ICL 2.14: Pharmacotherapy for PAH, Cough & Allergic Rhinitis

Question 1

what are the 5 groups of pulmonary hypertension?

Answer 1

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.)

Question 2

what is group 1 pulmonary HTN?

Answer 2

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

Question 3

what is the overall MOA of the drugs used for pulmonary HTN?

Answer 3

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

Question 4

what are class I-IV pulmonary HTN?

Answer 4

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

Question 5

what are the pathological changes that happen in pulmonary arterial hypertension?

Answer 5

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

Question 6

what is the NO/sGC/cGMP pathway that pulmonary HTN drugs work on?

Answer 6

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

2. anti-proliferative effects on vascular smooth muscle cells (VSMCs)
3. 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

Question 7

how is cGMP regulated in the NO/sGC/cGMP pathway?

Answer 7

(+) 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

Question 8

how do pulmonary HTN drugs alter the NO/sGC/cGMP pathway?

Answer 8

1. stimulation of sGC –> riociguat
2. inhibition of
   PDE5 –> sildenafil, tadalafil

Question 9

which drugs are PDE-5 inhibitors? what is their MOA?

Answer 9

1. sildenafil
2. tadalafil

they bind to catalytic site of PDE5, competitively & selectively inhibits PDE5 activity

Question 10

what are PDE5 inhibitors used for in relation to pulmonary HTN?

Answer 10

used in Group 1 (PAH) patients to improve exercise ability and delay clinical worsening

Question 11

what is an important pharmacokinetic aspect of PDE5 inhibitors that you need to be aware of?

Answer 11

1. they’re metabolized by CYP3A4 so avoid drugs that inhibit/promote this
2. avoid taking with other NO/sGC/cGMP pathway drugs, including recreational ones because it can cause severe hypotension
3. sudden vision/ hearing loss
4. blue-green tinting of vision due to inhibition of retinal PDE6

Question 12

what are the common side effects of PDE5 inhibitors? why?

Answer 12

1. nosebleeds due to cGMP anticoagulant effect
2. headache, flushing, erections, rhinitis due to cGMP vasodiation effect
3. GI (altered motility, dyspepsia) due to smooth muscle relaxation

Question 13

which drugs are sGC stimulators?

Answer 13

riociguat

it’s the only drug in the class!

Question 14

what are the uses of sGC simulators in relation to pulmonary HTN?

Answer 14

1. improves exercises capacity
2. PH Group 4 with CTEPH
3. improves exercise capacity and functional class

Question 15

what is the MOA of sGC stimulator

Answer 15

1. enhances NO binding to sGC, and

2. directly stimulates sGC which is good, since PAH involves ↓ NO production

Question 16

what are the pharmacokinetics of sGC stimulators?

Answer 16

1. significant inter-individual variability; requires dose titration
2. cleared by many paths –> no major interactions

Question 17

what are the side effects of sGC sitmulators?

Answer 17

1. GI (nausea, altered motility)
2. anemia, nosebleeds
3. hypotension, headache
4. requires BP monitoring
5. contraindicated in pregnancy!! requires monthly pregnancy testing

Question 18

what is a REMS program?

Answer 18

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

Question 19

what is the prostacyclin pathway?

Answer 19

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

2. vasodilation
3. anticoagulant effect

Question 20

how is cAMP regulated?

Answer 20

(+) 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

Question 21

how do drugs alter the prostacyclin pathway?

Answer 21

1. prostacyclin itself is given as a drug (epoprostanol)
2. prostacyclin analogs to activate IPR (treprostinil, ilopros)
3. other IP receptor agonists (selexipag) to activate IPR

Question 22

which drugs are prostacyclins?

Answer 22

epoprostenol

given via IV infusion

Question 23

what are the uses of prostacyclin drugs in relation to pulmonary HTN?

Answer 23

used for severe or high-risk PAH (WHO functional class III/IV)

improves functional class, hemodynamics, mortality

Question 24

what is the MOA of prostacyclin drugs?

Answer 24

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

Question 25

what are the pharmacokinetics of prostacyclin?

Answer 25

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

Question 26

what are the side effects of prostacyclin drugs?

Answer 26

1. headache, hypotension, flushing, dizziness 2. GI side effects (nausea, etc.), pain (jaw, muscle), bleeding 3. sudden discontinuation can cause rebound PH so you need to titrate it down

Question 27

which drugs are prostacyclin analogs?

Answer 27

1. treprostinil (inhaled, PO, IV, SC) | 2. iloprost (inhaled)

Question 28

what is the MOA of prostacyclin analogs?

Answer 28

activation of prostanoid receptors (e.g., IPR)

Question 29

what are the uses of prostacyclin analogs in relation to pulmonary HTN?

Answer 29

PO agents: Group 1 (PAH) functional class II/III improves hemodynamic parameters, symptoms, exercise capacity Parenteral agents: Group 1 functional class III/IV

Question 30

what are the pharmacokinetics of prostacyclin analogs?

Answer 30

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

Question 31

what are the side effects of prostacyclin analogs?

Answer 31

1. SC - pain at infusion site 2. 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

Question 32

which drugs are prostacyclin receptor agonists?

Answer 32

selexipag

Question 33

what is the MOA of prostacyclin receptor agonists?

Answer 33

non-prostanoid activation of IPR much higher selectivity for the IP (vs. other prostanoid) receptor

Question 34

what are the uses of treatment of prostacyclin receptor agonists?

Answer 34

treatment of PAH functional class II/III reduction in hospitalizations, slower disease progression

Question 35

what are the pharmacokinetics of prostacyclin receptor agonists?

Answer 35

it's a prodrug so CYP2C8 metabolizes selexipag to it's active form also requires dose titration, which can be lengthy and somewhat complex

Question 36

what are the side effects of prostacyclin receptor agonists?

Answer 36

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

Question 37

what is endothelia 1?

Answer 37

a super potent endothelial cell-derived vasoconstrictor it also is a mitogenic factor with proliferative effects on many cells, including VSMCs, myofibroblasts

Question 38

what is the endothelin-1 pathway associated with pulmonary HTN?

Answer 38

vasoconstrictor effects via Gq-coupled endothelin A (ETA) receptor vasodilation effects via ETB receptor

Question 39

how do drugs treating pulmonary HTN alter the endothelin-1 pathway?

Answer 39

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

Question 40

which drugs are endothelin receptor antagonists?

Answer 40

1. ambrisentan 2. bosentan 3. macitentan "entan"

Question 41

what is the MOA of endothelin receptor antagonists?

Answer 41

antagonist at ETA receptors also at ETB receptors too but there's no benefit to being a selective ETA antagonists

Question 42

what are the uses of endothelin receptor antagonists?

Answer 42

1. slows PAH progression, relieves symptoms PAH, functional class II/III 2. delays progression and clinical worsening 3. improves exercise tolerance and quality of life

Question 43

what are the side effects of endothelin receptor antagonists?

Answer 43

1. headache 2. rhinitis 3. anemia 4. peripheral edema 5. Hepatotoxicity; may increase liver enzymes (requires monitoring, especially bosentan) 6. risk of testicular atrophy, infertility 7. contraindicated in pregnancy due to embryo/fetal toxicity

Question 44

what are the pharmacokinetics of endothelin receptor antagonists?

Answer 44

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

Question 45

what is the treatment approach for treating pulmonary HTN?

Answer 45

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

Question 46

what is a cough?

Answer 46

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

Question 47

what are the 3 main methods for determining the efficacy of cough treatments?

Answer 47

1. subjective reports (surveys) 2. cough challenge test 3. 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

Question 48

how are cough medicines classified?

Answer 48

1. location of effect: central (CNS)/peripheral (outside CNS) 2. type of effect: antitussive (reflex inhibition)/protussive (minimizing secretions)

Question 49

which drugs are centrally-acting antititussives?

Answer 49

1. dextromethorphan (robitussin) | 2. codeine

Question 50

what is the MOA of centrally-acting antititussives?

Answer 50

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

Question 51

what is the pharmacokinetics of centrally-acting antititussives?

Answer 51

both dextromethorphan and codeine are metabolized to active metabolites by CYP2D6 CYP2D6 turns codeine into morphine....

Question 52

how does codeine work?

Answer 52

opioid receptor agonist antitussive effect at doses much lower than analgesic dose potential for opioid adverse effects = respiratory depression, pinpoint pupils and constiptation

Question 53

how does dextromethorphan work?

Answer 53

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)

Question 54

what is the efficacy of centrally-acting antititussives?

Answer 54

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

Question 55

which drugs are peripherally acting antitussives?

Answer 55

1. menthol (Vicks) 2. pectin (Luden's cough drops) 3. benzonatate

Question 56

how does menthol work?

Answer 56

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

Question 57

how does pectin work?

Answer 57

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

Question 58

how does benzonatate work?

Answer 58

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

Question 59

which drugs are mucociliary acting agents?

Answer 59

1. guaifenesin 2. NAC (N-acetylcysteine) 3. diphenhydramine these help thin mucus so you can get it out in a cough

Question 60

how does guaifenesin work?

Answer 60

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

Question 61

how does N-acetylcysteine work?

Answer 61

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!!

Question 62

how does diphenhydramine work?

Answer 62

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)

Question 63

what is an acute vs. subacute vs .chronic cough?

Answer 63

acute cough: lasting less than three weeks subacute cough: lasting between three and eight weeks chronic cough: lasting more than eight weeks

Question 64

how do you manage a cough?

Answer 64

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)

Question 65

what is allergic rhinitis?

Answer 65

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

Question 66

what are the 3 classes of drugs used to treat allergic rhinitis?

Answer 66

1. topical glucocorticoids 2. mast cell stabilizers 3. 2nd generation antihistamines 4. anticholinergics 5. sympathomimetics 6. anti-leukotrienes

Question 67

which drugs are topical glucocorticoids used for allergic rhinitis?

Answer 67

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!!!!

Question 68

which drugs are mast cell stabilizers used for allergic rhinitis?

Answer 68

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

Question 69

which drugs are 2nd generation antihistamines used for allergic rhinitis?

Answer 69

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)

Question 70

which drugs are anticholinergics used for allergic rhinitis?

Answer 70

ipratropium reduces rhinorrhea (reduces mucus secretion) side effects include epistaxis, nasal dryness, antimuscarinic effects

Question 71

which drugs are sympathomimetics used for allergic rhinitis?

Answer 71

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

Question 72

which drugs are anti-leukotrienes used for allergic rhinitis?

Answer 72

montelukast relieves most AR symptoms and congestion (reduces inflammatory mediators) generally well-tolerated

Question 73

how would you treat allergic rhinitis in children?

Answer 73

AR not common in kids because it requires repeated exposures 1. antihistamines - (sedating antihistamines can cause paradoxical agitation in infants, should be avoided); non-sedating antihistamines may be used with caution 2. cromolyn nasal spray – safe in infants, but less effective than glucocorticoids but still first choice 3. glucocorticoid nasal spray – for more severe symptoms (low dose)

Question 74

how would you treat allergic rhinitis in pregnancy/breastfeeding?

Answer 74

saline nasal sprays, topical decongestants for intermittent symptoms cromolyn, topical glucocorticoids, non-sedating antihistamines (for severe persistent symptoms)

Question 75

how would you treat allergic rhinitis in older adults?

Answer 75

nonsedating antihistamines avoid sedating antihistamines because there's reduced clearance with age, increased risk of confusion, constipation = Beers criteria