Malik: COPD, Asthma, Mucolytic Rx Flashcards
1
Q
What AE’s are associated with the methylxanthines?
A
- 5μg - 10μg/mL serum levels may cause nausea, vomiting, nervousness, headache and insomnia
- Serum levels > 20μg/mL cause vomiting, hypokalemia, hyperglycemia, tachycardia, cardiac arrhythmias, tremor, neuromuscular irritability and seizures
- May have beneficial effects in asthmatics or COPD pts resistant to glucocorticoids
- CYP450 metabolism -> narrow therapeutic index due to cardio- and neurotoxicity
2
Q
What does histamine do? How? What are the 1st and 2nd gen anti-histamines?
A
- Histamine released from mast cells and also produced in various tissues -> exerts many bio actions via stimulation of 4 subtypes (H1-H4)
- Stimulation of H1 receptors by histamine results in:
1. Allergic and inflammatory responses
2. Bronchoconstriction
3. Vasodilation and increased vascular permeability
4. Urticaria: wheel and flare reactions - 1st gen (sedative effects): Chlorpheniramine, Diphenhydramine, Promethazine
- 2nd gen (no sedative/CNS effects): Fexofenadine, Loratidine, Cetirizine
- NOTE: we will have another lecture on this
3
Q
Why are beta agonists more effective than anti-cholinergic drugs in preventing bronchospasm?
A
- While there is no direct SYM innervation to the bronchial smooth muscle, this muscle does have the highest density of B2 receptors (especially in the bronchioles, vs. the trachea and upper airways for muscarinic receptors)
- NOTE: epinephrine is the endogenous ligand that stimulates B2 (NOT norepinephrine)
4
Q
What is the MOA of N-Acetyl Cysteine? What is it used for?
A
- Breaks mucoprotein bonds by substituting a sulfhydryl radical (-HS)
- Given by aerosol or direct instalation into the ET tube
- Given orally to reduce liver injury with acetaminophen (Tylenol) overdose -> mix w/cola or given by nasogastric (NG) tube
1. Increases precursor to glutathione - Alternatives: Acetadote, Erdosteine, Carbocysteine
5
Q
What are some of the non-pharmacologic tx’s for cough (5)?
A
- Eliminating irritants
- Hard candies (i.e., jolly ranchers)
- Lozenges
- Humidifiers or vaporizers
- Hydration
6
Q
What are the treatment options for COPD?
A
-
Smoking cessation: nicotine replacement therapy
1. Bupropion (Wellbutrin: atypical anti-depressant that blocks nicotine receptors) +/- nicotine patch -
Bronchodilators: β2-Adrenergic receptor agonists
1. Short-acting to relieve acute symptoms: Albuterol or Terbutaline (IV)
2. Long-acting: 12-hr -> Salmeterol + Fluticasone, Formoterol + Budesonide; 24-hr -> Indacaterol, Vilanterol + fluticasone -
Anti-muscarinic agents:
1. Ipratopium (M2, M3; 4-5 hr)
2. Tiotropium (M3; 24 hr)
3. Umeclidinium bromide (M3 -> not selective for M3, but only binds to M2 for short time; 24 hr)
4. Umeclidnium/Vilanterol (β2 Agonist + M3; 24 hr) -
Theophylline and derivatives
1. Theophylline recruits HDAC2, reducing formation of 3-nitrotyrosine (anti-inflammatory effects at doses less than those required to inhibit PDE)
2. HDAC2 activity DEC w/high oxidative stress (smoke) -
Additional options:
1. Combo therapy of bronchodilators
2. Corticosteroids
3. Oxygen Therapy
4. Mucolytics (N-acetylcysteine: breaks down mucus)
5. Guaifenesin (expectorant -> Robitussin): stimulates the flow of respiratory tract secretion
6. Surgical treatment, incl. lung volume reduction or lung transplant
7
Q
What are Zafirlukast and Monteleukast?
A
- Block LTD4 receptors
- DEC bronchial reactivity and bronchoconstriction
- DEC mucosal hypersecretion and mucosal edema
- DEC airway inflammation
-
Aspirin-induced asthma: “effective in some patients
1. Aspirin blocks COX, shunting everything to the LT pathway in aspirin-induced asthma - NOTE: Zafirlukast not used as much as Monteleukast (Singulair)
8
Q
What are the side effects and contraindications for Dextromethorphan?
A
- Side effects: dizziness, drowsiness, nausea, vomiting, upset stomach, diarrhea, irritability, excitability, light headedness, and trouble sleeping
- Contraindications: peeps on monoamine oxidase inhibitor (MAOI) anti-depressants (INC Serotonin can be dangerous -> teen girl example w/OTC meds), advanced respiratory insufficiency (ARDS), hepatic disease, hypersensitivity to any of the ingredients of the product
9
Q
What are the 2 oral (systemic) decongestants?
A
-
Pseudoephedrine (Sudafed): indirectly-acting sympathomimetic
1. Releases NE from adrenergic NN (enters N, takes NE to synaptic cleft -> does not stimulate directly)
2. Minorly metabolized via N-demethylation to nor-pseudoephedrine (up to 88% of dose excreted in 36-hr urine) -> better bioavailability than phenylephrine (100% vs. 38%) -
Phenylephrine: directly stimulates alpha-adrenergic receptors on post-synaptic sites (ALPHA-1 selective)
1. Rapidly metabolized by MAO and COMT in GI mucosa, liver, and o/tissues - NOTE: both drugs have a short half-life (peak: 0.5-2 hrs)
10
Q
What are the pharmacologic tx options for cough?
A
-
Antitussives: drugs of choice 4 non-productive cough
1. Systemic agents:
a. Dextromethorphan
b. Diphenhydramine
c. Codeine
2. Topical agents:
a. Camphor
b. Menthol - Expectorants: DOC for productive cough with thick secretions -> Guaifenesin
11
Q
What is COPD?
A
- Progressive loss of airflow in lungs, resulting in broncho-constriction that is not fully reversible
1. Primarily caused by chronic inflammation -> two common forms are bronchitis and emphysema - Elastic parenchymal tissue is replaced by inelastic fibrotic tissue such that elastic recoil of lung is lost
1. Collapse of airways mid-exhalation leads to air trapping, loss of capacity and, in some cases, impaired gas exchange
12
Q
What is Dextromethorphan?
A
- MOA: suppresses cough reflex by direct action on cough center in the medulla of the brain
- Metabolized via CYP2D6 (same as codeine) into dextrorphan -> as active as parent drug
- Nonopioid, but equal potency to codeine
1. Onset: 15-30 min; duration: 3-6 hours
2. Wide margin of safety -> lg doses (12-75x TD doses produce dissociative hallucinogenic effect via INC serotonin)
a. Used recreationally -> may cause liver toxicity if abused if mixed w/acetaminophen - Active ingredient in many cold/cough meds: Mucinex, Robitussin, NyQuil, Vicks, Dimetapp
13
Q
What are some non-pharmaceutical ways to reduce mucus?
A
- Provide adequate hydration: increase fluid intake PO or IV
- Remove causative factors: smoking, pollutants, allergens
- Optimize tracheobronchial clearance
- Reduce inflammation
14
Q
What are the advantages/disadvantages of sprays vs. drops?
A
-
Sprays
1. Advantages: fast onset, inexpensive, easy to use, cover large SA
2. Disadvantages: imprecise dosage, tip tends to get blocked -
Drops:
1. Advantages: for small children
2. Disadvantages: awkward to use, cover limited SA, pass easily into larynx, easily contaminated if dropper touches nose
15
Q
Briefly describe the neural pathways for cough.
A
- Cough receptors (red) at airway bifurcations in the larynx and at the distal esophagus link to cough afferents through the vagus and superior laryngeal nerves to the cough center and cerebral cortex
- Efferent pathways coordinate the muscle response that leads to cough
16
Q
What are the steps of asthma therapy for those >= 12 y/o (chart)?
A
- Note: LTRA = leukotriene receptor antagonist
17
Q
Briefly describe what is going on at a molecular level in the nasal mucosa, and how we control that.
A
- Nasal mucosa highly vascularized
- Allergic activation of mast cells: release PGD2, LT’s, & histamine (can act on sensory fibers) -> INC bradykinin
- Message carried to brain -> INC PARA activity and DEC SYM, so INC secretion of mucosal glands
1. Reduced release of NE, causing vasodilation (via histamine, bradykinin, substance B, and CGRP bc no PARA innervation to blood vessels), congestion - Steroid sprays can reduce the inflammation, but anti-histamines needed and vasoconstrictive agents needed to DEC vasodilation -> vasoconstrictive agents DO NOT affect release of histamine, but are often COMBINED with anti-histamines
18
Q
What is the Cushingoid syndrome?
A
- Weight gain, esp abdomen, face (moon face), neck, and buffalo hump
- Thinning and leg/arm muscle weakness
- Thin skin, with easy bruising and stretch marks
- INC acne, facial hair growth, and scalp hair loss in women
- Ruddy complexion on the face and neck
- Often a neck skin darkening (acanthosis)
- Child obesity and poor growth in height
- High Blood pressure (usually)
19
Q
Why are nicotinic receptors important?
A
- Nicotinic receptors can directly polarize the nerve terminal and cause release of Ach, i.e., nicotine from smoking
1. The only receptor that will block ganglionic transmission is the nicotinic receptor
20
Q
How do sympathomimetics act in the nasal cavity? What are the dosage forms?
A
- Sympathomimetics: stimulate adrenergic receptors directly or indirectly
- Stimulation of alpha-adrenergic receptors constricts blood vessels throughout the body
1. Reduces supply of blood to the nose
2. DEC amt of blood in sinusoid vessels
3. DEC mucosal edema - Dosage forms: oral (systemic), topical, intranasal sprays, inhalation
21
Q
What are the 3 expectorants?
A
-
Iodines-iodinated glycerol (Expigen): unclear function, but can increase the production of serosal, watery fluid
1. Saturated solution of potassium iodide (SSKI) - Guaifenesin (Mucinex): at high doses, stimulates bronchial gland secretion
- Bromohexine (Bisolvon): secretolytic, INC production of serous mucus in resp tract and DEC viscosity of phlegm
22
Q
What is Codeine? Side effects and contraindications?
A
- Opioid analgesic and antitussive related to morphine
- Depresses cough reflex via direct action on cough center in the CNS (also mu receptors;
- Onset: 10-30 min; duration: 4-6 hrs
- About 10% of codeine metabolized to morphine and other products (CYP2D6); ingredient in many syrups
1. Can’t use in children (metabolism may vary)
2. If high conc of this enzyme, more of the drug will be metabolized to morphine, which has a higher incidence of respiratory depression - Side effects: CONSTIPATION, SEDATION, histamine release, vasodilation, orthostatic hypotension, dizziness, RESPIRATORY DEPRESSION (CAPS = all opioids cause)
- Contraindications: hypersensitivity, labor of premature birth, pregnancy category C (cranial malformations in animal studies), prostatic hypertrophy, peeps on sedatives, pts w/resp depression, asthma, COPD, post-tonsillectomy or adenoid sx (lymph tissue back of neck)
23
Q
What is non-productive cough? What things cause it?
A
- Dry hacking cough that does not remove sputum from the respiratory tract
1. Viral illness
2. Bronchospasm
3. Allergies
4. Asthma
5. Airway obstruction
6. GERD: acid can go all the way down into the larynx, and activate those receptors too
24
Q
What are mucolytics? When are they used?
A
- Promote the breakdown of mucus:
- Used in diseases with INC mucus production:
1. Cystic fibrosis
2. COPD
3. Bronchiectasis
4. Respiratory infections: TB
25
Q
What are the AE’s for Cromolyn?
A
- No systemic toxicity
- Unpleasant taste
- Irritation of trachea -> cough, and bronchospasm can occur after inhalation
- Rare AE’s: chest pain, restlessness, hypotension, arrhythmias, nausea, vomiting, CNS depression, seizures and anorexia
26
Q
What is productive cough? What types of secretions are possible?
A
- Wet cough with secretions
1. Clear - bronchitis
2. Purulent - bronchial infection
3. Yellow - inflammatory disorders
4. Malodorous - anaerobic infection
27
Q
What are the B2 agonists? SABA? LABA?
A
-
SABA: rescue medication; quick onset, and intermediate duration (3-6 hours)
1. Albuterol
2. Xopenox (R-isomer or albuterol)
3. Terbutaline (IV: ICU settings) -
LABA: used only in combo w/inhaled steroids; slower onset, and long duration (6-12 hours)
1. Salmeterol xinofoate, Salmeterol + Fluticasone
2. Formoterol fumarate, Formoterol fumarate + Budesonide, Formoterol + Mometasone
28
Q
What are bland aerosols? What are some types?
A
- Dilute the mucus molecules, aka, wetting agents (function may be more of an irritant than a wetter)
- Types:
1. Sterile/distilled water: humectant, dense aerosols
2. Normal (isotonic) saline
3. Hypertonic saline: INC mucus production
4. Hypotonic saline
29
Q
What are some of the complications of cough?
A
- Exhaustion
- Urinary incontinence
- Pain
- Insomnia
- Syncope
- Stroke
- Rib fractures
31
Q
What is Omalizumab? How is it administered/dosed?
A
-
Anti-IgE monoclonal Ab: binds to IgE and prevents IgE-instigated release of inflammatory mediators (IV admin)
1. Decreases allergic response - Reduces severity & frequency of asthma attacks
- Reducces requirement of inhaled corticosteroids -> better long-term asthma control (used in pts resistant to corticosteroids)
- Binds to the allergen binding site to prevent allergen from stimulating a response
- Administered every 2 or 4 weeks; dose based on weight
39
Q
What are the pharmacological actions of the glucocorticoids?
A
-
Pharmacological actions:
1. DEC production of inflammatory cytokines
2. Reduce mucus secretion
3. Reduce bronchial hyperactivity
4. Enhance the effect of β-2 adrenergic agonists -
NOTE: these are the -sones and -nides
1. Ciclesonide is a short-acting, “soft” steroid
40
Q
What are the actions of the methylxanthines?
A
- INC levels of cAMP (inhibiting PDE)
- Block muscle adenosine (A3) receptors
1. Adenosine is a breakdown product of ATP w/INC levels in asthmatics -> stimulates release of histamine from mast cells (via A3 receptors) - DEC release of mediators
- Bronchodilation
- Anti-inflammatory effect
- inotropy (strength of contraction) & chronotropy (rate)
- INC CNS activity
- INC gastric acid secretion
- Weak diuretic effect
- INC skeletal muscle strength (diaphragm)
44
Q
What are the differences between asthma and COPD (chart)?
A
KNOW THIS CHART
49
Q
Where do steroids, Zileuton, and Zafirlukast act on the AA pathway?
A
- Steroids stimulate synthesis of lipocortin and macrocortin that inhibit the functioning of PLA2
- Zileuton inhibits LT synthesis
- Zafirlukast is a competitive INH for LTC4, D4, and E4
- See image
52
Q
What is the proposed mech of corticosteroid action to suppress TH2 cell cytokine synthesis in allergic disease?
A
- Reduce transcription and production of IL-4, 5, and 13 (TH2 cytokines)
-
Compete with GATA-3 for its transport in the nucleus by binding with importin-alpha and importin-13
1. Phosphorylation of GATA-3 results in its transport into the nucleus, but glucocorticoids prevent this by competitive inhibition
2. Go to the nucleus and INH NFkB, DEC transcription of inflammatory genes, INC transcription of anti-inflam genes, and DEC mRNA stability of inflam cytokines (i.e., TNF-alpha, GM-CSF, IL-6, and COX-2)
53
Q
What are the structure and composition of mucus?
A
- Glycoprotein: large macromolecules
1. Strands of polypeptides (protein) make up backbone -> string of AA’s
2. Carb side chains
3. Chem bonds hold mucus together
a. Intramolecular: dipeptide links (connect AA’s)
b. Intermolecular: disulfide and H-bonds: connect adjacent macromolecules
56
Q
What are the methylxanthines?
A
- Related to caffeine -> PDE and adenosine inhibitors
1. Aminophylline
2. Theophylline
3. Diphylline
4. Oxtriphylline
57
Q
What is Combivent? Why use it?
A
- Inhaler to be taken at home that is a combo of Ipratropium and Albuterol (anti-cholinergic + beta-2 agonist)
- Combined therapy produces a greater improvement in lung function than either ipratropium or albuterol alone
- Indicated for COPD
59
Q
What are the 2 beta-agonist signalling pathways? Why is this important?
A
- Biased agonists -> want to isolate the classical signaling model (there are many different conformational states)
1. Classical: B2 receptor -> G protein -> adenylyl cyclase -> cAMP = DEC Ca + activated PKA (both of which inactivate myosin light chain kinase and activate myosing light chain phosphatase)
A. Combo of DEC IC Ca, INC membrane K conductance, and DEC myosin light chain kinase activity = smooth m. relaxation + bronchodilation
-
Alternative signalling (on the R): can lead to inflammation
- Also REMEMBER: Ca -> calmodulin -> INC MLCK -> constriction (so Ca sequestration in the classical pathway also encourages relaxation of smooth muscle)
63
Q
Briefly, what do LTB4, C4, D4, and E4 do?
A
- Do NOT memorize this pathway; FLAP leads to 5-HPETE synthesis, followed by LT synthesis
- LTB4: neutrophil chemoattractant
-
LTC4 & LTD4 (and E4?): mimic many symptoms of asthma
1. Bronchial hyper-reactivity, bronchoconstriction (WAY MORE POTENT THAN HISTAMINE), mucosal edema, and increased mucus secretion
70
Q
What is Doxapram?
A
- Activates peripheral carotid receptors
-
For use in:
1. Post-anesthesia respiratory depression
2. Drug-induced respiratory depression
3. Acute hypercapnia in COPD - Narrow margin of safety because it can cause seizures, increase BP, HR, and cause arrhythmias
- Short-acting, and given by infusion (IV)
71
Q
What are the AE’s of the inhaled vs. oral glucocorticoids?
A
-
Inhaled: oropharyngeal candidiasis, hoarseness, and dry mouth
1. DEC bone mineral density in premenopausal F
2. DEC rate of growth in children -
Oral: prolonged use
1. Glucose intolerance
2. INC BP & weight
3. Bone demineralization
4. Cataracts
5. Immunosuppression
6. Retarded growth in children
74
Q
Where are the muscarinic receptors in the lung?
A
- M1, M3: mucosal cells
- M2, M3: bronchial smooth muscle
- M2 receptors also on NN terminal -> Ach (-) feedback
