B Pharmacy Sem 5: Medicinal Chemistry II

Subject 1. Medicinal Chemistry II

 1. Antihistaminic agents
 2. Anti neoplastic agents
 3. Anti anginal agents, Diuretics & Anti hypertensive agents
 4. Anti arrhythmic drugs, Anti hyperlipidemic agents, Coagulants & Anticoagulants, Drugs used in Congestive Heart Failure
 5. Drugs acting on Endocrine system (steroids, sex hormones, oral contraceptives, corticosteroids, thyroid/antithyroid)
 6. Antidiabetic agents & Local Anesthetics

Unit 1: Antihistaminic Agents

This unit delves into the chemistry, pharmacology and therapeutic application of antihistamines—drugs that block histamine‑mediated responses primarily at the H₁ receptor. You’ll study histamine biosynthesis and storage, receptor subtypes and tissue distribution, the mechanism of action of H₁ antagonists, structure–activity relationships of first‑ and second‑generation agents, their pharmacokinetic profiles, clinical uses, and adverse effects.

1.1 Introduction to Histamine & Histaminergic Receptors
1.1.1 Histamine Biosynthesis & Storage

• Histidine Decarboxylation: formation of histamine from L‑histidine by histidine decarboxylase in mast cells, basophils, and ECL cells.

• Storage & Release: stored in granules; released upon IgE‑mediated degranulation or non‑immunologic triggers (physical, chemical stimuli).

1.1.2 Histamine Receptor Subtypes

• H₁ Receptors: Gq‑coupled; mediates smooth muscle contraction, vascular permeability, bronchoconstriction; targets of classic antihistamines.

• H₂ Receptors: Gs‑coupled; stimulates gastric acid secretion; antagonists used in ulcer disease.

• H₃/H₄ Receptors: presynaptic autoreceptor (H₃) modulating neurotransmitter release; H₄ in immune cells—emerging drug targets.

1.2 Mechanism of Action of H₁‑Receptor Antagonists

• Competitive Reversible Binding: most antihistamines bind the H₁ receptor without activating it, shifting dose–response curves to the right.

• Inverse Agonism: certain agents stabilize the inactive receptor conformation, reducing basal activity.

• Additional Effects: many first‑generation drugs cross the blood–brain barrier (sedation), block muscarinic/cholinergic, α‑adrenergic, or serotonergic receptors.

1.3 First‑Generation H₁ Antagonists
1.3.1 Chemical Classes & Representative Drugs

• Ethanolamines: diphenhydramine, clemastine

• Alkylamines: chlorpheniramine, brompheniramine

• Piperazines: hydroxyzine, cyclizine

• Phenothiazines (weak H₁ activity): promethazine

1.3.2 Pharmacokinetics & Adverse Effects

• PK: rapid absorption; extensive hepatic metabolism (CYP450), variable half‑lives.

• Side Effects: sedation, anticholinergic effects (dry mouth, urinary retention), hypotension, potential for overdose in children.

1.3.3 Structure–Activity Relationships

• Basic Ethanolamine Skeleton: two aromatic rings separated by an ether linkage to an amine—bulk and lipophilicity drive CNS penetration.

• Alkylamine Modification: para‑chlorination increases potency (chlorpheniramine).

1.4 Second‑Generation H₁ Antagonists

1.4.1 Key Drugs & Chemical Features

• Loratadine, Desloratadine: tricyclic with polar side chains—minimal CNS entry.

• Cetirizine, Levocetirizine: zwitterionic; low BBB penetration.

• Fexofenadine: carboxylated metabolite of terfenadine.

1.4.2 Clinical Advantages

• Selective Peripheral Action: reduced sedation and anticholinergic effects.

• Longer Duration: once‑daily dosing, high compliance.

1.5 Therapeutic Uses & Adverse Reactions

• Indications: allergic rhinitis, urticaria, conjunctivitis, pruritus, motion sickness (some first‑gen).

• Adverse Effects:

  • First‑Generation: sedation, cognitive impairment, antimuscarinic symptoms.

  • Second‑Generation: headache, dry mouth, rarely QT prolongation (astemizole, terfenadine now withdrawn).

1.6 Key Points for Exams

• Define histamine biosynthesis and receptor subtypes, and relate H₁ blockade to pharmacological effects.

• Compare mechanism and SAR of first‑ versus second‑generation H₁ antagonists.

• List common clinical uses and side‑effect profiles for representative antihistamines.

• Explain the concept of inverse agonism at H₁ receptors and its therapeutic relevance.

Unit 2: Anti‑Neoplastic Agents

This unit covers the chemistry, mechanisms of action, pharmacokinetics, therapeutic applications, and safety profiles of major classes of anti‑cancer drugs. Emphasis is placed on how structural features relate to activity (SAR), dosing considerations, and common adverse effects.

2.1 Introduction to Anti‑Neoplastic Therapy

Anti‑neoplastic agents are drugs used to treat malignant tumors by interfering with cell division, DNA synthesis, or signaling pathways essential for cancer cell survival and proliferation. Key concepts include:

• Cell Cycle Specificity: Agents that act in particular phases (e.g., S‑phase, M‑phase)

• Cell Cycle Nonspecificity: Agents effective irrespective of the cell cycle stage

• Therapeutic Index: Narrow—balancing tumor kill against toxicity to normal rapidly dividing cells

• Combination Therapy: Employing drugs with different mechanisms to prevent resistance and achieve synergistic cell kill

2.2 Alkylating Agents

These cell cycle–nonspecific drugs form covalent bonds with DNA, leading to cross‑linking, strand breaks, and apoptosis.

2.2.1 Classes & Representative Drugs

• Nitrogen Mustards: Cyclophosphamide, Ifosfamide

• Nitrosoureas: Carmustine (BCNU), Lomustine (CCNU)

• Platinum Compounds: Cisplatin, Carboplatin, Oxaliplatin

• Others: Busulfan, Melphalan

2.2.2 Mechanism of Action

• Generate electrophilic intermediates that alkylate N7 of guanine

• Intrastrand and interstrand cross‑links prevent DNA replication/transcription

2.2.3 Pharmacokinetics & Activation

• Cyclophosphamide: prodrug activated by hepatic CYP450 to 4‑hydroxycyclophosphamide

• Platinum analogs: aquation in plasma yields active species

2.2.4 Therapeutic Uses

• Cyclophosphamide: lymphomas, breast cancer, ovarian cancer

• Cisplatin: testicular, ovarian, bladder, lung cancers

2.2.5 Adverse Effects

• Myelosuppression (dose‑limiting)

• Mucositis, alopecia

• Nephrotoxicity (cisplatin), hemorrhagic cystitis (cyclophosphamide), pulmonary fibrosis (bleomycin)

2.3 Antimetabolites

These S‑phase–specific agents mimic natural substrates of DNA/RNA synthesis, causing faulty nucleic acids or inhibiting key enzymes.

2.3.1 Folate Analogues

• Methotrexate: competitive DHFR inhibitor → ↓ tetrahydrofolate → impaired thymidine/ purine synthesis

2.3.2 Pyrimidine Analogues

• 5‑Fluorouracil (5‑FU): converted to FdUMP → thymidylate synthase inhibition

• Cytarabine (Ara‑C): DNA chain termination

2.3.3 Purine Analogues

• 6‑Mercaptopurine (6‑MP): converted to TIMP → inhibits purine synthesis

• Fludarabine, Cladribine: incorporate into DNA causing strand breaks

2.3.4 Therapeutic Uses

• Methotrexate: leukemias, osteosarcoma, breast cancer

• 5‑FU: colorectal, breast, head & neck cancers

• Cytarabine: acute myeloid leukemia

2.3.5 Adverse Effects

• Mucositis, myelosuppression (methotrexate)

• Hand–foot syndrome, diarrhea (5‑FU)

• Neurotoxicity (fludarabine)

2.4 Plant‑Derived Natural Products

Primarily M‑phase–specific agents that target microtubules or topoisomerases.

2.4.1 Vinca Alkaloids

• Vincristine, Vinblastine: bind tubulin → inhibit polymerization → metaphase arrest

2.4.2 Taxanes

• Paclitaxel, Docetaxel: stabilize microtubules → prevent depolymerization

2.4.3 Camptothecins

• Irinotecan, Topotecan: inhibit topoisomerase I → DNA single‑strand breaks

2.4.4 Therapeutic Uses

• Vincristine: pediatric leukemias, lymphomas

• Paclitaxel: ovarian, breast, lung cancers

• Irinotecan: colorectal cancer

2.4.5 Adverse Effects

• Neurotoxicity (vincristine), myelosuppression (vinblastine)

• Peripheral neuropathy (taxanes)

• Diarrhea (irinotecan), myelosuppression

2.5 Cytotoxic Antibiotics

Nonselective cell cycle–nonspecific agents that intercalate DNA or generate free radicals.

2.5.1 Anthracyclines

• Doxorubicin, Daunorubicin: intercalation, topoisomerase II inhibition, free radical formation

2.5.2 Bleomycin

• Binds DNA → strand scission via free radicals

2.5.3 Therapeutic Uses

• Doxorubicin: breast, lymphomas, sarcomas

• Bleomycin: Hodgkin’s lymphoma, germ‑cell tumors

2.5.4 Adverse Effects

• Cardiotoxicity (anthracyclines; cumulative dose–dependent)

• Pulmonary fibrosis (bleomycin)

2.6 Hormonal & Targeted Therapies

Agents that modulate hormone receptors or specific molecular targets in cancer cells.

2.6.1 Hormonal Agents

• Tamoxifen: selective estrogen receptor modulator (SERM) in breast cancer

• Anastrozole, Letrozole: aromatase inhibitors in postmenopausal breast cancer

• Leuprolide: GnRH agonist for prostate cancer

2.6.2 Targeted Small Molecules & Biologics

• Imatinib: BCR‑ABL tyrosine kinase inhibitor in CML

• Trastuzumab: anti‑HER2 monoclonal antibody in HER2+ breast cancer

• Bevacizumab: anti‑VEGF antibody inhibiting angiogenesis

2.6.3 Adverse Effects

• Tamoxifen: risk of endometrial carcinoma, thromboembolism

• Imatinib: fluid retention, cytopenias

• Monoclonal antibodies: infusion reactions, hypertension (bevacizumab)

2.7 Key Points for Exams

• Classify anti‑cancer drugs by mechanism (alkylators, antimetabolites, plant alkaloids, antibiotics, hormones, targeted).

• Correlate drug structure/SAR with mechanism (e.g., nitrogen mustard bis‑chloroethyl groups, taxane core).

• Describe cell cycle specificity and its relevance to scheduling/combination therapy.

• List major toxicities and necessary protective measures (e.g., mesna for cyclophosphamide, dexrazoxane for doxorubicin).

• Explain rationale behind targeted therapies and the importance of molecular diagnostics (e.g., BCR‑ABL fusion).

Unit 3: Anti‑Anginal Agents, Diuretics & Anti‑Hypertensive Agents

This comprehensive unit explores three interrelated drug categories crucial for cardiovascular therapy: anti‑anginal drugs (relieving myocardial ischemia), diuretics (modulating fluid balance), and antihypertensives (lowering blood pressure). Emphasis is placed on mechanisms of action, structure–activity relationships, pharmacokinetics, therapeutic applications, and safety considerations.

3.1 Anti‑Anginal Agents

Anti‑anginal drugs improve myocardial oxygen supply–demand balance via vasodilation, reduced preload/afterload, or decreased heart rate and contractility.

3.1.1 Nitrates

• Mechanism: Prodrugs converted to NO → ↑ cGMP in vascular smooth muscle → venous (and at high doses, arterial) dilation.

• Drugs & SAR:

  • Glyceryl Trinitrate (GTN): short‑acting, sublingual.

  • Isosorbide Dinitrate/Mononitrate: longer‑acting; mononitrate more bioavailable.

  • Ester groups at positions 1,2,3 of glycerol backbone determine onset/duration.

• PK: Extensive first‑pass (GTN); mononitrate oral bioavailability ~100%.

• Clinical Uses: Acute angina attacks (GTN), prophylaxis (isosorbides).

• Adverse Effects: Headache, orthostatic hypotension, reflex tachycardia, tolerance (requires nitrate‑free interval).

3.1.2 β‑Adrenergic Blockers

• Mechanism: ↓ heart rate, contractility → ↓ O₂ demand; some (e.g., propranolol) also reduce BP.

• Classes:

  • Nonselective: Propranolol, Nadolol.

  • β₁‑Selective: Metoprolol, Atenolol.

  • With ISA: Pindolol (partial agonists).

• SAR: Aryloxypropanolamine core; para‑substituents modulate selectivity.

• PK: Variable lipophilicity; lipophilic (propranolol) crosses BBB.

• Uses: Chronic stable angina, silent ischemia.

• Adverse Effects: Bradycardia, fatigue, bronchospasm (nonselective), erectile dysfunction.

3.1.3 Calcium Channel Blockers (CCBs)

• Mechanism: Inhibit L‑type Ca²⁺ channels in vascular smooth muscle and myocardium → ↓ afterload and contractility.

• Classes & SAR:

  • Dihydropyridines: Nifedipine, Amlodipine (vascular selectivity; bulky aryl groups at C4).

  • Phenylalkylamines: Verapamil (cardioselective).

  • Benzothiazepines: Diltiazem (intermediate).

• PK: High first‑pass; long‑acting preparations available.

• Uses: Variant (Prinzmetal’s) angina (CCBs preferred), stable angina adjunct.

• Adverse Effects: Dihydropyridines—tachycardia, peripheral edema; verapamil—constipation, heart block; diltiazem—bradycardia.

3.2 Diuretics

Diuretics increase renal excretion of salt and water, reducing blood volume and preload, with secondary effects on vascular tone and BP.

3.2.1 Thiazide & Thiazide‑Like Diuretics

• Mechanism: Inhibit Na⁺/Cl⁻ cotransporter (DCT) → modest natriuresis.

• Drugs: Hydrochlorothiazide, Chlorthalidone, Indapamide.

• SAR: Benzothiadiazine ring; sulfonamide moiety essential for activity.

• PK: Onset 2 hrs, duration 12–24 hrs.

• Uses: Hypertension (first‑line), mild edema.

• Adverse Effects: Hypokalemia, hyperuricemia, hyperglycemia, hyponatremia.

3.2.2 Loop Diuretics

• Mechanism: Inhibit Na⁺/K⁺/2Cl⁻ cotransporter (thick ascending limb) → potent diuresis.

• Drugs: Furosemide, Bumetanide, Torsemide.

• SAR: Sulfonamide or sulfamoyl group plus phenoxyacetic acid (furosemide).

• PK: Rapid onset (30 min), duration 6 hrs.

• Uses: Acute pulmonary edema, severe edema, resistant hypertension.

• Adverse Effects: Hypokalemia, ototoxicity, dehydration, metabolic alkalosis.

3.2.3 Potassium‑Sparing Diuretics

• Mechanism & Drugs:

  • Aldosterone Antagonists: Spironolactone, Eplerenone.

  • Epithelial Na⁺ Channel Blockers: Amiloride, Triamterene.

• PK: Spironolactone prodrug; active metabolites long‑lasting.

• Uses: Combined with thiazides/loops to prevent K⁺ loss; heart failure (spironolactone).

• Adverse Effects: Hyperkalemia, gynecomastia (spironolactone).

3.3 Antihypertensive Agents

A broad array of drugs targeting different pathways to lower systemic vascular resistance and/or cardiac output.

3.3.1 ACE Inhibitors

• Mechanism: Block conversion of angiotensin I → II; ↓ aldosterone, ↓ vasoconstriction.

• Drugs & SAR: Captopril (thiol), Enalapril (ester prodrug), Lisinopril (active peptide).

• Uses: Hypertension, heart failure, diabetic nephropathy.

• Adverse Effects: Cough (bradykinin), angioedema, hyperkalemia.

3.3.2 Angiotensin II Receptor Blockers (ARBs)

• Mechanism: Competitive antagonism at AT₁ receptor.

• Drugs: Losartan, Valsartan, Telmisartan.

• SAR: Biphenyl tetrazole structure; acidic tetrazole mimics carboxylate.

• Uses: Similar to ACE inhibitors, useful if cough intolerable.

• Adverse Effects: Hyperkalemia, rare angioedema.

3.3.3 Direct Renin Inhibitor

• Drug: Aliskiren.

• Mechanism: Binds renin active site → ↓ angiotensin I generation.

• Uses: Hypertension; limited by side‑effect profile.

• Adverse Effects: Diarrhea, hyperkalemia, hypotension.

3.3.4 α‑Blockers

• Mechanism: α₁‑receptor antagonism → vasodilation.

• Drugs: Prazosin, Doxazosin.

• Uses: Hypertension with benign prostatic hyperplasia (BPH).

• Adverse Effects: Orthostatic hypotension, reflex tachycardia.

3.3.5 Central Sympatholytics

• Mechanism: ↓ central sympathetic outflow (α₂ agonism or imidazoline).

• Drugs: Clonidine, Methyldopa, Moxonidine.

• Uses: Resistant hypertension; methyldopa in pregnancy.

• Adverse Effects: Sedation, dry mouth, rebound hypertension on withdrawal.

Key Points for Exams

• Classify and contrast anti‑anginal mechanisms (nitrate vs. β‑blocker vs. CCB).

• Relate diuretic site of action in nephron to efficacy and electrolyte changes.

• Understand RAAS inhibition steps (renin, ACE, AT₁ receptor) and clinical implications.

• Memorize major adverse effect profiles (tolerance with nitrates, cough with ACE‑I, hypokalemia with thiazides, hyperkalemia with K⁺‑sparing).

• Integrate combined regimens (e.g., ACE‑I + thiazide; β‑blocker + nitrate) for optimized cardiovascular care.

Unit 6: Antidiabetic Agents & Local Anesthetics

6.1 Antidiabetic Agents

6.1.1 Insulin & Insulin Analogues

Definition: Exogenous preparations of human insulin or its molecular variants designed to replace or supplement endogenous insulin in diabetes.
Key Points:

• Mechanism: Binds the insulin receptor tyrosine kinase → promotes glucose uptake into muscle and fat (GLUT4 translocation), inhibits hepatic gluconeogenesis, and stimulates glycogen/lipid synthesis.

• Types & Profiles:

  • Rapid‑Acting (Lispro, Aspart, Glulisine): Onset 10–20 min; duration 3–5 h. Ideal for covering mealtime glucose spikes.

  • Short‑Acting (Regular): Onset 30–60 min; duration 6–8 h. Requires injection 30 min before meals.

  • Intermediate‑Acting (NPH): Onset 1–2 h; duration 12–18 h. Provides basal insulin when dosed twice daily.

  • Long‑Acting (Glargine, Detemir): Onset ~1 h; duration up to 24 h. Mimics basal insulin secretion with once‑daily dosing.

• Clinical Use: Type 1 diabetes (basal–bolus regimens), advanced type 2 diabetes.

• Adverse Effects: Hypoglycemia (most common), weight gain, lipodystrophy at injection sites.

6.1.2 Sulfonylureas & Meglitinides

Definition: Oral insulin secretagogues that close pancreatic β‑cell K_ATP channels to trigger insulin release.
Key Points:

• Mechanism (Shared): Block ATP‑sensitive K⁺ channels on β‑cells → membrane depolarization → Ca²⁺ influx → insulin exocytosis.

• Sulfonylureas (e.g., Glibenclamide, Glipizide, Glimepiride):

  • Duration: Long‑acting; typically once‑daily dosing.

  • Use: First‐ or second‐line add‑on in type 2 diabetes with residual β‑cell function.

  • Risks: Prolonged hypoglycemia (especially in the elderly), weight gain, possible secondary failure over time.

• Meglitinides (e.g., Repaglinide, Nateglinide):

  • Duration: Very short; peak effect within 1 h, duration 4 h.

  • Use: Target postprandial glucose; administer immediately before meals.

  • Risks: Hypoglycemia (less severe than sulfonylureas), modest weight gain.

6.1.3 Biguanides

Metformin

• Definition: A first‑line oral agent that reduces hepatic glucose production and improves peripheral insulin sensitivity.

• Mechanism: Activates AMP‑activated protein kinase (AMPK) → inhibits gluconeogenic enzymes, increases GLUT4‑mediated glucose uptake in muscle.

• Benefits: Lowers A1C by ~1–2%; weight neutral or modest loss; cardiovascular protection.

• Adverse Effects: Gastrointestinal upset (nausea, diarrhea), rare lactic acidosis (contraindicated in renal impairment).

6.1.4 Thiazolidinediones (Glitazones)

Pioglitazone, Rosiglitazone

• Definition: Insulin sensitizers that bind PPARγ nuclear receptors to modulate gene transcription in adipose tissue.

• Mechanism: ↑ adipocyte differentiation, ↑ GLUT4 expression, redistribute lipids away from muscle/liver.

• Benefits: Improve insulin sensitivity; durable glycemic control.

• Risks: Weight gain, fluid retention/edema, risk of heart failure exacerbation, increased fracture risk.

6.1.5 α‑Glucosidase Inhibitors

Acarbose, Miglitol

• Definition: Oral agents that delay carbohydrate absorption by inhibiting brush‑border α‑glucosidases in the small intestine.

• Mechanism: Slows breakdown of complex carbohydrates → blunts postprandial glucose rise.

• Adverse Effects: Flatulence, bloating, diarrhea due to undigested sugars in colon.

6.1.6 Incretin‑Based Therapies

• DPP‑4 Inhibitors (Sitagliptin, Saxagliptin):

  • Definition: Oral drugs that prevent degradation of GLP‑1 and GIP.

  • Mechanism: ↑ endogenous incretin levels → glucose‑dependent insulin secretion, ↓ glucagon.

  • Adverse Effects: Nasopharyngitis, headache; rare pancreatitis.

• GLP‑1 Receptor Agonists (Exenatide, Liraglutide):

  • Definition: Injectable peptides that mimic GLP‑1.

  • Benefits: Enhance insulin release, suppress glucagon, slow gastric emptying, promote satiety and weight loss.

  • Adverse Effects: Nausea, risk of pancreatitis.

6.1.7 SGLT2 Inhibitors

Dapagliflozin, Empagliflozin

• Definition: Oral agents that lower renal glucose reabsorption.

• Mechanism: Inhibit sodium‑glucose cotransporter 2 in proximal tubule → increased urinary glucose excretion.

• Benefits: Weight loss, blood pressure reduction, proven cardiovascular and renal protection.

• Adverse Effects: Genitourinary infections, volume depletion, rare euglycemic ketoacidosis.

6.2 Local Anesthetics

6.2.1 Chemical Classification

• Esters (Procaine, Tetracaine, Benzocaine):

  • Metabolized rapidly by plasma pseudocholinesterases → PABA byproducts (allergenic potential).

• Amides (Lidocaine, Bupivacaine, Mepivacaine, Prilocaine):

  • Metabolized hepatically by CYP450 → more stable; low allergy risk.

6.2.2 Mechanism of Action & SAR

• Mechanism: Uncharged form diffuses into nerve axon → protonation→ cation binds intracellular domain of voltage‑gated Na⁺ channels → prevents Na⁺ influx → no action potential propagation.

• SAR Elements:

  • Aromatic Ring: Lipophilicity → potency & duration.

  • Linkage (Ester vs. Amide): Metabolic stability and allergenicity.

  • Tertiary Amine: pKa determines fraction of unionized drug at physiologic pH → onset speed.

6.2.3 Pharmacokinetics & Administration

• Onset: Faster when pKa ≈ physiological pH (7.4).

• Duration: Proportional to lipid solubility & protein binding.

• Epinephrine Co‑administration: Vasoconstricts local vessels → prolongs effect, reduces systemic absorption.

• Routes: Topical, infiltration, peripheral nerve blocks, epidural/spinal anesthesia.

6.2.4 Toxicity & Management

• Local Reactions: Tissue irritation; transient neurologic symptoms (TNS) post‐spinal lidocaine.

• Systemic Toxicity:

  • CNS: Initial excitation (tremors, seizures) → depression (coma, respiratory arrest).

  • Cardiovascular: Hypotension, arrhythmias, cardiac arrest.

• Treatment: Supportive care; intravenous lipid emulsion therapy in severe cardiotoxicity.

Key Takeaways for Exams

1. Antidiabetics: Match each class to its mechanism, dosing profile, and principal adverse effects.

2. Insulin Regimens: Understand onset/duration curves for basal–bolus planning.

3. Local Anesthetics: Differentiate esters vs. amides by metabolism, allergy risk, and relate pKa/lipophilicity to clinical onset/duration.

4. Toxicity Management: Recognize hypoglycemia signs and local anesthetic systemic toxicity protocols.