L13a Treatment of Asthma Flashcards
Goals of Asthma Treatment
Control chronic symptoms
Maintain normal activity levels and exercise
Maintain near-normal pulmonary function
Prevent exacerbation of asthma (especially during winter time)
Minimize emergency department (ED)
treatments visits and hospitalizations
Avoid adverse effects of (abuse of) asthma medications
Asthma Treatments: Relievers
drugs that provide relief from (Acute) asthma symptoms. Normally rapid onset but short duration, cause airway Smooth-muscle relaxation. Patients should keep relievers on hand and take it only when they need it - during an asthma attack, or (sometimes) before exercising.
-sometimes used as a preventer (keep handy for life threatening asthma)
Asthma Treatments: Preventers
do not provide relief for an acute asthma attack, they are *“long-term control medications“ which have *Anti-inflammatory effects to prevent the acute asthma attack.
Patients take preventer medicines daily, even if they have no symptoms.
Asthma Treatments
Relievers
Preventers
Others
Three Types of Bronchodilators
Three types of bronchodilators:
- Inhaled beta-adrenergic agonists
- Anticholinergicagents
- Xanthine drugs
Benefits of Inhaled Beta-agonists in the management of Asthma
- Relief of bronchoconstriction due to smooth-muscle relaxation
- Marked protection against all nonspecific constrictor stimuli, such as cold air, methacholine and exercise (prevent exercise induced asthma)
- Reduced vascular permeability and edema
- Increased mucociliary clearance due to increased ciliary beat frequency
- May (partially) reduce inflammation due to inhibition of mediator release from inflammatory cells and priming of glucocorticoid receptors
Mechanism of relaxation of bronchial smooth muscle
- B2 agonists diffuses and bonds with B2 transmembrane receptor
- Gs activated. activates AC (adenylate cyclase)
- AC converts ATP –> cAMP
- Increase cAMP = increase PKA (protein kinase A)
- a) Increase Ca2+ activated K+ channel –> K+ release
b) Increase Na+/K+ ATPase
c) decrease PI (phosphatidylinositol) hydrolysis
d) Increase Na+/Ca2+ exchange
e) Reduce MLCK (Myosin Light Chain kinase)
all causing 6.
a) Smooth muscle relaxation
b) inhibits mediator release
Aspects of Bronchodilators (relievers)
Pharmacodynamics of different bronchodilators
Adverse effects and limitations
Different delivery systems and devices
A century of Progress: B-Agonist History
1000Bc Ma Haung (2000 years later w/o much improvement except opiate causing smooth muscle relaxation w. side effect) 1900 Epinephrine (injection)1 = first smooth muscle relaxation modern drug 1960= B2 Selective Albuterol = first B2 agonist bronchodilater became available in the market = start of modern treatments 1960-2000= Long acting B2 Selective Albuterol available
Theophylline
Inhibits cAMP - (PDE)-> AMP
Theophylline can retain increasing/high cAMP concentration
Charybdotoxin
Stops K+ release
Selectivity of B2 Adrenergics
alots of B2 agonists are non selective
- when the B2 receptors are activated: will cause
1. Smooth muscle relaxation
2. Reduced edema
3. Inhibit mediator release
B2 subtype cells
Smooth muscle Epithelium (airway) Submucosal glands (B1/B2) Care cells Cholinergic nerves Sensory nerves (B2/B3) Bronchial vessels (B2) Inflammatory cells (B2) -mast cells -macrophages -eosinophils -T-lymphocytes
Smooth muscle subtype and function
B2 Subtype
Function:
-Relaxation
-Inhibition of Proliferation
Epithelium (airway) subtype and function
B2 Subtype Function: -Increase ion transport -Secretion of inhibitory factor? -Increased ciliary beating -Increased mucociliary clearance
Submucosal glands and Clare cells subtype and function
Submucosal glands Subtype: B1/B2
Clare cells Subtype: B2
Function: Increased secretion
Cholinergic nerves subtype and function
B2 Subtype
Reduced ACh release
Sensory nerves subtype and function
B2/B3 subtype
Function
-Reduced neuropeptide release
-Reduced activation?
Bronchial vessels subtype and function
B2 subtype
Function:
Vasodilation
Inflammatory cells subtype and function
Subtype all: B2 Mast cells: Reduced mediator release Macrophages: No effects? Eosinophils: Reduced mediator release T-lymphocytes: Reduced cytokine release
Non B2 subtype only Cells
Submucosal glands: B1/B2
Sensory nerves: B2/B3
Heart Receptors and Effect if Stimulated
Receptors: B1 and B2 Effect if stimulation: -Increased contractility -Increased conduction velocity --> Increased HR heart rate
Arteriole Receptors and Effect if Stimulated
a1 and a2 Receptor = vasoconstriction
B2 Receptor = Vasodilation
Lung Receptors and Effect if Stimulated
B2 receptor
Effect if stimulated: Bronchodilation
Skeletal muscle Receptors and Effect if Stimulated
B2 receptor
Effect if stimulated: Increased contractility (tremor)
Fat cells Receptors and Effect if Stimulated
Receptors: a2, B1, B3
Effect if stimulated:
1. Lipolysis
2. Thermogenesis
-potential benefit by using B2 adrenergic receptor agonists
-after market use to use B2 adrenergic receptor agonist bronchodilator to try control weight
Receptor Distribution and actions in Various tissues
When useB2 adrenergic Receptor agonists
- stimulate B2 receptor in the lung
- also activate receptors in other tissues
- -> cause unwanted distal effects
- -> adverse effects (muscle tremor, increase HR)
- potential benefit in activating Fat cells B1 and B3 receptor for lipolysis and thermogenesis
3x Routes of administration
- Inhalation
- Oral
- Direct Endotracheal instillation
Benefits of Inhalation
High concentration on site
Achieve fast onset of action
Less adverse/systematic effects
Difficulties with Oral
Increase systemic effects of drug (increased chance of having adverse effects)
Why is the oral route of administration needed if we have a good method of inhaler for drug administration?
Sometimes Inhaler use is conditional on the patients condition
- if patient’s airways are completely blocked with sputum = cannot inhale drug into lung properly
- if patient cannot breath properly= difficult to deliver drug through inhilation
Direct Endotracheal instillation
used in emergency situation (for resuscitation)
Types of inhalers
- Metered dose inhalers: aerosol spray (deliver 15-20% of drug to lung. dont need to force to inhale in. little training to use device properly (cooperation b/w breathing and pushing puffer)
- Dry powder device: (5 micrometre. Delivers greater (25-30%) percent of drug to lung. Deliver drug by just breathing in air (no training). Not suitable for all kids (when cannot breath properly/not much forced breathing) (not suitable when the particles are too larger size)
Challenges of Inhaled Therapies for Young children
Small tidal volume (Vt) Small airways Rapid respiration Nose breathing Aversion to masks Cognitive ability Fussiness and crying -use a SPACER on young children
Why use a Spacer with an Inhaler?
Inhaler alone: 15-20% delivered to lung. 60-70% remainder is swallowed and leads to systematic effect (everywhere else)
Inhaler used with spacer device: 25-30% increased amount delivered to lung. Reduced chance of having systematic adverse effects
Nebulizers
Machine to create hot warm steam combined with medicines
-Schematic of vented, valved jet nebulizer, with pressured air supply and liquid reservoir containing drug
-household vs clinical
Positives:
1- warm moistured steam can comfort the airway (easy for patient to cough up sputum)
2- can combine 2-3 medications together
Negatives
1. require a well trained staff
2. require a machine
Two categories of B2-adrenoreceptor agonists
- Rapid onset of action:
- short acting: Fenoterol, Pirbuterol, Procaterol, Albuterol, Terbutalin
- long acting: Formoterol - Slow onset of action:
- long acting: Salmeterol
2x factors effecting the efficacy of the B2-adrenoreceptor agonists
- Onset of Action
- Duration of action
Acute attack 5-10 min: releive symptoms soon/rapid onset and long acting = Formoterol
Short Acting B2-Adrenoreceptor Agonsits
Rapid onset but short duration ◦ Maximum effect occurs within 30 minutes ◦ Duration of action: 4-6 hours Effective in preventing: exercise induced asthma, cold air and allergen triggered asthma Also are used for acute severe asthma. Use on an “As needed” basis Normally delivered Inhalation. -sometimes Oral:
Long Acting B2-Adrenoreceptor Agonsits (LABA)
Duration of action: (longer than 24 hrs) Use on a regular basis To prevent bronchospasm in patients requiring long-term bronchodilator therapy Inhaled corticosteroid (ICS) and LABA can be used as combined therapy.
Adverse effects of Short Acting B2-Adrenoreceptor Agonsits
- Tremor (B2 Skeletal muscle receptor)
- Tolerance (tachyphylaxis)
- down-regulation of B2 receptors (use high dose long term, receptor not sensitive to that agonist drug anymore)
- Note: if airways small/blocked with sputum, inhaler wont help (not down regulation) - Hypokalemia (K+ channel acitivated to release K+ outside of cell)
- Tachycardia (B2 heart receptor)
Adverse effect of Tolerance due to Short Acting B2-Adrenoreceptor Agonisits
Tolerance (tachyphylaxis)
-down-regulation of B2 receptors (use high dose long term, receptor not sensitive to that agonist drug anymore)
Combination therapy
better asthma control with combination therapy
-LABA w. ICS (anti-inflammatory drug)
1. Symptoms improved (reduces the risk of mild exacerbations)
2. significantly improves morning PEF
BUT
-FDA said this amount of medications may increase the chance of Severe asthma episodes, and death with these episodes
-Even though LABAs decrease the frequency of asthma episodes, these medicines may make asthma episodes more severe when they occur
+ increased production of gast
What is the reasoning behind combination therapy causing an increase severity of asthma episodes are increased gas production?
- rubberband (airway smooth muscle)
- rubber band expands like smooth muscle relaxation
- if constantly expand rubber band, it cannot return to its original shape
FDA recommendations
LABAs should not be used as the first line medicine to treat asthma
LABAs should only be added to the asthma treatment plan only if other medicines do not control asthma, including corticosteroids
LABAs do not relieve sudden wheezing. Always have a short acting bronchodilator with you to treat sudden wheezing
LongTerm B-agonists is a Preventer> reliever
Basic difference b/w Preventer and Reliever
Reliever: Smooth muscle relaxation
Preventer: Anti-inflammatory responses
What happens if beta2 agonists are used be healthy people?
Athletes: cyclists use during Tour De France + Tennis Player Alex Bogomolov + Horse Belles
-improve performance
Anticholinergic Agents
- Acetylchlorine can cause bronchoconstriction and mucus secretion in airway
- Acetylcholine (ACh) can be synthesized in parasympathetic nerves PARANS by choline acetyltransferase and stored in secretory vesicles
Anticholinergic Agent Schematic
- CNS –Vagus Parasymapthetic nerve –>
a) ACh release at parasympathetic ganglion
i) ACh release at smooth muscle (smooth muscle contraction)
ii) ACh release at submucosal gland (increase secretion)
iii) Increase inflammatory responses
b) Irritant receptors in airway epithelium
* Inflammatory cells can effect the smooth muscle and irritant receptors
* * Anticholinergics impact the Smooth muscle and Submucosal gland
Anticholinergic agents Selectivity
Currently available anticholinergic agents are non-selective, they block all Muscarinic receptors
Three main types of Anticholinergic agents
- Atropine
- Ipratropium Bromide
- Tiotropium Bromide
- these drugs can be combined with the B2 selective B2 agonists combination treatments for emergency situations (as act on different mechanism)
Ipratropium Bromide
Slow onset (60-90min), shorter duration (6-8hr)
Use on a Regular basis
Low side effect, Less Tachyphylaxis
Problems: reduced mucociliary clearance
Triotropium Bromide
-star treatment. treat asthma and COPD
Long-lasting muscarinic antagonist (> 24 hrs)
Equal affinity for M1, M2 and M3-receptors
Dissociates rapidly from M2 receptors (M2 is an inhibitory pathway. therefore if dissociate with M2 you inhibit others (M1 and M3)
Approximately 10-fold more potent than ipratropium bromide. (efficacy)
Problems with dry mouth in 10-15%.
Side effects: dry mouth (systematic effect), constipation, blurred vision and urinary retention…
Xanthine Drugs
-old (used for 50 years) Mechanisms of effects:
◦ Non-selective inhibition of phosphodiesterase: causes bronchodilation.
◦ Activation of histone deacetylases (HDAC): related
to anti-inflammatroy effects.
-has BOTH effects
◦ Non-selective antagonism of adenosine receptors
Xanthine Drug: Theophylline
Theophylline
Theophylline is a Xanthine Drug
- Inhibits PDE 3,4,7 –>
a) prevents cAMP –> AMP therefore increases cAMP conc –>
b) increase PKA conc –>
c) inflammatory cell inhibition. bronchodilation. increase ciliary beat frequency. Decrease airway smooth muscle mitogenesis. - Inhibits PDE5 –>
a) prevents cGMP –> GMP therefore increases cGMP conc –>
b) increase PKG conc –>
c) Bronchodilation
Adenosine Receptor Antagonism
Adenosine antagonism may be responsible for some of the effects associated with theophylline ◦ Arrhythmia ◦ CNS stimulation ◦ Gastric acid hypersecretion ◦ Diuresis (decreased edema)
Beneficial Positive Respiratory effects of Theophylline Xanthine Drug
Respiratory ◦ *Bronchodilation ◦ Decrease in static lung volumes ◦ *Improve gas exchange ◦ Respiratory stimulation ◦ *Increase diaphragm muscle strength and reduced diaphragm fatigue ◦ Improve respiratory muscle efficiency ◦ Increase mucociliary clearance ◦ *Decrease dyspnea ◦ Improve exercise ability ◦ Improve health status ◦ Reduction in airway inflammation
Beneficial Positive Non- Respiratory effects of Theophylline Xanthine Drug
Non-respiratory
◦ Improve cardiovascular performance
◦ Decrease pulmonary artery pressure
◦ Diuresis (reduce edema)
Side Effects of Theophylline Xanthine Drug
-Narrow therapeutic range (10-20g/mL) (therapeutic and toxic range are close to eachother. therefore overdose a little bit increased risk of problems)
-Toxicity can occur within the therapeutic range.
-Serum level monitoring is the only reliable
method of preventing toxicity
Side effects:
◦ Nausea/vomiting
◦ Headache
◦ Diarrhea
◦ Insomnia
◦ Hyperglycemia (usually from overdose)
◦ Seizures (usually from overdose)
◦ Arrhythmias (usually from overdose)
Clearance of Theophylline
Decrease clearance with heart failure, erythromycin, beta blocker, CYP1A2 polymorphism and ciprofloxacin. –> careful to overdose (narrow therapeutic range)
Increase clearance with smoking and phenytoin –> need to increase dose to have similar effect
