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Antimetabolite Chemotherapy

Antimetabolite chemotherapy Chemotherapy Osteosarcoma agents belong to the cell-cycle–specific drugs, which act on a specific phase of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle. Cancer cells more rapidly divide (or cycle) than normal cells, making them an easy target for chemotherapy Chemotherapy Osteosarcoma. The different cell-cycle phases include G1, S, G2, and M. Antimetabolites target the S phase S Phase Phase of the cell cycle following g1 and preceding g2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. Cell Cycle, when DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication occurs, thus inhibiting DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR) of tumor Tumor Inflammation cells. In this group, the drugs include antifolates (which block folic acid activity, an essential component of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure precursors), pyrimidine and purine analogs (which interfere with the process of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)), and ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism inhibitors (which reduce production of deoxyribonucleotides Deoxyribonucleotides A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. DNA Types and Structure). Cell-cycle–specific chemotherapy Chemotherapy Osteosarcoma drugs cannot differentiate healthy from cancerous cells, thus adverse effects are seen. Myelosuppression Myelosuppression Oxazolidinones is a common finding during treatment.

Last updated: Oct 27, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Cell-cycle kinetics

  • The cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle is a process of cell growth and maturation with several phases. 
  • Different phases and associated events:
    • G1 phase G1 Phase The period of the cell cycle preceding DNA replication in s phase. Subphases of g1 include ‘competence’ (to respond to growth factors), g1a (entry into g1), g1b (progression), and g1c (assembly). Progression through the g1 subphases is effected by limiting growth factors, nutrients, or inhibitors. Cell Cycle: cell growth in preparation for DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication
    • S phase S Phase Phase of the cell cycle following g1 and preceding g2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. Cell Cycle: DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication
    • G2 phase G2 Phase The period of the cell cycle following DNA synthesis (S phase) and preceding m phase (cell division phase). The chromosomes are tetraploid in this point. Cell Cycle: further cell growth (e.g., replication of organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles) in preparation for mitosis Mitosis A type of cell nucleus division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. Cell Cycle 
    • M phase: duplicated DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure separated and distributed to 2 identical daughter cells
Antimetabolite chemotherapy agents

Phases of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle

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Chemotherapy Chemotherapy Osteosarcoma

  • The goal of chemotherapy Chemotherapy Osteosarcoma is to stop cell growth or destroy cancerous cells.
  • Log-kill hypothesis Hypothesis A hypothesis is a preliminary answer to a research question (i.e., a “guess” about what the results will be). There are 2 types of hypotheses: the null hypothesis and the alternative hypothesis. Statistical Tests and Data Representation: Chemotherapy Chemotherapy Osteosarcoma dose kills the same fraction of tumor Tumor Inflammation cells, regardless of the size of the tumor Tumor Inflammation.
  • Antimetabolite chemotherapy Chemotherapy Osteosarcoma agents are cell-cycle–specific drugs (act on a specific phase of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle):
    • Effective against cells cycling at a rapid rate (moving through the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle)
    • Analogs for the units of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure, which when incorporated, stop DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR).
    • Target the S phase S Phase Phase of the cell cycle following g1 and preceding g2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. Cell Cycle of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle → inhibit normal DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)

Antimetabolite classification

The subtypes of antimetabolite chemotherapy Chemotherapy Osteosarcoma agents are:

  • Antifolates (folic acid antagonists):
    • Methotrexate
    • Pemetrexed
    • Pralatrexate
  • Pyrimidine analogs:
    • Fluoropyrimidines:
      • 5-Fluorouracil
      • Capecitabine
    • Deoxynucleoside (deoxycytidine) analogs:
      • Cytarabine
      • Gemcitabine
  • Purine analogs:
    • Thiopurines:
      • 6-Mercaptopurine
      • 6-Thioguanine
    • Fludarabine
    • Cladribine
    • Pentostatin
  • Ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2′-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism inhibitors: hydroxyurea

Drug resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing

  • Primary resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing is the absence of response on 1st exposure by some cancers due to genomic instability.
  • Acquired resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
    • ↑ Expression of MDR1 (multidrug resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics), encoding a P glycoprotein in the cell surface, which causes efflux of the drug
    • ↑ Ability to repair DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure 
    • ↑ Activity of tumor Tumor Inflammation cell enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, which inactivate anticancer drugs
    • Change in the sensitivity of the target enzyme to the drug
    • ↓ Conversion of prodrugs by tumor Tumor Inflammation cell enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Expression of glutathione or glutathione-associated proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, which conjugate some drugs 

Antifolates

Antifolate agents

  • Antimetabolite chemotherapy Chemotherapy Osteosarcoma agents that block folic acid activity to inhibit cell division Cell Division A type of cell nucleus division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. Cell Cycle
  • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 or folic acid is essential in providing methyl groups for precursors of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure.
  • Medications in this drug class inhibit dihydrofolate reductase Dihydrofolate Reductase Sulfonamides and Trimethoprim, in general:
    • Methotrexate 
    • Pemetrexed
    • Pralatrexate 
    • Proguanil Proguanil A biguanide compound which metabolizes in the body to form cycloguanil, an anti-malaria agent. Antimalarial Drugs (antimalarial)
    • Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim (antibiotic/ antibacterial Antibacterial Penicillins)

Methotrexate (MTX)

  • Folic acid analog 
  • Mechanism of action:
    • Binds to dihydrofolate reductase Dihydrofolate Reductase Sulfonamides and Trimethoprim (DHFR) → inhibits the formation of tetrahydrofolate Tetrahydrofolate Sulfonamides and Trimethoprim (FH₄) → ↓ DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)
    • Folylpolyglutamate synthetase (FPGS) adds glutamyl residues to the molecule, making the molecule unable to cross cell membranes.
    • This mechanism of ion trapping permits prolonged retention of MTX in the cell.
  • Mechanism of resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
    • Altered DHFR (poor binding to MTX)
    • Impaired MTX transport into cells
    • ↓ Polyglutamation
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: oral, intrathecal, IV, IM routes of administration
    • Distribution: 50% plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products protein-bound
    • Metabolism and excretion: 90% unchanged and excreted in the urine (renal)
  • Indications:
    • Oncology uses:
      • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
      • ALL
      • Head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess cancer
      • Cutaneous T-cell lymphoma Cutaneous T-Cell Lymphoma Non-Hodgkin Lymphomas
      • Gestational trophoblastic neoplasia
      • Non-Hodgkin lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
      • Osteosarcoma Osteosarcoma Osteosarcoma is a primary malignant tumor of the bone characterized by the production of osteoid or immature bone by the tumor cells. The disease is most common in children and young adults and most frequently affects growth plates of the long bones, although it can involve any bone. Osteosarcoma
    • Nonneoplastic:
      • Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis
      • Psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
      • Juvenile idiopathic arthritis Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis (JIA), formerly known as juvenile rheumatoid arthritis, is a heterogeneous group of inflammatory diseases characterized by inflammation of 1 or more joints and is the most common pediatric rheumatic disease. Juvenile Idiopathic Arthritis
  • Adverse effects:
    • Myelosuppression Myelosuppression Oxazolidinones: anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, and thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Hepatotoxicity Hepatotoxicity Acetaminophen: ↑ liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Immunosuppression
    • GI: stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia 
    • Nephrotoxicity Nephrotoxicity Glycopeptides: crystal nephropathy and direct tubular toxicity Toxicity Dosage Calculation
    • Neurotoxicity
    • Pulmonary toxicity Toxicity Dosage Calculation: interstitial pneumonitis Pneumonitis Human Herpesvirus 6 and 7
    • Dermatologic: Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome ( SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome), erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme, toxic epidermal necrolysis Toxic Epidermal Necrolysis Stevens-Johnson Syndrome (TEN)
  • Precautions:
    • Use chemotherapy-modulating agent L-leucovorin, a folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 analog.
    • Counteract antifolate effects (rescue cells from toxicity Toxicity Dosage Calculation).
    • Initiate within 24–36 hours of starting MTX.
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation
    • Hypersensitivity to any antifolate drugs Antifolate Drugs Antimalarial Drugs
    • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care (as drug causes neural tube Neural tube A tube of ectodermal tissue in an embryo that will give rise to the central nervous system, including the spinal cord and the brain. Lumen within the neural tube is called neural canal which gives rise to the central canal of the spinal cord and the ventricles of the brain. Gastrulation and Neurulation and other birth defects due to ↓ folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12)
  • Drug interactions:
    • Salicylates and NSAIDs NSAIDS Primary vs Secondary Headaches: ↑ drug levels
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: Antifolates generally reduce the therapeutic effects of inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination.
    • Live vaccines (avoid): Antifolates enhance the toxic effects of live vaccines.

Pemetrexed

  • Mechanism of action:
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: IV route of administration
    • Distribution: 80% protein-bound
    • Metabolism and excretion: minimal metabolism and up to 90% excreted unchanged in urine (renal)
  • Indications (labeled):
    • Mesothelioma Mesothelioma Malignant mesothelioma (usually referred to as simply “mesothelioma”) is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Malignant Mesothelioma 
    • Non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer 
  • Adverse effects:
    • Myelosuppression Myelosuppression Oxazolidinones
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions rash Rash Rocky Mountain Spotted Fever
    • Nephrotoxicity Nephrotoxicity Glycopeptides
    • Pulmonary toxicity Toxicity Dosage Calculation
    • GI: nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis
  • Precautions: prophylactic folic acid and vitamin B12 to ↓ hematologic and GI toxicity Toxicity Dosage Calculation
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation: hypersensitivity to any antifolate drugs Antifolate Drugs Antimalarial Drugs
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Salicylates and NSAIDs NSAIDS Primary vs Secondary Headaches: ↑ drug levels
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: Antifolates generally reduce the therapeutic effects of inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination.
    • Live vaccines (avoid): Antifolates enhance the toxic effects of live vaccines.

Pralatrexate

  • Mechanism of action:
    • Inhibits DHFR
    • Selectively enters cells expressing ↓ reduced folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 carrier Carrier Vaccination (RFC-1)
    • Also polyglutamated by FPGS
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: IV route of administration
    • Distribution: 67% protein-bound
    • Metabolism and excretion: minimally metabolized, with approximately 34% excreted unchanged in the urine
  • Indication: peripheral T-cell lymphoma Peripheral T-cell lymphoma A group of malignant lymphomas thought to derive from peripheral T-lymphocytes in lymph nodes and other nonlymphoid sites. They include a broad spectrum of lymphocyte morphology, but in all instances express t-cell markers admixed with epithelioid histiocytes, plasma cells, and eosinophils. Although markedly similar to large-cell immunoblastic lymphoma, this group’s unique features warrant separate treatment. Autosomal Dominant Hyperimmunoglobulin E Syndrome (relapsed or refractory) 
  • Adverse effects:
    • Myelosuppression Myelosuppression Oxazolidinones: anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, leukopenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia 
    • GI: nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation: hypersensitivity to any antifolate drugs Antifolate Drugs Antimalarial Drugs
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Salicylates and NSAIDs NSAIDS Primary vs Secondary Headaches: ↑ drug levels
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: Antifolates generally reduce the therapeutic effects of inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination.
    • Live vaccines (avoid): Antifolates enhance the toxic effects of live vaccines.

Comparison of antifolate agents

Table: Comparison of antifolate agents
Agent Mechanism of action Labeled indications Adverse effects Additional considerations
Methotrexate Inhibit DHFR
  • ALL
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Gestational trophoblastic neoplasia
  • Head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess cancer
  • Non-Hodgkin lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
  • Cutaneous T-cell lymphoma Cutaneous T-Cell Lymphoma Non-Hodgkin Lymphomas
  • Osteosarcoma Osteosarcoma Osteosarcoma is a primary malignant tumor of the bone characterized by the production of osteoid or immature bone by the tumor cells. The disease is most common in children and young adults and most frequently affects growth plates of the long bones, although it can involve any bone. Osteosarcoma
Add leucovorin to rescue cells from toxicity Toxicity Dosage Calculation.
Pemetrexed Inhibit:
  • Thymidylate synthetase
  • DHFR
  • GARFT
  • AICARFT
  • NSCLC
  • Mesothelioma Mesothelioma Malignant mesothelioma (usually referred to as simply “mesothelioma”) is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Malignant Mesothelioma
Add vitamin B12 and folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 to ↓ toxicity Toxicity Dosage Calculation.
Pralatrexate
  • Inhibit DHFR
  • ↑ Affinity to RFC-1 (better transport)
  • ↑ FPGS (↑ cytotoxic Cytotoxic Parvovirus B19 metabolites)
Peripheral T-cell lymphoma Peripheral T-cell lymphoma A group of malignant lymphomas thought to derive from peripheral T-lymphocytes in lymph nodes and other nonlymphoid sites. They include a broad spectrum of lymphocyte morphology, but in all instances express t-cell markers admixed with epithelioid histiocytes, plasma cells, and eosinophils. Although markedly similar to large-cell immunoblastic lymphoma, this group’s unique features warrant separate treatment. Autosomal Dominant Hyperimmunoglobulin E Syndrome Add vitamin B12 and folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 to ↓ toxicity Toxicity Dosage Calculation
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer

Pyrimidine Analogs

Pyrimidine antimetabolites

  • Cytotoxic Cytotoxic Parvovirus B19 chemotherapy Chemotherapy Osteosarcoma agents that inhibit DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR) through the effects of precursor analogs entering tumor Tumor Inflammation cells.
  • Background:
    • 4 bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance that are precursors: 
      • 2 pyrimidines Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine; thymine; and uracil) and form the basic structure of the barbiturates. Nucleic Acids: cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids and thymine Thymine One of four constituent bases of DNA. Nucleic Acids (in RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure: uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids instead of thymine Thymine One of four constituent bases of DNA. Nucleic Acids)
      • 2 purines Purines A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. Nucleic Acids: guanine Guanine Nucleic Acids and adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids
    • Purines Purines A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. Nucleic Acids and pyrimidines Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine; thymine; and uracil) and form the basic structure of the barbiturates. Nucleic Acids can be synthesized de novo, but some precursors are taken up by cells from the bloodstream:
      • Some bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance ( uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids) enter the cells, so analogs (5-fluorouracil, capecitabine) can be substitutes for these bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance.
      • Other bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance ( cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids, thymine Thymine One of four constituent bases of DNA. Nucleic Acids) are transported into cells as deoxynucleosides (such as deoxycytidine).
      • As such, deoxycytidine analogs (cytarabine, gemcitabine) can compete with deoxycytidine and gain cell entry.
  • These pyrimidine antimetabolites are transported into the tumor Tumor Inflammation cells and become activated intracellularly.

5-Fluorouracil (5-FU)

  • Fluorinated pyrimidine/fluoropyrimidine
  • Mechanism of action:
    • 5-FU activated to fluoro-uridine monophosphate (F-UMP), which inhibits cell growth by replacing uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids in RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure.
    • Also converted to 5-fluorodeoxyuridine monophosphate (5-FdUMP) → 5-FdUMP binds to thymidylate synthase Thymidylate synthase An enzyme of the transferase class that catalyzes the reaction 5, 10-methylenetetrahydrofolate and dump to dihydrofolate and dtmp in the synthesis of thymidine triphosphate. Purine and Pyrimidine Metabolism (TS)
    • Inhibition of TS → deoxyuridine monophosphate (dUMP) cannot be converted to deoxythymidine monophosphate (dTMP) → ↓ DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and protein synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Mechanism of resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
    • ↓ Activity of activating enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes of 5-FU
    • Amplification or mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of TS
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: administered IV (poor oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption)
    • Distribution: well distributed throughout, including in CSF
    • Metabolism: hepatic
    • Excretion: renal 
  • Indications (labeled):
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
    • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
    • Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
    • Pancreatic cancer
  • Adverse effects:
    • Myelosuppression Myelosuppression Oxazolidinones
    • Cardiovascular toxicity Toxicity Dosage Calculation: angina, arrhythmia, cardiac failure Cardiac failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
    • Neurotoxicity: headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, confusion, disorientation Disorientation St. Louis Encephalitis Virus
    • Rash Rash Rocky Mountain Spotted Fever, SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, TEN
    • Hand-and-foot syndrome (painful, erythematous swelling Swelling Inflammation of the hands and feet)
    • Hyperammonemic encephalopathy Encephalopathy Hyper-IgM Syndrome
    • Stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis, anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Precautions: dihydropyrimidine dehydrogenase (DPD) deficiency
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation: hypersensitivity to 5-FU
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
    • Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants: ↑ risk of bleeding

Capecitabine

  • Prodrug Prodrug Nitroimidazoles of 5-FU
  • Mechanism of action: 5-FU prodrug Prodrug Nitroimidazoles that is hydrolyzed to 5-FU
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: reduced by food
    • Distribution: approximately 35% bound to albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests
    • Metabolism: hepatic and tissue metabolism
    • Excretion: renal 
  • Indications (labeled):
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer (metastatic)
    • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
  • Adverse effects:
    • Myelosuppression Myelosuppression Oxazolidinones
    • GI toxicity Toxicity Dosage Calculation:
      • Mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis
      • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea: may be dose-limiting because of severity 
    • Cardiotoxicity: ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage, arrhythmia, cardiac failure Cardiac failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
    • Hand-and-foot syndrome
    • Hepatotoxicity Hepatotoxicity Acetaminophen (↑ bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism)
    • Neurotoxicity:
      • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
      • Encephalopathy Encephalopathy Hyper-IgM Syndrome
      • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
      • Neuropathy Neuropathy Leprosy
  • Precautions: dihydropyrimidine dehydrogenase deficiency: 
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation: hypersensitivity to capecitabine
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
    • Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants: ↑ risk of bleeding 
Capecitabine_structure

Structure of capecitabine

Image by Lecturio.

Cytarabine

  • Cytarabine (also called cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids arabinoside (ara-C)) is a cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids base combined with an arabinose Arabinose Antimycobacterial Drugs sugar, instead of deoxyribose Deoxyribose Nucleic Acids.
  • Deoxycytidine analog
  • Mechanism of action:
    • In the cell, cytarabine → ara-cytidine monophosphate (ara-CMP) via deoxycytidine kinase (dCK) → ara-cytidine triphosphate (ara-CTP)
    • Ara-CTP is in competition with deoxy-CTP to be incorporated into DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure by DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase.
    • When ara-CTP is incorporated, termination of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure chain elongation Elongation Polymerase Chain Reaction (PCR) occurs. 
    • Cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle does not continue → DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure breaks → cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
  • Mechanism of resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
    • Loss of dCK 
    • Up-regulation Up-Regulation A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (gene expression regulation), mRNAs, and proteins. Pharmacokinetics and Pharmacodynamics of cytidine deaminase (CDA; converts ara-C to the nontoxic metabolite ara-uridine)
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
      • IV administration
      • With ↑ CDA in the GI tract, oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption is poor.
    • Distribution: readily enters cells, crosses blood– brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification barrier
    • Metabolism and excretion: 
      • Metabolized in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
      • Primarily renally excreted (90% as metabolite uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids arabinoside) 
  • Indications:
    • ALL
    • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
    • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
    • Meningeal leukemia
  • Adverse effects:
    • Main toxic effect: myelosuppression Myelosuppression Oxazolidinones ( neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, leukopenia)
    • Others:
      • GI: mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis
      • Hepatotoxicity Hepatotoxicity Acetaminophen: ↑ transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis
      • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome), headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, neurotoxicity
      • Cardiotoxicity: angina, pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis
      • Hyperuricemia Hyperuricemia Excessive uric acid or urate in blood as defined by its solubility in plasma at 37 degrees c; greater than 0. 42 mmol per liter (7. 0 mg/dl) in men or 0. 36 mmol per liter (6. 0 mg/dl) in women. Gout
      • Cytarabine syndrome (6–12 hours after administration): fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, rash Rash Rocky Mountain Spotted Fever, conjunctivitis Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis, malaise Malaise Tick-borne Encephalitis Virus
  • Precautions: dose adjustment in hepatic and renal impairment
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation: hypersensitivity to cytarabine
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Deoxycytidine and analogs

Deoxycytidine and analogs:
Gemcitabine (difluoro analog) and cytarabine ( cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids arabinoside)

Image: “Structural formulae of deoxycytidine, gemcitabine, cytarabine, troxacitabine and PMEA” by Godefridus J Peters, et al AL Amyloidosis. License: CC BY 4.0, cropped by Lecturio.

Gemcitabine

  • Difluoro analog of deoxycytidine
  • Mechanism of action:
    • Gemcitabine is phosphorylated by dCK into gemcitabine monophosphate → gemcitabine diphosphate → gemcitabine triphosphate
    • Gemcitabine diphosphate inhibits ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2′-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism (which converts ribonucleotides to deoxyribonucleotides Deoxyribonucleotides A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. DNA Types and Structure) → ↓ DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)
    • Gemcitabine triphosphate (structurally similar to deoxycytidine triphosphate) is incorporated into DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure.
    • Incorporation into DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase inhibited → cessation of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR) → cellular death
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: IV administration
    • Distribution: widely distributed, minimal protein binding
    • Metabolism: metabolized intracellularly (into diphosphates and triphosphates) by kinases Kinases Macrolides and Ketolides 
    • Excretion: renal (> 92%)
  • Indications (labeled):
    • Non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
    • Pancreatic cancer
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
    • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
  • Adverse effects:
    • Myelosuppression Myelosuppression Oxazolidinones
    • Capillary leak syndrome Capillary leak syndrome A condition characterized by recurring episodes of fluid leaking from capillaries into extravascular compartments causing hematocrit to rise precipitously. If not treated, generalized vascular leak can lead to generalized edema; shock; cardiovascular collapse; and multiple organ failure. Hematopoietic Growth Factors (potentially lethal sudden capillary hyperpermeability → edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, ↓ albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests)
    • GI: mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • Hepatotoxicity Hepatotoxicity Acetaminophen: ↑ transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis
    • Hemolytic uremic syndrome Hemolytic uremic syndrome A syndrome that is associated with microvascular diseases of the kidney, such as renal cortical necrosis. It is characterized by hemolytic anemia; thrombocytopenia; and acute renal failure. Hypocoagulable Conditions
    • Pulmonary toxicity Toxicity Dosage Calculation
  • Precautions: discontinue if severe renal or hepatic toxicity Toxicity Dosage Calculation occurs
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation: hypersensitivity to gemcitabine
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
    • Coadministration with anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants increases the risk of bleeding.

Comparison of pyrimidine analogs

Table: Comparison of pyrimidine analogs
Agent Mechanism of action Labeled indications Adverse effects Additional considerations
5-FU Inhibits thymidylate synthetase
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
  • Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
  • Pancreatic cancer
  • Myelosuppression Myelosuppression Oxazolidinones
  • CV CV Vasculitides toxicity Toxicity Dosage Calculation
  • Neurotoxicity
  • Rash Rash Rocky Mountain Spotted Fever
  • Hand-foot syndrome
  • Ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance
  • ↑ Bleeding with warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants
In DPD deficiency: ↑ toxicity Toxicity Dosage Calculation
Capecitabine Prodrug Prodrug Nitroimidazoles of 5-FU (inhibits thymidylate synthetase)
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
  • Myelosuppression Myelosuppression Oxazolidinones
  • CV CV Vasculitides toxicity Toxicity Dosage Calculation
  • Neurotoxicity
  • GI toxicity Toxicity Dosage Calculation
  • Hand-foot syndrome
  • ↑ Bleeding with warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants
In DPD deficiency: ↑ toxicity Toxicity Dosage Calculation
Cytarabine Inhibits DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase
  • ALL
  • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
  • Meningeal leukemia
  • Myelosuppression Myelosuppression Oxazolidinones
  • Ara-C syndrome
  • GI toxicity Toxicity Dosage Calculation
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis
  • Hyperuricemia Hyperuricemia Excessive uric acid or urate in blood as defined by its solubility in plasma at 37 degrees c; greater than 0. 42 mmol per liter (7. 0 mg/dl) in men or 0. 36 mmol per liter (6. 0 mg/dl) in women. Gout
Gemcitabine Inhibits DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase and ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2′-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism
  • NSCLC
  • Pancreatic cancer
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
  • Myelosuppression Myelosuppression Oxazolidinones
  • Capillary leak syndrome Capillary leak syndrome A condition characterized by recurring episodes of fluid leaking from capillaries into extravascular compartments causing hematocrit to rise precipitously. If not treated, generalized vascular leak can lead to generalized edema; shock; cardiovascular collapse; and multiple organ failure. Hematopoietic Growth Factors
  • HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome
  • Pulmonary toxicity Toxicity Dosage Calculation
  • ↑ Bleeding with warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants
5-FU: 5-fluorouracil
CV CV Vasculitides: cardiovascular
HUS HUS Hemolytic uremic syndrome (HUS) is a clinical phenomenon most commonly seen in children that consists of a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Hemolytic uremic syndrome is a major cause of acute kidney injury in children and is most commonly associated with a prodrome of diarrheal illness caused by shiga-like toxin-producing bacteria. Hemolytic Uremic Syndrome: hemolytic uremic syndrome Hemolytic uremic syndrome A syndrome that is associated with microvascular diseases of the kidney, such as renal cortical necrosis. It is characterized by hemolytic anemia; thrombocytopenia; and acute renal failure. Hypocoagulable Conditions
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer

Purine Analogs

Analogs of adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids or guanine Guanine Nucleic Acids

  • These antimetabolites interfere or compete with nucleoside triphosphates in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and/or RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Generally possess excellent activity against leukemias and lymphomas
  • Medication in this drug class:
    • Thiopurines (inhibit de novo purine synthesis Synthesis Polymerase Chain Reaction (PCR)): 
      • 6-Mercaptopurine (6-MP): antineoplastic and immunosuppressive agent
      • 6-Thioguanine
      • Azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants (immunosuppressant): undergoes nonenzymatic reduction into 6-MP 
    • Fludarabine
    • Cladribine

6-Mercaptopurine

  • Mechanism of action:
    • Metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) into a metabolite thioinosine monophosphate (TIMP).
    • TIMP:
      • Outcompetes purine derivatives
      • Because TIMP is a poor substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes for guanylyl kinase, it accumulates in the cell, inhibiting enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in the purine synthesis Synthesis Polymerase Chain Reaction (PCR).
      • Metabolized to the triphosphate form → incorporated into DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure
  • Mechanism of resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
    • Lack of HGPRT
    • Alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma activity
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
      • Oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption reduced by food and antibiotics.
      • Oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption improved by MTX.
      • IV dose half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: approximately 1 hour
    • Distribution: poor CNS distribution
    • Metabolism: 
      • Hepatic metabolism via xanthine oxidase Xanthine oxidase An iron-molybdenum flavoprotein containing flavin-adenine dinucleotide that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an autosomal recessive trait, causes xanthinuria. Purine and Pyrimidine Metabolism
      • Methylation Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. . Glucocorticoids by thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring
    • Excretion: renal
  • Indication: ALL
  • Adverse effects:
    • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis suppression Suppression Defense Mechanisms
    • Hepatotoxicity Hepatotoxicity Acetaminophen
    • Immunosuppression
    • Photosensitivity Photosensitivity Tetracyclines
    • Secondary malignancy Malignancy Hemothorax
    • Macrophage activation Macrophage activation The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (maf) and the macrophage migration-inhibitory factor (mmif), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. IL-12 Receptor Deficiency syndrome or hemophagocytic lymphohistiocytosis Hemophagocytic lymphohistiocytosis A group of related disorders characterized by lymphocytosis; histiocytosis; and hemophagocytosis. The two major forms are familial and reactive. Epstein-Barr Virus (↑ risk in autoimmune disorders)
  • Precautions: 
    • Oral doses of 6-MP should be reduced when receiving the xanthine oxidase Xanthine oxidase An iron-molybdenum flavoprotein containing flavin-adenine dinucleotide that oxidizes hypoxanthine, some other purines and pterins, and aldehydes. Deficiency of the enzyme, an autosomal recessive trait, causes xanthinuria. Purine and Pyrimidine Metabolism inhibitor allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs, which can ↑ 6-MP.
    • Consider testing for deficiency of TPMT and nudix hydrolase 15 (nucleotide diphosphatase (NUDT15)): ↑ risk for severe toxicity Toxicity Dosage Calculation 
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation: hypersensitivity to 6-MP
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
    • Allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs: ↑ 6-MP
    • MTX: ↑ 6-MP
    • ↓ Effect of warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants
Structure of 6-mercaptopurine

Structure of 6-mercaptopurine

Image: “Mercaptopurine” by Fvasconcellos. License: Public Domain

6-Thioguanine

  • Mechanism of action:
    • Analog of guanine Guanine Nucleic Acids
    • Incorporates in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure → inhibits synthesis Synthesis Polymerase Chain Reaction (PCR) of purine nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids
  • Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: approximately 30% ( variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables)
    • Distribution: does not reach significant levels in CSF
    • Metabolism: hepatic via TPMT
    • Excretion: renal
  • Indication: AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • Adverse effects:
    • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis suppression Suppression Defense Mechanisms
    • Hepatotoxicity Hepatotoxicity Acetaminophen
    • Secondary malignancy Malignancy Hemothorax
    • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
    • Photosensitivity Photosensitivity Tetracyclines
  • Precautions: consider testing for deficiency of TPMT and NUDT15: ↑ risk for severe toxicity Toxicity Dosage Calculation 
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation: hypersensitivity to 6-thioguanine
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of 6-thioguanine

Structure of 6-thioguanine

Image: “6-Thioguanin” by NEUROtiker. License: Public Domain

Fludarabine

  • Mechanism of action:
    • Dephosphorylated in the plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products → enters cells → rephosphorylated into the active triphosphate
    • Inhibits DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase, ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2′-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism, DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure primase, and DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure ligase I
    • When incorporated into DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure → chain termination
    • When incorporated into RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure → inhibition of RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure processing and translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: oral and IV
    • Distribution: peak concentration in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products within 1.5 hours (with oral administration) 
    • Metabolism: dephosphorylated in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products into the active metabolite, which enters the cells
    • Excretion: renal
  • Indications: CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
  • Adverse effects:
    • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis suppression Suppression Defense Mechanisms
    • Autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity
    • Neurotoxicity (confusion, agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures)
    • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
  • Precautions: dose adjustment in renal impairment
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation:
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions:
    • Pentostatin: pulmonary toxicity Toxicity Dosage Calculation
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of fludarabine

Structure of fludarabine

Image: “Fludarabine” by Yikrazuul. License: Public Domain

Cladribine

  • Mechanism of action:
    • Purine nucleoside analog 
    • Prodrug Prodrug Nitroimidazoles that is converted to cladribine adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate (Cd-ATP).
    • Incorporates into DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure strand breaks → inhibition of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR) and repair
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
      • Administered orally and IV
      • Oral administration delayed by food
    • Distribution: 
      • 20% protein-bound
      • Penetrates CSF
    • Metabolism: prodrug Prodrug Nitroimidazoles (intracellular kinases Kinases Macrolides and Ketolides phosphorylate the drug)
    • Excretion: renal
  • Indications (labeled): 
    • Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have “hair-like projections” visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
    • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • Adverse effects:
  • Precautions: dose adjustment in renal and hepatic impairment
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation:
    • Hypersensitivity to cladribine
    • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care (teratogenic)
  • Drug interactions:
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of cladribine

Structure of cladribine

Image: “Cladribine” by Yikrazuul. License: Public Domain

Pentostatin

  • 2′-deoxycoformycin
  • Analog of the intermediate in the adenosine deaminase Adenosine deaminase An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism ( ADA ADA An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism) reaction 
  • Mechanism of action:
    • Inhibits ADA ADA An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs not deaminated to inosine
    • Effects: ↑ intracellular adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs and deoxyadenosine nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids → block DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics:
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: IV administration
    • Distribution: approximately 4% protein-bound
    • Metabolism and excretion: eliminated via kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy 
  • Indication: hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have “hair-like projections” visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
  • Adverse effects:
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation:
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care considerations: based on drug action and animal studies, may cause fetal harm
  • Drug interactions: 
    • Fludarabine: pulmonary toxicity Toxicity Dosage Calculation
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of pentostatin

Structure of pentostatin

Image: “Pentostatin” by Fvasconcellos. License: Public Domain

Comparison of purine analogs

Table: Comparison of purine analogs
Agent Mechanism of action Labeled indications Adverse effects Additional considerations
6-MP Purine antagonist (inhibits purine nucleotide synthesis Synthesis Polymerase Chain Reaction (PCR)) ALL
  • Myelosuppression Myelosuppression Oxazolidinones
  • Immunosuppression
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Secondary malignancy Malignancy Hemothorax
  • Photosensitivity Photosensitivity Tetracyclines
  • MAS
  • ↓ Effect of warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants
↓ Dose if taking allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs
6-TG Purine antagonist AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
Fludarabine Inhibits:
  • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase
  • Ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2′-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism
  • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure primase
  • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure ligase I
CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
  • Myelosuppression Myelosuppression Oxazolidinones
  • Autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity
  • Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Neurotoxicity
Avoid pentostatin (↑ pulmonary toxicity Toxicity Dosage Calculation)
Cladribine Inhibits:
  • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR) (producing DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure strand breaks)
  • Ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2′-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism
Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have “hair-like projections” visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
Pentostatin Inhibits adenosine deaminase Adenosine deaminase An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Purine and Pyrimidine Metabolism (↓ DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)) Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have “hair-like projections” visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia Avoid fludarabine (↑ pulmonary toxicity Toxicity Dosage Calculation)
MAS: macrophage activation Macrophage activation The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (maf) and the macrophage migration-inhibitory factor (mmif), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. IL-12 Receptor Deficiency syndrome
6-TG: 6-thioguanine

Hydroxyurea

  • Also known as hydroxycarbamide
  • Hydroxylated analog of urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle
  • Used to treat solid tumors and myeloproliferative diseases
  • Mechanism of action:
    • Inhibition of the enzyme ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2′-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism ( RR RR Relative risk (RR) is the risk of a disease or condition occurring in a group or population with a particular exposure relative to a control (unexposed) group. Measures of Risk
    • RR RR Relative risk (RR) is the risk of a disease or condition occurring in a group or population with a particular exposure relative to a control (unexposed) group. Measures of Risk mediates conversion ribonucleotides to deoxyribonucleotides Deoxyribonucleotides A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. DNA Types and Structure ( DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure precursors)
    • ↓ Production of deoxyribonucleotides Deoxyribonucleotides A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. DNA Types and Structure → ↓ DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR) and cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle replication
    • S-phase–specific cytotoxic Cytotoxic Parvovirus B19 effect on cells
  • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
    • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: oral administration, absorbed rapidly
    • Distribution: wide distribution (including the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification)
    • Metabolism: liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy (60%), GI tract 
    • Excretion: renal
  • Indications (labeled):
    • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
    • Noncancer indication: sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease
  • Adverse effects:
    • Myelosuppression Myelosuppression Oxazolidinones
    • Secondary malignancy Malignancy Hemothorax
    • Cutaneous vasculitic toxicities (ulcerations and gangrene Gangrene Death and putrefaction of tissue usually due to a loss of blood supply. Small Bowel Obstruction)
    • Pulmonary toxicity Toxicity Dosage Calculation
    • Hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia
    • Macrocytosis
    • Bacterial and viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
    • Mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
  • Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation:
  • Drug interactions:
    • Antiretroviral drugs ( didanosine Didanosine A dideoxynucleoside compound in which the 3′-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. Didanosine is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA by binding to reverse transcriptase; ddi is then metabolized to dideoxyadenosine triphosphate, its putative active metabolite. Anti-HIV Drugs and stavudine Stavudine A dideoxynucleoside analog that inhibits reverse transcriptase and has in vitro activity against HIV. Anti-HIV Drugs): pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis, peripheral neuropathy Neuropathy Leprosy, hepatotoxicity Hepatotoxicity Acetaminophen
    • Inactivated vaccines Inactivated vaccines Vaccines in which the infectious microbial nucleic acid components have been destroyed by chemical or physical treatment (e.g., formalin, beta-propiolactone, gamma radiation) without affecting the antigenicity or immunogenicity of the viral coat or bacterial outer membrane proteins. Vaccination: ↓ efficacy of vaccines 
    • Live vaccines: ↑ toxic effects of vaccines
Structure of hydroxyurea

Structure of hydroxyurea

Image: “Hydroxyurea-2D-skeletal” by Chem Sim 2001. License: Public Domain

Comparison with Other Chemotherapeutic Agents

Table: Comparison of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle dependent chemotherapy Chemotherapy Osteosarcoma drugs
Drug class Cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle phase affected Mechanism of action
Antifolates Cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle arrest at S phase S Phase Phase of the cell cycle following g1 and preceding g2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. Cell Cycle Inhibit:
Fluoropyrimidines Cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle arrest at S phase S Phase Phase of the cell cycle following g1 and preceding g2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. Cell Cycle Inhibit thymidylate synthase Thymidylate synthase An enzyme of the transferase class that catalyzes the reaction 5, 10-methylenetetrahydrofolate and dump to dihydrofolate and dtmp in the synthesis of thymidine triphosphate. Purine and Pyrimidine Metabolism
Deoxycytidine analogs Cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle arrest at S phase S Phase Phase of the cell cycle following g1 and preceding g2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. Cell Cycle Inhibit:
  • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure polymerase
  • Ribonucleotide reductase Ribonucleotide reductase An enzyme of the oxidoreductase class that catalyzes the formation of 2′-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. Purine and Pyrimidine Metabolism
Purine analogs Cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle arrest at S phase S Phase Phase of the cell cycle following g1 and preceding g2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. Cell Cycle Inhibition of de novo purine synthesis Synthesis Polymerase Chain Reaction (PCR)
Topoisomerase II inhibitors Topoisomerase II Inhibitors Compounds that inhibit the activity of DNA topoisomerase II. Included in this category are a variety of antineoplastic agents which target the eukaryotic form of topoisomerase II and antibacterial agents which target the prokaryotic form of topoisomerase II. Microtubule and Topoisomerase Inhibitors Cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle arrest at S and G2 phases Inhibit topoisomerase II Topoisomerase II DNA topoisomerases that catalyze ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. These enzymes bring about relaxation of the supercoiled DNA and resolution of a knotted circular DNA duplex. Fluoroquinolones
Taxanes Taxanes A group of diterpenoid cyclodecanes named for the taxanes that were discovered in the taxus tree. The action on microtubules has made some of them useful as antineoplastic agents. Microtubule and Topoisomerase Inhibitors Cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle arrest at metaphase Metaphase The phase of cell nucleus division following prometaphase, in which the chromosomes line up across the equatorial plane of the spindle apparatus prior to separation. Cell Cycle of the M phase Hyper-stabilization of microtubules Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin and are influenced by tubulin modulators. The Cell: Cytosol and Cytoskeleton
Vinca alkaloids Vinca Alkaloids A group of indole-indoline dimers which are alkaloids obtained from the vinca genus of plants. They inhibit polymerization of tubulin into microtubules thus blocking spindle formation and arresting cells in metaphase. They are some of the most useful antineoplastic agents. Microtubule and Topoisomerase Inhibitors Cell arrest during metaphase Metaphase The phase of cell nucleus division following prometaphase, in which the chromosomes line up across the equatorial plane of the spindle apparatus prior to separation. Cell Cycle of the M phase Binds to beta-tubulin and prevents microtubule polymerization
Chemotherapy comparison

Various chemotherapy Chemotherapy Osteosarcoma drugs and their effects on the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle

Image by Lecturio.

References

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