MED CHEM EXAM 3

Role of Aspirin

• Pain ↓

• Fever ↓

• Inflammation ↓

• Prevents clots (low dose)

MOA of Aspirin

Irreversibly inhibits COX enzymes
→ ↓ prostaglandins

What causes symptoms (pain, redness, swelling)?

• Prostaglandins (pain + fever)

• Cytokines (like TNF, IL-1, IL-6)

• Histamine (vasodilation)

These cause:

• ↑ blood flow → redness, heat

• ↑ leakage → swelling

• ↑ nerve sensitivity → pain

Acute vs Chronic Inflammation

Acute (short-term)

• Fast, resolves

• Cells: neutrophils

• Example: cut, infection

Chronic (long-term)

• Slow, damaging

• Cells: macrophages, T cells

• Leads to diseases like:

  • Arthritis

  • Diabetes

  • Heart disease

  • Cancer

Aspirin MOA

• MOA: Irreversibly inhibits COX enzymes → ↓ prostaglandins

• Uses: Relief of minor pains, fever, rheumatologic disease symptoms, and prevention of a MI.

• Rapidly de-acetylated to salicylic acid → further glucuronidated + glycine to be excreted.

• CI for active GI bleeds, hepatic impairment, post flu infection.

Aspirin’s therapeutic effects follow its inhibition of the ____ known cyclooxygenase enzymes

3

COX-1

• Constitutive (“always on”) enzyme involved in normal body functions (housekeeping)

• Ubiquitous within tissues (Especially platelets, stomach, kidneys).

• Stimulates the synthesis of PGs needed for tissue maintenance

• Downstream: Protects stomach lining, maintains kidney blood flow, promotes platelet aggregation

COX-2

• Inducible enzyme activated during inflammation

• Induced at sites of inflammation (blood vessels, fibroblasts, endothelial cells)

• Causes inflammation, pain, and fever

• Aspirin effect on COX-2: Weaker than COX-1 (~100x less potent).

COX-3

• Variant of COX-1 mainly in the brain

• Function: Likely involved in pain and fever (not fully understood)

• Aspirin effect on COX-3: Weak

Aspirin

Salsalate

Salicylic Acid Salts

Aspirin ADME

• Absorption

  • Oral BA → Affected by food, pH, formulation, gastric emptying, antacids

• Metabolism

  • Rapidly converted → salicylic acid (plasma esterases)

  • Salicylic acid → glycine (75%) + glucuronide (15%) conjugates by Phase II metabolism

• Excretion

  • Kidney (urine): salicylic acid + metabolites

CI of Aspirin

• Active GI bleeding

• Severe liver or kidney disease

• Children post-viral infection (flu/chickenpox) → risk of Reye syndrome

Adverse effects / precautions of Aspirin

• GI irritation, ulcers, bleeding (↑ risk in elderly, alcohol use, GI history)

• Increased bleeding risk (surgery, dental work, anticoagulants)

• May trigger asthma or allergic reactions (incl. anaphylaxis)

• Reye syndrome (rare but serious brain + liver damage)

• Pregnancy: potential fetal/infant risk

DDIs of Aspirin

• Other NSAIDs, antiplatelets, corticosteroids → ↑ GI/bleeding risk

• Anticoagulants (e.g., warfarin) → ↑ bleeding risk (↑ free drug)

• Methotrexate → ↓ renal clearance → ↑ toxicity

• Diuretics/aldosterone antagonists → ↓ effectiveness (↓ prostaglandins)

Aspirin History

• Ancient: Willow bark used for pain/fever (>3500 years)

• 1800s: Salicylates identified → aspirin developed; GI toxicity noted

• MOA discovered (1960–80): COX inhibition → ↓ prostaglandins & thromboxane

• Modern use: Pain/fever + antiplatelet (↓ MI, stroke, TIA); possible cancer & preeclampsia benefits

Salsalate

• Salicylic Acid Analog

• Reversible Inhibition of COX

• Less potent for pain and fever but equivalent for inflammation (RA) as Aspirin

• Minimal effect on the gastric mucosa → less damage than Aspirin

• No CV Benefit

Salicylic Acid Salts

• Salicylic Acid Analog

• Reversible Inhibition of COX

• Similar effect for pain, fever, and inflammation as Aspirin

• Lower effect on the gastric mucosa (than Salsalate) → even less damage than Aspirin

• No CV Benefit

Aspirin vs Salicylic Acid Analogs

Diflunisal

• Mechanism: Reversible non-selective COX inhibitor, more potent than Aspirin, less platelet inhibition

• Use: Symptomatic relief of mild–moderate pain, osteoarthritis, and rheumatoid arthritis (same).

• ADR: Same GI risk but better GI tolerance, no risk for Reyes, CI for HF patients.

Diflunisal

→ Di fluoro

Acetaminophen Uses

• Pain: headache, cold, toothache, backache, menstrual cramps

• Fever reduction

• Similar efficacy to aspirin for pain/fever

• No anti-inflammatory or anti-platelet effects

MOA of Acetaminophen

• Weak central COX peroxidase inhibition → ↓ CNS prostaglandins

• ↑ serotonergic descending pain pathways

• ↑ endocannabinoid + TRPV1 activity → analgesia

CIs for Acetaminophen

• Allergy to drug

• Severe liver disease

Warnings of Acetaminophen

• Overdose → severe hepatotoxicity → liver failure/death

• Caution: liver disease, alcohol use, malnutrition, renal impairment

• Stop if rash or hypersensitivity occurs

DDIs of Acetamiophen

CYP2E1 inhibitors → ↑ toxicity risk (hepatotoxicity)

Acetaminophen

Acetaminophen

• Use: Relief of minor aches and fever. (Difference from Aspirin → no antiplatelet/antiinflammatory effect)

• MOA: Inhibits COX enzymes, activates serotonergic inhibitory pathways, and activations endocannabinoids in the CNS.

• CI: Hypersensitivity to Acetaminophen + Hepatic Impairment

• CAN BE SUBSTITUTED FOR ASPIRIN FOR PAIN RELIEF/FEVER REDUCTION IN PATIENTS WITH GI ISSUES AND RISK FOR REYE’S SYNDROME

• DDI: CYP2E1 inhbiitors

Advantage of Acetaminophen > Aspirin

Safe alternative to aspirin in:

• GI bleeding risk

• Bleeding risk patients

• Children with viral illness (no Reye syndrome)

ADME of Acetaminophen

• Metabolism (main)

  • Phase II conjugation: Glucuronide & Sulfate

• Minor toxic pathway

  • CYP2E1 + CYP3A4 → NAPQI (toxic metabolite)

  • Normally detoxified by glutathione

  • Overdose → glutathione depleted → liver toxicity

• Alcohol interaction

  • Ethanol ↑ CYP2E1 → ↑ NAPQI → ↑ hepatotoxicity risk

• Brain metabolism

  • Deacetylation + conjugation with arachidonic acid (CNS-related pathway)

Pharmacologic Consequences of COX Inhibition

• COX-1/2: Homologous Enzymes that convert Arachidonic Acid → Prostaglandin H2

• Differ in regulation, tissue distribution, and predominant physiologica/pathophysiologic roles

• Clinical implication

  • COX inhibition → ↓ prostaglandins → ↓ pain, fever, inflammation, and/or protective functions depending on COX type inhibited

Aspirin’s Effect on Eicosanoids

PGs → Reduces inflammation and pain by decreasing PG synthesis

Thromboxanes → Reduces the risk of stroke/heart attack by decrease TX synthesis

• Decrease in PG and TX synthesis → Increases LT synthesis

Leukotriene → 3 Conjugated DB

What are the functions of Prostaglandins?

• Smooth Muscle → Can dilate or constrict vascular or uterine smooth muscle

• Inflammation → Pro-inflammatory; Pro-nociceptive

• Promotes Pain and Fever Response

→ PGE1 is important for GI protection and it’s synthesis is mediated by COX-1 (Main COX Enzyme blocked by Aspirin, less PGE1 → less cytoprotection of the GI → more GI effects as seen w/ Aspirin).

Misoprostol

→ Class: Prostaglandin Receptor Modulator Therapeutics

Omidenepag

→ Class: Prostaglandin Receptor Modulator Therapeutics

Latanoprost

→ Class: Prostaglandin Receptor Modulator Therapeutics

Eicosanoids: ____

Prostaglandins, Thromboxanes and Leukotrienes

→ Derived from AA

PG Structure SAR

• 5-membered ring (PENTAGON); C13-14 DB, C-15 Alpha OH

• Subclasses → Depend on Nature & Stereochemistry of C9,11 oxygens

• Roles in inflammation, pain, fever, blood flow, and smooth muscle contraction.

• Aspirin reduces inflammation and pain by decreasing PG biosynthesis.

Thromboxane SAR/Function

• Contains a 6-membered ring; C13-14 DB, C-15 Alpha OH

• Promotes platelet aggregation → Aspirin reduces the risk of stroke & heart attack by decreasing TX biosynthesis.

Prostacyclin & Thromboxane Biosynthesis

Selexipag

Selexipag

• IP Agonist

• Indication: Pulmonary HT

Leukotriene Functions

• Pro-inflammatory

• Lead to bronchoconstriction, leukocyte chemotaxis

• Drugs that inhibit Leukotrienes: Montelukast, Zafirlukast, Zileuton

Montelukast

Zafirlukast

Zileuton

CC: Chemical Mediators

• Prostaglandins: Pro-inflammatory, pro-nociceptive, promote pain & fever

• Prostacyclins (PG12): Vasodilation & bronchial relaxation

• Thromboxane: Strong stimulation of platelet aggregation

• Leukotrienes: Bronchoconstriction and Leukocyte Chemotaxis

Aspirin Effects on Chemical Mediators

• Mechanism: Irreversibly inhibits COX → ↓ arachidonic acid products

• ↓ Prostaglandins (PGs): ↓ pain, ↓ fever, ↓ inflammation

• ↓ Prostacyclin (PGI₂): ↓ vasodilation + ↓ anti-platelet effect

• ↓ Thromboxane A₂ (TXA₂): ↓ platelet aggregation (key antiplatelet effect)

• Leukotrienes: not blocked (can ↑ via shunting → bronchoconstriction risk)

• Net effect: analgesic + anti-inflammatory + strong antiplatelet effect

Thromboxane vs Prostacyclin

Thromboxane: Keep them Together

NSAIDs (COX inhibitors) — COX-1 vs COX-2

• COX-1 (protective enzyme)

  • Maintains stomach lining, kidneys, platelets

  • Inhibition → ↓ GI protection → ulcers/bleeding

  • Also → ↓ platelet aggregation (bleeding risk but cardioprotective in low-dose aspirin)

• COX-2 (inflammatory enzyme)

  • Drives pain, fever, inflammation

  • Inhibition → ↓ pain/inflammation

  • BUT → ↓ prostacyclin (PGI₂) with intact TXA₂ → ↑ clot risk (MI, stroke), ↑ BP, fluid retention

SAR of COX Inhibitors

• Core structure

  • Carboxylic acid (or bioisostere)

  • Short linker (n = 0–3, usually 1)

  • Aryl/heteroaryl ring(s)

  • Hydrophobic R groups

• How they bind COX

  • Carboxylate binds Arg120

  • Aromatic rings do π–π interactions (Tyr, Trp)

  • R groups improve fit + potency

• Key idea

  • Mimic arachidonic acid binding in COX active site

• Selectivity

  • Most NSAIDs: non-selective COX-1/COX-2

  • COX-2 selective drugs (coxibs): designed to reduce GI toxicity while keeping anti-inflammatory effect

Classes of NSAIDs

NSAIDs Impact on COX Enzymes

• COX-1 blocked → ↓ stomach protection + ↓ platelets → ulcers + bleeding (± cardioprotection)

• COX-2 blocked → ↓ pain/inflammation BUT ↓ PGI₂ → ↑ clot risk, ↑ BP, ↑ HF risk

Montelukast & Zafirlukast

• Leukotriene Receptor Antagonist (Suffix: -lukast)

• Indicated for asthma, exercise induced bronchoconstriction, allergic rhinitis

Zileuton

• 5-Lipoxygenase inhibitor

• Indicated for asthma

Indomethacin

Diclofenac

Ibuprofen

Naproxen

Meloxicam

Celecoxib

Indomethacin

• Class: Non-selective NSAID

• MOA: COX inhibitor (pseudo-irreversible), more potent than Aspirin (analgesic and antipyretic activity).

• Similar DDIs and effect of renal impairment as Aspirin

• BBW: ↑ CV thrombotic risk (MI, stroke), especially post-CABG

• Metabolism: Phase I Oxidation, Phase II Glucuronidation, Amide Hydrolysis → Inactive

Indomethacin SAR

Diclofenac

• Class: Non-selective NSAID with COX-2 preference

• Also inhibits:

  • 5-lipoxygenase

  • Phospholipase A₂

• Very potent analgesic (~100× aspirin)

• Use: Moderate-Severe Osteoarthritis, RA, and ankylosing spondylitis

• BBW: ↑ CV thrombotic risk (MI, stroke); Contraindicated post-CABG

• ADME: Phase I metabolism predominates, 4’ Hydroxy is the major metabolite → forms reactive quinoneimine.

Ibuprofen

• Use: OTC for temporary relief from pain

• MOA: Non-selective NSAID → equally potent w/ Aspirin

• ADR: Similar to Aspirin but better GI tolerance

• CI for use during pregnancy due to renal dysfunction and gestation disruption.

Ibuprofen ADME

• Given as racemic mixture (R/S)

• R → S conversion via AMACR → active form (S-ibuprofen)

• S-form = pharmacologically active; R-form is largely inactive

• Metabolism occurs before CYP oxidation to inactive metabolites

Naproxen

• Use: Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis

• Mechanism: Non-Selective NSAID → Equally potent w/ Aspirin, Ibuprofen

• Difference w/ Ibuprofen → Not a substrate for AMACR → GIVEN AS THE ACTIVE S ENANTIOMER.

• Similar ADRs as Ibuprofen

  • Slightly ↓ CV risk vs ibuprofen

  • Slightly ↑ GI bleed risk (esp. with alcohol)

Meloxicam

• MOA: “COX-2” preferring NSAID → 100x more potent than Aspirin, Ibuprofen

• Use: Chronic Treatment (*DIFFERENCE*) of Osteoarthritis and Rheumatoid Arthritis

• Once daily

• BBW: CI for CABG (NSAID Class Effect); increased risk of CV events.

COX-1 vs COX-2 Inhibition — Summary

• COX-1 (protective enzyme)

  • Maintains stomach lining, platelets, kidney blood flow

  • Inhibition → ↓ GI protection → ulcers, bleeding

  • ↓ Platelets → ↓ clotting (beneficial in low-dose aspirin)

  • Can cause bronchospasm

• COX-2 (inflammatory enzyme)

  • Drives pain, fever, inflammation

  • Inhibition → ↓ pain/inflammation

  • BUT ↓ prostacyclin → ↑ platelet activity + vasoconstriction

  • → ↑ CV risk (MI, stroke), ↑ BP, ↑ heart failure risk

Celecoxib

• Suffix: -coxib

• SELECTIVE NSAID → for COX-2 (Inflammatory)

• 10x more potent than Aspirin/Ibuprofen for Arthritis Pain Relief

• BBW: CI for CABG (NSAID Class Effect), analogous to Ibuprofen

• More COX-2 selectivity = less GI harm but more CV risk

  • → COX-2 Inhibitors are reserved for high risk GI patients.

NSAIDs: Difference

NSAIDs w/ lowest ADR RIsk

Naproxen → Low CV Risk

Celecoxib → Low GI Bleed Risk

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

• Class Indications: Rheumatoid Arthritis (RA), other autoimmune diseases.

• Class Goal: Dampen immune activation, slow joint destruction (unlike NSAIDs which only treat symptoms).

Disease-Modifying Anti-Rheumatic Drugs

• Doesn’t occur from joints, but from some flare up in joints

• MOA: Treat RA by dampening innate and adaptive immune activation, block cytokine signaling, and altering synovial cell behavior reducing joint inflammation and destructive remodeling.

Convential Synthetic DMARDs

• Agents that broadly modulate immune and inflammatory pathways associated with RA

• Drugs: Methotrexate (main drug), Leflunomide, Sulfasalazine, Hydroxychloroquine

• Used first line before or alongside other DMARDs and/or JAKis.

Methotrexate

Methotrexate

• Class: Conventional Synthetic DMARDs

• Main drug for RA & other autoimmune disorders

• MOA: Inhibits DHFR & increases extracellular adenosine

• Dose: Once weekly oral formulation (Class effect of DMARDs)

• HAS AN ACTIVE METABOLITE

• Co-administer folic acid to reduce GI toxicity/hepatotoxicity.

Methotrexate ADRs, CIs, BBW

• CI: Non-neoplastic diseases during pregnancy

• BBW: Serious ADRs and Embryo Toxicity (since inhibiting folate)

• Immunosuppressive → risk of opportunistic infections + can affect live vaccines administration

• DDI: NSAIDs reduce GFR (Increase drug levels) and antimicrobial drugs

Methotrexate (MTX) — Discovery & MOA

• Origin

  • Developed in 1940s from folate metabolism research in cancer cells

• Target pathway

  • Folate → needed for DNA synthesis (one-carbon transfer)

  • DHFR enzyme converts folate → active forms for DNA replication

• Mechanism

  • MTX inhibits dihydrofolate reductase (DHFR) → DHF can’t be converted to active THF

  • ~1000× stronger binding than folic acid

  • → ↓ tetrahydrofolate → ↓ DNA synthesis (blocks rapidly dividing cells)

• Clinical insight

  • High dose: anti-cancer (blocks tumor growth)

  • Low/intermittent dose: immunomodulation → ↓ inflammation in RA

Folic Acid vs Methotrexate

• Changes → increase potency of binding to DHFR

• Considered an “anchor drug” for RA

Methotrexate MOAs

1. Enters the cell via Folate Carrier (FTC) and Folate Receptor (FC)

2. MTX → MTX-PG by foly-polyglutamtyl synthese to prevent it’s efflux by the ATP Bindinf Casseste transporter

3. Inhibits several enzymes (*KNOW*) →

   1. Inhibits TYMPS (Thymidylate Synthetase) → Decrease pyrmidine synthesis.

   2. Inhibits ATIC → Increases adenosine which has vasodilatory and anti-inflammatory effects.

   3. Inhibits transmethylation of DNA, RNA, amino acids, etc needed for the cell to survive.

Leflunomide

• Class: Conventional Synthetic DMARDs

• Second line agent for RA (if fail Methotrexate)

• MOA: Inhibits DHODH → decreases pyrimidine synthesis (1/3 of the MOA of Methotrexate)

• Prodrug → Teriflunomide is the active form that exerts it’s effects.

• ADRs (similar to Methotrexate): BBW for fetal toxicity, hepatotoxicity, DDI with hepatoxic agents.

Leflunomide

Sulfasalazine

• Combined w/ Methotrexate to treat RA + ulcerative colitis

• MOA: Metabolized in the small intestine to Sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA).

  • 5-ASA Effect: Inhibits PG synthesis

  • SP: Increases adenosine + Reduces pro-inflammatory cytokines.

• ADR: No fetal toxicity (like Methotrexate and Leflunomide) but immunosuppression (class effect of conventional DMARDs).

Sulfasalazine

Hydroxychloroquine

• Class: Conventional Synthetic DMARDs

• Add on agent to Methotrexate (like Sulfasalazine) for RA + Malaria

• MOA: Increases the pH of T cells → blocks toll-like receptor activation and decreases cytokines

• Racemic Mixture

• ADRs: Bind to ion channels, effect anti-arrhythmic drugs, narrow TI drugs, cardiac effects and retinal effects (unique for this drug).

Hydrochrloquine

JAK Inhibitors

• Drugs: Tofacitinib, Upadacitinib, Baricitinib (Suffix: -tinib)

• MOA: Suppresses T-cell differentiation and proliferation, blocks B-cell signaling curbing pannus invasion, decreases TNF and IL-1 output.

• Can have higher or lower efficacy than Methotrexate or TNF blockers but the trade off is long-term safety.

• Black Box Warnings (vs. TNF blockers): Higher rate of death, MACE (heart attack/stroke), malignancy, thrombosis (PE/DVT).

JAK Inhibitors

Upadacitinib (LOOKS LIKE A U)

Tofacitinib

Baricitinib

Biologic DMARDs

• MOA: Inhibit Tumor-Necrosis Factors (TNF) → TNF drives synovial inflammation & joint damage

• Inhibition → Improves symptoms in RA (*synergistic w/ Methotrexate*)

• ADR: Immunosuppression (DMARD Class Effect), increases CV risk and does enhance malignancy risk (but no meaningful difference).

• Drugs: MABs

Biologic DMARDs (TNF Inhibitors)

• Drugs: Infliximab (chimeric), Adalimumab (human), Golimumab (human), Etanercept (fusion protein), Certolizumab (PEGylated Fab).

• Class Black Box: Serious infections (TB reactivation), malignancy (lymphoma).

• Key Exception (Certolizumab): Lacks Fc region → no mTNF-cell cytotoxicity/apoptosis → may be safer in pregnancy.

• Key Rule: MTX is required with Infliximab and Golimumab (recommended but not required for others).

MTX is required with ____ (TNF Inhibitors).

Infliximab and Golimumab

All TNF Inhibitors are SUBQ except…

Infliximab

Certolizumab has no ___

mTNF-cell Cytotoxicity or Apoptosis since this requires Fc Region