MOA and modes of delivery for drugs used in treatment of airway obstructions Flashcards
1. List the major drug classes used in management of asthma/COPD 2. Describe the mechanisms of action of drug classes used in asthma/COPD 3. Describe the major side effects and safety issues associated with these agents 4. Describe their pharmacokinetic issues particularly their modes of delivery
Targets for drug therapy (COPD and asthma)
- Bronchoconstriction
- Chronic inflammation (also restricting airways)
- Mucous plugs
- Remodelling
Drug therapy used - classes
- Bronchodilators (vs. bronchoconstriction)
- Corticosteroids (vs. inflammation)
- Leukotriene antagonists
- Monoclonal antibodies
Modes of delivery drug therapy
- Oral
- Injection
- Inhalation
* inhalation is the favored route - provides local effect
What type of agents will dilate bronchioles
a) Beta- 2 agonists
- short acting
- long acting
b) Anti-cholinergics
c) Methylxanthines
Development of beta-2 agonists
- epinephrine was used as bronchodilator (given way back when for people with problem breathing) - non selective alpha-beta agonist
- isoproterenol was then developed as a selective B1/B2 agonist
- still got side effects –> stimulating B1 receptors in heart = tachycardia
- developed B2 agonists
Beta-2 agonists MOA
1) Bind to B2 receptor on cell surface
2) B2 receptor is coupled to G protein
3) Activates Adenylate cyclase which converts ATP to cAMP
4) cAMP causes bronchodilation
Best treatment for
a) asthma
b) COPD
a) beta- 2 agonist
b) beta-2 agonist or anticholinergics (pretty similar)
Mode delivery beta-2 agonist
-inhalation route or else get some side effects
Types of Beta-2 agonists
1) Short-actin beta-2 agonist (SABAs)
2) Long-acting beta-2 agonist (LABAs)
3) Ultra-long acting beta-2 agonist
Salbutamol
- prototypical B-2 agonist
- aka ventalin
- a rescue drug because rapid onset (within a few minutes) - if someone is in bronchospasm
- well tolerated because delivered to site of action (not much systemic absorption)
- can get some tachycardia/palpitations and tremors (sign that asthma is out of control - because taking medication too frequently)
Why get tachycardia/palpatations as side effect of salbutamol
- B-2 agonist are not perfectly selective
- still getting some stimulation of B-1 receptors on the heart
Why get tremor as side effect of salbutamol
-B-2 receptors in skeletal muscle
Main function long acting B2-agonists
For maintenance/control of asthma
Prototype long-acting B2 agonist
Salmeterol
Duration Salmeterol
- approximately 12 hours (used twice a day)
- because dissociates from the receptor more slowly
- however slow onset of action (not for acute use)
Formoderole
- fast onset LABA (so also long acting B-agonist)
- could be used as rescue (not ideal)
Safety LABAs
- concern use in monotherapy
i. e. to use alone
Anti-cholinergic development
- people with asthma used to smoke belladonna leaves “asthma cigarettes”
- get atropine from belladona
- smoke is excellent method of delivery
- improvements on smoking = inhale atropine (eventually make inhalation devices)
- problem is atropine is systemically absorbed (unpleasant side effects)
- to limit its absorption - put charge on it (make more pola to reduce its ability to be absorbed across the membrane) = Ipratropium was born
- becomes the main inhaled anti-cholinergic
MOA Ipratroprium
- MI and especially M3 mediate bronchoconstriction in the lungs
- if block these get bronchodilation
Prototype long acting anticholinergic
Tiotropium
- a selective muscarinic antagonist
- long acting (whereas ipratropium was short acting)
Side effects of anticholinergics
- not much systemic absorption with inhalation route
- common side effect =dry mouth (alot of inhaled drug ends up in mouth)
Prototype methylxanthines
-theophylline (metabolite of caffeine)
Discovery of methylxanthines
- Strong coffee seemed to improve symptoms of asthma
- coffee is a methylxanthine - helps as a bronchodiator
MOA methylxanthines
- poorly defined with several contributing factors
- for sure are phosphodiesterase inhibitors (PDE)
- by inhibiting phosphodiesterase inhibits the break down of cAMP
- so get increased cAMP (to AMP) and increased bronchodilation
Side effects of methylxanthines
- narrow margin of safety
- side effects:
a) nausea, vomiting
b) stimulatory effect (derived from caffeine) - insomnia, tremor, restlessness
c) Serious effects - cardiac arrhythmias
d) drug interactions are common
Cortiosteroids derivation
-derived from cortisol
Corticosteroids MOA
- unsure of exactly (endogenous discovery)
- act in nucleus, promoting expression of some genes and inhibiting expression of others
1) Bind to intracellular receptor
2) Complex translocates to nucleus and stim/inhib expression of genes
Effects/Targets of corticosteroids
1) inhibit expression of:
a) pro-inflammatory cytokines
b) Cox-2
* *getting anti-inflammatory effects
2) Immunosuppressants (generally beneficial)
3) Significant metabolic effects (generally harmful)
Prototypical corticosteroid
-prednisone
Side effects of prednisone
- many metabolic/catabolic effects
a) osteoporosis
b) fat redistribution (moon face, buffalo hump)
c) obesity
d) hyperglycemia (drugs are glucocorticoids)
How to avoid side effects of corticosteroids
-instead of giving them orally /systemically have them inhaled to target lungs directly
Prototypes inhaled corticosteroids (ICS)
1) Budesonide
2) Fluticasone
Side effects of inhaled corticosteroids
1) Oral thrush
- overgrowth of candida due to deposition of steroid in the oral cavity
- to reduce rinse mouth after inhale
2) Dysphonia (hoarseness) - due to changes in vocal chords
-systemic effects can still occurs - particularly with long term use (osteoporosis)
Ciclesonide
- drug designed to really minimize the side effects of corticosteroids
- drug will have very limited systemic effects because is activated by esterases in the airways
Leukotrienes generation (what pathway)
- the lipoxygenase pathway (from Arachidonic acid)
- key enzyme = 5-lipoxygenase
Action of leukotrienes
- bind to various leukotrien receptors
- key receptor = LT1 which mediates bronchoconstriction and inflammation of airways
methods of inhibiting leukotrienes
1) Inhibit 5-lipoxygenase (no drugs that are safe have been developed)
2) Block LT1 receptor
Prototype leukotriene receptor antagonist (LTRA)
Montelukast
Advantage of montelukast
-allows oral dosing (so good for kids)
Disadvantage of montelukast
- not as efficacious as other agents
- the LT2 receptor mediates airway smooth muscle proliferation and likely plays a role in asthma
Prototype monoclonal antibody
Omalizumab
MOA of omalizumab
-prevent interaction of allergen with IgE (working on allergic component with asthma)
Mode of delivery omalizumab
-is an antibody (protein) therefore must be given by injection (subcutaneous) as protein will be denatured by stomach if taken orally
Advantage
-administered every few weeks
Disadvantage
- injection
- immune reaactions
- cost (1000 a month)
Combination therapy + 2 examples
-for maintenance therapy
-inhaled corticosteroids (ICS) + long-acting beta agonist (LABA)
ex:
Fluticasone + Salmeterol (Advair)
Budesonide + Formoterol (Symbicort)
Rationale for combination therapy
-use B-2 agonist chronically can get downregulation of B-2 receptors
(danger of using labas - loose ability to get rescue response from ventalin because ont have as many b-2 receptors)
-corticosteroids upregulate B2 receptors in the lungs - replenish so that when need rescue ventalin will work
Challenges with mode of delivery
- when inhaling a drug size does matter
- only about 10% of drug reaches alveoli
- focus on reducing particle size (if could smoke would get better delivery)
Nebulizer
- liquid form of drug is vapourized
- inhaled through a mask
- not very portable
Pressurized metered dose inhalers (MDI)
- delivers aerosolized particles
- but requires coordination
- much of drug ends up at the back of the throat
Dry powder inhaler
- metered dose of drug is loaded into the chamber
- patient inhales the dose
