Exam 1: Respiratory Drugs Flashcards
SNS versus PSNS effects on bronchioles
- SNS – bronchodilate, want to breathe better if running away
- PSNS – bronchoconstrict
Tell me about airway smooth muscle
o Airway smooth muscle extends as far distal as the terminal bronchioles
o Under the influence of both the PSNS and SNS
SNS innervation
o SNS fibers from the thoracic ganglia pass to the lungs to innervate the smooth muscles of the bronchi and pulmonary blood vessels
o Sympathetic tone – Bronchodilation via beta 2 receptors
- SNS innervate tracheobronchial blood vessels and glands
- Beta -adrenoceptor located in the smooth muscle of the blood vessels, skin muscle mesentary and bronchial smooth muscle
- β2-adrenoceptors, mediate relaxation of smooth muscle in blood vessels, bronchi, the uterus, bladder, and other organs
- β2-adrenoceptors thus cause
- widening of the airways (bronchodilation)
- Increased intracellular cyclic AMP
- Greater sensitivity to EPI vs NE
o Adrenergic β2
- Bronchial smooth muscle RELAXATION
- Relaxation of visceral smooth muscle (leads to?) muscle tremor
- Results in Bronchodilation(B2)
PSNS innervation
o PSNS innervation of these structures is via the VAGUS nerve
o Parasympathetic tone
- Bronchoconstriction via Muscarinic receptors M3 (and musc 1, not so much musc 2)
- Increased secretions
o PSNS reflex mediated
- muscarinic receptor predominated the airway smooth muscle.
- Stimulation of the vagus nerve leads to bronchoconstriction
- M3 receptors are pharmacologically most important
- M3 are found on the
- Bronchial smooth muscle
- Mediate bronchoconstriction via the activation of IP3 (inositol triphosphate) which → increases the intracellular Ca2+ concentrations
- Mediate mucus secretion
o Cholinergic
- Bronchial smooth muscle CONSTRICTION
- Pulmonary Blood Vessels - no dilation -Increased secretion of the bronchial glands
- Results in
- bronchoconstriction
- Increased mucus secretion
tx of laryngospasm vs bronchospams (In-class discussion)
• Laryngospasm
o Can break a laryngospasm with 3-5 mg rocuronium. Defasciculation dose.
• Bronchospasm – meds
o ***Volatiles EXCEPT DES (caustic) – bronchodilation
o Propofol
o O2
asthma (characteristics, causes episodes of, describe the airways)
o Extrinsic vs intrinsic
o Chronic inflammatory disorder of the airways characterized by increase responsiveness of the tracheobronchial tree to a variety of stimuli
o Variable airflow obstruction that is reversible
o This disorder causes recurrent episodes of: Wheezing, Breathlessness, Chest tightness, Cough (night and early a.m.), Tachypnea, Prolonged expiration phase of respiration, Fatigue
o Asthma creates airways that are -Inflamed, edematous airways -Bronchial hypersensitivity/reactivity to irritant stimuli -Difficulty with air outflow
3 characteristics of asthma, and the list of mediators that respond to activation of T2 lymphocytes and cytokines
o Disease is characterized by
• inflammation • hyper-reactivity • Reversible airway obstruction
o Airway hyper-responsiveness and inflammation from allergen in bronchial mucosa → activation of T2 lymphocytes and cytokine release [Degree of airway hyper-responsiveness and bronchoconstriction parallels the extent of inflammation]
o Mediators include: Eosinophils, mast cells, neutrophils, macrophages, basophils, T lymphocytes
(all have been implicated as histologic mediators)
^^ Talking about seeing these in the sputum! And COPD you’ll see more neutrophils and macrophages
o Other probable mediators of acute bronchoconstriction
- **cytokines, **interleukins (3,4,5), -arachidonic acid metabolites leukotrienes and prostaglandins,
- **histamine, adenosine, and platelet activating factor (starred ones were highlighted in ppt)
o Some asthmatics are atopic (produced by allergen) and have IgE synthesis and are considered to have atopic or extrinsic asthma
o Medications are aimed at flattening the response to mediators
“L-M(acrophages)-N(eutrophils)-O-COPD”
“Mast = m-asthma” + eosinophils, cytokines, T lymphocytes, interleukins, histamine
Look at this picture
risk factors for COPD
- Genes
- Smoking
- Age/gender
- Lung growth/devt
- Exposure to particles
- Cigarette smoke
- Occupational dusts and fumes
- Indoor air pollution (biomass fuels)
- SES
- Types of occupations
- Housing areas
- Work
- Health literacy
- Asthma/bronchial hyperreactivity
- Chronic bronchitis
- Infections
COPD/Emphysema/Bronchitis
- Obstruction is either not reversible or incompletely reversible by bronchodilators
- Cell death and destruction of the alveoli is due to impaired lung parenchyma, degraded matrix, and toxic actions of inflammatory cells (specifically macrophages and neutrophils)
- Results in enlargement of air spaces (barrel chest), fibrosis, and increased mucus production
- Steroids have limited effect on inflammation process in COPD
- Inhaled corticosteroids help in reducing frequency of exacerbations and
- Bronchodilators have modest role in air outflow with patient suffering from chronic breathlessness “worsened by exertion”
- Thickened PCM/ACP (pulm capillary membrane/alv…) ineffective gas exchange
tx of airway outflow disorders
- Step 1-Short-acting bronchodilators
- Step 2-Regular inhaled corticosteroid
- Step 3-Long-acting bronchodilators ** mainstay of asthma therapy
- Step 4-
- Phosphodiesterase Inhibitors
- Methylxanthines
- Leukotriene inhibitor
- Step 5-Oral corticosteroid
- Other-Cromolyns
list the 3 types of bronchodilators
- Beta-Adrenergic Agonists
- Anticholinergics
- Methylxanthines
B-adrenergic AGONISTS (we want to activate B2ARs)
name 3 of them, and say which receptors they target
describe which are short vs long-acting
MOA
- Variable receptor selectivity b2, b1
- Epinephrine - b2, b1, a
- Isoproterenol - b2, b1
- Metaproterenol - b2, b1
- Receptor selectivity b2
- Bind to b2 200-400 times more strongly than b1
- Short-acting
- Terbutaline, **Albuterol, Levalbuterol (isomer of albuterol, more b2 specific) - b2, Salbutamol
- Long acting
- Salmeterol
- MOA:
- Beta adrenergic receptors are coupled to stimulatory G proteins
- Activate adenylyl cyclase which increases the production of cAMP (adenosine monophosphate) → bronchodilation (by inhibiting release of Ca++)
- reduced intracellular Calcium release and alters membrane conductance
- Primary effect is to dilate the bronchi by a direct action on the B2 Adrenoceptors l
- Results in smooth muscle relaxation and bronchodilation l Inhibits mediator release from the mast cells l Increase mucus clearance by action on the cilia
“It’s B2 RELAX”
B2 agonist →
- ↓ Ca++
- ↑ cAMP (bc of ↑ adenylyl cyclase)
“It’s B2 use EPI > NE” (more sensitive to EPI)
NANC nerves
-
Non adrenergic Non-cholinergic nerves (NANC)
- Influences inflammation and smooth muscle tone.
- excitatory: release Substance P & neurokinin → neurogenic inflammation/bronchoconstriction
- inhibitory: releases NO & VIP (vasoactive intestinal peptide) → relaxation/bronchodilation
- “Substance P excites me! Neuro-kinda excited!” = bronchoconstriction
- “Inhibitory = NO! VIPs only.” = bronchodilation
B-Adrenergic AGONIST:
onset, duration
SEs
- Rapid onset of action - within minutes
- Short duration of action – 4-6 hours
- Good for use as Rescue inhaler
- Given via
- inhalation or aerosol
- Powder or Nebulized
- Orally or injected (SC)
- Short or long acting – usually just have pts take a couple puffs of their short-acting inhaler just before surgery
- Side Effects
- Minimized by inhalation delivery
- Tremor
- Increased heart rate
- Vasodilation
- Metabolic changes - Hyperglycemia, hypokalemia, and hypomagnesemia
Albuterol
- B-Adrenergic agonists
- Preferred selective beta 2 agonists
- Administered via metered dose
- 100 mcg/puff
- 2 puffs q 4-6 hours
- Nebulizer 2.5-5.0mg in 5ml of saline
- Duration of Action
- 4 hours with some relief evident up to 8 hours
- Additive effect with volatile anesthetics on bronchomotor tone. YAY
- 2 isomers
- R-albuterol levalbuterol more affinity for beta 2 **less SEs
- S-albuterol more affinity for beta1
- Side effects
- Tachycardia
- Hypokalemia
- Anesthesia use
- 4 puffs blunt AW responses to tracheal intubation in asthmatic patients.
- So 2-4 puffs, but usually 2.
- Just don’t use Des on asthmatic/respiratory patients.
Metaproterenol-Alupent
- beta 2 agonists for treatment of asthma
- Administered via metered dose
- Not to exceed 16 puffs/day
“Meta - max 16”
Pirbuterol 12 max doses (400 mcg) → Metaproterenol 16 max doses → Terbutaline 16-20 doses (2 puffs, 200 mcg each)
Pirbuterol-Maxair
- Beta 2 agonist
- ii (2?) puffs (400 mcg) via metered dose
- Not to exceed 12 inhalations/day
- Not usually used in OR
Pirbuterol 12 max doses (400 mcg) → Metaproterenol 16 max doses → Terbutaline 16-20 doses (2 puffs, 200 mcg each)
terbutaline
(also used to inhibit labor)
- Administered oral, **SC, inhalation
- Treat asthma
- SC administration resembles the response of epi
- SC Dose for child .01mg/kg
- Adult SC dose is 0.25mg q 15 min
- Metered dose inhaler 16-20 puffs/day
- Each dose is 200 mcgs
“tirbut - subcut (preferred)”
Pirbuterol 12 max doses (400 mcg) → Metaproterenol 16 max doses → Terbutaline 16-20 doses (2 puffs, 200 mcg each)
long-acting B-agonists
- Salmeterol - (combination drug -Fluticasone and Salmeterol) – steroids in this
- Formoterol
Muscarinic receptor antagonists
MOA
uses
- MOA
- Competitive antagonists at muscarinic acetylcholine receptors
- There are 3 muscarinic receptor subtypes expressed by the lung but M1 and M3 most important in mediating smooth muscle relaxation and decreased mucus gland secretion
- By antagonizing endogenous Ach →
- broncho-relaxation
- decreased mucus secretion
- Competitive antagonists at Muscarinic ACh receptors
- Muscarinic 1 & 3 subtype are the targets
- Uses
- Treatment of COPD
- Secondary line of treatment for asthma in patients resistant to beta agonist or significant cardiac disease
- Asthmatics should not be on long-acting B1 agonists, should be used with corticosteroid – could cause death. Anticholinergic would be 2nd line tx is not responding to that.
Bronchodilators, Anticholinergics, Muscarinic receptor antagonists:
Atropine
- naturally occurring alkaloid
- Anticholinergic
- Formally considered 1st line treatment for asthma
- Administered 1-2mg diluted in 3 to 5 ml of saline via nebulizer
- Highly absorbed across respiratory epithelium
- Causes systemic anticholinergic effects: Tachycardia, nausea, dry mouth, GI upset
(Can also use glycopyrrolate)
Bronchodilators, Anticholinergics, Muscarinic receptor antagonists::
Ipratropium bromide
- Short-acting
- Quaternary ammonium salt derivative of atropine
- Antagonizes the effect of endogenous acetylcholine at M3 receptor subtypes
- Administered via metered dose inhaler 40-80mcg in 2-4 puffs of via nebulizer
- Slow onset 30 minutes
- Duration of action 4-6 hours
- Not significantly absorbed compared to atropine
- Inadvertent oral absorption
- Dry mouth and GI upset
- Used in maintenance of COPD, AND in asthma if not responding to traditional tx
Bronchodilators, Anticholinergics, Muscarinic receptor antagonists:
Tiotropium
- Quaternary ammonium salt
- Long-acting anticholinergic
- Not significantly absorbed across resp epithelium which results in few side effects
- Approved by FDA for COPD
bronchodilators:
Methylxanthines - phosphodiesterase inhibitors (PDE-5 inhib’s)
(2 brands)
MOA, considerations for 3rd world countries, SEs
- MOA
- nonspecific inhibition of Phosphodiesterase isoenzymes (Types III and IV) which prevents cAMP degradation in airway smooth muscle as well as in inflammatory cells → airway relaxation and bronchodilation
- Clinical Applications: COPD, Asthma
- Theophylline, Aminophylline → LOTS of SEs, and have to monitor blood levels bc you can have toxicity quickly
- Because PDI have multiple mechanisms of actions and are nonselective they have multiple side effects and a narrow therapeutic index
- Theophylline
- Therapeutic plasma level of 10-20mcg/ml
- Toxic at >20mcg/ml
- Caution with Halothane (3rd world anesthesia/mission trip – might see either theophylline or halothane)
- Sensitize the myocardium to EPI – might see arrhythmias
- Theophylline
- Susceptible to drug-drug interactions due to metabolism by cytochrome P450
- such as cimetidine and antifungals (cytochrome P450 inhibitors)
- Metabolized in the liver and excreted in kidney
- Side Effects
- Headache
- Nausea/vomiting
- Irritability/restlessness
- Insomnia
- Cardiac arrhythmias
- Seizures
- Stevens Johnson Syndrome
types of anti-inflammatory agents (4)
- Inhaled Corticosteroids
- Cromolyns
- Leukotriene Inhibitors
- Anti-IgE Antibodies
inhaled corticosteroids (4 brands)
MOA
considerations
SEs
- Brands
- triamcinolone
- fluticasone
- beclamethasone
- budesonide
- “TF, BB? You have asthma - you should be on an inhaled corticosteroid!”
- Major preventive treatment for patients with asthma
- MOA- Alter genetic transcription
- Increases transcription of genes for b2 receptor and anti-inflammatory proteins
- Decreases transcription of genes for pro-inflammatory proteins
- Induce apoptosis in inflammatory cells (eosinophils, TH2 lymphocytes)
- Indirect inhibition of mast cells over time
- Reverses many features of asthma
- Used as Suppressive therapy, not a cure
- Inhaled corticosteroids
- Reduce the number of inflammatory cells in the airways and the damage to airway epithelium
- Vascular permeability is reduced which decreases airway edema
- Overall reduction in airway hyper-responsiveness
- Inhaled Corticosteroids considered the most important drug in management of asthma
- Inhaled Corticosteroids
- Beclomethasone
- Triamcinolone
- Fluticasone
- Budesonide
- May consider the use of corticosteroid administration 1-2 hours pre-op
- They prolong the response of beta agonists
- May consider 5-day course of combined corticosteroid and albuterol to minimize the risk of intubation evoked bronchospasm
- Only 25% of inhaled corticosteroids reaches airway
- 80-90 % of the inhaled dose reaches oropharynx and is swallowed (unless mouth is rinsed after using the inhaler)
- Higher airway concentration than same dose given PO
- Systemic effects are decreased thru inhalation
- Side Effects:
- Oropharyngeal candidiasis
- osteopenia/osteoporosis,
- delayed growth in children,
- hoarseness,
- hyperglycemia
- rinse mouth after using the inhaler to try to prevent this
anti-inflammatory agents: Cromolyn
MOA
principle use
SEs
“Cromo-lyn, hista-min(e), sev-en (days before effects start)”
- Not used often - usually used as a suppressive therapy if other things aren’t working!
- Stabilize mast cells
- MOA
- Inhibits antigen-induced release of histamine
- including the release of inflammatory mediators from eosinophils, neutrophils, monocytes, macrophages, lymphocytes and leukotrienes from pulmonary mast cells
- Inhibits immediate allergic response to an antigen but not the allergic response once it has been activated
- Administered via inhalation 8-10% enters the systemic circulation
- Take 4 times daily
- Principle use: Prophylactic therapy of bronchial asthma
- Does not relieve an allergic response after initiation – only works as a preventative med!!
- Must be used for 7 days before you start to see an effect
- Not used as a rescue inhaler
- Side effects are rare
- Infrequent but serious side effects include:
- laryngeal edema
- angioedema,
- urticaria,
- anaphylaxis
anti-inflammatory agents: leukotriene inhibitors
2 prototypes, with 2 different MOAs
“In Zi-LIEU of arachidonic acid converting to leukotriene, causes hepatotoxicity”
“Monte-sits on the-Cysteinyl lukotriene 1 receptor, prevents binding. Make sure it’s the Single (Singulair) agent, bc if you add Warfarin → ↑ PT”
- Inhibitors of leukotriene pathway are useful drugs for bronchial asthma
- Leukotreines are synthesized from arachidonic acid when inflammatory cells are activated
- Not effective in the treatment of ACUTE Asthma attacks
- Few extrapulmonary effects
- Drug prototypes
- Zileuton
- Montelukast
- Zileuton
- Lipoxygenase inhibitor which blocks the biosynthesis of leukotrienes from arachidonic acid – blocks biosynthesis
- Produces bronchodilation, improves asthma symptoms, and has shown long-term improvement in PFT
- Low bioavailability, low potency, and significant adverse effects
- Hepatotoxic – 2% in people have hepatitis from this
- Not widely used
- Montelukast-Singulair
- Leukotriene receptor antagonists block the mechanism of bronchoconstriction and smooth muscle effects. – blocks receptor from accepting the leukotriene
- This drug blocks the ability of leukotrienes to bind to Cysteinyl-Leukotriene 1 receptor
- Improve bronchial tone, pulmonary function, and asthma symptoms
- Caution with co- administration with warfarin which could result in prolonged PT
anti-inflammatory agents: Anti-IgE Antibodies
- Asthma
- Prominence of IgE mediated allergenic responses
- Removal of IgE antibodies from circulation would mitigate the acute response of the inhaled allergen
- Omalizumab—monoclonal antibody derived from DNA **the brand you’ll see
- Given in the early and late phase of asthmatic response, LAST DITCH
- Given SQ for 2-4 weeks/parenterally infused (comes IV or subcutaneous)
- High cost and inconvenience
- Omalizumab
- Humanized mouse monoclonal antibody
- Binds to IgE
- Decreases quantity of circulating IgE
- Prevents binding of IgE to mast cells
- Down-regulation of receptors
- In response to the lower levels of circulating IgE; receptors on the mast cells, basophils and dendritic cells are down-regulated.
- Rare Adverse Effect: triggering of an immune response
Down-regulation of receptors is the opposite of what I would’ve thought. SO think of it like this: mast cells notice decreased IgE floating around, thinks “they don’t need me right now” and down-regulates receptors. But if IgE does hit one of the receptors → triggers immune response!
- Respiratory Airway/Treatment Bronchospasm Summary - describe shortly what each one does
- Bronchodilation
- B2 adrenergic agonists
- Methylxanthines/PDE Inhibitors
- Anticholinergics
- Inflammation and mucous
- Steroids
- Cromolyn
- Leukotriene inhibitors
- IgE (last ditch)
- Bronchodilation
- Respiratory Airway/Treatment Bronchospasm Summary
- Bronchodilation
- B2 adrenergic agonists; Sympathomimetics- 3,5 cAMP production → bronchodilation
- Methylxanthines/PDE Inhibitors- Inhibit breakdown of 3,5 cAMP (not usually used anymore)
- Anticholinergics → competitive inhibition of cholinergic receptors with acetylcholine → block constriction
- Usually used for COPD
- Inflammation and mucous
- Steroids-decrease mucosal edema (mainstay tx for asthma)
- Cromolyn-Mast cell stabilization
- Leukotriene inhibitors –block the synthesis or action (blocks synthesis or blocks the receptors)
- IgE (last ditch)
- Bronchodilation
