9. Antiasthmatic Drugs Flashcards

1
Q

Asthma

• Excessive irritability of the respiratory tree precipitated by:
– Extrinsic factors: ____ (pollen, cat hair) or ____ (pollution – SO2, cold air)
– Intrinsic factors: ____ (URI) or ____

A

allergen
irritant

infection
emotional distress

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2
Q

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
A
constriction
hypertrophy
submucosal
viscous mucous
mucous plugs

inflammatory
tolerant
downregulation

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3
Q

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
A

bronchoconstriction
mast cell
histamine
PAF

AA
LT
PG

PLA2
bronchoconstrictors
NSAID/aspirin
leukotrienes

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4
Q

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

A
chemotactic
ECF and NCF
eosinophils
lymphocytes
cytokines
major basic protein
bronchoconstrictive
hyperactivity
air
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5
Q

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
A

B2 agonists
prophylaxis

inflammatory
acute
exercise

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6
Q

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 \_\_\_\_
A
phospholipase A2
LT
PG
eosinophils
increasing
mast cells
cAMP
LT
late
permissive
upregulate
catecholamines
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7
Q

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
A
late
early
direct bronchodilator
while
intracellular
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8
Q

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 \_\_\_\_
A
corticosteroid-binding globulin (CBG)
receptor complex with Hsp90
Hsp
dimerize
quickly
prophylactically
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9
Q

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.

A

topical aerosols (inhalants)
lower
systemic
systemic absorption

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10
Q

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
A

beclamethasone
flunisolide
fluticasone
triamcinolone

candidal infections
dry mouth
osteoporosis
hypothalamic-pituitary-adrenal axis
immunosuppressive
vitamin D
Ca++
hypoglycemic
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11
Q

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)
A
acute exacerbations
diminishing
10
prednisolone
methylprednisolone
hour
10

hypothalamic-pituitary-adrenal axis
blood sugar
cataracts
body

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12
Q

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
A
cromolyn sodium
non-bronchodilating
acute
degranulation
Ca++
exercise
asthma
early and late phases
hypereactivity

dosing requirements
toxic
permanently

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13
Q

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
A
bronchoconstriction
capillary permeability
edema
mucous
mucociliary

ASA (NSAID)
airlow obstruction

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14
Q

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
A
zileuton
chronic
6
headaches
liver enzymes
CYP2C9
CYP1A2
warfarin and theophylline

bronchodilators
liver enzymes

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15
Q

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
A

zafirlukast
oral
CYP2C9
liver enzymes

montelukast
oral
liver toxicity
warfarin
perenial

first
day
B2 agonists

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16
Q

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
A
parenterally
anti IgE
mast cell degranulation
IL13
eosinophil
dendritic cell
fibroblast

IL5
eosinophil

injection
B2 agonists
2-4

17
Q

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

A
B2
bronchi
cAMP
mediator
acute
18
Q

Isoproterenol (Isuprel®)

  • ____
  • Stimulates ____ receptors
  • Increases in ____ and ____ common
  • Produces ____• Problem: it’s non-selective > stimulates B1 and B2 receptors > not good in an ____
A
inhalant
B1 and B2
HR
contraction force
tachyarrhythmia's
asthmatic
19
Q

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
    • B1 is not desirable in an asthmatic attack
    • Vasoconstrict vs vasodilation
    ○ Use of different ____
A
1:1000
A1, B1 and B2
tachycardia
BV
status asthmaticus
B2 inhalants
anaphylactic
receptors
20
Q

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.

A

several

21
Q
  • 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

A
  1. 034
  2. 017
  3. 0085
22
Q

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
A
slow
A1, B1 and B2
norepinephrine
tachyphylaxis
nocturnal wheezing
tachycardia
BBB
insomnia
herbal ephedra
methamphetamine
23
Q

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
A

inhalant and pull
OH
B2

inhalant and injection
B2
premature labor

isoproterenol

24
Q

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
A

inhalant and pill
B2 agonist
metaproterenol
longer

inhalant
longest acting
dosing
slower

25
Q

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
• [???]
A
PDE3 and PDE4
adenosine
catecholamine release
antiinflammatory
pill and injection

low
5-15
insomnia
seizures

CYP1A2
erythromycin
carbamazepine

bronchoconstriction
pill
aminophylline
blood levels
tendons
26
Q

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
A
permanently
atropine-like
antimuscarinic
ACh
mast
slower
albuterol + ipatropium
bad taste
xerostomia

bronchoconstrictor