W6 Respiratory Pharmacology 3 Flashcards
Muscarinic receptors
What is the aim of muscarinic receptor antagonists
- M3 has the biggest effect in bronchial smooth muscles
- To block postsynaptic M3 receptors
Muscarinic receptor antagonists: Mechanisms
M2 reduces amount of Ach released- inhibits contraction
M3 leads to contraction
–Although effects are limited by lack of selectivity leading to antagonism of M2 autoreceptors–
Muscarinic antagonists used are non-specific
- Therefore
– Limited effect on smooth muscle contraction
– Bronchodilatory effect (?) - BUT
– reduces mucus build up (M3 increases gland secretion)
– may increase muco-cillary clearance - No effect on late phase of asthma
What are the types of Muscarinic receptor antagonists? (2)
Generally Most use in COPD (rather asthma) but see guidelines
- Ipratropium
* Derivative of N-isopropylatropine
* Onset of action 30 mins; lasts 3-5 hours
* Not selective for M receptor subtypes - Tiotropium
* longer-acting
* once daily dosing
* More lipophilic
Muscarinic receptor antagonists: What are the Unwanted effects? (4)
Adverse effects
* Minimal when inhaled
* Anti-muscarininc side effects –
Common
1. dry mouth (M3 effects on salivary
glands)
2. GI tract effects
Uncommon include
3. Exacerbation of angle closure
glaucoma
4. Urinary retention
- Asthma
– May be used as an adjunct to Beta
2 agonists and steroids
– Bronchospasm (precipitated by
beta antagonists) - COPD (esp LAMA)
– See practice guidelines
Xanthines: Mechanisms
MoA= Not clear…
* Phosphodiesterases (PDEs) - enzymes
regulate intracellular levels cAMP (and
cGMP)
– Phosphodiesterase (PDE) metabolises cAMP
* Methylxanthines inhibit PDE,
– maintaining high cAMP levels
What are the types of Xanthines? (2)
- Theophyline
– Quite insoluble
– Narrow therapeutic index
– Many drug-drug interactions
(CytP450) - Aminophyline
– More soluble than theophyline
Xanthines
Both Orally (modified release formulas)
Aminophyline IV in acute severe asthma
What are the unwanted effects of Xanthines?
- Used for relief of bronchospasm in COPD
- Stem from effects on other systems
– Eg CNS, CVS
– Nervousness, insomnia - Narrow therapeutic Window
– Serious CVS CNS
– Cardiac dysrhythmia (can be fatal)
– Seizures (at only slightly above therapeutic range)
– Monitor - PK
– Absorption from gut unpredictable / varies between individuals - Inconjunction Variable plasma half life – use as modified release
- Metabolised by P450 enzymes in liver
– Plasma concentration decreased by drugs that induce P450 enzymes - Eg carbamazepine, phenytoin
– Plasma concentration increased by drugs that inhibit P450 enzymes - Eg erythromycin
Leukotriene receptor antagonists:
What is their mechanism?
Drugs: Leukasts
* Cysteinyl leukotrienes (e.g. LTD4) act on CysLT1 receptor in respiratory mucosa
– Airway inflammation & hyper-reactivity
* Montelukast & Zafirlukast antagonise the CysLT1 receptor
What are Leukotrienes?
Where are they formed?
- Arachidonic acid metabolites
- Leukotrienes
- Synthesized from arachidonic acid and bind to receptors on target tissues
- Formed in various cells, mostly LEUKocytes including activated mast cells and eosinophils
- Activation of cysteinyl leukotriene receptor
- Leukocyte recruitment
- mucus secretion
- vascular permeability / airway oedema
- smooth muscle contraction
Leukotriene receptor antagonists: (LTRA)
How does it work?
- Prevents bronchoconstriction mediated by LTs
- Inhibit early & late phase responses to irritants in asthma
- Generally taken orally with inhaled corticosteroid
- Not used widely
- Relax airways in mild asthma
– Not as effective as salbutamol
– Or ICS - Additive
- Few side effects
– GI effects
Histamine H1 receptor antagonists/ anti histamines
- Mast cell degranulation and release of histamine – important in early phase
of allergic asthma in particular / some exercise induced asthma and other
types - Histamine binds to H1 receptor
- Mucus secretion / SOME (Bronchoconstriction)
- BUT: Histamine H1 receptors proven to be of little clinical benefit in asthma
- May be mildly effective in mild atopic asthma but not routinely used
- May inhibit triggers
What are the functions of Anti-inflammatory Drugs?
- Used to reduce severity and frequency of asthma attacks
- Limit progression of disease by inhibiting remodelling
- Reduce night-time asthma attacks by preventing late-phase
Glucocorticoids
- Main drugs used for their anti-inflammatory
properties in asthma - Not bronchodilators (don’t relieve early phase)
- Prevent the progression of chronic asthma
- Effective in acute severe asthma
- Wide range of effects
- Add-on inhalational therapy in asthma when
bronchodilator is used more than once daily
Glucocorticoids: Mechanisms
Therapeutic effects:
Immunosuppression
– IL-10 –Decreases cytokine formation–
decreases recruitment and activation of inflammatory T cells
ie inhibits responses responsible for production of IgE and its receptors and for recruiting eosinophils – A process that begins in early phase and causes late phase of asthma – inhibiting late phase
Anti-inflammatory
– induces pathways that
* inhibits phospholipase A2
* decreased inflammatory mediators (Prostanoids & leukotrienes)
− also suppress COX-2 induction thus ↓inflammatory prostanoid production
– can reduce severity of early phase response and prevent late phase response
Glucocorticoids: Mechanisms
* Inhibit inflammatory cascade (previous 2 slides)
* Upregulate Beta 2 adrenoreceptors
– Potentiate effect
– Remember regular use of Beta 2 adrenoreceptor agonists (LABA) should be accompanied by ICS
* Eventually reduce number of mast cells
– May have some effect on early phase
