1. Alkylating agents are a class of anticancer drugs that work by introducing alkyl groups onto DNA, interfering with DNA separation and cell division. Common alkylating agents include nitrogen mustards, cyclophosphamide, ifosfamide, busulfan, nitrosoureas, thiotepa, and procarbazine.
2. These drugs are metabolized in the liver and form reactive metabolites that alkylate guanine bases in DNA, forming crosslinks that prevent cell division. Many require metabolic activation and have toxic metabolites that can cause side effects like hemorrhagic cystitis.
3. Co-administration of drugs like mesna and sodium thiosulfate can help detoxify toxic
This document provides an overview of anti-cancer drugs, beginning with an introduction to cancer and statistics on cancer cases in Iraq. It then discusses the classification of anti-cancer drugs according to their chemical structure and mechanisms of action. Specifically, it covers alkylating agents including nitrogen mustards, alkyl sulphonates, nitrosoureas, and aziridines. It provides details on the structures, mechanisms of action, uses, and side effects of common alkylating agents like cyclophosphamide, ifosfamide, busulfan, carmustine, and thiotepa. The document focuses on describing the chemical properties and metabolic pathways that allow these drugs to damage cancer cell DNA and induce cell death.
This document discusses several alkylating agents used to treat cancer: cyclophosphamide, melphalan, chlorambucil, busulfan, and thiotepa. It describes the structures, mechanisms of action, structure-activity relationships, and therapeutic uses of each drug. The key mechanisms involve alkylation of DNA at guanine residues, which causes cross-linking between strands and inhibits processes like replication and transcription, ultimately leading to cell death. The aromatic, chloroethyl, and amino groups influence stability, distribution, and oral availability of the drugs. Collectively, these alkylating agents are used to treat hematological and solid tumors.
Platinum drugs like cisplatin, carboplatin, and oxaliplatin have been used successfully to treat cancers for decades. They work by binding to and damaging DNA, which kills tumor cells. Cisplatin was the first such drug developed but caused severe side effects. This led researchers to develop analogs with improved tolerability profiles. Carboplatin and oxaliplatin were created and are now also approved for use, with carboplatin having less kidney toxicity and oxaliplatin showing activity against cisplatin-resistant cancers. Ongoing research focuses on developing newer platinum complexes and drug delivery methods to expand use and reduce side effects.
The document discusses various chemotherapeutic agents used to treat cancer and other conditions. It defines key terms related to chemotherapy and describes the mechanisms of action, uses, and toxicities of different classes of cytotoxic drugs including alkylating agents, antimetabolites, anti-mitotic agents, antibiotics, and enzymes. Common drug regimens and chemotherapy strategies such as combination, neoadjuvant, adjuvant, and maintenance chemotherapy are also outlined.
Cancer occurs due to genetic changes in cells that lead to uncontrolled growth. Anticancer drugs target features of cancer cells, including their DNA, to interfere with cell division and cause cell death. The main classes of anticancer drugs are alkylating agents, antimetabolites, antibiotics, and plant alkaloids. Alkylating agents like cyclophosphamide cause DNA damage. Antimetabolites like methotrexate interfere with DNA synthesis. Antibiotics such as doxorubicin intercalate DNA. Side effects depend on the drug but can include suppression of the immune system and damage to organs.
This document provides information on various types of antineoplastic (anti-cancer) agents, including their mechanisms of action and pharmacological properties. It discusses alkylating agents such as cyclophosphamide and cisplatin, which damage DNA and prevent cell replication. It also covers antimetabolites that interfere with nucleic acid synthesis, including methotrexate which inhibits dihydrofolate reductase, and 5-fluorouracil which inhibits thymidylate synthetase. The document provides details on the classification, mechanisms, uses and side effects of different classes of antineoplastic agents.
1. Alkylating agents are a class of anticancer drugs that work by introducing alkyl groups onto DNA, interfering with DNA separation and cell division. Common alkylating agents include nitrogen mustards, cyclophosphamide, ifosfamide, busulfan, nitrosoureas, thiotepa, and procarbazine.
2. These drugs are metabolized in the liver and form reactive metabolites that alkylate guanine bases in DNA, forming crosslinks that prevent cell division. Many require metabolic activation and have toxic metabolites that can cause side effects like hemorrhagic cystitis.
3. Co-administration of drugs like mesna and sodium thiosulfate can help detoxify toxic
This document provides an overview of anti-cancer drugs, beginning with an introduction to cancer and statistics on cancer cases in Iraq. It then discusses the classification of anti-cancer drugs according to their chemical structure and mechanisms of action. Specifically, it covers alkylating agents including nitrogen mustards, alkyl sulphonates, nitrosoureas, and aziridines. It provides details on the structures, mechanisms of action, uses, and side effects of common alkylating agents like cyclophosphamide, ifosfamide, busulfan, carmustine, and thiotepa. The document focuses on describing the chemical properties and metabolic pathways that allow these drugs to damage cancer cell DNA and induce cell death.
This document discusses several alkylating agents used to treat cancer: cyclophosphamide, melphalan, chlorambucil, busulfan, and thiotepa. It describes the structures, mechanisms of action, structure-activity relationships, and therapeutic uses of each drug. The key mechanisms involve alkylation of DNA at guanine residues, which causes cross-linking between strands and inhibits processes like replication and transcription, ultimately leading to cell death. The aromatic, chloroethyl, and amino groups influence stability, distribution, and oral availability of the drugs. Collectively, these alkylating agents are used to treat hematological and solid tumors.
Platinum drugs like cisplatin, carboplatin, and oxaliplatin have been used successfully to treat cancers for decades. They work by binding to and damaging DNA, which kills tumor cells. Cisplatin was the first such drug developed but caused severe side effects. This led researchers to develop analogs with improved tolerability profiles. Carboplatin and oxaliplatin were created and are now also approved for use, with carboplatin having less kidney toxicity and oxaliplatin showing activity against cisplatin-resistant cancers. Ongoing research focuses on developing newer platinum complexes and drug delivery methods to expand use and reduce side effects.
The document discusses various chemotherapeutic agents used to treat cancer and other conditions. It defines key terms related to chemotherapy and describes the mechanisms of action, uses, and toxicities of different classes of cytotoxic drugs including alkylating agents, antimetabolites, anti-mitotic agents, antibiotics, and enzymes. Common drug regimens and chemotherapy strategies such as combination, neoadjuvant, adjuvant, and maintenance chemotherapy are also outlined.
Cancer occurs due to genetic changes in cells that lead to uncontrolled growth. Anticancer drugs target features of cancer cells, including their DNA, to interfere with cell division and cause cell death. The main classes of anticancer drugs are alkylating agents, antimetabolites, antibiotics, and plant alkaloids. Alkylating agents like cyclophosphamide cause DNA damage. Antimetabolites like methotrexate interfere with DNA synthesis. Antibiotics such as doxorubicin intercalate DNA. Side effects depend on the drug but can include suppression of the immune system and damage to organs.
This document provides information on various types of antineoplastic (anti-cancer) agents, including their mechanisms of action and pharmacological properties. It discusses alkylating agents such as cyclophosphamide and cisplatin, which damage DNA and prevent cell replication. It also covers antimetabolites that interfere with nucleic acid synthesis, including methotrexate which inhibits dihydrofolate reductase, and 5-fluorouracil which inhibits thymidylate synthetase. The document provides details on the classification, mechanisms, uses and side effects of different classes of antineoplastic agents.
Alkylating agents are a class of cytotoxic chemotherapy drugs that work by adding alkyl groups to electron-rich nucleophilic atoms in DNA, RNA, and proteins, forming covalent bonds. This disrupts the DNA structure and prevents cell division. The two main types are monofunctional agents that bind one DNA strand, and bifunctional agents that form cross-links between both strands. Common alkylating agents include nitrogen mustards, nitrosoureas, alkyl sulfonates, and aziridines. They are used to treat many cancers but can cause toxic effects like myelosuppression, cystitis, and secondary cancers due to their DNA damaging properties. Resistance mechanisms include increased glutathione and DNA repair pathways
This document discusses cancer and chemotherapy. It provides an overview of cancer physiology, causes, stages of development and treatments. It describes different classes of chemotherapeutic agents including alkylating agents, antimetabolites, anthracyclines and bleomycin. For each drug class and individual drugs, it discusses mechanisms of action, clinical applications, pharmacokinetics, resistance mechanisms and common adverse effects.
This document summarizes various alkylating agents used to treat cancer. It describes how alkylating agents work by forming covalent bonds with DNA to prevent replication. Specific agents discussed include nitrogen mustard, cyclophosphamide, chlorambucil, melphalan, nitrosoureas like carmustine, alkyl sulfonates like busulfan, ethylenimines like dacarbazine, temozolomide, altretamine, and thiotepa. For many of these, the synthesis and mechanisms of action are outlined. Alkylating agents can cause adverse effects like myelosuppression, sterility, and increased leukemia risk.
The document discusses various classes of antineoplastic agents (cancer drugs) including their mechanisms of action and clinical applications. It describes how alkylating agents like cyclophosphamide work by alkylating DNA, which can cause cross-linking and inhibit DNA synthesis and function. Antimetabolites like methotrexate inhibit key enzymes involved in DNA synthesis. The document provides examples of several alkylating agents and antimetabolites, and discusses their mechanisms of action, common uses in treating different cancer types, typical administration routes, and common side effects.
This document provides an overview of cancer chemotherapy. It discusses the goals of cancer chemotherapy as being cure, control, or palliation depending on the cancer stage. It then reviews some key developments in cancer chemotherapy over time, including the 1940s-50s seeing the first successful chemotherapy drugs and the 1970s being considered the "Golden Age" with the development of drug combinations and new classes of drugs. The rest of the document discusses various aspects of chemotherapy drugs and mechanisms, including specific drug classes and examples, cell cycle phases, drug combinations, and newer targeted therapies and immunotherapies.
33- ANTICANCER.pptx pharmacology for studentsFranciKaySichu
This document provides information on anticancer agents and their mechanisms of action. It begins by describing the differences between normal and cancer cells and classifications of cancers. It then discusses the cell cycle and how some anticancer drugs target specific phases. The main classes of anticancer drugs covered include alkylating agents, antimetabolites, antitumor antibiotics, mitotic spindle agents, topoisomerase inhibitors, and platinum coordination complexes. For each class, specific drugs are named and their mechanisms of action and indications are explained. Adverse effects are also discussed.
Cancer is characterized by abnormal cell growth and division that can spread to other tissues. There are several main types of cancer classified by the tissues they originate from. Chemotherapeutic drugs target rapidly dividing cancer cells and can be classified based on their site of action in the cell cycle or chemical structure. Major classes of chemotherapeutics include alkylating agents, platinum coordination complexes, and antimetabolites. Alkylating agents directly damage DNA through alkylation, inhibiting cell division. Platinum complexes like cisplatin bind DNA and cause crosslinking. Antimetabolites interfere with DNA and RNA synthesis by mimicking normal cell metabolites.
Alkylating agents are a class of antineoplastic chemicals that work by cross-linking DNA strands, particularly at the guanine's N-7 position. This prevents cancer cells from repairing and replicating their DNA, hindering proliferation. Specific alkylating agents discussed include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, thiotepa, and busulfan. The toxicity and activity of these agents depends on factors like the replacement of nitrogen with sulfur, the presence of a 2-chloroethyl group to generate an aziridine cation, and addition of aromatic rings which can improve stability, distribution, and local/rapid action.
1. Chemotherapeutic agents can be classified according to their chemical structure, mechanism of action, or cell cycle specificity. Common classes include alkylating agents, antimetabolites, antitumor antibiotics, and mitotic spindle agents.
2. The mechanisms of action of these drug classes vary but include alkylating DNA, inhibiting nucleic acid synthesis, interfering with transcription and RNA synthesis, and influencing protein synthesis and function. Many agents act during specific phases of the cell cycle.
3. Examples of specific chemotherapeutic drugs discussed include cyclophosphamide, cisplatin, methotrexate, 5-fluorouracil, vincristine, paclitaxel, doxorubicin,
This document discusses anticancer drugs, also known as chemotherapy drugs. It describes the main classes of anticancer drugs, including alkylating agents, antimetabolites, cytotoxic antibiotics, hormones, and enzymes. Alkylating agents work by alkylating DNA and inhibiting its replication. Common alkylating agents include cyclophosphamide and cisplatin. Antimetabolites are structurally similar to essential metabolites and interfere with DNA synthesis, examples include methotrexate and fluorouracil. Cytotoxic antibiotics like doxorubicin act directly on DNA. The document also covers the mechanisms of action, clinical uses, and side effects of several important chemotherapy drugs.
Anti-Rhumatics in Renal and Liver impairmentRehab Rayan
The document outlines the contributions of team members to a project on disease-modifying antirheumatic drugs (DMARDs) used to treat rheumatoid arthritis. It assigns team members to discuss specific DMARDs and other drug classes. It will cover D-penicillamine, azathioprine, antimalarials, sodium aurothiomalate, corticosteroids, NSAIDs, celecoxib, rituximab, abatacept, TNF-alpha antagonists, and provide a summary. The toxicity profiles, particularly renal and hepatic toxicity, of several DMARDs will be discussed including D-penicillamine, cyclosporine, azathioprine, methotrexate,
Brief review of renal failure with chemotherapeutic agentsKasarla Dr Ramesh
Chemotherapy drugs can damage the kidneys through various mechanisms. Cisplatin is one of the most nephrotoxic drugs that directly injures the proximal tubules. Symptoms of kidney damage include decreased urine output and blood in the urine. Kidney function is assessed through blood tests of creatinine and BUN. Prevention strategies for cisplatin nephrotoxicity include IV fluids, sodium thiosulfate, and dose modifications based on glomerular filtration rate. Methotrexate requires monitoring and urine alkalinization due to precipitation in acidic urine causing tubular injury. Gemcitabine can cause thrombotic microangiopathy requiring dose reductions with glomerular filtration rate below 30 mL/
Anticancer drugs: Classification , general toxicity and Alkylating agents.Ameena Kadar
Neoplasm or cancer is one of the dangerous condition. Here we discuss about cancer and it's drug classification, general toxicity and brief description about Alkylating agents.
1. The document provides an overview of cancer chemotherapy, including targets, classification of drugs, mechanisms of drug resistance, and new approaches.
2. It discusses various classes of chemotherapy drugs like alkylating agents, antimetabolites, plant alkaloids, and antibiotics. Specific drugs like cyclophosphamide, methotrexate, vinblastine, and doxorubicin are described in terms of their mechanisms and toxicities.
3. Newer targeted therapies like imatinib are also mentioned, reflecting the evolution toward more precise inhibition of molecular targets driving cancer growth.
Alkylating agents and antimetabolites are two classes of chemotherapy drugs. Alkylating agents work by binding to DNA and RNA, causing crosslinking or breaks that prevent replication. The main types are nitrogen mustards, alkyl sulphonates, nitrosoureas, and thiazines. Antimetabolites mimic normal metabolites and inhibit DNA or RNA synthesis by becoming incorporated. Major types are folate antagonists like methotrexate, pyrimidine analogs like 5-fluorouracil, and purine analogs like mercaptopurine. Both classes cause bone marrow suppression and gastrointestinal toxicity, and resistance can develop through drug inactivation or changes to drug targets.
The document discusses various drugs used in cancer treatment, including their mechanisms and classifications. It describes several classes of drugs such as alkylating agents, platinum coordination complexes, and antimetabolites. Alkylating agents like nitrogen mustards work by alkylating DNA at guanine residues to cause crosslinking. Platinum drugs like cisplatin form DNA crosslinks by binding to nucleophilic sites. Common side effects of these drugs include nausea, vomiting and myelosuppression. The document provides details on specific drugs from each class, their uses, mechanisms and adverse effects to summarize the main therapeutic approaches in cancer chemotherapy.
This document discusses anticancer drugs and their mechanisms of action. It begins by defining cancer and describing different types. Anticancer drugs are then classified into groups including alkylating agents, antimetabolites, antibiotics, plant products, and hormones. The mechanisms of several drug classes are explained, such as how alkylating agents form reactive groups that bind to and break DNA. Newer drugs like temozolomide and pemetrexed are also introduced along with their uses and mechanisms. In summary, the document provides an overview of cancer types and classifications, along with explanations of established and newer anticancer drug mechanisms of action.
A 50-year-old man undergoing chemotherapy for a malignant tumor develops megaloblastic anemia. This is likely caused by methotrexate inhibiting folate metabolism. Folic acid supplementation could have prevented the toxicity. Anthracyclines like doxorubicin can cause cardiac toxicity through free radical generation, sometimes requiring dexrazoxane treatment. Bleomycin can cause pulmonary fibrosis.
Alkylating agents are a class of cytotoxic chemotherapy drugs that work by adding alkyl groups to electron-rich nucleophilic atoms in DNA, RNA, and proteins, forming covalent bonds. This disrupts the DNA structure and prevents cell division. The two main types are monofunctional agents that bind one DNA strand, and bifunctional agents that form cross-links between both strands. Common alkylating agents include nitrogen mustards, nitrosoureas, alkyl sulfonates, and aziridines. They are used to treat many cancers but can cause toxic effects like myelosuppression, cystitis, and secondary cancers due to their DNA damaging properties. Resistance mechanisms include increased glutathione and DNA repair pathways
This document discusses cancer and chemotherapy. It provides an overview of cancer physiology, causes, stages of development and treatments. It describes different classes of chemotherapeutic agents including alkylating agents, antimetabolites, anthracyclines and bleomycin. For each drug class and individual drugs, it discusses mechanisms of action, clinical applications, pharmacokinetics, resistance mechanisms and common adverse effects.
This document summarizes various alkylating agents used to treat cancer. It describes how alkylating agents work by forming covalent bonds with DNA to prevent replication. Specific agents discussed include nitrogen mustard, cyclophosphamide, chlorambucil, melphalan, nitrosoureas like carmustine, alkyl sulfonates like busulfan, ethylenimines like dacarbazine, temozolomide, altretamine, and thiotepa. For many of these, the synthesis and mechanisms of action are outlined. Alkylating agents can cause adverse effects like myelosuppression, sterility, and increased leukemia risk.
The document discusses various classes of antineoplastic agents (cancer drugs) including their mechanisms of action and clinical applications. It describes how alkylating agents like cyclophosphamide work by alkylating DNA, which can cause cross-linking and inhibit DNA synthesis and function. Antimetabolites like methotrexate inhibit key enzymes involved in DNA synthesis. The document provides examples of several alkylating agents and antimetabolites, and discusses their mechanisms of action, common uses in treating different cancer types, typical administration routes, and common side effects.
This document provides an overview of cancer chemotherapy. It discusses the goals of cancer chemotherapy as being cure, control, or palliation depending on the cancer stage. It then reviews some key developments in cancer chemotherapy over time, including the 1940s-50s seeing the first successful chemotherapy drugs and the 1970s being considered the "Golden Age" with the development of drug combinations and new classes of drugs. The rest of the document discusses various aspects of chemotherapy drugs and mechanisms, including specific drug classes and examples, cell cycle phases, drug combinations, and newer targeted therapies and immunotherapies.
33- ANTICANCER.pptx pharmacology for studentsFranciKaySichu
This document provides information on anticancer agents and their mechanisms of action. It begins by describing the differences between normal and cancer cells and classifications of cancers. It then discusses the cell cycle and how some anticancer drugs target specific phases. The main classes of anticancer drugs covered include alkylating agents, antimetabolites, antitumor antibiotics, mitotic spindle agents, topoisomerase inhibitors, and platinum coordination complexes. For each class, specific drugs are named and their mechanisms of action and indications are explained. Adverse effects are also discussed.
Cancer is characterized by abnormal cell growth and division that can spread to other tissues. There are several main types of cancer classified by the tissues they originate from. Chemotherapeutic drugs target rapidly dividing cancer cells and can be classified based on their site of action in the cell cycle or chemical structure. Major classes of chemotherapeutics include alkylating agents, platinum coordination complexes, and antimetabolites. Alkylating agents directly damage DNA through alkylation, inhibiting cell division. Platinum complexes like cisplatin bind DNA and cause crosslinking. Antimetabolites interfere with DNA and RNA synthesis by mimicking normal cell metabolites.
Alkylating agents are a class of antineoplastic chemicals that work by cross-linking DNA strands, particularly at the guanine's N-7 position. This prevents cancer cells from repairing and replicating their DNA, hindering proliferation. Specific alkylating agents discussed include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, thiotepa, and busulfan. The toxicity and activity of these agents depends on factors like the replacement of nitrogen with sulfur, the presence of a 2-chloroethyl group to generate an aziridine cation, and addition of aromatic rings which can improve stability, distribution, and local/rapid action.
1. Chemotherapeutic agents can be classified according to their chemical structure, mechanism of action, or cell cycle specificity. Common classes include alkylating agents, antimetabolites, antitumor antibiotics, and mitotic spindle agents.
2. The mechanisms of action of these drug classes vary but include alkylating DNA, inhibiting nucleic acid synthesis, interfering with transcription and RNA synthesis, and influencing protein synthesis and function. Many agents act during specific phases of the cell cycle.
3. Examples of specific chemotherapeutic drugs discussed include cyclophosphamide, cisplatin, methotrexate, 5-fluorouracil, vincristine, paclitaxel, doxorubicin,
This document discusses anticancer drugs, also known as chemotherapy drugs. It describes the main classes of anticancer drugs, including alkylating agents, antimetabolites, cytotoxic antibiotics, hormones, and enzymes. Alkylating agents work by alkylating DNA and inhibiting its replication. Common alkylating agents include cyclophosphamide and cisplatin. Antimetabolites are structurally similar to essential metabolites and interfere with DNA synthesis, examples include methotrexate and fluorouracil. Cytotoxic antibiotics like doxorubicin act directly on DNA. The document also covers the mechanisms of action, clinical uses, and side effects of several important chemotherapy drugs.
Anti-Rhumatics in Renal and Liver impairmentRehab Rayan
The document outlines the contributions of team members to a project on disease-modifying antirheumatic drugs (DMARDs) used to treat rheumatoid arthritis. It assigns team members to discuss specific DMARDs and other drug classes. It will cover D-penicillamine, azathioprine, antimalarials, sodium aurothiomalate, corticosteroids, NSAIDs, celecoxib, rituximab, abatacept, TNF-alpha antagonists, and provide a summary. The toxicity profiles, particularly renal and hepatic toxicity, of several DMARDs will be discussed including D-penicillamine, cyclosporine, azathioprine, methotrexate,
Brief review of renal failure with chemotherapeutic agentsKasarla Dr Ramesh
Chemotherapy drugs can damage the kidneys through various mechanisms. Cisplatin is one of the most nephrotoxic drugs that directly injures the proximal tubules. Symptoms of kidney damage include decreased urine output and blood in the urine. Kidney function is assessed through blood tests of creatinine and BUN. Prevention strategies for cisplatin nephrotoxicity include IV fluids, sodium thiosulfate, and dose modifications based on glomerular filtration rate. Methotrexate requires monitoring and urine alkalinization due to precipitation in acidic urine causing tubular injury. Gemcitabine can cause thrombotic microangiopathy requiring dose reductions with glomerular filtration rate below 30 mL/
Anticancer drugs: Classification , general toxicity and Alkylating agents.Ameena Kadar
Neoplasm or cancer is one of the dangerous condition. Here we discuss about cancer and it's drug classification, general toxicity and brief description about Alkylating agents.
1. The document provides an overview of cancer chemotherapy, including targets, classification of drugs, mechanisms of drug resistance, and new approaches.
2. It discusses various classes of chemotherapy drugs like alkylating agents, antimetabolites, plant alkaloids, and antibiotics. Specific drugs like cyclophosphamide, methotrexate, vinblastine, and doxorubicin are described in terms of their mechanisms and toxicities.
3. Newer targeted therapies like imatinib are also mentioned, reflecting the evolution toward more precise inhibition of molecular targets driving cancer growth.
Alkylating agents and antimetabolites are two classes of chemotherapy drugs. Alkylating agents work by binding to DNA and RNA, causing crosslinking or breaks that prevent replication. The main types are nitrogen mustards, alkyl sulphonates, nitrosoureas, and thiazines. Antimetabolites mimic normal metabolites and inhibit DNA or RNA synthesis by becoming incorporated. Major types are folate antagonists like methotrexate, pyrimidine analogs like 5-fluorouracil, and purine analogs like mercaptopurine. Both classes cause bone marrow suppression and gastrointestinal toxicity, and resistance can develop through drug inactivation or changes to drug targets.
The document discusses various drugs used in cancer treatment, including their mechanisms and classifications. It describes several classes of drugs such as alkylating agents, platinum coordination complexes, and antimetabolites. Alkylating agents like nitrogen mustards work by alkylating DNA at guanine residues to cause crosslinking. Platinum drugs like cisplatin form DNA crosslinks by binding to nucleophilic sites. Common side effects of these drugs include nausea, vomiting and myelosuppression. The document provides details on specific drugs from each class, their uses, mechanisms and adverse effects to summarize the main therapeutic approaches in cancer chemotherapy.
This document discusses anticancer drugs and their mechanisms of action. It begins by defining cancer and describing different types. Anticancer drugs are then classified into groups including alkylating agents, antimetabolites, antibiotics, plant products, and hormones. The mechanisms of several drug classes are explained, such as how alkylating agents form reactive groups that bind to and break DNA. Newer drugs like temozolomide and pemetrexed are also introduced along with their uses and mechanisms. In summary, the document provides an overview of cancer types and classifications, along with explanations of established and newer anticancer drug mechanisms of action.
A 50-year-old man undergoing chemotherapy for a malignant tumor develops megaloblastic anemia. This is likely caused by methotrexate inhibiting folate metabolism. Folic acid supplementation could have prevented the toxicity. Anthracyclines like doxorubicin can cause cardiac toxicity through free radical generation, sometimes requiring dexrazoxane treatment. Bleomycin can cause pulmonary fibrosis.
Similar to Nitrogen Mustards -Medicinal Chemistry --------College of Pharmacy (20)
This document summarizes several protozoal diseases and their treatment with anti-parasitic drugs. It discusses the diseases giardiasis and amebiasis caused by the protozoa Giardia lamblia and Entamoeba histolytica respectively. It also discusses trichomoniasis caused by Trichomonas vaginalis. The main drugs used to treat these diseases are metronidazole, tinidazole, and nitazoxanide. It provides details on the mechanisms of action and metabolism of these drugs. It also briefly discusses diloxanide furoate and leishmaniasis.
This document summarizes various anti-malarial agents. It discusses the classes of drugs used to treat malaria, including cinchona alkaloids, 4-aminoquinolines, 8-aminoquinolines, diaminopyrimidines, amino alcohols, artemisinins, antibiotics, and fixed combinations. Key drugs discussed include chloroquine, primaquine, pyrimethamine, atovaquone-proguanil, and artemisinin derivatives. The document also briefly discusses vaccine development efforts for malaria.
This document discusses antifungal drugs. It begins by describing common fungal infections that antifungals treat, such as ringworm and athlete's foot. It then discusses the different types of fungal infections including superficial infections of the skin and internal organ infections. The document outlines the main biochemical targets of antifungals and describes the structure and mechanisms of several major classes of antifungal drugs, including azoles, polyenes like amphotericin B and nystatin, and the heterocyclic compound griseofulvin. It provides details on specific antifungals like their structures, mechanisms of action, uses, and side effects.
1. The document discusses several classes of anticancer drugs including antimetabolites, anthracyclines, and natural products.
2. It focuses on antimetabolites such as pyrimidine and purine analogs that interfere with DNA synthesis including 5-fluorouracil, capecitabine, cytarabine, gemcitabine, and 6-mercaptopurine.
3. The mechanisms of these drugs and how they inhibit key enzymes like thymidylate synthase and dihydrofolate reductase is explained.
This document summarizes different classes of anthelmintic drugs used to treat helminth infections. It discusses the chemical structures, mechanisms of action, and metabolism of various classes including benzimidazoles (e.g. albendazole, mebendazole), piperazines (e.g. piperazine citrate, diethylcarbamazine citrate), heterocyclics (e.g. oxamniquine, praziquantel), vinyl pyrimidines (e.g. pyrantel palmoate), amides (e.g. niclosamide), and natural products (e.g. ivermectin). It provides details on the
Parkinson's disease is caused by a loss of dopamine-producing neurons in the substantia nigra. Symptoms include tremors, stiffness, and impaired movement. Anti-Parkinsonian drugs work by increasing dopamine levels in the brain. These include dopamine precursors like levodopa, dopamine receptor agonists, MAO-B inhibitors, COMT inhibitors, and anticholinergic agents. Newer treatments include the dopamine releaser amantadine and drugs that target the adenosine A2A receptor like istradefylline. Deep brain stimulation is also used to treat motor symptoms.
Barbiturates are central nervous system depressants that were historically used as sedatives, hypnotics, and anticonvulsants. They work by enhancing the effects of the neurotransmitter GABA. While largely replaced by safer benzodiazepines, barbiturates are still used for certain medical purposes. Their structure is based on barbituric acid, with activity requiring lipophilic 5,5-disubstitutions for blood-brain barrier crossing. Mechanisms of action, classifications by duration, and metabolism pathways are described.
This document provides information about benzodiazepines, including their history, mechanisms of action, structures, and metabolism. Benzodiazepines work by enhancing the effects of the inhibitory neurotransmitter GABA in the brain. They are commonly used to treat anxiety, insomnia, seizures and muscle spasms. The first benzodiazepine developed was chlordiazepoxide in 1955. Key structural features that influence their pharmacological properties include functional groups at the 1st, 2nd, 3rd, 4th, 5th and 7th positions of the benzodiazepine ring system. Metabolism and elimination pathways determine a benzodiazepine's duration of action from short-acting to long-acting
This document provides an overview of β-lactam antibiotics, including penicillins. It begins by classifying common antibiotics and listing their mechanisms of action. It then focuses on β-lactam antibiotics, describing their structure and major subclasses like penicillins, cephalosporins, carbapenems, and monobactams. Specific penicillins are discussed in depth, highlighting their structures, spectra of activity, stability properties, and mechanisms of resistance. β-lactamase inhibitors like clavulanic acid are also introduced.
This document provides information about anti-viral drugs. It begins by defining viruses and their structure. It then discusses different classes of anti-viral drugs, including those that block viral attachment and entry, inhibit penetration, act as uncoating inhibitors, and are nucleic acid inhibitors that target polymerases or reverse transcriptase. Specific drugs are discussed for each class, along with their mechanisms of action, structures, and importance for treating various viral diseases like HIV, hepatitis, herpes, and influenza.
The document discusses various antiepileptic drugs (AEDs) and their mechanisms of action. It covers major classes of AEDs including valproic acid, phenytoin, carbamazepine, lamotrigine, topiramate, and zonisamide. The main mechanisms of AEDs are enhancement of GABA activity, inhibition of sodium channels, and inhibition of calcium channels. The document discusses the metabolism, pharmacokinetics, indications, contraindications and side effects of the various AEDs. It provides details on the chemical structures and metabolic pathways of many commonly used AEDs.
This document summarizes antipsychotic drugs used to treat psychosis and schizophrenia. It discusses the typical and atypical classes, and provides examples from each class including phenothiazines, butyrophenones, diphenylbutylpiperidines, and others. It describes the mechanism of action involving dopamine receptor antagonism, especially at D2 receptors. Side effects like extrapyramidal symptoms are addressed. Structure-activity relationships are outlined for key drug families.
This document discusses various classes of sedative-hypnotic drugs, including barbiturates and benzodiazepines. It provides details on the classification, mechanisms of action, structure-activity relationships, metabolism and adverse effects of barbiturates. Barbiturates such as phenobarbital, amobarbital and pentobarbital are described according to their duration of action. Their mechanisms involve facilitating GABA neurotransmission. However, barbiturates now see minimal use due to risks of tolerance, dependence and toxicity. Newer drugs like zolpidem and zaleplon were developed to avoid these issues.
Sedative and hypnotic Drugs/ Medicinal Chemistry III (Part One)NarminHamaaminHussen
Sedative and hypnotic drugs act on the central nervous system by depressing activity. Sedatives decrease excitement without causing drowsiness, while hypnotics produce sleep. The same drugs can act as sedatives at low doses and hypnotics at higher doses in a dose-dependent manner. Most sedatives and hypnotics work by enhancing the effects of the inhibitory neurotransmitter GABA at GABAA receptors. Benzodiazepines are a commonly used class of sedative and hypnotic drugs that work through this GABAergic mechanism of action. Their effects and pharmacokinetic properties depend on their chemical structure and metabolism.
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
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A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Kat...rightmanforbloodline
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
8 Surprising Reasons To Meditate 40 Minutes A Day That Can Change Your Life.pptxHolistified Wellness
We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
2. History of Alkylating agents
▪ Alkylating agents are the oldest and most common class of anticancer drugs
▪ During World War I, sulfur mustard gas was used as a devastating weapon due to its effects
on the skin, eyes, and lungs. However, it was observed that exposure to sulfur mustard also
led to bone marrow suppression and lymphoid aplasia. This prompted researchers to explore
its potential as an antitumor agent.
3. Chemistry of the Alkylating Agents
▪ The alkylating agents are compounds that work by adding an alkyl group(highly reactive chemical group
)to the N-7 position of guanine base of the DNA molecule to form irreversible covalent bond.
▪ The major targets of drug action are nucleophilic groups present on DNA (especially the 7-position of
guanine).
▪ The general mechanism for alkylation involves nucleophilic attack by of DNA and
RNA
▪ This alkylation of DNA leads to the formation of DNA crosslinks, intrastrand and interstrand DNA adducts,
and DNA-protein crosslinks. Alkylation of DNA is thought to lead to cell death.
▪ Potential mechanisms of cell death include activation of apoptosis caused by p53 activation and
disruption of the template function of DNA
4. Mechanism of Action of Alkylating Agents
N7-Guanine
1
Formation of
Aziridinium cation
1
Formation of
Aziridinium cation
2
Attachment of the Aziridinium
cation to N7 position of
guanine
3
Formation of cross bridges,
bonds between atoms in the
DNA
4
N7-N7 bisguanyl
DNA cross link
Nitrogen Mustard
5. Alkylation converts a base
into a leaving group, allowing
water attack to lead to
depurination and loss of
genetic information if not
repaired by the cell.
Depurination
N-7 position Guanine
Alkylating agents
7. Alkylating agents
Effective against
▪ Alkylating agents have shown efficacy against a wide range of cancers, including solid
tumors(e.g., breast, ovarian, uterus, lung, bladder cancers) , and hematological
malignancies such as leukemia, lymphoma, and multiple myeloma .
Solid Tumors
Hematological Tumors
8. Common Side effects of Alkylating agents:
▪ Bone marrow suppression (anemia, neutropenia, and thrombocytopenia)
▪ Gastrointestinal effects( nausea, vomiting, diarrhea, or mucositis)
▪ Hair loss (alopecia)
▪ Reproductive toxicity (infertility)
▪ Neurotoxicity (such as the nitrosoureas)
▪ Nephrotoxicity (cisplatin)
▪ Increased risk of secondary cancers (such as leukemia)
10. Nitrogen Mustards
▪ Nitrogen Mustards was the first alkylating agents.
▪ Chemotherapy was initially successfully developed by Drs. Goodman and
Gilman, who also developed the first medication, "mustine" or
"mechlorethamine," for the treatment of leukemia and lymphoma.
▪ Nitrogen mustards are not related to the mustard plant or its pungent
essence, allyl isothiocyanate; the name comes from the pungent smell of
chemical weapons preparations.
▪ The term mustard obtain from mustard gas.
▪ Nitrogen mustards (NMs) are cytotoxic organic compounds with the bis(2-
chloroethyl)amino ((ClC2H4)2NR) functional group.
12. SARS of Nitrogen Mustards
1- The bis (2-choroethyl) group is essential for activity.
Other halogens than chloride decrease activity.
Increase or decrease in ethylene between Cl & N abolish the activity
2- The nitrogen with ethyl halo group makes Aziridinium ion at physiological pH. This
Aziridinium causes the alkylation of the DNA in biological system.
N-7 position of guanine
13. 3- The aliphatic nitrogen mustard Mechlorethamine (1st nitrogen mustard ) is having extremely
high reactivity and limited use.
▪ The methyl group is weak electron donating and has high nucleophilicity.
▪ The lack of selectivity of mechlorethamine led to attempts to improve on the agent.
▪ One rationale was to reduce the reactivity by reducing the nucleophilicity of nitrogen,
thereby slowing aziridinium cation formation. This could be accomplished by replacement of
the weakly electron-donating methyl group with groups that were electron withdrawing.
High nucleophilicity
(weak e-donating )
14. 4- Melphalan and chlorambucil were developed that have phenylalanine
and amino phenyl butyric acid in the structure , respectively.
Aromatic group with electron withdrawing may decrease the
nucleophilicity of nitrogen atom and reduced carbonium ion formation
5- The binding to amino acids and substituted phenyl group allowed
the oral route availability of these drugs.
6- In addition, the presence of the aromatic ring maintains the molecule
more stable ,enabling a better distribution of the drug throughout the
body
forming cation
15. 7- Bendamustine , which is another mustard has a benzimidazole ring that provides
stability to the molecule and a local and faster action, observed by the shorter half-life.
16. 8- Prodrugs cyclophosphamide and ifosfamide ,oxazaphosphorines is inactive when
administrated by the presence of oxazaphosphorine ring.
9- Nitrogen mustards agents require an electronegative group in their structure ,for instance
,chloride , to induce poles in molecules and electron acceptor group as nitrogen, so that the
formation of ions able to alkylate DNA and protein occur.
17. What differentiates aromatic nitrogen mustards from aliphatic ones?
1. Aliphatic mustard is highly toxic
and lacks selectivity
2. Aromatic nitrogen mustards may
have enhanced selectivity due to
the presence of the benzene
ring.
3. Aromatic nitrogen mustards
decrease reactivity by lowering
nitrogen nucleophilicity, slowing
aziridinium cation formation by
replacing weakly electron-
donating methyl groups with
electron-withdrawing ones
4. Oral use of aromatic nitrogen
mustard is acceptable; it is less
toxic than aliphatic
18. ➢ Mechlorethamine(Chlormethine )(mustine)
▪ Is highly reactive, in fact, too reactive and therefore nonselective, making it unsuitable for
oral administration is taken only by slow iv infusion(is available in 10-mg vials , direct injection into the
tumor) and it used to treat Hodgkin’s lymphoma and non-Hodgkin’s lymphoma.
▪ The major use is in Hodgkin’s disease and in the MOPP regimen (mechlorethamine, vincristine,
procarbazine, and prednisone).
▪ Chlormethine is so reactive with water that is marketed as a dry solid (HCl salt) and
aqueous solutions are prepared immediately prior to injection. To prevent the hydrolysis reaction and
helps to maintain its stability.
▪ Skin toxicity is one of mechlorethamine's major disadvantages
18
Aliphatic Nitrogen mustards
19. ▪ Mustards such as mechlorethamine are classified as dialkylating agents in that one mustard molecule can
alkylate two nucleophiles.
▪ The initial acid– base reaction is necessary to release the lone pair of electrons on nitrogen, which
subsequently displaces chloride to give the highly reactive aziridinium cation.
▪ Nucleophilic attack can then occur at the aziridinium carbon to relieve the small ring strain and neutralize the
charge on nitrogen. This process can then be repeated provided a second leaving group is present
Alkylation of nucleophilic species by nitrogen mustards. 19
aziridinium
20. ▪ Skin toxicity due to nitrogen mustard extravasation is
severe and typically prolonged over several months.
▪ Sodium thiosulfate is believed to chemically neutralize
reactive mechlorethamine-alkylating species and thus
decrease skin toxicity.
▪ Mechanism of action Neutralizes mechlorethamine
to form nontoxic thioesters that are excreted in the
urine.
▪ In cases of extravasation (drug escapes from the
intravenous vein into the surrounding tissue, this can
cause local pain accompanied by burning or stinging,
blistering, erythema, swelling, and tenderness.), the
antidote sodium thiosulfate (Na2S2O3), a strong
nucleophile, may be administered.
▪ It is capable of reacting with electrophilic sites on
the mustard, and once reaction has occurred, the
resulting adduct has increased water solubility and may
be readily eliminated.
▪Cancer patients are at an increased risk of extravasation
because of the fragility of their veins resulting from
radiation, previous chemotherapy treatments, or
malnutrition
Antidote of Mechlorethamine ✓ Inject 2 ml of the sodium thiosulfate solution for each
milligram of mechlorethamine suspected to have
extravasated. Inject the solution subcutaneously into
the extravasation site using a 25-gauge or smaller
needle (change needle with each injection).
20
21. Aromatic Nitrogen Mustards
➢ Chlorambucil
▪ Very slow acting
▪ Highly selective on lymphoid tissue ,very little effect on myeloid tissue
▪ It is primarily used in the treatment of chronic lymphocytic leukemia (CLL), a type of cancer that affects the
white blood cells, and lymphomas, which are cancers of the lymphatic system.
▪ Chlorambucil and melphalan, have electron-withdrawing groups substituted on the nitrogen atom. This
alteration reduces the nucleophilicity of the nitrogen and renders the molecules less reactive
▪ Suitable only for oral administration.
▪ It is a highly lipophilic drug but is also a weak acid and can therefore be taken up into cells by passive diffusion.
▪ The lower extracellular pH of tumour tissue compared to normal tissue may increase the intracellular uptake
of chlorambucil by increasing the amount of free acid.
22. ➢Melphalan
▪ Melphalan chemically is 4-[bis(2-chloroethyl)amino]-L-phenylalanine and it is a phenylalanine
derivative of nitrogen mustard that acts as a bifunctional alkylating agent.
▪ Because L-phenylalanine is a precursor to melanin, it was thought that L-phenylalanine
nitrogen mustard might accumulate in melanomas.
▪ Used in multiple myeloma, ovarian cancer and Malignant melanoma
▪ Suitable for oral administration and Iv infusion
23. ➢ Melphalan flufenamide (Melflufen)
▪ It is a novel derivative of melphalan, an alkylating agent used in cancer chemotherapy.
▪ It is first-in-class peptide- conjugate prodrug
▪ Melphalan flufenamide is indicated in combination with dexamethasone for the treatment
of adults with relapsed or refractory multiple myeloma.
▪ Melphalan flufenamide was approved for medical use in the United States in February
2021and in the European Union in August 2022.
24. Compared to traditional melphalan, melphalan flufenamide offers several potential
advantages:
➢ Enhanced Selectivity:
▪ Melphalan flufenamide is a first-in-class peptide- conjugate prodrug that targets
aminopeptidases and rapidly releases alkylating agents into tumor cells.
▪ Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity
▪ Enhancing its selectivity and potentially reducing toxicity to healthy tissues.
25. ➢ Cyclophosphamide:
▪ Cyclophosphamide, is an alkylating agent chemically related to nitrogen-mustard and is also an
immunosuppressive agent.
▪ Cyclophosphamide is one of the most widely used cytotoxic agents, often in combination or
sequentially with other antineoplastic agents.
▪ Used in the treatment of a wide variety of cancers, including breast cancer, nonHodgkin’s
lymphoma, chronic lymphocytic leukemia, ovarian cancer, bone and soft tissue sarcoma
▪ Cyclophosphamide is available in 25- and 50-mg tablets for oral administration and 100-, 200-, 500-
, 1,000-, and 2,000-mg vials for IV use
25
26. ➢ Activation of Cyclophosphamide
▪ Cyclophosphamide is a prodrug (inactive) that requires biotransformation by a group of P450 cytochrome
enzymes into phosphoramide mustard (active compound) to exert its cytotoxicity.
▪ In the initial activation reaction, the carbon-4 of the oxazaphosphorine ring is hydroxylated.
▪ The product 4-hydroxycyclo-phosphamide (4-OH-CPA) exists in equilibrium with its acyclic tautomer
aldophosphamide, which breaks down by spontaneous β elimination, to release phosphoramide mustard and
acrolein
▪ While phosphoramide mustard is thought to be the active alkylating species, acrolein is an unwanted
byproduct, responsible for hemorrhagic cystitis.
▪ Alternatively, aldophosphamide may be oxidized to the inactive metabolite carboxyphosphamide by
aldehyde dehydrogenase.
▪ The other principal inactive metabolite,dechloroethylcyclophosphamide, is produced by a separate oxidative
N-dealkylationreaction, also catalysed by CYP3A4 .
▪ Cyclophosphamide’s cytotoxic effect is mainly due to cross-linking of strands of DNA and RNA of tumour cell.
▪ Clinically important side effects are cardiac dysfunctions at high-doses;and haemorrhagic cystitis may
develop after high or prolonged dosage
▪ In the case of cyclophosphamide, it was initially believed that the drug could be selectively activated in cancer
cells because they were believed to contain high levels of phosphoramidase enzymes.
27. Metabolic and chemical activation of cyclophosphamide
Toxic metabolite
Inactive
In Liver
27
Active
4-OH-CPA
How does ALDH work in a cell?
carboxyphosphamide
Aldophosphamide
PM
90%
28.
29.
30. 30
Hemorrhagic Cystitis caused by Acrolein
▪ Acrolein is a toxic aldehyde that can cause severe damage to different
tissues in the body, including the urinary bladder.
▪ Acrolein, when excreted in urine, directly interacts with the urothelium,
a crucial regulator of bladder function.
▪ Acrolein causes bladder damage through reactive oxygen species and
nitric oxide production, leading to lipid peroxidation, protein oxidation,
DNA damage, depletion of nicotinamide, NAD, and ATP, ultimately
causing necrotizing cell death.
▪ Ifosfamide is more toxic than cyclophosphamide .
▪ Ifosfamide should not be administered without the use of an
uroprotective agent such as mesna
Cyclophosphamide
or
ifosfamide
Cyclophosphamide
urothelium
31. ➢ Detoxification of Acrolein:
▪ MESNEX (Mesna) is a detoxifying agent to inhibit the hemorrhagic cystitis induced by
cyclophosphamide or ifosfamide.
▪ The active ingredient, Mesna, is a synthetic sulfhydryl compound designated as sodium-2-
mercaptoethane sulfonate
▪ The mechanism of action of MESNA (thiol (-SH)) involves its ability to react with and neutralize the toxic
metabolites of ifosfamide and cyclophosphamide, which are known as acrolein and 4-
hydroxycyclophosphamide, respectively.
▪ MESNEX injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide or
cyclophosphamide dosage (w/w) at the time of ifosfamide or cyclophosphamide administration.
▪ The recommended dose of oral Mesna is 40% of the cyclophosphamide or ifosfamide dose, given prior to
antineoplastic agents and then repeated at 2 hours and 6 hours after the cyclophosphamide/ifosfamide
dose.
32. Coadministration of Mesna is recommended with Cyclophosphamide and Ifosfamide
Detoxification of cyclophosphamide by Mesna
32
33. ➢ Ifosfamide (Iphosphamide, IFEX):
▪ A synthetic analog of cyclophosphamide
▪ Ifosfamide is available in 1- and 3-g vials for IV administration as Food and Drug Administration (FDA)-
approved third-line therapy in the treatment of testicular cancer.
▪ Also been utilized in the treatment of a wide variety of cancers including Hodgkin’s and non-Hodgkin’s
lymphoma, soft tissue sarcoma, germ cell tumors, small cell lung cancer, non–small cell lung cancer
(NSCLC), cancers of the head and neck, bladder cancer and cervical cancer.
Adverse effect: Hemorrhagic cystitis
▪ Coadministration of mesna is recommended.
▪ In contrast to cyclophosphamide, there is a greater amount of deactivation of the agent by N-
dechloroethylation and subsequently more chloroacetaldehyde is produced, which may result in a greater
amount of neurotoxicity and nephrotoxicity than seen with cyclophosphamide.
▪ Neurotoxicity, which is associated with the production of chloroacetaldehyde presents as confusion,
seizure, weakness, and hallucination, and coma may occur.
33
35. Question
1. Design and synthesize a novel nitrogen mustard with high selectivity, low toxicity, and oral
activity based on recent articles.
2. What is the protective effect of cyclophosphamide against hepatotoxicity?
3. What is the role of oxidative stress and immune system in the bladder toxicity of
cyclophosphamide and ifsofsamide?