Exam 3 Drugs

ACS initial therapy

• Morphine

• Oxygen

• Nitroglycerin

• Aspirin

• DC NSAIDS

Morphine

• MOA: opioid agonist (mu receptors)

• indication: pain unrelieved by NG

• decrease pain, O2 demand, preload

• SE: hypersensitivity, hypotension, respiratory depression

• CI: hypotension, respiratory depression, obtundation, confusion

• Monitor: CP, signs of confusion, decreased O2 sat

Oxygen

• indication: O2 < 90%

• monitor: pulse Ox, RR, diaphoresis, CP, ECG

Nitroglycerin

• MOA: activate guanylate cyclase to increase cGMP → vasodilator

• indication: persistent ischemia sx, HF, HTN

• SL/spray → pre hospital

• IV → inpt for pain for 1st 48H

• do not continue at exclusion of BB/ACEi 

• NO MORTALITY benefit

• vasodilator → reduce preload, afterload

• SE: headache, hypotension, tolerance, tachycardia

• CI: sildenafil/vardenafil in past 24H, tadalafil in past 48H; SBP <90, HR <50, right ventricular infarction

• Monitor: BP, DC is SBP drops 30+, headache, flushing

Aspirin

• MOA: irreversible COX inhibitor → antiplatelet by reduction of TXA2

• Indication: immediately before or after presentation to hospital; maintenance antithrombotic

  • not recommended as primary prevention for stroke

• CI: true allergy (airway swelling, treatment required, profound platelet drop, severe bleeding)

• Monitor: s/sx bleeding if platelets low

Clopidogrel

• MOA: irreversible P2Y12 ADP receptor inhibitor → antiplatelet 

  • prodrug

• Indication: LD before PCI, maintenance post ACS

• SE: bleeding, N/V/D, TTP

• CI: active bleeding, severe bleeding risk, hypersensitivity

• monitor: S/Sx bleeding

• PGx: affected by CYP2C19

  • do not use in PM, IM

• Surgery: DC 5 days prior

Prasugrel

• MOA: irreversible P2Y12 inhibitor → antiplatelet

• Indication: in planned PCI for STEMI/NSTEMI

• administer LD during PCI

• SE; bleeding (higher vs. clopidogrel), N/V/D, TTP

• CI: history of stroke/TIA, 75+ yo, planned surgery, unknown coronary anatomy, active bleeding, hypersensitivity

• Monitor: S/Sx bleeding

• Pearls:

  • consider in pts who had stent thrombosis despite aspirin+plavix DAPT, high risk of recurrent MI (DM or prior STEMI)

  • prodrug no PGx

• Surgery: DC 7 days before

Ticagrelor

• MOA: reversible P2Y12 inhibitor

• reduce CVD, stroke, MI, and stent thrombosis mortality vs clopidogrel

• Indication: ACS PCI

• SE: dyspnea, bradycardia, heart block, gynecomastia

• CI: history of intracranial hemorrhage, severe hepatic impairment,active bleeding, bradycardia, strong CYP 3A inhibitor/inducer, fibrinolytics within 48H

• DDI: admin with lovastatin/simvastatin → greater statin related ADE

• Surgery: DC 3-5 days prior

Cangrelor

• MOA: P2Y12 inhibitor → IV antiplatelet

• Indication: adjunct to PCI to reduce risk of periprocedural MI, repeat recascularization, stent thrombosis in pts NOT on P2Y12i/GP2b3ai

• SE; bleeding, renal insufficiency

• CI: hypersensitivity, active bleeding

Heparin

• MOA: bind antithrombin III → inactivate IIa, Xa → inhibit fibrin/ fibrinogen conversion

• Indication: thrombosis prophylaxis, VTE tx, DIC

• SE: bleeding, HIT, hemorrhage, allergy

• DDIs; cephalosporins/penicillins, NSAIDs

• Monitor: CBC (HgB, platelets), aPTT or anti-Xa

  • anti-Xa more specific, but aPTT used in first 48H if pt was on oral Xa inhibitor

Enoxaparin

• MOA: Bind Antithrombin III → inhibit Factor Xa, IIa → inhibit fibrin/fibrinogen conversion

  • more selective for Xa

• Indication: VTE prophylaxis and tx,unstable angina/non-Q-wave MI

• SE: bleeding, HIT, anemia, diarrhea, nausea, thrombocytopenia

• CI: active bleeding, history of HIT, recent stroke, avoid in epidurals, spinal punctures → can cause spinal hematoma leading to paralysis

• Monitor: S/Sx bleeding, CBC (Hb, Plts)

  • anti-factor Xa levels 4H after 4th dose

  • ONLY for: pregnancy, BMI<18.5 or 30+, CrCl<30 or variable

• Pearls: more predictable, longer half-life, and better bioavailability vs heparin

Dalteparin

• LMWH

• same drug info as enoxaparin

Factor Xa inhibitors

• Fondaparinux (Arixtra)

• Rivaroxaban

• Apixaban

Fondaparinux

• MOA: Factor Xa inhibitor (Injectable)

• Indication; STEMI/NSTEMI without PCI, VTE prophylaxis/treatment

• SE; bleeding, nausea, vomiting, constipation, rash, thrombocytopenia, hemorrhage

• CI : CrCl<30, BW < 50 kg (for surgery)

• Monitor: S/Sx bleeding, CBC (Hb, Hct, plts)

• Surgery: DC 24H prior

• Caution: bleeding risk increased in renal impairment and weight <50; needle guard may cause allergic reaction in latex allergy

Rivaroxaban

• MOA: Factor Xa inhibitor

• Indication: VTE prophylaxis in medically ill and surgery, VTE tx, AFib, HIT, PAD with Aspirin

• CI: CrCl <15

• SE: hemorrhage, anemia, thrombocytopenia

• Monitor: CBC (Hgb, platelets), SCr

• Pearls:

  • Once daily missed dose → take as soon as you remember on day, do NOT double

  • BID missed dose → CAN take 2 doses at once (max 2 tabs or 30 mg per day)

  • with food

Apixaban

• MOA: Factor Xa inhibitor

• Indication: VTE prophylaxis and tx

• SE: hemorrhage, anemia, thrombocytopenia

• Monitor: CBC (HgB, platelets)

• pearls:

  • no renal adjustment

  • with or without food

Edoxaban

• MOA: factor Xa inhibitor

• Indication: VTE treatment AFTER 5-10 days parenteral anticoag

  • not rec in mechanical heart valves, moderate-severe mitral stenosis

• SE: Hemorrhage, anemia, thrombocytopenia

• Monitor: CBC (HgB, platelets), SCr

Warfarin

• MOA: Vitamin K antagonist → blocks gamma-carboxylation of prothrombin → inhibit II, VII, IX, X and proteins C/S

• Indication: VTE prophylaxis/tx, MI, AFib, mechanical prosthetic valves 

• SE: hemorrhage, necrosis, hypercoagulation, birth defects, abortion, atheroembolism (purple toe syndrome)

• Monitor: INR, CBC (HgB, Platelets)

• Pearls:

  • must bridge with parenteral for 5 days and 2 consecutive INRs at goal bc protein C/S inhibited before clotting factors

  • contraindicated in pregnancy

  • consistent intake of vitamin K foods

• PGx:

  • Direct target for PD: VKORC1

    • sensitivity at drug target

    • decreased fx → greater sensitivity → lower dose

    • most commonly mutated in white

  • Indirect target for PD: CYP4F2

    • those with decreased fx → more vitamin K available → need higher dose

    • affects vitamin K in cycle

  • Metabolized by CYP2C9

    • Black pts → screen for *5, *6, *8, *11 for decreased fx

• DDI: Amiodarone → decrease warfarin dose 30-50%; antibiotics, antifungals

Dabigatran

• MOA: direct thrombin (IIa) inhibitor

• Indication: VTE prophylaxis, treatment after 5-10 days of parenteral anticoagulation

• SE: bleeding, GI effects, hypersensitivity

• Monitor: CBC (HgB, platelet), SCr

• CI: CrCl < 30 or dialysis, CrCl <50 with P-gp inhibitors

• DDIs

  • PgP inducers (avoid)

  • PgP inhibitors: increase exposure, avoid if CrCl < 50

• Storage

  • keep in original container

  • good for 4 months after opening

  • swallow whole with full glass of water

Argatroban

• MOA: direct thrombin (IIa) inhibitor

• Indication: HIT treatment, pref in renal dysfunction

  • IV

• SE: bleeding

• CI: active bleeding

• Monitor: S/Sx bleeding, CBC (Hb, hct, plts), hepatic fx (dose adjust)

Bivalirudin

• MOA: direct thrombin (IIa) inhibitor

• Indication: HIT tx, pref in liver dysfunction, PCI

  • IV

• SE: bleeding, hypotension

• CI: active bleed

• Monitor: S/Sx bleeding, CBC (Hb, Hct, plts), dose adjust for renal fx

• Surgery: DC 3H prior

GPIIb/IIIa inhibitors

• Abciximab

• Eptifibatide

• Tirofiban

Abciximab

• MOA: GPIIb/IIIa inhibitor → anti-platelet

• Indication: STEMI PCI

  • not routine, use for pts undergoing PCI with large thrombus burden

  • bailout therapy

• SE: bleeding, hypotension, Thrombocytopenia

• CI: active bleeding, thrombocytopenia, prior stroke, use for medical management

• no renal adjustment (cleared by reticuloendothelial system)

Eptifibatide

• MOA: GPIIb/IIIa inhibitor → anti-platelet

• Indication: STEMI PCI, NSTEMI PCI

  • bailout therapy

• SE: bleeding

• CI: active bleeding, thrombocytopenia, prior stroke

• Monitor: SCr (reduce by 50% if CrCl < 50)

Tirofiban

• MOA: GPIIb/IIIa inhibitor → anti-platelet

• Indication: STEMI PCI, NSTEMI PCI

  • bailout therapy

• SE: bleeding

• CI: active bleeding, thrombocytopenia, prior stroke

• monitor: SCr (reduce by 50% if CrCl < 30)

Dipyridamole

• MOA: PDE inhibitor, adenosine reuptake inhibitor → increase cAMP in platelet → antiplatelet 

• Indication: adjunct to warfarin, stroke prevention

• SE: hypotension, headache, rash

Fibrinolytics

• Alteplase, Reteplase, Tenecteplase

• MOA: tissue plasminogen activator (convert plasminogen to plasmin to degrade fibrin)

  • tenecteplase more specific to fibrin, resistant to PAI-I, longer half-life (given as IV bolus)

• Indication: Acute STEMI (wihin 12H of onset), PE, Acute ischemic stroke (within 4.5H onset)

  • must be 18+, Blood glucose > 50, BP < 185/110

• SE: bleeding, reperfusion arrhythmias, cholesterol embolization after reperfusion, anaphylaxis (more w streptokinase)

• CI: any prior intracranial hemorrage, known structural cerebrovascular lesions, malignant neoplasms, ischemic stroke within 3 months, active bleeding, significant closed head trauma within 3 months

• Monitor: CBC (Hb, Hct), Pt/PTT, fibrinogen levels

Cilostazol

• MOA: PDE3 inhibitor → increase cAMP → vasodilator, anti-platetet

• Indication: claudication, improve sx and increase walking distance

  • DC if no improvement after 3 months

  • ideally, try smoking cessation and exercise therapy first

• SE: headache, tachycardia, diarrhea, decreased survival in CHF, palpitations, peripheral edema, thrombocytopenia/leukopenia

• CI: Heart failure

• PK:

  • highly protein bound

  • major substrate of CYP 3A4, 2C19

    • decrease to 50mg BID with inhibitors

  • smoking decreases exposure by 20%

Vorapaxar

• MOA: PAR-1 receptor antagonist → inhibit platelet

• indication: uncertain role as adjunct with aspirin or clopidogrel in symptomatic PAD

• SE: bleeding

• CI: history of stroke, TIA, or intracranial hemorrhage, active pathological bleeding

• Monitor: bleeding, no renal adjustment needed, not rec in severe hepatic impairment

• PK: 

  • highly protein bound

  • major 3A4 substrate

    • avoid use with strong inhibitors/inducers

  • 8 day half life

  • fecal elim

Endothelin-1 Receptor Antagonist

• Ambrisentan, Macitentan, Bosentan

• first-line for PAH combined with PDE-5i

• MOA: bind to ETa receptor → prevent vasoconstriction

• SE: headache, flushing, increased liver enzymes, leg edema, decreased hemoglobin

• CI: pregnancy (teratogenic)

• Pearls: REMS program

Ambrisentan

• ETRA

• selective for ETa

• non-sulfonamide

• propanoic-acid class

Bosentan

• ETRA

• black box warning for liver injury

• reduce dose or stop tx if LFTs 3-5x upper limit

• may introduce if LFTs return to pretx levels

• monitor LFTs at baseline, then monthly

• sulfonamide

Macitentan

• ETRA

• sulfamide

• 50x increased ETa selectivity, longest half life → non-competitive inhibitor

Riociguat

• MOA: soluble guanylate cyclase stimulator →increase NO → vasodilator

• SE: headache, flusing, dyspepsia, nasal congestion, UTI, diarrhea, dizziness

• Ci: pregnancy, with PDE-5 inhibtiors

• pyrazolopyridine with aminopyrimidine, organofluorine compound, and carbamate ester

PDE-5 Inhibitors

• sildenafil, tadalafil

  • sildenafil is IV and PO

• MOA: inhibit PDE-5 →vasodilator

• Indication: first line for PAH dual therapy with ETRA

• SE: headache, flushing, dyspepsia, nasal congestion, UTI, diarrhea, dizziness, vision changes, backpain, myalgia

• CI: with nitrates or riociguat, bosentan decreases conc

Sildenafil

• PDE5 inhibitor

• tablet and IV

• mimics cGMP purine ring

• pyrazolopyrimidine

• high selectivity for PDE5

• cannot use nitroglycerin within 24h of use

Tadalafil

• PDE5 inhibitor

• tablet

• pyrazinopyridoindole, benzodioxole

• carboline-based compound with vasodilatory activity

• cannot use nitroglycerin within 48H of use

Prostacyclin Receptor Agonist Analogues

• Epoprostenol, Treprostinil, Iloprost, Selexipag

• MOA: bind to prostacyclin receptor and activate Gs-AC-cAMP-PKA pathway → vasodilation

• Indication: for class ¾ PAH

• SE: headache, flushing, palpitation, jaw pain, bone pain, orthostatic hypotension, blood stream infection

Epoprostenol

• Prostacyclin analogue

• short half life → continuous IV

• may cause SOB, worsened eye pressure, worsened urinary retention

Iloprost

• prostacyclin analogue

• inhaled

• half life ~ 30 min

Treprostinil

• prostacyclin analogue

• SC, IV, Inhalation

• 4H half life

Selexipag

• prostacyclin analogue

• prodrug

• PO

• not routinely prescribed, more freq DC due to SE

• better to introduce earlier (6 months) with other agents

Sotatercept

• MOA: activin signaling inhibitor → anti-proliferative

• recombinant DNA biologic

  • extracellular domain of ActRIIa

  • Fx domain of IgG

• Indication: adjunct to current therapy, not monotherapy

  • SC Q21 days

• SE: headaches, epitaxis, rash, diarrhea, dizziness, erthema, erythrocytosis, thrombocytopenia, bleeding, impaired fertility

• CI: pregnancy (fetal tox)

Calcium Channel Blockers

• DHP → Amlodipine, nifedipine, nicardipine, clevidipine

• Non-DHP → diltiazem, verapamil

• Indication: firstline Raynoud’s (DHP), positive vasoreactors in PAH, first-line HTN, useful in isolated systolic HTN

  • nicardipine, clevidipine → cross BBB, pref in stroke

  • use nifedipine, amlodipine, or diltiazem for PAH(do not use verapamil bc negative inotrope, negative chronotrope)

• SE: peripheral edema, flushing/heat sensation, syncope, palpitation, hypotension

  • do not use NonDHP in LV dysfunction

Amlodipine

• DHP CCB

• strong affinity for cell membranes

• long-acting

Nifedipine

• DHP CCB

• inhibitor of L-type voltage gated calcium channels

• long acting

Diltiazem

• non-DHP CCB

• slow acting

• binds to extracellular site of alpha-1C subunit of channel IV or S6 segment of domain III

• requires voltage-induced conformation change

FXIa inhibitors

• asundexian, milvexian

• new PO DOACS

• target intrinsic pathway of coagulation

• potentially safer than current DOACs (FXI may be essential for thrombosis but dispensable for hemostasis)