JM Topics Revision PDF

**[JM TOPICS:]** The basis of drug targeting -- Drug Discovery P1 Lecture 1 Receptor Subtype Specific drug targeting : - Agonist -increase effects - Antagonists -- decrease effects Dual effects of Ach -- Dale Experiment:  1. Low dosage of **Ach e...

**[JM TOPICS:]** The basis of drug targeting -- Drug Discovery P1 Lecture 1 Receptor Subtype Specific drug targeting : - Agonist -increase effects - Antagonists -- decrease effects Dual effects of Ach -- Dale Experiment:  1. Low dosage of **Ach e.g 2ug** activates M3 receptors -- this stimulates (NO ) from endothelial cells resulting smooth muscle relaxation = **Vasodilation ( bp decrease )** 2. Higher dosage of **Ach e.g 50 ug r**esults in receptors ( M3 vasolation , M2 for heart rate reduction ) activated. Nicotinic receptors activated from adrenal medulla and sympathetic ganglia. The effects... - The Vasolation via NO -- Bp drops - Bradycardia via M2 ( heart rate reduction) - This stimulates sympathetic neurons = **Vasoconstriction and adrenaline release** 3. **Atropine 2mg** ( Muscarinic Blocker ) this action blocks ( M2 and M3 receptors ) -- this prevents vasodilation and Bradycardia = Vasoconstriction and Bp Increases 4. Large doses of **Ach 50 mg** results in STRONG effect of M3 = LOW BP SIGNIFCANTLY, M2 = BRADYCARDIA , this has nicotinic effects with **TRANSIENT vasoconstriction and BP increases ,** so therefore without Atropine results in Muscarinic effects dominate = BP decreases, with Atropine = Muscarinic effects blocked= nictoninic effects dominate = BP increases **Vasodilation**: - **M3 receptors** on vascular endothelium stimulate **nitric oxide (NO)** release → Smooth muscle relaxation → Blood pressure decreases. - **Note**: This effect is indirect and only occurs in intact endothelium. **Bradycardia**: - **M2 receptors** in the sinoatrial (SA) node reduce heart rate by decreasing cyclic AMP. **Decreased Contractility**: - **M2 receptors** in the atria reduce cardiac output. This results in atrioventricular condition decreases strength of Atrium contraction **Nicotinic Effects of Ach:** Tachycardia -- the increase of atrio-ventricular condition and this increases Bp due to stimulation of sympathetic ganglia = Secondary Tachycardia - **tachycardia** (an abnormally fast heart rate) can occur as a result of ACh binding to nicotinic receptors located in sympathetic ganglia, which are part of the autonomic nervous system. - This stimulation leads to the release of norepinephrine from sympathetic nerve terminals. - **Sympathetic activation** increases heart rate and force of contraction, and leads to a rise in blood pressure. - This phenomenon is referred to as **secondary tachycardia**, which occurs due to an increase in sympathetic nervous system activity (often a reflex response to other factors like decreased blood pressure or other stimuli). This effect is part of the **sympathomimetic** response, which mimics the action of the sympathetic nervous system. **Asthma:** **beta-adrenergic agonist salbutamol -- inhaler** **Agonism** ( increases effect of drug targeting ) - Such as Adrenaline used to treat asthma however side effects are the following: - High blood pressure - Tachycardia - Atrial and ventricular fibrillation - Dry mouth etc. Example: Receptor subtype Specific Drug targeting ( Adrenaline non specific asthma )  - Adrenaline ( Epinephrine ) non specific drug and can bind to multiple adrenergic receptors such as α1, α2, β1, and β2. -- these located in different tissues this adrenaline action to these receptors produces various effects = Bronchiolar dilation. 1. Adrenaline released from adrenal medulla, enters bloodstream this circulates throughout body and binds to adrenergic receptors located various target cells. 2. β2 receptors ( smooth muscle of bronchioles ) -- where Adrenaline binds to them activates cascade of intracellular signalling pathways ( G protein coupled receptors ) = Increase intracellular cyclic AMP ( cAMP ) via adenylyl cyclase, so therefore the higher cAMP activates protein Kinase A, which then leads to phosphorylation of various target proteins. 3. Then smooth relaxation occurs when PKA inhibits MLCK in bronchioles relaxes = Bronchodilation. - **α1 receptors** cause vasoconstriction (narrowing of blood vessels), increasing blood pressure. - **α2 receptors** have an inhibitory effect on neurotransmitter release, generally leading to a decrease in sympathetic tone. - **β1 receptors** primarily affect the heart, increasing heart rate and force of contraction, which also helps to circulate adrenaline more efficiently throughout the body. **Overview of Adrenergic Receptors** 1. **Adrenaline and Adrenergic Receptors:**\ Adrenaline (epinephrine) binds to adrenergic receptors, which are G-protein-coupled receptors (GPCRs). There are two main classes of adrenergic receptors: - **Alpha (α):** Subtypes include α₁ and α₂. - **Beta (β):** Subtypes include β₁, β₂, and β₃. 2. **Tissue-Specific Expression:**\ Different adrenergic receptor subtypes are expressed in specific tissues, allowing adrenaline to exert diverse effects throughout the body. **Physiological Effects of Each Receptor Subtype** 3. **α₁-Adrenergic Receptors:** - Found in **vascular smooth muscle**. - Activation causes **vasoconstriction**, leading to increased blood pressure. 4. **α₂-Adrenergic Receptors:** - Located in **presynaptic nerve terminals**. - Inhibits norepinephrine release, providing **negative feedback regulation**. 5. **β₁-Adrenergic Receptors:** - Predominantly in the **heart**. - Activation increases **heart rate** (positive chronotropy) and **contractility** (positive inotropy), enhancing cardiac output. 6. **β₂-Adrenergic Receptors:** - Found in **bronchial smooth muscle** and **skeletal muscle blood vessels**. - Activation causes **bronchodilation** and **vasodilation**, improving oxygen delivery and blood flow. 7. **β₃-Adrenergic Receptors:** - Present in **adipose tissue**. - Stimulates **lipolysis**, breaking down fat for energy during stress responses. **Mechanism of Receptor Activation** 8. **G-Protein Coupling and Second Messengers:** - α₁: Activates Gq proteins, increasing intracellular calcium through the phospholipase C (PLC) pathway. - α₂: Activates Gi proteins, inhibiting adenylyl cyclase and reducing cAMP levels. - β₁, β₂, and β₃: Activate Gs proteins, increasing cAMP levels and triggering protein kinase A (PKA) activity. **Integration of Effects** 9. **Synergistic and Opposing Roles:**\ The combined actions of these receptor subtypes enable adrenaline to finely tune the **fight-or-flight response**. For example: - **Cardiovascular System:** β₁ increases cardiac output, while α₁ mediates vasoconstriction to redirect blood to vital organs. - **Respiratory System:** β₂ ensures bronchodilation, facilitating oxygen uptake. **Pre-eclampsia** **Receptor subtype Specific Drug targeting -- Antagonism** **Pathophysiology:** - The cause of pre-eclampsia remains unknown - Placental dysfunction may be the cause - This may initiate the systemic vasospasm, ischemia, and thrombosis. - Eventually damages maternal organs. **1. Administration of Ketanserin** - Ketanserin is administered to the patient either orally or intravenously, depending on the clinical situation and the route chosen by the healthcare provider. - Once in the bloodstream, it circulates throughout the body and reaches its target tissues, including blood vessels and smooth muscle. **2. Binding to 5-HT2A Receptors** - 5-HT2A Receptors are present in various tissues, including blood vessels (endothelium and smooth muscle). - Ketanserin acts as an antagonist at the 5-HT2A receptors. This means that it binds to the 5-HT2A receptors, preventing serotonin (5-HT) from activating these receptors. - Serotonin typically promotes vasoconstriction when it binds to 5-HT2A receptors, so blocking this receptor helps reduce vasoconstriction and improve blood vessel dilation. - This action is particularly important in reducing the vascular resistance seen in pre-eclampsia, which can help lower blood pressure. **3. Binding to α1-Adrenergic Receptors** - In addition to the 5-HT2A receptor, Ketanserin also acts as an antagonist at the α1-adrenergic receptors. - These receptors are located on the smooth muscle of blood vessels. When activated by norepinephrine, they cause vasoconstriction. - By blocking the α1 receptors, Ketanserin prevents this vasoconstriction, leading to blood vessel relaxation and contributing to reduced blood pressure. - This antagonism also helps in reducing the peripheral vascular resistance, which is elevated in pre-eclampsia due to abnormal vascular function. **4. Increased Vascular Relaxation and Lowered Blood Pressure** - With both the 5-HT2A receptor and α1-adrenergic receptor blocked, vascular smooth muscle relaxation occurs. - The arteries and arterioles relax, leading to decreased vascular resistance and lowered blood pressure. - This reduction in blood pressure is crucial in managing pre-eclampsia, as it helps prevent complications like stroke, organ damage, and placental insufficiency. **5. Improvement in Endothelial Function** - Endothelial dysfunction is a key feature of pre-eclampsia, where the blood vessels\' ability to dilate properly is impaired. - By antagonizing 5-HT2A receptors, Ketanserin can help improve endothelial function, as the 5-HT2A receptor plays a role in regulating blood vessel dilation and contraction. - This improvement in endothelial function further contributes to better blood flow to organs like the kidneys, liver, and placenta, which are often affected in PE. **6. Reduction in Inflammation** - Serotonin is involved in inflammatory responses. By blocking the 5-HT2A receptors, Ketanserin may help reduce the inflammatory cascade that contributes to the progression of pre-eclampsia. - Reducing inflammation can prevent tissue damage and improve maternal and fetal outcomes. **7. Overall Effect and Outcome** - The overall effect of Ketanserin's antagonism on 5-HT2A and α1-adrenergic receptors leads to a combination of lowered blood pressure, improved endothelial function, and reduced vascular resistance. - These actions would be beneficial in the treatment of pre-eclampsia, potentially alleviating some of the vascular dysfunction, reducing the risk of severe complications, and improving fetal perfusion. **8. Monitoring and Adjustments** - Ketanserin would be carefully monitored in the clinical setting, especially during pregnancy, to assess its effectiveness in lowering blood pressure and improving overall maternal well-being. - The drug's effects would be monitored through blood pressure measurements, urine analysis, and potentially other parameters like kidney function to ensure it is having the desired effect without adverse outcomes. **Vasodilator Factors:** **Nitric Oxide (NO):** Often reduced in PE, contributing to impaired vasodilation and increased vasoconstriction. **Prostacyclin (PGI2):** Reduced in PE, leading to less vasodilation and more vasoconstriction. **Endothelium-Derived Hyperpolarizing Factor (EDHF):** Impaired in PE, reducing its ability to promote vasodilation and increasing vascular resistance. **5-Hydroxytryptamine (5-HT):** Elevated levels in PE may promote vasoconstriction, further raising blood pressure. **Vasoconstrictor Factors:** 1. **Endothelin:** - Vasoconstrictor peptide produced by endothelial cells. - It binds to ETA and ETB receptors on smooth muscle cells, causing vasoconstriction. - Plays a significant role in regulating vascular tone, especially in conditions like pre-eclampsia. 2. **Superoxide:** - Reactive oxygen species (ROS) that can promote vasoconstriction. - Superoxide can inactivate nitric oxide (NO), reducing its vasodilatory effects and contributing to increased vascular resistance. - Elevated in conditions like pre-eclampsia, where oxidative stress is higher. 3. **Vasoconstrictor Prostaglandins:** - Some prostaglandins (such as thromboxane A2) act as vasoconstrictors, promoting blood vessel narrowing. - They play a role in platelet aggregation and vascular tone regulation. In pre-eclampsia, the balance shifts, and the vasoconstrictor prostaglandins may be increased. 4. **5-Hydroxytryptamine (5-HT):** - Also known as serotonin, acts as a vasoconstrictor through 5-HT2A receptors on vascular smooth muscle. - High levels of serotonin can contribute to increased vasoconstriction, raising blood pressure. **Summary of Vasoconstrictor Factors:** - Endothelin: Vasoconstrictor peptide. - Superoxide: Reactive oxygen species that reduce NO availability, increasing vasoconstriction. - Vasoconstrictor Prostaglandins: Prostaglandins like thromboxane A2 cause vasoconstriction. - 5-Hydroxytryptamine (5-HT): Serotonin that promotes vasoconstriction. **In pre-eclampsia, these factors are typically increased, leading to vascular dysfunction, vasoconstriction, and high blood pressure.** **How do they both link to Pre-eclampsia :** **Link Between Vasodilation and Vasoconstriction:** Balance and Regulation: Vasodilation and vasoconstriction are opposing forces, but they are complementary in maintaining proper blood flow and pressure. The body adjusts vascular tone by modulating the activity of both processes. For example, when blood pressure drops, the body may respond with vasoconstriction to increase vascular resistance and raise blood pressure. Conversely, if blood pressure is too high or blood flow to tissues needs to be increased (such as during exercise), vasodilation occurs. Endothelial Control: The endothelium (lining of blood vessels) plays a central role in regulating both processes by releasing various molecules that can cause either dilation or constriction. The balance between vasodilatory factors (e.g., NO, prostacyclin, EDHF) and vasoconstrictor factors (e.g., endothelin, 5-HT, superoxide) determines the vascular tone and blood pressure. Imbalance in Conditions (e.g., Pre-eclampsia): In conditions like pre-eclampsia, the balance shifts toward increased vasoconstriction due to reduced levels of vasodilators (NO, prostacyclin, EDHF) and increased levels of vasoconstrictors (endothelin, 5-HT). This results in elevated blood pressure, vascular dysfunction, and impaired organ perfusion. **1. Impaired Vasodilation:** In a healthy pregnancy, **vasodilation** helps increase blood flow to the placenta and other tissues, supporting fetal growth and maternal health. However, in **pre-eclampsia**, this vasodilation process is impaired due to: - **Reduced Nitric Oxide (NO)**: NO is a key vasodilator produced by endothelial cells. In PE, endothelial dysfunction occurs, and there is a **decrease in NO production**, leading to **increased vascular resistance** and impaired vasodilation. - **Reduced Prostacyclin (PGI2)**: PGI2, another important vasodilator, is also decreased in PE. This impairs the ability of blood vessels to dilate, further contributing to **high blood pressure**. - **Decreased Endothelium-Derived Hyperpolarizing Factor (EDHF)**: EDHF is another factor involved in vasodilation, but in PE, its production is also impaired, contributing to **reduced vascular relaxation**. **2. Excessive Vasoconstriction:** In PE, **vasoconstriction** is increased due to elevated levels of vasoconstrictor factors: - **Increased Endothelin**: Endothelin is a potent vasoconstrictor that binds to receptors on vascular smooth muscle, causing **narrowing of the blood vessels**. In PE, there is an increase in endothelin production, contributing to **increased vascular resistance** and **elevated blood pressure**. - **Increased 5-Hydroxytryptamine (5-HT)**: Elevated levels of serotonin in PE can lead to **increased vasoconstriction**. Serotonin constricts blood vessels, further raising blood pressure. - **Increased Vasoconstrictor Prostaglandins (e.g., Thromboxane A2)**: Thromboxane A2 is a vasoconstrictor prostaglandin that is often increased in PE. This promotes blood vessel constriction and further elevates blood pressure. - **Increased Superoxide**: Superoxide is a reactive oxygen species that can **neutralize NO** (a vasodilator), leading to further endothelial dysfunction and promoting **vasoconstriction**. **3. Impaired Placental Blood Flow:** - The imbalance between vasoconstriction and vasodilation leads to **reduced placental blood flow**. The **placenta** becomes poorly perfused, which can lead to **fetal growth restriction** and other complications. - The **increased vasoconstriction** and **reduced vasodilation** result in **poor perfusion of the uterus and placenta**, contributing to **hypoxia** (lack of oxygen) and other problems in pregnancy. **4. Increased Blood Pressure (Hypertension):** - As a result of impaired vasodilation and excessive vasoconstriction, **vascular resistance increases**, leading to **high blood pressure (hypertension)**, which is a hallmark of pre-eclampsia. - **Increased blood pressure** puts a strain on the heart, kidneys, and other organs, and can lead to complications such as **proteinuria** (protein in the urine) and **organ dysfunction**. **5. Endothelial Dysfunction and Inflammation:** - **Endothelial dysfunction** plays a central role in pre-eclampsia, where the endothelial cells lining the blood vessels fail to maintain normal function. This dysfunction results in: - **Increased permeability** of blood vessels. - **Reduced production of vasodilators** (e.g., NO, prostacyclin). - **Increased secretion of vasoconstrictors** (e.g., endothelin, thromboxane A2). - This leads to **inflammation** and further damage to the vasculature, contributing to the development of pre-eclampsia. **6. Systemic Effects of Pre-Eclampsia:** As a result of impaired vasodilation and excessive vasoconstriction: - **Elevated blood pressure** (hypertension) damages organs, especially the **kidneys**, **liver**, and **brain**, leading to complications such as **kidney damage**, **liver dysfunction**, **seizures**, and **stroke**. - The **fetus** may suffer from **intrauterine growth restriction (IUGR)** due to reduced placental blood flow and oxygen supply. **Summary of Mechanisms Leading to Pre-Eclampsia:** 1. **Reduced vasodilation** due to decreased NO, prostacyclin, and EDHF. 2. **Increased vasoconstriction** due to elevated endothelin, serotonin, vasoconstrictor prostaglandins, and superoxide. 3. **Impaired placental blood flow**, leading to fetal growth restriction and hypoxia. 4. **Increased blood pressure** (hypertension) due to elevated vascular resistance. 5. **Endothelial dysfunction** and inflammation, causing further damage to the blood vessels and organs. This imbalance between vasoconstriction and vasodilation contributes to the characteristic symptoms of **pre-eclampsia**, including **hypertension**, **proteinuria**, and potential organ damage.  - **5-HT7 = Vasodilation** - **5-HT2A = Vaconstriction** **Dual effects of 5HT in blood vessels:** **1. Vasoconstriction:** Receptors involved: 5-HT2A receptors on smooth muscle. Mechanism: Serotonin binds to 5-HT2A receptors, triggering a signaling pathway that increases intracellular calcium, causing smooth muscle contraction and narrowing of blood vessels, which raises blood pressure. **2. Vasodilation:** Receptors involved: 5-HT1B and 5-HT7 receptors. Mechanism: Activation of these receptors increases cAMP, which reduces intracellular calcium, relaxing smooth muscle and widening blood vessels, lowering blood pressure. **3. Context-Dependent Effects:** In certain tissues, serotonin causes vasoconstriction (e.g., in skeletal muscle) and vasodilation (e.g., in the brain) depending on receptor types and local conditions. In summary, serotonin can either constrict or dilate blood vessels, depending on the specific receptor it binds to and the context. **The effects of ketanserin (Ket) in vessels** Ketanserin works through its actions as an antagonist at serotonin and adrenergic receptors, which leads to its therapeutic effects, primarily as an antihypertensive agent. Here\'s how it works: **1. Blocking 5-HT2A Serotonin Receptors:** Target: 5-HT2A receptors located on vascular smooth muscle. Action: Ketanserin binds to and blocks these receptors, preventing serotonin (5-HT) from binding and causing vasoconstriction. Result: This prevents blood vessel narrowing (vasoconstriction) and causes vasodilation, leading to a decrease in blood pressure. **2. Blocking Alpha-1 Adrenergic Receptors:** Target: Alpha-1 adrenergic receptors on vascular smooth muscle. Action: Ketanserin also blocks the effects of norepinephrine (a sympathetic neurotransmitter) on these receptors, which would normally cause vasoconstriction through sympathetic nervous system activation. Result: By blocking these receptors, vasodilation occurs, further contributing to reduced blood pressure. **3. Overall Effect:** Vasodilation: Both receptor blockades lead to the relaxation of blood vessels, reducing vascular resistance. Lowered Blood Pressure: The reduction in vascular resistance and vasodilation results in lowered systemic blood pressure, making ketanserin effective for treating hypertension. **4. Minimal Impact on Heart Rate:** Unlike other antihypertensive drugs, ketanserin does not significantly affect heart rate. **Drug Discovery cycle:** A diagram of a company\'s process 1. **Compound Collections**: - A library of chemical compounds is used as a starting point for screening potential drug candidates. 2. **Primary Assays (High Throughput, In Vitro)**: - Initial testing of compounds to identify those with desirable biological activity. This process uses automated systems to screen large numbers of compounds quickly. 3. **Secondary Assays (Efficacy, Bioavailability, Toxicity, In Vivo)**: - Further testing to evaluate the most promising compounds for their efficacy, bioavailability, and toxicity in more complex biological systems, often including animal models. 4. **Lead Compounds and Structure-Activity Relationships (SAR)**: - Identified compounds with desirable activity undergo detailed analysis to understand how structural changes influence their biological activity, forming the SAR profile. 5. **Structural Characterization of Protein-Ligand Complex**: - Detailed examination of how the lead compounds interact with their target proteins. This information is critical for designing improved compounds. 6. **Chemical Synthesis**: - Modifications and synthesis of new compounds based on SAR and structural insights. 7. **Design**: - Rational design of new compounds, informed by structural data and SAR, to improve properties like potency, selectivity, and safety. 8. **Candidate Drug**: - The final result is a drug candidate ready for further development, including clinical trials. **Key Pathways:** - **Direct Pathway**: From \"Design\" to \"Structural Characterization\" and back. - **Indirect Pathway**: Involves iterative synthesis and testing cycles before reaching lead compound identification. **[Structured-based drug design ( SBDD) ]** 4. Discovery Phase: - Potential therapeutic target and active ligands are identified and cloned. - Production, extraction, purification of proteins. - The 3D structure determination using algorithms. - Docking and binding sites are identified. 2\. **The 2^nd^ Phase:** - The top hits are synthesized and optimized. - Selective modulation of the target protein are tested *in vitro*. - Efficacy, affinity, and potency of the selected compounds are evaluated. - Determination of the 3D structure of the target protein to understand molecular recognition. - Structural insights into the ligand--protein complex 3\. The 3rd and Final Phases: - The third phase includes clinical trials of the lead compounds. - Those compounds that pass the clinical trials proceed to the fourth phase. - Governmental and independent approval for marketing is sort - Drug is distributed in the market for clinical use. **Genetic variations in drug therapy -- Polymorphism**  One of the major causes of interindividual variation of drug effects is genetic variation of drug metabolism. Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions. Effect of genetic polymorphisms on individuals' drug response. Pharmacokinetics and pharmacodynamics are main determinants of interindividual differences in drug responses. Genetic polymorphism in genes related to these processes may result in mild to severe variations in drug responses. ADRs, adverse drug reactions. **Metabolic Syndromes -- Introduction:** - Cluster of conditions occurring together that increase risk of heart disease, Stroke, Type 2 diabetes **What causes metabolic syndromes?** - Life style factors, like smoking drinking and stress - Genetic factors such as Glycogen branching Enzyme - Abdominal Obesity **What are the components of metabolic syndromes** - **Elevated waist circumference** (≥88cm for women; ≥102 cm for men). - **Elevated triglycerides** (≥ 150 mg/dL) or drug treatment foe elevated triglycerides - **Low HDL** (,40 mg/dL for men; \20--30 minutes) can cause irreversible myocardial damage, leading to myocardial infarction (heart attack). **Clinical Features:** 1. **Angina Pectoris (Chest Pain):** - Tight, squeezing pain or discomfort, typically felt in the chest, radiating to the left arm, neck, jaw, or back. - Can be stable (on exertion) or unstable (at rest). 2. **Dyspnea:** - Shortness of breath due to reduced cardiac output. 3. **Fatigue and Weakness:** - Due to insufficient blood supply to vital organs. 4. **Palpitations:** - Awareness of irregular or rapid heartbeats. 5. **Silent Ischemia:** - Asymptomatic ischemia, more common in diabetic patients. **Diagnosis:** 1. **Electrocardiogram (ECG):** - ST-segment depression or T-wave inversion indicates ischemia. - ST-segment elevation suggests acute infarction. 2. **Stress Testing:** - Exercise ECG or imaging to evaluate ischemia under stress. 3. **Coronary Angiography:** - Visualizes blockages in coronary arteries. 4. **Blood Tests:** - Troponins (specific markers of myocardial injury). **Management:** 1. **Acute Treatment:** - **Nitro-glycerine:** Dilates coronary arteries to improve blood flow. - **Oxygen Therapy:** Ensures adequate oxygen delivery. - **Antiplatelets (e.g., Aspirin):** Prevents clot formation. 2. **Chronic Management:** - **Beta-Blockers:** Reduce myocardial oxygen demand by lowering heart rate. - **Statins:** Lower cholesterol to prevent atherosclerosis progression. - **ACE Inhibitors:** Improve cardiac function and reduce afterload. 3. **Revascularization Procedures:** - **Percutaneous Coronary Intervention (PCI):** Balloon angioplasty with stent placement. - **Coronary Artery Bypass Grafting (CABG):** Surgical rerouting of blood around blocked arteries. **Prevention:** - Control risk factors: - Hypertension, diabetes, and hyperlipidemia. - Healthy lifestyle: - Regular exercise, a balanced diet, and smoking cessation. - Regular follow-ups for individuals with a history of cardiovascular disease. **Ischemia and Angina Pectoris:** **1. Ischemia** **Definition:**\ Ischemia is a condition where there is insufficient blood flow (and oxygen supply) to a tissue or organ due to an obstruction or narrowing of blood vessels. In the heart, this affects the myocardium (myocardial ischemia). **Key Points of Myocardial Ischemia:** - Occurs due to an imbalance between oxygen supply and demand in the myocardium. - Most commonly caused by atherosclerosis of the coronary arteries. **2. Angina Pectoris** **Definition:**\ Angina pectoris is a clinical symptom of myocardial ischemia, characterized by chest pain or discomfort caused by inadequate oxygen supply to the myocardium. **Types of Angina Pectoris:** 1. **Stable Angina:** - Occurs during physical exertion or emotional stress. - Pain subsides with rest or nitroglycerin. - Cause: Fixed coronary artery stenosis. 2. **Unstable Angina:** - Occurs unpredictably, even at rest. - Indicates a higher risk of myocardial infarction. - Cause: Rupture of atherosclerotic plaque and partial thrombus formation. 3. **Variant (Prinzmetal) Angina:** - Caused by coronary artery spasms, not related to physical exertion. - Often occurs at rest and is relieved by vasodilators. **Pathophysiology of Ischemia Leading to Angina** 1. **Reduced Coronary Blood Flow:** - Due to atherosclerosis, thrombosis, or coronary artery spasm. 2. **Oxygen Supply-Demand Imbalance:** - Increased myocardial oxygen demand (e.g., during exercise, tachycardia). - Decreased oxygen supply (e.g., due to reduced coronary perfusion). 3. **Cellular Changes:** - Reduced ATP production impairs cardiac muscle contraction. - Lactate accumulation triggers nociceptors, causing chest pain. **Clinical Features of Angina Pectoris** - **Chest Pain:** - Typically retrosternal, with radiation to the left arm, jaw, or neck. - Described as squeezing, pressure, or heaviness. - **Duration:** - Stable angina: Pain lasts a few minutes and resolves with rest. - Unstable angina: Prolonged pain not relieved by rest. - **Associated Symptoms:** - Shortness of breath, diaphoresis (sweating), nausea, or dizziness. **Diagnosis** 1. **Electrocardiogram (ECG):** - ST-segment depression or T-wave inversion during angina. - Variant angina may show ST-segment elevation during an episode. 2. **Stress Test:** - Induces ischemia via exercise or pharmacological agents. 3. **Coronary Angiography:** - Gold standard to identify coronary artery blockages. 4. **Cardiac Biomarkers:** - Normal in angina but elevated in myocardial infarction. **Management** **Acute Management of Angina:** 1. **Nitroglycerin:** - Relieves pain by dilating coronary arteries and reducing myocardial oxygen demand. 2. **Oxygen Therapy:** - For patients with low oxygen saturation. 3. **Antiplatelets (e.g., Aspirin):** - Prevents clot formation. **Chronic Management:** 1. **Medications:** - **Beta-Blockers:** Reduce heart rate and oxygen demand. - **Calcium Channel Blockers:** Relieve coronary artery spasm. - **Statins:** Lower cholesterol and stabilize plaques. - **ACE Inhibitors:** Improve cardiac function and reduce afterload. 2. **Lifestyle Modifications:** - Smoking cessation, regular exercise, and a healthy diet. 3. **Revascularization Procedures:** - **Percutaneous Coronary Intervention (PCI):** Balloon angioplasty with stent placement. - **Coronary Artery Bypass Grafting (CABG):** Surgical rerouting of blood around blocked arteries. **Complications** - Progression to **acute coronary syndrome (ACS)** (unstable angina or myocardial infarction). - Chronic ischemia leading to **heart failure** or arrhythmias. **What is Intermittent Claudication:** **Definition:**\ Intermittent claudication is a clinical symptom characterized by muscle pain, cramping, or discomfort in the lower limbs (usually the calves) during physical activity, such as walking, that resolves with rest. It is a hallmark symptom of **peripheral arterial disease (PAD)** caused by insufficient blood flow to the muscles during exercise. **Pathophysiology:** 1. **Atherosclerosis in Peripheral Arteries:** - Narrowing or blockage of arteries (typically in the lower extremities) due to plaque buildup reduces blood supply to muscles during activity. 2. **Oxygen Supply-Demand Mismatch:** - During exercise, muscles require more oxygen. - Reduced blood flow causes tissue ischemia and pain. 3. **Relief with Rest:** - When activity stops, oxygen demand decreases, and the ischemic pain subsides. **Clinical Features:** 1. **Pain Location:** - Typically felt in the calves, but can also occur in the thighs, buttocks, or feet depending on the site of arterial obstruction. 2. **Nature of Pain:** - Cramping, aching, or burning sensation. - Gradual onset during activity and relief within minutes of rest. 3. **Severity:** - Correlates with the extent of arterial blockage. Severe cases may progress to **rest pain** or **critical limb ischemia**. 4. **Associated Signs:** - **Cold or pale skin** in the affected limb. - **Hair loss, brittle nails, or ulcers** on the legs or feet. - **Weak or absent peripheral pulses.** **Common Causes:** 1. **Atherosclerosis:** - The most common cause of intermittent claudication. 2. **Risk Factors for Atherosclerosis:** - Smoking. - Diabetes mellitus. - Hypertension. - Hyperlipidemia. - Advanced age. 3. **Other Causes:** - Arterial embolism. - Vasculitis (inflammatory arterial diseases). - Entrapment syndromes (e.g., popliteal artery entrapment). **Diagnosis:** 1. **Ankle-Brachial Index (ABI):** - Compares blood pressure in the ankle and arm. An ABI \