1. Sympathomimetic Bronchodilators Flashcards
what are the 2 autonomic nerve fibers?
and what do they communicate with?
cholinergic and adrenergic
communicate with neurotransmitters
what are the 2 main autonomic neurotransmitters? what are they released by?
acetylcholine (released by cholinergic fibers) and norepinephrine/noradrenaline (released by adrenergic fibers)
what area of the spinal cord innervates the SNS?
thoracolumbar
length of pre vs post ganglionic fibers in the SNS
short pre, long post
what is the general action of alpha receptors?
vasoconstriction/vasopressor effects
what is the general action of beta 1 receptors?
increased myocardial conductivity, HR, and contractile force
what is the action of beta 2 receptors? Where are they found?
bronchodilation, inhibition of inflammatory mediator release, stimulation of mucociliary clearance, found throughout the tracheal tree and in the smaller airways
adrenergic bronchodilators are agents that stimulate which fibers?
sympathetic nervous fibers
what is the action of catecholamines (adrenergic bronchodilators) at the cellular level?
G protein couples the adrenergic receptor to the effector enzyme, initiates cell response (relaxation of airway smooth muscle)
B-adrenergic activate a _______ messenger system, list the steps.
secondary
- adenylyl cycles induction
- increase in intracellular cAMP
- inactivation of protein kinases
- decrease in intracellular calcium
- smooth muscle relaxation
what is the mechanism of action for indirect-acting sympathomimetics?
promote the accumulation of NE at the synapse…leads to nonspecific adrenceptor activity in the post-synaptic cell
what is the mechanism of action for direct-acting sympathomimetics? what are the results?
acts like NE, binds with adrenoceptors (creates complexes)
increased HR, airway smooth muscle relaxation, increased BP, glycogenolysis, skeletal muscle tremor, CNS stimulation
what are the components of a basic catecholamine structure?
catechol nucleus (benzene ring + 2 hydroxyl groups) and amine side chain
the keyhole theory of Beta 2 specificity states that…
addition of complex groupings to amine side chains increase beta 2 specificity
allows sympathomimetic drug to conform more closely to beta 2 receptors on airway smooth muscle (activation of secondary messenger system)
where does metabolism of catecholamines occur by MAO? mechanism of action?
in the neurons, oxidative deamination (removal of NH2)
where does metabolism of catecholamines occur by COMT? mechanism of action?
in non-neuronal tissues (kidney/liver), methylation to the OH- at carbon 3
what special consideration should be taken to prevent quick breakdown of catecholamines by COMT?
avoid oral administration
stereoisomers are also known as…
enantiomers or isomers
dextrorotatory (d, +) = _-epinephrine
S
levorotatory (l, -) = _-epinephrine
R
what are the physiological effects on (R) isomer/levo-isomer vs. (S) isomer/dextro-isomer
(R) isomer/levo-isomer produces bronchodilation
(S) isomer/dextro-isomer less active on adrenergic receptors
what is the ratio of a racemic mixture of both isomers?
50:50
list some clinical indications of adrenergic bronchodilators.
reversible airflow obstruction: asthma, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, etc.
what are the 3 ways to classify bronchodilators?
rate of onset, peak effect, duration of action
what is the duration of ultra-short acting adrenergic bronchodilators? give an example.
< 3 hours
ex. epinephrine
what is the duration of action of short-acting adrenergic bronchodilators? give an example.
4-6 hours
ex. salbutamol
what is the duration of action of long-acting adrenergic bronchodilators? give an example.
12 hours
ex. salmeterol
what is the duration of action for ultra-long acting adrenergic bronchodilators? give an example.
24 hours
ex. indacaterol
epinephrine and adrenaline stimulate which receptor(s)? what systemic effects should you expect?
both A and B receptors, will expect to see cardiac stimulation and vasoconstriction
Epinephrine:
onset of action? peak effect? degraded by? routes of administration? adverse effects? special considerations?
3-5 min
5-20 min
COMT
inhalation, injection (parenteral/IM)
tachycardia, increase BP, tremor, headache, insomnia
readily inactivated by heat, light, or air
Racemic epinephrine:
receptor activity? degraded by? typically used to relieve what? duration of action? dose?
equivalent A and B activity (lack selectivity) rapid inactivation by MAO/COMT used to relieve upper airway swelling 0.5-2 hours 2.5-5mg of 1mg/ml solution
at which 2 carbon groups is an OH removed to form a resorcinol agent? what does this prevent? what is the outcome?
4 and 5
prevents inactivation by COMT
lengthens duration of action
Metaproterenol:
type? onset of action? peak effect? duration?
short-acting
1-5 min
30-60 min
4-6 hours
terbutaline:
type? selective B2 activity? resists methylation? classified as?
short-acting
yes (bulky terminal N-butyl group on amine side chain)
yes, resists COMT
SABA
at which carbon is an OH substituted in the cathechol nucleus to create saligenin bronchdilators? what does this prevent? active on which receptor? type?
carbon 3
prevents inactivation by COMT
B2 preferential effects
short and long acting
Salbutamol:
type of saligenin? receptor activity? onset of action? peak effect? duration of action? special considerations?
short-acting
B2 preferential activity
15 min
30-60 min
4-6…up to 12 hours (with extended release)
prepared as racemic mixture (d and l isomers)
list the delivery forms of salbutamol
extended release oral tablets, MDI (100mcg), DPI (200mcg), IV solution (1000mcg/ml)
what are the current dosages for nebulized treatments of salbutamol?
inhalation solution: 5.0mg/ml diluted with NaCl
pre-mixed nebules: 2.5mg diluted in 2.5ml of NaCl or 5.0mg diluted in 2.5ml of NaCl
salbutamol is the drug of choice for relieving ____ airflow obstruction.
acute
what effect does salbutamol have on K+ levels in the body? special considerations?
decreases serum potassium levels (pushes extracellular K+ into intracellular spaces)
can be used to shift k+ in patients with hyperkalemia and should be used with caution in patients with hypokalemia
what are the doses of salbutamol dependent on? what are the appropriate doses for regular use? what are the appropriate doses for relief of an exacerbation?
age
1-2 puffs via MDI with spacer Q4-6H, not exceeding 4-8 puffs per day
3-6 puffs via MDI with spacer Q15-30min OR 2.5-5.0mg nebulized
what is salbutamol known to interact with?
MAOI, some beta-blockers (propanolol), other bronchodilators (terbutaline), diuretics, digoxin
levosalbutamol:
type of saligenin? what type of isomer? receptor activity? how does it compare to salbutamol?
short-acting
R-isomer
100X more affinity for B2 receptor than d-isomer
mixed studies say you’re able to give lower doses and that it lasts longer (3-8 hours)
long-acting saligenins aim for a duration of ____ hours and are classified as ____. What is the purpose?
12+ hours, LABAs
reduce frequency of administration, increases patient compliance, manages nocturnal symptoms
Salmeterol:
onset of action? peak effect? length of action?
14-22 min
3-5 hours
12+ hours
what is the lipophilic arrangement of salmeterol? why is this important? which inhibtor(s) does salmeterol resist?
lipophilic tail, hydrophilic head
contributes to increased duration of action, increased lipid solubility allows drug to access phospholipid bilayer, attaches to exosite anchor to provide sustained stimulation
non-catecholamine structure resists degradation by MAO and COMT
Formoterol:
type of saligenin? onset of action? peak effect? duration of action? receptor activity?
long acting 15 min 30-60min 12+ hours fast/long acting B2 agonist
what are 4 resulting isomers of the 2 asymmetric centers of formoterol?
SS, RR, SR, RS
what allows formoterol to have some lipid solubility?
lipophilic tail allows for retention in cell membrane where it can be stored with sustained stimulation of B2 receptor
Indacaterol:
classified as? duration of action? unique structure? dose?
LABA
24 hours
heterocyclic ring attached to saligenin nucleus + multi-ring structure attached to terminal amine (highly resistant to MAO/COMT)
75mcg capsule via DPI OD to control severe COPD
list some precautions with adrenergic bronchodilators.
cardiac effects, tolerance, loss of bronchoprotection, CNS effects, fall in PaO2, metabolic disturbances, paradoxic bronchospasm, sensitivity to additives
what are some specific cardiac effects related to adrenergic bronchodilators?
tachycardia, increased CO/O2 consumption, increased BP, palpitations
what does the 20% rule state?
if HR increases by 20% or more, the treatment should be discontinued and another therapy should be considered
down-regulation refers to…
In what types of drugs can this be seen?
How can it be reversed?
long term desensitization of B receptors to B2 agonists, caused by a decrease in the # of B receptors
SABAs and LABAs
reversed with concurrent corticosteroid use
bronchoprotective effect refers to airway reaction to ________________.
Protective effect found to decline more rapidly than what? What does this lead to?
bronchoprovocation
bronchodilating effect
leads to bronchial hyper-responsiveness
what are some specific CNS effects that can be seen with adrenergic bronchodilators?
headache, nervousness, irritability, anxiety, insomnia, tremors
Why can a fall in PaO2 be seen when administering adrenergic bronchodilators?
regional alveolar hypoxia causes vasoconstriction and administration of B agonist can increase perfusion in under-ventilated lung regions (due to the vasodilation), which will worsen V/Q mismatch
What are some specific metabolic disturbances that can be seen when administering adrenergic bronchodilators?
increased blood glucose and insulin levels (problematic for diabetics) and decreased serum potassium levels (concern for patients with cardiac disease)
What is paradoxic bronchospasm related to? How long the bronchospasm last? If sensitivity exists, consider what?
related to propellants used in MDI
typically lasts < 3 min
consider DPI
What are some specific additives that pose a concern when administering adrenergic bronchodilators?
sulfite preservatives, benzalkonium chloride (BAC), ethylenediamine tetra-acetic acid (EDTA - sulphite + acid pH = sulfurous acid and sulfur dioxide), and hydrochloric/sulfuric acids
How should you monitor effectiveness of an adrenergic bronchodilator?
ongoing respiratory assessment (RR + pattern, SpO2, BS before/after, WOB, cardiac response (HR, BP), monitor flow rates (peak flow, bedside spirometry), capnography, ongoing pulse assessment (20% rule), ABGs, pulse oximetry
