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Cardiac Pharmacology: Difference between revisions
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''Heather Melrose, Jonas de Jong'' | ''Heather Melrose, Jonas de Jong'' | ||
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==Renin-Angiotensin-Aldosterone System== | ==Renin-Angiotensin-Aldosterone System== | ||
[[Image:Renin-angiotensin-aldosterone_system.png|thumb|right|500px|RAAS schematic]] | |||
The renin-angiotensin-aldosterone system (RAAS) is an important hormone-based pathway within the body that regulates fluid balance and thus systemic blood pressure. The system is activated by decreases in blood volume or pressure detected in two ways: a drop in blood pressure detected by baroreceptors (pressure sensors) located in the carotid sinus or a drop in flow rate through the kidneys, detected by the juxtaglomerular apparatus. The body responds to these stimuli to effect a restoration in blood pressure via the actions of three hormones; renin, angiotensin and aldosterone. Following the detected drop in blood pressure, the enzyme renin is released from specialised cells within the kidney. The substrate of renin is the inactive precursor of angiotensin I, angiotensinogen. Angiotensin I is then enzymatically converted by angiotensin converting enzyme (ACE) into angiotensin II, a hormone with various actions throughout the body that ultimately increase blood pressure, restoring fluid balance within the body. | The renin-angiotensin-aldosterone system (RAAS) is an important hormone-based pathway within the body that regulates fluid balance and thus systemic blood pressure. The system is activated by decreases in blood volume or pressure detected in two ways: a drop in blood pressure detected by baroreceptors (pressure sensors) located in the carotid sinus or a drop in flow rate through the kidneys, detected by the juxtaglomerular apparatus. The body responds to these stimuli to effect a restoration in blood pressure via the actions of three hormones; renin, angiotensin and aldosterone. Following the detected drop in blood pressure, the enzyme renin is released from specialised cells within the kidney. The substrate of renin is the inactive precursor of angiotensin I, angiotensinogen. Angiotensin I is then enzymatically converted by angiotensin converting enzyme (ACE) into angiotensin II, a hormone with various actions throughout the body that ultimately increase blood pressure, restoring fluid balance within the body. | ||
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==Neural Control of the Cardiovascular System== | ==Neural Control of the Cardiovascular System== | ||
[[File:Sympathic_parasympathic.svg|thumb]] | [[File:Sympathic_parasympathic.svg|thumb|400px|Interaction between the sympathic and parasympathic nervous system and the heart]] | ||
===Sympathetic (Adrenergic) Nervous System=== | ===Sympathetic (Adrenergic) Nervous System=== | ||
The adrenergic nervous system is a vital component of many processes throughout the body, including the cardiovascular system. Circulating catecholamines (e.g. adrenaline and noradrenaline) bind to and activate adrenergic receptors on cell membranes. Adrenergic receptors are a class of G-protein coupled receptors that elicit a variety of tissue-specific effects and exist in several subtypes. | The adrenergic nervous system is a vital component of many processes throughout the body, including the cardiovascular system. Circulating catecholamines (e.g. adrenaline and noradrenaline) bind to and activate adrenergic receptors on cell membranes. Adrenergic receptors are a class of G-protein coupled receptors that elicit a variety of tissue-specific effects and exist in several subtypes. | ||
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==Platelet/Clotting System== | ==Platelet/Clotting System== | ||
[[File:Platelet_receptors.svg|thumb|400px|Platelet activation and inhibition operates through surface receptors on platelets. Feedback loops enhance platelet activation (e.g. ADP released by platelets increases platelet activation, through the ADP receptor)]] | |||
Platelets (also known as thrombocytes) are small cells lacking nuclei that are responsible for haemostasis, or blood clotting. Damage or injury leading to blood loss and exposure of extracellular collagen fibres is detected, activating platelets. Once activated, platelets become adhesive, sticking to both the damaged vessel wall and each other, forming a clump of cells, or ‘clot’, helping to dam the vessel leak. They then begin to secrete cytokines that encourage invasion of fibroblasts present in the surrounding tissue which form a more permanent patch, either by creating healthy tissue, or depositing extracellular matrix to form a scar. | Platelets (also known as thrombocytes) are small cells lacking nuclei that are responsible for haemostasis, or blood clotting. Damage or injury leading to blood loss and exposure of extracellular collagen fibres is detected, activating platelets. Once activated, platelets become adhesive, sticking to both the damaged vessel wall and each other, forming a clump of cells, or ‘clot’, helping to dam the vessel leak. They then begin to secrete cytokines that encourage invasion of fibroblasts present in the surrounding tissue which form a more permanent patch, either by creating healthy tissue, or depositing extracellular matrix to form a scar. | ||
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Drugs such as abciximab and tirofiban prevent clotting via inhibition of the glycoprotein IIb/IIIa receptor preventing both platelet activation and aggregation. | Drugs such as abciximab and tirofiban prevent clotting via inhibition of the glycoprotein IIb/IIIa receptor preventing both platelet activation and aggregation. | ||
== Understanding the Cholesterol/LDL System in Cardiovascular Health == | |||
The cholesterol/LDL (low-density lipoprotein) system plays a pivotal role in cardiovascular health, acting as a key component in the development of atherosclerosis, a primary cause of cardiovascular diseases (CVD). This system's importance lies in its contribution to the transport of cholesterol, a vital lipid molecule, throughout the body. Cholesterol is essential for various biological functions, including the synthesis of cell membranes, hormones, and vitamin D. However, its management within the circulatory system is crucial to preventing adverse cardiovascular outcomes. | |||
==== Cholesterol Transport and LDL's Role ==== | |||
Cholesterol travels through the bloodstream encapsulated within lipoproteins, which are particles made up of lipids and proteins. These lipoproteins are classified based on their density; low-density lipoproteins (LDL) and high-density lipoproteins (HDL) are among the most significant in terms of cardiovascular risk. LDL is often referred to as "bad" cholesterol because it contributes to the formation of plaque, a thick, hard deposit that can clog arteries and make them less flexible, a condition known as atherosclerosis. HDL, on the other hand, is known as "good" cholesterol because it helps remove cholesterol from the arteries, transporting it back to the liver for excretion or reuse. | |||
==== LDL and Atherosclerosis ==== | |||
When LDL cholesterol levels are high, LDL particles can penetrate the endothelial lining of the arteries, becoming oxidized by free radicals. This oxidized LDL is recognized by the immune system as a foreign invader, attracting macrophages that ingest the LDL, transforming into foam cells. These foam cells accumulate to form fatty streaks, the earliest signs of atherosclerosis. Over time, these fatty streaks can develop into larger plaques, which can narrow the arteries and restrict blood flow. If a plaque ruptures, it can lead to the formation of a blood clot, which can cause a heart attack or stroke. | |||
==== Regulation of Cholesterol/LDL Levels ==== | |||
The body's cholesterol levels are regulated by a complex interplay of synthesis, absorption, and excretion. The liver synthesizes cholesterol and secretes it into the bloodstream as part of very low-density lipoproteins (VLDL). As VLDL particles deliver their triglyceride content to cells, they become LDL particles. The liver also plays a key role in removing excess cholesterol from the blood, using receptors that bind to LDL particles and remove them from circulation. | |||
Dietary intake of cholesterol and saturated fats can influence LDL levels, as can genetic factors, such as mutations in the LDL receptor gene, which can lead to familial hypercholesterolemia, a condition characterized by very high levels of LDL cholesterol and an increased risk of heart disease. Lifestyle factors, including diet, exercise, and smoking cessation, are primary interventions for managing LDL levels, alongside pharmacological treatments such as statins, which lower cholesterol levels by inhibiting its synthesis in the liver. | |||
==== The Integral Role of LDL in Cardiovascular Health ==== | |||
Understanding the cholesterol/LDL system is essential for the prevention and management of cardiovascular diseases. By maintaining healthy levels of LDL cholesterol through lifestyle modifications and, when necessary, medication, individuals can significantly reduce their risk of developing atherosclerosis and its associated complications. This system's management is a cornerstone of cardiovascular health, underscoring the importance of regular monitoring and proactive interventions to maintain heart health and prevent disease. | |||
To manage cardiovascular risk factors like serum lipids, various medication groups are essential: | |||
* '''Statins''' (e.g., Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin) lower cholesterol by inhibiting HMG-CoA reductase. | |||
* '''Fibrates''' (e.g., Fenofibrate, Gemfibrozil) target triglycerides and increase HDL. | |||
* '''PCSK9 inhibitors''' (e.g., Evolocumab, Alirocumab) significantly reduce LDL cholesterol by blocking PCSK9 protein. | |||
* '''Bempedoic acid''' lowers LDL-C by inhibiting ATP citrate lyase. | |||
These medications, alongside lifestyle modifications, form the cornerstone of cardiovascular disease prevention and management. | |||
==Pharmacokinetics== | ==Pharmacokinetics== | ||
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|Transplant patients (with high LDL-C): Class IIbC <cite>Esc6</cite> | |Transplant patients (with high LDL-C): Class IIbC <cite>Esc6</cite> | ||
|Gastro-intestinal disturbance including diarrhoea (4.1%) and abdominal pain (3.0%); headache, fatigue (2.4%); myalgia, arthralgia (3.0%), sinusitis (3.6%), pharyngitis (2.3%), viral infection (2.2%), coughing (2.3%), hypersensitivity reactions including rash, angioedema, and anaphylaxis, hepatitis,pancreatitis, cholelithiasis, cholecystitis, thrombocytopenia, raised creatine kinase, myopathy, and rhabdomyolysis | |Gastro-intestinal disturbance including diarrhoea (4.1%) and abdominal pain (3.0%); headache, fatigue (2.4%); myalgia, arthralgia (3.0%), sinusitis (3.6%), pharyngitis (2.3%), viral infection (2.2%), coughing (2.3%), hypersensitivity reactions including rash, angioedema, and anaphylaxis, hepatitis,pancreatitis, cholelithiasis, cholecystitis, thrombocytopenia, raised creatine kinase, myopathy, and rhabdomyolysis | ||
|- | |||
|rowspan="3"|PCSK9 Inhibitors | |||
|Evolocumab, Alirocumab, Inclisiran | |||
|Primary hypercholesterolemia, Mixed Dyslipidemia, Homozygous Familial Hypercholesterolemia | |||
|Evolocumab: 140mg every 2 weeks or 420mg once monthly | |||
Alirocumab: 75mg to 150mg every 2 weeks | |||
Inclisiran dosages according to specific treatment regimes | |||
|Primary hypercholesterolemia and Mixed Dyslipidemia: Class I; Homozygous Familial Hypercholesterolemia: Class I <cite>Esc2</cite> <cite>Esc3</cite> | |||
|Injection site reactions (5.9%), nasopharyngitis (5.5%), upper respiratory tract infections (2.3%), flu (3.1%), back pain (3.2%), hypersensitivity reactions including rash, pruritus (1.7%), and rare cases of neurocognitive effects such as memory loss or confusion. | |||
|} | |} | ||