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CARD № 5 — Clinical Pharmacology

Question 1: Glycopeptides

Mechanism of Action

Glycopeptides inhibit bacterial cell wall synthesis by binding with high affinity (noncovalent) to the D-alanyl-D-alanine terminus of cell wall precursor units. This blocks, via steric hindrance, both:

Transglycosidase-mediated polymerization of the peptidoglycan backbone
PBP-mediated cross-linking of cell wall units

Because of their large molecular size, they cannot penetrate the outer membrane of gram-negative bacteria, limiting their activity exclusively to gram-positives.

The lipoglycopeptides (telavancin, dalbavancin, oritavancin) dimerize and anchor their lipid moiety into the bacterial membrane, enhancing binding. Telavancin and oritavancin also have a second mechanism — direct disruption of the bacterial membrane — leading to faster bactericidal activity.

Spectrum of Activity

Vancomycin (prototype glycopeptide) is active against the vast majority of gram-positive organisms:

MRSA (methicillin-resistant S. aureus)
Penicillin-resistant streptococci
Ampicillin-resistant enterococci
Clostridium difficile (oral route)
Intrinsically resistant: Lactobacillus, Leuconostoc, Pediococcus, Erysipelothrix, most VRE
Essentially all gram-negatives and mycobacteria are resistant

Indications

MRSA infections (bacteremia, skin/soft-tissue, bone/joint, pneumonia, endocarditis)
Community-acquired bacterial meningitis (empiric, when penicillin-resistant S. pneumoniae suspected)
C. difficile-associated diarrhea (oral vancomycin)
Nosocomial meningitis (ventriculitis — intraventricular administration)
Surgical prophylaxis in β-lactam allergy or high MRSA risk
Vascular catheter infections (gram-positive organisms)
Empiric therapy in febrile neutropenia

Side Effects

Adverse Effect	Details
Red Man Syndrome	Rapid IV infusion → flushing, erythema, urticaria, tachycardia, hypotension — due to mast cell histamine release (not true allergy). Prevented by slow infusion ± antihistamines.
Nephrotoxicity	Dose-related; risk increased by coadministration with aminoglycosides or certain penicillins. Telavancin may be more nephrotoxic.
Ototoxicity	Auditory and vestibular toxicity, especially at high concentrations or with loop diuretics.

Contraindications

Hypersensitivity to glycopeptides
Severe pre-existing renal impairment (use with dose adjustment and TDM)
Caution in pregnancy (telavancin is teratogenic — Category C)
Oritavancin with warfarin (minor CYP interaction — requires careful monitoring)

Drug Interactions

Aminoglycosides → additive nephrotoxicity and ototoxicity
Loop diuretics (furosemide) → additive ototoxicity
Penicillins (certain) → may increase nephrotoxicity risk
Oritavancin + warfarin → monitor INR closely (CYP interaction)

Question 2: NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

Mechanism of Action

NSAIDs inhibit cyclooxygenase (COX) enzymes (COX-1 and COX-2) — the enzymes that catalyze the first step in prostanoid (prostaglandin) biosynthesis. This reduces the synthesis of prostaglandins and thromboxanes, producing:

Anti-inflammatory effect (mainly via COX-2 inhibition)
Analgesic effect (COX-2 inhibition reducing peripheral sensitization)
Antipyretic effect (COX-2 in the hypothalamus)

Aspirin is unique — it irreversibly acetylates cyclooxygenase. All other NSAIDs are reversible inhibitors.

COX-1 is constitutively expressed and protects the gastric mucosa and promotes platelet aggregation. COX-2 is inducible at sites of inflammation. This explains why COX-1 inhibition causes GI adverse effects.

Classes (chemical derivatives):

Salicylic acid: Aspirin, diflunisal, salsalate
Propionic acid: Ibuprofen, naproxen, ketoprofen
Acetic acid: Diclofenac, indomethacin, ketorolac, etodolac
Enolic acid: Meloxicam, piroxicam
Fenamates: Mefenamic acid, meclofenamate
Selective COX-2 inhibitor: Celecoxib

Spectrum / Indications

Rheumatoid arthritis and osteoarthritis
Acute pain, post-operative analgesia
Dysmenorrhea
Fever (antipyretic)
Gout (indomethacin)
Headache/migraine
Aspirin (low dose): Prevention of cardiovascular events (MI, stroke) via irreversible COX-1 inhibition → reduced platelet TXA₂

Side Effects

System	Effects
GI	Nausea, dyspepsia, peptic ulcer, GI bleeding (from COX-1 inhibition reducing mucosal protection)
Renal	Decreased renal perfusion → acute kidney injury, fluid retention, hypertension, hyperkalemia
Cardiovascular	Increased risk of MI and stroke (especially COX-2 selective agents, e.g., celecoxib)
Hematologic	Inhibition of platelet aggregation → increased bleeding time
Respiratory	Aspirin-exacerbated respiratory disease (aspirin-sensitive asthma, nasal polyps)
Hepatic	Hepatotoxicity (rare, mainly with diclofenac)
CNS	Tinnitus, headache (especially salicylate toxicity/"salicylism")
Pregnancy	Premature closure of ductus arteriosus (third trimester — avoid)
Reye's Syndrome	Aspirin in children with viral illness — fatal hepatic encephalopathy

Contraindications

Active peptic ulcer or GI bleeding
Severe renal or hepatic impairment
Aspirin hypersensitivity / NSAID-induced asthma
3rd trimester pregnancy
Children with viral infections (aspirin — Reye's syndrome)
Post-CABG surgery (NSAIDs, especially celecoxib)

Drug Interactions

Warfarin/anticoagulants → increased bleeding risk (especially aspirin)
Antihypertensives (ACEi, ARBs, diuretics) → reduced antihypertensive effect; ACEi + NSAID → increased nephrotoxicity
Lithium → NSAIDs reduce renal lithium clearance → lithium toxicity
Methotrexate → NSAIDs reduce renal clearance → methotrexate toxicity
Corticosteroids → additive GI ulceration risk
SSRIs + NSAIDs → increased GI bleeding risk
Probenecid (uricosuric) + aspirin → aspirin inhibits uric acid excretion (interaction antagonistic)

Prescription Examples

Prescription 1 — Vancomycin (Glycopeptide)

Rp.:  Sol. Vancomycini 0.5 g
      D.t.d. No. 10 in fl.
      S. Dissolve in 100 mL of 0.9% NaCl.
         Administer IV infusion over 60 min, every 6 hours
         (dose: 15 mg/kg q6h or 30–45 mg/kg/day in 2–4 divided doses).
         Monitor renal function and drug levels (trough: 10–20 mg/L).

Prescription 2 — Ibuprofen (NSAID)

Rp.:  Tab. Ibuprofeni 0.4 g
      D.t.d. No. 20
      S. Take 1 tablet (400 mg) orally 3 times daily after meals.
         Maximum daily dose: 1200 mg (OTC) or up to 2400 mg (Rx).
         Take with food or milk to reduce GI irritation.

Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics; Lippincott Illustrated Reviews: Pharmacology

Ins in short

CARD № 5 — Short Summary

Q1: Glycopeptides (Vancomycin, Teicoplanin)

Mechanism: Bind D-Ala-D-Ala terminus of cell wall precursors → block peptidoglycan synthesis (transglycosylation + cross-linking) → bactericidal against gram-positives only.

Spectrum: Gram-positive only — MRSA, PRSP, enterococci, C. difficile. No gram-negative activity.

Indications: MRSA infections, endocarditis, meningitis, C. difficile diarrhea (oral), surgical prophylaxis in β-lactam allergy.

Side Effects:

Red Man Syndrome (rapid infusion → flushing, hypotension)
Nephrotoxicity (dose-related)
Ototoxicity (tinnitus, hearing loss)

Contraindications: Hypersensitivity, severe renal impairment (use with caution + dose adjust).

Interactions: Aminoglycosides & loop diuretics → ↑ nephro/ototoxicity.

Prescription:

Rp.: Sol. Vancomycini 0.5 g
D.t.d. No. 10 in vial
S. IV infusion over 60 min, 15 mg/kg q6h

Q2: NSAIDs (Ibuprofen, Diclofenac, Aspirin, Celecoxib)

Mechanism: Inhibit COX-1 & COX-2 → ↓ prostaglandin synthesis → anti-inflammatory, analgesic, antipyretic. Aspirin = irreversible inhibitor; others = reversible.

Spectrum/Indications: Arthritis, acute pain, fever, dysmenorrhea, gout (indomethacin). Aspirin (low dose) = cardiovascular prophylaxis.

Side Effects:

GI ulceration/bleeding (COX-1 inhibition)
Nephrotoxicity (↓ renal perfusion)
Platelet inhibition → bleeding
CV risk ↑ (COX-2 selective agents)
Aspirin in children → Reye's syndrome
Avoid in 3rd trimester (ductus arteriosus closure)

Contraindications: Active peptic ulcer, renal/hepatic failure, NSAID-induced asthma, 3rd trimester pregnancy, post-CABG.

Interactions:

Warfarin → ↑ bleeding
ACEi/ARBs → ↑ nephrotoxicity
Methotrexate/Lithium → toxicity (↓ renal clearance)
Corticosteroids → ↑ GI risk

Prescription:

Rp.: Tab. Ibuprofeni 0.4 g
D.t.d. No. 20
S. 1 tab orally 3× daily after meals

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