Drugs for Pulmonary Hypertension and DVT/PE (Wolff)

Question 1

What are the 5 drug classes used to treat Pulmonary Hypertension? (P/EA/PI/GCS/C)

Answer 1

prostanoids, endothelin antagonists, PDE 5 inhibitors, Guanylate cyclase sensitizers, CCBs

Question 2

What are the 4 Prostanoids used for Pulmonary Hypertension? (E/T/I/S)

Answer 2

epoprostenol
treprostinil
iloprost
selexipag

Question 3

What are the 3 Endothelin antagonists used for Pulmonary Hypertension? (B/A/M)

Answer 3

bosentan
ambrisentan
macicentan

Question 4

What are the 2 PDE 5 inhibitors (S/T) and what is the 1 guanylate cyclase sensitizer (R) used for Pulmonary Hypertension?

Answer 4

PDE 5 –> sildenafil and tadalafil

GCS –> riociguat

Question 5

What is a known genetic mutation that is linked to PAH and what are two drugs that can cause PAH? (Fen/Phen)

Answer 5

Genetics: BMPR2 (bone morphogenic protein receptor 2)
- seen in < 25% of idiopathic PAH

Drugs: fenfluramine/phentermine
- weight loss pills

Question 6

What is the difference between these WHO FC for PAH:

Class 1
Class 2
Class 3
Class 4

Answer 6

1. pulmonary HTN without resulting limitation of physical activity
2. pulmonary HTN with SLIGHT limitation of physical activity; ordinary activity causes symptoms
3. pulmonary HTN with MARKED limitation of physical activity; less than ordinary activity causes symptoms; still comfortable at rest
4. pulmonary HTN with INABILITY to carry out physical activity without symptoms; manifest signs of RIGHT HEART FAILURE

Question 7

What is the Vasopressor Test and what are positive findings?

Answer 7

• recommended that Group 1 PAH undergo vasopressor testing; administration of short-acting vasodilators

(+) = PAP dec. > 10 mmHg, MPAP < 40 mmHg, or CO is unchanged or increased

• see more response from idiopathic, familial, or anorexigen-induced PAH

50% of these patients benefit from treatment with CALCIUM CHANNEL BLOCKERS - nifedipine, diltiazem, amlodipine

Question 8

Epoprostenol

What is its MOA, what is it used for, how is it administered, and what is its major serious adverse effect?

Answer 8

MOA: mimics endogenous prostacyclin –> vascular relaxation/inhib. platelet agg. and exerts effects by binding to G-protein on cell membrane to generate cAMP; used for PAH

• administered as continuous IV due to 6 minute half-life; used with pump that can keep the drug COLD

AE: sepsis due to chronic catheter

Question 9

Treprostinil

What is its MOA, what is it used for, how is it administered, and what is its major adverse effect?

Answer 9

MOA: mimics endogenous prostacyclin –> vascular relaxation/inhib. platelet agg. and exerts effects by binding to G-protein on cell membrane to generate cAMP; used for PAH

• administered with pump IV in dilution 1:2 and DOESN’T require refrigeration; has 4 hour half-life
  
  • used to be SubQ but was too painful

AE: sepsis due to chronic catheter

Question 10

Iloprost

What is its MOA, what is it used for, how is it administered, and what is its major adverse effect?

Answer 10

MOA: mimics endogenous prostacyclin –> vascular relaxation/inhib. platelet agg. and exerts effects by binding to G-protein on cell membrane to generate cAMP; used for PAH

• administered by INHALATION 6-9x day

AE: fainting due to hypotension (especially if SBP < 85 mmHg)

Question 11

Selexipag

What is its MOA, what is it used for, and how is it administered?

Who benefits from this medication?

Answer 11

MOA: mimics endogenous prostacyclin –> vascular relaxation/inhib. platelet agg. and exerts effects by binding to G-protein on cell membrane to generate cAMP; used for PAH

• administered ORALLY twice daily, but is EXPENSIVE

kids with PAH and/or their caregivers often refuse central line for IV, so this is a good alternative

Question 12

Bosentan

What is its MOA, what is it used for, how is it administered, and what are its two serious adverse effects?

What are two drug interactions this drug has?

Answer 12

MOA: nonspecific ETa and ETb endothelin receptor blocker used for PAH

• administered ORALLY

AE: hepatotoxicity and teratogenesis

DI: accelerates metabolism of WARFARIN and ORAL CONTRACEPTIVES
- all patients MUST use 2 forms of birth control

Question 13

Ambrisentan

What is its MOA, what is it used for, how is it administered, what is its serious adverse effect?

What are its drug interactions?

Answer 13

MOA: selective ETa receptor blocker used for PAH

• administered ORALLY

AE: teratogenesis (does NOT DAMAGE LIVER)

DI: does NOT accelerate Warfarin or oral contraceptive metabolism, but pts should STILL USE 2 forms of contraception

Question 14

Macitentan

What is it and what is its half-life?

Answer 14

• non-selective Endothelin Antagonist

- half-life of 18 hrs allows for one/day dosing

Question 15

Sildenafil

What is its MOA, what is it used for, how is it administered, and what are its 3 most common complications (H/F/D)?

What is Tadalafil?

Answer 15

MOA: selectively blocks phosphodiesterase Type 5, an enzyme that breaks down cGMP, and is used to treat PAH

• administered ORALLY with a 4 hr half-life

AE: headache, flushing, dyspepsia

• mild hypotension when used alone
• inc. hypotension with alpha-blockers/nitrates

Tadalafil = LONGER half-life than Sildenafil

Question 16

Riociguat

What is its MOA, what is it used for, how is it administered, and what are its two major adverse effects?

Answer 16

MOA: sensitizes soluble guanylate cyclase to NO by stabilizing NO-sGC binding AND directly stimulates sGC independent of NO; used to treat PAH and type 4 PH

• administered ORALLY with half-life of 12 hours

AE: may cause fetal harm and should NOT be administered with NO donors or Type 5 PDE inhibitors

Question 17

What is a very common PAH drug combination used to PAH patients?

Answer 17

tadalafil + ambrisentan

Question 18

What are 3 Tissue-type Plasminogen Activator Drugs that can be used for thrombus busting? (A/R/T)

How do these drugs work?

Answer 18

TpD = Alteplase, Reteplase, Tenecteplase
- all end in suffix “-teplase”

• activate plasminogen in thrombus ONLY

Question 19

What are the 5 Parenteral indirect thrombin/Xa inhibitors that can be used for DVT and PE? (H/E/D/T/F)

Answer 19

heparin

enoxaparin, dalteparin, tinzaparin

fondaparinux

Question 20

What are the 2 Parenteral direct thrombin inhibitors that can be used for DVT and PE? (B/A)

Answer 20

bivalirudin, argatroban

Question 21

DVT and PE Drug Treatment

What is the Oral coumarin derivative?

What are the 3 Oral direct Factor Xa inhibitors? (R/A/E)

What is the Oral direct thrombin inhibitor?

Answer 21

CD: warfarin

XaI: ribaroxaban, apixaban, endoxaban

TI: dabigatran

Question 22

Heparin

What is its MOA, what does it block, and what is its antidote?

How does it affect pregnancy?

Answer 22

MOA: binds to/activates antithrombin III to inhibit Factor Xa and thrombin (blocks generation and inactivates thrombin)

• large negative charge, cannot cross membranes

Antidote: Protamine
Pregnancy: doesn’t cross placenta, so CAN use in pregnancy

Question 23

Heparin

What are 3 major contraindications to use? (T/B/S)

What is Heparin-induced Thrombocytopenia?

Answer 23

1. thrombocytopenia
2. uncontrollable bleeding
3. surgery involving brain, eye, spinal cord

Heparin-induced Thrombocytopenia

• reduced platelet counts w/paradoxical inc. in thrombotic events
• Abs to heparin-platelet complexes

LMW heparins can also cause thrombocytopenia and severe bleeding

Question 24

Enoxaparin, Dalteparin, Tinzaparin

What is their MOA, what are they used for, and what is their antidote?

How do they affect pregnancy?

Answer 24

MOA: shorter length heparin molecules that selectively block Factor Xa but NOT thrombin; used for DVT and red thrombus prevention

• FIRST CHOICE TREATMENTS FOR DVT
• easier to use (can be used at home; long 1/2 lives)

Antidote: protamine
Pregnancy: SAFE

Question 25

Fondaparinux What is its MOA, what is it used for, and what is its antidote? How is it administered and what does it NOT potentially cause in patients?

Answer 25

MOA: synthetic pentasaccharide that selectively inhibits Factor Xa and prevents DVT - more effective than Enoxaparin, but inc. bleeding risk - can be used in conjunction with Warfarin - administered SubQ with 17-21 hr 1/2 life Antidote: NONE (not affected by protamine) - does NOT cause Heparin-induced Thrombocytopenia

Question 26

Bivalirudin (Hirudin-analog) What is its MOA, what drug is it commonly used with, and how is it administered? What is its antidote?

Answer 26

MOA: synthetic peptide that directly (reversibly) inhibits thrombin; given w/GP IIb/IIIa antagonists in pts. undergoing coronary angioplasty - must be given IV like heparin (expensive though!!) Antidote: NONE

Question 27

Argatroban What is its MOA, what is it used for, and how is it administered? What patient population is it used in?

Answer 27

MOA: directly binds to catalytic site of thrombin and reduced new thrombus development, specifically pts. with Heparin-induced thrombocytopenia - treatment monitored with aPTT - given IV (short half-life)

Question 28

Warfarin What is its MOA, what is it used for, and what is it NOT useful for? What is a consideration when using this drug?

Answer 28

MOA: vitamin K antagonist that dec. production of active forms of calcium-dependent clotting factors (2, 7, 9, 10) and protein C/S (anti-clotting factors) - for long-term thrombosis prophylaxis - for mechanical heart valves and atrial fibrillation - NOT useful for emergencies (delayed effects) **remember: slow onset and slow offset, monitor frequently when other drugs are added/subtracted**

Question 29

Warfarin What is a major complication of use and how can it be corrected? What is its effect in pregnancy?

Answer 29

MC: BLEEDING; if occurs, discontinue immediately - effects can be reversed with Vitamin K (12-24 hrs) - give fresh blood for quick change - can cause cutaneous necrosis (loss of Protein C causes procoagulant state) Pregnancy: DO NOT USE ON PREGNANT PTS - crosses the placenta **has greatest affects on Factor VII and Protein C**

Question 30

Rivaroxaban (Apixaban, Endoxaban) What is its MOA, what are its 2 uses, and what is its antidote? How does it affect pregnancy?

Answer 30

MOA: direct inhibitor of Factor X (binds in active center); used for DVT prevention and stroke prevention in pts with nonvalvular A Fib (not as good w/mechanical valve) Antidote: andexanet alfa Pregnancy: appears UNSAFE - do NOT use with other anticoagulants - avoid in pts. with renal/hepatic involvement

Question 31

Dabigatran What is its MOA, what is it used for, and what is it contraindicated in? What is its antidote?

Answer 31

MOA: reversible direct thrombin inhibitor that has advantages over Warfarin (no monitor, lower bleeding risk, same dosing) - used for stroke and systemic embolism prevention - in pts. with nonvalvular Atrial Fibrillation CI: pts. with MECHANICAL HEART VALVES - also pills are unstable (bleeding major concern) Antidote: idarucizumab

Question 32

What is definitive imaging used to diagnose PE?

Answer 32

CT Pulmonary Angiography

Question 33

What are two surgical preventative measures for DVT and PE?

Answer 33

1. IVC filter used to break apart thrombi | 2. stent placement in common iliac veins to help keep them open

Question 34

What is the treatment for PE due to air?

Answer 34

- position patient in left later decubitus position with head down OR use Trendelenburg machine to avoid further venous embolization - immediately administer high flow oxygen/mechanical ventilation --> inc. rate with which the embolized air is resorbed - secure access for administration of IV fluids and/or vasopressors to restore adequate tissue perfusion

Question 35

What is the treatment for PE due to fat?

Answer 35

- no definitive treatments available; treatment is largely supportive while fat emboli resolve spontaneously - can give fluid resuscitation, oxygenation, rare use of vasopressors +/- noninvasive/invasive mechanical support - corticosteroids and heparin are NOT commonly used