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Pulmonary system > MOA and modes of delivery for drugs used in treatment of airway obstructions > Flashcards

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

1
Q

Targets for drug therapy (COPD and asthma)

A
  1. Bronchoconstriction
  2. Chronic inflammation (also restricting airways)
  3. Mucous plugs
  4. Remodelling
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2
Q

Drug therapy used - classes

A
  1. Bronchodilators (vs. bronchoconstriction)
  2. Corticosteroids (vs. inflammation)
  3. Leukotriene antagonists
  4. Monoclonal antibodies
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3
Q

Modes of delivery drug therapy

A
  1. Oral
  2. Injection
  3. Inhalation
    * inhalation is the favored route - provides local effect
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4
Q

What type of agents will dilate bronchioles

A

a) Beta- 2 agonists
- short acting
- long acting
b) Anti-cholinergics
c) Methylxanthines

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5
Q

Development of beta-2 agonists

A
  • 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
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6
Q

Beta-2 agonists MOA

A

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

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7
Q

Best treatment for

a) asthma
b) COPD

A

a) beta- 2 agonist

b) beta-2 agonist or anticholinergics (pretty similar)

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8
Q

Mode delivery beta-2 agonist

A

-inhalation route or else get some side effects

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9
Q

Types of Beta-2 agonists

A

1) Short-actin beta-2 agonist (SABAs)
2) Long-acting beta-2 agonist (LABAs)
3) Ultra-long acting beta-2 agonist

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10
Q

Salbutamol

A
  • 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)
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11
Q

Why get tachycardia/palpatations as side effect of salbutamol

A
  • B-2 agonist are not perfectly selective

- still getting some stimulation of B-1 receptors on the heart

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12
Q

Why get tremor as side effect of salbutamol

A

-B-2 receptors in skeletal muscle

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13
Q

Main function long acting B2-agonists

A

For maintenance/control of asthma

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14
Q

Prototype long-acting B2 agonist

A

Salmeterol

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15
Q

Duration Salmeterol

A
  • approximately 12 hours (used twice a day)
  • because dissociates from the receptor more slowly
  • however slow onset of action (not for acute use)
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16
Q

Formoderole

A
  • fast onset LABA (so also long acting B-agonist)

- could be used as rescue (not ideal)

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17
Q

Safety LABAs

A
  • concern use in monotherapy

i. e. to use alone

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18
Q

Anti-cholinergic development

A
  • 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
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19
Q

MOA Ipratroprium

A
  • MI and especially M3 mediate bronchoconstriction in the lungs
  • if block these get bronchodilation
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20
Q

Prototype long acting anticholinergic

A

Tiotropium

  • a selective muscarinic antagonist
  • long acting (whereas ipratropium was short acting)
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21
Q

Side effects of anticholinergics

A
  • not much systemic absorption with inhalation route

- common side effect =dry mouth (alot of inhaled drug ends up in mouth)

22
Q

Prototype methylxanthines

A

-theophylline (metabolite of caffeine)

23
Q

Discovery of methylxanthines

A
  • Strong coffee seemed to improve symptoms of asthma

- coffee is a methylxanthine - helps as a bronchodiator

24
Q

MOA methylxanthines

A
  • 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
25
Q

Side effects of methylxanthines

A
  • 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
26
Q

Cortiosteroids derivation

A

-derived from cortisol

27
Q

Corticosteroids MOA

A
  • 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
28
Q

Effects/Targets of corticosteroids

A

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)

29
Q

Prototypical corticosteroid

A

-prednisone

30
Q

Side effects of prednisone

A
  • many metabolic/catabolic effects
    a) osteoporosis
    b) fat redistribution (moon face, buffalo hump)
    c) obesity
    d) hyperglycemia (drugs are glucocorticoids)
31
Q

How to avoid side effects of corticosteroids

A

-instead of giving them orally /systemically have them inhaled to target lungs directly

32
Q

Prototypes inhaled corticosteroids (ICS)

A

1) Budesonide

2) Fluticasone

33
Q

Side effects of inhaled corticosteroids

A

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)

34
Q

Ciclesonide

A
  • 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
35
Q

Leukotrienes generation (what pathway)

A
  • the lipoxygenase pathway (from Arachidonic acid)

- key enzyme = 5-lipoxygenase

36
Q

Action of leukotrienes

A
  • bind to various leukotrien receptors

- key receptor = LT1 which mediates bronchoconstriction and inflammation of airways

37
Q

methods of inhibiting leukotrienes

A

1) Inhibit 5-lipoxygenase (no drugs that are safe have been developed)
2) Block LT1 receptor

38
Q

Prototype leukotriene receptor antagonist (LTRA)

A

Montelukast

39
Q

Advantage of montelukast

A

-allows oral dosing (so good for kids)

40
Q

Disadvantage of montelukast

A
  • not as efficacious as other agents

- the LT2 receptor mediates airway smooth muscle proliferation and likely plays a role in asthma

41
Q

Prototype monoclonal antibody

A

Omalizumab

42
Q

MOA of omalizumab

A

-prevent interaction of allergen with IgE (working on allergic component with asthma)

43
Q

Mode of delivery omalizumab

A

-is an antibody (protein) therefore must be given by injection (subcutaneous) as protein will be denatured by stomach if taken orally

44
Q

Advantage

A

-administered every few weeks

45
Q

Disadvantage

A
  • injection
  • immune reaactions
  • cost (1000 a month)
46
Q

Combination therapy + 2 examples

A

-for maintenance therapy
-inhaled corticosteroids (ICS) + long-acting beta agonist (LABA)
ex:
Fluticasone + Salmeterol (Advair)
Budesonide + Formoterol (Symbicort)

47
Q

Rationale for combination therapy

A

-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

48
Q

Challenges with mode of delivery

A
  • 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)
49
Q

Nebulizer

A
  • liquid form of drug is vapourized
  • inhaled through a mask
  • not very portable
50
Q

Pressurized metered dose inhalers (MDI)

A
  • delivers aerosolized particles
  • but requires coordination
  • much of drug ends up at the back of the throat
51
Q

Dry powder inhaler

A
  • metered dose of drug is loaded into the chamber

- patient inhales the dose

Pulmonary system (19 decks)

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