CHF and Other CV Drugs PDF

Pharmacotherapeutics 10.22.24 Congestive Heart Failure F sympatheticoverload heartisnteffective hastoworkharder norep THRTBP Drugs that are used for CHF have 2 primary goals: ◦ Improve the myocardial contraction force – positive inotrop...

Pharmacotherapeutics 10.22.24 Congestive Heart Failure F sympatheticoverload heartisnteffective hastoworkharder norep THRTBP Drugs that are used for CHF have 2 primary goals: ◦ Improve the myocardial contraction force – positive inotropic agents ◦ Decrease cardiac workload – by affecting the heart or peripheral vasculature or by controlling fluid volume I increashtractivity reduce sympatheticinnervation HR reduces heartworksmoreeffectively Congestive Heart Failure Drugs that increase myocardial contraction force (+ inotropic agents) ◦ Cardiac Glycosides – Digoxin ◦ Adrenergic drug ◦ PDE inhibitors Agents that decrease cardiac workload ◦ ACE inhibitors ◦ ARBs ◦ Beta Blockers ◦ Diuretics (spironolactone) ◦ Vasodilators ◦ Entresto firstline for CHF ◦ SGLT-2 inhibitors Drug Breakdown for CHF  There are 2 cardiac glycosides: digoxin and digitoxin Only digoxin (Lanoxin) is used in the U.S. don'thaveto knowwhy Digoxin improves pumping action of the heart Increases cardiac output at rest and with exercise increasescalcium concentration in Increases exercise tolerance because the heart is able to myocardium pump more effectively initiation Not used as a primary agent for treatment Digoxin Decreases the symptoms of heart failure and the number of hospitalizations with CHF Works by increasing intracellular calcium concentration which facilitates interaction between actin and myosin filaments in the myocardial cell Digoxin Not only affects contractility, but also has an inhibitory effect on the sympathetic nervous system ◦ This decreases the stress on the failing heart ◦ Slows the HR ◦ Slows impulse conduction through the heart (slows AV node conduction) ◦ Because of this it can also be used to treat certain arrhythmias Digoxin  Digoxin Toxicity ◦ Potentially fatal reaction to high doses of this drug ◦ Narrow TI ◦ Signs of toxicity: ◦ GI distress (nausea, vomiting, diarrhea) common Nystagmus ◦ CNS disturbances (drowsiness, fatigue, confusion, visual disturbances) ◦ Abnormalities in cardiac function (arrhythmias, premature ventricular contractions, v-tach, heart blocks) ◦ As toxicity increases V-fib and death could occur is c ◦ Antidote ◦ DigiFab Digoxin Adverse Effects Renin-Angiotensin System Renin-angiotensin system is often activated in patients who have CHF how This causes vasoconstriction which increases the work of the heart even more This activation also stimulates aldosterone production which stresses the cardiovascular system more because salt and water are retained Very successful in treating HTN Successful in treating CHF when the heart failure is due to reduced L ventricular function (systolic heart failure) Decrease mortality in those with CHF ◦ Have been shown to increase the lifespan Early use of them can prevent or delay disease progression ACE Inhibitors Suppress the enzyme that converts angiotensin I to angiotensin II Limits vasoconstriction This decreases afterload (resistance the heart pushes against) which reduces work of the heart Angiotensin II promotes abnormal growth and remodeling of the heart and thickening of the peripheral vessel walls ◦ It is responsible for pathological changes to the L ventricle with CHF ◦ Preventing these changes also reduces the workload of the heart ACE Inhibitors Inhibit aldosterone secretion Angiotensin II promotes aldosterone secretion which ACE promotes water retention Inhibitors Inhibition of this is beneficial to those with CHF because it reduces fluid volume  ARBs ◦ Prevent angiotensin II from binding to the receptors on vascular tissues ◦ This limits vasoconstriction and results in vasodilation ◦ Are as effective as ACE inhibitors in treating heart failure and reducing mortality ◦ Used mainly for those that have not tolerated ACE inhibitors ◦ Entresto-co-formulated ARB and neprilysin inhibitor Angiotensin valvar Receptor Blockers SAUDITRA  ang pan nature peptide ettects angiotensininterest whyweneedare http://dx.doi.org/10.1016/j.ddstr.2013.11.002 Figure 1. Angiotensin receptor neprilysin inhibitors have the potential to modulate two counter-regulatory neurohormonal systems in HF: the renin–angiotensin–aldosterone system and natriuretic peptide system [6, 8, 12 and 27]. ANG: angiotensin; ARNI: angiotens... Thomas H. Langenickel, William P. Dole Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure Drug Discovery Today: Therapeutic Strategies, Volume 9, Issue 4, 2013, e131–e139 10/18/2024 PHM 6210 14  Low incidence of side effects Skin rashes GI discomfort Dizziness ACE inhibitors: persistent dry cough Side Effects: ACE Inhibitors and ARBs Lessen the increased sympathetic activity that occurs with CHF Reduce mortality and morbidity associated with this disease One of the principal treatments of CHF Often used along with ACE inhibitors and other medications to provide optimal treatment Beta Blockers  Side Effects ◦ Excessive inhibition of the heart – abnormally slow HR and reduced contraction force Beta Blockers  Increase the excretion of sodium and water Reduce congestion in the lungs and peripheral tissues by excreting excess fluid retained in these tissues Decrease the amount of fluid the heart must pump (cardiac preload) which reduces the heart’s workload Mineralocorticoid receptor antagonist—type of diuretic; can enhance diuresis by another diuretic and help prevent hypokalemia Diuretics Diuretics – Side Effects Disturbances in electrolytes and fluid balances Volume depletion, hyponatremia, hypokalemia, altered pH balance Increased arrhythmias Monitor patients on diuretics for fatigue, confusion and nausea which could indicate the presence of drug induced electrolyte and fluid imbalances Mineralocorticoid receptor antagonists--hyperkalemia Drugs that vasodilate the peripheral vessels Peripheral vascular resistance is reduced The amount of blood returning to the heart is decreased (cardiac preload) Vasodilators And the pressure against which the heart must beat is reduced (afterload) Headache Dizziness Hypotension Orthostatic hypotension May cause reflexive tachycardia in certain patients – HR increase trying to maintain adequate BP Vasodilators – Side Effects  notpothole'd to's heart failure a SGLT-2 Inhibitors Originally approved for management of Type 2 DM Reduces major adverse CV events (mortality, nonfatal stroke, nonfatal MI I “flozin”—dapagliflozin, empagliflozin, sotagliflozin reduce mortality morbidity whenusedforheartfailure mon increasesglucosesecretion Coagulation Hemostasis Hemostasis—the process or mechanism that leads to cessation of bleeding Four stages ◦ Constriction of damaged blood vessel ◦ Formation of temporary platelet plug ◦ Activation of coagulation cascade ◦ Formation of “fibrin plug” or the final clot ◦ With platelets and fibrin polymer ◦ Seals area until tissue regeneration occurs (then clot is dissolved) Normally clotting factors in the blood stream interact with damaged vessels to create a clot Inadequate clotting can lead to excessive blood loss Overactive clotting can lead to thrombus formation or thrombogenesis ◦ Can lead to vessel occlusion  Figure 11.11 Blood clot formation amie whereas hessiiture Copyright © McGraw Hill LLC. All rights reserved. No reproduction or distribution without the prior written consent of McGraw Hill LLC. 25 Hemostasis Normal hemostasis is a balance between too much and too little blood coagulation In cases of clinical concerns (hypercoagulation, hypocoagulation), normal hemostasis can be achieved through medications deficit attesting Thrombus (clot) formation is treated with drugs that prevent clot formation (anticoagulants and antiplatelet drugs) or drugs that remove clots (fibrinolytics) Inadequate clotting is treated by replacing the missing clotting factor  Hemostasis Hemostasis can be influenced by hyperlipidemia ◦ Dyslipidemia is associated with elevated platelet count, platelet activity, hypercoagulability, and impaired fibrinolysis ◦ LDL, VLDL, and HDL proteins include those that are involved in blood clotting ◦ Ex: VLDL has VWF and other ◦ Ex: LDL has VWF, plate GP1balpha and others tie betweendystipedimiaclots 1 Lowering plasma lipid levels through medications is done to prevent atherosclerosis and is done in conjunction with lifestyle modifications iiiiii Blood Clots Clotting factors circulate in the bloodstream and are responsible for clot formation When a blood vessel is damaged a cascade of events occurs – one of the clotting factors is activated which leads to the next factor’s activation, etc. Drugs to Treat Blood Clots 1. Anticoagulants ◦ Control the synthesis and function of clotting factorsmadeinliver ◦ Used to prevent clot formation in the venous system (venous thrombosis) 2. Antiplatelets ◦ Inhibit abnormal platelet activity by preventing thrombus formation in arteries that could lead to MI or CVA (ischemic) 3. Fibrinolytics ◦ Facilitate destruction of clots which re-establishes blood flow through vessels Anticoagulants Heparin (low MW or unfractionated) Warfarin (Coumadin) nolonger abrandn ame discontinued Direct thrombin inhibitors don'tweatefibrinplug Factor Xa inhibitors (DOACs) toa Used to treat abnormal clots in the venous systems ◦ DVTs – piece of the clot can break off, thromboembolism, and travel to the lungs (PE) These drugs are used to treat venous thrombosis and thromboembolism and prophylactically for those at risk for DVTs MIorstroke startanticoagulantusage Initial anticoagulation options Administered between days 0-10 after diagnosis of DVT or PE For most patients ◦ Oral factor Xa inhibitors or direct thrombin inhibitors ◦ Direct-acting oral anticoagulants (DOACs) ◦ Prevent prothrombinase complex from forming ◦ Rivaroxaban or apixaban impib one ◦ Direct thrombin inhibitors ◦ Dabigatran (typically LMW heparin should be administered for 5 days prior to starting) Other options ◦ LMW heparinlowmolecularweight ◦ Subcutaneous injection ◦ Anticoagulant effects are seen almost immediately ◦ Fondaparinux ◦ Unfractionated heparin Unfractionated heparin (Heparin) Source: porcine or bovine intestines Administration: ◦ Treatment after diagnosis: IV, dose based on weight ◦ Prophylaxis to avoid venous thromboembolism (e.g. post orthopedic surgery such as hip fracture, hip or knee replacement): subcutaneously q. 8-12 h; 10-15 days minimally; dosage not weight based aPPT (activated partial thromboplastin time; intrinsic and common pathways) monitored frequently to determine clotting time (normal is 25-35 sec) Inactivates thrombin and other coagulation factors Half-life abut 30 min (very patient dependent) ◦ This can be good if patient needs to have a procedure. Heparin can be stopped and cleared in 60-90 minutes.  Low Molecular Weight Heparin Derived from chemical or enzymatic depolymerization of unfractionated heparin eiesbecome ◦ MW 4-5 kDa compared to 12-16 kDa for heparin u niform one ◦ Shorter chains of LMW heparin result in a longer half-life and they are more predictable in response andpredictable Enoxaparin (Lovenox), tinzaparin, dalteparin (all end in –parin) Administered via subcutaneous injection once daily Can be administered at home Often used for several weeks following discharge from the hospital Can be used periprocedural, but must be stopped ~24 hours prior to procedure Warfarin Brand name Coumadin has been discontinued Warfarin--primary drug used in the long-term prevention of venous thrombosis Interferes with Vitamin K metabolism in the liver which impairs the hepatic synthesis of several clotting factors Narrow therapeutic range Administered orally Dosing tricky (impacted by genetics variations, drug interactions, diet) Bleeding risk greater than with DOACs, but efficacy can be greater for certain indications (e.g. pts with mechanical heart valves) Takes several days to be effective (can’t be used for initial therapy) Patient may be started on heparin with this for several days and then the heparin is discontinued once the Coumadin is effective Warfarin Patients taking this drug long-term need to be monitored to ensure it is at a therapeutic dose Prothrombin time and INR are measured (clotting times) ◦ Determines how quickly blood clots howlongdoesittakebloodtoclot ◦ Measures extrinsic pathway again ◦ Acceptable clotting INR range is 2-3 The clotting cascades. The intrinsic cascade (which has less in vivo significance in normal physiologic circumstances than the extrinsic cascade) is initiated when contact is made between blood and exposed negatively charged surfaces. The extrinsic pathway is initiated on vascular injury which leads to exposure of tissue factor, TF (also identified as factor III), a subendothelial cell-surface glycoprotein that binds phospholipid. The green dotted arrow represents a point of crossover between the extrinsic and intrinsic pathways. The two pathways converge at the activation of factors X to Xa. Factor Xa has a role in the further activation of factors VII to VIIa as depicted by the green arrow. Active factor Xa hydrolyzes and activates prothrombin to thrombin. Thrombin can then activate factors XI, VIII, and V, furthering the cascade. Ultimately the role of thrombin is to convert fribrinogen to fibrin and to activate factors XIII to XIIIa. Factor XIIIa (also termed transglutaminase) cross-links fibrin polymers solidifying the clot. HMWK: high-molecular-weight kininogen. PK: prekallikrein. PL: phospholipid. Citation: Chapter (Reproduced 33 Blood Coagulation, with King MW. permission High-Yield from themedicalbiochemistrypage, Q & A Review LLC.) for USMLE Step 1: Biochemistry and Genetics; 2023. Available at: https://accesspharmacy.mhmedical.com/content.aspx?sectionid=269377546&bookid=3231 Accessed: August 09, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved Anticoagulants – Side Effects Hemorrhage ◦ Increased bleeding can be severe with heparin and warfarin ◦ Blood in stool or urine, bleeding gums, heavy menstrual flow ◦ Back pain or joint pain could indicate internal bleeding May decrease platelets – thrombocytopenia ◦ This may resolve on its own or could result in a severe autoimmune situation that results in increased thrombosis throughout the vascular tissues GI distress, skin reactions From: Chapter 9 Blood Composition and Function Medical Physiology: Principles for Clinical Medicine, 6e, 2023 Heparin Legend: Hemostasis. Date of download: 8/9/2023 Copyright © Wolters Kluwer  Antiplatelet Drugs Prevent excessive clotting caused by increased platelet activity Primarily used to prevent the formation of arterial clots ◦ Example: those that cause arterial occlusion or cerebral infarction Examples: ◦ Aspirin, adenosine-diphosphate (ADP) receptor blockers, & glycoprotein IIb-IIIa receptor blockers I MOAfromNSAIDslides Aspirin Antiplatelet drug – suppresses natural platelet aggregation Prevents platelet-induced thrombosis Effect is found at low dose: 75-325 mg/day ◦ Low dose is 81 mg and will be effective for many patients Aspirin irreversible affects platelets – aspirin reaches a platelet and inhibits it for the remainder of its life (7-8 days) platelet lifetime Aspirin Helps prevent ischemic strokes May increase risk for hemorrhagic stroke Can be used to prevent DVT Can be used as an adjunct to heparin or warfarin which usually treat DVTs ADP Receptor Blockers Adenosine diphosphate (ADP) is a chemical that increases platelet activation By blocking the receptor, clotting is reduced Examples: Plavix (clopidogrel) Used primarily to prevent thrombosis in patients who are at risk for an MI or ischemic stroke (those with unstable angina, a-fib, etc.)  Glycoprotein IIb-IIIa Receptor Blockers Inhibit platelet aggregation by binding to and blocking the activation of GpIIb-IIIa on platelet membrane Decreases platelet cross-linking (bridging to each other) by fibrinogen Most powerful inhibitors of platelet activity I Used to prevent thrombosis in those undergoing angioplasty and other interventions aoristfainting Adverse Effects of Antiplatelet Drugs Increased risk of bleeding Hypotension GI distress Aspirin – gastric irritation, can be toxic to liver and kidney at high doses Fibrinolytics (Thrombolytic agents) Facilitate the breakdown and help to dissolve clots that have already formed They activate an enzyme responsible for digesting fibrin Used to re-open blood vessels Essential in treating those with MI ◦ Can re-establish blood flow when used at onset of MI (effective for 12 hours after onset) ◦ Decreases morbidity and mortality following an MI ◦ Administration one hour within onset of MI reduces mortality by 50% ◦ Administered via intravenous injection into the systemic circulation Fibrinolytics Can cause intracranial hemorrhage or other bleeding problems because they stimulate clot breakdown in all tissues Contraindicated in those with a history of hemorrhagic stroke, active internal bleeding, or other factors that would create an increased risk for hemorrhage Fibrinolytics Can be used to dissolve clots in the peripheral arteries (example: femoral, popliteal) and can be used to dissolve DVTs Can be used for PEs Also used to treat shunts and bypass grafts that have been occluded Fibrinolytics – t-Pa Tissue plasminogen activator (t-Pa) is a fibrinolytic that is given intravenously and causes clot breakdown by activating plasmin Can successfully treat MIs mustbeadministeredwin24hrsfors trokes  Blood Clots To break down a clot, tissue plasminogen activator (t-PA) is given & converts plasminogen to plasmin ◦ When a clot is forming, strands of fibrin bind together to form a meshlike structure which is the framework of a clot ◦ Plasmin is also called fibrinolysin and it is an enzyme that directly breaks down the fibrin mesh and destroys the clot Clot or Not? Reviewing the Reciprocal Regulation Between Lipids and Blood Clotting Ziyu Zhang, Maya Rodriguez, and Ze Zheng, Arteriosclerosis, Thrombosis, and Vascular Biology (2024) Volume 44, Number 3 https://doi.org/10.1161/ATVBAHA.123.318286 Adverse Effects of Fibrinolytics Hemorrhage ◦ Intracranial hemorrhage in patients who have a pre-existing risk (advanced age, HTN, history of hemorrhagic stroke) Excessive bleeding may occur during wound care dressing changes Itching Nausea Allergic reaction - anaphylaxis Treatment of Clotting Disorders Hemophilia ◦ Unable to synthesize adequate amounts of specific clotting factors ◦ Develop joint problems due to intra-articular bleeding ◦ Missing clotting factor needs to be replaced ◦ May be done prophylactically or acutely Treatment of Clotting Disorders Liver needs adequate vitamin K in order to produce clotting factors Insufficient vitamin K in the body will result in impaired clotting factor production and excessive bleeding Administration of exogenous Vitamin K can resolve this Vitamin K is given to newborns to prevent hemorrhage (newborns can’t make it the first 5-8 days after birth) Anti-hyperlipidemic Agents  Hyperlipidemia Abnormally high concentration of lipids in the blood ◦ Causes atherosclerosis Primary cause of cardiovascular disease High density lipoproteins (HDLs) –beneficial protein complexes or “good cholesterol” in the FIEFS bloodstream Low density lipoproteins (LDLs) – “bad cholesterol” decrease meas Triglycerides – a type of lipid (fat) in the blood wi Hyperlipidemia Treatment of hyperlipidemia focuses on increasing the HDLs and lowering the LDLs and/or triglycerides Medications are used when these levels can’t be adequately adjusted through lifestyle modification – low fat diets, weight reduction, regular exercise and smoking cessation Examples: Statin drugs, Fibric Acids, cholesterol absorption inhibitor dongpithuit juice  Statin Drugs Lipitor (atorvastatin), Crestor (rosuvastatin), lovastatin, simvastatin Reduce cholesterol production especially in liver cells increases Reduces LDL receptors on liver cells to increase the amount taken up in the liver; thereby, removing from blood. Statins decrease triglycerides and increase HDL levels mallamt moderateamt Statins decrease mortality and morbidity in those with high cholesterol Statins are important in treating cardiovascular disease May have anti-cancer effects Firstvineafterlifestylemoditilations itmocoagulaseinhibitors Fibric Acids Aka: fibrates Decrease triglyceride levels Can produce increases in HDL levels and help lower LDL levels  Ezetimibe Blocks cholesterol absorption in intestines by 50% Second-line therapy I prevents cholesterol fromenteringbloodstream Statin should be co-administered itnotlevelswandbodywillstart tomakemore notusedprophylactically  familialRish Bempedoic acid Inhibits cholesterol synthesis in liver LDL receptor upregulation Works in same pathway as statins l Recommended to take with statins way inhibitsotherenzymesinpain Adverse Effects of Lipid Lowering Drugs GI distress (nausea, diarrhea) Liver dysfunction, gallstones, pancreatitis Cardiovascular problems: arrhythmias Tendon rupture (bempedoic acid) Statin-associated muscle adverse effects ◦ Myalgias (could include muscle aches, soreness, stiffness, tenderness, cramps with or shortly after exercise) ◦ Risk increased if combine with other lipid-lowering drugs ◦ Myopathy – muscle pain, inflammation and weakness; rare ◦ Can progress to rhabdomyolysis if not caught early ◦ If this occurs discontinue the statin drug and rest 4-6 weeks