Cardiovascular Pharmacology Quiz

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Questions and Answers

What effect do b-blockers have on heart rate (HR) and cardiac output (CO)?

They increase HR and CO.

They decrease HR and increase CO.

They decrease both HR and CO. (correct)

They increase contractility, leading to a higher CO.

What is the role of baroreceptors in response to vasodilators causing a drop in blood pressure?

They stimulate PNS activity to reduce heart rate.

They decrease the signaling to increase HR.

They inhibit the production of renin by juxtaglomerular cells.

They increase SNS signaling to raise HR and CO. (correct)

Which type of b-blockers are preferred to preserve beneficial B2-AR receptor responses?

b1-selective blockers. (correct)

a1 and b1 mixed antagonists.

Non-selective b-blockers.

Cardioselective agents.

How do b-blockers affect reflex actions to raise blood pressure?

They diminish reflex actions to raise BP. Signup and view all the answers

What consequence can occur from excessive reflex tachycardia?

Potential damage to the heart. Signup and view all the answers

What is one of the primary effects of nitric oxide (NO) on vascular smooth muscle cells?

Inhibits calcium release Signup and view all the answers

In what conditions is reduced NO bioavailability thought to occur?

Hyperlipidemia and obesity Signup and view all the answers

What is the primary therapeutic action of nitrates in the treatment of angina?

Reducing preload on the heart Signup and view all the answers

What happens when there is prolonged use of nitrates?

Development of tolerance Signup and view all the answers

What is a common side effect of dihydropyridine (DHP) calcium channel blockers?

Reflex tachycardia Signup and view all the answers

Which enzyme is involved in the development of nitrate tolerance?

ALDH2 Signup and view all the answers

What is a significant challenge when using nitrates for heart conditions?

Development of tolerance with prolonged use Signup and view all the answers

What is the primary effect of non-dihydropyridine (non-DHP) calcium channel blockers?

Decrease heart rate and conduction Signup and view all the answers

What is the role of MLCK in vascular smooth muscle cells?

It activates MLC phosphorylation. Signup and view all the answers

Which molecule is responsible for activating soluble guanylate cyclase in vascular smooth muscle cells?

Nitric oxide (NO) Signup and view all the answers

What effect does PKG have on vascular smooth muscle contraction?

It activates myosin light chain phosphatase. Signup and view all the answers

How does cAMP contribute to smooth muscle dilation?

By activating protein kinase A (PKA). Signup and view all the answers

What is one way that vessel dilation can occur?

Activation of nitric oxide synthase. Signup and view all the answers

What is the primary action of PKA in vascular smooth muscle compared to its action in the heart?

It inhibits contraction in smooth muscle, but promotes it in the heart. Signup and view all the answers

The generation of cyclic-GMP in vascular smooth muscle cells primarily leads to which of the following effects?

Inhibition of vascular smooth muscle contraction. Signup and view all the answers

Which effect results from the stimulation of a2 receptors in the brain?

Decreased sympathetic nervous system outflow Signup and view all the answers

Nitrates, serving as potent vasodilators, primarily cause the release of which substance?

Nitric oxide (NO) Signup and view all the answers

Which drug is preferred for treating pregnancy-induced hypertension?

Methyldopa Signup and view all the answers

What is a major side effect associated with the use of methyldopa compared to clonidine?

Sodium and water retention Signup and view all the answers

Which of the following a1-AR antagonists is likely to cause more adverse events compared to thiazide diuretics?

Doxazosin Signup and view all the answers

What mechanism do a1-AR antagonists use to reduce systemic vascular resistance (SVR)?

Inhibiting vascular smooth muscle contraction Signup and view all the answers

Why are a2-agonists considered alternative treatments for hypertension?

They work centrally to reduce SNS signaling. Signup and view all the answers

What effect does abrupt discontinuation of a2-agonists like clonidine have?

Significant increase in blood pressure Signup and view all the answers

Which of the following is NOT a first-line therapeutic class for hypertension?

a2-AR agonists Signup and view all the answers

What is the primary mechanism by which beta-blockers decrease heart rate?

Decrease Na+ influx through funny channels Signup and view all the answers

What effect do beta-blockers have on cardiac output (CO)?

Decrease CO by reducing heart rate and contractility Signup and view all the answers

Which generation of beta-blockers is designed to be selective to beta-1 receptors while preserving beta-2 mediated vasodilation?

Second and third generations Signup and view all the answers

What is a known side effect of beta-blockers in relation to reflex tachycardia?

They minimize reflex tachycardia during blood pressure lowering Signup and view all the answers

Which statement accurately describes the action of beta-1 adrenergic receptors when activated?

Increase heart rate and contractility Signup and view all the answers

What is the role of PKA activation in the context of beta-1 adrenergic receptor stimulation?

Promotes Ca++ release through RyR and external Ca++ channels Signup and view all the answers

Which of the following beta-blockers is known to have an NO donor moiety to promote dilation?

Nebivolol Signup and view all the answers

What are beta-blockers NOT primarily responsible for?

Increasing heart rate Signup and view all the answers

What is the primary function of Calcium Channel Blockers (CCBs) in relation to vascular smooth muscle?

Reduce vasoconstriction Signup and view all the answers

Which of the following statements about DHP and non-DHP CCBs is correct?

DHP primarily affects vascular function, while non-DHP mainly impacts cardiac function. Signup and view all the answers

What is the role of K+ channels on vascular smooth muscle plasma membranes?

Induce hyperpolarization to promote vasodilation Signup and view all the answers

Which of the following is a characteristic of K+ channel openers?

Minoxidil is used only when other drugs are ineffective. Signup and view all the answers

What is the effect of a2-AR agonists on blood pressure?

Decrease blood pressure through direct vasoconstriction Signup and view all the answers

How do Diltiazem and Verapamil impact heart rate?

They block recovery of calcium channels necessary for action potential propagation. Signup and view all the answers

Which of the following best describes the function of PKA and PKG in relation to vascular smooth muscle?

They promote vasodilation by activating K+ channels. Signup and view all the answers

What adverse effect is associated with the use of Minoxidil?

Hypotension Signup and view all the answers

Study Notes

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.

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Description

Test your knowledge on the effects of b-blockers and nitrates on heart rate and blood pressure. This quiz covers the role of baroreceptors, nitrate tolerance, and various types of calcium channel blockers. Explore the pharmacological impacts on vascular smooth muscle cells and associated therapeutic actions.