Flashcards in Respiratory Pharmacology Deck (58):
What are the major classes of bronchodilator drugs?
1) βeta2 agonists (short and long acting)
What are examples of short and long acting Beta2 agonist bronchodilators?
1) Short acting => Albuterol (rescue)
2) Long acting => Salmeterol (used for maintenance)
What is an example of an anticholinergic bronchodilator?
Ipratropium bromide/Tiotropium br.
What is an example of an anti-inflammatory bronchodilator?
Give the brief summary of Beta 2 agonist action on smooth muscle
βeta2 agonist binds to beta2 receptor which via G protein stimulates adenylyl cyclase ---> increases cAMP--> protein kinases -> reduces [Ca 2+]i ---> relaxes smooth muscle
What are the additional actions of Beta 2 agonists a part from bronchodilation/relaxation?
1. Enhance mucociliary clearance
2. Decrease microvascular permeability
3. Suppress mediator release from inflammatory cells
Describe the systemic pharmacokinetics of beta 2 agonists.
1) Reasonable oral absorption (especially in children/elderly --> liquid/tablet)
- Variable- presystemic metabolism
2) Metabolism COMT/MAO
3) Bioavailability 15-70%
4) T1/2 --> 6-8h
Describe the inhaled pharmacokinetics of beta 2 agonists (i.e. albuterol).
-8-15% of dose reaches systemic circulation
-Low systemic concentrations (MDI - 90 mcg Alb = Cmax 1-2 mcg/L)
Describe the oral pharmacodynamics of beta 2 agonists.
Onset 30-60 min: peak 1-3 h., duration 6-8h
Describe the inhaled pharmacodynamics of beta 2 agonists (albuterol).
-Onset: 15-30 min duration 4-6 h
-βeta2 selectivity reduced at high doses
-Tolerance/tachyphylaxis => tendency to become desensitized (increase dosage)
What are the cardiovascular adverse effects of beta 2 agonists?
- Tachycardia, palpitations, flushing
- Exacerbation of angina/arrhythmias
- Vasodilates Pulm Art -> V/Q mismatch
What are the CNS adverse effects of beta 2 agonists?
What are the metabolic adverse effects of beta 2 agonists?
- Hypokalemia => especially important in patients with cardiac/arrhythmia issues
When do most adverse effects of beta 2 agonists occur?
Toxicity/adverse effects generally happen when given at milligram dosages (in contrast to microgram)
What is the mechanism of action of salmeterol?
lipophilic arm of salmeterol binds more readily and longer (at multiple sites that can alternate)
-> binds at an active and exosite
Why should long acting beta 2 agonist be used with glucosteroids?
Maintenance beta 2 agonist should be used with steroids to reduce the chance/number of sudden death syndrome.
Describe the pharmacodynamics of anti-cholinergics (ipatromium).
Slower rate of onset
Not as much bronchodilation as albuterol
Describe the pharmacokinetics of inhaled ipatromium.
- 8-15 % of dose reaches bronchi
- < 1% of dose reaches systemic circulation
- Inactive metabolites in urine
- Duration of action 6-8 h
What are the adverse effects associated with ipatromium?
- Bitter taste --> compliance (adherence) issues
- ACh effects: rare and mainly at high doses
- Drying of secretions does not occur
What is the major pro/con of tiotropium?
Tiotropium pro => longer acting (~ 24h) dry powder
con => ACh effects seen in patients with severe renal impairment
What is an example of inhaled corticosteroid?
What are some examples of systemic inhaled corticosteroids?
Hydrocortisone; Prednisone; Methylprednisolone
What are the indications for systemic use of corticosteroids in asthma?
1) Acute severe asthma
2) Chronic maintenance therapy
What are the indications of inhaled use of corticosteroids in asthma?
1) Prophylaxis in mild/moderate or refractory asthma
2) Combined with systemic steroids in chronic asthma--> reduces systemic dose
What enzymes do corticosteroids inhibit and what is the overall effect?
Inhibits enzymes producing PGs, LTs and TX e.g. PLA2 via lipocortin, COX-2.
=> anti-inflammatory mechanism
What mediators do corticosteroids block in gene transcription? What is the overall effect
1) Inhibits gene transcription of pro-inflammatory cytokines e.g. IL-1,TNF-alpha,GM-CSF, IL-3,4,5 & 6
2) Directly counteracts the positive effects of several cytokines on transcription factors AP-1 and NF-KB
=> anti-inflammatory mechanism
What enzymes do corticosteroids induce and what is the effect?
Induce enzymes e.g. ACE and NEP which degrade bradykinin (can lead to bronchoconstriction/cough) and tachykinin
=> anti-inflammatory mechanism
What sort of receptor transcription do corticosteroids increase? What is the overall effect?
Increases βeta2 receptor transcription
Corticosteroid inhibition of TNF has what effect?
Inhibition of TNF reduces cell trafficking and reduces expression of cell adhesion molecules
Corticosteroids induce apoptosis in what kinds of cells?
Induces apoptosis in eosinophils
=> anti-inflammatory effect
How do corticosteroids inhibit plasma exudation?
Inhibits plasma exudation from venules by synthesis of an antipermeability factor- vasocortin
Describe the pharmacokinetics of corticosteroids.
MDI Rx: ~ 10% dose -->bronchi
~ 90% --> oropharynx and swallowed
Metabolism – hepatic CYP3A
Low systemic concentrations
- Half life of 2 hrs
What are the local adverse effects of corticosteroids?
- Thrush (C. Albicans) 10-15% of patients
- Hoarse voice
What are the acute systemic adverse effects of corticosteroids?
2) Metabolic => hyperglycemia and Na/water retention
3) Signs of suppressed immune system (infection)
4) Acute proximal myopathy
What are the chronic systemic adverse effects of corticosteroids?
1) HPA (hypothalamic-pituitary-adrenal)-axis suppression
=> adrenal suppression
2) Cushingnoid appearance
4) Opportunistic infection
5) Peptic ulcer
7) Posterior cataracts
8) Inhibition of bone growth (children)
10)Aseptic necrosis (femoral head)
*Don't need to memorize all, just understand that corticosteroids can be toxic
What are 3 major classes of anti-inflammatory drugs to treat asthma/COPD/allergic rhinitis?
1) Leukotriene antagonists
2) Cromokalim derivatives
3) Histamine pharmacology
What is an example of a leukotriene antagonist?
What are the major properties of leukotrienes (i.e. why are they bad?)?
-Increase vascular permeability --> edema
- Increase mucus secretion => decreased mucociliary clearance
- Stimulate phospholipase A2
- Release prostaglandins and thromboxanes
- Increase cellular infiltrate into the airways
What is the mechanism of action of montelukast?
- Competitive inhibitor at the Cys LT1 receptor
- Plasma concentrations => LTD4 decreases in airway conductance
- Blocks PAF induced airway hyper-responsiveness
- Attenuates response to inhaled antigens & cold air
What are the indications for Montelukast?
- Prophylactic and chronic maintenance therapy
- Often used in combination with other anti-asthma Rx
- Useful for aspirin induced asthma
*Effective and safe in children
*Not as good a bronchodilator as βeta2 agonists
Describe the pharmacodynamics of Montelukast.
-Bronchodilatation within 1-2 h
-Duration of receptor blockade 10-14 h
Describe the pharmacokinetics of Montelukast.
-Good oral absorption-Tmax 3-4 h.
-Food decreases bioavailability by 40%
-T1/2 = 3-6 hours (maybe 20 hours in elderly)
-Hepatic metabolism - CYP3A /2C9
What are the major adverse effects of Montelukast?
Overall well tolerated:
- GI; nausea and vomiting
- CNS; mild headaches
- Hepatitis; transaminitis (reversible)
- Churg-Strauss vasculitis ?
What are pertinent drug-drug interactions with Montelukast?
CYP 450 inducers reduce AUC by 40%
What are the major second line anti-asthma drugs?
-Anti-histamines (H1blockers) => Fexofenadine
-Steroid sparing=> Methotrexate, Azathioprine (6-MP)
-Monoclonal antibody=> Omalizumab
How does Omalizumab work (10-12k/yr)?
Anti-IgE monoclonal antibody
- given subcutaneously every 2-3 weeks (some hypersensitivity problems)
What are some adverse effects of Omalizumab?
- Possible long term toxicity
- Gastrointestinal upsets
What drugs are contraindicated in ASthamtic patients?
- Beta antagonists (blockers); propanolol > metoprolol
= > will exacerbate bronchoconstriction
- Cholinergic agonists; e.g. carbachol
- Adenosine => acute broncospasm
- Aspirin & NSAIDs (2-7% asthmatics)
* ACE-inhibitors (ie lisinopril) => dry cough
What are the major types of therapy for allergic rhinitis?
1) Reduce exposure to allergens
2) Oral anti-histamine (Anti-H1)
3) Topical disodium cromoglycate
4) Topical glucocorticosteroids - “Xnase”
5) Topical ipratropium bromide
6) Immunotherapy and desensitization
What are the uses of Disodium Cromoglycate (Cromolyn)?
- Allergic rhinitis and conjunctivitis
- Prophylaxis in exercise induced asthma (No MDI in US)
- Mastocytosis (mast cell disease-esp children)
What is the mechanism of action of disodium cromoglycate (Cromolyn)?
- Inhibits chloride channels and calcium flux --> reduces release of preformed cytokines from T cells and eosinophils
-Suppresses effects of kinins on inflammatory cells
What are the adverse effects of Disodium Cromoglycate (Cromolyn)?
*Generally very well tolerated
- Nasal stinging, Headache, nausea
Describe the pharmacokinetics of H1 receptor antagonists.
- Well absorbed orally
- Diphenhydramine T1/2 = 6-8h; Fexofenadine T1/2 = 25h.
- Hepatic metabolism by CYP3A.
- Enters CSF/CNS well => induces drowsiness due to anti-cholinergic and anti-serotonin components
What are the uses/indications for H1 receptor antagonists?
- Allergic reactions, allergic rhinitis,
- “cold” remedies
- Anti-emetics and anti-motion sickness
Describe the pharmacodynamics of H1 receptor antagonists.
Competitive inhibition at H1 receptors. (H1 receptors couple to IP3 and increase Ca2+)
What are the major adverse effects of H1 receptor antagonists?
1) CNS: Drowsiness, sedation, confusion, esp. 1st gen. drugs 1st gen. are anti-5HT1 and anti-cholinergic
2) Headaches; GI disturbances (constipation)
Second generation: 1) No ACh. effects, less drowsiness, headaches & GI disturbance
What are the drug-drug interactions/contraindications for H1 receptor antagonists?
- Inhibitors of metabolism -->Prolong QTc --> VT
- PD interaction: Increased sedation with e.g. EtOH