Drugs for asthma and allergy

Question 1

List the pharmacologic strategies used to modulate allergic inflammatory reactions and describe the rationales for their use.

Answer 1

1. Use short- and fast- acting beta-agonists as needed
2. Preferred treatment = inhaled corticosteroid (beclomethasone, budesonide, ciclesonide, flunsolide, flutcasone, mometasone)
   a. alternative tx: cromolyn (mast cell stabilizer, QID dosing), Theophylline (a methylxanthine; has narrow TI)
3. Preferred tx: low dose inhaled corticosteroid + long-acting beta-agonist OR medium dose inhaled corticosteroid
   a. Adding LABA = improves control
   b. Alternative: low-dose inhaled corticosteroid + LTRA, theophylline, or Zileuton
   i. Lesser benefit with alternative
   c. Avoid LABA alone!
4. Preferred tx: medium dose inhaled ICS + LABA → greater efficacy
   a. Alternative: medium dose ICS + LTRA, Theophylline or Zileuton
5. Preferred tx: high dose ICS + LABA and consider Omalizumab (anti-IgE)
6. Preferred: high dose ICS + LABA + oral corticosteroid and consider Omalizumab

Question 2

List the drugs used to treat acute asthmatic episodes and describe the mechanistic basis for their actions

Answer 2

Rescue drugs = provide immediate relief of symptoms

Include:
Beta-agonists:
•	Albuterol
•	Pirbuterol
•	Levalbuterol

Anticholinergics:
• Not yet FDA approved for asthma
• Ipratropium
• Tiotropium

Question 3

List the drugs used for long-term therapy of chronic asthma and explain the rationale for their use.

Answer 3

Controller drugs = provide long-term relief of symptoms; reduces impairment and risk

Include:
o	Inhaled corticosteroids
o	Long lasting beta-agonists
o	Combinations of ICS/LABA
o	Leukotriene modifiers
o	Mast cell stabilizers
o	Methyxanthines
o	Immunomodulators

Question 4

Compile a list of drugs or drug groups that are relatively or absolutely contraindicated for patients with asthma, and state their main problems.

Answer 4

Avoid long-acting beta-agonists alone (formoterol, salmeterol) 
Avoid beta-blockade (HT, CVD, ophalmic):
o	Propranolol
o	Atenolol
o	Metroprolol
NSAIDs:
o	Aspirin → aspirin sensitive asthma
o	5-20 % of adult asthma patients

Question 5

Antihistamines

Answer 5

• Histamine → vasodilation, increased vasopermeability, smooth muscle contraction (airway)

Histamine receptors:
o	H1: pruritis, vascular permeability
o	H2: gastric H+, vascular permeability
•	Used for reflux therapy (ranitidine, famotidine) 
o	H3: presynaptic receptor –CNS
o	H4: leukocytes = cytokine production 

Antihistamines: H1 receptor antagonists
o Involved in allergic inflammation
o Use H1 blockers to treat allergies:
–First generation: chlorpheniramine, diphenhydramine
• Some anti-cholinergic effects (sedation)
–Second generation: cetirizine, fexofenadine, loratidine
• Have less CNS effects (sedation)

Actions: antagonize histamine’s action on blood vessels and nerves
No effect on asthma
Toxicity:
• Sedation, fatigue, insomnia, mouth dryness, teratogenicity in some (fexofendine)
• Anticholinergic effects: temperature regulation, decreased diaphoresis, vision, cognition

Question 6

Leukotriene inhibitors

Answer 6

• Leukotrienes = LTC4, LTD4, LTE4
Cause: vasodilation, vascular permeability, mucous production, smooth muscle contraction (airway)

Leukotriene receptor antagonists:
o Zileuton, Montelukast and Zafirlukast

Actions:
Montelukast and Zafirlukast
• Antagonists for cysteinyl-leukotriene receptors (CysLT1)
• Bronchodilation
• Anti-inflammatory effect (mild)
Zileuton
• Inhibits production of leukotrienes and inhibits 5-lipoxygnease
• Result = inhibits production of cysLT and LTB4

Toxicity:
• Montelukast and Zafirlukast = well tolerated; some concern about suicidal ideation
• Zileuton = potential liver toxicity, decreases warfarin clearance; not used in children

Question 7

Inhaled Corticosteroids

Answer 7

Anti-inflammatory:
o	Modulate cytokine/chemokine expression
o	Promote Eosinophil apoptosis
o	Decrease leukotriene production
o	Decrease vascular permeability 
o	Prevents “late-phase” response

Inhaled corticosteroids:
o Beclomethasone, budesonide, flunisolide, triamcinolone, mometasone, ciclesonide

Treat: allergic rhinitis, asthma

Toxicity:
o Nosebleeds (intranasally)
o Oral thrush (inhaled)

Question 8

Oral Corticosteroids

Answer 8

• Includes: prednisone, methylprednisolone

Mechanism:
o Global suppression of inflammatory pathways
o Promote phagocytosis of apoptotic Eosinophils and neutrophils

Toxicity
o Mood disturbances
o Increased appetite, weight gain
o Impaired glucose tolerance in diabetics
o Candidiasis, opportunistic infections for doses > 20 mg/day used for at least 1 month
o Osteoporosis

Question 9

Beta-agonists

Answer 9

Short-acting
Include: 
•	Albuterol
•	Pirbuterol
•	Salbutamol
•	Levalbuterol 
Mechanism: 
•	Relaxation of airway smooth muscle
Toxicity:
•	Generally well-tolerated
•	High doses = tachycardia, arrhythmia, CNS effects

Long-acting
Include:
• Salmeterol
• Formoterol
Mechanism:
• Lipohilic so keeps drug in membrane longer = longer duration of action
Beta-2 receptor desensitization
• With long term exposure → downregulates receptor expression on most cells except airway smooth muscle cells
Toxicity
• Increased mortality (trials are re-evaluating safety)

Question 10

Mast cell stabilizers

Answer 10

Cromolyn
o	Not used often anymore
Mechanism:
o	Not well understood
o	Stabilize mast cells = make activation less likely
o	Decrease cellular chloride influx
Toxicity = well-tolerated

Question 11

Methylxanthines

Answer 11

Theophylline
o Not used often anymore

Mechanism:
o Phosphodiesterase inhibitor
o Antagonist for adenosine receptor
o Result = bronchial smooth muscle relaxation

Toxicity:
o Headaches, palpitations, nausea, emesis, tachycardia, arrythmias, seizures, death
o Narrow TI (requires close monitoring of serum levels)

Question 12

Omalizumab

Answer 12

• Biologic agent = humanized monoclonal Ab against Fc portion of IgE

Mechanism:
o Sequesters IgE = prevents IgE from binding Fc receptors on basophils and mast cells
o Result: decrease in FcER1 on cell surface

If serum IgE too high = can’t use Omalizumab (not enough drug can be delivered to sequester IgE)

Toxicity
o Injection site reactions (common)
o Black box warning: anaphylactic events

Question 13

List the antihistamines

Answer 13

chlorpheniramine
diphenhydramine
cetirizine
fexofenadine
loratidine

Question 14

List the Beta-2 agonists

Answer 14

albuterol
pirbuterol
levalbuterol
salmeterol
formoterol

Question 15

List the anticholinergic agents

Answer 15

ipratropium

tiptropium

Question 16

list the mast cell stabilizer

Answer 16

cromolyn

Question 17

list the methylxanthines

Answer 17

theophylline

Question 18

list the biologic agents

Answer 18

omalizumab

Question 19

list the corticosteroids

Answer 19

beclomethasone
budesonide
flunisolide
fluticasone
tramcinolone
mometasone
prednisone
methylprednisolone

Question 20

list the leukotriene modifiers

Answer 20

montelukast
zafirlukast
zileuton