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CLINICAL APPLICATIONS OF CARDIOVASCULAR PATHOPHYSIOLOGY & PHARMACOLOGY FIRNAAZ MOHIDEEN Cardiovascular pathologies are often interlinked, so many of the drugs we will ! consider today can be used for a wide range of cardiovascular diseases. Most conditions have conservative, medical and surgical treatment options, but ! we will exclusively focus on the medical (ie: pharmacological) therapies.CASE #1 “A 73Y F presents to her GP with a six-month history of dull, squeezing pain in her central chest that comes on when she is walking to the shops or gardening, which seem to disappear within a few minutes after she sits down. She denies any radiation of the pain to her left arm, shoulder, neck or jaw but does note feeling breathless when they happen. She is moderately hypercholesterolaemic but has no other significant past medical history.”  What is the most likely diagnosis?  What is the underlying pathophysiology of this condition?  What are some pharmacological therapies we could use?STABLE (EXERTIONAL) ANGINA  fibrofatty atheromatous plaques build up in coronary arteries over a long time causing progressive stenosis of the functional end-arteries supplying the myocardium  at rest:  sufficient supply of oxygenated blood to meet resting myo2ardial O demand  likely with compensation by resting coronary arteriolar vasodilatation and development of collaterals (in long-term)  on exertion:  insufficient supply of oxygenated blood to meet elevated myocardial O 2emand  myocardial ischaemia  ↑ anaerobic respiration → ↑ release of lactate → ∴ anginal chest painPHARMACOLOGICAL TREATMENTS?  nitrovasodilators  β-blockers 2+  Ca -channel blockers  ranolazine  ivabradine  K -channel openers  aspirin  statinsNITROVASODILATORS  Nitrovasodilators are good for terminating acute episodes of stable angina, especially when given as a spray or a sub-lingual tablet.  EXAMPLES:  GTN; isosorbide mononitrate; amyl nitrate  MECHANISM OF ACTION:  form NO that diffuses into vascular smooth muscle cells to cause NO-mediated vasodilatation of blood vessels (esp. coronary collaterals and central veins)  HOW DOES THIS TREAT STABLE ANGINA?  ↑ perfusion of oxygenated blood to myocardiumβ-BLOCKERS  β-blockers are useful in treatment of many cardiovascular pathologies including long-term management of angina.  EXAMPLES:  propranolol; atenolol; bisoprolol; carvedilol; nebivolol  MECHANISM OF ACTION:  reduce catecholaminergic (sympathetic) effects on the cardiovascular system by antagonism of G -coupled β -adrenoceptors in the heart (SAN/AVN/myocardium), kidneys and brain s 1  carvedilol and nebivolol have additional cardioprotective actionsWHAT ARE THE EFFECTS OF β -AR AGONISM ON THE CVS? 1  NA/ADR stimulate G -csupled β -AR1 → Gα stimusates AC → ↑ cyclisation of ATP to cAMP → ↑ [cAMP]  on heart:  ↑ chronotropy  ↑ inotropy  ↑ lusitropy  on kidneys:  ↑ activity of renin-angiotensin-aldosterone system  on brain:  ↑ sympathetic outflow  overall effect:  ↑ cardiac output  ↑ blood volume  ↑ ABPβ-BLOCKERS  HOW DOES THIS TREAT STABLE ANGINA?  ↓ in heart rate increases proportion of cardiac cycle in diastole  ∴ ↑ perfusion of oxygenated blood to myocardium  ↓ in myocardial contractility  ∴ ↓ myocardia2 O demand  ↓ in blood volume → ↓ preload → ↓ myocardial work  ∴ ↓ myocardia2 O demand  ↓ in ABP → ↓ afterload → ↓ myocardial work  ∴ ↓ myocardial O demand 2CALCIUM CHANNEL BLOCKERS 2+  Ca -channel blockers are useful in treatment of many cardiovascular pathologies including long-term management of angina.  EXAMPLES:  amlodipine (dihydropyridine); verapamil (phenylalkylamine); diltiazem (benzothiazepine)CALCIUM CHANNEL BLOCKERS  MECHANISM OF ACTION:  DHP CCBs:  preferentially block inactivated L-type Ca s in vascular smooth muscle of peripheral arterioles V  non-DHP CCBs:  preferentially block rapidly opening and closing L-type Ca s in nodal tissues and ventricular myocardium of heart V  HOW DOES THIS TREAT STABLE ANGINA?  DHP CCBs:  ↓ Ca2+influx into vascular smooth muscle of peripheral arterioles → ↓ peripheral arteriolar vasoconstriction  ∴ ↓ TPR → ↓ ABP → afterload → ↓ myocardial work → ↓ myocardial2O demand  non-DHP CCBs: 2+  ↓ Ca influx into SAN/AVN → ↓Ca-L ↓ rate of depolarisation → ↓ in heart rate → ↑ proportion of cardiac cycle in diastole  ∴ ↑ perfusion of oxygenated blood to myocardium 2+  ↓ Ca influx into ventricular myocardium lower heart rate) → ↓ in myocardial contractility  ∴ ↓ myocardial 2 demandRANOLAZINE  MECHANISM OF ACTION:  inhibits late iNain cardiomyocytes to ultimately reduce end-diastolic ventricular wall stiffness and compression of vessels supplying the myocardium  HOW DOES THIS TREAT STABLE ANGINA?  ↑ perfusion of oxygenated blood to myocardiumIVABRADINE  MECHANISM OF ACTION:  inhibits HCN channels in SfN → ↓ I → ↓ heart rate → ↑ proportion of cardiac cycle in diastole  HOW DOES THIS TREAT STABLE ANGINA?  ↑ perfusion of oxygenated blood to myocardiumOTHER PHARMACOLOGICAL TREATMENTS TO CONSIDER? +  K -channel openers  aspirin  statinsCASE #2 “A 65Y M presents to A&E with a four-hour history of central, crushing chest pain that fails to respond to his reliever glyceryl trinitrate spray. He feels nauseous and is sweating profusely, complaining of discomfort in his neck and jaw. He is a lifelong smoker and has a past medical history of type II diabetes mellitus, hypertension and hypercholesterolaemia.”  What is the most likely diagnosis?  What investigations could we do?  What is the underlying pathophysiology of this condition?  What are some pharmacological therapies we could use?MYOCARDIAL INFARCTION  INVESTIGATIONS?  basic obs.  ECG  blood tests  esp. serial ‘cardiac biomarker’ tests sub-endocardial transmural  imaging ischaemia/infaischaemia/infarction  CXR  CTCA  echo.  cardiac MRIMYOCARDIAL INFARCTION  infarction = necrosis due to ischaemia  ∴ ‘myocardial infarction’ specifically refers to necrosis (cell death) of cardiomyocytes secondary to a prolonged restriction of delivery of sufficient oxygenated blood  possible causes: 1. high demand in context of a large fibrofatty atheromatous plaque  → stenosis or occlusion of that coronary artery 2. formation of a thrombus on an unstable, ruptured plaque  → stenosis or occlusion of that coronary artery 3. formation of emboli from parts of thrombus forming on a ruptured plaque (‘thromboembolus’) or from ruptured plaque fragments themselves (usually lipid masses released from central core of plaque)  → stenosis or occlusion of a distal coronary arteryPHARMACOLOGICAL TREATMENTS?  anti-platelets  aspirin  P2Y 12receptor antagonists  GPIIb/IIIa receptor antagonists  anti-coagulants  fondaparinux  low molecular weight heparins  morphine  oxygen  nitrovasodilators  β-blockers  statinsASPIRIN  300 mg stat. dose of aspirin should be given immediately to limit potential damage that could occur.  MECHANISM OF ACTION:  irreversibly inhibits COX-1 (by acetylation of Ser-530 in active site) to shift homeostatic balance away from platelet-derive2 TXA and towards endothelium- derived P2I  HOW DOES THIS TREAT MYOCARDIAL INFARCTION?  vasodilatation  ∴ ↑ perfusion of oxygenated blood to myocardium  inhibits platelet aggregation  ∴ ↓ risk of developing thrombus/thromboembolusP2Y RECEPTOR ANTAGONISTS 12  P2Y12 receptor antagonists may be taken with aspirin (and GPIIb/IIIa receptor antagonists) in suspected unstable angina or myocardial infarction.  EXAMPLES:  clopidogrel; prasugrel; ticagrelor  MECHANISM OF ACTION:  inhibits binding of A12receptor on platelets  HOW DOES THIS TREAT MYOCARDIAL INFARCTION?  inhibits ADP-mediat12 P2Y -dependent platelet activation and aggregation  ∴ ↓ risk of developing thrombus/thromboembolusGPIIB/IIIA RECEPTOR ANTAGONISTS  GPIIb/IIIa receptor antagonists may be taken with aspirin (and P2Y 12 receptor antagonists) in suspected unstable angina or myocardial infarction.  EXAMPLES:  eptifibatide; tirofiban; abciximab  MECHANISM OF ACTION:  inhibits glycoprotein IIb/IIIa receptors needed for fibrinogen bridging  eptifibatide; tirofiban; abciximab  inhibits vitronectin receptors needed for platelet aggregation  abciximab  prevents cross-linking between platelets and between platelets and foreign surfaces  HOW DOES THIS TREAT MYOCARDIAL INFARCTION?  inhibits platelet aggregation  ∴ ↓ risk of developing thrombus/thromboembolusCOAGULATION CASCADE  Thrombosis may arise from inappropriate activation of normal haemostasis mechanisms, such as aberrant activity of the coagulation cascade.ANTI-COAGULANTS  Certain anti-coagulants used prophylactically to prevent a secondary thrombosis or thromboembolism (hence re- infarction) in patients with recent unstable angina or myocardial infarction or in certain treatment procedures for myocardial infarction.  FONDAPARINUX or LMWHs (eg: dalteparin):  binds AT-III to accelerate AT-III-dependent inhibition of factor Xa  ↓ conversion of prothrombin to thrombin  ↓ conversion of fibrinogen to fibrin  HOW DOES THIS TREAT MYOCARDIAL INFARCTION?  ↓ risk of developing thrombus/thromboembolusOTHER PHARMACOLOGICAL TREATMENTS TO CONSIDER?  morphine  oxygen  nitrovasodilators  β-blockers  statinsCASE #3 “A 76Y F presents with a three-month history of bilateral leg swelling, progressively decreasing exercise capacity and increasing fatigue. On examination, she has low blood pressure and a raised jugular venous pressure. Two years ago, she suffered a full-thickness anterior myocardial infarction that was managed pharmacologically.”  What is the most likely diagnosis?  What is the underlying pathophysiology of this condition?  What are some pharmacological therapies we could use? Specific Dx for this patient? chronic heart failure with reduced HEART FAILURE left ventricular ejection fraction due to previous full-thickness anterior myocardial infarction  “a clinical syndrome that occurs when the activity of the heart is insufficient to meet the demands for oxygen delivery to tissues due to some underlying problem with cardiac structure or function”  ∴ heart failure is by itself never a final diagnosis  HF-REF:  enlarged ‘floppy’ ventricles fill with blood but pump out <40%  ∴ systolic dysfunction  ie: main problem is with systole (ventricular contraction)  HF-PEF:  ‘stiff’ ventricles fill with less blood than normal but pump out >40-50%  ∴ diastolic dysfunction  ie: main problem is with diastole (ventricular filling)HEART FAILURE Causes of HFrEF? Causes of HFpEF? coronary artery disease; hypertension myocardial infarction dilated cardiomyopathy genetic/familial • genetic/familial • hypertrophic cardiomyopathy • viral • restrictive cardiomyopathy • autoimmune • alcohol • drugs • peri-partum acute myocarditis infiltrative diseases • amyloidosis • sarcoidosis valvular heart disease valvular heart diseaseHEART FAILURE  In a failing heart, a given increase in ventricular end- diastolic pressure does not achieve as large an increase in the cardiac output [CO vs. EDP curve has fallen down].  patient operates much ‘higher up’ the CO curve (at or beyond the plateau) than normal just to maintain a sufficient cardiac output  body attempts to compensate by fluid retention (↑ MSFP), arteriolar vasoconstriction (↑ TPR) and venoconstriction (↑ MSFP)  such compensatory mechanisms shift VR curve upwards, which causes a minimal/negligible increase in CO but a massive rise in RAP/CVP  left-sided heart failure:  → failure: hypoperfusion of systemic tissues/organs  ← failure: pulmonary oedema  right-sided heart failure:  → failure: hypoperfusion of lungs  ← failure: peripheral oedema; hepatic congestion; renal congestion  Since problems arise from the body’s attempts to compensate, targeting systems regulating blood volume and blood pressure can be effective.PHARMACOLOGICAL TREATMENTS?  diuretics  ACEIs/ARBs  ARNIs  SGLT2 inhibitors  β-blockersDIURETICS  Diuretics are useful both acutely and in the long-term management of patients with heart failure.  MECHANISM OF ACTION:  loop diuretics: inhibit NKCC2 on TAL of LoH  eg: furosemide; bumetanide  thiazide/thiazide-like diuretics: inhibit NCC on cortical TAL of LoH and early DCT  eg: hydrochlorothiazide; bendroflumethiazide; metolazone; indapamide  K -sparing diuretics: block ENaCs on apical membrane or antagonise mineralocorticoid receptors in principal cells of late DCT  eg: amiloride; triamterene; spironolactone; canrenone; eplerenone  HOW DOES THIS TREAT HEART FAILURE?  diuresis reduces extracellular fluid (∴ circulating) volume  acutely:  alleviates pulmonary/peripheral oedema  in long-term:  ↓ in blood volume → ↓ preload → ↓ myocardial work  ∴ ↓ myocardia2 O demand  ↓ in ABP → ↓ afterload → ↓ myocardial work  ∴ ↓ myocardia2 O demandDIURETICSACEI S /ARB S  ACEIs/ARBs are excellent for the long-term management of heart failure (and many other cardiovascular pathologies), as they have a proven benefit in reducing morbidity (ie: hospitalisations) and mortality (ie: death).  EXAMPLES:  ramipril; captopril; lisinopril; perindopril; enalapril  MECHANISM OF ACTION:  ACEIs: inhibit ACE → ↓ conversion of AI to AII → ↓ effects of AII  ARBs: competitive antagonism of type I AII1receptors (AT R) → ↓ effects of AII  HOW DOES THIS TREAT HEART FAILURE?  natriuretic diuresis reduces extracellular fluid (∴ circulating) volume  ↓ in blood volume → ↓ preload → ↓ myocardial work  ∴ ↓ myocardial O demand 2  ↓ in CO → ↓ in ABP → ↓ afterload → ↓ myocardial work  ∴ ↓ myocardia2 O demand  ↓ in peripheral arteriolar vasoconstriction ↓ TPR → ↓ ABP → afterload → ↓ myocardial work  ∴ ↓ myocardi2l O demandACEIS/ARB SOTHER PHARMACOLOGICAL TREATMENTS TO CONSIDER?  β-blockers  ARNIs  renin inhibitors  SGLT2 inhibitors  VRAsCASE #4 “A 45Y M undergoes a routine health check-up and has a blood pressure reading of 153/95 mmHg. Even after conservative non-pharmacological management, his home blood pressure readings remain at 147/91 mmHg.”  Why is it important to treat hypertension?  What are some pharmacological therapies we could use?HYPERTENSION  Even though hypertension may be clinically silent for many years, it can cause significant arterial and end-organ damage in the long-term so we must treat hypertension to avoid adverse sequelae.  Consequences:  atherosclerosis  HFrEF  macrovascular damage  eg: aneurysm  microvascular damage in kidneys, retina, etc.PHARMACOLOGICAL TREATMENTS?  ACEIs/ARBs  Ca -channel blockers  thiazide-like diuretics  spironolactone  β-blockers  α-blockers  K -channel openersANY QUESTIONS? fam51@cam.ac.uk