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Cyclosporine (Cyclosporin A / CsA) — Complete Reference

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1. ORIGIN & CHEMICAL CLASSIFICATION

1. Calcineurin inhibitors — Cyclosporine, Tacrolimus
2. Costimulation blocker — Belatacept
3. mTOR inhibitors — Sirolimus, Everolimus
4. Antiproliferatives — Azathioprine, Mycophenolate
5. Corticosteroids

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2. MECHANISM OF ACTION

Antigen presentation by APC
          ↓
T-cell receptor (TCR) activation
          ↓
Transmembrane signal → ↑ Intracellular Ca²⁺
          ↓
Ca²⁺ + Calmodulin → activates CALCINEURIN (serine/threonine phosphatase)
          ↓
Calcineurin dephosphorylates NFAT (cytoplasmic)
          ↓
NFAT translocates to NUCLEUS
          ↓
NFAT + nuclear partners → transcription of IL-2, IL-3, IL-4, TNF-α, IFN-γ, GM-CSF
          ↓
T-cell activation and proliferation

━━━━━━━━ CYCLOSPORINE BLOCKS HERE ━━━━━━━━
CsA enters T-cell cytoplasm
     ↓
Binds CYCLOPHILIN (immunophilin receptor)
     ↓
CsA–Cyclophilin complex binds CALCINEURIN
     ↓
CALCINEURIN IS INHIBITED
     ↓
NFAT remains phosphorylated → CANNOT enter nucleus
     ↓
No IL-2 / cytokine transcription → T-cell NOT activated

• Suppresses both humoral and cell-mediated immunity (primarily T-cell dependent)
• Blunts expression of antiapoptotic proteins in lymphocytes
• Increases TGF-β — a potent inhibitor of IL-2–stimulated T-cell proliferation
• Does NOT inhibit early T-lymphocyte signal transduction phases

Cyclosporine, a cyclic polypeptide of 11 amino acids produced by Beauveria nivea, inhibits calcineurin activity. — Goodman & Gilman's, p. 793

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3. IMMUNOSUPPRESSANT SITE-OF-ACTION OVERVIEW

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4. FORMULATIONS & PHARMACOKINETICS

⚠️ Critical: SANDIMMUNE and NEORAL are NOT interchangeable without close monitoring. Inadvertent substitution can cause graft loss or toxicity. — Goodman & Gilman's, p. 793

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5. DOSAGE

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6. THERAPEUTIC USES

6A. Transplantation (Primary Indication)

• Kidney, liver, heart transplant — cornerstone of maintenance immunosuppression
• Used in combination with corticosteroids + azathioprine/mycophenolate ± sirolimus
• Bone marrow / stem cell transplant — prevention of graft-versus-host disease (GVHD); standard prophylaxis with methotrexate

6B. Autoimmune & Rheumatologic Conditions

6C. 🦴 Uses in Orthopedics

Sulfasalazine and cyclosporine may control the acute inflammation in psoriatic arthritis, but have not been found helpful in arresting the progression of clinical and radiologic damage. — Medscape/GRAPPA guidelines

In rheumatoid arthritis, cyclosporine is used in severe cases that have not responded to methotrexate. — Goodman & Gilman's, p. 793–794

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7. SIDE EFFECTS

Major Adverse Effects Flowchart

CYCLOSPORINE ADMINISTRATION
          |
    ┌─────┴──────┐
    │            │
RENAL         CARDIOVASCULAR
Nephrotoxicity    Hypertension
(dose-related,    (~50% renal tx;
reversible)       ~100% cardiac tx)
    |
    ├── Acute: vasoconstriction
    └── Chronic: interstitial fibrosis
          |
    Differentiate from REJECTION
    (requires renal biopsy)

          |
    ┌─────────────────────────────┐
    │    METABOLIC EFFECTS        │
    ├── Hyperkalemia              │
    ├── Hyperuricemia → Gout      │
    ├── Hyperlipidemia (LDL↑)     │
    ├── Hyperglycemia / DM        │
    └── Hyperuricemia             │
    └─────────────────────────────┘

          |
    ┌─────────────────────────────┐
    │  COSMETIC / DERMAL         │
    ├── Hirsutism (excess hair)   │
    ├── Gingival hyperplasia      │
    └─────────────────────────────┘

          |
    ┌─────────────────────────────┐
    │   NEUROLOGICAL             │
    ├── Tremor                   │
    ├── Headache                 │
    ├── Paresthesias             │
    ├── Mental confusion         │
    ├── Hallucinations           │
    ├── Seizures (rare)          │
    └── Posterior reversible     │
        encephalopathy (PRES)    │
    └─────────────────────────────┘

          |
    ┌─────────────────────────────┐
    │    ONCOLOGIC               │
    ├── ↑ Risk lymphoma          │
    ├── Post-transplant           │
    │   lymphoproliferative       │
    │   disorder (PTLD)          │
    └── Skin malignancy          │
    └─────────────────────────────┘

          |
    ┌─────────────────────────────┐
    │    INFECTIOUS              │
    └── Opportunistic infections  │
        (fungal, viral, bacterial)│
    └─────────────────────────────┘

Gingival Hyperplasia (clinical photos):

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8. DRUG INTERACTIONS

DRUGS THAT INCREASE CsA LEVELS (CYP3A4 inhibitors — ↑ toxicity):
  ├── Ca²⁺ channel blockers: verapamil, nicardipine
  ├── Antifungals: fluconazole, ketoconazole, itraconazole
  ├── Antibiotics: erythromycin, clarithromycin
  ├── Glucocorticoids: methylprednisolone
  ├── HIV protease inhibitors: indinavir
  ├── Other: allopurinol, metoclopramide
  └── GRAPEFRUIT JUICE (CYP3A4 + P-gp inhibition) ⚠️

DRUGS THAT DECREASE CsA LEVELS (CYP3A4 inducers — ↓ efficacy):
  ├── Antibiotics: rifampin, nafcillin
  ├── Anticonvulsants: phenobarbital, phenytoin
  └── Other: octreotide, ticlopidine

DRUGS WITH ADDITIVE TOXICITY:
  ├── NSAIDs → additive NEPHROTOXICITY ⚠️ (critical in orthopedics!)
  ├── Sirolimus → ↑ nephrotoxicity + hyperlipidemia (time-separate dosing required)
  ├── Tacrolimus → synergistic nephrotoxicity (avoid combination)
  └── Methotrexate → ↑ MTX levels; both levels must be monitored closely

CYCLOSPORINE AS INHIBITOR (inhibits CYP3A4 + P-glycoprotein):
  ├── ↑ prednisolone, digoxin, statins levels
  └── ↑ methotrexate levels

Orthopedic Alert: NSAIDs (commonly used post-surgery) combined with cyclosporine can cause additive nephrotoxicity. — Goodman & Gilman's, p. 794

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9. MONITORING

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10. CONTRAINDICATIONS & PRECAUTIONS

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11. PREVENTION & MANAGEMENT OF SIDE EFFECTS

SIDE EFFECT          PREVENTION / MANAGEMENT
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Nephrotoxicity    → Lowest effective dose; avoid NSAIDs/nephrotoxins;
                    monitor creatinine; biopsy if graft dysfunction
Hypertension      → ACE inhibitors or CCBs (amlodipine preferred);
                    avoid diltiazem/verapamil (↑ CsA levels)
Gingival hyperplasia → Good oral hygiene; consider switch to tacrolimus
Hirsutism         → Cosmetic management; switch to tacrolimus if severe
Hyperlipidemia    → Statins (monitor statin levels — CsA ↑ statin AUC);
                    pravastatin is preferred (less CYP3A4 interaction)
Hyperkalemia      → Low potassium diet; avoid K-sparing diuretics
Hyperuricemia     → Dose reduction; allopurinol (caution: ↑ CsA levels);
Tremor            → Dose reduction
Opportunistic     → PCP prophylaxis (TMP-SMX); antifungal prophylaxis
infections          in high-risk patients; CMV prophylaxis post-transplant
Malignancy risk   → Avoid prolonged high-dose use; sun protection;
                    annual skin surveillance

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12. IMMUNOSUPPRESSION DRUG CLASS COMPARISON TABLE

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13. SUMMARY FLOWCHART: Cyclosporine Use in Orthopedic/Rheumatologic Practice

PATIENT PRESENTS WITH INFLAMMATORY ARTHRITIS
(RA / Psoriatic Arthritis / Reactive Arthritis)
                  │
                  ▼
        First-line DMARDs attempted?
        (MTX, Sulfasalazine, Leflunomide)
                  │
          NO ─────┴───── YES
          │                │
     Start 1st-line     Adequate response?
      DMARD therapy       │
                    NO ───┴─── YES
                    │           │
                    ▼        Continue
           Consider CYCLOSPORINE
           (2.5–4 mg/kg/day PO ÷ 2 doses)
                    │
             Can combine with MTX
            (monitor BOTH drug levels)
                    │
                    ▼
          BASELINE ASSESSMENTS:
          BP, Creatinine, CBC, LFTs,
          Lipids, Uric acid, Urinalysis,
          CsA trough level
                    │
                    ▼
           ONGOING MONITORING (monthly)
                    │
          ┌─────────┴──────────┐
          │                    │
     Adequate           Inadequate response
      response           or intolerable
          │               side effects
          ▼                    │
     Continue at          ┌────┴─────┐
     lowest effective     │          │
      dose             Dose       Switch to
                      adjust    Tacrolimus or
                                Biologic DMARD

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Key Clinical Pearls for Orthopedic Surgeons

1. NSAIDs + CsA = additive nephrotoxicity — use with extreme caution perioperatively; prefer paracetamol/opioids post-op in transplant/RA patients on CsA
2. Perioperative CsA management: Do not abruptly stop; consult rheumatology/transplant team; IV conversion if patient cannot take oral
3. Wound healing: Unlike sirolimus/mTOR inhibitors, CsA does not directly impair wound healing, but immunosuppression increases infection risk
4. Infection risk: Screen for TB, hepatitis B/C before starting; fungal/bacterial prophylaxis is mandatory in post-transplant orthopedic cases
5. Gout flares: CsA causes hyperuricemia — manage with colchicine (caution: CsA ↑ colchicine levels → toxicity); avoid allopurinol without dose adjustment
6. Drug switching: Switching between formulations (Sandimmune ↔ Neoral) or generic substitution requires heightened monitoring

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• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 39 (Immunosuppression)
• Fitzpatrick's Dermatology, Chapter 192 (Calcineurin Inhibitors)
• Lippincott Illustrated Reviews: Pharmacology, Chapter 38 (Immunosuppressants)
• Harrison's Principles of Internal Medicine 22E, Chapter on Immunosuppressive Therapy
• Bailey & Love's Short Practice of Surgery 28E, Chapter 88–89 (Transplantation)
• American College of Rheumatology (ACR), updated February 2025
• GRAPPA guidelines for Psoriatic ArthritisThis covers everything requested. Here's a quick orientation to the sections:

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🔬 CYCLOSPORINE (Cyclosporin A / CsA) — Complete Clinical Reference

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SECTION 1 — CLASSIFICATION

Origin

Pharmacological Classification

IMMUNOSUPPRESSANT DRUGS
│
├── 1. CALCINEURIN INHIBITORS (CNIs) ◄─── CYCLOSPORINE is here
│      ├── Cyclosporine (binds CYCLOPHILIN)
│      └── Tacrolimus   (binds FKBP-12)
│
├── 2. mTOR INHIBITORS
│      ├── Sirolimus (Rapamycin)
│      └── Everolimus
│
├── 3. COSTIMULATION BLOCKERS
│      └── Belatacept
│
├── 4. ANTIPROLIFERATIVES / ANTIMETABOLITES
│      ├── Mycophenolate mofetil (MMF)
│      └── Azathioprine
│
└── 5. CORTICOSTEROIDS
       └── Prednisolone, Methylprednisolone

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SECTION 2 — MECHANISM OF ACTION

Visual Diagram (Fitzpatrick's Dermatology, Fig. 192-2):

Step-by-Step Molecular Cascade

NORMAL T-CELL ACTIVATION:
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
APC presents peptide (in MHC groove) to T-cell receptor
              ↓
    TCR + CD3 complex activation
              ↓
    Transmembrane signalling → ↑↑ intracellular Ca²⁺
              ↓
    Ca²⁺ binds CALMODULIN
              ↓
    Ca²⁺–Calmodulin activates CALCINEURIN
    (serine/threonine phosphatase: CnA catalytic + CnB regulatory subunits)
              ↓
    Calcineurin DEPHOSPHORYLATES cytoplasmic NFAT (NFATc)
              ↓
    NFATc translocates to NUCLEUS
              ↓
    NFATc + NFATn complex → binds cytokine gene promoters
              ↓
    TRANSCRIPTION: IL-2, IL-3, IL-4, TNF-α, IFN-γ, GM-CSF
              ↓
    T-cell ACTIVATION → PROLIFERATION → IMMUNE RESPONSE

━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
HOW CYCLOSPORINE BLOCKS THIS:
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
CsA (lipophilic) → freely diffuses into T-cell cytoplasm
              ↓
    Binds CYCLOPHILIN (immunophilin receptor, high affinity)
              ↓
    CsA–Cyclophilin complex → BINDS CALCINEURIN
              ↓
    CALCINEURIN IS INHIBITED (phosphatase activity blocked)
              ↓
    NFATc remains PHOSPHORYLATED → CANNOT enter nucleus
              ↓
    NO cytokine gene transcription
              ↓
    NO IL-2 production → T-cell NOT activated
              ↓
    IMMUNOSUPPRESSION achieved

"CsA inhibits T-cell activation mediated by antigens by blocking the downstream signalling cascade of the T-cell receptor, but it does not inhibit the early phases of T-lymphocyte signal transduction." — Fitzpatrick's Dermatology, p. 3550

Additional Immune Effects

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SECTION 3 — SITE OF ACTION AMONG IMMUNOSUPPRESSANTS

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SECTION 4 — FORMULATIONS & PHARMACOKINETICS (ADME)

Formulations

⚠️ Critical safety point: SANDIMMUNE and NEORAL are NOT bioequivalent and cannot be substituted without close monitoring. Inadvertent substitution can cause graft loss or toxicity. — Goodman & Gilman's, p. 793

Pharmacokinetics Summary

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SECTION 5 — DOSAGE

Therapeutic Drug Monitoring Targets

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SECTION 6 — THERAPEUTIC USES

6A — Transplantation

• Kidney, liver, heart transplant: cornerstone CNI immunosuppression in combination regimens
• Bone marrow / stem cell transplant: GVHD prophylaxis (combined with methotrexate — standard regimen)
• Initial dose delayed in renal transplant until threshold renal function attained

6B — Rheumatologic / Musculoskeletal Conditions

Rheumatoid Arthritis — the Inflammation Cascade CsA Targets:

6C — 🦴 Uses Specific to Orthopedics

TRANSPLANT PATIENT ON CYCLOSPORINE → ORTHOPEDIC SURGERY
                    │
    ┌───────────────┼───────────────┐
    │               │               │
 CONTINUE        MONITOR         AVOID
CsA throughout  blood levels    NSAIDs
 perioperative    daily         (additive
  period       perioperatively nephrotoxicity)
    │               │               │
 If NPO →      Adjust dose for    Use
  IV CsA        fluid dilution   paracetamol/
  (~1/3 oral)  and drug          opioids
               interactions    post-op

"Patients with organ transplants should be continued on immunosuppressant medications unless directed otherwise by transplant physician." — Froedtert Hospital Perioperative Medication Guidelines

"Clinically significant reductions of cyclosporine blood levels can be caused by dilution with massive fluid infusion perioperatively and cardiopulmonary bypass." — IARS Anesthesia & Analgesia

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SECTION 7 — SIDE EFFECTS

Master Adverse Effects Flowchart

CYCLOSPORINE ADVERSE EFFECTS
              │
    ┌─────────┼──────────────────────┐
    │         │                      │
RENAL    CARDIOVASCULAR          METABOLIC
    │         │                      │
Nephrotoxicity  Hypertension     ┌───┴────────────────────┐
(majority of    (~50% renal tx;  │ Hyperlipidemia (↑LDL)  │
 patients)      ~100% cardiac)   │ Hyperkalemia            │
    │                            │ Hyperuricemia → GOUT    │
 Acute:                          │ Hyperglycemia / DM      │
 renal vasoconstriction          │ Hypomagnesemia          │
 (reversible with                └────────────────────────┘
  dose reduction)
 Chronic:
 interstitial fibrosis
              │
    ┌─────────┼────────────────────────┐
    │         │                        │
COSMETIC  NEUROLOGICAL           ONCOLOGICAL
    │         │                        │
Hirsutism  Tremor (common)      ↑ Lymphoma risk
Gingival   Headache             Post-transplant
hyperplasia Paresthesias         lymphoproliferative
            Mental confusion     disorder (PTLD)
            Hallucinations       Skin malignancy
            Seizures (rare)      (SCC > BCC)
            PRES
              │
    ┌─────────┼─────────────┐
    │         │             │
INFECTIONS  GI           OTHER
    │         │             │
Opportunistic  Nausea     Pancreatitis
infections     Vomiting   Hepatotoxicity
(fungal,       Diarrhea   Dyspnea
bacterial,
viral — CMV)

Gingival Hyperplasia — Clinical Photographs

Comparison: Cyclosporine vs. Tacrolimus Side Effects

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SECTION 8 — DRUG INTERACTIONS

From Fitzpatrick's Dermatology (comprehensive table):

⚠️ Orthopedic Alert — NSAIDs + Cyclosporine: Additive nephrotoxicity. Commonly used post-op analgesics (diclofenac, naproxen, ketorolac) must be avoided or used with extreme caution in patients on cyclosporine. — Goodman & Gilman's, p. 794

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SECTION 9 — MONITORING

Monitoring Protocol Flowchart

INITIATE CYCLOSPORINE
         │
BASELINE ASSESSMENTS
─────────────────────────────────────────────
 • Blood pressure (both arms)
 • Serum creatinine + eGFR
 • Full blood count (CBC)
 • Liver function tests
 • Fasting lipid panel
 • Uric acid
 • Blood glucose / HbA1c
 • Urinalysis (proteinuria)
 • CsA baseline levels (trough C0 or C2)
 • Dermatologic exam (skin cancer baseline)
         │
FIRST 3 MONTHS (most intensive)
─────────────────────────────────────────────
 • BP: at each visit
 • Creatinine: every 2 weeks
 • CsA trough (C0): weekly → every 2 weeks
 • C2 if used: exactly 2 h after dose
 • CBC + LFTs: monthly
         │
MONTHS 3–12 (stable phase)
─────────────────────────────────────────────
 • BP + Creatinine: monthly
 • CsA trough: monthly
 • Lipids + uric acid: every 3–6 months
 • Annual skin surveillance (SCC risk)
         │
TARGETS / ACTION THRESHOLDS
─────────────────────────────────────────────
 • Creatinine rise >30% from baseline
   → REDUCE DOSE or STOP
 • BP >130/80 → Antihypertensive (amlodipine
   preferred; avoid diltiazem/verapamil)
 • eGFR declining trend → Consider switch
   to tacrolimus or non-CNI

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SECTION 10 — CONTRAINDICATIONS

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SECTION 11 — PREVENTION & MANAGEMENT OF SIDE EFFECTS

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SECTION 12 — MAINTENANCE IMMUNOSUPPRESSANT COMPARISON TABLE

Orthopedic Note on Sirolimus: Unlike cyclosporine, sirolimus significantly impairs wound healing — this is a critical distinction when managing post-surgical patients.

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SECTION 13 — CLINICAL DECISION FLOWCHART: Cyclosporine in Orthopedic / Rheumatologic Practice

PATIENT WITH INFLAMMATORY JOINT DISEASE
(RA / Psoriatic Arthritis / Reactive Arthritis)
                       │
                       ▼
       ┌───────────────────────────────┐
       │   STEP 1: FIRST-LINE DMARDs   │
       │ Methotrexate (MTX)            │
       │ Sulfasalazine                 │
       │ Hydroxychloroquine            │
       └───────────────┬───────────────┘
                       │
              Adequate response?
              YES ─────┴────── NO
               │                 │
          Continue            3–6 months
         & Monitor            inadequate
                                 │
                                 ▼
         ┌─────────────────────────────────────┐
         │  STEP 2: CONSIDER CYCLOSPORINE       │
         │  Indication:                         │
         │  • RA refractory to MTX              │
         │  • Severe psoriatic arthritis         │
         │  • Cannot use biologics              │
         │  Dose: 2.5–4 mg/kg/day PO ÷ 2       │
         └────────────────┬────────────────────┘
                          │
         Can add MTX to CsA? YES — monitor BOTH levels
                          │
            ┌─────────────▼────────────────────┐
            │   BASELINE ASSESSMENTS           │
            │ BP, Cr, eGFR, CBC, LFTs,         │
            │ Lipids, Uric acid, UA, CsA level  │
            └─────────────┬────────────────────┘
                          │
              Monitor q2 weeks × 3 months
              then monthly
                          │
               ┌──────────┴──────────┐
               │                     │
        Adequate response        Inadequate response
        & tolerable                or side effects
               │                     │
          Continue at           ┌────┴──────────────┐
          lowest effective      │                    │
           dose                Dose              Switch to:
                               adjust         • Tacrolimus
                                              • Biologic DMARD
                                                (TNF-i, IL-17-i)
                                              • JAK inhibitor

━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
PERIOPERATIVE PATHWAY (Orthopedic Surgery)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Patient on CsA → ELECTIVE ORTHO SURGERY
         │
         ├─ TRANSPLANT patient → CONTINUE CsA throughout
         │                       (consult transplant team)
         │
         ├─ RA/PsA patient (non-severe SLE) → CONTINUE CsA
         │                                    (ACR guidelines)
         │
         ├─ NPO perioperatively → SWITCH to IV CsA (~1/3 oral dose)
         │
         ├─ AVOID NSAIDs postoperatively (additive nephrotoxicity)
         │   → Use paracetamol, opioids, COX-2 (with caution)
         │
         ├─ Monitor CsA blood levels DAILY perioperatively
         │
         └─ Check for drug interactions with anesthetic agents
            and antibiotics used

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KEY CLINICAL PEARLS — Quick Reference

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References

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., Chapter 39
• Fitzpatrick's Dermatology, 9th ed., Chapter 192 (Calcineurin Inhibitors)
• Lippincott Illustrated Reviews: Pharmacology, 8th ed., Chapter 38
• Harrison's Principles of Internal Medicine, 22nd ed. (2025)
• Bailey & Love's Short Practice of Surgery, 28th ed., Chapters 88–89
• Sabiston Textbook of Surgery, 21st ed.
• National Kidney Foundation Primer on Kidney Diseases, 8th ed.
• ACR 2017 Guideline — Perioperative Management of Antirheumatic Medications
• ACR Patient Education — Cyclosporine (updated February 2025)
• GRAPPA Guidelines for Psoriatic Arthritis