PharmTher - Pulm HTN - Quizzam 3

Vasodilators

-prostanoids

-endothelin receptor antagonists (ERA)

-phosphodiesterase-5 inhibitors

-soluble guanylate cyclase inhibitors

epoprostenol (Flolan, Veletri)

what is an example of a prostanoid?

PGI2 (prostacyclin analogue)

-induces potent vasodilation of all vascular beds; potent inhibitor of platelet aggregation and has cytoprotective and antiproliferative activities

Eprostenol

-indicated for NYHA Class III-IV, but preferred in NYHA IV

-increases exercise capacity, improves pulmonary hemodynamics, QOL, and survival

-IV has a short half-life (3-5 min), must be admin via continuous IV infusion

dose escalation

tolerance develops to Epoprostenol over time, so ______________ required over time in order to maintain response

NYHA IV

what class of pulm HTN is epoprostenol preferred for?

Epoprostenol dose-limiting ADE

-jaw pain

-hypotension

-HA, N/V, bleeding, flushing, diarrhea, abdominal cramping, backache

rebound HTN

interrupted therapy of epoprostenol can cause what?

Epoprostenol rebound HTN

-s/s in as little as 30 min

-death in as little as 12 hr

-backup pump and spare drug cartridge recommended

Flolan Stability

-Room temp: 8 hr

-Ice packed: 24 hr

-Refrigerated: 48 hr

Veletri Stability

-room temp: 48 hr

-refrigerated: 5 days

Other Prostanoids

-Treprostinil --> parenteral admin

-Treprostinil --> inhalation, titrate up to a max of 9 breaths 4x daily

-Treprostinil --> oral admin

-Iloprost --> inhalation admin

Ambrisentan

what is an example of an endothelin-1 receptor antagonist?

ET-1

-peptide produced mainly by vascular endothelial cells

-powerful vasoconstrictor

Ambrisentan

-indicated for NYHA FC II-III

-outcomes: increases exercise capacity, improves pulmonary hemodynamics and functional class and time to clinical worsening

-favorable survival data in cohort studies

Ambrisentan - Dosing

-oral

-initial 5 mg once daily

-may increase to 10 mg once daily after ~4 weeks as tolerated

Ambrisentan ADE

-HA

-edema

-flushing

-dyspepsia

-nasal congestion

-decreased Hb/Hct

3 months

Ambrisentan ADE usually resolve after first ____________ of therapy

diuretic

ambrisentan may require a dose increase of ___________ therapy to help with ADE

cyclosporine and ketoconazole

what are the drug interactions for ambrisentan?

letairis education and access program

ambrisentan is available through what program?

Sildenafil and Tadalafil

what are examples of phosphodiesterase-5 inhibitors?

Sildenafil (viagra or revatio)

-preferential pulmonary vasodilation

-indicated: NYHA FC II-IV

-outcomes: improves exercise capacity, pulmonary hemodynamics, and functional class

-Dosing: PO or injection

Sildenafil ADE

-HA, flushing, epistaxis, dyspepsia, diarrhea

-Vision Changes: blue-tinted vision, sudden loss of vision

Tadalafil (Cialis or Adcirca)

-similar outcomes, indications, and adverse events as sildenafil

-PO

-CrCl <30 L/min or HD = avoid

organic nitrates

PDE-5 inhibitors should not be used in patients taking ______________ d/t risk of severe hypotension

24 hr, 48 hr

if an organic nitrate is to be used, discontinue sildenafil x _________, and tadalafil x ________ prior to starting nitrate

discouraged

when a PDE-5 inhibitor is used for PAH, concurrent use of an additional PDE-5 inhibitor for ED is _____________ d/t additional risk of SE

Riociguat

what is an example of a soluble guanylate cyclase stimulator?

Riociguat

-guanylate cyclase = only known receptor for nitric oxide

-indicated: NYHA FC II-IV

-outcomes: improved exercise capacity, pulmonary hemodynamics, functional class, dyspnea score, and decreases clinical worsening

Riociguat ADE

-HA

-dizziness

-peripheral edema

-dyspepsia

-diarrhea

-N/V

teratogenicity

what is the black box warning for riociguat?

PAH Drug Classes

-prostanoids

-Endothelin-1 receptor antagonists

-PDE-5 inhibitors

-soluble guanylate cyclase stimulators

vasodilator challenge

Calcium channel blockers are an initial option for PAH, but only in patients who respond to what?

no

are CCBs used in chronic treatment of PAH?

combo

if monotherapy is ineffective for PAH, _______ therapy should be considered, but no single combo stands out from the rest in terms of improved efficacy and survival

PAH Therapy Goals

-alleviation of symptoms

-improvement in the QOL

-slow disease progression

-improvement in survival

high

is there high or low morbidity and mortality in females with PAH during pregnancy/pp?

Avoid Meds - PAH

-vasoactive decongestants (pseudoephedrine)

-cardio-depressant antihypertensives (b-blockers)

-if on warfarin, watch for DI!

Avoid - PAH

-pregnancy

-strenuous physical activity

-high altitudes

-vasoactive decongestants, cardio-depressant antihypertensives

-watch warfarin for DI

Diuretics

-supportive tx for PAH

-when fluid overload present (JVD, abd distension, or LE edema), esp with signs/symptoms of right-sided HF

-ex: furosemide

Warfarin - PAH

-demonstrated survival benefit

-Goal: INR 1.5-2.5 in all patients with idiopathic PAH and patients with advanced dz (WHO-FC III and IV or receiving parenteral therapy)

-presence of traditional risk factors for VTE (HF and sedentary lifestyle)

Digoxin - PAH

-used for PAH with right-sided HF along with diuretics

-atrial tachyarrhythmias present

Oxygen - PAH

-goal is to maintain arterial O2sat >92%

Low Risk PAH

-WHO-FC I-II

-no clinical signs of HF

-no progression of symptoms or syncope

Intermediate Risk (5%-10%) - PAH

-WHO-FC: III

-no clinical signs of HF

-slow progression of sx

-occasional syncope

High Risk - PAH (>10%)

-clinical signs of right heart failure present

-rapid progression of sx

-repeated syncope

-WHO-FC: IV

ambrisentan + tadalafil or other ERA + PDE-5 inhibitor

what is the initial oral combo therapy for low to intermediate risk PAH?

ERA, PDE-5 inhibitor, riociguat, selexipag

what is the initial monotherapy (less preferred) for FC II PAH?

inhaled or parenteral prostacyclin

what is the initial monotherapy (less preferred) for FC III PAH?

PCA + ERA and/or PDE5-inhibitor or riociguat

what is the initial combo therapy with IV PCA for high risk PAH?

lung transplant

what should you also be assessing high risk PAH pts for?

Acute Vasodilator Challenge

-done during right-heart catheterization

-IPAH and PAH associated with underlying processes in the absence of RHF is more likely to respond

->20% decrease in MPAP to <40 mmHg with unchanged or increased CO

-FAIL if decreased CO

assess tx for CCB

what is the point of the acute vasodilator challenge?

initial response

between 10-15% of patients have ____________ to acute vasodilator challenge, meaning they have hemodynamic changes as soon as vasodilator is admin

sustained

-25-50% of those who had the initial response have a ___________ response, meaning they continue to respond to CCB therapy after several months

Calcium Channel Blockers

-only systemic antihypertensives to show benefit in PAH

-no FDA indication for PAH

-outcomes: may provide symptomatic relief and improve NYHA classification for responders

CCB ADE

-hypotension, peripheral edema (may lead to discontinuation)

-verapamil has significant cardiodepressive properties - AVOID in patients with PAH

verapamil

what CCB should you avoid in patients with pulm HTN?

amlodipine, diltiazem ER, nifedipine

what are the common CCBs used for PAH tx?

Functional Assessment Class I

patients with PAH in whom there is no limitation of usual physical activity; ordinary physical activity does not cause increased dyspnea, fatigue, chest pain, or presyncope

Functional Assessment - Class II

-patients with PAH who have mild limitation of physical activity

-there is no discomfort at rest, but NL physical activity causes increased dyspnea, fatigue, chest pain, or presyncope

Functional Assessment - Class III

-patients with PAH who have marked limitation of physical activity

-there is no discomfort at rest, but less than NL physical activity causes increased dyspnea, fatigue, chest pain, or presyncope

Functional Assessment - Class IV

-patients with PAH who are unable to perform any physical activity at rest and who may have signs of right ventricular failure

-dyspnea and/or fatigue may be present at rest, and symptoms are increased by almost any physical activity

Conventional Therapy - PAH

-oral anticoagulants

-diuretics

-oxygen

-digoxin

Prostacyclin Analogs

-induce potent vasodilation of pulmonary vascular beds

-epoprostenol, treprostinil, and iloprost

-admin: oral, inhaled, subq, and intravenous

IV - Prostacyclin Analogs

-reserved for high-risk patients and are used in combo with endothelin receptor antagonists, PDE-5 inhibitors, and riociguat

epoprostenol

what is the only prostacyclin analog that demonstrates survival?

Oral Combo Therapy

-recommended initially for patients with PAH at low-to-intermediate risk for mortality at 1 year

-options include endothelin-receptor antagonists, phosphodiesterase-5 inhibitors, riociguat, and selexipag

-agents improve exercise capacity, functional class, and hemodynamics in PAH

CCBs

-only considered in a small number of patients who have a positive response to acute vasoreactivity testing

-small number of patients have a long-term response

Respiratory Failure

-syndrome in which resp system fails in one or both of its gas exchange functions --> tissue hypoxia

Type I Resp Failure

-problem with oxygenation

-hypoxemic RF

Type II Resp Failure

-problem with CO2 elimination

-hypercapnic RF

Supportive Care - Mechanical Vent

-supplemental O2

-sedation

-analgesia

-paralysis

-venous thromboembolism prophylaxis

Sedation

-Goal: comfortable, calm patient who is arousable and cooperative

dose reduction

if a patient on sedation is not arousable, what should you do?

more meds

if a patient on sedation is too awake, they may require _____________ if dys-synchronous with ventilator

light sedation

maintaining ___________ in adult ICU patients is associated with improved clinical outcomes

Sedated

difficult to arouse, but awakens to verbal stimuli or gentle shaking, follows simple commands then drifts off again

Analgesia-first sedation

should be used in mechanically vented adult ICU patients because it improves tolerance and decreases oxygen consumption

Sedation - Agent Choice

-etiology of the distress

-expected duration of therapy

-clinical status of the patient

-potential interactions with other drugs

Sedative-Hypnotics

-diazepam

-lorazepam

-midazolam

Narcotic Analgesics

-fentanyl

-hydromorphone

-morphine sulfate

-remifantanil

propofol

what is the anesthetic sedatives commonly used in sedation and analgesia in critically ill patients?

dexemdetomidine

what is the alpha2 agonist commonly used in sedation and analgesia in critically ill patients?

Neuroleptics - Critically ill patients

-haloperidol

-olanzapine

-quetiapine

-risperidone

Sedation and Analgesia Algorithm

-1: intermittent bolus injection of analgesic (e.g., fentanyl)

-2: 1 + continuous IV infusion of analgesic

-3: 1 + 2 + intermittent bolus injection of sedative (propofol, midazolam)

-4: 1 + 2 + 3 + CIVI of sedative (propofol, midazolam, dexmedetomidine)

Excessive Sedation

associated with significant morbidity and potentially mortality

sedation vacation and spontaneous breathing trial

shown to prevent excessive drug accumulation, shorten duration of mechanical ventilation and reduce ICU length of stay

prolonged periods

since many of these patients have impaired hepatic and renal function, sedatives and opiates may accumulate in critically ill patients when given for ______________.

Propofol (diprivan)

-often used for sedation in the ICU

-admin by continuous IV infusion

-affects hemodynamic profile

-titratable, neuro evals

rapid sedation and awakening

Propofol is indicated for patients who require frequent neuro exams because of its short DOA causing what?

Propofol Mechanism

enhances activity of GABA, an inhibitor NT in the CNS

<1 min

what is the onset of propofol?

3-10 min

what is the duration of propofol in short-term use?

Propofol

-shorter ICU length of stay and duration of mechanical vent compared to benzos

-potentially less delirium

-causes hypotension, esp with bolus dosing

-monitor triglycerides weekly

-elim not impaired by hepatic or renal dysfunction

Propofol Related Infusion Syndrome (PRIS)

-rare complication associated with high dose/prolonged use: >80 mg/kg/min and >5-10 days

-acute refractory bradycardia, severe metabolic acidosis, cardiovascular collapse, rhabdo, hyperlipidemia, renal failure and hepatomegaly

-incidence unknown, but prob <1%

-mortality variable but high (33%-66%)

PRIS Tx

discontinuation of propofol infusion and supportive care

Dexmedetomidine

-often used for sedation in the ICU

-admin by continuous IV infusion

-affects hemodynamic profile

-dissociative neurologic state

Dexmedetomidine

-selective a2-adrenergic agonist with sedative and minimal analgesic properties

-shorter ICU length of stay and duration of mechanical vent compared to benzos

-potentially less delirium

-no overwhelming differences vs propofol with outcomes