Case 3: Patient M., 57 y/o — Right Knee Pain

Station 1

1. Diagnosis

• Age 57, female
• Mechanical pain pattern (worsens with exertion, end of day)
• Morning stiffness (mild, typically <30 min in OA)
• Mildly elevated CRP (low-grade inflammation typical of OA)
• Gradual onset

2. P-Drug (Personal Drug of Choice)

3. Dosage Form

4. Dosage

Station 2

5. Pharmacokinetics

• Absorption: Readily absorbed after oral administration
• Metabolism: Extensively metabolized in the liver by CYP2C9
• Excretion: Metabolites excreted in feces and urine
• Half-life: ~11 hours → allows once or twice daily dosing
• Caution: Reduce dose in moderate hepatic impairment; avoid in severe hepatic or renal disease
• Drug interactions: CYP2C9 inhibitors (e.g., fluconazole) increase celecoxib plasma levels

6. Mechanism of Action

• COX-2 is the inducible isoform upregulated at sites of inflammation — its inhibition reduces synthesis of prostaglandins (PGE₂, PGI₂) responsible for pain, swelling, and fever
• COX-1 (constitutive) is largely spared → gastric mucosal protection and platelet function are preserved
• Inhibition of COX-2 is reversible (unlike aspirin's irreversible COX-1 inhibition)

7. Prescription

Rp.: Celecoxib 200 mg
D.t.d. No. 30 in caps.
S.: Take 1 capsule (200 mg) orally twice daily,
    with food. Duration: 4 weeks.

#Physician signature / Date

Station 3

8. Duration of Treatment

9. Side Effects

Note: The GI benefit of celecoxib is lost if low-dose aspirin is co-administered.

10. Contraindications

• Active peptic ulcer / GI bleeding (history of ulcer is a relative contraindication — celecoxib is safer than non-selective NSAIDs but not risk-free)
• Severe hepatic impairment
• Severe renal impairment
• Known sulfonamide hypersensitivity (celecoxib contains a sulfonamide moiety)
• Anaphylactoid reaction to aspirin or other NSAIDs
• Established ischemic heart disease, peripheral arterial disease, cerebrovascular disease
• Pregnancy (especially 3rd trimester)
• Heart failure

1. Carbapenems & Monobactams

CARBAPENEMS

Mechanism of Action

Imipenem is inactivated by renal dehydropeptidase-I → must be co-administered with cilastatin (inhibitor of that enzyme). Meropenem and ertapenem are stable and do not require cilastatin.

Spectrum of Action

• MRSA, E. faecium, C. difficile, Stenotrophomonas maltophilia, Burkholderia cepacia

Indications

• Severe/complicated intra-abdominal, urinary tract, skin/soft tissue, pulmonary infections
• Nosocomial (hospital-acquired) infections — especially ICU-level
• Febrile neutropenia (imipenem or meropenem ± aminoglycoside)
• Infections caused by ESBL-producing or multidrug-resistant gram-negatives
• Mixed aerobic/anaerobic infections

Side Effects

• GI: Nausea, vomiting, diarrhea (most common)
• CNS: Seizures — most common with imipenem (especially in renal failure); meropenem and ertapenem much less likely
• Infusion site reactions
• Skin rash
• Cross-allergy with penicillins — <1% incidence

Contraindications

• Hypersensitivity to carbapenems
• Use with caution in patients with penicillin allergy (low cross-reactivity)
• Imipenem: avoid in CNS infections (seizure risk) → prefer meropenem for meningitis
• Dose reduction required in renal insufficiency (all carbapenems cleared renally)

Drug Interactions

• Valproic acid: carbapenems markedly reduce valproate serum levels (↓ up to 60–90%) → risk of seizure breakthrough — avoid combination
• Probenecid: inhibits renal tubular secretion of meropenem → increases meropenem levels
• Ganciclovir + imipenem → increased risk of seizures
• Antagonism with other β-lactams in certain organisms (avoid combining)

MONOBACTAMS

Mechanism of Action

Spectrum of Action

Indications

• Gram-negative aerobic infections in patients allergic to penicillins/cephalosporins (no cross-reactivity with aztreonam for most penicillin-allergic patients)
• UTI, bacteremia, pneumonia, intra-abdominal and gynecologic infections (gram-negative only)
• Used in combination when gram-positive/anaerobic coverage is also needed

Side Effects

• Generally well tolerated
• GI: nausea, vomiting, diarrhea
• Skin rash, phlebitis at injection site
• Rarely: hepatotoxicity (transaminase elevation)
• Seizures (very rare)

Contraindications

• Known hypersensitivity to aztreonam
• Note: Cross-reactivity exists between aztreonam and ceftazidime (share identical side chain) — avoid if ceftazidime-allergic

Drug Interactions

• Few clinically significant interactions
• Avoid nephrotoxic combinations (aminoglycosides) without monitoring
• Aztreonam/avibactam (newer combination) extends spectrum to metallo-β-lactamase producers

2. Inhaled Glucocorticosteroids (ICS)

Mechanism of Action

1. Genomic (slow, hours): Glucocorticoids diffuse into cells → bind cytoplasmic glucocorticoid receptor (GR) → GR-drug complex translocates to nucleus → binds glucocorticoid response elements (GREs) → transactivation (induces anti-inflammatory proteins: lipocortin/annexin-1, IκB) and transrepression (suppresses NF-κB and AP-1 → reduces transcription of pro-inflammatory cytokines: IL-1, IL-4, IL-5, TNF-α, GM-CSF)
2. Result: Decreased mast cell degranulation, eosinophil recruitment, mucus secretion, airway edema, and bronchial hyperresponsiveness
3. ICS act locally in airways — direct topical anti-inflammatory effect with minimal systemic absorption at standard doses

Spectrum / Pharmacological Effects

• Reduce airway inflammation (eosinophilic, allergic, non-allergic)
• Reduce bronchial hyperreactivity (not immediate bronchodilation)
• Decrease mucus hypersecretion
• Decrease frequency and severity of exacerbations
• Do not have direct bronchodilator effect (unlike β₂-agonists)

Indications

• Bronchial asthma — cornerstone of maintenance therapy for persistent asthma (mild, moderate, severe)
• COPD (moderate-severe, exacerbation-prone) — in combination with LABA ± LAMA
• Allergic rhinitis (intranasal formulations)
• Eosinophilic bronchitis

Dosage Forms & Drugs

• Budesonide (Pulmicort): 200–400 mcg/day
• Fluticasone propionate (Flixotide): 100–500 mcg/day
• Beclomethasone: 100–400 mcg/day
• Often combined with LABA (e.g., salmeterol/fluticasone = Seretide, formoterol/budesonide = Symbicort)

Side Effects

Prevention of local effects: Rinse mouth after each dose; use spacer device with MDI

Contraindications

• Hypersensitivity to the specific ICS or excipients
• Not for acute bronchospasm (no immediate bronchodilator effect)
• Active pulmonary tuberculosis (relative CI — ICS may worsen)
• Severe fungal/viral respiratory infections (relative CI)
• Avoid abrupt discontinuation in long-term users (adrenal suppression risk)

Drug Interactions

• CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, itraconazole): inhibit metabolism of fluticasone and budesonide → markedly increased systemic levels → risk of iatrogenic Cushing's syndrome and adrenal suppression — significant clinical risk especially with HIV protease inhibitors + fluticasone
• Combination with LABA: synergistic (LABA upregulates GR; ICS prolongs LABA effect) — preferred combination in asthma step-up therapy
• Live vaccines: high-dose systemic steroids → immunosuppression; less relevant with standard ICS doses
• Anticholinergics/β₂-agonists: additive bronchodilation — beneficial combination

1. Carbapenems & Monobactams

CARBAPENEMS

Imipenem is degraded by renal dehydropeptidase-I → given only with cilastatin. Meropenem/ertapenem are stable alone.

• Gram-negatives: Enterobacteriaceae, P. aeruginosa*, Acinetobacter*, ESBL-producers
• Gram-positives: streptococci, MSSA, penicillin-resistant pneumococci
• Anaerobes: B. fragilis, Clostridium spp.
• *Ertapenem has no activity vs P. aeruginosa / Acinetobacter
• NOT covered: MRSA, E. faecium, C. difficile, Stenotrophomonas

• Severe nosocomial/ICU infections
• ESBL-producing gram-negative infections (drug of choice)
• Febrile neutropenia
• Mixed aerobic-anaerobic infections
• MDR gram-negative infections

• Nausea, vomiting, diarrhea
• Seizures (especially imipenem in renal failure; meropenem much safer)
• Skin rash, infusion site reactions
• Cross-allergy with penicillins (<1%)

• Hypersensitivity to carbapenems
• Imipenem contraindicated in CNS infections (seizure risk) → use meropenem instead
• Dose reduction in renal insufficiency (all renally cleared)

• Valproic acid → carbapenems drastically reduce valproate levels (↓60–90%) → seizure risk → avoid combination
• Ganciclovir + imipenem → additive seizure risk
• Probenecid → increases meropenem levels

MONOBACTAMS

• Enterobacteriaceae, P. aeruginosa, H. influenzae, Neisseria
• No activity vs gram-positives or anaerobes

• Gram-negative infections in patients with penicillin/cephalosporin allergy (safe alternative — minimal cross-reactivity)
• UTI, bacteremia, pneumonia, gynecological infections (gram-negative)
• Always combine with agents covering gram-positives/anaerobes when needed

• GI: nausea, diarrhea
• Skin rash, phlebitis
• Rarely: hepatotoxicity

• Hypersensitivity to aztreonam
• Cross-reactive with ceftazidime (identical side chain) — avoid if ceftazidime-allergic

• Few significant interactions
• Monitor renal function if combined with aminoglycosides

2. Inhaled Glucocorticosteroids (ICS)

1. Enter airway cells → bind cytoplasmic glucocorticoid receptor (GR)
2. GR-drug complex → nucleus → binds GREs:
   • Transrepression: suppresses NF-κB and AP-1 → ↓ IL-1, IL-4, IL-5, TNF-α, GM-CSF
   • Transactivation: induces anti-inflammatory proteins (lipocortin/annexin-1, IκB)
3. Result: ↓ eosinophil recruitment, mast cell degranulation, mucus secretion, airway edema, bronchial hyperresponsiveness
4. Act topically in airways → minimal systemic absorption at standard doses
5. Not bronchodilators — effect develops over days to weeks

• Bronchial asthma — cornerstone of maintenance therapy for all persistent asthma
• COPD (severe, frequent exacerbations) — with LABA ± LAMA
• Allergic/eosinophilic airway disease

Prevention: rinse mouth after each dose; use spacer with MDI

• Hypersensitivity to ICS
• Acute bronchospasm (no immediate effect — use SABA)
• Active pulmonary TB (relative)
• Severe respiratory fungal/viral infections (relative)

• CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir/HIV PIs): inhibit metabolism of fluticasone/budesonide → systemic accumulation → iatrogenic Cushing's syndrome, adrenal suppression — clinically important
• LABA combination (salmeterol, formoterol): synergistic — LABA upregulates GR; ICS prolongs LABA activity → preferred step-up therapy
• Other bronchodilators (β₂-agonists, anticholinergics): additive bronchodilation — beneficial

Case 20: Herpes Labialis (Cold Sore)

Station 1

• Oral: 400 mg × 3 times/day or 200 mg × 5 times/day
• Topical: apply to affected area 5 times/day (every 4 hours while awake)

Station 2

• Routes: oral, IV, topical
• Oral bioavailability: ~15–30% (low) → valacyclovir (prodrug) gives much higher levels
• Distribution: widely throughout body including CSF
• Metabolism: partially hepatic → inactive metabolite
• Excretion: urine (glomerular filtration + tubular secretion)
• Caution: accumulates in renal failure

1. Acyclovir (guanosine analog) enters virus-infected cells
2. Phosphorylated to acyclovir-monophosphate by herpesvirus thymidine kinase (TK) — virus-infected cells are selectively targeted
3. Host cell kinases convert it to acyclovir triphosphate
4. Competes with deoxyguanosine triphosphate → incorporated into viral DNA by viral DNA polymerase → premature chain termination → viral replication halts
5. Minimal toxicity to host cells (host TK does not phosphorylate acyclovir efficiently)

Rp.: Tab. Acyclovir 400 mg
D.t.d. No. 21
S.: Take 1 tablet (400 mg) orally
    3 times daily for 7 days.

Station 3

• Acute episode: 5–7 days
• Suppressive therapy (frequent recurrences): 400 mg twice daily for 6–12 months

• Oral: headache, nausea, vomiting, diarrhea
• Topical: local irritation, mild burning/stinging, pruritus
• IV (high dose): transient renal dysfunction (crystalluria — ensure hydration), neurotoxicity (rare)
• Resistance (rare, mainly in immunocompromised): via altered/deficient TK

• Hypersensitivity to acyclovir or valacyclovir
• Severe renal impairment (dose reduction required)
• Use with caution in pregnancy (category B — generally considered safe but consult)
• Not curative — does not eliminate latent virus in dorsal root ganglia