lesson 11 Flashcards
Speak about the physical factors, metabolis and nural control that control the coronary flow and the relation between oxygen demand and supply
there are physiological factors that regulate the coronary flow, and they are: physical factors, the vascular control by metabolites and the neural and humoral control.
For what concerns the physical factors, coronary arteries irrorate the heart, we have the ones that remain in the surface (epicardial) and then the endocardial ones, which penetrate the tissue. during the systole the blood pressure is very high, meaning that blood cannot enter the heart chambers, So the blood does not get there until we have the relaxation phase, at this point only the heart will be fully irrorated since the pressure is much lower.
In this graph we can see how the blood flow changes during systole and diastole, where coronary blood flow happens: in red we see the coronary flow which changes with the pressure so it is different when looking at the systole or diastole, in black we see how the aortic pressure changes, as we said it is higher during the systole and lower during the diastole. The flow also depends on the length of the diastolic period: if the heart rate increases we will have shorter diastolic period and thus a shorter coronary blood flow.
There is also a specific pathological situation concerning the *aortic valve*. This valve is normally open or closed, but we may have a stenosis in which we have narrow open position and also an impaired non-complete closure. This situation can reduce the coronary blood flow and cause ischemic chest pain called angina. In the second graph we see how the pressure changes during systole and diastole both at the level of and the ventricle, and also how the difference in pressure between the aorta and the ventricle during the diastole allows the blood to flow into the heart chambers.
Let’s now talk about the vascular control by metabolites and mediators: the regulation of the coronary blood flow involves sensors detecting the partial pressure of O2 in coronary arteries. A reduction of this pressure triggers a compensatory mechanism, leading to coronary artery dilation. This response relies on a healthy endothelium, which releases signals for vasodilation. Mediators such as adenosine and nitric oxide contribute to vasodilatory effects.
Finally there is a neural and humoral control on the blood flow, though less significant, neural and humoral control involves the sympathetic system, which exert only a small direct effect on the coronary circulation, the larger coronary vessels possess α adrenoceptors, while the smaller vessels have β2 adrenoceptors, the first ones cause contraction and the second one relaxation. Coronary vessels are also innervated by purinergic, peptidergic and nitrergic nerves, also basal coronary blood flow in patients with angiographically normal coronary arteries is altered by about one-third by selective inhibition of NOS1.
What are the two main ischemic heart diseases? speak about CAD
When the oxygen supply is insufficient, ischemic heart diseases may ensue, giving rise to ischemic attacks in the affected area. This condition manifests in two distinct forms: Chronic Coronary Artery Disease, described as stable angina, and Acute Coronary Syndrome.
- Chronic Coronary Artery Disease (Stable Angina): Characterized by an imbalance between oxygen supply and demand, the primary focus of pharmacological intervention is to restore this equilibrium. Drugs aim to address the imbalance that occurs during activities and stress, seeking to enhance oxygen delivery to the myocardium.
- Acute Coronary Syndrome: In this form, occlusion in the large coronary vessels is prevalent, necessitating the restoration of lumen patency to prevent tissue necrosis. This acute condition demands a different pharmacological approach than the stable angina associated with chronic coronary artery disease.
First of all let’s talk about coronary artery disease (CAD), Coronary arteries exhibit the ability to increase the blood flow, especially during conditions such as exercise. Hyperemic stress, induced by factors like emotional stress, can compromise coronary vasodilatory reserve, leading to an imbalance between oxygen demand and supply. This imbalance may result in functional cardiac abnormalities, manifesting as poor contraction in the ischemic portion of the myocardium. Imbalances in myocardial oxygen supply and demand predominantly arise from coronary flow reduction and endothelial dysfunction.
Coronary flow reduction can occur also due to occlusions, such as plaque formation in the epicardial vessels. This reduction affects not only these large vessels but also extends to endothelial vessels, resulting in an overall decrease in myocardial perfusion. In stable angina, atherosclerotic plaques form, narrowing the vessel lumen. The stability of these plaques prevents disruption, even during increased workload. Consequently, reduced blood flow during low workload does not elicit pain. However, as workload intensifies, the reduction in blood flow becomes critical, leading to insufficient oxygen supply and subsequent chest discomfort. Discomfort, akin to chest pressure known as angina pectoris, is experienced during coronary blood flow reduction, serving as an indicative signal of an ischemic attack. Understanding these pathophysiological mechanisms is crucial for tailoring effective pharmacological interventions in ischemic heart disease.
The manifestation of symptoms is intricately linked to the degree of coronary artery occlusion. Patients leading a sedentary lifestyle may remain asymptomatic due to adequate oxygen circulation at rest, despite having an 89% occlusion. Conversely, even a 50% occlusion can induce angina during physical activity. The insidious nature of coronary occlusion often leads to unnoticed issues until symptoms, such as pain during activities like climbing stairs, become apparent.
Endothelial dysfunctions plays a pivotal role in abnormal vascular tone, disrupting the delicate control of smooth muscle contraction. It is manifested by abnormal vascular tone **and prothrombotic properties. **
- abnormal vascular tone: while mental stress or physical exertion can activate the sympathetic nervous system and trigger catecholamine-mediated vasoconstriction, normal vascular dilation is facilitated by endothelial-derived nitric oxide (NO). However, when the endothelium is compromised, reduced production of vasodilators allows catecholamines to dominate, resulting in abnormal vascular tone.
- prothrombotic properties: additionally, endothelial dysfunction can contribute to blood coagulation (thrombosis) at the site of injury. Endothelium-derived NO and prostacyclin, with potent antiplatelet effects, become diminished when endothelial damage occurs.
Speak about acute coronary syndrome
Acute coronary syndrome or ACS represents sudden events significantly impacting coronary blood flow. Unstable angina, a type of ACS, arises from the rupture of an atherosclerotic plaque. The exposed collagen attracts platelets, leading to platelet aggregation and thrombus formation, consequently reducing the coronary lumen.
Two distinct types of myocardial infarction (MI) characterize ACS: Non-ST-segment elevation MI (NSTEMI) and ST-segment elevation MI (STEMI).The primary difference lies in the extent of coronary occlusion: STEMI involves complete occlusion, while NSTEMI involves partial occlusion. NSTEMI poses a higher risk for recurrent ischemia, while STEMI implies acute myocardial injury with necrosis of downstream tissue and an increased risk of sudden cardiac death.
The severity of ischemic events depends on factors such as the mass of myocardium supplied by the occluded artery, the duration of total occlusion, and the degree of collateral circulation. The central goal of management is reperfusion, achievable through pharmacological or surgical interventions.
Which drugs can be used to cure coronary artery disease?
Pharmacological interventions aim to restore the delicate balance between oxygen demand and supply. This involves modulating demand by reducing it or enhancing supply. The priority is to re-establish the patency of the occluded epicardial coronary artery. However lifestyle modifications are also very important to mitigate risks. As for the drugs, statins, for instance, play a role in reducing LDL cholesterol and plaque formation.
Oxygen demand is linked to heart rate, contractility, preload, and afterload, modulating heart rate and contractility can be achieved in many ways:
- using beta blockers
- using organic nitrates which act on impedance and resistance. These 2 are used for decreasing the O2 demand
- vasodilators contribute to coronary blood flow improvement.
- Statins and antiplatelet drugs, such as aspirin, are recommended for those who have already experienced cardiovascular events to prevent recurrence. These 2 are used for increasing the O2 supply
- using calcium channel blockers which can both decrease oxygen demand and increase its supply
Beta adrenoceptor antagonists also called beta blockers, serve as cornerstone agents in chronic angina management. By reducing heart rate and contractility, beta blockers prolong the diastolic period, facilitating myocardial perfusion during this crucial phase. They decrease both resting and peak heart rates during exercise, delaying the onset of angina. Dosage adjustment aims to maintain a resting heart rate around 50 beats/min and a peak heart rate during exertion at approximately 110 to 120 beats/min. They are first-choice drugs.
Often, beta blockers are co-administered with organic nitrates or calcium channel blockers for enhanced efficacy.
Notably, individuals engaging in exercise, such as gym activities, may be required to provide an electrocardiogram certification due to the potential use of beta blockers in their regimen.
Calcium channel blockers, known for their antiarrhythmic properties, exert their effects by blocking L-type calcium channels, resulting in decreased intracellular calcium concentration. This reduction in cardiac oxygen demand is complemented by their action on calcium channels in arterial smooth muscles, promoting vasodilation and increased blood flow. Therefore, they simultaneously decrease oxygen demand and enhance oxygen supply.
The distinct classes of calcium channel blockers elicit varied inotropic effects on cardiac myocytes.
Dihydropyridines, for example nifedipine, exhibit greater selectivity for peripheral vasculature calcium channels. While not utilized as antiarrhythmics due to their focus on smooth muscle L-type voltage-gated ion channels, they effectively increase myocardial oxygen supply by blocking calcium-mediated increases in coronary vasomotor tone. Calcium channel blockers prove as efficacious as beta-blockers in treating chronic stable angina. Calcium channel blockers demonstrate efficacy, especially when combined with beta-blockers. This combination proves highly effective in countering arterial vasospasms.
Another class integral to angina management is represented by nitrates, historically the drug of choice. Administered sublingually, these small pills ensure rapid absorption, inducing dilation and addressing both sides of the oxygen demand-supply equation. Nitrates reduce preload and increase blood flow through vasodilation. Additionally, they serve to prevent platelet aggregation and thrombi formation. Patches are an alternative delivery method, though nitrates are generally not employed preventatively due to rapid tolerance development. Preventing thrombus formation is pivotal in individuals experiencing a first myocardial attack.
Another drug very much used for these problems is aspirin. Maintaining patency and averting thrombi formation infact, involves the administration of cardioaspirin at lower dosages, targeting platelet cyclooxygenase irreversibly. This prevention strategy is particularly significant, as platelets lack a nucleus, preventing the production of additional cyclooxygenase. Individuals on low-dose cardioaspirin exhibit reduced cardiovascular risk, extending its utility to preventing transient ischemic attacks and strokes.
Metabolic modulators are still under investigation. Ranolazine is a notable metabolic modulator, demonstrating efficacy in optimizing cardiac function during exertion and reducing angina frequency. While its mechanism remains unclear, it is believed to act on potassium channels, impeding repolarization and refractory period.
Patients with cardiovascular issues often find themselves taking a bunch of medications, including lipid-lowering agents like statins to reduce LDL cholesterol. Lifestyle modifications, such as dietary changes and exercise like long walks or cycling, play a pivotal role in modulating coronary blood flow. Striking a balance is crucial, as excessive oxygen intake must be avoided to prevent potential complications.
Following a myocardial infarction, rest is discouraged to train the endothelium to produce metabolic modulators, enhancing ATP utilization efficiency.
What drugs can be used for ACS, in particular for unstable angina?
Prompt intervention is imperative in cases of unstable angina, as progression to acute myocardial infarction is a significant risk. Aggressive treatment, which includes statins and antianginal drugs like nitroglycerin, heparin, and aspirin, can substantially diminish this risk.
In patients with a lesser risk normally antianginal drugs or Aspirin/Heparin are administered
- Among antianginal drugs we have nitroglycerin, whih is commonly administered initially through intravenous administration, followed by long-acting oral nitrate preparations as needed, with caution due to the development of tolerance. Co-administration of beta-adrenergic antagonists is crucial to reduce myocardial oxygen demand.
- Heparin and aspirin are vital in preventing thrombi formation, significantly reducing the risk of recurrent cardiovascular events. Despite a potential increase in bleeding risk, the clinical benefits of these agents outweigh the adverse effects. For patients at risk of cardiac events, the decision to risk bleeding is often considered a safer alternative. Maintaining a healthy lifestyle, combined with these pharmacological interventions, remains a cornerstone in preventing and managing cardiovascular complications
For people with a higher risk there are other kind of drugs which are normally administered:
- Antiplatelet agents, including GPIIb.IIA antagonists and ADP receptor antagonists, are employed selectively in high-risk cases. Glycoprotein IIb/IIIa antagonists prove to be highly effective antiplatelet agents. These agents play a crucial role in the process of platelet aggregation by inhibiting the binding of fibrinogen to activated platelets through the GPIIb–IIIa receptors. By disrupting this pivotal step, these antagonists limit the size of the platelet plug. However, it’s essential to note that studies indicate an increased risk of bleeding outcomes with GPIIb–IIIa antagonists compared to direct thrombin inhibitors like bivalirudin. Consequently, thrombin inhibitors might be preferred to mitigate bleeding risks. Another class of potent antiplatelet agents includes ADP receptor antagonists. Platelet ADP receptor antagonists, such as clopidogrel (an irreversible antagonist) and ticagrelor (a reversible one), are commonly employed in the treatment of patients with acute coronary syndromes (ACS). Unlike clopidogrel, these agents are prodrugs requiring metabolic transformation to become active. Prasugrel, however, stands out as it does not require hepatic conversion from a prodrug form, making it independent of the patient’s genetic code. Consequently, prasugrel exhibits fewer “non-responders,” ensuring higher antiplatelet activity and rapid bioavailability after oral administration.
- Direct thrombin inhibitors like bivalirudin may also be considered in certain situations. In the realm of antithrombotic agents, their primary use lies in adjunctive antithrombotic therapy during surgical procedures to restore vessel patency. Despite the undeniable efficacy of these antiplatelet and antithrombotic agents, it is crucial to carefully weigh their benefits against the risk of bleeding. The integration of these agents into comprehensive cardiovascular therapy requires a judicious assessment of individual patient profiles and tailored treatment strategies.
How do we cure STEMI?
When confronted with ST-elevation myocardial infarction (STEMI), characterized by complete occlusion of the coronary lumen due to plaque and thrombus formation, the use of aspirin and heparin alone may prove insufficient. The urgency of reperfusion prompts the need for thrombolytic drugs capable of digesting the formed thrombus. Additionally, surgery such as angioplasty or, in severe cases, emergency coronary artery bypass, become imperative.
Thrombolytic agents play a crucial role in the pharmacologic management of STEMI. Streptokinase, although effective, faces limitations, infact it is produced by a bacteria: streptococcus, and since it is produced by an external organism our immune system produces antibodies against it, so we use other compounds to fight this immunogenicity, like alteplase, an endogenous agent. The timeliness of thrombolytic administration is fundamental, with a twofold improvement in survival rates observed when administered within 2 hours of symptom onset compared to delays beyond 6 hours. This underscores the direct relationship between vessel occlusion duration and infarction extent, emphasizing the importance of swift intervention.
In contrast to thrombolysis, primary angioplasty, when executed within 90 minutes of presentation, offers a mortality benefit. This approach involves the use of drug-eluting stents, which release medications to enhance coronary artery patency during the initial period.
