Resp Lecture 9

Front 1

Why pharmacological intervention?

Back 1

Example of an allergic airway disease asthma-likedisease that can be treated
• Episodic reversible airflow limitation
- bronchoconstriction
- Mucus overproduction
• Airway inflammation

Front 2

What does allergy airway obstruction result in?

Back 2

Either over mucous production, inflammation, oedema, or constriction of the smooth muscle cells.

Front 3

What are some of the treatment options for feline asthma?

Back 3

(also for Asthma-like ‘heaves’ or Recurrent Airway Obstruction (RAO in horses)

• bronchodilators: restricts constriction (relaxing airways)
• anti-inflammatory: Corticoid steroids, stop over activity of the immune system.
Mucalictics: act to make the mucous less sticky

Front 4

What are the aims of treatment for lower airway disease?

Back 4

– control inflammation,
– minimise bronchoconstriction,
– minimise long term damage (chronic disease can result in the buildup of scar tissue)

Front 5

How does Ca2+ play a role in treatment?

Back 5

Smooth muscle contraction is very much dependent on the level of Ca2+ in the cell. Regulated through the membrane and the sarcoplasmic reticulum and mitochondria which stores the Ca2+. Once the Ca2+ is released, the muscle contracts. If we want relaxation, we need to remove the Ca2+ from inside the cell.

Front 6

How does Ca2+ initiate smooth muscle contraction?

Back 6

Ca2+ enters the cell and binds to calmodulin (Ca2+-calmodulin)
Ca2+-calmodulin activates the myosin kinase
The activated myosin kinase adds a phosphate group onto the myosin activating it (now it can bind to actin contracting the muscle).
The phosphatases take the phosphate groups off and inactive the muscle contraction.

Front 7

Steps in the smooth muscle contraction

Back 7

Stimulus-->Ca2+ released-->Myosin + P (myosin is phosphorylated and becomes activated)-->thick and thin filament engagement-->contraction (lattice collapse)

Front 8

What are the steps in smooth muscle relaxation

Back 8

This is the objective of the medicine (bronchodilators)
Withdrawal of the stimulus-->Ca2+ uptake in the sarcoplasmic reticulum (the Ca2+ levels in the cell drop)-->myosin loses its P-->Thin filament/thick filament disengagement--> relaxation (lattice is normal shape)

Front 9

What are the classes of the bronchodilators?

Back 9

• Beta-2 adrenoceptoragonists (main ones)
• Phosphodiesteraseinhibitors
• Muscarinic receptorantagonists

Front 10

How do bronchodilators work?

Back 10

1. They increase adenyl cyclase-->increased cAMP-->relaxation
2. Inactivation of Myosin Light Chain Kinase (that's how we get muscle relaxation)
3. Increased mucociliary clearance

Front 11

Molecular actions of Beta 2 agonists in relaxing airway smooth muscle.

Back 11

Binds with Beta 2 receptor.
Through the g-protein coupled receptor, stimulates adenylate cyclase to convert ATP into cyclic AMP.
Cyclic AMP increases the levels of Protein Kinase A which through a series of reactions will lead to muscle relaxation

Front 12

What does protein kinase A result in?

Back 12

1. Increases the Ca2+/K+ Channel activity
2. Decreased PLC-IP3-Ca2+ pathway activity
3. Increased Na+/Ca2+ exchange
4. Increased Na+, Ca2+-ATPase
5. Decreased MLCK (myosin light chain kinase)
All of these will lower the levels of Ca2+ within the cell.

Front 13

What are some of the agonist drugs that behave similarly to adrenaline and noradrenaline?

Back 13

Isoproterenol and Albuterolol: Short chain, short duration (4-8hrs)
Salmeterol and Formoterol: These go into the membrane of the smooth muscle cell; much longer acting (8-12hrs)

Front 14

When we're developing therapeutic drugs what do we want to aim for?

Back 14

Increased Beta-2 selectivity (this helps to limit the side effects)
Increased duration of action

Front 15

Clenbuterol

Back 15

Not good in race horses, limits their performance.
• Works best when used in conjunction with allergenand dust avoidance, &/or anti-inflammatoryadministration.
• Minimal extra-pulmonary effects- transitory increasein heart rate and decrease in BP
• Side effects at high doses are beta-1 effectstachycardia,excitement and sweating
• Avoid use in pregnant mares near term as beta-2receptors on myometrium inhibit uterine contractionUsed to relieve airway obstruction associated withinflammatory lung diseases in horses.

Front 16

How do Phosphodiesterase inhibitor work?

Back 16

They inhibit phosphodieterase.
It works to increase cAMP levels. Phosphodiesterase breaks down cAMP into AMP. The inhibitors work to prevent this reaction and achieve muscle relaxation. They're not as effective as the beta-agonists (which increase cAMP). If you don't have much to start with (because so many have been broken down already), you won't have many more to break down=less effective.

Front 17

Phosphodiesterase inhibitors

Back 17

Theophylline and aminophylline (also caffeine and theobromine)

Front 18

Phosphodiesterase inhibitors: Mechanism

Back 18

Block phosphodiesterase mediated breakdown of cAMP, andtherefore cause:
- relaxation of airways
- increased heart rate and (?) increase in cardiac output
- CNS stimulation
• Bronchodilation not as effective as the beta agonists, but useful adjuncttherapy in asthma and COPD.

Front 19

Phosphodiesterase inhibitors unwanted side effects include

Back 19

– CNS stimulation- tremor, nervousness
– Diuresis as a result of increased renal blood flow
• Narrow therapeutic window: other drugs can increase or decreaseclearance in liver
– GI symptoms- nausea, vomiting, anorexia with increasing dose.
Below 30, no effect. Between 30-100 works, above 100, unwanted side effects-need to get the dosing just right

Front 20

What are the effects of Theophylline on the airway cells

Back 20

Bronchodilation, decreased leakage, increased strength?, decreased inflammatory cells

Front 21

How does Theophylline affect eosinophils?

Back 21

decreases the number

Front 22

How does theophylline impact T-lymphocytes?

Back 22

Decreases the cytokins

Front 23

How does theophylline impact mast cells

Back 23

decrease mediators

Front 24

How does theophylline impact macrophages?

Back 24

decreases cytokines

Front 25

How do muscarinic antagonists work?

Back 25

AcH will cause constriction at the muscarinic receptors; block them.

Front 26

What are the two different types of muscarinic antagonists?

Back 26

Glycopyrrolate (aerosol or IM)
Ipratroprium (competitie muscarinic AcH receptor antagonist)

Front 27

What are the different muscarinic receptor antagonist structures?

Back 27

Atropine
Scopolamine
Homatropine
Pirenzepine
Ipratropium
Tiotropium
Tolterodine

Front 28

How does the parasympathetic (vagus nerve) play a role in the control of airway calibre and muscarinic antagonism

Back 28

More vagal tone causes the airway to constrict. Use the muscarinic to act on the receptor causing relaxation

Front 29

What is the mechanism of action for corticosteroids?

Back 29

Corticoid steroids and beta agonists are better together than alone, synergistic. The corticoid steroids increase the Beta 2 receptors.
They go through the wall of the cell and bind with internal receptors within the cell. The receptor goes in and acts in the nucleus to prevent the transcription of the inflammatory genes. Very effective in allergy airway disease.

Front 30

What is the effect of corticosteroids on inflammation?

Back 30

Decreases cytokines and mediators in the epithelial cells
Decreases leaking of the endothelial cells.
Increases the Beta 2 receptors and decrease the cytokines of the smooth muscle
Decreases the mucous secretions

Front 31

What is the impact of corticoid steroids on eosinophils?

Back 31

Less numbers

Front 32

What is the impact of corticoid steroids on T-lymphocytes?

Back 32

decreased cytokines

Front 33

What is the impact of corticoid steroids on mast cells?

Back 33

decreased numbers

Front 34

What is the impact of corticoid steroids on macrophages?

Back 34

decreased cytokines

Front 35

What is the impact of corticoid steroids on dendrites?

Back 35

decreased numbers

Front 36

What is the deposition of inhaled drugs?

Back 36

Ideally the drugs are given as an aerosol, the more drug that goes into the lungs, the better the effects (less side effects).

Front 37

What are the size of the droplets for the aerosol?

Back 37

no greater than 2 microns across. Any greater than that will end up in the trachea, any smaller than that will end up in the gas exchange region and will likely go systemic. You want it to settle in the small airways.

Front 38

Sodium cromoglycate

Back 38

An anti-inflammatory. Mast cell stabolizer (prevents them from releasing granules-->only useful as last resort)

Front 39

Antitussives

Back 39

cough suppressants
Opioids and antihistamines

Front 40

Mucolytics

Back 40

Increased mucous clearance, change character of mucous. Makes the mucous less sticky and easier to cough up.

Front 41

What stimulates MCC?

Back 41

Mucociliary clearance is stimulated by adrenergic stimulation (beta-2 receptor agonists)