Calcium Channel Blockers (CCBs) PDF

Calcium Channel Blockers (CCBs) Erin Bruce, Ph.D Learning Objectives Discuss the role of calcium in vascular and cardiac tissues Explain the mechanism of action of CCBs Compare and contrast the key classes of CCBs (dihydropyridines and non- dihydropyridines) Identify the common indica...

Calcium Channel Blockers (CCBs) Erin Bruce, Ph.D Learning Objectives Discuss the role of calcium in vascular and cardiac tissues Explain the mechanism of action of CCBs Compare and contrast the key classes of CCBs (dihydropyridines and non- dihydropyridines) Identify the common indications, precautions, adverse events, and drug interactions associated with therapeutic use of CCBs Abbreviations VGCCs – Voltage Gated Calcium Channels CCBs – Calcium channel blockers DHPs – Dihydropyridines Non-DHPs – Non-dihydropyridines CO – Cardiac Output TPR – Total Peripheral Resistance SA Node – Sinoatrial node AV Node – Atrioventricular node MOA – Mechanism of Action ADME – Absorption, Distribution, Metabolism, Elimination CYP3A4 – Cytochrome P450 3A4 Pharmacotherapies for Hypertension Diuretics – Promote sodium and water filtration ACEi, ARBs, Renin inhibitors – Block effects of RAAS Beta-Blockers – Block SNS affect on the heart (block increase in HR and contractility) Alpha-antagonists – Block SNS induced vasoconstriction Vasodilators and Calcium Channel Blockers – NO donors, cGMP activators (Viagra) – CCBs also affect heart rate and contractility Calcium Channel Basics Voltage Gated – They open at specific voltage thresholds Membrane bound Only permeable to Calcium Intracellular calcium – Powerful second messenger regulating almost every aspect of cell function – Levels are kept low so that there is a targeted response to Ca++ influx – High intracellular levels are cytotoxic (induce apoptosis)  Two basic subtypes of VGCCs T-Type Ca++ channel – Transient (Rapidly closes) – Low-Voltage Activated (LVA) opens around -55mV L-Type Ca++ channel – Long-Lasting (Slow to Close) – High-Voltage Activated (HVA) Opens at around -40mV Review of Cardiac Ca++ Handling Action Potentials in the Heart: Nodal (Slow) Phase 4 (”Resting” TMP) TMP: Transmembrane Potential 1. Ih/If – the “funny” current Opens in response to hyperpolarization Slow depolarization Slow Na+ ion channel (channel permeable to both Na+ and K+) Start of Prepotential 2. ICaT – Transient Ca+ Current Opens in response to slow depolarization from “funny current” Completes Prepotential Phase 0 (Depolarization) 1. IcaL - Long lasting Ca+ Channel opens Transmembrane Potential (TMP) threshold is reached Depolarization Phase 3 (Repolarization) 1. Ik – delayed rectifier K+ Channel Opens to counteract increase in Ca+ Causes brief plateau before return to resting TMP as Ca+ channels close Action Potentials in the Heart: Cardiomyocytes (Rapid) Phase 0 Opening of fast Na channel Opening of slow L-Type Ca++ Channel Rapid depolarization Phase 1 Inactivation of Na channel Increase in Ca++ current Transient increase in K due to drop in Na Transient Repolarization Phase 2 Ca++ channel is slow to close Decrease in K permeability Delays Repolarization (Plateau Phase) Phase 3 Ca++ channel is now closed Increase in K permeability (K efflux) Repolarization Phase 4 Resting membrane potential (-90 mV) Cardiac Excitation-Contraction Coupling L-Type Ca2+ channel is not mechanically linked to RyR on SR Calcium-induced Calcium Release (CICR) Small influx of extracellular Ca2+ leads to large release of Ca2+ from SR Cardiac SERCA has phospholamban (PLB) Inhibitory of Ca2+ reuptake (slows it down) Na+/Ca2+ exchanger (NCX) moves Ca+ from inside the cell to outside Cardiomyocyte contraction relies on Extracellular Ca2+ Review of Smooth Muscle Ca ++ Handling  Smooth Muscle Blood Vessels, digestive, respiratory, urinary, and reproductive tracts and organs. Involuntary: Multiple activation pathways – Autonomic: SNS – – alpha-receptors vasoconstrict; – beta-2 receptors vasodilate; PsNS – acetylcholine binds muscarinic receptors to vasodilate – Endocrine and Paracrine substances causing vasoconstriction or dilation – Pacemaker activity (peristalsis in GI system) – Mechanical responses Smooth Muscle Excitation Contraction Coupling Ca2+ enters through L-Type Ca2+ channel Ca2+ activates Calmodulin Calmodulin activates Myosin Light Chain Kinase (MLCK). MLCK phosphorylates and activates Myosin allowing it to bind actin Release of ADP+Pi causes power stroke ATP binding leads to release from actin Myosin Light Chain Phosphatase dephosphorylates and inactivates myosin causing cell to relax Pharmacomechanical coupling Contraction of smooth muscle in response to an agent that does not produce a change in membrane potential Direct action on MLCK, MLCP, or Caldesmon/Calponin (tonic inhibitors of ATPase activity in absence of Ca2+/Calmodulin) Most substances still act to increase intracellular Ca2+, just don’t cause a depolarization event. Just because they don’t have to change membrane potential, doesn’t mean they can’t. They often link to membrane ion channels via second messengers, leading to changes in TMP Test your Knowledge In what phase of the cardiomyocyte action potential does excitation contraction coupling primarily occur? a) Phase 0 b) Phase 2 c) Phase 3 d) Phase 4 15 Summary There are 2 main types of VGCCs, L- Type and T-Type Ca++ levels are highly regulated in the cell Ca++ influx is essential for cardiac muscle contraction Ca++ enters Smooth muscle cells via L- Type Ca++ channels 16 CCBs Mechanism of Action Erin Bruce, PhD Learning Objectives Discuss the role of calcium in vascular and cardiac tissues Explain the mechanism of action of CCBs Compare and contrast the key classes of CCBs (dihydropyridines and non- dihydropyridines) Identify the common indications, precautions, adverse events, and drug interactions associated with therapeutic use of CCBs 18  Blocking VGCCs in the Heart Cardiomyocytes: Nodal Cells: Slow Rapid Depolarization Depolarization 19  Would Heart Rate increase or decrease? Blocking an ion channel means less ions can get in The channel is less permeable to Ca++ Blocking the L-Type CC has If the channel is negative chronotropic actions less permeable, the threshold for Blocking the T-Type CC has depolarization will negative chronotropic actions take longer to reach HR Decreases  Would contractility be affected? Decreased permeability to Ca++ means less Ca++ influx Blocking the L-Type CC has Decreases CICR negative chronotropic and ionotropic actions Less Ca++ released from SR Decreased contractility Figure 13.6 B) Koeppen and Stanton. Berne & Levy Physiology (2017) How does this affect Blood Pressure? Ohm’s Law: ΔP = F x R or as we think about it: BP = CO x TPR CO = SV x HR CCBs decrease SV and HR Therefore, BP decreases due to ↓CO (F) Blocking VGCC in Smooth Muscle Less Ca2+ influx Less activation of Calmodulin Less activation of MLCK Fewer myosin heads binding to actin Weak power stroke No constriction How does this affect Blood Pressure? Ohm’s Law: ΔP = F x R or as we think about it: BP = CO x TPR CCBs decrease constriction/resistance Therefore, BP decreases due to ↓TPR Additional affect on BP: Aldosterone Both T-Type and L-Type VGCCs found aldosterone producing cells in adrenal cortex Ca++ regulates key steps in Remember, Aldosterone is a steroid and can move freely aldosterone synthesis through the cell membrane. It is Increase in intracellular Ca++ leads to secreted from the cell as soon as it is synthesized. increased aldosterone synthesis Therefore CCBs, reduce aldosterone synthesis and secretion How does this affect Blood Pressure? Lower Aldosterone production means decreased sodium and water retention in the kidney, reduced blood volume, decreased cardiac output, and decreased blood pressure. Aldosterone is also a vasoconstrictor, therefore, less aldosterone means decreased resistance Test your knowledge A new calcium channel blocker binds both T-type and L-type Calcium Channels. What affect does this have on vasoconstriction? a) Increased vasoconstriction b) Decreased vasoconstriction c) No change in vasoconstriction Summary CCBs can inhibit either L-Type, T-Type or both Ca++ channels, but are often most selective for L-type VGCCs CCB therapy reduces blood pressure by decreased cardiac output and total peripheral resistance CCBs: Classes and Indications Erin Bruce, PhD Learning Objectives Discuss the role of calcium in vascular and cardiac tissues Explain the mechanism of action of CCBs Compare and contrast the key classes of CCBs (dihydropyridines and non- dihydropyridines) Identify the common indications, precautions, adverse events, and drug interactions associated with therapeutic use of CCBs 30  General ADME of CCBs Absorption – Nearly complete (low secretion) but most have significant ‘first-pass effect’ Distribution – Generally have high protein binding (70-98%) Metabolism – Many CCBs metabolized by cytochrome P450 (CYP) 3A4 Elimination – Half-life vary widely from 1.3-64 hrs – Have various formulations available 31 Short vs. Long Acting CCBs with short half-lives cause rapid change in BP – Can be associated with dizziness and flushing, and can also lead to reflex tachycardia Long half-life or sustained release CCBs have less reflex tachycardia, dizziness, and flushing Most CCBs on the market either have long half-lives or are sold in extended release formulations 32 2 main classes of CCBs Non-Dihydropyridines (Non- DHPs) – Benzothiazepines (Diltiazem) – Phenylalkylamines (Verapamil) Dihydropyridines (DHPs) – Amlodipine, clevidipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, nimodipine 33  DHPs vs Non-DHPs Both Non-DHPs can directly affect Inhibit L-Type calcium chronotropic (↓HR), inotropic channels in arterial smooth (↓contractility), dromotropic muscles promoting vasodilation and (↓conduction velocity) ↓TPR Non-DHPs DHPs Less potent More potent vasodilators, vasodilators, but have more but have less effect on CO effect on CO 34 DHPs vs. Non DHPs Blood pressure = CO x TPR Comparative effects of common CCBs Non-DHPs DHPs Additional Approved Indications for DHPs Angina (chest pain or discomfort caused by hypoxia of cardiac tissue) – Decreased TPR leads to increased venous return and therefore increased oxygen supply to coronary arteries with each beat Note: DHPs are also not used as – The best anti-anginal DHPs are more first line for supraventricular selective for coronary blood vessels tachycardia or atrial fibrillation due to lack of direct effects on L-type Amlodipine, nifedipine, nicardipine channels in cardiac tissue – Due to lace of more direct effects on CO, DHPs would generally NOT be considered as first line for angina, but could be used as an adjunct therapeutic  Precautions – Non-DHPs Advanced heart block – Reducing AV node conduction with Non-DHP could exacerbate existing heart block Severe aortic stenosis – Vasodilatory effect will lower CO and further reduce oxygen supply to the heart Cardiogenic shock – Further reduce HR and BP Beta1 – Adrenergic receptor antagonists We will cover Beta-Blockers in the next lecture series – Avoid combining non-DHPs with BBs in patients with low HR Precautions-DHPs Severe Aortic stenosis – Vasodilatory effect will lower CO and further reduce oxygen supply to the heart Cardiogenic shock – Further reduce BP Other general/relative considerations for both DHPs and Non-DHPs Liver Failure – CCBs are predominantly metabolized via the liver Gastroesophageal Reflux Disease (GERD) – CCBs reduce lower esophageal sphincter contraction – enhancing GERD symptoms Adverse Events associated with Non-DHPS First Degree AV block Bradycardia Exacerbation of chronic heart failure or cardiac pulmonary edema – All of the above due to effects on cardiomyocytes Uncommon: Constipation - elevations of liver enzymes – Due to a reduction in GI motility caused by - Fatigue, nervousness, drowsiness, inhibition of GI smooth muscle contraction depression, insomnia, confusion (CNS – Is greatest with Verapamil (~10%; also occurs with effects) diltiazem) - Gingival hyperplasia Nausea and vomiting, diarrhea, anorexia - Skin reactions - Urinary retention Flushing, headache, peripheral edema, dizziness Adverse Events associated with DHPs Peripheral edema Nausea and vomiting, diarrhea, anorexia Uncommon: Flushing, headache, dizziness - Constipation - Elevations of liver enzymes - Fatigue, nervousness, drowsiness, depression, insomnia, confusion (CNS effects) - Gingival hyperplasia - Skin reactions - Urinary retention Drug Interactions – Avoid combining CCBs with: Anasthetics Amiodarone (anti-arrythmic) Digoxin (for heart failure and some arrythmias) Beta-Blockers Prednisone Use caution in combining with other drugs metabolized by CYP3A4 Drug Interactions – Avoid combining CCBs with: Drugs that directly inhibit CPY3A4 – Can increase levels of CCBs Protease inhibitors Azole antifungals SSRIs Grapefruit juice CPY3A4 inducers – Can decrease levels of CCBs – Rifampin (an antibiotic) Test your Knowledge A patient with hypertension has a history of tachycardia (elevated HR). What might be the best CCB to prescribe? a) Amlodipine b) Nifedipine c) Verapamil d) Captopril Summary There are two main classes of CCBs – Non-DHPs – DHPs Non-DHPs have a more direct effect on CO DHPs have a greater effect on vasodilation CCBs should not be given with other heart failure drugs that could lead to an additive effect and cause hypotension CCBs should not be given with drugs that either inhibit or induce CPY3A4, as they are metabolized by this enzyme in the liver