PROCESSES AND PATHWAYS

Sustained arterial hypertension damages the blood vessels in the kidney, heart, and brain

What is the rationale for treating hypertension according to the Joint National Committee?

An increase in office blood pressure bears an independent continuous relationship with the incidence of several cardiovascular events

What relationship does increased blood pressure have according to the European Guidelines?

Prevent damage to blood vessels and subsequently reduce morbidity and mortality rates

What does effective pharmacologic lowering of blood pressure achieve?

Usually asymptomatic until overt end damage is imminent or has already occurred

What is the typical symptom status of hypertension?

If blood pressure is greater than or equal to 180 over 110 millimeters of mercury and there is evidence of cardiovascular disease

Under what conditions might a hypertension diagnosis be made on a single office visit?

Elevated blood pressure during doctor's visits but normal blood pressure at home

What is the characteristic pattern of White Coat Hypertension?

Normal blood pressure during doctor's visits but elevated blood pressure at home

What is the characteristic pattern of Masked Hypertension?

Genetics, psychological stress, environmental factors, and dietary factors

What are the common multifactorial causes of Essential Hypertension?

Blood Pressure equals Cardiac Output multiplied by Peripheral Vascular Resistance

What is the formula defining blood pressure?

Constriction

What change in arterioles leads to increased peripheral resistance and high blood pressure?

Increased venous return

What effect of postcapillary venules leads to increased cardiac output?

Increase blood pressure

What is the major effect of the Renin-Angiotensin-Aldosterone System (RAAS)?

Vasoconstriction

What effect does Angiotensin have in the RAAS system?

Sodium retention leading to water retention and increased cardiac output

What major effect does Aldosterone have in the RAAS system?

Lower peripheral vascular resistance and blood volume

What is the function/effect of RAA Inhibitors?

Side effects may be compounded despite being more efficacious

Why should drugs from the same drug class or category NOT be combined?

Increase blood pressure and may blunt the effect of antihypertensives

What is the effect of NSAIDs (except aspirin) and decongestants on antihypertensive therapy?

Promotes sodium, potassium, and water excretion in the distal convoluted tubules

What is the mechanism of action of Thiazide Diuretics in the short term?

Decrease peripheral vascular resistance

What additional long-term effect do Thiazide Diuretics have besides decreasing blood volume?

Efflux of sodium creates an electrical gradient, thus promoting the reabsorption of calcium

What process causes hypercalcemia as a side effect of Thiazide Diuretics?

Diuretic effect will lead to fluid contraction

What physiological change caused by Thiazide Diuretics leads to Metabolic Alkalosis?

Secretion of thiazides competes with uric acid for the same organic acid transporter

What process causes hyperuricemia as a side effect of Thiazide Diuretics?

Decrease in insulin secretion because of hypokalemia

What is the proposed cause of hyperglycemia as a side effect of Thiazide Diuretics?

Block the sympathetic system

What is the function of Sympathoplegic Agents?

Lowers heart rate and blood pressure

What is the effect of Beta-blockers (BBs) via blocking of adrenaline and noradrenaline?

Lowers heart rate, contractility, and afterload

How do Beta-blockers reduce myocardial oxygen demand?

Prolongs the diastolic phase of the cardiac cycle

How does the reduced heart rate caused by Beta-blockers increase oxygen supply to the myocardium?

Blocking beta 2 receptors, which normally cause bronchodilation

Why are non-selective Beta-blockers contraindicated in patients with Asthma or COPD?

Rebound tachycardia and hypertension

What results from the abrupt withdrawal of Clonidine and Beta-blockers?

Block alpha 1 receptors leading to vasodilation

What is the mechanism of action of alpha 1-Blockers?

Inhibit adrenergic outflow from the brainstem

What is the effect of centrally-acting alpha 2 agonists acting on alpha receptors in the medulla of the brain?

Relaxes vascular smooth muscles

What is the function/effect of Direct Vasodilators?

Blocks calcium channels in arteriolar smooth muscles

What is the primary mechanism of action of Dihydropyridine Calcium Channel Blockers (CCBs)?

Arterial vasodilation

What is the final hemodynamic result of Dihydropyridine CCBs blocking calcium channels in arteriolar smooth muscles?

Expansion of cranial vessels

What vasodilatory effect of CCBs causes headache?

Precapillary dilation and reflex postcapillary constriction

What mechanism causes peripheral edema as a side effect of CCBs, especially Amlodipine?

Slows atrioventricular nodal conduction

What additional key mechanism of action do non-Dihydropyridine CCBs possess compared to Dihydropyridine CCBs?

Inhibition of Angiotensin Converting Enzyme (ACE)

What is the primary mechanism of action of ACE Inhibitors?

Decreased Angiotensin II synthesis

What is the effect of inhibiting ACE?

Arteriolar vasodilation

What is the final hemodynamic effect of decreased Angiotensin II synthesis?

Enhanced bradykinin and substance P production

What causes the side effects of dry cough and angioedema associated with ACE Inhibitors?

Blocked Angiotensin II leads to blocked Aldosterone which leads to hyperkalemia

What chain of events caused by ACE inhibitors leads to hyperkalemia?

Inhibits the mechanism that constricts the efferent arteriole to maintain adequate glomerular pressure

Why are ACE inhibitors contraindicated in bilateral renal artery stenosis?

Blocks the binding of Angiotensin II to smooth muscle receptors

What is the mechanism of action of Angiotensin II Receptor Blockers (ARBs)?

Block the binding of renin to the receptor on angiotensinogen

What is the mechanism of action of Direct Renin Inhibitors?

Inhibits conversion of angiotensinogen to Angiotensin I

What is the effect of blocking the binding of renin to angiotensinogen?

Promote sodium and water excretion in the collecting duct renal tubules

What is the primary mechanism of action of Aldosterone Receptor Blockers?

Blood flow from the coronary arteries to the myocardium is decreased

What is Ischemia?

Blood flow is completely cut off

What is Infarction?

Disruption of coronary plaque, leading to local platelet aggregation and thrombosis

What event is common to most clinical presentations of Acute Coronary Syndromes (ACS)?

Directed at decreasing myocardial oxygen demand

What are the pathophysiological principles that underlie therapy for exertional angina?

Faster heart rate, higher systolic blood pressure, higher myocardial wall stress, and more myocardial contractility

What are the four determinants of myocardial oxygen demand?

Coronary artery diameter and tone, collateral blood flow, perfusion pressure, and heart rate (duration of diastole)

What are the determinants of myocardial oxygen supply?

Coronary perfusion occurs during diastole

When does coronary perfusion occur?

Present for the first time, change their usual pattern, occur at rest, and are resistant to nitrates

What four characteristics define Unstable Angina Pectoris symptoms?

Converted to Nitric Oxide (NO) in the vascular endothelial cells

What happens to circulating nitrates in the blood vessels as part of the MOA?

Activates guanylyl cyclase (GC)

What enzyme is activated by Nitric Oxide (NO) in smooth muscle cells?

Converts GTP into cyclic GMP (cGMP)

What reaction is catalyzed by activated guanylyl cyclase?

Inhibition of the L-Type calcium channels (LTCC) and activation of the Myosin Light Chain Phosphatase (MLCP)

What two key effects result from increased cyclic GMP in smooth muscle cells?

Dephosphorylation of Myosin Light Chains

What action of MLCP causes smooth muscle relaxation and vasodilation of smooth muscle cells?

Reduced preload and afterload

What is the final hemodynamic effect of vasodilation in peripheral vasculature caused by nitrates?

Decreasing venous return to the heart

What action of nitrates increases venous capacitance?

Decreasing peripheral arteriolar resistance

What action of nitrates reduces afterload?

Increases the pressure gradient for perfusion across the ventricular wall

What additional benefit does reducing preload provide, favoring subendocardial perfusion?

Dilation of meningeal arterial vessels

What action of nitroglycerin causes headache as a common side effect?

Increased incidence of major bleeding events

What adverse effect is associated with combining aspirin and clopidogrel?

Reduces the progression of atherosclerosis and reduces the risk of coronary thrombosis and myocardial infarction

What are the goals of using non-antianginal drugs in coronary artery disease (CAD)?

Irreversibly inactivating the thromboxane-synthesizing COX-1 in platelets

What is the mechanism of action of Aspirin in reducing thrombus formation?

Block the proaggregatory effect of ADP

What is the mechanism of action of Thienopyridines, which are ADP receptor antagonists?

Interfere with either two signaling pathways (Thromboxane A2 and ADP) or the major common pathway (GpIIb/IIIa fibrinogen receptor)

What is the mechanism by which antiplatelet agents are cornerstone therapy for Acute Coronary Syndrome (ACS)?

Blocks the late inward sodium current in cardiomyocytes

What is the primary mechanism of action of Ranolazine?

Blocks increase in intracellular calcium through the sodium-calcium exchanger

What effect of Ranolazine reduces calcium overload and diastolic wall stress?

Selective blocker of hyperpolarization-activated HCN ion channels

What is the mechanism of action of Ivabradine?

Selectively inhibits the funny channel pacemaker current (If current)

What specific current is inhibited by Ivabradine to reduce heart rate?

Reducing heart rate

What is the sole explanation for the antianginal effects of Ivabradine?

Affects retinal HCN channels

What is the mechanism explaining the visual disturbances (phosphenes) caused by Ivabradine?

Has nitrate-like cGMP-dependent properties and acts as an agonist at ATP-sensitive potassium channels

What is the dual mechanism of action of Nicorandil?

Inhibits long-chain three-ketoacyl coenzyme A thiolase

What is the mechanism of action of Trimetazidine?

Leads to a partial shift of oxygen generation from the fatty acid beta-oxidation pathway toward the glucose pathway

What metabolic effect of Trimetazidine makes it beneficial in ischemia?

Reduces mortality

What outcome do Statins achieve in patients with coronary artery disease?

Decreasing platelet activation and coagulation

What is one pleiotropic effect of Statins that decreases thrombogenicity?

Increasing nitric oxide bioactivity and decreasing endothelin

What are the effects of Statins on endothelial function?

Reducing macrophages and inflammation

What are the effects of Statins on immune injury?

Decrease in at 1 receptors and decrease in free radicals

What are the antioxidant effects of Statins?

Reduces the magnitude of the calcium current through the slow channel and decreases the rate of recovery of the channel

What is the mechanism by which Verapamil works?

Depress the rate of the sinus node pacemaker and slow atrioventricular conduction

What effect do Verapamil and Diltiazem have at clinically used doses?

Reflex activation of the sympathetic nervous system

What causes tachycardia and abrupt decrease in blood pressure associated with immediate-release Nifedipine?

Increased hydrostatic pressure in the lower extremities owing to precapillary dilation and reflex postcapillary constriction

What causes peripheral edema associated with Calcium Channel Blockers, especially Amlodipine?

Increases the propensity for atrioventricular block or severe depression of ventricular function

What is the risk associated with concurrent intravenous Verapamil and intravenous beta-blocker administration?

Reducing myocardial oxygen demand through decreasing heart rate, myocardial contractility, and ventricular wall stress

How do the principal antianginal agents improve the balance of myocardial oxygen supply and demand?

Attenuate the increase in left ventricular end-diastolic volume

What is the effect of Nitrates increasing venous capacitance when combined with beta-blockade?

Decrease in cardiac output will lead to a decrease in carotid sinus firing which in turn will increase sympathetic discharge

What is the initial physiological pathway response to decreased cardiac output in Heart Failure?

Activates renin release and leads to an increase in force, rate, and preload

What is the compensating effect of increased sympathetic discharge following a decrease in cardiac output?

Increase in Angiotensin II which increases preload, afterload, and remodeling

What is the consequence of reduction in renal blood flow causing renin release in heart failure?

Systolic heart failure

What is Heart failure with reduced ejection fraction (HFrEF) also known as?

Diastolic heart failure

What is Heart failure with preserved ejection fraction (HFpEF) also known as?

Heart has thin walls and weak contractility

What is the characteristic appearance of the left ventricle in Heart failure with reduced ejection fraction (HFrEF)?

Walls of the heart are very thick and there is relaxation abnormality

What is the characteristic appearance of the heart in Heart failure with preserved ejection fraction (HFpEF)?

Reduces salt and water retention, edema, and symptoms

What is the primary mechanism of action of Diuretics in heart failure?

Reduces venous pressure and ventricular preload

What is the effect of Diuretics reducing salt and water retention?