9. Antiasthmatic Drugs Flashcards
Asthma
• Excessive irritability of the respiratory tree precipitated by:
– Extrinsic factors: ____ (pollen, cat hair) or ____ (pollution – SO2, cold air)
– Intrinsic factors: ____ (URI) or ____
allergen
irritant
infection
emotional distress
Asthma Characteristics
- Bronchial and bronchiolar ____
- ____ of bronchial smooth muscle
- ____ edema
- Hypersecretion of ____
- Presence of intraluminal ____
- There’s also an underlying ____ component
- Hit with B2 agonists - become ____ to them, and there’s a ____ of beta receptors and they stop working as well
constriction hypertrophy submucosal viscous mucous mucous plugs
inflammatory
tolerant
downregulation
There is typically both an early phase and a late phase response induced by various inflammatory mediators.
v Early response – ____ within within 20 minutes after exposure to an extrinsic or intrinsic bronchospastic stimulus. Probably caused by ____ mediators such as ____, proteases (heparin), ____ and leukotrienes (LTD4)
cell membrane fragments > via (PLA2) > ____ > (via LO) ____ or (via COX) to ____
• Corticosteroids block \_\_\_\_ - will limit the amount of LTs that are synthesized • Drugs that also block lipoxygenase and leukotrienes directly ○ LTs are potent \_\_\_\_ • 1-3% of asthmatics are \_\_\_\_ sensitive ○ If they ingest, can precipitate in asthmatic attack § If you block COX, shunt the pathway to \_\_\_\_ □ Bigger concern than the sulfite sensitive asthmatics > what do you take for headache/sprained ankle? > advil/aleve then they're sensitive; or acetomeniphen > start wheezing, aspirin/NSAID sensitive asthmatic
bronchoconstriction
mast cell
histamine
PAF
AA
LT
PG
PLA2
bronchoconstrictors
NSAID/aspirin
leukotrienes
v Late response – Begins 3 -4 hours and peaks 4 – 8 hours after exposure to extrinsic or intrinsic stimuli. Initial activation of mast cells release ____ factors (____) which attracts inflammatory cells into area (____, neutrophils, ____). These cells and mast cells release ____ (TNFα) and proteins (____) which recruit more inflammatory cells and starts the inflammatory ____ reaction over again by the additional release of mediators. Also leads to bronchial ____. As a result non allergic stimuli (like breathing ____) may trigger bronchoconstriction
chemotactic ECF and NCF eosinophils lymphocytes cytokines major basic protein bronchoconstrictive hyperactivity air
Treatment goals
- In Past: Enhanced contraction of bronchial smooth muscle was considered the major pathological event – so ____ were the drugs of choice not only for acute attacks but for ____.
- Now: It is recognized that asthma is also a persistent ____ disease and the regular use of antiinflammatory drugs (inhaled glucocorticoids or oral leukotriene modulators) are now also recommended. β2 agonists reserved for treating ____ attacks or pretreatment to prevent ____-induced asthma.• [???]
• Cingulair
○ Prototype LT receptor antagonist
• B2 agonists occasionally use them for pretreatment of exercise-induced asthma
B2 agonists
prophylaxis
inflammatory
acute
exercise
Corticosteroids (glucocorticoids)
• Block ____ so both ____ synthesis and ____ synthesis reduced.
• Decrease migration of a number of inflammatory cells including ____
• Enhance β2 adrenergic response by ____
number of β2 receptors in human lung tissue and WBC including ____.
In mast cell: 5’ AMP > (via adenylate cyclase) to ____
• In asthma, the therapuetic event is the blockade of \_\_\_\_ synthesis ○ Blocking one step before lipoxygenase and COX • Eosinophil response as part of asthmatic attack ○ Come on in the \_\_\_\_ phase of the asthmatic attack • Have \_\_\_\_ effect on sympathetic nervous system ○ Makes it work better ○ In asthma, they \_\_\_\_ B2 receptors § Drive the cAMP § Get a bigger response to \_\_\_\_
phospholipase A2 LT PG eosinophils increasing mast cells cAMP
LT late permissive upregulate catecholamines
Corticosteroids continued
- Prevents ____ phase of asthmatic attack. Not good at stopping ____ phase – not a ____.
- Takes a ____ (several hours usually) to work. Receptor is ____ – drug must penetrate cell membrane, bind to receptor, be translocated to the nucleus and bind to DNA affecting transcription and translation of proteins.
- Mineralocorticoid activity - H2O and Na+ retention; but the ones that treat asthma have low MC activity
- The receptor dimerizes, then translocates to the nucleus
late early direct bronchodilator while intracellular
Steroid MOA: Transcriptional Regulation
• Steroids bind to \_\_\_\_; then released and binds \_\_\_\_ (warm up the temp > Hsp release); knocks the \_\_\_\_ off; and then the receptors \_\_\_\_ (replication of the receptor); enters the nucleus; affecting DNA>RNA, then RNA>protein, and then get a response ○ Drugs will not come on \_\_\_\_ ○ Good at \_\_\_\_ treating the inflam phase of this disease ○ Reduce the need for \_\_\_\_
corticosteroid-binding globulin (CBG) receptor complex with Hsp90 Hsp dimerize quickly prophylactically
Individual Corticosteroid Drug
• ____ are formulations of choice. Deposit drug
directly in lung at much ____ dose than required orally. Also cuts down on ____ absorption of steroid. Steroids that were chosen have the least amount of ____ via the inhalation route.
topical aerosols (inhalants)
lower
systemic
systemic absorption
Topical (inhaled) Steroid Drugs
- ____ (Beclovent®)
- ____ (Aerobid®)
- ____ (Flovent®)
- ____ (Azmacort®)
AEs: ____ of the oral cavity fairly common. Occasional ____ and hoarseness. Systemic side effects like ____, increase blood sugar, suppression of the ____ are rare.
• Most end in -asone, or -olone • Candidal infections ○ \_\_\_\_ ○ Localized • Taken for a while (via mouth, usually), and they do get into the BS > cause osteoporosis > interfere with interaction of \_\_\_\_ ○ Do not get enough Ca++ from the gut > turn on PTH > increase blood levels of \_\_\_\_, and causes bone resorption • Patient is under surgical stress, or walking into frigid air > the body releases cortisol, and now the axis is suppressed > can become \_\_\_\_ > unconscious and shock very quickly ○ Not an issue with the inhaled version
beclamethasone
flunisolide
fluticasone
triamcinolone
candidal infections dry mouth osteoporosis hypothalamic-pituitary-adrenal axis immunosuppressive vitamin D Ca++ hypoglycemic
Oral (systemic) Glucocorticoids)
• Employed in ____ exacerbations of asthma
where response to β2 agonist therapy is ____ because of tolerance. Usually treated for no more than ____ days to avoid systemic side effects.
• ____ (Deltasone®), ____ (Medrol®). Takes at least an ____ to kick in and maximum effect takes up to ____ hours
• AEs – with more prolonged dosing include: suppression of the ____, osteoporosis,
increased ____ increased risk of infection, ____.
• People are having lots of attacks, and are becoming tolerant to B2 agonists ○ There's a downregulation of B2 receptors § Restore B2 receptor sensitivity • Used only short-term • Pills that take a long time to work • Infections all over the \_\_\_\_ (not just the mouth)
acute exacerbations diminishing 10 prednisolone methylprednisolone hour 10
hypothalamic-pituitary-adrenal axis
blood sugar
cataracts
body
Non-steroidal Prophylactic Drugs
- ____ (Intal®), Nedocromil (Tilade®)-inhalants
- Drugs are ____, ineffective in ____ attack
- Prevent mast cell ____ by decreasing ____ influx.
- Used prophylactically to prevent ____-induced and chronic ____ attacks
- Inhibits both ____ including airway ____
- Decreases ____ of more toxic drugs - β2 agonists, corticosteroids and theophylline
- Least ____ of antiasthmatics – poorly absorbed because > 99% ____ charged. Occasional coughing, dry mouth, allergic reactions.
• Not good for acute attacks ○ For this, want bronchodilation • Mainly act on mast cells • Very little systemic absorption bc they're permanently charged • Good SE profile
cromolyn sodium non-bronchodilating acute degranulation Ca++ exercise asthma early and late phases hypereactivity
dosing requirements
toxic
permanently
Leukotriene Modifiers
vRationale: Leukotrienes (LTC4, LTD4) stimulate ____, increase ____ leading to ____ in smooth muscles of bronchi, stimulate ____ secretion and impair ____ clearance.
These drugs either reduce leukotriene synthesis (lipoxygenase inhibitors) or block the leukotriene receptor.
Very effective drugs in preventing ____ induced asthma but not as effective as corticosteroids in improving ____ in other asthma types.
• Inhibit lipoxygenase that converts AA to LT, or they block the LT receptor
bronchoconstriction capillary permeability edema mucous mucociliary
ASA (NSAID)
airlow obstruction
5 – Lipoxygenase Inhibitor
• ____ (Zyflo®) – maintenance therapy for ____ asthma as pill every ____ hours. Reduces leukotriene synthesis by 70%.
– AEs: ____, GI irritation, occasional elevations in ____ (get them off drug)
– Drug interactions: It’s a ____ and ____ inhibitor so it blocks the metabolism of ____.
• Not good in acute attacks • Taken to reduce the amount of \_\_\_\_ that asthmatics may need, and in order to reduce the amount of \_\_\_\_ (low TI) • Elevations in liver enzymes; potentially liver damage and inflammation • 2C9 is the primary system for metabolizing warfarin • 1A2 is responsible for theophylline detoxification ○ Theophylline is demethylated caffeine
zileuton chronic 6 headaches liver enzymes CYP2C9 CYP1A2 warfarin and theophylline
bronchodilators
liver enzymes
Leukotriene Receptor Antagonists
- ____ (Accolate®) – BID ____ drug. ____ inhibitor so it increases blood levels of warfarin. Elevations in ____ and severe hepatotoxicity occasionally reported. Need to monitor
- ____ (Singulair®) – OD ____ drug. ____ not reported. No interactions with ____. Also approved for ____ (dog and cat dander).• Zarfirlukast was the ____ LT receptor antagonist
• Montelukast
○ Once a ____ oral drug
○ Taking it for seasonal allergies, and to dogs and cats
• Not good for acute attacks
○ By taking these, people will have fewer attacks and won’t have to use ____ as often
zafirlukast
oral
CYP2C9
liver enzymes
montelukast oral liver toxicity warfarin perenial
first
day
B2 agonists
BIOLOGICS
- ALL TAKEN ____
- Omalizumab–humanized ____ monoclonal antibody. IgE important for ____
- Lebrikizumab, Tralokinumab–humanized mononclonal antibodies against ____. IL-13 responsible for ____, macrophage and ____ activation, airway remodeling via ____ proliferation and activation
- Mepolizumab, Relizumab–monoclonal antibodies directed against ____. IL-5 is heavily involved in the regulation of ____ differentiation, proliferation and activation• Taken by ____
• When steroids and ____ are not working well
• Subcutaneous injections every ____ weeks
• Bottom ones are directed against IL (IL13 and IL5)
○ Profound effects on reducing eosinophil activation
○ Test for having too many eosinophils
parenterally anti IgE mast cell degranulation IL13 eosinophil dendritic cell fibroblast
IL5
eosinophil
injection
B2 agonists
2-4
Βeta-2 Adrenergic Drugs - MOA
• Directly stimulate ____ receptors on ____ and bronchioles
• In mast cells, increase ____ by enhancing the action of adenylate cyclase which in turn decreases ____ release
• Employed in managing ____ attacks
ATP > (via adenylate cyclase) > cAMP > (via PDE3) > 5’AMP
B2 bronchi cAMP mediator acute
Isoproterenol (Isuprel®)
- ____
- Stimulates ____ receptors
- Increases in ____ and ____ common
- Produces ____• Problem: it’s non-selective > stimulates B1 and B2 receptors > not good in an ____
inhalant B1 and B2 HR contraction force tachyarrhythmia's asthmatic
Epinephrine (Adrenalin®)
- Inhalant and subcutaneous/IM injection at ____ concentration (0.3 – 0.5 ml)
- Stimulates ____ receptors so ____ is common
- α1 agonist effect constricts ____ in airway and reduces mucosal edema
- Subcutaneous injection reserved for ____ not responding to ____
- Overkill for asthma
- Unlike an anaphylactic reaction, stimulating B1 receptors in asthma is not favorable
- 1:1000 cxn is more for treating an ____ reaction drug and not an asthmatic attack
• Vasoconstrict vs vasodilation
○ Use of different ____
1:1000 A1, B1 and B2 tachycardia BV status asthmaticus B2 inhalants anaphylactic receptors
Anaphylactic Dose = 1:1000 = 1 gram/1000 ml = 1000 mg/1000 ml = 1 mg/ml.
Typical volume = 0.3 ml = 0.3 mg subcutaneous, intramuscular, into or under tongue. Have available in pre-loaded syringe.
May have to give ____ doses.
several
- 1:50,000 = 1gram/50,000ml = 1000mg/50,000ml = 0.02 mg/ml x 1.7 ml/carpule = ____ mg/carpule
- 1:100,000 = 1gram/100,000ml = 1000mg/100,000ml = 0.01 mg/ml x 1.7 ml/carpule = ____ mg/carp
• 1:200,000 = 1gram/200,000ml
= 1000mg/200,000ml = 0.005 mg/ml x 1.7 ml/carpule =____ mg/carp
- 034
- 017
- 0085
Ephedrine and Pseudoephedrine
(Sudaphed®)
- A pill so ____ acting
- Stimulates ____ receptors by direct and indirect mechanisms (____ release)
- Indirect action can lead to ____
- Sometimes taken at night to prevent ____
- ____ common
- Crosses ____ so nervousness and ____ are also reported
- Used to be a component of the ____ until FDA banned its sale
- Can be converted to ____
- [???]
- Tachyphylaxis - rapid development of tolerance
- Drugs are excitatory in the CNS
slow A1, B1 and B2 norepinephrine tachyphylaxis nocturnal wheezing tachycardia BBB insomnia herbal ephedra methamphetamine
Beta-2 Selective Agonists
- Metaproterenol (Alupent®) – ____. Same structure as isoproterenol except ____ group moved from C4 to C5 on benzene nucleus. Push dose and you can lose ____ selectivity
- Terbutaline (Brethaire) – ____. A congener of metaproterenol with greater ____ selectivity. Used also to stop ____ contractions.• Less cardiac stimulation than ____
• Not as quite B2 selective as some of the newer ones
• Terbutaline
○ Used in asthma
○ B2 receptors relax uterus
§ Used for women who go into labor, and then can stop the uterine contraction
inhalant and pull
OH
B2
inhalant and injection
B2
premature labor
isoproterenol
Beta-2 Agonists continued
- Albuterol (Proventil®)–____. Most commonly prescribed ____. Selectivity for β2 receptor greater than ____ and also a ____ acting drug.
- Salmeterol (Serevent®)–____. ____ (12 hours) of the β2 selective agents. Less problem with development of tolerance because of less frequent ____. However ____ onset (10 minutes) than other inhalants.
- For an acute attack > inhalant
inhalant and pill
B2 agonist
metaproterenol
longer
inhalant
longest acting
dosing
slower
Theophylline (Theodur®)
Blocks \_\_\_\_. CAMP > AMP Blocks \_\_\_\_ receptors Stimulates \_\_\_\_ \_\_\_\_ effects \_\_\_\_ (aminophylline)
____ therapeutic index
Ø ____ ug/ml = therapeutic range
Ø < 20 ug/ml = ____, vomiting, headache
Ø > 30 ug/ml = ____, cardiac arrhythmias, death
Drug interactions – ____ substrate
Ø____ and ciprofloxacin increase blood levels ØPhenobarbital and ____ decrease blood levels
• Blocks breakdown of cAMP • Major interaction: adenosine receptor blocker ○ Adenosine can cause \_\_\_\_ ○ Inhibitory NT • Almost always given as a \_\_\_\_ • Aminophylline is used in status asthmaticus ○ If someone is on a beta blocker, cannot use the B2 agonist; use \_\_\_\_ because it works via a different mechanism • Low TI; crosses the BBB ○ How do you know? Testing \_\_\_\_ • Seizures ○ Adenosine is an inhibitory NT in the brain • Cipro is used for UTI ○ Quinilones can make \_\_\_\_ tight ○ Photosensitizers • [???]
PDE3 and PDE4 adenosine catecholamine release antiinflammatory pill and injection
low
5-15
insomnia
seizures
CYP1A2
erythromycin
carbamazepine
bronchoconstriction pill aminophylline blood levels tendons
Ipatropium (Atrovent®)
- ____ charged ____ molecule, ____
- Blocks ____ action at M3 receptor
- Some decrease in mediator release from ____ cells
- ____ onset (20minutes) than β2 agonists
- ____ = Combivent®
- ____ and ____ most common AEs• Acetylcholine is a ____
• Likely to see xerostomia
○ Because of muscarinic cholinergic antagonists
permanently atropine-like antimuscarinic ACh mast slower albuterol + ipatropium bad taste xerostomia
bronchoconstrictor
