Asthma Therapies and Management

Therapies

• Types of therapies available to understand
• Sites of action of novel drugs to understand for the treatment of asthma

Asthma Management in Adults

• The evaluation involves assessing symptoms, measuring lung function, checking inhaler technique, and adhering to treatment plans.
• Adjust self-management plans, moving up or down as appropriate for asthma control.

Short-Acting Agonists

• Are used as needed, but consider moving up if using them three times a week or more.

Beta-2 Adrenoceptor Agonists

• Examples include salbutamol, salmeterol, and formoterol.
• These drugs relax smooth muscle for symptomatic relief, functioning through a cyclic AMP-dependent mechanism in airway smooth muscle.

Long-Acting Beta-Adrenoceptor Agonists

• Have lipophilic groups that interact with exo-sites on the receptor, locking the ligand onto the receptor binding site.

Salmeterol

• Is more potent than salbutamol is at the receptor, requiring lower doses.
• It binds more strongly to the receptor with a longer action (12 hours vs. 4 hours).
• Causes less desensitization than salbutamol.

Desensitization

• Short action has been a major problem for B2-adrenoceptor agonists
• A factor in the short duration of action, which is a loss in response to the agonist over time.
• Phosphorylation of the receptor by GRK enables binding of beta-arrestin
• Subsequent internalization of the receptor.

Salmeterol Desensitization

• In response to this drug, desensitization might be reduced because it is a partial agonist relative to adrenaline.
• Less phosphorylation of GRK occurs
• Less internalization of the Beta-2 adrenoceptor occurs

Other Important Actions

• Inhibition of inflammatory mediator release occurs in mast cells with lymphocyte activation inhibited due to Beta-2-adrenoceptor agonists

Cholinergic Transmission

• Is inhibited through inhibition of cholinergic acetylcholine release.

Vascular Permeability

• May be reduced by B-adrenoceptor agonists

Muco-ciliary clearance

• Occurs through increased ciliary beats that clear mucous.

Routes of Administration for Asthma Medication

• Inhaled routes may involve a metered dose inhaler with only 10% of the drug reaching the lung.
• Nebulizers and dry powder inhalers are used for those who cannot use metered inhalers.
• Oral routes are a last option due to side effects.
• Intravenous and intramuscular routes are necessary for acute asthma and given as a drip or bolus injection, mostly with terbutaline.

Issues with Systemic Delivery

• Beta-2-adrenoceptor agonists elicit vasodilation and relaxation of vascular smooth muscle.
• Blood flow increases and BP falls.
• Reflex increases in tachycardia and cardiac output can also occur.
• Metabolic processes increase, including glucose, fatty acids, ketone bodies, and high-density lipoprotein levels.
• Tremors can increase in skeletal muscle.

Steroid Drugs

• Glucocorticoids dampen down many aspects of inflammation related to asthma.
• These are widely used by inhalation via beclomethasone, budesonide, and fluticasone as prophylactic therapy.
• Oral steroid is prednisolone
• Intravenous steroids are hydrocortisone and methylprednisolone.
• Glucocorticoids are considered first line therapy for asthma

Steroid Action

• Lipocortin is an edogenous inhibitor of PLA2.

Multiple Targets for Steroids

• Inflammatory cells and structural cells are covered via corticosteroids
• Inflammatory cells include eosinophils, T-lymphocytes, mast cells, macrophages, and dendritic cells.
• Structural cells include epithelial and endothelial cells, airway smooth muscle, and mucus glands.

The Beneficial Effects of Steroids

• include the reduction in the synthesis of mediators (LTC&D4, histamine)
• Inhibition of cytokine synthesis of TNFα, IL-1
• Inhibition of chemokine synthesis
• Adhesion molecule expression on endothelial cells
• Inhibits migration and activation of immune cells
• T-cells, B-cells, macrophages are all inhibited
• The apoptosis of immune cells (programmed cell death) is induced.

Synergy Between Beta-2 Agonists and Steroids

• Two different pathways regulate to give a bigger effect like inhibition of cytokine production.
• Steroids increase Beta2 receptor expression.
• Salbutamol increases Glucocorticoid Receptor expression

Common Prednisone Side Effects

• Weight gain and water retention
• Mood changes
• Increased appetite
• Blurred vision
• Dizziness
• Moon face
• Insomnia
• Shortness of breath
• Headache
• Suppressed immune system
• Numbers of tingling in arms or legs
• Sweating or rashes

Leukotrienes and their Inhibition

• Mediators and cytokines can activate PLA2 to cause LT
• Aspirin-induced asthma prevalence is the atherosclerois pathway.

Montelukast

• Functions as a CysLT1 receptor antagonist that may be used in the treatment plans

CysLT1 Receptor

• Is a GPCR linked to Gq/PLC/IP3/Ca2+, causing contraction of airways smooth muscles.

Leukotriene Inhibitors

• Leukotriene B4 is a neutrophil chemoattractant.
• Leukotriene C4, D4 cause bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucous hypersecretion.
• Zafirlukast and montelukast are Leukotriene D4 receptor antagonists which can treat mucosal edema and mucous hypersecretion
• 5-lipoxygenase, inhibited by zileuton, is the enzyme in leukotriene synthesis.
• It is effective in aspirin-induced asthma for reducing asthma exacerbations.
• Montelukast unique side effect is Eosinophilia and Churg Strauss Syndrome (eosinophilic granulomatosis in small blood vessels).
• Zileuton major side effect is liver toxicity

Xanthines

• Are anti-asthmatic drugs, e.g., theophylline and profylline.

Xanthines Mechanism

• As an adenosine receptor antagonist, xanthines block the inhibitory action of adenosine upon adenylyl cyclase.
• Allows intracellular cyclic AMP to accumulate and promote relaxation
• As a phosphodiesterase inhibitor, relaxation of the smooth muscle is achieved by blocking reduction in intracellular cyclic AMP.

Effects of Theophylline in Asthma

• Smooth muscle relaxation
• Inhibit anaphylactic release of mediators (mast cells)
• Suppresses oedema
• Central stimulation of ventilation
• Side effects include GI issues, seizures, and palpitations

Specific PDE Inhibitors

• PDE inhibitors would would be good in asthma or even COPD yes roflumilast
• PDEs switch off cAMP and cGMP
• Theophylline inhibits several PDEs

Biologics

• Target Th2 cytokines using antibody-based treatments
• Treatments are directed to target cytokines or leucocytes

Antibodies Specialist Care

• Tralokinumab, lebrikizumab, dupilumab, mepoluzimab, and omalizumab.

Learning Points

• Relaxing smooth muscle to give symptomatic relief in airways
• Trying to cut down inflammation to reduce triggers and lung damage
• More targeted biologics that use immunology for serious conditions.