Hypertension: Causes, Treatments, and Side Effects

Posted on Dec 29, 2024 in Biology

Hypertension: Pathogenesis, Drugs, Mode of Action, and Side Effects

Pathogenesis of Hypertension

Hypertension results from complex interactions between genetic, environmental, and physiological factors that affect blood pressure regulation.

Key Mechanisms

  1. Increased Systemic Vascular Resistance (SVR):
    • Chronic vasoconstriction due to:
    • Increased activity of the renin-angiotensin-aldosterone system (RAAS).
    • Enhanced sympathetic nervous system (SNS) activation.
    • Structural changes in blood vessels (vascular remodeling) increase resistance.
  2. Altered Renal Function:
    • Impaired sodium excretion leads to volume overload.
    • Sodium retention increases cardiac output and blood pressure.
  3. Endothelial Dysfunction:
    • Reduced nitric oxide (NO) production and increased oxidative stress impair vasodilation.
    • Endothelin-1, a potent vasoconstrictor, is overproduced.
  4. Genetic and Environmental Factors:
    • Genetic predisposition, obesity, high salt intake, stress, and physical inactivity exacerbate the condition.

Drugs Used in Hypertension

  1. Angiotensin-Converting Enzyme (ACE) Inhibitors

    Examples: Enalapril, Ramipril, Lisinopril

    Mechanism of Action:

    • Inhibit the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.
    • Reduce aldosterone secretion, decreasing sodium and water retention.
    • Promote vasodilation, reducing SVR and blood pressure.

    Side Effects: Dry cough (due to bradykinin accumulation), hyperkalemia, angioedema, hypotension

  2. Angiotensin II Receptor Blockers (ARBs)

    Examples: Losartan, Valsartan

    Mechanism of Action:

    • Block angiotensin II type 1 (AT1) receptors, preventing vasoconstriction and aldosterone secretion.
    • Lower blood pressure by reducing preload and afterload.

    Side Effects: Hyperkalemia, hypotension, less risk of cough or angioedema compared to ACE inhibitors

  3. Calcium Channel Blockers (CCBs)

    Examples: Amlodipine, Nifedipine, Diltiazem, Verapamil

    Mechanism of Action:

    • Block calcium influx into vascular smooth muscle and cardiac cells.
    • Dihydropyridines (e.g., Amlodipine) primarily cause vasodilation.
    • Non-dihydropyridines (e.g., Verapamil) reduce heart rate and contractility.

    Side Effects: Dizziness, peripheral edema (dihydropyridines), bradycardia (non-dihydropyridines), constipation

Diuretics

Examples: Hydrochlorothiazide (thiazide), Furosemide (loop), Spironolactone (potassium-sparing)

Mechanism of Action:

  • Thiazides inhibit sodium and chloride reabsorption in the distal tubules, reducing blood volume.
  • Loop diuretics block Na+/K+/2Cl- reabsorption in the ascending loop of Henle for stronger diuresis.
  • Spironolactone antagonizes aldosterone, reducing sodium retention and potassium excretion.

Side Effects:

  • Thiazides: Hypokalemia, hyponatremia, hyperglycemia.
  • Loop diuretics: Electrolyte imbalance, dehydration.
  • Spironolactone: Hyperkalemia, gynecomastia.

Beta-Blockers

Examples: Atenolol, Metoprolol, Propranolol

Mechanism of Action:

  • Block beta-adrenergic receptors, reducing heart rate and myocardial contractility.
  • Decrease renin secretion, lowering blood pressure.

Side Effects:

  • Bradycardia, fatigue, hypotension, bronchospasm (in non-selective agents)

Alpha-Blockers

Examples: Prazosin, Doxazosin

Mechanism of Action:

  • Block alpha-1 adrenergic receptors on vascular smooth muscle, causing vasodilation and reducing SVR.

Side Effects:

  • Orthostatic hypotension, dizziness, headache.

Central Acting Agents

Examples: Clonidine, Methyldopa

Mechanism of Action:

  • Stimulate alpha-2 adrenergic receptors in the brain, reducing sympathetic outflow.
  • Decrease heart rate, cardiac output, and SVR.

Side Effects:

  • Sedation, dry mouth, rebound hypertension on abrupt withdrawal.

Direct Vasodilators

Examples: Hydralazine, Minoxidil

Mechanism of Action:

  • Relax vascular smooth muscle, directly reducing SVR.

Side Effects:

  • Reflex tachycardia, fluid retention, hypertrichosis (Minoxidil).

Nitrates

Mechanism of Action (MOA):

Nitrates act by releasing nitric oxide (NO), which causes vasodilation:

  1. NO Release and cGMP Production:
    • Nitrates are converted to nitric oxide in vascular smooth muscle.
    • NO stimulates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP).
  2. Smooth Muscle Relaxation:
    • cGMP decreases intracellular calcium, leading to relaxation of vascular smooth muscle.
  3. Hemodynamic Effects:
    • Venodilation: Reduces preload
    • Arterial Dilation (at high doses): Reduces afterload, decreasing myocardial oxygen demand.
    • Coronary Artery Dilation: Improves blood flow to ischemic myocardium.

Therapeutic Effects:

  • Reduce myocardial oxygen demand (primary effect).
  • Increase oxygen supply by dilating coronary arteries.
  • Relieve symptoms of angina and improve exercise tolerance

Side Effects:

  1. Cardiovascular:
    • Hypotension: Excessive vasodilation may cause dizziness, fainting.
    • Reflex Tachycardia: Increased heart rate as a compensatory response to hypotension.
  2. Neurological:
    • Headache, Dizziness
  3. Other Effects:
    • Flushing: Due to peripheral vasodilation.
    • Nausea and Vomiting: Rare but may occur.
  4. Tolerance:
    • Prolonged use leads to reduced efficacy
  5. Severe Effects (Rare):
    • Methemoglobinemia: High doses can cause increased levels of methemoglobin, reducing oxygen delivery.

Key Points:

  • Contraindications: Avoid with phosphodiesterase-5 inhibitors (e.g., Sildenafil) due to the risk of severe hypotension.
  • Common Uses: Acute angina, chronic angina prophylaxis, heart failure with reduced ejection fraction.

Nitrates are highly effective in relieving anginal symptoms but must be used judiciously to avoid tolerance and adverse effects.

Congestive Heart Failure

Pathogenesis of CHF

CHF results from the heart’s inability to pump blood effectively, leading to:

  1. Decreased Cardiac Output due to myocardial damage or pressure/volume overload.
  2. Neurohormonal Activation: Increased SNS and RAAS activity worsens the condition by promoting vasoconstriction and fluid retention.
  3. Cardiac Remodeling: Structural changes (hypertrophy, fibrosis) impair heart function.
  4. Fluid Retention: Pulmonary congestion and peripheral edema occur due to reduced cardiac output.

Drugs Used in CHF

  1. ACE Inhibitors (e.g., Enalapril, Ramipril)
    • MOA: Inhibit RAAS, reduce vasoconstriction and myocardial remodeling.
    • Effect: Decrease preload and afterload, improving cardiac output.
  2. ARBs (e.g., Losartan, Valsartan)
    • MOA: Block angiotensin II receptors, reducing vasoconstriction and fluid retention.
    • Effect: Reduce preload and afterload, improving heart function.
  3. Beta-Blockers (e.g., Bisoprolol, Carvedilol)
    • MOA: Block beta-receptors, reducing heart rate and myocardial oxygen demand.
    • Effect: Improve ventricular function and reduce mortality.
  4. Mineralocorticoid Receptor Antagonists (e.g., Spironolactone, Eplerenone)
    • MOA: Block aldosterone, reduce sodium retention and fibrosis.
    • Effect: Decrease fluid retention and improve heart function.
  5. Diuretics (e.g., Furosemide, HCTZ)
    • MOA: Increase sodium and water excretion, reducing fluid overload.
    • Effect: Relieve pulmonary congestion and edema.
  6. SGLT2 Inhibitors (e.g., Empagliflozin, Dapagliflozin)
    • MOA: Inhibit SGLT2, promoting diuresis and reducing cardiac workload.
    • Effect: Decrease preload and afterload, improving symptoms.
  7. Vasodilators (e.g., Hydralazine, Nitrates)
    • MOA: Dilate blood vessels, reducing preload (venous dilation) and afterload (arterial dilation).
    • Effect: Reduce heart workload and improve blood flow.
  8. Ivabradine
    • MOA: Slows heart rate by inhibiting the funny current (If) in the SA node
    • Effect: Reduces myocardial oxygen demand without affecting contractility.
  9. Digoxin
    • MOA: Increases contractility and slows heart rate via vagal stimulation.
    • Effect: Improves cardiac output and controls atrial fibrillation.
  10. ARNI (e.g., Sacubitril/Valsartan)
    • MOA: Inhibits neprilysin and blocks angiotensin II receptors.
    • Effect: Enhances natriuresis, reduces vasoconstriction, and improves heart function.

Acute Iron Poisoning: Treatment

  1. Initial Assessment and Stabilization

    • Airway, Breathing, Circulation (ABC): Ensure proper oxygenation and ventilation. Manage shock or respiratory distress if present.
    • History: Obtain details on the amount and time of iron ingestion, especially in children.

  2. Gastric Decontamination

    • Activated Charcoal: Not effective for iron poisoning as it does not bind to iron.
    • Gastric Lavage: Considered if the ingestion occurred within 1 hour and the patient is symptomatic (particularly in large or dangerous doses).
    • Whole-Bowel Irrigation: For large ingestions or if iron tablets are seen in the stool, polyethylene glycol (PEG) may be used to clear the gastrointestinal tract.

  3. Antidote: Deferoxamine

    • Mechanism of Action: Deferoxamine binds free iron, forming a stable complex (ferrioxamine), which is then excreted in the urine.
    • Indication: Used in severe poisoning (e.g., shock, altered mental status, serum iron levels >500 mcg/dL).
    • Administration: Intravenous or intramuscular administration, often in the hospital setting, for rapid iron removal

  4. Supportive Care

    • IV Fluids, Monitoring, Blood Transfusions

Mechanism of Action of Digitalis (Digoxin)

Digoxin, a cardiac glycoside, is primarily used in the treatment of heart failure and certain arrhythmias, such as atrial fibrillation. Its mechanism of action is multifaceted and can be summarized as follows:

  1. Inhibition of Na+/K+-ATPase Pump:

    Digoxin inhibits the Na+/K+-ATPase pump on the cell membrane of cardiac myocytes. This pump normally expels sodium ions from the cell and imports potassium ions. By inhibiting this pump, digoxin increases intracellular sodium levels.

  2. Increased Intracellular Calcium:

    The elevated intracellular sodium concentrations reduce the function of the sodium-calcium exchanger, which normally expels calcium ions from the cell in exchange for sodium. As a result, calcium accumulates within the cell, enhancing the force of myocardial contraction (positive inotropic effect).

  3. Increased Vagal Tone:

    Digoxin increases vagal (parasympathetic) activity, which slows down the electrical conduction through the atrioventricular (AV) node. This helps to control the heart rate, particularly in conditions like atrial fibrillation, where it reduces the rapid ventricular response by slowing conduction through the AV node.

  4. Reduced Sympathetic Activity:

    By increasing vagal tone and inhibiting sympathetic nervous system activity, digoxin helps to balance the autonomic nervous system in heart failure, reducing the detrimental effects of excessive sympathetic stimulation.

Clinical Effects

  • Increased Cardiac Output: The positive inotropic effect improves the heart’s ability to pump blood, beneficial in heart failure.
  • Rate Control: The negative chronotropic effect helps control heart rate in atrial fibrillation and atrial flutter.

Mechanism of Action of Calcium Channel Blockers (CCBs)

Calcium Channel Blockers (CCBs) are a class of drugs commonly used to treat hypertension, angina, and certain arrhythmias. Their primary mechanism of action is the inhibition of calcium influx through voltage-gated L-type calcium channels, which are found in the heart, smooth muscle, and blood vessels.

  1. Blocking Calcium Channels:

    CCBs bind to and inhibit the L-type calcium channels in the cell membranes of smooth muscle cells and cardiomyocytes (heart muscle cells). This prevents calcium ions from entering the cells, thereby reducing intracellular calcium levels.

  2. Vascular Smooth Muscle Relaxation:

    In the blood vessels, especially the arteries, reduced calcium entry causes smooth muscle relaxation and vasodilation. This results in a decrease in peripheral vascular resistance, leading to lower blood pressure (especially in hypertension).

  3. Reduction of Myocardial Contractility (Negative Inotropic Effect):

    In the heart, reduced calcium influx leads to a decrease in myocardial contractility, which can be helpful in conditions like angina (where the heart is under increased oxygen demand). The reduced contractility decreases myocardial oxygen consumption.

  4. Slowing of Conduction and Heart Rate (Negative Chronotropic and Dromotropic Effects):

    CCBs also reduce the influx of calcium into the sinoatrial (SA) node and atrioventricular (AV) node, slowing the depolarization rate. This results in a slower heart rate (negative chronotropic effect) and a slower conduction velocity (negative dromotropic effect), which is particularly useful in controlling arrhythmias such as supraventricular tachycardia (SVT).

Clinical Effects

  • Lower Blood Pressure: Through vasodilation.
  • Angina Relief: By reducing myocardial oxygen demand.
  • Arrhythmia Management: By slowing conduction through the AV node.

Penicillin G

Mechanism of Action (MOA)

  • Penicillin G inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs).
  • PBPs are essential for cross-linking peptidoglycan, a key structural component of the bacterial cell wall.
  • Inhibition of peptidoglycan synthesis weakens the cell wall, leading to osmotic imbalance and bacterial lysis (bactericidal effect).
  • Penicillin G is highly effective against gram-positive bacteria and some anaerobes but has limited activity against gram-negative organisms due to their outer membrane.

Adverse Effects

  1. Hypersensitivity Reactions: Most common adverse effect, ranging from rash and fever to severe anaphylaxis.
    • Cross-reactivity with other beta-lactams may occur.
  2. Gastrointestinal Issues: Nausea, vomiting, diarrhea.
    • Rarely, it causes antibiotic-associated pseudomembranous colitis.
  3. Hematologic Effects: Rarely causes hemolytic anemia, leukopenia, or thrombocytopenia.
  4. Neurological Effects: High doses, especially in renal impairment, may cause seizures.
  5. Injection Site Reactions: Localized pain or phlebitis with IV administration.

Uses

  1. Gram-Positive Infections: Streptococcal infections, pneumococcal infections, and endocarditis.
  2. Anaerobic Infections: Tetanus and gas gangrene caused by Clostridium species.
  3. Syphilis: First-line treatment for all stages of syphilis.
  4. Actinomycosis: Chronic infections caused by Actinomyces species.
  5. Meningitis: Effective for Neisseria meningitidis.
  6. Anthrax: Used against Bacillus anthracis.

Heparin

Mechanism of Action (MOA):

Heparin is an anticoagulant that works by enhancing the activity of antithrombin III, a naturally occurring inhibitor of blood clotting. Its actions include:

  1. Inhibition of Thrombin and Factor Xa:
    • Heparin binds to antithrombin III, causing a conformational change that significantly enhances its ability to inactivate thrombin (factor IIa) and factor Xa.
  2. Prevention of Fibrin Formation:
    • By inhibiting thrombin and factor Xa, heparin prevents the conversion of fibrinogen to fibrin, which is essential for clot formation. This reduces the ability of blood to form clots.
    • Heparin does not dissolve existing clots but prevents the formation of new clots and the extension of existing ones.

Uses:

Heparin is used for various conditions requiring anticoagulation, such as:

  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE)
  • Acute coronary syndrome (ACS), including unstable angina and myocardial infarction (MI)
  • Prevention of clotting during dialysis
  • Preventing clot formation during surgeries (e.g., cardiac surgery, orthopedic surgery)
  • Stroke prevention in patients with atrial fibrillation or mechanical heart valves

Adverse Effects (ADRs):

  1. Bleeding
  2. Heparin-Induced Thrombocytopenia (HIT)

Platinum-Based Drugs in Chemotherapy

Mechanism of Action (MOA):

Platinum-based drugs, such as cisplatin, carboplatin are alkylating agents used in chemotherapy.

  1. DNA Binding and Crosslinking:
    • Platinum drugs enter the cell and are activated inside by hydrolysis. Once activated, they form highly reactive platinum complexes that bind to the DNA.
  2. DNA Crosslinking:
    • These platinum complexes bind covalently to the purine bases of DNA, forming intrastrand or interstrand crosslinks. This prevents DNA unwinding, blocking DNA replication and transcription.
  3. Inhibition of Cell Division and Apoptosis:
    • The damage to DNA induces cell cycle arrest, primarily at the G2/M phase, leading to apoptosis of the cancerous cells.

Uses:

Platinum-based drugs are used to treat a variety of cancers, including:

  • Testicular cancer, Ovarian cancer, Non-small cell lung cancer (NSCLC), Bladder cancer, Head and neck cancers, Colon cancer (especially with oxaliplatin

Adverse Effects (ADRs):

  1. Nephrotoxicity: Cisplatin
  2. Ototoxicity: Platinum drugs, especially cisplatin
  3. Peripheral Neuropathy: tingling and numbness
  4. Nausea and Vomiting, 5. Myelosupression

Anti-Leprosy Regimen

Leprosy is treated with a combination of antibiotics to prevent resistance and ensure effective eradication of Mycobacterium leprae, the causative agent.

  1. Multidrug Therapy (MDT):
    • Rifampicin: 10 mg/kg once a month, as it is highly effective against M. leprae and helps prevent relapse.
    • Dapsone: 100 mg daily, which inhibits folic acid synthesis and helps control the infection.
    • Clofazimine: 50 mg daily and 300 mg once a month for multibacillary leprosy (higher bacterial load) to suppress bacterial growth and reduce inflammation.
  2. Duration of Treatment:
    • Paucibacillary leprosy: 6 months of MDT.
    • Multibacillary leprosy: 12 months of MDT.
  3. Supportive Care:
    • In addition to MDT, steroids may be used for treating reactions (inflammatory episodes).
    • Pain management and wound care are also important for managing complications, such as nerve damage and ulcers.

Adverse Effects:

  • Rifampicin: Hepatotoxicity, orange-red discoloration of urine.
  • Dapsone: Hemolysis (especially in G6PD deficiency), skin rashes.
  • Clofazimine: Skin discoloration, gastrointestinal disturbances.

Antifungals: MOA, ADR, and Uses

  1. Azoles (e.g., Fluconazole)
    • MOA: Inhibit ergosterol synthesis.
    • ADR: Liver toxicity, GI upset, skin rash.
    • Uses: Candidiasis, aspergillosis, cryptococcosis.
  2. Echinocandins (e.g., Caspofungin)
    • MOA: Disrupt fungal cell wall synthesis.
    • ADR: Fever, rash, liver enzyme elevation.
    • Uses: Candida, Aspergillus infections.
  3. Polyenes (e.g., Amphotericin B)
    • MOA: Bind to ergosterol, causing cell membrane damage.
    • ADR: Nephrotoxicity, infusion reactions.
    • Uses: Severe systemic fungal infections.
  4. Allylamines (e.g., Terbinafine)
    • MOA: Inhibit ergosterol synthesis.
    • ADR: Hepatotoxicity, GI upset.
    • Uses: Dermatophyte infections, onychomycosis.
  5. Griseofulvin
    • MOA: Inhibit fungal cell division.
    • ADR: Hepatotoxicity, photosensitivity.
    • Uses: Dermatophyte infections.

Pathogenesis of Angina

Angina is caused by an imbalance between myocardial oxygen demand and oxygen supply.

Types:

  1. Stable Angina: Due to fixed atherosclerotic plaque, causing reduced blood flow during exertion.
  2. Unstable Angina: Rupture of plaque with thrombus formation, leading to reduced blood flow even at rest.
  3. Prinzmetal Angina: Coronary vasospasm leads to transient ischemia.

Drugs Used in Angina

  1. Nitrates
    • Example: Nitroglycerin, Isosorbide dinitrate
    • MOA: Converted to nitric oxide (NO), activates guanylate cyclase, increases cyclic GMP → smooth muscle relaxation → coronary artery and venodilation → reduced preload and myocardial oxygen demand.
  2. Beta-Blockers
    • Example: Metoprolol, Atenolol
    • MOA: Block β1 receptors → reduce heart rate and contractility → decreased myocardial oxygen demand.
  3. Calcium Channel Blockers (CCBs)
    • Example: Amlodipine (dihydropyridine), Verapamil, Diltiazem (non-dihydropyridine)
    • MOA: Inhibit L-type calcium channels → reduced vascular smooth muscle contraction → vasodilation → decreased afterload and oxygen demand.
    • Non-dihydropyridines also decrease heart rate and contractility.
  4. Antiplatelet Agents
    • Example: Aspirin, Clopidogrel
    • MOA: Inhibit platelet aggregation to prevent thrombus formation.
    • Aspirin: Irreversible COX-1 inhibitor → decreases thromboxane A2.
    • Clopidogrel: P2Y12 receptor antagonist → inhibits ADP-mediated platelet aggregation.
  5. Ranolazine
    • MOA: Inhibits late sodium current → reduces intracellular calcium → decreased wall tension and oxygen consumption.
  6. Statins
    • Example: Atorvastatin, Rosuvastatin
    • MOA: Inhibit HMG-CoA reductase → decrease cholesterol synthesis → stabilize atherosclerotic plaques.

Secondary Prophylaxis in Angina

  • Lifestyle modifications: Smoking cessation, healthy diet, exercise.

Pharmacological:

  1. Antiplatelet agents: Aspirin, Clopidogrel to prevent thrombotic events.
  2. Statins: Reduce LDL cholesterol and stabilize plaques.
  3. ACE inhibitors/ARBs: Reduce afterload, improve endothelial function (in patients with comorbid hypertension/diabetes).
  4. Beta-blockers: Prevent recurrent ischemia by lowering myocardial workload.

Pathogenesis of Megaloblastic Anemia

Caused by defective DNA synthesis due to a deficiency of

  1. Vitamin B12 (Cobalamin)
  2. Folic Acid

Results in impaired nuclear maturation and formation of large, immature red blood cells (megaloblasts).

Drugs Used in Megaloblastic Anemia

  1. Vitamin B12 (Cyanocobalamin)
    • MOA: Acts as a cofactor for:
    • Methionine synthase: Converts homocysteine to methionine, regenerating tetrahydrofolate (THF) for DNA synthesis.
    • Methylmalonyl-CoA mutase: Converts methylmalonyl-CoA to succinyl-CoA, important in fatty acid metabolism.
    • Indication: Pernicious anemia, dietary deficiency, or malabsorption.
    • Route: IM or oral (depending on severity).
  2. Folic Acid
    • MOA: Converted to tetrahydrofolate (THF) → serves as a donor of one-carbon units for purine and thymidylate synthesis, essential for DNA synthesis.
    • Indication: Nutritional deficiency, pregnancy (to prevent neural tube defects), alcoholism.
  3. Combination Therapy
    • Vitamin B12 and folic acid are often given together, as isolated folic acid supplementation in B12 deficiency can mask neurological symptoms while correcting anemia.

Key Points for Exam

  • Megaloblastic anemia drugs are corrective therapies aimed at replenishing deficient cofactors for DNA synthesis.
  • Focus on pathogenesis-based treatment to address the underlying cause.

Fibrates in Hypertriglyceridemia (5 Marks)

Mechanism of Action (MOA):

Activate PPAR-α, resulting in:

1. Increased Lipoprotein Lipase Activity: Enhances triglyceride breakdown.

2. Decreased VLDL Production: Reduces hepatic secretion of triglyceride-rich lipoproteins.

3. Increased HDL Synthesis: Stimulates apolipoprotein A-I and A-II production.

Examples:

Fenofibrate, Gemfibrozil.

Indications:

Severe hypertriglyceridemia.

Prevention of pancreatitis in very high triglyceride levels.

Adverse Effects:

Myopathy (especially with statins).

Gallstones due to increased biliary cholesterol excretion.

Gastrointestinal discomfort.

Key Points:

Reduce triglycerides by 20–50%.

Mild increase in HDL levels.


Thiazides: MOA, ADR, and Uses

1. Mechanism of Action (MOA):

Inhibit Na+/Cl- co-transporter in the distal convoluted tubule.

Reduces sodium and chloride reabsorption, increasing urine output (diuresis).

Lowers blood volume, leading to decreased blood pressure.

2. Adverse Drug Reactions (ADR):

Electrolyte Imbalances:

Hypokalemia (low potassium)

Hyponatremia (low sodium)

Hypomagnesemia (low magnesium)

Hypercalcemia (high calcium)

Metabolic Effects:

Hyperglycemia (increased blood sugar)

Hyperlipidemia (elevated cholesterol and triglycerides)

Hyperuricemia (increased uric acid, can lead to gout)

Dehydration: Excessive fluid loss leading to low blood volume.

Skin Reactions: Rashes, photosensitivity (increased sun sensitivity).

Other: Dizziness, fatigue, weakness, erectile dysfunction.

3. Uses:

Hypertension: First-line treatment for high blood pressure (reduces blood volume and vascular resistance).

Edema: Reduces fluid retention in conditions like heart failure, liver cirrhosis, and chronic kidney disease.

Calcium Nephrolithiasis: Prevents recurrent calcium kidney stones by reducing calcium excretion.

Heart Failure: Often used in combination with other drugs to manage symptoms and fluid buildup.

Thiazide diuretics are effective for managing hypertension and edema, but they require monitoring for electrolyte disturbances and metabolic changes. They are commonly prescribed as part of long-term management for patients with heart failure or chronic kidney disease.


Statins: Pharmacology (5 Marks)

Mechanism of Action (MOA):

Inhibit HMG-CoA reductase: Reduces cholesterol synthesis in the liver.

Increases LDL receptors, leading to enhanced LDL clearance from the bloodstream.

Uses:

1. Hyperlipidemia: Lowers LDL cholesterol and total cholesterol in patients with high lipid levels.

2. Cardiovascular Disease Prevention: Reduces the risk of heart attack, stroke, and other cardiovascular events in both primary and secondary prevention.

3. Atherosclerosis: Slows the progression of atherosclerotic plaques in arteries.

4. Hyperlipoproteinemia: Effective in treating lipid abnormalities like familial hypercholesterolemia.

Adverse Effects:

1. Myopathy: Muscle pain or weakness, with rare severe cases of rhabdomyolysis (muscle breakdown).

2. Hepatotoxicity: Elevated liver enzymes (monitor liver function).

3. Gastrointestinal issues: Nausea, diarrhea, or abdominal discomfort.

4. Diabetes risk: Long-term use may increase the risk of type 2 diabetes.

Key Points:

First-line treatment for hyperlipidemia, especially for high LDL cholesterol.

Effective in preventing cardiovascular events (heart attack, stroke).

Regular monitoring of liver function and muscle health is recommended.

Contraindicated in pregnancy and active liver disease.

Common drugs include Atorvastatin, Simvastatin, and Rosuvastatin.


Medications Contraindicated During Pregnancy with Safer Alternatives

The use of certain medications during pregnancy can harm the fetus, but safer alternatives are available. Below is a detailed explanation for MBBS students:


1. Teratogenic Medications

Antiepileptics:

Contraindicated:

Valproate (Neural tube defects, cardiac anomalies).

Phenytoin (Fetal hydantoin syndrome).

Carbamazepine (Neural tube defects).

Safer Alternatives:

Levetiracetam or Lamotrigine (considered safer with minimal teratogenic effects).

Isotretinoin (Retinoids):

Contraindicated:

Isotretinoin (Craniofacial, cardiac, CNS malformations).

Safer Alternatives:

Azelaic acid or topical erythromycin for acne.

Warfarin (Oral Anticoagulant):

Contraindicated:

Warfarin (Fetal warfarin syndrome: nasal hypoplasia, limb defects).

Safer Alternative:

Low Molecular Weight Heparin (LMWH) or unfractionated heparin.

Methotrexate:

Contraindicated:

Methotrexate (Neural tube defects, limb abnormalities).

Safer Alternative:

Sulfasalazine (for rheumatoid arthritis) or surgical/medical management of ectopic pregnancy under guidance.



2. Antibiotics

Tetracyclines:

Contraindicated:

Tetracycline (Tooth discoloration, bone growth suppression).

Safer Alternative:

Amoxicillin or cephalexin.

Aminoglycosides:

Contraindicated:

Gentamicin, Streptomycin (Ototoxicity, nephrotoxicity).

Safer Alternative:

Penicillins or cephalosporins.

Fluoroquinolones:

Contraindicated:

Ciprofloxacin, Levofloxacin (Cartilage toxicity, arthropathy).

Safer Alternative:

Amoxicillin or azithromycin.


3. Hormonal Medications

Estrogens and Progestins:

Contraindicated:

High-dose hormonal contraceptives (risk of fetal malformations).

Safer Alternative:

Non-hormonal contraception methods during pregnancy are preferred.


4. Antihypertensive Medications

ACE Inhibitors (e.g., Enalapril, Lisinopril) and ARBs (e.g., Losartan):

Contraindicated:

Risk of renal dysplasia, fetal hypotension, and oligohydramnios.

Safer Alternatives:

Methyldopa, labetalol, or nifedipine.



5. NSAIDs

Contraindicated:

Aspirin, ibuprofen, indomethacin (risk of premature ductus arteriosus closure and oligohydramnios in the third trimester).

Safer Alternative:

Paracetamol for pain relief.

6. Psychiatric Medications

Lithium:

Contraindicated:

Causes Ebstein’s anomaly (cardiac defect).

Safer Alternative:

Lamotrigine or atypical antipsychotics like olanzapine.

Benzodiazepines:

Contraindicated:

Risk of neonatal sedation, withdrawal symptoms.

Safer Alternative:

Non-pharmacological therapies or SSRIs like sertraline if anxiety is severe.

Why Some Drugs Are Given on an Empty Stomach

Some medications, like proton pump inhibitors (e.g., omeprazole), require an acidic environment for absorption, which is optimal on an empty stomach. Taking such drugs with food may reduce their efficacy.