pulmonary pharmacology 1 Flashcards
what is asthma?
•Episodic Airways Obstruction due to;
–Bronchospasm - bronchial smooth muscle hyperactivity
–Cholinergic nerve over-activity
–Increased mucus secretion
–Pulmonary inflammation
•
•Symptoms
–Dyspnoea
–Wheezing,
–Cough
What causes asthma?
genetic predisposition -
environmental factors
- infections (particlarly viral)
- allergens
- pharmacological triggers like NSAIDs, or beta blockers
- exercise (we don’t know why- but we assume the cold air elicits an inflammatory response)
- emotional stress
etc
describe the pathophysiology of asthma?
- overactivity of cholinergic signaling causing the msucles to contract
- exposure to the trigger allergen is bound to IgE linked to mast cells
- leads to other inflammatory mediators to drive vasodilation and these chemokines and cytokines stimulate production of mucus etc.
- further plasma leakage and dilation lead to more constriction of the airway
how does the autonomic nervous system contribute to the pathophysiology of asthma?
parasympathetic =
- Predominant innervation of airway smooth muscle - Vagus (Xth)
- Occupation of M3 receptors by Ach causes bronchoconstriction and increased mucous secretion.
sympathetic =
- No direct sympathetic supply of smooth muscle.
- Circulating adrenaline acts at B2 adrenoceptors on airway smooth muscle, and inhibits bronchoconstriction.
how do beta 2 agonists work?
normally adrenaline binds to the receptor, which turns on adenylate cyclase - producing cyclic AMP which activate protein kinase A - which activates a number of pathways to relax the smooth muscle
- Causes relaxation of bronchial smooth muscle (bronchodilation) by increasing cAMP via G-protein linked activation of adenylate cyclase.
- Inhibits mediator release from mast cells
- May also increase mucociliary clearance
what is the short acting beta2 agonist drug we use
Salbutamol (Ventolin)
Terbutaline
what LONG acting beta 2 agonist do we use?
Salmeterol / Formoterol / Indacaterol / Vilanterol
Long acting compounds bind to an exoreceptor beside the B2 receptor causing repeated activation
- these are particularly good for patients who have poorly controlled asthma or COPD
what are the systemic side effects of Beta2 agonists?
Systemic Side Effects:
tremor,
arrhythmias (when they bind to beta 1)
hypokalemia (due to beta 2 adrenergic receptors in the pancreas secreting insulin and therefore potassium)
muscle cramps, (very rarely, rhabdomyolysis)
MLC20 is responsible for what?
when it is phosphorylated = contraction
when it is dephosphorylated = relaxation
He always asks about Classes of drugs- not individual drugs just so you know
how do muscarinic antagonists work?
inhibit action of acetyl choline at M1 M2 and/or M3
(odd numbered are attached to activating receptors)
how do xanthines work?
Inhibition of phosphodiesterase (PDE), the enzyme that degrades cAMP. Increased concentrations of cAMP cause bronchodilation. (this blocking also prevents the release of cytokines from immune cells- preventing further immune response)
Inhibition of the release of intracellular calcium, thereby decreasing smooth muscle contraction (bronchoconstriction)
Competitive antagonism of adenosine on the adenosine receptor
what are the side effects of xanthines?
narrow therapeutic range
can caue nausea, anorexia, arrythmias, and nervousness/tremor/seizures
what are the pharmacokinetics of xanthines?
Metabolised in the liver
T1/2 increased by liver disease, heart failure and
decreased by smoking and heavy drinking
where is xanthine metabolised?
in the liver by cytochrome P450 1A2 - therefore you should avoid other drugs which can compete for this binding site (like erythromicin)
If you do give another P450 drug, it can result in reduced plasma concentrations and decreased effects of drugs which are extensively metabolised by these enzymes
describe the inflmmatory response in asthma
allergen recognized by IgE
mast cell releases histamine - broncho constriction
Interleukins - inflammation and mucosal oedema
how do glucocorticoids work?
binds to receptor and translocates to the nucleus - when the receptor is bound to the steroid it binds to glucocorticoid response element - switching on target gene that is anti-inflammatory in nature
- It can also transprepress - where it translates into the nucleus and it not only upregulates anti-inflammatory genes, but it also downregulates inflammatory genes (so long as there is no coactivator present)
- it can also form a repressive complex with transcription factors - stopping them from interacting witht the promoter regions that drive inflammation
what is the net effect of corticosteroids?
upregulation of anti-inflammatory mediators
down regulation of inflammatory mediators -
why is it dangerous to give glucocorticoids orally too often?
b/c adding artificial glucocorticoids we turn off the negative feedback loop that naturally occurs with our pituitary gland -
therefore we have longterm adrenal suppression - which can lead to Cushing’s syndrome etc. -
what is the effect of glucocorticoids on your metabolism?
can lead to glucose intolerance over long term use
how do Cromones work?
they block the degranulations of mast cells - they essentially stabilize the mast cells by inhibiting Ca+ influx
they have a bit of a bronchodilatory effect - by inhibition of sensory neurons
they also reduce IgE production and inhibit eosinophil accumulation in lungs
why are Cromones used in younger patients?
Whilst not as effective as inhaled steroids, fewer side effects.
Hence first choice anti-inflammatory agent in children
what is the precursor of leukotrienes?
arachidonic Acid
What are the two types of leukotriene modifyiers?
receptor antagonists and inhibitors of 5-lipoxygenase
