Lecture 23 - Overview: Pulmonary Disease Management

characteristics of asthma

• Airflow obstruction

• Bronchial hyper-responsiveness

• Underlying inflammation (and resulting mucus production)

types of asthma

extrinsic/allergic + intrinsic

goal of acute asthma care

manage bronchial constriction

goal of chronic asthma care

manage inflammation

strategies to control broncoconstriction

A. Adrenergic stimulation (short and long acting 2 selective agonists)

B. Cholinergic blockade (cholinergic antagonists)

C. Histaminergic mediation of inflammation (chromone mast cell stabilizers)

how do beta agonists help bronchodilate

increase conversion of ATP to cAMP, which increases bronchodilation

how does theophylline help with bronchodilation

prevents cAMP breakdown by inhibiting PDE

how do muscarinic antagonists help with bronchodilation

block ACh to prevent airway constriction

how to manage both bronchoconstriction and inflammation

• manage arachionic acid cascade (PLA2, COX, leukotrienes)

• inhibit phosphodiesterase

Glucocorticoids ____ the biosynthesis of Lipocortin 1, and it ___ PLA2

induce; inhibits

why do glucocorticoids reduce inflammation and bronchoconstriction

by doing their thing with lipocortin, they decrease prostaglandin production

GCs and histamine synthesis

Glucocorticoids inhibit the synthesis and release of histamine from mast cells (it’s a potent bronchoconstrictor)

where do leukotrienes come from

arachidonic acid + 5-lipooxygenase activating protein (FLAP)

why are COX inhibitors not good for asthma

they increase arachidonic acid by limiting COX, but still leave the leukotriene pathway open

diclofenac MOA

1. inhibit COX pathways

2. inhibit arachidonic acid release / stimulate uptake

FLAP inhibitor MOA

decrease leukotriene production to lessen bronchoconstriction

FLAP inhibitor small SAR

hydroxyurea helps “bind to enzyme”

what happens when leukotriene receptors triggered

increased Ca2+ and less cAMP; manifests as airway hyperreactivity, bronchoconstriction, mucus secretion

Cysteinyl Leukotriene LT1 Receptor antagonist MOA

used at maintenance therapy to prevent bronchoconstriction (not cause dilation)

required structural feature(s) of Cysteinyl Leukotriene LT1 Receptor antagonist

• C1 carboxylate

• acidic or other negatively charged functional grouo

• H-bond acceptor functional grouo

• 3 hydrophobic regions (mimic leukotriene lipophilic tail) —> usually Ar

PDE inhibitor MOA

inhibit phosphodiesterase (PDE) to keep cAMP longer by structurally mimicking it in PDE active site