Drugs for asthma Flashcards
Pathophysiological features of asthma
mucosal edema
secretion of mucus
bronchoconstriction
Treatment for bronchial asthma
Bronchodilators
1. beta 2 adrenergic receptors agonists
-SABA: salbutamol
-LABA: salmeterol
2. antimuscarinic (M2/M3)
-SAMA: ipratropium bromide
-LAMA: tiotropium
3. PDE inhibitor
-theophylline
anti-inflammatory
1. corticosteroids
-inhaled corticosteroids: beclomethasone, fluticasone
-oral/IV corticosteroids: prednisolone
2. Anti-IgE antibodies: omalizumab
3. leukotriene pathway inhibitors
-receptor antagonists: montelukast, zafirlukast
-5-lipoxygentase inhibitor: zileuton
MOA of the most potent bronchodilators for treatment of asthma
beta 2 agonist (works like adrenaline)
SABA: salbutamol
LABA: salmeterol
MOA
+receptor activate adenylyl cyclase which turns ATP into cAMP. cAMP activates PKA which phosphorylate myosin light chain kinase (MLCK), resulting in relaxation of bronchial smooth muscle [bronchodilation] Besides, PKA also stimulates Ca-activated K channel to open, more potassium leaks out (hyperpolarisation) which causes relaxation
Differences of salbutamol and salmeterol
Salbutamol SABA
-hydrophilic
-short duration (cannot store in lipid)
-rapid onset
-seen in MDI & nebulizer
Salmeterol LABA
-lipophilic
-long duration
-slow onset
-seen in MDI
pharmacological effects of beta 2 adrenergic agonists like salbutamol and salmeterol
bronchodilator due to
a. Reduced Intracellular Calcium Levels: One of the primary effects of cAMP signaling is the inhibition of intracellular calcium release from intracellular stores (like the sarcoplasmic reticulum) in smooth muscle cells.
b. Inhibition of Calcium Entry: cAMP also reduces the influx of extracellular calcium ions (Ca2+) through voltage-gated calcium channels in the smooth muscle cell membrane. This decreased calcium entry is crucial for bronchodilation.
inhibition of inflammatory mediator release from mast cells and monocytes
enhance mucociliary clearance
expectoration of bronchial tract
beta 2 agonists (salbutamol and salmeterol) : adverse drug reactions
skeletal muscle tremors
nervousness
increased HR/reflex tachycardia due to vasodilation
MOA of bronchodilators: muscarinic antagonist (M2/M3) blocks muscarinic acetylcholine receptors=G protein-coupled receptors
SAMA: ipratropium bromide
LAMA: tiotropium
BLOCKS
M2 (cardiac, presynaptic autoreceptor) INHIBITORY
reduce cAMP
inhibit Ca channel, high K conductance
inhibit heart and presynaptic
inhibit respiratory ciliary activity
M3 ( resp tract, glandular) EXCITATORY
increase IP3, DAG
increase intracellular Ca
low K conductance=depolarization
bronchoconstriction
secrete glandular mucus
enhance mucociliary clearance
uses and adverse effects of muscarinic antagonists: Ipratropium and tiotropium
Ipratropium
non-selective muscarinic (M2 & M3)
acute, prophylaxis
treat COPD, CVS in elderly
Tiotropium
selective (M3)
longer duration of action
1st line therapy in COPD
Adverse effects
dry mouth
nausea
constipation
urinary retention
exacerbation of angle-closure glaucoma
MOA, pharmacological effects and uses of bronchodilators: methylcanthine (theophylline) PROTOTYPE
theophylline
MOA
inhibits PDE =increase cAMP [effects similar to beta agonist]
pharmacological effect
bronchodilation: stabilise mast cells, inhibit release of inflammatory mediators, increase mucocilliary function
*rarely used, not as effective as SABA
-uses/indications: bronchial asthma, prophylaxis for nocturnal asthma, bronchospasm + bronchitis (COPD)
pharmacokinetics of methyxanthines (theophylline)
metabolised by cytochrome P450 in liver=potential drug-drug interactions
rapidly absorbed from GIT
narrow therapeutic effect
adverse effects of methylxanthines (theophylline)
oral, slow IV ONLY
CNS (agitation, insomnia, nervousness, convulsions), CVS (tachycardia, arrhythmia), respiratory AE
Anti-inflammatory agents: corticosteroids aka glucocorticoids for asthma treatment
reduce inflammation
reduce hyperactivity
reduce responsiveness to stimulus
DOES NOT CAUSE BRONCHODILATION= does not help in asthma attack
prototype for corticosteroids aka glucocorticoids
prednisolone (oral)
hydrocortisone (IV)
beclomethasone (inhale) aka ICS
major mechanism:
effects on inflammatory mediators and cells
Corticosteroids aka glucocorticoids: Effects on inflammatory mediators
inflammatory stimuli acts on phospholipase A2, corticosteroids inhibit phospholipase A2 which inhibits Arachidonic acid
corticosteroids has gene repression effects
reduce cytokine (IL-1, 6, 10) and TNF alpha
reduce eosinophils
promote production & expression of IgE & its receptors
corticosteroids’ effects on inflammatory cells
inflammatory cells:
less cytokines
less mast cells, less eosinophil and T lymphocyte
less macrophage
less dendritic cell
structural cells:
less cytokines and mediators from epithelial cells
less endothelial leak
increase beta 2 receptors on airway smooth muscle
reduce mucus secretion
systemic corticosteroids cannot be used for a long period of time due to its adverse effects
weight gain. drug-induced diabetes, easy bruising
AE of inhalation of corticosteroids
low dose- local effects: oral candidiasis
high dose-long duration-systemic effects: cataract, glaucoma
side note:
**gargle and Rinsing the mouth after inhaling corticosteroids,
Preventing Oral Thrush: One of the potential side effects of inhaled corticosteroids is the development of oral thrush (oral candidiasis). This is a fungal infection caused by the yeast Candida albicans. Rinsing the mouth with water or brushing your teeth after inhaling corticosteroids helps remove any medication residue from the oral cavity, reducing the risk of oral thrush. This is particularly important for those who use high doses of inhaled corticosteroids or those who are more susceptible to fungal infections.
interaction between corticosteroids and LABA(fixed dose)
corticosteroids: anti-inflammatory
LABA: bronchodilation
aka seretid
Seretide is a brand name medication that contains a combination of two active ingredients:
- Salmeterol: Salmeterol is a long-acting beta-2 agonist (LABA). It works by relaxing the muscles in the airways, which helps to open up the air passages and make it easier to breathe. LABAs are used to provide long-term control of asthma and chronic obstructive pulmonary disease (COPD) symptoms. They are not intended for rapid relief of acute symptoms but rather for ongoing management.
- Fluticasone Propionate: Fluticasone is an inhaled corticosteroid (ICS). It works by reducing inflammation in the airways, which is a key component of asthma and COPD. By decreasing inflammation, fluticasone helps to prevent and control symptoms such as wheezing, shortness of breath, and cough.
The combination of a LABA (salmeterol) and an ICS (fluticasone) in Seretide is commonly used for the management of asthma and COPD in individuals whose symptoms are not well-controlled by an ICS alone. It provides both bronchodilation (opening up of airways) and anti-inflammatory effects.
MOA of leukotriene pathway inhibitor (STEP UP TREATMENT):
LOX inhibitor : zileuton
inhibit 5-lipoxygenase (LOX) , inhibit the formation of leukotriene
CAN relieve symptoms of bronchial asthma
indications, pharmacokinetics and AE of leukotriene pathway inhibitor: zileuton
indications:
prophylaxis
chronic treatment in adults and kids over 12
cannot reverse bronchospasm in ACUTE asthma attack
pharmacokinetics: orally
AE: LIVER TOXICITY need to monitor liver function
MOA, indications, pharmacokinetics and AE of leukotriene RECEPTOR inhibitors: zafirlukast, montelukast
MOA:
as the name goes
Indications:
prophylaxis
chronic treatment in adults and kids over 6
Pharmacokinetics: orally
AE: LIVER TOXICITY IN ZAFIRLUKAST hence less prescribed
MOA of anti-IgE therapy: Omalizumab
recombinant humanised monoclonal antibody to IgE
+IgE via Fc
suppress mast cell response to allergens
indications and AE of omalizumab
indications:
reduced in severity and freq of asthma attacks (high cost)
AE:
anaphylactic reaction
pain and inflammatory reaction at site of injection
Cromolyn sodium (less commonly used)
MOA:
interferes with antigen-antibody reaction of mast cell
indications:
prophylaxis of chronic asthma
AE:
nasal stinging
nasal irritation
