MEcahnism of action of drugs in respiratory disease Flashcards
Which group of drugs are aimed for relief of symptoms?
Bronchodilatrs - rescue from bronchospasm
Which group of drugs are aimed for the Propholaxis of the disease?
Anti-inflammatories: Limit frequency of attacks, the severity of attacks, and limit structural remodelling
What are the drugs that are Bronchodilators?
1) Beta2 agonists: Long (Salmeterol) and short acting (Salbutamol)
2) Muscarinic receptor antagonists (antimuscarinic): long (Tiotropium) and short acting (ipatropium)
3) Xanthines: Theophylline or Aminophylline
4) Histamine receptor antagonists (antihistamines)
5) Leukotrine receptor antagonist (montelukast)
What are the drugs that are Anti-inflammatory?
1) Inhaled corticosteroids (budesonide, fluticasone, memetasone etc)
2) Cromones (cromoglicate, Nedocromil)
3) Anti-immunoglobulin E (omalizumab) very expensive
4) Leukotrine recepotr antagonist (montelukast)
What is the mechanism of action of the B2 adrenoreceptor agonist?
When a B2 agonist binds to a B2 adrenoreceptor, it activates Adenylyl Cyclase via a Gs protein. Activated Adenylyl cyclase will increase intracellular cAMP (cyclic AMP). cAMP goes on to activate protein kinase A which goes on to phosphorylate many targets leading to a reduction in intracellular calcium and therefore bronchodilation.
Activated Protien Kinase A also leads to the activation of Potassium channels leading to hyperpolarisation of teh cells (potassium leaving) that reduces the number of Calcium channels open. This reduces the rate of entry of calcium thereore means a decresaed contraction.
Along with the opening of potassium channels, there is a decrease in phosphoinositide hydrolysis, increased Sodium/Potassium ATPase, and decreased Myosin Light chain kinase activity which all lead t bronchodilation.
Why is affecting the Myosin Light chain having an effect on the bronchoconstriction?
The myoisn light chain kinase is normally required to phosphorylate myosin so that it binds to actin. Therefore inhibiting the light chain myoisn kinase will lead to less contraction.
What is the Sodium/Potassium ATPase involved in the mecahnism of action of B2 agonists?
This enzyme causes an incarease in the hyperpolarisation of cells in the lung by increasing the Potassium leak out of the cells so a bigger stimuli is required to cause a contraction.
What is the mechanism of action of Xanthines?
These work by inhibiting Phosphoideterase (PDE) which decreases the amount of cAMP metabolised therefore cAMP levels remain high leading to smooth muscle relaxation (bronchodilation).
Increasing the levels of cAMP will also prevent inflammatory cell activation.
Xanthines also cause a stimulation of the respiratory control centre.
What is Theophylline and what are its disadvantages/
It is a Xanthine and is used if inhilation treatment is not sufficent to control symptoms.
It is insoluble in water therefore difficult to work with. It has a very narrow therapeutic index and also has many drug-drug interactions.
What is the mecahnsim of action of Muscarinic Receptor Antagonist?
These are anticholinergics. They block the activation of M3 receptors on the post synaptic membrane in the lung, therefore causing bronchodilation. M3 receptors are the target because they are limited to the lung, therefore there are less side effects. Anticholinergics are selective to M3, so at low concentrations, will bind to only M3, but high concentrations will cause bidning to other muscarinic receptors e.g. M1, leading to side effects.
What is the normal mechanism of bronchoconstriction through acetyl choline?
Acetylcholine is released from the pre-ganglionic nerve to the synapse in te lung. The Ach will bind to M1 receptors on the post-ganglionic nerve causing an action potential to be generated which will go on to release Ach at the neuromuscular synapse. Ach will bind to M3 receptors, stimulating smooth muscle contraction and narrowing of the airways.
Why are anticholinergics targeting M3 receptors and not M1?
M3 receptors are limited to the lung, while M1 receptors are all over the body therefore targeting these would lead to unwanted side effects.
Why is there a limited concnetration that Anticholinergics will work in?
If the concentration is initially too low to cause bronchodilation and is therfore increased, then some of the drug will bind to M2 autoreceptors, which will cause an increase in the amount of Ach released into the neurmuscular junction. The increased Ach will compete for binding with the increased Muscarinic antagonist, therefore there is no benefit in the increase in the drug concentration.
What are muscarinic antagonists best to treat?
COPD
What do we know about the SHort-acting Muscarinic Antagonist?
Ipratropium: Has an onset of action of 30 mins and a duration of action of 3-5 hours. It is not selective between Muscarinic receptors therefore can’t distingush between M2 and M3 subtypes. It does decrease Mucous secretion.
