Respiratory pharmacology Flashcards
(32 cards)
Airway remodelling in asthma
Inflammation stimulates smooth muscle cell proliferation, causing a THICKENING OF THE WALL of the bronchus.
- Epithelial alterations with the shedding of the epithelium
- Upregulation of growth factors, cytokines and chemokines
Airway remodelling in COPD
Inflammation causes accumulation of mucopolysaccharides in the submucosal layer, they act as a glue and thus the wall becomes less elastic.
-> bronchoconstriction is irreversible in these patients
Action of glucocorticoids
They act on NFkB, negatively regulate IL-4, IL-5, Il-13. Thus, they interfere with inflammation, symptomatic bronchoconstriction and remodelling.
Glucocorticoids
- bind to the GRE inducing an increased transcription of IkBalpha
- behave as IkBalpha, direct interaction between NFkB and th glucocorticoid receptor in a monomeric form
Which is the main etiological cause in asthma?
Immunological e.g. allergies
Which are the 2 main etiological causes in COPD?
Smocking and pollution
Phases of asthma attack
- Immediate phase: histamine or leukotrines
- Late phase: inflammation based on cytokines released by T-lymphocytes
Use of antihistaminic drugs
Not useful in asthma or COPD, just in rhinasthma (when allergic rhinitis is present together with asthma). Even with the latter intranasal glucocorticoids is better.
Beta 2 adrenergic agonist: location and mechanism
Location: on SMCs and on inflammatory cells
Mechanism: they are GPCR, coupled to Gs, thus stimulating adenylate cyclate which lead to an increase in cAMP. Thus PKA is activated and phosphorylates MLCK and MLCP. The first is inhibited, the latter is activated. So the regulatory chain of myosin is dephosphorylated and muscle relaxation occurs.
-> bronchodilation.
Additional actions
- activation of mucociliary clearance
- inhibition of cholinergic transmission
- decrease plasma exudation
- increase surfactant levels
- modulators of the immune response since receptors are also present on inflammatory cells. Even if they undergo a rapid desensitization
Difference in use between short- acting and long- acting beta 2 agonists and explanation
Short acting: used in acute attack situations
Long acting: delayed onset, longer lasting action. Used for long-term therapy
Anticholinergics mechanism
- Antagonists at muscarinic receptors
- Inhibit bronchoconstriction
Which is the main neurotransmitter responsible for bronchodilation
Adrenaline! Released by the adrenal medulla as rescue mechanism e.g. during exercise
Noradrenaline is mainly used for regulating vessels and secretion, not really for bronchoconstriction.
Which part of the ANS is responsible for bronchoconstriction? And for bronchodilation?
Parasympathetic nervous system -> bronchoconstriction
Sympathetic nervous system -> bronchodilation
Mechanism of sensitive fibers on SMCs
Sensitive fibers are activated by irritants in the bronchus and initiate a reflex which cause the release of Ach. This leads to bronchoconstriction (defence mechanism). Cough is induced.
Adverse drug reactions to B2 agonista
- Tachycardia because of B2 receptors in the heart (present until desensitization)
- Shivering due to the presence of B2 receptors in skeletal muscles
- Hyperglycemia due to the presence of B2 receptors in skeletal muscles regulating metabolism
Corticosteroids administration for COPD and asthma is local, enteral or parenteral?
Realistic pharmacokinetics
Local! Otherwise it would be very dangerous. The drug is deposited in the respiratory airways during inspiration.
90% swallowed -> GI tract -> systemic circulation -> adverse drug reactions but a big portion is inactivated by the liver
10% has a topical effect in the lungs
Oral corticosteroids: no first-pass metabolism
List of inhaled glucocorticoids
- Fluticasone
- Budesonide
- Flunisolide
- Beclomethasone
- Monetazione
- Triamcinolone
Why could it be better to treat asthmatic kids with corticosteroids?
TNF alpha interferes with growth. Asthmatic kids treated without corticosteroids were shown to grow less.
Innervation of the lung
- Sympathetic: for circulation and secretion (especially aqueous). It causes vasodilation only in rescue mechanisms
- Parasympathetic: vagus nerve -> release of Ach -> activation of muscarinic receptors on SMCs (especially M1 and M3) -> contraction and mucous production
- NANC fibers (travel with the vagus nerve too): control bronchodilation in the resting state. Release of NO and some peptides (VIP) on SMCs -> activation of guanylyl cyclase -> production of cGMP -> activation of PKG -> inhibition of bronchoconstriction.
Why Ca2+ blockers are not used in asthma?
Ca2+ channels are expressed much more on SMCs of vessels but not on the SMCs of the bronchi.
Role of M2 muscarinic receptors
Auto receptors regulating the release of Ach. Present at preterminal level. Inhibit further release of Ach by causing an increase in K+ currents in the nerve (the terminal is hyperpolarized) -> calcium channels don’t open and neurotransmitters are not released
Antimuscarinic drugs
SMCs relaxation + inhibition of mucus production
Because of the localization of muscarinic receptors, these drugs are indicated more in COPD than in asthma.
In asthma a combination of B2 agonists and glucocorticoids is sufficient.
Ipratroprium and tiotropium
Antimuscarinic non - specific drugs. They block everything also M2 receptors
→ inhibit bronchoconstriction
→ inhibit mucous secretion
B2 agonists on immune cells
Dampening of the immune response.
Negative correlation between cAMP levels in immune cells and the degree of immune response.
Rapid desensitization
Apremilast
Specific blockage of PDE4 which is on inflammatory cells. PDE4 normally degrades cAMP thus once inhibited, levels of cAMP increases leading to a dampening of the immune response.
- PKA phosphorylates NFkB decreasing it’s activity
- phosphorylation of corticosteroid receptors, increasing their activity
- Stimulates CREB
