Cardiovascular Medications: Overview

Cardiovascular Medications

• Learning objectives involve identifying indications, mechanisms of action (MOA), adverse events, and therapeutic considerations for various cardiovascular medications.

Cardiac Medications

• Medications can be categorized as nitrates, anti-thrombotics, statins, and anti-arrhythmics.
• Nitrates are used for ischemic conditions like angina and myocardial infarction (MI).
• Anti-thrombotics, including antiplatelets and anticoagulants, prevent clot formation in conditions like atrial fibrillation, MI, cerebrovascular accident (CVA), deep vein thrombosis (DVT), and pulmonary embolism (PE).
• Fibrinolytics are "clot busters" used in CVA.
• Statins reduce cholesterol and treat atherosclerosis.
• Anti-arrhythmics treat heart arrhythmias.

Angina Treatment Options

• Common drugs for angina pectoris treatment include vasodilators (nitrates, calcium blockers) and cardiac depressants (beta-blockers).

Nitrates

• Nitrates directly act on vascular smooth muscle, leading to relaxation of blood vessels and vasodilation.
• They reduce preload and afterload, decreasing the heart's workload and oxygen demand.
• Nitrate forms include IV, sublingual spray, chewable tablets, oral tablets, and topical transdermal patches.
• Sublingual nitrates are the drug of choice for acute angina attacks, providing immediate symptom relief.

About Sublingual Nitroglycerine

• Sublingual nitroglycerin should be stored in a glass brown bottle to limit light exposure.
• It has a short shelf life of 6 months if unopened, and 3 months once opened.
• A tingling sensation indicates that the drug is active.
• After the first dose, relief should occur within 1-2 minutes.
• A second dose can be taken if symptoms persist after 5 minutes, up to 3 doses in 15 minutes.
• Lack of relief may indicate a possible MI.
• Adverse effects (AE) include reflex tachycardia, dizziness, orthostatic hypotension (OH), and weakness.

Management of Unstable Angina/MI

• When a cardiac event is suspected, immediately chew 325 mg of non-enteric coated aspirin.
• Up to 3 doses of nitroglycerin can be administered over 15 minutes and IV nitroglycerin may be started in the emergency department (ED).
• ECG determines the type of cardiac event (STEMI vs NSTEMI).
• STEMI (ST segment elevation MI) treatment includes a thrombolytic agent, aspirin, nitrates, and beta-blockers.
• Clopidogrel, GP IIb/IIIa inhibitors, and LMWH may also be given.
• NSTEMI (non-ST segment elevation MI) treatment involves heparin instead of thrombolytics.

Antithrombotics

• Antiplatelets prevent thrombus formation, including aspirin and ADP receptor inhibitors.
• Anticoagulants prevent initial thrombus formation and extension of existing thrombi.
• Parenteral anticoagulants include heparin, LMWH, direct thrombin inhibitors, and fondaparinux.
• Oral anticoagulants include Vitamin K antagonists, direct thrombin inhibitors, and Factor Xa inhibitors.
• Fibrinolytics lyse active thrombi, including alteplase, tenecteplase, reteplase, urokinase, and streptokinase.
• All antithrombotics carry a risk of bleeding.
• Antithrombotic drugs target different components in thrombus formation.
• Antiplatelets target the primary component in arterial thrombosis ("white clot").
• Anticoagulants target the primary component in venous thrombosis ("red clot").
• Fibrinolytics target platelets and fibrin.
• A thrombus forms when fibrin binds platelets together.
• Fibrin is formed through a pathway that starts with collagen and von Willebrand factor involving ADP and thromboxane A2, which antiplatelet drugs act on.
• Platelet-fibrin is formed through another pathway that anticoagulation drugs act on.

Coordinated Role of Platelets and the Coagulation System in Thrombogenesis

• Vascular injury occurs, exposing collagen and von Willebrand factor (VWF).
• Platelets adhere to collagen and VWF, releasing ADP and thromboxane A2.
• ADP and thromboxane A2 recruit more platelets, which are then activated.
• Glycoprotein IIb/IIIa receptors undergo a conformational change leading to more platelet aggregation.
• Vascular injury exposes tissue factors.
• Tissue factor triggers the coagulation pathway and thrombin generation.
• Thrombin recruits more platelets and converts fibrinogen to fibrin.
• Fibrin binds platelets together to form the platelet/fibrin thrombus.

Location of Medication Impact

• Aspirin inhibits COX-1 and TXA2.
• Clopidogrel, prasugrel, ticagrelor, and cangrelor inhibit ADP.
• Vorapaxar inhibits thrombin.
• Abciximab, eptifibatide, and tirofiban inhibit GPIIb/IIIa activation.

Aspirin

• Aspirin inhibits both COX-1 and COX-2, reducing production of thromboxane A2 and inhibiting platelet aggregation.
• At low doses (81 mg), aspirin primarily inhibits COX-1 for cardiovascular protection.

ADP Receptor Inhibitors (Irreversible)

• Clopidogrel (Plavix) and prasugrel (Effient) are irreversible ADP receptor inhibitors.
• The active metabolite irreversibly blocks ADP receptor binding, decreasing platelet aggregation for the platelet's lifespan (7-10 days).
• They are used after acute coronary syndrome (ACS) with percutaneous coronary intervention (PCI) and stroke.
• ACS includes NSTEMI, STEMI, and unstable angina (UA); PCI is a percutaneous coronary intervention.
• ADP receptor inhibitors are generally well-tolerated, but bleeding is a major concern, requiring monitoring of symptoms and labs (Hgb/Hct).
• Focus is on clopidogrel (Plavix).
• Metabolism involves CYP2C19 to active metabolite.
• Boxed warnings indicate decreased efficacy in some genetic variants with CYP2C19 poor metabolizers (present in 50% of Asians, 30% of African-Americans, and 25% of Caucasians).

ADP Receptor Inhibitors (Reversible)

• Ticagrelor (Brilinta) is a reversible inhibitor.
• It reversibly binds the ADP receptor on the platelet surface, decreasing platelet aggregation.
• It is used for ACS (up to 1 year or more after MI).

Anticoagulants

• Parenteral anticoagulants include heparin and low-molecular weight heparin (LMWH) like enoxaparin (Lovenox).
• Oral anticoagulants (PO) include vitamin K antagonists like warfarin (Coumadin), direct thrombin inhibitors like dabigatran (Pradaxa), and Factor Xa inhibitors like rivaroxaban (Xarelto) and apixaban (Eliquis).
• Direct oral anticoagulants (DOACs) are all renally eliminated.

Simplified Coagulation Cascade

• Fibrin acts as a "mesh" to create a clot and must be converted from fibrinogen.
• Tissue factor (TF) is exposed after injury.
• TF along with activated factors (F) VIIa, IXa, Xa, VIIIa, and Va convert prothrombin to thrombin (factor IIa).
• Thrombin (FIIa) then converts fibrinogen to fibrin.

Heparin

• Heparin can be administered IV or subcutaneously.
• It potentiates the action of antithrombin, inactivating thrombin and factors FIXa, FXa, FXIa, FXIIa, which prevents the conversion of fibrinogen to fibrin.
• Treatment doses require monitoring of aPTT levels.
• Heparin-induced thrombocytopenia (HIT) occurs when the body creates antibodies that bind to heparin on the platelet surface, activating platelets, causing clotting, and lowering platelet levels.
• It is treated with direct thrombin inhibitors or Factor Xa inhibitors.

LMWH

• LMWH can be administered IV or subutaneously, including enoxaparin (Lovenox), tinzaparin (Innohep), and dalteparin (Fragmin).
• Like heparin, LMWH potentiates the action of antithrombin but has a greater effect on inhibiting FXa than thrombin.
• It is preferred over heparin because of more simple dosing, no monitoring required, and a lower risk of HIT.

Warfarin-Vitamin K Antagonist (VKA)

• Warfarin (Coumadin) is administered orally.
• Active vitamin K is required for the synthesis of factors VII, IX, X, and II, and proteins C and S.
• Warfarin binds to VKORC1, an enzyme that converts inactive vitamin K to active vitamin K, leading to depletion of vitamin K stores, thus inhibiting the synthesis of factors VII, IX, X, and II.
• Warfarin does not have an immediate effect, requiring 3-5 days for full effect and longer to stabilize the dose.
• Doses may be frequently changed and even vary based on the day of the week.
• As a narrow therapeutic index (NTI) drug, requires frequent monitoring of international normalized ratio (INR; normal ~1).
  • An INR of 2-3 is needed for atrial fibrillation (AF) or venous thromboembolism (VTE).
  • An INR of 2.5-3.5 is needed for mechanical heart valves.
• If INR is low, the patient is at risk for increased clot formation.
• Effects are metabolized by CYP2C9; genetic variants of CYP2C9 and VKORC1 can increase bleeding risk unless the dose is adjusted.
• It has many drug interactions and food interactions and important to maintain a stable intake of Vitamin K containing food.

Direct Thrombin Inhibitors

• Dabigatran (Pradaxa) is an oral direct thrombin inhibitor.
• It binds directly and reversibly to thrombin with high selectivity, inhibiting the conversion of fibrinogen to fibrin.
• There is less intracranial bleeding compared to warfarin, but more GI bleeding; high risk of GI bleeding in people over 75 years old.
• Other adverse effects include dyspepsia (10%), which can be minimized by taking it with food.

Factor Xa Inhibitors

• Rivaroxaban (Xarelto) and apixaban (Eliquis) are oral Factor Xa inhibitors
• Selectively and reversibly bind FXa stopping further coagulation cascade
• There is less intracranial bleeding than warfarin but rivaroxaban has more gi bleed.
• All DOACs : shorter duration of action than warfarin so less preferred if the patient is not compliant but is more convenient when needing to hold it before a procedure.

Monitoring with Antiplatelets and AntiThrombotics

• BLEEDING:
  • Bleeding around gums when brushing teeth.
  • Black, tarry stool. -Blood in urine. -Some bruising expected but excessive bruising that lingers.
  • Seek medicine help if nosebleed or a cut won't stop bleeding.
  • Seek medicine help if hit head during a fall.
• CLOTTING:
  • Red, swollen, warm extremity, usually unilateral and in calf.
  • SOB, chest pain, cough.

Fibrinolytics(AKA-thrombolytics)

• Clot-busters: alteplase, tenecteplase, reteplase, urokinase, streptokinase are most commonly administered through IV.
• MOA
  • Mimic endogenous tissue plasminogen activator (TPA) converts plasminogen to plasmin= plasmin breaks fibrin links in the thrombus and used to treat after stroke, MI PE

Therapeutic Concerns about Anti-thrombotic Drugs

• FALLS: Even an "easy" fall could cause significant interal bleeding.
• PT treatments: Debridement, techniques, DTM/percussion CONTRAINDICATED.
• Observe for: Nosebleeds, bruising, pain in back, abdomen, joints (internal bleeding).
• Heparin and warfarin vs LMWH are more high risk:
  • lab values need to be considered: PT PTT, aPTT and INR
  • aF/DVT/PE 2.0-3 greater risk of bleeding

Atherosclerotic Medications

• Atherosclerosis is a narrowing and hardening of the arteries.
• Atherosclerosis is when lipoproteins in the blood are made of triglycerides and cholesterols and are made of VLDL, LDL, HDL
• In simplified terms low LDL's are good( less likely to oxidize and form plaques) and high HDL is good) takes up LDL from peripheral tissues and transports back to the liver.
• Goal is to reduce risk of MI and stroke

Statins

• Statins block HMG-COA reductase which blocks cholesterol synthesis
• Common AE: myaligia
  • Large proximal muscle group
    • Likely with lower doses
    • Likely with pravastatin, rosuvastatin because more hydrophilic
    • Likely in elderly female, low BMI, Asian descent, excess alcohol, high levels physical activity and trauma, and combo with interacting meds
    • Myopathy/rhabdomyolisis is rare - more risk with drug-drug interactions(Especially fibrates)
• Myositis/Myalgia presents with muscle pain, fatigue/ weakness, creatinine kinase (Ck) > 10 times upper normal limit.
• Persists muscle effects/ degree to which statins unmask vs induce muscle disease is unclear. Exacerbates known muscle conditions (1.e M.G).

Therapeutic Concerns with Statins

• Grapefruit juice inhibits CYP3A4 that is linked to statin rhabdomyolysis
  • There's also a CYP3A4 competition for common metabolic pathway which means polypharmacy increases competition which increases statin concentration= dose - related statin AE
  • If CYP3A4 inhibits- 6 fold increase associated with hospitalizations with myopathy from rhabdomyolysis in pt with lipid therapy.
  • Liver/Kidney function can affect pharmacokinetics= Differences in CYP pathways leads to altered pharmacokinetics

Arrhythmia and Antiarrhythmic Medications

• Arrythmia or dysrhythmia- disturbance of heart rate or rhythm to an abnormal rate of impulse from the SA node/abnormal conduction of impulses.
  • Classified by origin: Ventricular or atrial(supraventricular); Pattern Fibrillation/ flutter

Cardiac Arrythmias: Disturbance of Rate or Rhythm

• Sinoatrial node = responsible for regulating the number of heart beats/rhythm