

Anticholinergic adverse effects
dry mouth, altered taste, coughing after administration

Pharmacological effects of steroids
Anti-inflammatory effects: inhibit accumulation of macrophages and leukocytes, inhibit phagocytosis, inhibit lysosomal enzyme release, inhibit release of mediators of inflammation

Beneficial effects of steroids in COPD
decrease severity and frequency of exacerbations, decrease systemic inflammation, decreases rate of decline

Adverse effects of steroids in COPD
oropharyngeal candidiasis, dysphonia, can decrease adherence to tx and quality of life

COPD exacerbation
a change in pt’s baseline dyspnea, cough and/or sputum production that is beyond normal day to day variations, acute.

COPD exacerbation management
Inhaled bronchodilators (Beta 2 agonists with and without anticholinergics), oral glucocorticosteroids

COPD history/considerations
History- sudden sever exacerbations, previous intubations, ICU, hospitalizations, CVD?, how often are they using SABA? Slower to heal due to hypoxic state and inhales steroids, mouth breathing leading to dry mouth, may need portable Os with NC

Asthma treatment acute

Asthma maintenance

COPD treatment acute
SABA, short acting anticholinergic

COPD maintenance
LABA, +/- long acting anticholinergic

beta 2 adrenergic bronchodilators (front door bronchodilators) – short acting beta 2 agonists SABA rescue/ quick relief medications indicated for treatment of acute episodes of bronchospasm -albuterol (ventolin or Proventil) = dose 2.5 mg in 3 ml NS Q1-Q6 hours …

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What components of the sympathetic nervous system are innervated by cholinergic fibers? adrenal medulla and sweat glands ACh acts are 2 types of receptors: nicotinic and muscarinic. What types of receptors are these? nicotinic ACh receptors are Na+/K+ channels muscarinic …

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