Wk 1 Drug Treatments - CVD 2024 PDF

Pharmacological Treatments Cardiovascular Diseases Dr Lujain Alsadder Learning Objectives Describe the role of the vascular endothelium and the targets used to treat coagulation disorders. Revise the renin-angiotensin-aldosterone (RAAS) system Explain the mechanisms of action of dr...

Pharmacological Treatments Cardiovascular Diseases Dr Lujain Alsadder Learning Objectives Describe the role of the vascular endothelium and the targets used to treat coagulation disorders. Revise the renin-angiotensin-aldosterone (RAAS) system Explain the mechanisms of action of drugs used to control hypertension through their action on the RAAS, and name examples. Describe the major classes of drugs and their mechanism of action to treat cardiovascular diseases such as stable angina, acute coronary syndrome, heart failure and arrhythmia. 2  Cardiovascular Diseases Cardiac - ischaemic heart disease, myocardial infarction, heart failure Vascular: Valvular diseases: aortic, Peripheral arterial disease, rheumatic heart disease cerebrovascular disease, Myocardial, pericardial hypertension, kidney disease Congenital Arrhythmia 3  Impact of Cardiovascular Diseases In England and Wales, 55,064 of deaths (10.4%) were due to ischaemic heart diseases (IHDs); this was the second leading cause of death in 2019 (Public Health England, 2019) An estimated 17.9 million people died from CVDs in 2019, representing 32% of all global deaths. Of these deaths, 85% were due to myocardial infarction and stroke (WHO, 2019) In England, CVD accounted for 1 million hospital admissions in 2019/20, leading to 5.5 million bed days and costing the NHS an estimated £7.4 billion (Kings Fund, 2022). 4 Learning Objectives Describe the role of the vascular endothelium and the targets used to treat coagulation disorders. Revise the renin-angiotensin-aldosterone (RAAS) system Explain the mechanisms of action of drugs used to control hypertension through their action on the RAAS, and name examples. Describe the major classes of drugs and their mechanism of action to treat cardiovascular diseases such as stable angina, acute coronary syndrome, heart failure and arrhythmia. 5 Vascular endothelium Vascular endothelium has a pivotal role in the regulation of vascular tone, controlling tissue blood flow and inflammatory responses and maintaining blood fluidity. Inflammation, high blood pressure. high circulating cholesterol (LDL)..etc accelerate endothelial damage and dysfunction (Sena et al., 2013) 6 7 Statins (e.g. atorvastatin) HMG-CoA (hydroxymethylglutaryl- coenzyme A) reductase is the rate limiting step in cholesterol synthesis Statins are competitive inhibitors of HMG-CoA Decreased hepatic cholesterol synthesis upregulates LDL receptor synthesis Increases clearance from blood Decrease plasma triglycerides and increase HDL 8  Aspirin (anti-platelets) Low dose inhibits COX-1, high dose inhibits COX-2 COX-1 converts arachidonic acid into prostaglandin H2 (PGH2), a precursor for other prostaglandins PGH2 is converted to thromboxane A2 Potent stimulator of platelet aggregation Aspirin is an irreversible inhibitor of COX in platelets Covalently binds to the enzyme Platelets cannot make new protein 9  P2Y12 Antagonists (anti-platelets) Clopidogrel/Ticagrelor ADP is found in platelets and stimulates platelet aggregation Positive feedback mechanism for platelet aggregation P2Y12 receptors found on platelets Inhibition of P2Y12 has anti- platelet aggregation properties Prevents thrombus formation 10  Thrombolytic (fibrinolytic) therapy Plasminogen activators Used to activate plasminogen to drive fibrin degradation, dissolving blood clots and restoring blood flow. Complications: bleeding 11  Anticoagulants (blood thinners) Different targets on the coagulation pathway Direct Xa inhibitors Direct Thrombin inhibitors Vitamin K antagonists Indirect Thrombin (Warfarin) inhibitors (Heparin) 12 Learning Objectives Describe the role of the vascular endothelium and the targets used to treat coagulation disorders. Revise the renin-angiotensin-aldosterone (RAAS) system Explain the mechanisms of action of drugs used to control hypertension through their action on the RAAS, and name examples. Describe the major classes of drugs and their mechanism of action to treat cardiovascular diseases such as stable angina, acute coronary syndrome, heart failure and arrhythmia. 13 Renin-Angiotensin-Aldosterone System (RAAS) Activation of the RAAS system 1. Sympathetic nerve activation (via β1- adrenoceptors) 2. Renal artery hypotension (e.g. systemic hypotension or renal artery stenosis) 3. ↓sodium delivery to the distal tubules of the kidney Aldo: Aldosterone; AI: Angiotensin I; AII: Angiotensin II; SVR: Systemic vascular resistance; ACE: Angiotensin converting enzyme; JG: Juxtaglomerular Fountain, 2019 & Klabunde, CV physiology 14  Image Renin inhibitors ACE inhibitor Therapeutic targets: RAAS System Angiotensin II Receptor Blocker Thiazide diuretics Loop diuretics Mineralocorticoid receptor antagonist (K sparing diuretics) ↑Na+ reabsorption  ↑BP 15 Learning Objectives Describe the role of the vascular endothelium and the targets used to treat coagulation disorders. Revise the renin-angiotensin-aldosterone (RAAS) system Explain the mechanisms of action of drugs used to control hypertension through their action on the RAAS, and name examples. Describe the major classes of drugs and their mechanism of action to treat cardiovascular diseases such as stable angina, acute coronary syndrome, heart failure and arrhythmia. 16 Hypertension ↑ BP = ↑ CVD risk 17 eshonline.org  Hypertension: approach to management 18 oronary artery disease; C: CVD: Cardiovascular disease Hypertension: lifestyle modification Salt and sugar reduction Smoking and alcohol reduction Caffeine reduction Stress management Weight management Exercise (NICE, 2023) 19  Major classes of antihypertensive agents Natriuresis (Na+ excretion) reduces blood volume, venous return, cardiac output and BP 20 ACE-Inhibitors Mechanism of action: Inhibit ACE  ↓Angiotensin II (potent vasoconstrictor) vasodilation of small resistance arteries ↓systemic vascular resistance & ↓BP Side effects: cough and angioedema 21 Increased vascular permeability, angioedema 22 Thiazide diuretics Thiazide diuretics inhibit the Na- Cl co-transporter in the distal convoluted tubule Natriuresis (loss of Na) → Loss of water → ↓ blood volume, venous return & cardiac output → ↓ BP 23 Loop diuretics Loop diuretics inhibit the luminal Na/K/2Cl co- transporter in the thick ascending limb of the loop of Henle Increased delivery of Na to the distal tubule enhances K secretion into the urine 24 Calcium Channel Blockers CCBs block the Ca2+ influx in vascular smooth muscle cells (VSMCs), cardiac myocytes and cardiac nodal tissue (SAN and AVN). Non-dyhydropyridine non-DHPs do not end in – ine (diltiazem and verapamil), but dihydropyridines (DHPs) do end in –ine (amlodipine). DHPs have vascular selectivity: DHPs block VSMCs Ca2+ channel preferentially to cardiomyocytes Non DHP e.g., verapamil and diltiazem have cardiac selectivity, i.e., they are more effective in cardiac muscle than in VSMCs. 25 Calcium Channel Blockers ICS: Impulse Conduction System Sueta, Tabata & Hokimoto (2017) 26 Adrenergic receptors blockers (Beta 1 and Alpha 1) Alpha 1 blockers: vasodilation  decreased Total Peripheral Resistance/Systemic Vascular Resistance reduced blood pressure Beta blockers: decreased contractile force (ionotropy), decreased heart rate (chronotropy) 27 Examples -olol -pril -sartan -semide -thiazide -ine -none 28 Management of Hypertension 29 Learning Objectives Describe the role of the vascular endothelium and the targets used to treat coagulation disorders. Revise the renin-angiotensin-aldosterone (RAAS) system Explain the mechanisms of action of drugs used to control hypertension through their action on the RAAS, and name examples. Describe the major classes of drugs and their mechanism of action to treat cardiovascular diseases such as stable angina, acute coronary syndrome, heart failure and arrhythmia. 30  Coronary Artery Disease: Stable angina and Acute Coronary Syndrome 31 As needed: OR Nitrates - Glycerol TriNitrate (GTN) 1. Either 2. Switch Beta Blocker Calcium Channel Blocker *Do not prescribe non DHP and Beta Blockers together. 32 Nitrates Increased NO Activation of guanylyl cyclase downstream phosphorylation pathway Nitrates not to be used with: Hypotensive patients Patients using phosphodiesterase inhibitors (excess vasodilation) Patients who need maintenance of preload (preload-dependant) 33  Nitroglycerin (NTG), Glyceryl Trinitrate ↑ NO Venodilation  ↓ blood flow to heart  ↓ Preload (stretching of the heart)  ↓ contraction  ↓ myocardial oxygen demand Side Effect Profile: Headache, Dizziness, Reflex tachycardia 34  Beta blockers ↓HR, Negative ionotropic effect, ↓ BP & ↓ myocardial oxygen demand 35  Heart failure Heart failure is caused by a structural and/or functional abnormality that produces raised intracardiac pressures and/or inadequate cardiac output at rest and/or at exercise. When cardiac output is insufficient to meet the body’s metabolic requirements. The goals of treatment in patients with HF are to improve their clinical status, functional capacity & quality of life, prevent hospital admission & reduce mortality (NICE, 2023) 36 Classification of Heart Failure o Reduced ejection fraction (HFrEF = systolic failure), including less than 40% o Preserved ejection fraction (HFpEF = diastolic failure), above and including 50%. (BMJ, 2023) 37 pEF (EF >50%) mrEF (EF 40%) rEF (EF