Respiratory Pharmacology Flashcards
What is the effect of histamine in allergy?
Hist–>H1R–>Gq–>IP3–>Ca
- adds to PNS pathway
- bronchiole constriction
Draw how an allergen causes inflammation in the respiratory tract.
Respiratory Pharm
IgE
- primary ig involved in immunoresponses
- triggers mast cell degranulation
Histamine
stimulation of H1 R
lungs-vasoconstriction
vascular smooth muscle-relaxation
Leukotrienes
- stimulate CysLT1 R
- vasoconstriction, bronchospasm, increased vascular permeability
What are 4 treatment strategies for inflammation in the respiratory tract, asthma and allergy?
- bronchodilators
- antiinflammatory agents/immune modulators
- Inhaled formulations
- systemic
What are 3 bronchodilators?
- beta2 AR agonists (salbutamol, salmeterol)
- anticholinergics (tiotropium)
- methylxanthines (theophylline)
What are 3 antiinflammatory agents/immune modulators?
- corticosteroids (flucticasone, prednisone)
- antileukotrienes (montelukast, zileuton)
- antihistamines (diphenhydramine, loratadine)
Explain inhaled formulations in their treatment of asthma and allergy?
- applied topically to the lungs
- drugs act locally
- most have limited systemic absorption
Explain systemic in their treatment of asthma and allergy?
- modulation of pro inflammatory mediators
- oral/IV steroids in more severe cases (asthma attacks)
What is the therapeutic approach for asthma?
- patients started on SABA- used at onset of symptoms
- as disease progresses or if symptoms not well controlled treatment is stepped up
- SABA used as rescue medication
B2 adrenergic R agonists-SABA
- short acting beta agonists
- salbutamol
- structurally similar to NE
- onset= 5 min, duration=3-8 hr
- administered as needed
- overuse leads to red in clinical efficacy–> patients requiring >2 doses/ week have therapy stepped up
Desensitization & Downregulation of β2-AR
- Agonist binds to receptor, initiates response
- Activated receptor phosphorylated and bound to β-arrestin, prevents further response
- Receptor complex internalized (endocytosis)
- Dephosphorylation by phosphatase
- Recycling of receptor to cell surface • These steps cause desensitization
- Excessive stimulation can trigger receptors to be degraded
• Resulting in down-regulation
What is the difference between GPCR desensitization vs downregulation
Desensitization
-Within minutes of exposure
-Reapplication of agonist generates full response
Downregulation
-Usually hours of exposure (varies)
-Reapplication of agonist generates partial or no response
Long Acting Beta Agonists (LABAs)
- salmeterol
- long C chain through to act as anchor in receptor, prolongs duration of action
- onset-20 mins
- duration-12 hrs
- administered on a scheduled basis
- cannot be used as rescue med-onset too slow
How does salmeterol prevent desensitization?
- binds to B2 AR in a way that reduces beta arrestin binding
- allows prolonged duration of action
Methylxanthines-theophylline
- structurally related to caffeine
- promote bronchodilation (increased breakdown of cAMP)
- administered orally 400-600mg/day
- systemic side effects (CNS stimulation/heart palpitations)
Anticholinergics-Tiotropium
- block the actions of M3 cholinergic R in the lungs
- inhaled
- non selective
- charged molecule reduces systemic absorption
- often combined w/ beta2 AR for synergistic effect
Corticosteroids
- active intracell glucocorticoid R
- modify gene Tc
- primary therapeutic benefit are anti-inflammatory effects
Systemic Corticosteroids (prednisone)
- many useful indications
- high rate of side effects
Inhaled corticosteroids (fluticasone)
- localized effects in the lungs
- reduce inflammation in the airways
- administered daily to reduce and prevent inflammation
- local immunosuppressive effects in the oral cavity (thrush infection)
Antileukotrienes
- long term use reduces the severity of the allergic response
- oral admin provides ease of use and systemic response
- leukotriene receptor antagonist: montelukast, competitive antagonist of CysLT1 R
Zileutin
Antileukotriene
- 5-lipoxygenase inhibitor
- reduce production of LTA4
Antihistamines
-inverse agonist of H1 receptors
