Cardiovascular Pharmacology Quiz

Vasodilators and Adrenergic Antagonists

• Vasodilators and adrenergic antagonists are used to manage blood pressure.
• Blood pressure regulation involves vasodilation and vasoconstriction.
• Vasodilators induce vasodilation, increasing blood vessel diameter, decreasing resistance, and lowering blood pressure.
• Direct vasodilators include nitrates, hydralazine, and PDE5i.
• Calcium channel blockers, alpha2 agonists, alpha1 antagonists, and beta blockers are adrenergic antagonists.
• Blood pressure (BP) is determined by cardiac output (CO) and systemic vascular resistance (SVR).
• CO = Stroke Volume (SV) x Heart Rate (HR).
• SV is influenced by preload, afterload, and contractility.
• Preload is venous return, afterload is blood pressure and cardiac wall stress, and contractility is the force of heart contraction.
• Vasoconstriction decreases blood vessel radius, increasing resistance, and raising blood pressure.
• Vasodilation increases blood vessel radius, decreasing resistance, and lowering blood pressure.
• Vascular smooth muscle (VSMC) contraction and dilation are regulated by molecular pathways.

Blood Pressure Basics

• Cardiac output (CO) is calculated as the product of mean arterial pressure (MAP) and systemic vascular resistance (SVR).
• MAP = CO * SVR
• Blood pressure is dependent on cardiac output (HR and SV) and systemic vascular resistance.
• Preload, afterload, and contractility influence stroke volume (SV).

Vasoconstriction and Vasodilation

• Vasoconstriction decreases the radius of blood vessels and increases resistance, contributing to higher blood pressure.
• Conversely, vasodilation increases the radius of blood vessels and decreases resistance, leading to lower blood pressure.

Molecular Basis of Smooth Muscle Contraction

• Agonists activate receptors that open plasma membrane calcium channels.
• Depolarization of smooth muscle, and/or signaling, releases calcium.
• Intracellular calcium stores are released by IP3 receptors.
• Calcium activates MLCK, leading to MLC phosphorylation.
• Rho kinase is activated in parallel with MLCK to avoid MLC dephosphorylation.
• MLC phosphorylation activates myosin and causes subsequent vessel contraction.

Molecular Basis of VSMC Dilation

• Receptor-activated signaling cascades activate nitric oxide synthase (eNOS) within endothelial cells.
• Nitric oxide (NO) diffuses into VSMCs and activates soluble guanylyl cyclase (SGC).
• SGC converts GTP to cyclic GMP (cGMP).
• cGMP activates protein kinase G (PKG).
• PKG coordinates actions in VSMC to limit contraction and promotes dilation.
• cGMP action includes decreasing calcium influx/release, decreasing MLC phosphorylation, and increasing potassium efflux (K+ efflux).

PKA and Smooth Muscle Dilation

• In smooth muscle, vasodilators activate adenylate cyclase, producing cAMP.
• cAMP activates PKA.
• PKA negatively regulates MLCK, along with activation of MLCP, reducing smooth muscle contraction.
• PKA's effects in smooth muscle are opposite to its effects in the heart.

Summary of VSMC Signaling

• Signaling mechanisms exist for both contraction and dilation in VSMCs.
• Contraction involves signaling cascades culminating in MLC phosphorylation, increasing vessel tone.
• Dilation involves initiating NO synthesis ultimately leading to PKG activation, promoting relaxation.

Nitrates

• Nitrates are potent vasodilators.
• Nitrates cause the release of nitric oxide (NO).
• NO donors primarily dilate veins, decreasing venous return (preload).
• Nitrates have minimal effects on resistance arterioles, thus not significantly changing afterload and systemic pressure.

Nitrates: Compounds

• GTN (nitroglycerin) is a rapid-acting nitrate.
• ISDN (isosorbide dinitrate) and ISMN (isosorbide-5-mononitrate) provide longer-acting effects.
• Sodium nitroprusside is a potent vasodilator, but has a short half-life (used in emergencies).

NO in Smooth Muscle Cells

• NO produced in the endothelium diffuses to VSMCs.
• It activates guanylate cyclase, leading to increased cGMP.
• PKG promotes vasodilation by inhibiting calcium channels and by activating myosin phosphatase.

Reduced NO and Endothelial Dysfunction

• NO availability is reduced in several diseases, leading to impaired dilation and dysfunction.
• Factors contributing to reduced NO availability include conditions such as diabetes, hyperlipidemia, and inflammation.
• These conditions can inhibit NO production and/or promote NO degradation.

Nitrates and Areas of Action

• Nitrates primarily affect veins, decreasing preload and venous return to the heart, which reduces myocardial workload and oxygen demand.
• Nitrates also dilate larger conduit vessels, increasing blood flow.
• Nitrates have a limited effect on arterioles (resistance vessels), causing only mild decrease in afterload.

Nitrate Tolerance

• Prolonged or frequent nitrate use can lead to tolerance and decreased effectiveness.
• Tolerance mechanisms involve changes in processing enzymes and potential damage to signaling pathways.
• Strategies to prevent nitrate intolerance include using avoidance of high doses, or intermittent therapy.

Hydralazine

• Hydralazine is a potent arteriolar vasodilator that acts directly on VSMCs.
• Its mechanism of action involves opening K+ channels and inhibiting Ca++ release, which ultimately causes vasodilation.
• Hydralazine can decrease reactive oxygen species.
• The drug may stimulate local vasodilator production (eg. VEGF, PGI2).

Hydralazine Treatment

• Hydralazine's onset of action is within 1-2 hours (oral) with a longer half-life.
• It's commonly used in combination with NO donors for emergency treatment and chronic treatment.
• Usage with caution due to potential for acute/extreme drops in blood pressure during use, requiring monitoring of other organ systems during treatment.
• Baroreflex-mediated reflex tachycardia is a potential adverse effect.

Hydralazine Summary

• Hydralazine is a potent arteriolar vasodilator, but affects veins or preload less than NO donors.
• It reduces vascular contraction via lower ROS production.
• It increases K+ channel activation which promotes vasodilation.
• Reflex tachycardia is a notable adverse effect.

PDE5 Inhibitors

• PDE5 inhibitors, like sildenafil, tadalafil, vardenafil, and avanafil, elevate cGMP levels in smooth muscle.
• cGMP activates PKG, promoting relaxation and vasodilation.
• The effects are primarily in pulmonary vasculature.
• They have strong anti-fibrotic and vasodilatory properties.
• PDE5 inhibitors are often associated with hypotension and are contraindicated with nitrates and other vasodilators.

PDE5 in Smooth Muscle Cells

• NO activates guanylate cyclase which converts GTP to cGMP.
• Increased cGMP due to PDE5 inhibitors leads to elevation of cGMP levels.
• PKG promotes dilation through inhibiting calcium channels and activating myosin phosphatase.
• Vasodilation is achieved through preventing cGMP breakdown by PDE5 inhibitors.

PDE5i

• Sildenafil, tadalafil, vardenafil, and avanafil are PDE5 inhibitors.
• They are more effective in pulmonary vasodilation than systemic dilation.
• Adverse effects include headaches, flushing, dyspepsia, and loss of vision.

Nitrates and PDE5 Inhibitors

• Combining nitrates and PDE5 inhibitors can significantly lower blood pressure due to the combined effect of vasodilation.
• Nitrates and PDE5 inhibitors cannot be used together; a time-interval separation is required between dosages.

PDE5 Summary: Things to Know

• PDE5 breaks down cGMP, antagonizing NO-cGMP-PKG pathway-dependent vasodilation.
• PDE5 inhibitors promote cGMP accumulation and have anti-fibrotic and vasodilatory effects.
• These are used in pulmonary circulation and are contraindicated with nitrates or sGC stimulators to avoid hypotension.

Ca Channels and Ca Channel Blockers

• Voltage-gated calcium channels, particularly L-type channels, are key players in cellular calcium regulation.
• These channels have 5 subunits, and the a1 subunit is crucial for pore formation.
• Calcium channel blockers (CCBs) influence calcium entry into cells.
• Verapamil and Diltiazem are examples of non-dihydropyridines.

Ca++ Channel Blockers

• Dihydropyridines reduce peripheral and coronary vascular resistance.
• Non-dihydropyridines block SA/AV node and cardiac Ca++ channels to reduce HR and vascular resistance.

Ca++ Channels and Vasoconstriction

• Ca++ influx through voltage-gated channels initiates signalling cascades.
• This further triggers intracellular Ca++ release and activates MLC phosphorylation cascades.
• The result of these cascades is increased contraction in vascular smooth muscle.
• These blockers have little effect on inducing venous dilation.

Main Effects of Ca++ Channel Blockers

• DHP and non-DHP Ca++ channel blockers increase systemic vasodilation by decreasing resistance.
• They decrease afterload on the heart.
• They decrease cardiac contractility, especially with non-DHP blockers, diminishing cardiac output and subsequently blood pressure and reducing afterload.
• Non-DHP blockers reduce heart rate by influencing SA/AV node conduction.

Types of Ca++ Channel Blockers

• Dihydropyridines primarily affect vascular smooth muscle, increasing vasodilation.
• Nondihydropyridines mainly affect cardiac tissue, slowing heart rate and decreasing conduction.

Ca Channel Blockers: Side Effects

• Dihydropyridines (DHPs) can lead to reflex tachycardia due to blood pressure drops, causing an increase in heart rate. These effects are reduced with slow-release formulations.
• Non-DHPs like Verapamil and Diltiazem have a lesser effect on reflex tachycardia as they directly affect heart rate.

Summary: CCB

• Calcium channel blockers (CCBs) reduce calcium entry into vascular smooth muscle and cardiomyocytes.
• This inhibits contraction and thus reduces afterload.
• They decrease cardiomyocyte contractility initiated by calcium.
• Reduce HR, mainly with non-DHPs and have contraindications with other dilators.

K+ Channels and Vasodilation

• K+ channels on vascular smooth muscle plasma membranes promote vasodilation.
• Ca++ channel activation causes Ca++ influx which depolarizes the cell.
• Opening K+ channels hyperpolarizes the cell which decreases intracellular calcium and promotes vasodilation and limits contraction.

K+ Channels in Vasomotor Regulation

• K+ channels help regulate vascular tone through hyperpolarization of smooth muscle.
• Both PKA and PKG can activate K+ channels further promoting vasodilation and reducing contraction or vascular tone.

K+ Channels Openers

• Minoxidil and diazoxide open K+ channels, resulting to vasodilation, used in resistant hypertension but with risks of hypotension.

α2-AR Agonists

• α2-adrenergic receptor agonists, like clonidine and methyldopa, primarily decrease blood pressure by centrally acting on the brain's vasomotor center, reducing sympathetic outflow.
• Reduced sympathetic stimulation causes decreased HR, decreased vascular constriction, and decreased systemic vascular resistance.

α2-AR Agonists Summary

• Clonidine and methyldopa reduce blood pressure by centrally reducing SNS outflow, resulting in decreased HR and SVR.
• Common side effects include sodium/water retention and orthostatic hypotension when discontinued abruptly.

α1-AR Antagonists

• α1-adrenergic receptor antagonists block NE-mediated vasoconstriction, and thereby reduce systemic vascular resistance (SVR).
• These work directly on the vasculature to cause vasodilation.
• Side effects include orthostatic hypotension, especially with initial dosage increases.

α1-AR Antagonists Summary

• α1-receptor antagonists, like doxazosin and prazosin, block α1-mediated vasoconstriction. They decrease vascular resistance, and may cause orthostatic hypotension especially with initial dosage or increasing dosages.

α-AR Agents and BP Summary

• α2 agonists centrally reduce SNS activity, decreasing sympathetic stimulation of the vasculature resulting in lower blood pressure. This is a alternative to first-line medications.
• α1 antagonists directly reduce vascular resistance, decrease systemic vascular resistance, lowering blood pressure. This can be used when unresponsive to other treatments.

Beta-Blockers

• Beta blockers mainly target β1 adrenergic receptors on the heart which reduces HR, and contractility thereby reducing cardiac output and blood pressure.
• There are also β2 receptors that are located in vascular smooth muscle, which lead to vasodilation.
• Non-selective beta-blockers block both β1 and β2 receptors, but beta1 selective blockers primarily target β1 receptors.

Beta-blockers Summary

• Beta-blockers decrease heart rate (HR) and contractility, lowering cardiac output (CO) and systemic vascular resistance (SVR), reducing blood pressure.
• Beta-blockers are commonly used but not typically cause vasodilation.
• Reflex tachycardia is a potential adverse effect that can result from sudden drop in blood pressure that can be countered with Beta-blockers.

Reflex Tachycardia

• When vasodilators reduce blood pressure, baroreceptors initiate a reflex to increase sympathetic activity.
• This leads to increased heart rate (HR) and force of contraction to compensate for the reduced pressure, potentially causing reflex tachycardia.
• Beta-blockers inhibit the reflex tachycardia, limiting the rebound tachycardia.

Summary: β-Blockers and BP

• Pure β-blockers primarily reduce HR and cardiac contractility, thereby reducing CO and SVR, lowering blood pressure.
• B1 selective blockers preserve β2 effects.

Preferred Combinations for Hypertension

• Preferred combinations, such as ACEi/CCB, ARB/CCB, ACEi/thiazide and ARB/thiazide, are often effective for managing hypertension.

A Note About The Upcoming Test

• Read questions thoroughly.
• Be aware that isolated correct statements may be inappropriate in the context of the full question.
• Evaluate answer options in relation to the entire question; an isolated factually correct statement may not be the best answer in the overall problem context.