Unit 1: Drugs Acting on the Cardiovascular System

Definition

This unit explores pharmacotherapies that modulate cardiac output, vascular resistance, blood volume, and lipid metabolism to manage disorders such as hypertension, angina, heart failure, arrhythmias, and dyslipidemias.

1.1 Hemodynamics & Vascular Tone

• Key Concepts:

  • Cardiac Output (CO): CO = Heart Rate × Stroke Volume; influenced by preload, afterload, contractility, and autonomic tone.

  • Systemic Vascular Resistance (SVR): Determined by arteriolar tone; primary target for many antihypertensives.

  • Mean Arterial Pressure (MAP): MAP ≈ (CO × SVR) + Central Venous Pressure.

• Drug Effects:

  • Vasodilators: ↓ SVR (e.g., hydralazine, nitrates)

  • Inotropes: ↑ contractility (e.g., digoxin, dobutamine)

  • Chronotropes: Modulate heart rate via SA/AV nodes (β‑blockers, CCBs)

1.2 Congestive Heart Failure (CHF) Agents

• Diuretics: Reduce preload by promoting sodium/water excretion

  • Loop: Furosemide (↑ efficacy; acute decompensation)

  • Thiazide: Metolazone (add‑on to loop in refractory edema)

  • Aldosterone Antagonists: Spironolactone (mortality benefit in HFrEF)

• ACE Inhibitors/ARBs:

  • Mechanism: ↓ Ang II → vasodilation, ↓ aldosterone, ↓ remodeling

  • Drugs: Enalapril, Lisinopril; Losartan, Valsartan

• β‑Blockers:

  • Mechanism: ↓ sympathetic drive, ↑ ejection fraction over time

  • Drugs: Carvedilol, Metoprolol succinate

• Vasodilators:

  • Hydralazine + Isosorbide dinitrate: Particularly in African‑American patients

  • ARNI: Sacubitril/Valsartan (superior to ACE‑I alone)

• Positive Inotropes:

  • Digoxin: Na⁺/K⁺‑ATPase inhibition → ↑ intracellular Ca²⁺; symptomatic relief

  • Dobutamine, Milrinone: Used in acute decompensation; limited long‑term use

1.3 Antihypertensive Agents

• Diuretics: (see CHF section) first‑line for most patients

• ACE Inhibitors & ARBs: (see CHF) also renoprotective in diabetes

• Calcium Channel Blockers:

  • Dihydropyridines: Amlodipine (vasoselective)

  • Non‑DHPs: Verapamil, Diltiazem (cardioselective; rate control)

• β‑Blockers: (see CHF) also for post‑MI patients

• α₁‑Blockers: Prazosin (adjunct in BPH)

• Central Agents: Clonidine, Methyldopa (pregnancy)

• Direct Renin Inhibitor: Aliskiren (limited use)

1.4 Antianginal Drugs

• Nitrates:

  • Mechanism: NO donor → ↑ cGMP → venodilation → ↓ preload

  • Agents: GTN (sublingual), Isosorbides (oral)

• β‑Blockers: (see above) ↓ O₂ demand via HR/contractility reduction

• Calcium Channel Blockers: (see above) vasodilate and/or ↓ contractility

• Ranolazine: Inhibits late Na⁺ current → ↓ diastolic wall tension; adjunct in refractory angina

1.5 Antiarrhythmic Drugs

Classified by Vaughan‐Williams:

• Class I (Na⁺ Blockers):

  • IA: Quinidine (↑ APD)

  • IB: Lidocaine (↓ APD)

  • IC: Flecainide (↔ APD)

• Class II (β‑Blockers): Propranolol, Esmolol

• Class III (K⁺ Blockers): Amiodarone, Sotalol

• Class IV (Ca²⁺ Blockers): Verapamil, Diltiazem

• Others: Adenosine (SVT), Digoxin (AV node blockade)

1.6 Antihyperlipidemic Agents

• Statins:

  • Mechanism: HMG‑CoA reductase inhibition → ↓ cholesterol synthesis, ↑ LDL receptors

  • Drugs: Atorvastatin, Rosuvastatin

• Bile Acid Sequestrants: Cholestyramine (↑ fecal cholesterol excretion)

• Fibrates: Gemfibrozil (PPARα agonist → ↓ TG, ↑ HDL)

• Niacin: ↓ VLDL production; ↓ LDL; ↑ HDL

• PCSK9 Inhibitors: Alirocumab (monoclonal Ab → ↑ LDL‑R recycling)

Key Points for Exams

1. Link hemodynamic parameters (CO, SVR) to drug classes and clinical effects.

2. Outline first‑line agents for CHF and hypertension, noting mortality benefits.

3. Match antianginal strategies (↓ preload vs. ↓ afterload vs. ↓ HR) to drug mechanisms.

4. Classify antiarrhythmics by ion‐channel targets and major side effects.

5. Describe lipid‑lowering agents’ mechanisms and place in therapy for cardiovascular risk reduction.

Unit 2: Therapy of Shock; Hematinics; Coagulants & Anticoagulants; Fibrinolytics; Antiplatelets; Plasma Volume Expanders; Diuretics & Antidiuretics

Definition

This unit covers acute and chronic interventions for cardiovascular collapse (shock), management of anemias (hematinics), modulation of hemostasis (coagulants, anticoagulants, fibrinolytics, antiplatelets), restoration of intravascular volume, and pharmacologic control of fluid balance via diuretics and antidiuretics.

2.1 Therapy of Shock

2.1.1 Classification of Shock

• Hypovolemic: ↓ circulating volume (hemorrhage, dehydration)

• Cardiogenic: ↓ pump function (MI, cardiomyopathy)

• Distributive: Vasodilation, ↑ capillary permeability (sepsis, anaphylaxis, neurogenic)

• Obstructive: Mechanical obstruction (tamponade, PE)

2.1.2 Initial Management

• Airway, Breathing, Circulation (ABC): Secure airway, oxygenate, control hemorrhage

• Fluid Resuscitation:

  • Crystalloids: Normal saline, Ringer’s lactate—restore intravascular volume

  • Colloids: Albumin, gelatin—expand plasma oncotic pressure

2.1.3 Vasopressors & Inotropes

• Norepinephrine: α₁ > β₁ agonist; first‑line in septic shock—vasoconstriction, modest ↑ CO

• Dopamine: Dose‑dependent effects; low doses (renal perfusion), moderate (β₁ inotropy), high (α₁ vasoconstriction)

• Dobutamine: β₁ > β₂ agonist; ↑ contractility with vasodilation—cardiogenic shock

• Vasopressin: V₁ receptor agonist; adjunct in refractory septic shock—vasoconstriction

Key Points

• Early goal‑directed therapy in sepsis: target MAP ≥ 65 mm Hg, CVP 8–12 mm Hg.

• Titrate vasopressors to clinical endpoints; monitor lactate clearance.

2.2 Hematinics

Definition

Agents that correct or prevent anemia by supplying or facilitating the utilization of essential components for erythropoiesis.

2.2.1 Iron Preparations

• Oral: Ferrous sulfate, ferrous gluconate—best absorbed in acidic pH; take with vitamin C

• Parenteral: Iron sucrose, ferric carboxymaltose—used in CKD, intolerance to oral iron

• Adverse Effects: GI upset, constipation (oral); anaphylaxis rare (IV)

2.2.2 Vitamin B₁₂ & Folic Acid

• Vitamin B₁₂ (Cobalamin): Cyanocobalamin IM/SC; corrects pernicious anemia; neurologic toxicity if delayed

• Folic Acid: Oral; prevents neural tube defects; masks B₁₂ deficiency if used alone

• Adverse Effects: Generally well tolerated; high-dose folate can conceal B₁₂ deficiency.

2.3 Coagulants & Anticoagulants; Fibrinolytics; Antiplatelets

2.3.1 Coagulants (Pro‑coagulant Therapies)

• Vitamin K: Phytonadione; reverses warfarin-induced coagulopathy

• Protamine Sulfate: Neutralizes heparin (UFH > LMWH)

• Tranexamic Acid / Aminocaproic Acid: Lysine analogues—antifibrinolytics that block plasminogen activation

2.3.2 Anticoagulants

• Unfractionated Heparin (UFH): Potentiates antithrombin III → inactivates IIa & Xa; monitored by aPTT

• Low‑Molecular‑Weight Heparin (LMWH): Enoxaparin; preferential Xa inhibition; predictable PK, no routine monitoring

• Vitamin K Antagonists (Warfarin): Blocks vitamin K epoxide reductase → ↓ II, VII, IX, X; monitored by INR

• Direct Oral Anticoagulants (DOACs):

  • Dabigatran: Direct IIa inhibitor

  • Rivaroxaban, Apixaban: Direct Xa inhibitors

2.3.3 Fibrinolytics

• tPA (Alteplase), Reteplase, Tenecteplase: Convert plasminogen → plasmin → degrade fibrin clot

• Indications: Acute MI, ischemic stroke (within window), massive PE

• Adverse Effects: Bleeding, intracranial hemorrhage

2.3.4 Antiplatelets

• Aspirin: Irreversible COX‑1 inhibition → ↓ TXA₂ synthesis

• P2Y₁₂ Inhibitors: Clopidogrel, Prasugrel, Ticagrelor—block ADP‑mediated platelet aggregation

• GP IIb/IIIa Inhibitors: Abciximab, Eptifibatide—prevent fibrinogen bridging

Key Points

• Balance thrombotic vs. bleeding risk; choose agent based on indication, monitoring, and reversal options.

2.4 Plasma Volume Expanders

Definition

Colloidal or crystalloid solutions administered to increase intravascular volume when blood products are not immediately available.

• Crystalloids: Normal saline, Ringer’s lactate—diffuse into interstitial space; inexpensive

• Colloids:

  • Albumin: Human plasma protein; maintains oncotic pressure

  • Synthetic (Hetastarch, Gelatins): Larger molecules remain intravascular longer; risk of coagulopathy and AKI

Key Points

• Crystalloids first for initial resuscitation; colloids reserved when larger volume expansion needed without interstitial edema.

2.5 Diuretics & Antidiuretics

2.5.1 Diuretics

• Loop Diuretics: Furosemide—high‑ceiling; inhibit Na⁺/K⁺/2Cl⁻ in TAL; use in edema, hypertension

• Thiazides: Hydrochlorothiazide—moderate natriuresis; first‑line hypertension

• Potassium‑Sparing: Spironolactone (aldosterone antagonist), Amiloride (ENaC blocker)

2.5.2 Antidiuretics

• Desmopressin (DDAVP): V₂ receptor agonist; increases renal water reabsorption; treats central DI, von Willebrand disease

• Conivaptan, Tolvaptan: V₂ antagonists; aquaretics for hyponatremia in SIADH

Key Points

• Choose diuretic by site of action and desired electrolyte effect; monitor for volume depletion, electrolyte disturbances.

• Antidiuretics modulate water excretion independently of sodium.

Key Takeaways for Exams

1. Shock Management: Recognize shock types; apply fluids and choose appropriate vasopressors/inotropes.

2. Hematinics: Match iron, B₁₂, and folate therapies to anemia types; note adverse effects.

3. Hemostasis: Classify agents by mechanism—procoagulant, anticoagulant, fibrinolytic, antiplatelet—and their clinical uses and monitoring.

4. Volume Expanders: Differentiate crystalloids vs. colloids; understand distribution and indications.

5. Fluid Balance: Select diuretics by nephron site; use antidiuretics for water‑handling disorders.

Unit 3: Autacoids & Related Drugs

Definition

Autacoids are biologically active, locally acting signaling molecules—often termed “local hormones”—that regulate inflammation, vascular tone, and platelet function. This unit also covers related pharmacotherapies for inflammation and gout.

3.1 Histamine & Antihistaminics

3.1.1 Histamine

• Synthesis & Release: Formed from L-histidine by histidine decarboxylase in mast cells, basophils, gastric ECL cells. Released via immunologic (IgE-mediated) or nonimmunologic triggers.

• Receptors:

  • H₁: Gq-coupled; mediates vasodilation, vascular permeability, bronchoconstriction

  • H₂: Gs-coupled; stimulates gastric acid secretion

  • H₃/H₄: Autoreceptors and immune-cell modulators (emerging drug targets)

3.1.2 Antihistaminic Agents

• H₁ Antagonists:

  • First-Generation: Diphenhydramine, Chlorpheniramine—sedating, anticholinergic side effects

  • Second-Generation: Cetirizine, Loratadine—peripherally selective, non-sedating

• H₂ Antagonists: Ranitidine, Famotidine—reduce gastric acid in peptic ulcer disease

3.2 Serotonin (5-HT) & Modulators

3.2.1 Serotonin

• Synthesis & Function: Derived from tryptophan; CNS neurotransmitter and peripheral mediator (GI motility, vascular tone, platelet aggregation).

• Receptors: Multiple subtypes (5-HT₁–₇) with distinct effects.

3.2.2 Pharmacologic Agents

• 5-HT₁ Agonists (Triptans): Sumatriptan, Rizatriptan—migraine relief via cranial vasoconstriction and inhibition of neuropeptide release.

• 5-HT₃ Antagonists: Ondansetron, Granisetron—antiemetics for chemotherapy-induced nausea.

• Other Modulators:

  • Buspirone: 5-HT₁A partial agonist—anxiolytic

  • Cyproheptadine: 5-HT₂ antagonist—appetite stimulant, serotonin syndrome treatment

3.3 Eicosanoids: Prostaglandins, Thromboxanes & Leukotrienes

3.3.1 Biosynthesis

• Arachidonic Acid Pathway: Phospholipase A₂ releases AA → COX (PGs, TXs) and LOX (LTs) pathways.

3.3.2 Prostaglandins & Thromboxanes

• Prostaglandins (PG):

  • PGE₂, PGI₂: Vasodilation, inhibit platelet aggregation, mediate pain and fever

  • PGF₂α: Uterine contraction

• Thromboxane A₂ (TXA₂): Vasoconstriction, platelet aggregation

3.3.3 Leukotrienes

• LTB₄: Chemoattractant for neutrophils

• LTC₄, LTD₄, LTE₄: Bronchoconstrictors (key in asthma pathophysiology)

3.4 Kinins & Angiotensin

3.4.1 Bradykinin

• Function: Potent vasodilator, increases vascular permeability, mediates pain.

• Metabolism: Inactivated by kininases (ACE).

3.4.2 Renin-Angiotensin System

• Angiotensin II: Powerful vasoconstrictor; stimulates aldosterone secretion.

• Pharmacologic Inhibitors:

  • ACE Inhibitors: Captopril, Enalapril—reduce Ang II, increase bradykinin (cough/angioedema risk)

  • ARBs: Losartan, Valsartan—selective AT₁ blockade without bradykinin accumulation

3.5 NSAIDs & Related Anti-Inflammatories

3.5.1 NSAIDs

• Mechanism: Reversible COX-1/COX-2 inhibition → ↓ PG synthesis

• Agents:

  • Nonselective: Ibuprofen, Diclofenac—analgesic, antipyretic, anti-inflammatory; GI and renal side effects

  • COX-2 Selective: Celecoxib—reduced GI toxicity; cardiovascular risk

3.5.2 Paracetamol (Acetaminophen)

• Mechanism: Central COX inhibition; minimal anti-inflammatory effect

• Use: Analgesic and antipyretic; hepatotoxicity in overdose

3.5.3 Corticosteroids (overview)

• Mechanism: Inhibit phospholipase A₂ and COX-2 transcription → broad anti-inflammatory effects

• Agents: Prednisone, Dexamethasone; adverse effects include immunosuppression, metabolic disturbances

3.6 Anti-Gout Agents

3.6.1 Uricostatic & Uricosuric Drugs

• Xanthine Oxidase Inhibitors: Allopurinol, Febuxostat—reduce uric acid production

• Uricosurics: Probenecid, Sulfinpyrazone—increase renal excretion of uric acid

3.6.2 Anti-Inflammatory & Colchicine

• Colchicine: Inhibits microtubule polymerization in neutrophils—prevents acute gout flares; GI toxicity

• NSAIDs & Glucocorticoids: For acute attacks

3.7 Antirheumatic Drugs

3.7.1 Conventional DMARDs

• Methotrexate: Inhibits dihydrofolate reductase; first-line for rheumatoid arthritis

• Sulfasalazine, Hydroxychloroquine: Immunomodulatory; slower onset

3.7.2 Biologic DMARDs

• TNF-α Inhibitors: Etanercept, Infliximab—block proinflammatory cytokine

• Other Biologics: Tocilizumab (IL-6 receptor), Rituximab (CD20)

Key Points for Exams

1. Autacoid Classes: Match histamine, serotonin, eicosanoid, bradykinin, and angiotensin pathways to drug targets and clinical indications.

2. NSAIDs vs. Steroids: Compare mechanisms, therapeutic uses, and adverse-effect profiles.

3. Gout Management: Distinguish between uricostatic, uricosuric, and anti-inflammatory strategies.

4. DMARDs: Outline conventional vs. biologic agents and their principal mechanisms in rheumatoid arthritis therapy.

5. Integration: Understand interplay of autacoids in inflammation, vascular tone, and platelet function to guide pharmacotherapy choices.

Unit 4: Endocrine Pharmacology

Definition

This unit addresses drugs that modulate hormone systems—pituitary, thyroid, calcium‑regulating axes, glycemic control, and adrenal corticosteroids—detailing their mechanisms, clinical uses, and safety profiles.

4.1 Pituitary Hormones & Analogues

4.1.1 Growth Hormone (GH) & Somatostatin Analogues

• Somatropin (Recombinant GH):

  • Mechanism: Binds GH receptor → IGF‑1 production → promotes linear growth, protein synthesis.

  • Uses: GH deficiency in children/adults, Turner syndrome, chronic renal insufficiency.

  • Adverse: Edema, arthralgia, insulin resistance.

• Octreotide / Lanreotide (Somatostatin Analogs):

  • Mechanism: Inhibit GH and various GI hormone release.

  • Uses: Acromegaly, carcinoid syndrome, VIPomas.

  • Adverse: GI disturbances, gallstones.

4.1.2 Vasopressin & Desmopressin

• Desmopressin (DDAVP):

  • Mechanism: V₂ receptor agonist → ↑ renal water reabsorption; VWF release from endothelium.

  • Uses: Central diabetes insipidus, von Willebrand disease, mild hemophilia A.

  • Adverse: Hyponatremia, headache.

• Vasopressin:

  • Uses: Vasodilatory shock (as adjunct), bleeding esophageal varices (via V₁ vasoconstriction).

  • Adverse: Ischemia at high doses.

4.2 Thyroid Hormones & Antithyroid Agents

4.2.1 Thyroid Hormone Replacement

• Levothyroxine (T₄):

  • Mechanism: Converted peripherally to T₃ → nuclear thyroid hormone receptor activation.

  • Uses: Hypothyroidism, myxedema coma (IV).

  • Adverse: Signs of hyperthyroidism if overdosed (tachycardia, weight loss).

• Liothyronine (T₃):

  • Use: Rare; rapid correction in myxedema coma.

4.2.2 Antithyroid Drugs

• Thioamides (Methimazole, Propylthiouracil):

  • Mechanism: Inhibit thyroid peroxidase (block iodination/coupling); PTU also blocks peripheral T₄→T₃ conversion.

  • Uses: Graves’ disease, preparation for thyroid surgery.

  • Adverse: Agranulocytosis, hepatotoxicity (PTU).

• Inorganic Iodides (Lugol’s Solution):

  • Mechanism: Acute Wolff–Chaikoff effect → inhibit hormone release.

  • Use: Thyroid storm, preoperative prep.

• Radioiodine (¹³¹I):

  • Mechanism: β‑emitter destroys follicular cells.

  • Use: Definitive therapy for hyperthyroidism.

  • Adverse: Hypothyroidism common.

4.3 Calcium‑Regulating Hormones

4.3.1 Vitamin D Analogues

• Ergocalciferol / Cholecalciferol: Prohormones converted to 1,25‑(OH)₂D (calcitriol).

• Calcitriol: Active form; ↑ intestinal Ca²⁺ absorption, bone resorption.

• Use: Rickets/osteomalacia, hypoparathyroidism.

• Adverse: Hypercalcemia, hypercalciuria.

4.3.2 Bisphosphonates & Calcitonin

• Bisphosphonates (Alendronate, Zoledronate):

  • Mechanism: Inhibit osteoclast-mediated bone resorption.

  • Use: Osteoporosis, Paget’s disease.

  • Adverse: Esophagitis, osteonecrosis of jaw.

• Calcitonin (Salmon):

  • Mechanism: Inhibits osteoclasts; lowers serum Ca²⁺.

  • Use: Paget’s disease, hypercalcemia.

  • Adverse: Tachyphylaxis, nasal irritation (nasal spray).

4.4 Insulin & Oral Hypoglycemics

4.4.1 Insulins (see Unit 6.1.1 for full profiles)

• Rapid, short, intermediate, and long‑acting analogues tailored for basal–bolus regimens.

4.4.2 Oral Hypoglycemics (overview)

• Metformin: AMPK activation → ↓ hepatic gluconeogenesis; first‑line in type 2 DM.

• Sulfonylureas / Meglitinides: K_ATP channel blockers → insulin release.

• Thiazolidinediones: PPARγ agonists → ↑ insulin sensitivity.

• DPP‑4 Inhibitors / GLP‑1 Agonists / SGLT2 Inhibitors: Incretin-based and renal glucose excretion modulators (see Unit 6.1.6–7).

4.5 ACTH & Corticosteroids

4.5.1 Adrenocorticotropic Hormone (ACTH)

• Cosyntropin (Synthetic ACTH):

  • Mechanism: Stimulates adrenal cortisol production.

  • Use: Diagnostic ACTH stimulation test for adrenal insufficiency.

  • Adverse: Pain at injection site.

4.5.2 Glucocorticoids & Mineralocorticoids

• Glucocorticoids (Prednisone, Dexamethasone):

  • Mechanism: Bind cytoplasmic receptors → modulate transcription of inflammatory genes.

  • Uses: Inflammatory/autoimmune diseases, asthma/COPD, transplant rejection.

  • Adverse: Cushingoid features, osteoporosis, hyperglycemia, immunosuppression.

• Mineralocorticoid (Fludrocortisone):

  • Mechanism: Enhance renal Na⁺ reabsorption, K⁺ excretion.

  • Use: Primary adrenal insufficiency (Addison’s).

  • Adverse: Hypertension, hypokalemia.

Key Takeaways for Exams

1. Pituitary: Differentiate GH therapy vs. somatostatin analogues and their indications.

2. Thyroid: Recall T₄ vs. T₃ replacement, thioamide actions, and iodine therapies.

3. Calcium Homeostasis: Match vitamin D analogues, bisphosphonates, and calcitonin to bone disorders.

4. Glycemic Agents: Review insulin regimens and major oral drug classes.

5. Adrenal: Understand ACTH testing and balance glucocorticoid/mineralocorticoid uses and side effects.

Unit 5: Sex Hormones, Anabolic Steroids, Oral Contraceptives & Uterine Drugs

Definition

This unit examines endogenous sex steroid hormones and their synthetic analogues, anabolic agents, contraceptive regimens, and drugs affecting uterine contractility, detailing their pharmacodynamics, clinical indications, and adverse effects.

5.1 Sex Steroids & Anabolic Steroids

5.1.1 Estrogens

• Mechanism: Bind intracellular estrogen receptors (ERα/ERβ) → regulate transcription of target genes.

• Agents & Uses:

  • 17β‑Estradiol, Conjugated Equine Estrogens: Hormone replacement therapy (HRT) for menopausal symptoms, osteoporosis prevention.

  • Ethinyl Estradiol: Component of combined oral contraceptives.

• Adverse Effects: Thromboembolism, breast/endometrial hyperplasia, nausea.

5.1.2 Progestins

• Mechanism: Bind progesterone receptor → prepare endometrium for implantation, maintain pregnancy.

• Agents & Uses:

  • Medroxyprogesterone Acetate, Norethindrone: HRT opposed cycles, abnormal uterine bleeding.

  • Levonorgestrel: Emergency contraceptive (IUD or “morning‑after” pill).

• Adverse Effects: Irregular bleeding, weight gain, mood changes.

5.1.3 Androgens & Anabolic Steroids

• Mechanism: Bind androgen receptor → promote protein synthesis, muscle growth.

• Agents & Uses:

  • Testosterone Esters (enanthate, cypionate): Hypogonadism, delayed puberty.

  • Oxandrolone, Nandrolone: Promote weight gain in catabolic states (burns, HIV cachexia).

• Adverse Effects: Virilization in women, acne, hepatotoxicity (17α‑alkylated), dyslipidemia.

5.2 Oral Contraceptives

5.2.1 Combination Pills (Estrogen + Progestin)

• Mechanisms:

  1. Suppress hypothalamic GnRH → ↓ FSH/LH → inhibit ovulation

  2. Thicken cervical mucus → impede sperm

  3. Induce endometrial atrophy → prevent implantation

• Formulations:

  • Monophasic: Fixed dose throughout cycle

  • Multiphasic: Varying hormone levels to reduce side effects

• Adverse Effects: Breakthrough bleeding, thromboembolism risk, nausea, breast tenderness.

5.2.2 Progestin‑Only Pills (“Mini‑Pill”)

• Mechanism: Thickened cervical mucus; ovulation suppression less consistent.

• Agents: Norethindrone, Desogestrel.

• Use: Women with estrogen contraindications (e.g., breastfeeding, clot risk).

• Adverse Effects: Irregular bleeding, headache.

5.3 Emergency Contraception

• Levonorgestrel (High‑Dose Progestin): Single dose within 72 h → delays ovulation.

• Ulipristal Acetate: Selective progesterone receptor modulator; effective up to 120 h post‑coitus.

• Adverse Effects: Nausea, abdominal pain, menstrual irregularities.

5.4 Uterine Drugs

5.4.1 Oxytocics

• Oxytocin:

  • Mechanism: GPCR activation in myometrium → ↑ Ca²⁺ → uterine contraction.

  • Uses: Labor induction/augmentation, postpartum hemorrhage control.

  • Adverse Effects: Uterine hyperstimulation, water intoxication (antidiuretic effect).

• Ergot Alkaloids (Methylergometrine):

  • Mechanism: Partial agonist at α‑adrenergic, serotonergic, and dopaminergic receptors → sustained uterine tone.

  • Uses: Postpartum hemorrhage.

  • Adverse Effects: Hypertension, vasospasm.

5.4.2 Tocolytics

• Beta₂‑Agonists (Ritodrine, Terbutaline): Relax uterine smooth muscle via cAMP ↑.

• Calcium Channel Blockers (Nifedipine): Inhibit L‑type Ca²⁺ channels → reduce contractions.

• NSAIDs (Indomethacin): Inhibit prostaglandin synthesis → decrease uterine activity.

• Magnesium Sulfate: Competes with Ca²⁺; neuroprotective for fetus in preterm labor.

• Adverse Effects: Tachycardia, hypotension, fetal effects (NSAIDs).

Key Takeaways for Exams

1. Sex Steroids: Contrast estrogen vs. progestin actions, indications, and risks.

2. Anabolic Steroids: Recognize clinical uses vs. abuse potential and hepatic risks.

3. Contraceptives: Explain mechanisms of combination and progestin‑only pills and emergency methods.

4. Uterine Drugs: Match oxytocics and tocolytics to their receptor targets and clinical scenarios.

5. Safety Profiles: Identify major adverse effects and contraindications for each class.

Unit 6: Bioassay

Definition

Bioassay is the quantitative measurement of a drug’s potency or concentration by comparing its biological effect to that of a standard preparation. It ensures batch‑to‑batch consistency and guides dosage by correlating a known biological response with drug amount.

6.1 Principles of Bioassay

6.1.1 Types of Bioassays

• In Vivo Bioassays: Measure drug effects in whole animals (e.g., reduction in blood glucose, blood pressure change).

• In Vitro Bioassays: Use isolated tissues or cell preparations (e.g., muscle contraction, enzyme activity).

6.1.2 Quantitative Methods

• Quantal (All‑or‑None) Assays: Determine the dose at which a specified proportion of subjects exhibit a response (e.g., ED₅₀ causing glycosuria in 50% of animals).

• Graded (Continuous) Assays: Record the magnitude of response (e.g., force of contraction) at various doses to construct a dose–response curve.

6.1.3 Analytical Approaches

• Parallel Line Assay: Log–dose response lines for test and standard are plotted; parallelism confirms similar mechanism, and relative potency is the horizontal displacement.

• Slope Ratio Assay: Applicable when slopes differ; potency ratio derived from comparing dose–response slopes and intercepts.

6.2 Bioassay of Key Drugs

6.2.1 Insulin

• Preparation: Use diabetic or normal rabbits/mice.

• Assay: Inject graded doses; measure blood glucose reduction at fixed intervals.

• End‑Point: Dose required to lower blood glucose by a set percentage (e.g., 30%).

6.2.2 Oxytocin

• Preparation: Isolated uterine strips from late‑pregnant rats.

• Assay: Cumulative addition of sample to organ bath; measure contraction amplitude on an isometric transducer.

• End‑Point: Dose producing a defined contractile force.

6.2.3 Vasopressin (Antidiuretic Hormone)

• Preparation: Rat or rabbit kidney clearance model or isolated vascular smooth muscle.

• Assay: Monitor increase in urine osmolality or pressor response (rise in mean arterial pressure) following graded doses.

• End‑Point: Dose yielding predetermined change in renal water reabsorption or MAP.

6.2.4 ACTH (Adrenocorticotropic Hormone)

• Preparation: Rat adrenal gland assay or measurement of plasma corticosterone in adrenalectomized rats.

• Assay: Inject standard and test doses; quantify serum corticosterone by immunoassay.

• End‑Point: Dose required to elevate corticosterone to a specific level.

6.2.5 d‑Tubocurarine

• Preparation: Isolated frog or rat phrenic nerve–diaphragm preparation.

• Assay: Apply nerve stimulations and record twitch height before and after toxin addition.

• End‑Point: Concentration causing 50% reduction in twitch response.

6.2.6 Digitalis Glycosides

• Preparation: Isolated guinea pig or rabbit atrium/ventricular strip.

• Assay: Measure positive inotropic effect (increased contraction force) in response to drug.

• End‑Point: Dose producing a defined increase in contractile force.

6.2.7 Histamine & 5‑Hydroxytryptamine (Serotonin)

• Preparation: Isolated guinea pig ileum or rat fundic strip.

• Assay: Record smooth muscle contraction following graded concentrations.

• End‑Point: EC₅₀—the concentration eliciting 50% of maximal contraction.

Key Takeaways for Exams

1. Differentiate in vivo vs. in vitro bioassays and quantal vs. graded responses.

2. Describe parallel line and slope ratio methods to determine relative potency.

3. Match each hormone or toxin to its classical bioassay preparation and end‑point measurement.

4. Interpret dose–response data to calculate ED₅₀, EC₅₀, and potency ratios.

5. Recognize the importance of bioassay in ensuring biological activity and batch consistency.