asthma and copd meds

beta 2 receptor:

what type of receptor

related to what neurotransmitter?

symp or parasymp?

activation leads to?

adrenergic receptor

related to epi

symp

bronchodilation

m3 receptor:

what type of receptor

related to what neurotransmitter?

symp or parasymp?

activation leads to?

muscarinic receptor

acetylcholine AcH

parasymp

activation leads to bronchoconstriction and mucus prod

most effective tx for airway remodeling and how

inhaled corticosteroids

- suppress inflammation, reduce eosinophils, prevent fibrosis

what are essential for relieving acute asthma sx and what do they directly affect

broncodilators

reduce SM contraction

what do corticosteroids target and why are they essential for long-term asthma management

they are potent immunomodulators

trigger release of inflammatory mediators, leading to immediate sx and long term structural airway changes

what do we need to measure for copd

eosinophils

the primary treatment for copd

is it reversible

bronchodilators

highly variable but bronchodilators can partially improve

preferred route of delivery for asthma & COPD

inhaled

does inhaled route have low or high systemic absorption

lower

is inhaled route slow or rapid onset and what med is especially important for this

rapid

bronchodilator - acute attack tx

optimal particle size for airway deposition is between?

2-5µm

what happens in inhaled route if particles are too small? too large?

too small - exhaled

too large - trapped in upper airways

are inhaled meds subject to first pass metabolism

no

what inhaled route is easier to use during resp distress

nebulizer

what inhaled route is easier for older people that have problems with timing with metered dose inhaler

dry powder inhaler

is dry powder inhaler used for acute attack

no

traditional pressured metered dose inhaler (pMDI) vs hydrofluoroalkane propelled inhaler (HFA)

- what is used as propellant and which is worse for environment

- small or large particles to treat what area of lungs?

- which has higher systemic absorption

- which is used more now

pmdi: chlorofluorocarbons (bad from environment)

hfa: hydrofluoroalkane (safe)

pmdi: larger particles, get trapped in upper airways

hfa: smaller particles, reach parenchyma

pmdi lower systemic absorption, hfa higher absorption

hfa used now

inhaled route that is delivered as micronized powder and requires minimized inspiratory flow

difficult for kids

dry powder inhalers

inhaled route that is vibration or stream of o2

- deliver much higher doses than mdi

- useful in acute exacerbation and good for kids

nebulizer

inhaled route tool

- large volume chamber that attaches to metered dose inhaler

- reduces the velocity of particles entering the upper airways and the amount of drug that lands in the oropharynx

- helpful for patients who have trouble timing an MDI (children, elderly, other)

space chambers "spacers"

which is preferred inhaled or oral

ALWAYS oral

for inhaled route, how much higher do doses need to be

20x

what drug must be given orally

theophylline

oral or parenteral drugs that are used for exacerbations

corticosteroids

route used for treatment of severe acute exacerbations

parenteral

how are biologics typically delivered and in what population is this useful

subq

severely ill pts who cannot absorb from gi tract

oral vs inhaled onset of action

albuterol and formoterol

albuterol: oral 30 min, inhaled 5 min

formoterol: oral 30-60 min, inhaled 5 min

bronchodilator moa

relax airway smooth muscle reversing obstruction and restoring airflow

- can also prevent bronchoconstriction when used prophylactically.

do bronchodilators treat underlying inflammation

no

2 classes of bronchodilators

b2 adrenergic agonists sympathomimetics

anticholingeric agents (muscarinic receptor antagonists)

how b2 agonist cause muscle relaxation

bind to b2 receptors on airway SM --> trigger signaling kinase increase cyclic amp (CAMP) and increase protein kinase A --> muscle relaxation

what is bronchodilator of choice for asthma b2 agonist or anticholinergic agent

b2 agonist

what 2 things does b2 agonist inhibit release of

release of constrictive mediators from mast cells --> reduce airway swelling by decreasing microvascular leakage, improve mucociliary clearance

reduce ach release from nerves causing vagal constriction

types of b2 agonists

SABA - short acting beta 2 agonist

LABA - beta 2 agonist

types of SABAs

albuterol, levalbuterol

can b2 agonists be used for monotherapy

no!!!

LABA examples

formoterol

LABA vs SABA onset of action and duration

LABA variable onset, long duration up to 24 hr

SABA rapid onset short duration

what is the only LABA that can be used for rescue therapy and why

formoterol, rapid onset of action

are SABAs used for rescue inhaler

yes!

b2 agonist that combines synergistic meds in same device for better adherence, consistent delivery and better outcomes

ICS SABA

SABA SAMA

ICS LABA

LABA LAMA ICS

LABA LAMA

combo inhalers

bronchodilators that are combos with other bronchodilators (ex. SABA/SAMA, LABA/LAMA) are often used for what condition

copd

side effects of b2 agonists

muscle tremors

tachycardia

palpitations

hypokalemia (↑ risk of arrythmia) * rare

ventilation-Perfusion (V/Q) mismatch

metabolic effects (increase in free fatty acids, insulin, glucose, pyruvate and lactate) * only seen with large systemic doses

tolerance

what can occur with b2 agonist use with time and what can prevent this

tolerance

ics can prevent

studies have shown that the more frequently patients use beta-2 agonists what occurs

more likely they are to die

- not causal, more frequent use indicates more severe asthma

what is contraindicated in pts with covid due to what side effect

LABA salmeterol

using with paxlovid --> increased CV risk - QT prolongation and tachycardia

what is contraindicated with b2 agonist and what are examples of these meds? what does using them together cause

non selective beta blocker (propranolol, nadolol)

block bronchodilation and bronchospasm

what conditions should we be careful using b2 agonists with

heart disease / arrhythmias

severe hypertension

hyperthyroidism

diabetes (may ↑ glucose)

hypokalemia

pheochromocytoma

muscarinic antagonist moa

competitive antagonism of endogenous acetylcholine (Ach) at muscarinic receptors causing inhibition of bronchial smooth muscle constriction

what does ach do to resp system, what do antimuscarinics do

bronchoconstriction and tracheobronchial mucus secretion

- antimuscs antagonize these effects --> bronchodilation and decreased mucus secretion

- also prevent structural fibrosis and neutrophilic inflammation caused by Ach

do antimuscarinics have a significant effect on chronic inflammation associated with asthma & COPD

NO

which is more effective in asthma b2 agonist or antimusc

b2

when can antimusc be used with asthma

pt maxed out on b2 agonist

acute severe asthma attack

which is more effective in copd b2 agonist or antimusc

antimusc

what is one of the few reversible elements in copd and what drug targets this

increased vagal tone

antimusc

what drug can reduce air trapping and improve exercise tolerance in copd

antimusc

what antimusc is most commonly used in copd and why?

what does consistent use do

LAMA - only dosed once daily compared to SABA 3-4x a day

improved lung function and health status

do antimusc affect disease progression

no

most popular SAMA

ipratropium bromide

what are commonly used in copd pts due to additive effects

anticholinergic + b2 agonist - SABA/SAMA and LABA/LAMA

what is used in copd pts with high eosinophils

LABA/LAMA/ICS

tiotropium bromide, aclidinium bromide, and glycopyrrolate bromide are examples of

LAMAs

side effects of anticholinergics

rebound increase in airway --> responsiveness after discontinuation (need taper)

bitter taste --> noncompliance

glaucoma

bronchoconstriction

mydriasis, dry mouth, urinary retention

what conditions are contraindicated for anticholinergics and what effect do they have

don't DRIP

Drain eyes - increase glaucoma pressure

Retain urine - BPH/obstruction

Impair intestines - ileus/obstruction

Paralyze - exacerbate myasthenia gravis

what medication contraindicates anticholinergic use and what occurs with combined use

other anticholinergics (diphenhydramine, oxybutynin, amitriptyline)

additive anticholinergic effects - inc urinary retention, constipation, confusion

nebulized ipratropium side fx

may precipitate glaucoma in elderly

ipratropium bromide rare side fx

paradoxical bronchoconstriction

phosphodiesterase inhibitors moa

increases cAMP which leads to smooth muscle relaxation and reduced inflammatory cell activity

phosphodiesterase inhibitor class

antiinflammatory, not bronchodilator

phosphodiesterase inhibitor is used for

copd, being studied for ashtma

what does phosphodieseterase do normally and what does inhibiting it do

enzyme that breaks down cAMP and gAMP --> act as second messengers in cells to regulate SM tone, inflammatory cell activation, cardiac contractility, platelet aggregation

inhibition: SM relaxation and decreased inflammatory cell activity

predominant phosphodiesterase isoform in inflammatory cells

PDE4

nonselective PDE4 inhibiter with oral administration

metabolized CYP3A4 and CYP1A2 enzymes

roflumilast

what pts is roflumilast used for

add on tx for pts with copd who have maxed out therapeutic algorithm and keep having exacerbations

does roflumilast impact sx and lung function? what does it do

no

only reduces exacerbation rate

FEV1 required for roflumilast

less than 50% predicted

do CYP3A4/CYP1A2 inhibitors inc or dec roflumilast levels?

what about CYP inhibitors?

increase both

side effects of roflumilast and contraindications

GI: nausea, diarrhea, weight loss

neuropsychiatric: anxiety, insomnia, depression, rarely suicidal ideation

headache

caution w severe liver disease, significant weight loss, uncontrolled depression

example of methyxanthine

theophylline

methylxanthine aka theophylline moa

and how effective is it

weak, non-selective PDE inhibitor → ↑ cAMP → mild bronchodilation

- not very effective, we have other meds that work a lot better

how is methylxanthine aka theophylline monitored and why? where is it metabolized?

must check levels and modify dose accordingly until optimal levels are achieved and then if change in clearance is suspected

narrow therapeutic range: 5-15 mg/L

- large variation in dosing amounts patients due to differences in plasma clearance

- metabolized in the liver via CYP1A2 - many factors can affect clearance

routes of methylxanthine aka theophylline administration and which is not recommended?

IV - used for many years in the treatment of acute severe asthma

Oral immediate-release (tablet or elixir) - wide fluctuations in plasma levels (not recommended)

Slow-release oral - twice daily recommended

what conditions are methylxanthine aka theophylline used for and are they the best option

bronchodilator for copd (others are superior)

acute severe asthma via IV (less effective than inhaled b2 agonist)

controller for asthma (ICS more effective, can be added to ICS)

methylxanthine aka theophylline side fx and what levels indicate toxicity risk

GI: nausea, vomiting

CNS: headache, irritability, insomnia → seizures at high levels

Cardiac: tachycardia, arrhythmias

Other: tremor, reflux, diuresis

Toxicity risk ↑ if levels > 15 mg/L

when is magnesium sulfate used as a bronchodilator and what is it often added to

acute severe asthma - only for life threatening attacks NOT routine use

beta 2 agonists - when added gives improvement in lung function

what does hpa axis control and how does it do this

HPA axis controls release of cortisol

- when there is enough, it negative feedbacks hypothalamus CRH (cortisol releasing hormone) and pituitary ACTH release that stimulate cortisol production

functions of cortisol

maintain BP

glucose metabolism

modulate immune system, inflammation, stress

maintain vascular reactivity

what does ACTH released by pituitary gland control production of

cortisol and aldosterone

how does RAAS system control aldosterone

juxtaglomerular cells of RAAS in the kidney sense a drop in blood pressure and release renin --> converts angiotensinogen which stimulates the release of aldosterone from the adrenal cortex

what does aldosterone release do and under what conditions will this occur

stimulates sodium reabsorption and raises bp

glucocorticoid vs mineralocorticoid effects

glucocorticoid - anti-inflammatory and immunosuppressive

mineralocorticoid - sodium retention, potassium loss, fluid balance regulation

all corticosteroids have what 2 effects

glucocorticoid and mineralocorticoid activities

relative potency of a corticosteroid (glucocorticoid vs mineralocorticoid effect) is compared to the potency of what drug

hydrocortisone

corticoidsteroid moa

CCSs enter target cells and bind to glucocorticoid receptors (GRs) in the cytoplasm

- binds to target genes and increases transcription

- interact with protein transcription factors to repress them (which is anti-inflammatory)

corticosteroid effects with asthma

what do they do to inflammatory cells, airway inflammation, vascular permeability, mucus secretion, and beta 2 receptor response

decrease inflammatory cells: reduce eosinophils, mast cells, and cytokine release

decrease airway inflammation: suppress cytokine and mediator production

decrease vascular permeability: stabilize endothelium, reducing edema

decrease mucus secretion: decrease mucus gland activity

increase beta-2 receptor response: enhance receptor expression and bronchodilation

what does pt need to do after taking ics and what does it do

rinse their mouth

- reduces systemic absorption and thrush risk

what is the cornerstone of asthma management and every pt should be on

ICS

is ics useful for copd

no much less effective than for astma

who can ics reduce exacerbations in and at what eosinophil level? who is it contraindicated in?

how should it be given

pts with T2 inflammation

eosinophils of over 300 cells/microliter

pneumonia or mycobacteiral infx risk

always give as triple inhaler ics-laba-lama

how do beta 2 agonists and steroids work in synergy

steroids inc number of b2 receptors in lungs and make them more receptive --> better bronchodilation

beta agonists help steroid receptors move into cell nucleus where steroids can turn off inflammation genes more effectively