List the drug that can cause bone marrow suppression
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I now have comprehensive data from Harrison's, Lippincott, Goodman & Gilman, and Kaplan & Sadock. Here is the full, organized answer:
Drugs That Can Cause Bone Marrow Suppression (Myelosuppression)
Bone marrow suppression (myelosuppression) results in decreased production of red cells, white cells, and/or platelets. Drugs cause it either by predictable, dose-dependent mechanisms or by idiosyncratic reactions.
1. Cytotoxic / Chemotherapy Agents (Dose-dependent - Affect ALL recipients)
These are the most potent and reliable causes of myelosuppression. Maximal neutropenia typically occurs 6-14 days after dosing.
Alkylating Agents
| Drug | Notes |
|---|---|
| Cyclophosphamide | Myelosuppression + hemorrhagic cystitis |
| Chlorambucil | Leukemia risk with prolonged use |
| Busulfan | Used in bone marrow conditioning; profound suppression |
| Nitrogen mustard (mechlorethamine) | One of the first chemotherapy agents |
| Melphalan | Used in multiple myeloma |
| Procarbazine | Delayed marrow toxicity (~6 weeks after dosing) |
Nitrosoureas (Delayed Toxicity ~6 weeks)
| Drug |
|---|
| Carmustine (BCNU) |
| Lomustine (CCNU) |
| Streptozocin |
Antimetabolites
| Drug | Notes |
|---|---|
| Methotrexate | Antifolate; leucovorin rescue used |
| 6-Mercaptopurine (6-MP) | Thiopurine; TPMT deficiency increases risk |
| 5-Fluorouracil (5-FU) | |
| Cytarabine (Ara-C) | Profound; used in AML |
| Gemcitabine | |
| Fludarabine | |
| Nelarabine | T-cell leukemia/lymphoma |
| Flucytosine (5-FC) | Antifungal - converted to 5-FU by gut bacteria |
| Cladribine | |
| Pentostatin |
Anthracyclines / Antitumor Antibiotics
| Drug |
|---|
| Doxorubicin |
| Daunorubicin |
| Idarubicin |
| Epirubicin |
| Bleomycin (less common) |
| Mitomycin C |
Topoisomerase Inhibitors
| Drug | Notes |
|---|---|
| Irinotecan | Myelosuppression + severe diarrhea |
| Topotecan | Second-line for CNS lymphoma |
| Etoposide (VP-16) | |
| Teniposide (VM-26) |
Vinca Alkaloids & Taxanes
| Drug |
|---|
| Vincristine (less myelosuppressive than others) |
| Vinblastine |
| Paclitaxel |
| Docetaxel |
Alkylating-like Agents
| Drug | Notes |
|---|---|
| DTIC (dacarbazine) | Delayed marrow toxicity |
| Temozolomide | Delayed marrow toxicity; used in brain tumors |
2. Immunosuppressants
| Drug | Mechanism / Notes |
|---|---|
| Azathioprine | Thiopurine; bone marrow suppression + hepatotoxicity; risk increased in TPMT-deficient patients |
| Mycophenolate mofetil | Suppresses lymphocyte proliferation; marrow suppression + GI intolerance |
| Methotrexate (low-dose) | Used in RA/psoriasis; dose-dependent marrow toxicity |
| Cyclophosphamide | Also used as immunosuppressant |
| Tacrolimus / Sirolimus | Less direct, but monitor CBC |
| Leflunomide | Pancytopenia risk |
3. Antibiotics
| Drug | Mechanism |
|---|---|
| Chloramphenicol | Classic cause - two mechanisms: (1) reversible dose-dependent suppression; (2) irreversible idiosyncratic aplastic anemia (1:25,000-40,000 exposures) |
| Sulfonamides (trimethoprim-sulfamethoxazole) | Antifolate mechanism; neutropenia and thrombocytopenia |
| Penicillins (high-dose) | Rare; idiosyncratic |
| Linezolid | Thrombocytopenia most common; onset 7-10 days; reversible on stopping |
| Ganciclovir / Valganciclovir | Significant neutropenia in transplant patients |
| Zidovudine (AZT) and other NRTIs | Macrocytic anemia, neutropenia; common in HIV treatment |
| Dapsone | Hemolytic anemia + methemoglobinemia |
4. Anticonvulsants
| Drug | Notes |
|---|---|
| Carbamazepine | One of the most important causes; agranulocytosis + aplastic anemia; do NOT combine with clozapine |
| Phenytoin (hydantoins) | Idiosyncratic agranulocytosis |
| Valproic acid | Thrombocytopenia; dose-related |
| Phenobarbital | Rare |
| Felbamate | Aplastic anemia - prominent black box warning |
| Phenacemide | |
| Stiripentol | Transient aplastic anemia/leukopenia reported |
5. Antipsychotics
| Drug | Notes |
|---|---|
| Clozapine | Most important cause - agranulocytosis in ~1-2% of patients; mandatory weekly/biweekly CBC monitoring (REMS program); contraindicated with carbamazepine |
| Phenothiazines (e.g., chlorpromazine) | Less common; idiosyncratic |
6. Anti-inflammatory / Analgesic Agents
| Drug | Notes |
|---|---|
| Phenylbutazone | High-risk; aplastic anemia and agranulocytosis; largely withdrawn |
| Indomethacin | |
| Ibuprofen | Rare idiosyncratic |
| Sulindac | |
| Aspirin | Rare |
| Gold salts | Used in RA; aplastic anemia/agranulocytosis risk |
| Penicillamine | Agranulocytosis + thrombocytopenia |
7. Antithyroid Drugs
| Drug | Notes |
|---|---|
| Propylthiouracil (PTU) | Agranulocytosis (most serious ADR) |
| Methimazole | Agranulocytosis; dose-related at high doses |
| Methylthiouracil |
8. Other Drug Categories
| Drug / Category | Notes |
|---|---|
| Allopurinol | Associated with aplastic anemia (rare) |
| Acetazolamide / Methazolamide | Carbonic anhydrase inhibitors; sulfonamide-related |
| Cimetidine, chlorpheniramine | Antihistamines; rare aplastic anemia |
| Captopril (and some other ACE inhibitors) | Agranulocytosis (rare) |
| Quinacrine, chloroquine, mepacrine | Antiprotozoals |
| Ticlopidine | Thrombotic thrombocytopenic purpura (TTP) + neutropenia |
| Linezolid | Thrombocytopenia (mentioned above) |
| Heavy metals: gold, arsenic, bismuth, mercury | |
| Estrogens (high-dose) | Suppression of erythropoiesis |
| Interferon-alpha | Significant cytopenias |
Summary by Cell Line Affected
| Cell Line | Key Culprit Drugs |
|---|---|
| Granulocytes (agranulocytosis) | Clozapine, carbamazepine, chloramphenicol, PTU, methimazole, phenylbutazone, penicillamine, gold |
| Platelets (thrombocytopenia) | Linezolid, valproate, heparin (HIT), quinine, thiazides, alcohol |
| Red cells (aplasia) | Chloramphenicol (aplastic anemia), parvovirus-related drugs, felbamate |
| All cell lines (pancytopenia) | Cytotoxics, azathioprine, methotrexate, chloramphenicol (idiosyncratic) |
Key clinical pearl: Myelosuppression from cytotoxic agents is dose-dependent and expected (all patients), while drug-induced aplastic anemia from agents like chloramphenicol, carbamazepine, and felbamate is idiosyncratic (rare, unpredictable, not dose-related).
- Harrison's Principles of Internal Medicine 22E, Decreased Production section & Table 107-3 (Aplastic Anemia Etiologies)
- Lippincott Illustrated Reviews: Pharmacology, Alkylating Agents & Topoisomerase Inhibitors tables
- Goodman & Gilman's Pharmacological Basis of Therapeutics, Myelosuppression section
- Kaplan & Sadock's Synopsis of Psychiatry, Clozapine section
List the antibiotics that can cause bone marrow suppression
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Excellent data from multiple authoritative textbooks. Here is the comprehensive, well-organized answer:
Antibiotics That Can Cause Bone Marrow Suppression
Antibiotics cause bone marrow suppression (myelosuppression) through several mechanisms: direct cytotoxic effects on marrow precursors, antifolate activity, mitochondrial toxicity, or idiosyncratic immune-mediated destruction.
1. Chloramphenicol - THE Classic Antibiotic Cause
This is the most notorious antibiotic for bone marrow suppression. It causes toxicity by two distinct mechanisms:
| Mechanism | Type | Features |
|---|---|---|
| Dose-related reversible suppression | Predictable | Inhibits mitochondrial protein synthesis in erythroid precursors, impairing iron incorporation into heme; occurs when plasma levels ≥25 μg/mL; reverses on stopping |
| Idiosyncratic aplastic anemia | Unpredictable | ~1 in 30,000 courses; unrelated to dose; often fatal pancytopenia; irreversible; increased risk of acute leukemia in survivors |
- Aplastic anemia = 70% of all blood dyscrasias from chloramphenicol
- Remainder: hypoplastic anemia, agranulocytosis, thrombocytopenia
- Proposed mechanism: conversion of the nitro group to a toxic intermediate by intestinal bacteria
- Applies to ALL routes of administration (including topical eye drops in predisposed individuals)
2. Linezolid (Oxazolidinone)
- Causes myelosuppression including anemia, leukopenia, pancytopenia, and thrombocytopenia
- Thrombocytopenia is the most common effect, onset 7-10 days into therapy
- Risk increases significantly with therapy ≥2 weeks
- Mechanism: inhibits mitochondrial protein synthesis (similar to chloramphenicol, as both target the 50S ribosomal subunit)
- Reversible on drug discontinuation
- Weekly CBC monitoring mandatory for courses >2 weeks
- Also causes peripheral and optic neuropathy with prolonged use
- Same class: Tedizolid (similar risk, slightly lower)
3. Trimethoprim-Sulfamethoxazole (TMP-SMX / Co-trimoxazole)
- Both components are antifolates - they block folate synthesis/utilization needed for DNA synthesis in marrow precursors
- Causes: megaloblastic anemia, neutropenia, thrombocytopenia
- Risk is highest in patients already folate-deficient (alcoholics, malnourished, elderly)
- Particularly significant in HIV-positive patients on TMP-SMX prophylaxis
- Drug-induced autoimmune neutropenia (hapten mechanism via sulfonamide component)
- Leucovorin (folinic acid) can partially counteract the myelosuppression
4. Flucytosine (5-FC) - Antifungal Antibiotic
- Converted intracellularly (and by gut bacteria) to 5-fluorouracil (5-FU), which directly suppresses bone marrow
- Causes: neutropenia and thrombocytopenia
- Dose-related and reversible when serum concentrations kept <100 μg/mL
- Serum level monitoring is mandatory to avoid toxicity
- Risk is amplified when combined with amphotericin B (which impairs renal excretion of flucytosine, raising its levels)
- Used for cryptococcal meningitis; always combined with amphotericin B (never monotherapy - rapid resistance develops)
5. Ganciclovir / Valganciclovir (Antiviral Antibiotics)
- Most common dose-limiting toxicity is bone marrow suppression
- Causes: neutropenia (up to 50% of IV ganciclovir patients) and thrombocytopenia
- Neutropenia can be severe (Grade 3/4) requiring dose adjustment or drug discontinuation
- Valganciclovir (oral prodrug) carries the same risk
- G-CSF (filgrastim) can be used to treat ganciclovir-induced neutropenia
- Additive myelosuppression with zidovudine (AZT) - combination should be used with extreme caution
6. Zidovudine (AZT) and Other NRTIs
| Drug | Effect |
|---|---|
| Zidovudine (AZT) | Macrocytic anemia + neutropenia; inhibits mitochondrial DNA polymerase-γ in erythroid precursors; dose-dependent |
| Stavudine (d4T) | Anemia (less common) |
| Didanosine (ddI) | Rare myelosuppression |
- Mechanism: incorporate into mitochondrial DNA of hematopoietic cells, impairing replication
- Risk is greatly increased when AZT is combined with ganciclovir
7. Pyrimethamine (Antiparasitic Antibiotic)
- Dihydrofolate reductase (DHFR) inhibitor - antifolate mechanism
- Causes bone marrow suppression (megaloblastic anemia, leukopenia, thrombocytopenia)
- Leucovorin (folinic acid) 10-20 mg/day is always given concurrently to prevent marrow toxicity
- Used for toxoplasmosis (with sulfadiazine) and malaria (Fansidar = pyrimethamine + sulfadoxine)
- Risk is compounded when combined with sulfonamides (double antifolate effect)
8. Dapsone
- Used for leprosy, PCP prophylaxis, dermatitis herpetiformis
- Can cause agranulocytosis and bone marrow failure as part of DDS syndrome (dapsone hypersensitivity syndrome)
- DDS syndrome fatality rate: ~10% (death from liver failure, sepsis, bone marrow failure)
- Also causes hemolytic anemia (especially in G6PD-deficient patients) - not strictly marrow suppression but relevant hematotoxicity
- Dapsone must be stopped immediately if agranulocytosis develops
9. Sulfonamides (as a class)
- Idiosyncratic aplastic anemia and agranulocytosis
- Also cause drug-induced autoimmune neutropenia (hapten mechanism)
- Examples: sulfadiazine, sulfamethoxazole, sulfasalazine
- Risk identified in large European epidemiological studies as one of the top causes of drug-associated aplastic anemia
10. Other Antibiotics with Lower / Rarer Risk
| Drug | Effect |
|---|---|
| Penicillins (high-dose) | Idiosyncratic neutropenia (rare); hapten-mediated |
| Vancomycin | Neutropenia with prolonged use |
| Cephalosporins | Very rare idiosyncratic neutropenia |
| Metronidazole | Rare leukopenia with prolonged use |
| Isoniazid (INH) | Rare agranulocytosis |
| Rifampicin | Thrombocytopenia (immune-mediated); rare aplasia |
| Amphotericin B | Normocytic anemia (suppresses erythropoietin production); not direct marrow suppression |
Quick Reference Summary
| Antibiotic | Cell Line Mainly Affected | Mechanism | Reversibility |
|---|---|---|---|
| Chloramphenicol | All (pancytopenia) | Mitochondrial protein synthesis inhibition; idiosyncratic toxic intermediate | Dose-related: reversible; Idiosyncratic: often irreversible |
| Linezolid | Platelets > all | Mitochondrial toxicity (50S inhibitor) | Reversible |
| TMP-SMX | Neutrophils, RBCs | Antifolate | Reversible |
| Flucytosine | Neutrophils, platelets | 5-FU metabolite | Reversible (dose-related) |
| Ganciclovir/Valganciclovir | Neutrophils > platelets | Direct marrow toxicity | Partially reversible; G-CSF helps |
| Zidovudine (AZT) | RBCs, neutrophils | Mitochondrial DNA polymerase inhibition | Reversible |
| Pyrimethamine | All (megaloblastic) | DHFR inhibition (antifolate) | Reversible with leucovorin |
| Dapsone | Neutrophils (agranulocytosis) | Idiosyncratic (DDS syndrome) | Requires drug withdrawal |
| Sulfonamides | All (aplastic anemia) | Idiosyncratic | Variable; often fatal if complete aplasia |
Sources:
- Goodman & Gilman's Pharmacological Basis of Therapeutics - Chloramphenicol: Hematological Toxicity; Linezolid: Myelosuppression
- Harrison's Principles of Internal Medicine 22E - Oxazolidinones; Flucytosine; Leprosy Treatment; Aplastic Anemia Etiology (Table 107-3)
- Fishman's Pulmonary Diseases and Disorders - Causes of Neutropenia (Table)
- Goldman-Cecil Medicine - Ganciclovir/Valganciclovir Toxicity
- Katzung's Basic and Clinical Pharmacology 16E - Chloramphenicol Adverse Reactions
- Washington Manual of Medical Therapeutics - Linezolid; Pyrimethamine
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