Introduction to Cardiovascular Pharmacology PDF

Introduction to Cardiovascular Pharmacology Todd Gundrum, PharmD [email protected] 1 Learning Objectives By the end of this session, you will be able to meet the following learning objectives: 1. Explain the molecular mechanism of action of these cardiovascular drugs. 2. D...

Introduction to Cardiovascular Pharmacology Todd Gundrum, PharmD [email protected] 1 Learning Objectives By the end of this session, you will be able to meet the following learning objectives: 1. Explain the molecular mechanism of action of these cardiovascular drugs. 2. Describe the routes of administration and the elimination processes of presented drugs. 3. Describe the main adverse effects. 4. Describe the clinically important drug interactions. 5. Recall the pharmacology of medications presented in prior lectures that are utilized in the management of cardiovascular disorders. 2  Introduction Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels and they include: coronary heart disease – disease of the blood vessels supplying the heart muscle; cerebrovascular disease – disease of the blood vessels supplying the brain; peripheral arterial disease – disease of blood vessels supplying the arms and legs; rheumatic heart disease – damage to the heart muscle and heart valves from rheumatic fever, caused by streptococcal bacteria; congenital heart disease – malformations of heart structure existing at birth; Heart attack (myocardial infarction) – reduction in blood flow to the heart Arrhythmia – change to the normal sequence in the heartbeat Hypertension – elevated blood pressure 3  Physiology Review Regulation of Blood Pressure Blood pressure (BP) = Cardiac Output (CO) x Total peripheral resistance (TPR) Cardiac Output = Stroke Volume (SV) x Heart Rate (HR); three variables affect the SV: 1. Contractility 2. Preload 3. Afterload Stroke volume increases when there is: An increase in contractility An increase in preload A decrease in afterload 4 Diuretics 5 Background Basic videos on Nephron Structure and Function Nephrons - Filtration and Reabsorption Basics (youtube.com) Nephrology - Physiology Reabsorption and Secretion (youtube.com) USMLE® Step 1 High Yield: Nephrology: Diuretics (youtube.com) Focus on Loop, Thiazide, and Spironolactone (Aldosterone Antagonist) 6 Where do Thiazides diuretics act? Loop diur- Osmotic etics diuretics 7  Loop diuretics Furosemide, torsemide Sulfonamides (SO2-N chemical group) Ethacrynic acid Not a sulfonamide Site of action Na+-K+-2Cl- symporter (NKCC2) Thick ascending limb of Henle’s loop (TAL) Luminal (apical) membrane Na+-K+-2Cl- symporter cotransports Na+, K+ and Cl- across a cell membrane Ratio of 1:1:2 (therefore electroneutral) 8 Loop diuretics Loop diuretics inhibit the Na+-K+-2Cl- symporter leading to: 1. Decreased lumen-positive potential Causes a reduction in divalent cation (Ca2+ and Mg2+) reabsorption 2. Decreased hypertonicity of the medulla Therefore, a decreased ability of the kidney to concentrate the urine 3. Inhibition of macula densa sensitivity This occurs through inhibition of Na+ and Cl- transport by the Na+-K+-2Cl- symporter into the macula densa, which can then no longer sense salt concentration in the tubular fluid 4. Increased GFR, due to a) Inhibition of tubuloglomerular feedback (links [Na+] in distal tubule to GFR) b) Stimulation of renin release from the adjacent juxtaglomerular cells 9 Loop diuretics: renal effects Increased renal excretion of: Na+, Cl-, K+, H+, Ca2+ (sulfonamides also increase the excretion of HCO3-) Urine pH: acid Acid-base balance: metabolic alkalosis Both diluting and concentrating capacities of the kidney are decreased Efficacy of diuretic effect: high the maximum increase in Na+ excretion is 20-25% of the filtered Na+ load the diuretic effect remains even when the GFR is less than 30 mL/min Duration of diuretic effect: 2-8 hours 10  Loop diuretics: adverse effects Metabolic effects Hypokalemic metabolic alkalosis (same mechanism as thiazides) In part by increased Na+ delivery to the CCT, leading to increased secretion there of K+ and H+ In part by increased urine flow along the CCT (it sweeps K+ downstream so maintaining K+ gradient) Can be reversed by K+ replacement and correcting hypovolemia Hyperuricemia Loop and thiazide diuretics are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid (potential for hyperuricemia) Hypomagnesemia, hypocalcemia Results from the decrease in lumen positive potential in the thick ascending limb of Henle Can be reversed by supplements Hypovolemia A direct consequence of diuretic action Prevention is by lowering dose 11  Loop diuretics: other effects Cardiovascular Postural hypotension (if hypovolemia develops) Ototoxicity Tinnitus, hearing loss (dose-related, reversible and likely due to alteration in the electrolyte composition of the endolymph) Most common with rapid infusion and in patients with poor renal function or taking other ototoxic agents (e.g. aminoglycoside antibiotics) More common with ethacrynic acid Allergic reactions Sulfonamide loop diuretics (e.g. furosemide, torsemide) may cause skin rash Rare, potentially lethal Exfoliative dermatitis, Stevens-Johnson syndrome, agranulocytosis, aplastic anemia 12  Loop diuretics: therapeutic uses Acute pulmonary edema Heart failure Edema Associated with chronic renal failure or nephrotic syndrome Ascites Associated with hepatic cirrhosis or right-sided heart failure Hypertension When associated with renal insufficiency or heart failure Hypercalcemia 13  Thiazides Hydrochlorothiazide, chlorthalidone Mechanism of action Thiazide diuretics inhibit the Na+-Cl- symporter Results in reduced reabsorption of NaCl Early distal convoluted tubule (DCT) NCC is responsible for NaCl reabsorption from the lumen into early DCT epithelial cells 14  Thiazides: renal effects Increased renal excretion of: Na+, K+, H+, Cl-, HCO3- Decreased renal excretion of: Ca2+, NH4+, uric acid Effect on Ca2+ is due to increased reabsorption via the Na+-Ca2+ exchanger on the basolateral membrane Urine pH: slightly alkaline (in part due to weak inhibition of carbonic anhydrase), if any change at all Acid-base balance: metabolic alkalosis Kidney diluting capacity: decreased Efficacy of diuretic effect: moderate The maximum increase in Na+ excretion is 5-10% of the filtered Na+ load The diuretic effect disappears if the glomerular filtration rate is less than 30 mL/min) Duration of diuretic effect (single dose): variable (6-48 hours) 15 Thiazides: metabolic adverse effects Hypokalemic metabolic alkalosis (same mechanism as loop diuretics) In part by increased Na+ delivery to the CCT, leading to increased secretion there of K+ and H+ In part by increased urine flow along the CCT (it sweeps K+ downstream so maintaining K+ gradient) Can be reversed by K+ replacement and correcting hypovolemia Hyperglycemia Impairment in insulin release and in cellular glucose utilization Can unmask latent diabetes mellitus Hyperlipidemia Unknown mechanism, but often resolves on long-term administration Hypovolemia Due to diuretic effect, therefore dose dependent 16 Thiazides: metabolic adverse effects (con’t) Hyperuricemia Hypercalcemia Inhibition of NCC leads to increased Ca2+ reabsorption in DCT Increased intracellular Ca2+ increases activity of basolateral Na+-Ca2+ exchanger Hyponatremia (rare, but can be fatal) Water and Na+ are lost from the body, but Na+ loss is greater ADH secretion limits water loss Genitourinary Sexual dysfunction (dose-related, up to 30% of patients after chronic treatment) Allergic reactions Thiazides are sulfonamides and may cause skin rash Rare, potentially lethal Exfoliative dermatitis, Stevens-Johnson syndrome, agranulocytosis, aplastic anemia 17 Thiazides: therapeutic uses Hypertension (a first line treatment and the first choice of diuretics) Edema associated with diseases of: heart (i.e. heart failure) kidney (i.e. nephrotic syndrome) (loop diuretics are usually preferred) Calcium nephrolithiasis, idiopathic hypercalciuria. 18 Potassium sparing diuretics - aldosterone (mineralocorticoid) receptor antagonists Aldosterone is a natural agonist of aldosterone receptors Nuclear/steroid receptor Receptor activation causes gene transcription and the synthesis of aldosterone- induced proteins Increases ENaC channel and Na+,K+-ATPase expression Causes Na+ and water retention and increases K+ and H+ excretion Spironolactone and eplerenone are aldosterone receptor antagonists Block the effects of aldosterone This results in reduced ENaC channel and Na+,K+-ATPase expression and reduced K+ and H+ excretion 19 Potassium sparing diuretics: renal effects Increased renal excretion of: Na+, Cl-. Decreased renal excretion of: K+, Ca2+, H+ Urine pH: alkaline Acid-base balance: potential for hyperchloremic metabolic acidosis H+ excretion is reduced, production of new HCO3- is reduced Kidney diluting and concentrating capacity: unaffected 20  Potassium sparing diuretics: adverse effects All drugs Hyperkalemia (up to 20% of patients). It can lead to asthenia, muscular weakness, paresthesias, diarrhea, bradycardia, AV block (in serious cases asystole or ventricular fibrillation may ensue) Metabolic acidosis (by inhibiting H+ secretion, only with high doses) Potential for hyperchloremia, because of reduced plasma HCO3- Spironolactone vs eplerenone Spironolactone also antagonizes androgen receptors: sexual dysfunction (> 40%); gynecomastia, menstrual irregularities (by enhancing estrogen and inhibiting testosterone effects) Eplerenone is more selective for aldosterone receptor with less antagonism of androgen receptors 21  Potassium sparing diuretics: therapeutic uses Spironolactone, eplerenone Systolic heart failure Primary hyperaldosteronism (adrenal adenoma, adrenal hyperplasia) Secondary hyperaldosteronism (due to hepatic cirrhosis, congestive heart failure, nephrotic syndromee, renal artery stenosis) Treatment and prevention of hypokalemia (i.e. in response to therapy with loop or thiazide diuretics 22 Relative efficacy Diuretic class Site of action Mechanism of action Relative efficacy Loop diuretics TAL of Henle loop Inhibit Na+-K+-2Cl- symporters 15 Thiazides and congeners EDT Inhibit Na+-Cl- symporters 5 Aldosterone antagonists Late distal convoluted Block aldosterone 1 tubule and cortical (mineralocorticoid) receptors collecting tubule (CCT) TAL – thick ascending limb; EDT – early distal tubule; CCT – cortical collecting tubule 23 Adrenergic Blockers 24  Semester 1 Review Adrenergic Receptors These receptors are located throughout the body: Alpha-1, Alpha-2 Beta-1, Beta-2 Norepinephrine (NE) and epinephrine (E) bind to the adrenergic receptors and produce many physiological effects. NE and E will bind to the alpha-1 and beta-1 receptors and cause the following cardiac mediated effects: Alpha-1: Beta-1: Vasoconstriction Increase HR Increase Peripheral Increase Contractility Resistance Semester 1: Introduction to ANS Function 25  Beta blockers Metoprolol is a beta-receptor antagonist/blocker It is highly selective for beta-1 receptors Metoprolol will decrease heart rate and contractility Therapeutic uses of beta blockers: Hypertension Heart Failure Myocardial Infarction Angina Arrhythmias 26  Inhibitors of the Renin- Angiotensin-Aldosterone System 27  Physiology Review Inhibitors of the Renin-Angiotensin-Aldosterone System 1. A reduction in blood pressure at the afferent arteriole of the kidney stimulates renin release from the kidneys. 2. When renin is released into the blood, it acts upon a circulating substrate called angiotensinogen, which is secreted from the liver. 3. Angiotensinogen is cleaved by renin to form angiotensin I (Ang I). 4. Vascular endothelium (primarily in the lungs) has an enzyme called angiotensin converting enzyme (ACE), which cleaves Angiotensin I to form angiotensin II (Ang II). 28 29  Inhibitors of the Renin-Angiotensin-Aldosterone System Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 30 31  Inhibitors of the Renin-Angiotensin-Aldosterone System ACE-inhibitors end in the suffix “-pril” Lisinopril, enalapril, captopril,… Block the conversion of angiotensin I to angiotensin II decreases the production of angiotensin II (a potent vasoconstrictor), this leads to a decrease in peripheral resistance -> afterload is reduced decrease the secretion of aldosterone, resulting in decreased sodium and water retention -> preload is reduced ACE-inhibitors do not reflexively increase cardiac output, heart rate, or contractility ☺ Therapeutic uses of ACE-inhibitors Hypertension Congestive Heart Failure Coronary artery disease Myocardial Infarction 32  Angiotensin-converting enzyme inhibitor is a potent inhibitor of kininase II, which facilitates the breakdown of bradykinin. An increase in bradykinin levels results in continued prostaglandin E2 synthesis, vasodilation, increased vascular permeability, and increased interstitial fluid. Inhibition of kininase II therefore leads to the accumulation of bradykinin and prostaglandins (and substance P): these are protussive mediators in the respiratory tract ACE-inhibitors may therefore cause a persistent dry cough and angioedema 33  Inhibitors of the Renin-Angiotensin-Aldosterone System Angiotensin II Receptor Blockers (ARBs) end in the suffix “-sartan” Losartan, candesartan, valsartan,… Inhibit binding to AT1 angiotensin II receptor decreases the production of angiotensin II (a potent vasoconstrictor), this leads to a decrease in peripheral resistance -> afterload is reduced decrease the secretion of aldosterone, resulting in decreased sodium and water retention -> preload is reduced No effect on bradykinin Uses similar to ACE-I Direct Renin Inhibitor Aliskiren 34 Calcium Channel Blockers 35  CCBs Mechanism of Action Block L type calcium channels resulting in preventing the entry of calcium ions into smooth muscle cells of artery walls, SA node, AV node, and atrial and ventricular cardiac fibers 36 CCBs Classes: Dihydropyridine (DHP) “…pine” – amlodipine, nifedipine, nicardipine act predominantly on arteries to reduce SVR and arterial pressure Adverse effect = reflex tachycardia CV uses = HTN, Angina Non-dihydropyridine (Non-DHP) Verapamil – selective for myocardium Diltiazem – act on both myocardium and arteries Adverse effect = bradycardia CV uses – HTN, Angina, Arrhythmia, Preserved EF Heart Failure 37 Anticoagulant Drugs Semester 2: Drugs for Hemostasis 38 Antiplatelet Therapies Antiplatelet Drugs CV Indications Drug Indication Aspirin Prevention CV events Acute MI Atrial Fibrillation ADP receptor ACS after PCI Blockers MI Stroke PAD GP IIb/IIIa Inhibitors ACS PCI PDE Inhibitors Stroke (with aspirin) PAD 39 Warfarin 40  Warfarin Pharmacokinetics: Administration: Oral (100% bioavailability) Highly bound to albumin (99%) Peak effects: 72 – 96 hours after initiation Does not affect circulating VitK dependent factors Therapeutic Use in CV disease: Atrial fibrillation Valvular heart disease Severe low EF heart failure 41 Heparin & Low Molecular Weight Heparins Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved 23 from https://bookshelf.vitalsource.com/#/books/9781496386113/ Heparin / LMWH Pharmacokinetics Administration: IV, SC Onset of action: IV (within minutes), SC (1-2 hours) UFH has unpredictable PK so monitor (aPTT), LMWH have more predictable PK so monitoring not necessary for most patients Therapeutic Use: both prophylaxis and treatment of thromboembolic diseases Unstable angina and acute myocardial infarction “Bridging” therapy 43 Novel Oral Anticoagulants (NOACs) Apixaban Dabigatran Edoxaban Rivaroxaban Mechanism Factor Xa Direct Factor Xa Factor Xa of action Inhibitor Thrombin Inhibitor Inhibitor Inhibitor Cardiac Non- Non- Non- Non- Indication (s) Valvular Valvular Valvular Valvular Atrial Atrial Atrial Atrial Fibrillation Fibrillation Fibrillation Fibrillation Post ACS Reversal Andexanet or Idarucizumab 4F-PCC Andexanet Agent 4F-PCC or 4F-PCC 44  Direct Thrombin Inhibitors (bivalirudin, argatroban) Mechanism of action DTIs bind to the active site of both free and fibrin-bound thrombin, thus preventing its coagulant activity. Pharmacokinetics Bivalirudin and argatroban are parenteral DTIs Therapeutic Uses: an alternative to heparin in patients with or at risk of heparin-induced thrombocytopenia. patientsundergoing PCI. 32  Fibrinolytics Fibrinolytic/thrombolytic agents are used to lyse already-formed clots Thrombolytic agents act by converting the inactive zymogen plasminogen to the active protease plasmin. Tissue plasminogen activator (t-PA) achieves this: t-PA is a serine protease produced by human endothelial cells; it is a potent activator of plasminogen. Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. Alteplase is recombinant t-PA [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 36 https://accessmedicine-mhmedical- com.rossuniversity.idm.oclc.org/book.aspx?bookid=3191 47 https://accessmedicine-mhmedical- com.rossuniversity.idm.oclc.org/book.aspx?bookid=3191 48