ICL 2.14: Pharmacotherapy for PAH, Cough & Allergic Rhinitis Flashcards
what are the 5 groups of pulmonary hypertension?
group 1: pulmonary arterial HTN
group 2: PH from left sided heart failure
group 3: PH from chronic hypoxic lung disease
group 4: PH from chronic blood clots
group 5: unclear multifactorial mechanisms (sarcoidosis, hematological disorders, etc.)
what is group 1 pulmonary HTN?
pulmonary arterial HTN
blood vessels become thickened and hard (cellular proliferation) and narrow (vasoconstriction)
the net effect is that the heart weakens from working harder to pump blood
what is the overall MOA of the drugs used for pulmonary HTN?
drugs mainly work by causing vasodilation and blocking cellular proliferation
most drug therapy is directed toward group 1 (PAH), and Group 4 to some extent
what are class I-IV pulmonary HTN?
class I: no limitations in daily physical activities; no symptoms of dyspnea with routine exertion
class II: mild symptoms with exertion, including dyspnea and faitigue; no symptoms at rest
class III: moderate dyspnea with routine actives and activities of daily living; no symptoms at rest
class IV: inability to perform even minimal activities; signs and symptoms of right heart failure may be present; dyspnea present at rest
what are the pathological changes that happen in pulmonary arterial hypertension?
in group 1 HTN there’s decreased NO and prostacyclin/increased endothelin
the five main drug classes act on these 3 pathways: NO, prostacyclin and endothelin
what is the NO/sGC/cGMP pathway that pulmonary HTN drugs work on?
GTP is converted to cGMP via sGC
cGMP is broken down into to GMP via PDE5
cGMP decreases Ca+2 which leads to:
1. vasodilation
- anti-proliferative effects on vascular smooth muscle cells (VSMCs)
- anticoagulant effect
so cGMP is good for preventing pulmonary HTN so the two drugs types that are used either activate sGC to make cGMP or they block PDE5 to prevent the breakdown of cGMP
how is cGMP regulated in the NO/sGC/cGMP pathway?
(+) NO made by endothelial cells moves into VSMCs, binds and activates soluble guanylate cyclase (sGC), which catalyzes cGMP synthesis
(-) PDE5 enzymes in VSCMs convert cGMP to 5’GMP, which terminates cGMP’s activity
how do pulmonary HTN drugs alter the NO/sGC/cGMP pathway?
- stimulation of sGC –> riociguat
- inhibition of
PDE5 –> sildenafil, tadalafil
which drugs are PDE-5 inhibitors? what is their MOA?
- sildenafil
- tadalafil
they bind to catalytic site of PDE5, competitively & selectively inhibits PDE5 activity
what are PDE5 inhibitors used for in relation to pulmonary HTN?
used in Group 1 (PAH) patients to improve exercise ability and delay clinical worsening
what is an important pharmacokinetic aspect of PDE5 inhibitors that you need to be aware of?
- they’re metabolized by CYP3A4 so avoid drugs that inhibit/promote this
- avoid taking with other NO/sGC/cGMP pathway drugs, including recreational ones because it can cause severe hypotension
- sudden vision/ hearing loss
- blue-green tinting of vision due to inhibition of retinal PDE6
what are the common side effects of PDE5 inhibitors? why?
- nosebleeds due to cGMP anticoagulant effect
- headache, flushing, erections, rhinitis due to cGMP vasodiation effect
- GI (altered motility, dyspepsia) due to smooth muscle relaxation
which drugs are sGC stimulators?
riociguat
it’s the only drug in the class!
what are the uses of sGC simulators in relation to pulmonary HTN?
- improves exercises capacity
- PH Group 4 with CTEPH
- improves exercise capacity and functional class
what is the MOA of sGC stimulator
- enhances NO binding to sGC, and
2. directly stimulates sGC which is good, since PAH involves ↓ NO production
what are the pharmacokinetics of sGC stimulators?
- significant inter-individual variability; requires dose titration
- cleared by many paths –> no major interactions
what are the side effects of sGC sitmulators?
- GI (nausea, altered motility)
- anemia, nosebleeds
- hypotension, headache
- requires BP monitoring
- contraindicated in pregnancy!! requires monthly pregnancy testing
what is a REMS program?
risk evaluation and mitigation
FDA mandation that certain safety things are put in place like having to be certified to be able to perscribe a certain drug
what is the prostacyclin pathway?
prostacyclin binds to IPR receptor which activates Gs coupled protein receptor which activates adenylyl cyclase
ATP is then converted into cAMP
cAMP can be broken down into AMP via PDE
cAMP decreases Ca+2 levels which leads to:
1. antiproliferative effect
- vasodilation
- anticoagulant effect
how is cAMP regulated?
(+) adenylyl cyclase (AC) catalyzes cAMP synthesis from ATP; AC is activated by Gs-coupled GPCRs like the prostaglandin IP receptor
(-) PDE enzymes convert cGMP to 5’GMP, which terminates cGMP’s activity
how do drugs alter the prostacyclin pathway?
- prostacyclin itself is given as a drug (epoprostanol)
- prostacyclin analogs to activate IPR (treprostinil, ilopros)
- other IP receptor agonists (selexipag) to activate IPR
which drugs are prostacyclins?
epoprostenol
given via IV infusion
what are the uses of prostacyclin drugs in relation to pulmonary HTN?
used for severe or high-risk PAH (WHO functional class III/IV)
improves functional class, hemodynamics, mortality
what is the MOA of prostacyclin drugs?
paracrine activation of IPR receptor
paracrine signalizing differs from endocrine in that it’s more local effects; it targets a nearby cell so they don’t have to go very far and breakdown very fast
endocrine signaling molecules have a much longer half life
what are the pharmacokinetics of prostacyclin?
it’s a paracrine activation of IPR which means it targets a nearby cell so they don’t have to go very far and breakdown very fast
this means it has a 6 minute half life and you have to give it via a titrated infusion via a central catheter
the prostacyclin molecules are also super unstable and require special handling like making sure it’s at the right temperature etc but it’s really effective so it’s worth the hassle
what are the side effects of prostacyclin drugs?
- headache, hypotension, flushing, dizziness
- GI side effects (nausea, etc.), pain (jaw, muscle), bleeding
- sudden discontinuation can cause rebound PH so you need to titrate it down
which drugs are prostacyclin analogs?
- treprostinil (inhaled, PO, IV, SC)
2. iloprost (inhaled)
what is the MOA of prostacyclin analogs?
activation of prostanoid receptors (e.g., IPR)
what are the uses of prostacyclin analogs in relation to pulmonary HTN?
PO agents: Group 1 (PAH) functional class II/III improves hemodynamic parameters, symptoms, exercise capacity
Parenteral agents: Group 1 functional class III/IV
what are the pharmacokinetics of prostacyclin analogs?
short half life but longer than epoprostenol
inhaled agents must be dosed 5-10x / day so that’s why they’re given via a SC pump usually and with the inhaled ones there’s a loss of effect at night while sleeping
what are the side effects of prostacyclin analogs?
- SC - pain at infusion site
- inhaled – some local effects (cough, irritation, bronchospasm)
similar to prostacyclin side effects so also headache, hypotension, flushing, dizziness, GI side effects (nausea, etc.), pain (jaw, muscle), bleeding
minimized systemic effects
which drugs are prostacyclin receptor agonists?
selexipag
what is the MOA of prostacyclin receptor agonists?
non-prostanoid activation of IPR
much higher selectivity for the IP (vs. other prostanoid) receptor
what are the uses of treatment of prostacyclin receptor agonists?
treatment of PAH functional class II/III
reduction in hospitalizations, slower disease progression
what are the pharmacokinetics of prostacyclin receptor agonists?
it’s a prodrug so CYP2C8 metabolizes selexipag to it’s active form
also requires dose titration, which can be lengthy and somewhat complex
what are the side effects of prostacyclin receptor agonists?
pulmonary edema in patients with pulmonary veno-occlusive disease
similar to prostacyclin side effects so also headache, hypotension, flushing, dizziness, GI side effects (nausea, etc.), pain (jaw, muscle), bleeding
what is endothelia 1?
a super potent endothelial cell-derived vasoconstrictor
it also is a mitogenic factor with proliferative effects on many cells, including VSMCs, myofibroblasts
what is the endothelin-1 pathway associated with pulmonary HTN?
vasoconstrictor effects via Gq-coupled endothelin A (ETA) receptor
vasodilation effects via ETB receptor
how do drugs treating pulmonary HTN alter the endothelin-1 pathway?
Several antagonists have been developed to block ET1 binding to the ETA (or ETA + ETB)
oddly, selective antagonism of ETA does not translate to better clinical response
which drugs are endothelin receptor antagonists?
- ambrisentan
- bosentan
- macitentan
“entan”
what is the MOA of endothelin receptor antagonists?
antagonist at ETA receptors
also at ETB receptors too but there’s no benefit to being a selective ETA antagonists
what are the uses of endothelin receptor antagonists?
- slows PAH progression, relieves symptoms
PAH, functional class II/III
- delays progression and clinical worsening
- improves exercise tolerance and quality of life
what are the side effects of endothelin receptor antagonists?
- headache
- rhinitis
- anemia
- peripheral edema
- Hepatotoxicity; may increase liver enzymes (requires monitoring, especially bosentan)
- risk of testicular atrophy, infertility
- contraindicated in pregnancy due to embryo/fetal toxicity
what are the pharmacokinetics of endothelin receptor antagonists?
all are CYP3A4 substrates so they have significant CYP3A4 interactions and gets broken down by this enzyme
bosentan specifically also induces 3A4 enzymes which means it moves into the nucleus and binds to transcription factors and turns on production of more 3A4 –> you need to keep this in mind because it ↓oral contraceptive levels
what is the treatment approach for treating pulmonary HTN?
vasoreactivity testing identifies the 10-20% of patients who may respond to CCB therapy
people who are low risk/functional class I/II may be treated with single drug
class II/III initially treated with combination therapy = ERA, cGMP path drug or PDE5I in any combination –> *BUT avoid combo of PDE5I + riociguat
class III/IV, high risk add on parenteral prostacyclin or analog – reserved for really sick people
what is a cough?
cough normally produced via mechanical or chemical stimulation of sensory receptors in the lower pharynx, larynx, trachea and lower airways
signal goes to cough center in brain, triggering reflex motor response
motor response is coordinated contraction / relaxation of muscles to produce cough
what are the 3 main methods for determining the efficacy of cough treatments?
- subjective reports (surveys)
- cough challenge test
- cough counting (preferred method)
test of the same agent by the 3 different methods often produces conflicting results
also placebo effect has impact on cough
how are cough medicines classified?
- location of effect: central (CNS)/peripheral (outside CNS)
- type of effect: antitussive (reflex inhibition)/protussive (minimizing secretions)
which drugs are centrally-acting antititussives?
- dextromethorphan (robitussin)
2. codeine
what is the MOA of centrally-acting antititussives?
MOA: act in CNS; thought to suppress medullary cough center, lowering cough threshold but we aren’t super sure
used for chronic and disease-related cough; both found in numerous cough medications
what is the pharmacokinetics of centrally-acting antititussives?
both dextromethorphan and codeine are metabolized to active metabolites by CYP2D6
CYP2D6 turns codeine into morphine….
how does codeine work?
opioid receptor agonist
antitussive effect at doses much lower than analgesic dose
potential for opioid adverse effects = respiratory depression, pinpoint pupils and constiptation
how does dextromethorphan work?
it’s an isomer of codeine analog (only acts at σR)
it’s also an antagonist at glutamate NMDA receptors
potential for abuse like other NMDAR antagonists because it produces a high
overdose can cause serotonin syndrome, respiratory depression (responds to naloxone)
what is the efficacy of centrally-acting antititussives?
codeine: modern studies consistently find that codeine is not superior to placebo
dextromethorphan: effective in subjective evaluations and challenge test (not cough counting); has most solid evidence for efficacy of all cough medications
which drugs are peripherally acting antitussives?
- menthol (Vicks)
- pectin (Luden’s cough drops)
- benzonatate
how does menthol work?
it’s a peripherally acting antitussive that chemically stimulates cold-sensitive TRPM8 receptors
used to relieve throat irritation, minor pain
little clinical evidence for antitussive effect
how does pectin work?
it’s a peripherally acting antitussive that temporarily has mucoprotective effects (coats mucous membranes)
pectin is a GRAS food substance, but has many medical uses
how does benzonatate work?
it’s a peripherally acting antitussive that is structurally related to local anesthetics (has anesthetic effects); depresses activity of cough reflex mechanoreceptors in lung tissues
CNS and GI side effects, including hallucinations; dangerous in overdose
good evidence for efficacy, although depends on type of cough
which drugs are mucociliary acting agents?
- guaifenesin
- NAC (N-acetylcysteine)
- diphenhydramine
these help thin mucus so you can get it out in a cough
how does guaifenesin work?
it’s a mucociliary acting agent that’s the only FDA-approved expectorant
irritant to gastric vagal receptors, reduces mucus viscosity by reducing adhesiveness, surface tension, hydration –> so basically it irritates vagal receptors to force you to cough and reduces mucus viscosity
evidence supports decreased mucus viscosity, enhanced mucus clearance
how does N-acetylcysteine work?
it’s a mucociliary acting agent that’s classified as a mucolytic; cleaves disulfide linkages in mucus
used in cough associated with COPD, cystic fibrosis (
it’s an antidote for aspirin overdose!!
how does diphenhydramine work?
it’s a mucociliary acting agent that’s a first-generation (sedating) antihistamine
demonstrated efficacy in cough challenge test (2nd generation agents do not suppress cough)
what is an acute vs. subacute vs .chronic cough?
acute cough: lasting less than three weeks
subacute cough: lasting between three and eight weeks
chronic cough: lasting more than eight weeks
how do you manage a cough?
most times they’re self limiting
most cough remedies have not been rigorously tested for efficacy (study design is often categorized as “fair” or “poor”)
FDA does not recommend OTC cough and cold agents in children younger than 2 years old (petition led to voluntary labeling in 2008)
many other disease-specific treatments that improve cough symptoms (e.g., antibiotics)
also some investigational / off-label drugs (e.g., lidocaine, pregabalin)
what is allergic rhinitis?
type I hypersensitivity reaction that causes inflammation of the nasal mucosa, resulting from action of allergens on mast cells
mechanisms are similar to those of asthma so many of the same drugs are used
what are the 3 classes of drugs used to treat allergic rhinitis?
- topical glucocorticoids
- mast cell stabilizers
- 2nd generation antihistamines
- anticholinergics
- sympathomimetics
- anti-leukotrienes
which drugs are topical glucocorticoids used for allergic rhinitis?
fluticasone (nasal spray)
used for prophylaxis since they move into the nucleus and alter transcription so full effect takes 2-3 weeks
it relieves most AR symptoms and congestion
this is the most effective option for treating allergic rhinitis!!!!
which drugs are mast cell stabilizers used for allergic rhinitis?
cromolyn (inhaled)
relieves most AR symptoms and congestion
it’s given for prophylaxis, give 20 min before exposure
super safe, but less effective than glucocorticoids
which drugs are 2nd generation antihistamines used for allergic rhinitis?
fexofenadine (allegra;oral) and azelastine (nasal spray, eye drop)
relieves itching, rhinorrhea, does not relieve congestion
side effects include sedation especially 1st generation but 2nd generation is better because they don’t cross BBB
these are the most frequently used drug for AR!! (not used for asthma)
which drugs are anticholinergics used for allergic rhinitis?
ipratropium
reduces rhinorrhea (reduces mucus secretion)
side effects include epistaxis, nasal dryness, antimuscarinic effects
which drugs are sympathomimetics used for allergic rhinitis?
pseudoephedrine, phenylephrine (Sudafed®)
it’s a decongestant that acts by being an α1 vasoconstriction effect in nasal vasculature
side effects include insomnia, nervousness, increased BP, HR
which drugs are anti-leukotrienes used for allergic rhinitis?
montelukast
relieves most AR symptoms and congestion (reduces inflammatory mediators)
generally well-tolerated
how would you treat allergic rhinitis in children?
AR not common in kids because it requires repeated exposures
- antihistamines - (sedating antihistamines can cause paradoxical agitation in infants, should be avoided); non-sedating antihistamines may be used with caution
- cromolyn nasal spray – safe in infants, but less effective than glucocorticoids but still first choice
- glucocorticoid nasal spray – for more severe symptoms (low dose)
how would you treat allergic rhinitis in pregnancy/breastfeeding?
saline nasal sprays, topical decongestants for intermittent symptoms
cromolyn, topical glucocorticoids, non-sedating antihistamines (for severe persistent symptoms)
how would you treat allergic rhinitis in older adults?
nonsedating antihistamines
avoid sedating antihistamines because there’s reduced clearance with age, increased risk of confusion, constipation = Beers criteria
