Pharmacology of Anti-Anginal Drugs PDF

Pharmacology of Anti-Anginal Drugs PHARD 0585-0595-0995 Dr. Prasanth Puthanveetil, PhD Jan 7th, 2025 12/20/2024 1  Learning objectives Students should be able to understa...

Pharmacology of Anti-Anginal Drugs PHARD 0585-0595-0995 Dr. Prasanth Puthanveetil, PhD Jan 7th, 2025 12/20/2024 1  Learning objectives Students should be able to understand; 1. Overview of Ischemic Heart Disease 2. Types and causes of Angina 3. Classification of anti-anginal medications 4. Mechanism of action of anti-anginal agents 5. Adverse effects and drug-drug interaction of anti-anginal agents 12/20/2024 2 Ischemia – Imbalance in myocardial oxygen demand and supply The myocardial oxygen demand is regulated by the heart rate, cardiac contractility, and the wall tension. The oxygen supply is determined by coronary blood flow and regional or tissue specific blood flow 12/20/2024 3  Ischemic Heart Diseases (IHD) Common Markers for MI- a) CK-MB, b) Troponin T- and I 12/20/2024 4 Images adopted from - https://www.thrombosisadviser.com  Angina Pain or Discomfort- > due to lack of Oxygen supply to the Cardiac muscles. It is not a disease but an indication or serious symptom of hidden cardiovascular complication – Coronary Artery Disease/Ischemic Heart Disease. 12/20/2024 5 Image adapted from - https://www.cancercarewny.com/content.aspx?chunkiid=12056  Types of Angina ◆ Stable Angina ◆ Unstable Angina ◆Variant or Prinzmetal Angina ◆ Microvascular Angina 12/20/2024 6  Pathophysiology - Angina Variant/Prinzmetal Malfunctioning of Nitric Oxide (Prinzmetal) mediated Vasodilation https://healtheappointments.com/chapter-6-ischemic-heart-disease-essays/2/ 12/20/2024 7 Image adapted from Med Sci Monit. 2012 Dec;18(12):RA173-80.  Microvascular Angina Impairment in micro vessels due to; Imbalance in neural factors (NA, Ach) Endothelial factors Myogenic contribution Metabolic stress 12/20/2024 8 Image Source from - https://www.bhf.org.uk  Anti-Anginal Medications Rationale – Agents that could decrease myocardial oxygen demand or increase myocardial oxygen supply Classification of Antianginal medication a) Organic nitrates- Nitric Oxide donors b) Inward Na+ channel Inhibitor-Ranolazine- (Ranexa) c) Hyperpolarization activated Cyclic Nucleotide gated channel (HCN) inhibitor -Ivabradine- (Corlanor) d) Calcium Channel Blockers- (covered on antihypertensives) e) Beta blockers- (covered on antihypertensives) 12/20/2024 9  Organic Nitrates High Potency Nitrates – GTN / Nitroglycerin - (Nitrostat, Nitrolingual, GoNitro), Pentaerythritol tetranitrate (PETN or PETN). Low Potency Nitrates – ISMN- Isosorbide mononitrate and ISDN- Isosorbide dinitrate. 12/20/2024 10  MOA of Organic Nitrates Bioactivation Bioactivation in in ER Mitochondria Primary mandatory Step Nitrite or Xanthine Oxidase 12/20/2024 11 Image modified from Thomas Münzel et al. Circ Res. 2005;97:618-628  MOA of Organic Nitrates 1 ) High potency nitrates under low dose; (GTN, PETN) ❖ Undergoes bioactivation by mitochondrial aldehyde dehydrogenases (ALDH2) to form nitrite. ❖ Nitrite then either by reaction with mitochondrial cytochrome oxidase or Xanthine Oxidase get converted to NO (Nitric Oxide) 2) High potency nitrates under high dose;(GTN, PETN) ❖ Along with the previously mentioned mitochondrial route, they also get activated by ER residing CYP P450 system to release NO 3) Low potency nitrates. (ISDN, ISMN) ❖ Known to utilize the ER residing CYP 450 system to get bio-activated and release NO irrespective of the dose. Released NO-> soluble Guanylate Cyclase-> cGMP ->cGK-1 -> Relaxation of Vascular Smooth Muscle Cells 12/20/2024 12  Systemic positive effects of Nitrates 1) On Vascular Smooth muscle – NO because of their ability to relax veins can increase venous capacitance and reduces the preload. Ultimately decreasing incidences of MI and heart failure 2) NO can cause an increase in cGMP inside platelets which results in prevention of aggregation. The property is made use of in unstable angina. 12/20/2024 13 Diabetes 2016 Jun; 65(6): 1487-1489. https://doi.org/10.2337/dbi16-0014  Adverse effects of Nitrates The most common adverse effect is because nitrites react with hemoglobin to form methemoglobin, a molecule with low affinity for oxygen, leading to a condition of oxygen deprivation called pseudocyanosis. It could be fatal, so monitoring is required Hypotension. It may cause reflex tachycardia (adaptive response) ultimately resulting in increased oxygen demand. 12/20/2024 14  Tolerance for Nitrovasodilators Overdose could lead to ROS (reactive oxygen species) generation following Nitrate therapy. Excess ROS can down regulate NO by converting them to peroxynitrite levels. ROS Nitric Oxide Peroxynitrite 12/20/2024 15  DDI- Nitrates Most prominent interaction with PDE -5 inhibitors (Sildenafil Citrate, Tadalafil)- Known to potentiate hypotensive risks. At times could induce reflex tachycardia followed by MI. Nitroglycerin is known to prevent the first pass metabolism of Ergotamine/dihydroergotamine increasing their bioavailability. In excess ergot alkaloids could precipitate angina so should be avoided in patients who are on nitrates. 12/20/2024 16 Ranolazine- Inward Na+ Current/ Channel inhibitor (RANEXA®) Myocardial Ischemia is accompanied by an increase in Inward Na+ Current. This is accompanied by a Na+ overload in myocardial tissue Excess Ca 2+ Increased Na+ then cause an increase in Ca 2+ entry through Na+-Ca2+ exchanger This enhanced Ca 2+ overload could increase in contractility followed by increased myocardial oxygen demand which can debilitate the cardiac muscle function 12/20/2024 17 Image adopted from - Giorgio Minotti. Journal of Pharmacology and Experimental Therapeutics September 2013, 346 (3) 343-349  Ranolazine- MOA MOA -By inhibiting Inward Na+ channel decreases the excess Na+ load. Indirectly preventing excess Ca2+ overload. This reduces the myocardial oxygen demand. It can be co-administered with other anti-anginal drugs. 12/20/2024 18 Image adopted from - Giorgio Minotti. Journal of Pharmacology and Experimental Therapeutics September 2013, 346 (3) 343-349  Adverse effects, contraindications and drug interaction QT prolongation. Contraindicated in patients with pre-existing QT prolongation as it can lead to torsade de pointes and ventricular tachyarrhythmia. Inhibits the CYP3A4/5 and CYP2D6 enzymes- drug interaction exist with ketoconazole, itraconazole, and quinidine. 12/20/2024 19  Ivabradine (Corlanor®) Increased SA nodal activity can lead to increased contractility and enhanced myocardial oxygen demand. The hyperpolarization activated cyclic nucleotide gated channels (HCN) play a major role. Ivabradine – MOA: It involves inhibition of Na+ entry (inward funny current) through HCN in the SA node with reduction in heart rate leading to reduced myocardial oxygen demand. Na+ This property will be made use of in angina. Ivabradine 12/20/2024 Role of ivabradine in management of stable angina in patients with different clinical profiles. 20 Kaski JC, et.al, Open Heart. 2018 Mar 9;5(1):e000725. Figures from https://www.corlanorhcp.com/mechanism-of-action/ Adverse effects: Bradycardia Atrial fibrillation Visual disturbances Contraindications:- In decompensated heart failure, prior history of bradycardia or atrial fibrillation(SA nodal dysfunction). Also, in Hepatic dysfunction and pregnant women because known to cause fetal toxicity. 12/20/2024 21  Ivabradine- drug interactions Not recommended to use along with the strong cytochrome P450 3A4 (CYP3A4) inhibitors like antibiotic Clarithromycin, anti-fungal agent like Ketoconazole, and drugs used for HIV therapy like Indinavir. 12/20/2024 22  Calcium Channel Blockers – Verapamil, Diltiazem, and Amlodipine MOA: ✓Bind to the α1 subunit of the L-type Ca2+ channel (α1 subunit is the main pore-forming unit of the calcium channel) ✓ As a result, there is decrease in heart rate and force of contraction along with vasodilation 12/20/2024 23  Comparison of the various CCBs https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=194547378&gbosContainerID=0&gbosid=0&groupID=0 12/20/2024 24  Adverse Effects and Drug Drug Interactions Headache and dizziness are some of the common adverse effects. Serious adverse effects include – bradycardia, asystole and exacerbation of heart failure. So contraindicated in patients suffering from congestive heart failure, SA or AV nodal dysfunction. CCBs are metabolized by intestinal and liver CYP3A4 enzymes, so anti-retroviral drugs and grapefruit which could inhibit CYP3A4 enhances CCB toxicity and CYP3A4 inducers like Rifampicin and Carbamazepine reduces bioavailability. 12/20/2024 25  Beta blockers Most commonly used ones include- β 1 specific blockers (Atenolol, Metoprolol or Bisoprolol). Used in conditions of exertional angina, patients with a prior MI history, and for stable and unstable angina. MOA:- By blocking specifically the β 1 receptors in cardiovascular tissue, it leads to negative chronotropic and inotropic effects. As a result, myocardial oxygen demand and use is decreased. (β 1 receptors are also known to regulate HCN channel activity in pacemaker cells (SA node) along with their direct stimulatory effects on cardiac muscle) 12/20/2024 26  Adverse effects and DDI Bradycardia. Rarely cause Left Ventricular Dysfunction. DDI- Cholestyramine and Colestipol decrease the absorption of beta blockers, resulting in reduced bioavailability of beta (β) blockers. β blockers also have shown to interfere with the clearance of lidocaine. 12/20/2024 27  Drugs used for Angina- Summary Ranolazine, Ivabradine – decrease myocardial Na+ level Anti-hyperlipidemics, Antiplatelets 12/20/2024 28  Bibliography 1. Goodman & Gilman, The Pharmacological Basis of Therapeutics 14th Ed. 2. Katzung BG, Basic and clinical pharmacology 15th Ed. 3. Golan DE, Principles of Pharmacology 3rd Ed. 12/20/2024 29  General Reading 12/20/2024 30  Organic – Short and Long acting Nitrates Nitrates need to be bioactivated Short-acting; Nitroglycerin-→sublingual -->10–30 min Isosorbide dinitrate -> sublingual -> ->10–60 min Amyl nitrite, inhalant → 3–5 min 12/20/2024 31  Organic- Long acting Nitrates Nitroglycerin, oral sustained-action 6.5–13 mg per 6–8 hours Nitroglycerin, slow-release, buccal 1–2 mg per 4 hours Nitroglycerin, slow-release patch, transdermal 10–25 mg per 24 hours Isosorbide dinitrate, sublingual 2.5–10 mg per 2 hours Isosorbide dinitrate, oral 10–60 mg per 4–6 hours Isosorbide dinitrate, chewable oral 5–10 mg per 2–4 hours Isosorbide mononitrate, oral 20 mg per 12 hours 6–10 hours Pentaerythritol tetranitrate (PETN) 50 mg per 12 hours 10–12 hours 12/20/2024 32