Cardiovascular Therapeutics_ Midterm 6.57.56 PM.pdf

Cardiovascular Therapeutics: Midterm MAP= (2xDBP + SBP)/3 INTRODUCTION TO CARDIOVASCULAR MEDICATIONS 1. B-Adrenergic Agonists and Antagonists (beta blockers): a. Beta receptors: G-protein coupled receptors stimulate activity of adenylyl cyclase to promote con...

Cardiovascular Therapeutics: Midterm MAP= (2xDBP + SBP)/3 INTRODUCTION TO CARDIOVASCULAR MEDICATIONS 1. B-Adrenergic Agonists and Antagonists (beta blockers): a. Beta receptors: G-protein coupled receptors stimulate activity of adenylyl cyclase to promote conversion of ATP to cAMP. i. Contractility: the ability of the heart muscle (myocardium) to contract and generate force. ii. Conduction velocity: the speed at which an electrical impulse travels through the heart’s conduction system. The heart relies on these electrical signals to coordinate the timing of heartbeats, ensuring that the chambers contract in a synchronized manner to pump blood efficiently. b. B-receptors are post synaptic, leading to tissue specific physiological effects. c. B-blockers competitively antagonize the B receptors d. Key physiological effects of B receptor agonism  Acebutolol, penbutolol, pindolol: can cause mild agonism Bisoprolol and nadolol heavily dependent on renal function Indication of B-blockers: Cardiac Indications Noncardiac Indications Angina: chest pain or discomfort that Elevated intraocular pressures occurs when the heart muscle doesn't (timolol) get enough oxygen-rich blood. Essential tremor (propranolol) Arrhythmias Migraine prophylaxis (propranolol, Atrial fibrillation: heart arrhythmia timolol) (irregular heartbeat) that occurs when the electrical signals in the atria (the upper chambers of the heart) become chaotic. This causes the atria to quiver or "fibrillate" instead of contracting normally. As a result, the heart may not pump blood efficiently, leading to various health risks. Hypertension Heart failure with reduced ejection fraction: heart's left ventricle cannot pump blood effectively, leading to a reduced amount of blood being ejected with each heartbeat. The ejection fraction (EF) is a measurement of the percentage of blood leaving the left ventricle each time the heart contracts. Myocardial infarction: heart attack  Pharmacokinetics of B-blockers: ○ Well absorbed with peak concentrations 1-3 hours after oral dose Carvedilol should be taken with meals to improve bioavailability ○ Metoprolol and propranolol also available as IV solutions Esmolol is IV only ○ Propranolol is highly lipophilic and readily crosses the BBB ○ Atenolol: most hydrophilic, heavily dependent on renal function ○ Half life: 3-10 hours for most Esmolol ~10 minutes Betaxolol, nadolol, nebivolol ~11-30 hours ○ Carvedilol, metoprolol, propranolol: extended release versions Metoprolol tartrate (immediate), succinate (extended) ○ Hepatically cleared: carvedilol, labetalol, metoprolol, propranolol ○ Renally cleared: acebutolol, atenolol, betaxolol, bisoprolol, nadolol, nebivolol, sotalol Class-Wide Adverse Drug Reactions: ○ Bradyarrhythmias (decreased heart rate) ○ Bronchospasm (drug-dose dependent) ○ Fatigue, insomnia, sleep disturbance: More common with lipophilic B-blockers (e.g. propranolol). Overtime tends to go away ○ Hypotension ○ Masking of hypoglycemia: When blood sugar levels drop, the body typically responds with a "fight or flight" response, releasing adrenaline (epinephrine) and other stress hormones. This causes symptoms like rapid heartbeat, sweating, and shakiness, which alert a person to low blood sugar. Beta-blockers block the action of adrenaline and other similar hormones by binding to beta-adrenergic receptors. As a result, the typical symptoms of hypoglycemia, such as increased heart rate and trembling, may be diminished or less noticeable. ○ Metabolic: hypercholesterolemia, hypertriglyceridemia ○ Withdrawal: rebound tachycardia, hypertension, and/or ischemia (insufficient blood flow to a part of the body, usually resulting in a shortage of oxygen and nutrients necessary for cellular metabolism. This reduced blood flow can lead to tissue damage or death if not promptly addressed.) Precautions and Contraindications: ○ Carvedilol: CYP2D6 (major), P-gp inhibitor (also known as multidrug resistance protein 1 (MDR1), is a protein that functions as a drug transporter. It plays a  critical role in the body’s ability to expel various substances, including drugs, from cells.) ○ Metoprolol: CYP2D6 (major) ○ Propranolol: CYP2D6 (major) 2. Calcium Channel Blockers: a. L-Type Channels i. Myocardium, SA/AV nodes, vascular smooth muscle ii. CCB: decrease contractility, result in vasodilation iii. These are specific types of voltage-gated calcium channels that are primarily responsible for the influx of calcium ions during the action potential in cardiac and smooth muscle cells. They play a crucial role in muscle contraction and electrical conduction. iv. Myocardium: CCB decreases contractility v. SA/AV nodes: decreases automaticity and conduction velocity (slow heart rate) 1. Automaticity in the heart refers to the ability of cardiac cells, particularly those in the sinoatrial (SA) node and other parts of the conduction system, to generate electrical impulses spontaneously without external stimulation. vi. Vascular smooth muscle: relaxation (peripheral vasodilation, coronary artery vasodilation, decreased GI tone) DHP vs non-DHP: bind on different locations on L-type channels Different affinities for cardiac and smooth muscle cells  Indications: ○ Non-DHP: Hypertension Ischemic heart disease: reduced blood flow to the heart muscle due to the narrowing or blockage of the coronary arteries. This decreased blood flow can lead to various symptoms and complications, including angina (chest pain) and heart attacks. "Isch-": This comes from the Greek word "ischos", which means "a holding back" or "stopping." "-emia": This suffix is derived from the Greek word "haima" or "aima", which means "blood." Supraventricular tachyarrhythmias: group of abnormal rapid heart rhythms originating above the ventricles, specifically in the atria or the atrioventricular (AV) node. These arrhythmias are characterized by an unusually fast heart rate, often greater than 100 beats per minute, and are caused by disruptions in the heart’s normal electrical conduction pathways. ○ DHP: Hypertension Ischemic heart disease PK: ○ Rapid onset IV (within minutes) Verapamil, diltiazem, nicardipine, clevidipine ○ Short acting IV: Clevidipine (t1/2 15 mins) Nicardipine (t1/2 40-60 mins) ○ Nifedipine IR Too rapid and dramatic onset of effect, therefore PO/SL administration of nifedipine IS not recommended ○ Amlodipine intrinsically has a long t1/2 and long duration of action ○ CCBs are cleared HEPATICALLY Safe in renal insufficiency, prone to CYP and P-gp DDI (primarily CYP3A4) ADRs: ○ GI (constipation, GERD) Calcium ions are crucial for muscle contraction, including in the smooth muscle of the GI tract. When calcium channels are blocked, the influx of calcium into these smooth muscle cells is reduced. This decreased calcium availability impairs the ability of smooth muscle cells to contract properly, leading to reduced peristalsis (the coordinated contractions that move food  through the intestines). The reduced contraction of smooth muscle in the intestines leads to decreased GI motility. This slower movement of the intestinal contents can result in prolonged transit time, leading to constipation. ○ Peripheral edema (arterial vasodilation) ○ Non-DHP more likely to cause bradycardia DDIs: ○ Verapamil (2D6, P-gp): digoxin, new oral anticoagulants, simvastatin ○ Diltiazem (3A4): ranolazine, simvastatin ○ Amlodipine (3A4): simvastatin 3. ACE inhibitors, ARBs, ARNI a. ACE inhibitors: block the activity of ACE, also decreased breakdown of bradykinin i. ACE breaks down bradykinin b. ARBs (Angiotensin Receptor Blocker): blocks binding of angiotensin II Type1 receptor. c. Neprilysin inhibitors: block the activity of neprilysin i. Decreases breakdown of bradykinin and natriuretic peptides ii. Bradykinin, which promotes blood vessel dilation and a lowering of blood pressure.  d. Indications: i. ACEi/ARBs: 1. Acute coronary syndrome 2. Heart failure with reduced EF 3. Hypertension 4. Proteinuric chronic kidney disease ii. ARNI 1. Heart failure with reduced and preserved EF e. Pharmacokinetics: i. All are generally long acting with long half life eliminations and delayed onset of effect (antihypertensive effect may not be seen for a few days) 1. Captopril is the shortest acting ACEi (half life ~2 hours) ii. Cleared renally and may accumulate in renal dysfunction 1. Fosinopril and moexipril not cleared renally iii. Enalaprilat only IV ACEi, used for hypertensive crises. f. Precautions and Contraindications: i. Acute kidney injury 1. However, a small (