Cytotoxic agents like alkylating agents and antimetabolites are commonly used in dermatology for cancer treatment and severe dermatologic diseases. Alkylating agents like cyclophosphamide and chlorambucil directly damage DNA through alkylation and crosslinking, inhibiting cell replication. Common side effects include bone marrow suppression, carcinogenesis, and gastrointestinal issues. Antimetabolites like methotrexate, azathioprine, and mycophenolate mofetil interfere with DNA synthesis during the S phase of the cell cycle. They are used as immunosuppressants and for inflammatory conditions. Side effects include bone marrow suppression, infections due to immunosuppression, and hepatotoxicity or neph
Cyclosporine is an immunosuppressive drug that was originally isolated from fungi in 1970 and approved by the FDA for transplant rejection in 1983. It is a cyclic polypeptide consisting of 11 amino acids that acts by inhibiting T cell activation through the calcineurin/NFAT pathway. It has since been approved for treating various dermatological conditions like psoriasis, atopic dermatitis, and pyoderma gangrenosum. While effective, cyclosporine use can cause nephrotoxicity, hypertension, and increased risk of infection and skin cancer with long term use. It can also interact with various other drugs that are metabolized through the CYP3A4 pathway.
This document summarizes methotrexate, an antimetabolite drug used to treat various conditions like psoriasis and rheumatoid arthritis. It discusses methotrexate's structure, mechanism of action, administration, indications, contraindications, dosing, monitoring guidelines, adverse effects and drug interactions. The summary describes methotrexate as a folic acid analogue that inhibits dihydrofolate reductase, interfering with DNA synthesis and having anti-inflammatory effects. It lists approved uses including psoriasis and potential off-label uses, and emphasizes monitoring blood work and liver biopsies when using long-term.
Methotrexate is a folic acid analogue that inhibits dihydrofolate reductase and is used to treat various inflammatory and proliferative skin conditions. It can be administered orally, intravenously, intramuscularly or subcutaneously. It is well distributed throughout the body except in the brain. Around 50% is bound to plasma proteins and it has a terminal half-life of 10-27 hours. It works by inhibiting DNA synthesis and blocking T cell migration. Common side effects include gastrointestinal upset and hepatotoxicity. It is contraindicated in pregnancy due to risk of teratogenicity. Monitoring for toxicity and supplementing with folic acid can help reduce adverse effects.
This document discusses retinoids, which are compounds that have biological activity similar to vitamin A. It covers the history, structures, mechanisms of action, classifications, effects, and clinical uses of various retinoids. Key points include: retinoids are used topically and orally to treat acne, psoriasis, and other skin conditions; isotretinoin is very effective for nodular cystic acne; acitretin is used for psoriasis; and retinoids work by regulating cell growth and differentiation through retinoid receptors. Side effects and appropriate dosing are also addressed.
This document provides information on the pharmacotherapy of scabies. It discusses the pathophysiology, clinical presentation, principles of treatment, and various antiscabietic drugs used to treat scabies. Permethrin 5% cream is the drug of choice for treating scabies. It is more effective than lindane and safe for all ages. Proper treatment involves applying the medication over the entire body from neck to toes once a week for two weeks. Patients must also be given instructions to launder clothing and bedding after treatment to prevent reinfestation.
This document summarizes information about retinoids in dermatology. It discusses the history, structure, and classification of natural and synthetic retinoids. It describes the mechanism of action of retinoids involving retinoid receptors and their effects on keratinization, sebaceous glands, and inflammation. Specific retinoids discussed include tretinoin, isotretinoin, acitretin, and bexarotene. Indications for topical and oral retinoid therapy are provided.
This seminar presentation discusses the uses of dapsone, colchicine, and thalidomide in dermatology. For dapsone, it provides a detailed history, mechanisms of action, indications, dosing, administration, and adverse effects. It is commonly used to treat dermatitis herpetiformis, leprosy, and other chronic inflammatory dermatoses. For colchicine, it discusses the mechanisms of action, pharmacokinetics, and various dermatological uses including papulosquamous dermatoses, recurrent aphthous stomatitis, Behcet's syndrome, bullous diseases, vasculitis, and others. Adverse effects include gastrointestinal issues and bone marrow
Pharmacology of antimalarial drugs with treatment of malaria. mechanism of action, uses, adverse effects of antimalarial drugs like chloroquine, quinine, artemisinin compounds.
Cyclosporine is an immunosuppressive drug that was originally isolated from fungi in 1970 and approved by the FDA for transplant rejection in 1983. It is a cyclic polypeptide consisting of 11 amino acids that acts by inhibiting T cell activation through the calcineurin/NFAT pathway. It has since been approved for treating various dermatological conditions like psoriasis, atopic dermatitis, and pyoderma gangrenosum. While effective, cyclosporine use can cause nephrotoxicity, hypertension, and increased risk of infection and skin cancer with long term use. It can also interact with various other drugs that are metabolized through the CYP3A4 pathway.
This document summarizes methotrexate, an antimetabolite drug used to treat various conditions like psoriasis and rheumatoid arthritis. It discusses methotrexate's structure, mechanism of action, administration, indications, contraindications, dosing, monitoring guidelines, adverse effects and drug interactions. The summary describes methotrexate as a folic acid analogue that inhibits dihydrofolate reductase, interfering with DNA synthesis and having anti-inflammatory effects. It lists approved uses including psoriasis and potential off-label uses, and emphasizes monitoring blood work and liver biopsies when using long-term.
Methotrexate is a folic acid analogue that inhibits dihydrofolate reductase and is used to treat various inflammatory and proliferative skin conditions. It can be administered orally, intravenously, intramuscularly or subcutaneously. It is well distributed throughout the body except in the brain. Around 50% is bound to plasma proteins and it has a terminal half-life of 10-27 hours. It works by inhibiting DNA synthesis and blocking T cell migration. Common side effects include gastrointestinal upset and hepatotoxicity. It is contraindicated in pregnancy due to risk of teratogenicity. Monitoring for toxicity and supplementing with folic acid can help reduce adverse effects.
This document discusses retinoids, which are compounds that have biological activity similar to vitamin A. It covers the history, structures, mechanisms of action, classifications, effects, and clinical uses of various retinoids. Key points include: retinoids are used topically and orally to treat acne, psoriasis, and other skin conditions; isotretinoin is very effective for nodular cystic acne; acitretin is used for psoriasis; and retinoids work by regulating cell growth and differentiation through retinoid receptors. Side effects and appropriate dosing are also addressed.
This document provides information on the pharmacotherapy of scabies. It discusses the pathophysiology, clinical presentation, principles of treatment, and various antiscabietic drugs used to treat scabies. Permethrin 5% cream is the drug of choice for treating scabies. It is more effective than lindane and safe for all ages. Proper treatment involves applying the medication over the entire body from neck to toes once a week for two weeks. Patients must also be given instructions to launder clothing and bedding after treatment to prevent reinfestation.
This document summarizes information about retinoids in dermatology. It discusses the history, structure, and classification of natural and synthetic retinoids. It describes the mechanism of action of retinoids involving retinoid receptors and their effects on keratinization, sebaceous glands, and inflammation. Specific retinoids discussed include tretinoin, isotretinoin, acitretin, and bexarotene. Indications for topical and oral retinoid therapy are provided.
This seminar presentation discusses the uses of dapsone, colchicine, and thalidomide in dermatology. For dapsone, it provides a detailed history, mechanisms of action, indications, dosing, administration, and adverse effects. It is commonly used to treat dermatitis herpetiformis, leprosy, and other chronic inflammatory dermatoses. For colchicine, it discusses the mechanisms of action, pharmacokinetics, and various dermatological uses including papulosquamous dermatoses, recurrent aphthous stomatitis, Behcet's syndrome, bullous diseases, vasculitis, and others. Adverse effects include gastrointestinal issues and bone marrow
Pharmacology of antimalarial drugs with treatment of malaria. mechanism of action, uses, adverse effects of antimalarial drugs like chloroquine, quinine, artemisinin compounds.
This document discusses topical corticosteroids (TCS). It begins by describing the discovery and structure of corticosteroids. It then covers the pharmacokinetics of TCS, noting they are distributed in the skin and absorbed systemically before being metabolized in the liver. The potency of a TCS preparation depends on its structure, vehicle, and skin condition. The document outlines the anti-inflammatory, antiproliferative, and atrophogenic mechanisms of action of TCS. It concludes by listing common indications and side effects of TCS.
This document summarizes information about the drug dapsone, including:
1. Dapsone was invented in the early 20th century and is commonly used to treat leprosy in combination with other drugs.
2. It is absorbed after oral administration and metabolized in the liver. Common side effects include anemia, nausea, and rashes.
3. Analytical methods like HPLC and spectroscopy can be used to detect and quantify dapsone in samples.
- Macrolides are a class of antibiotics that are produced by Streptomyces bacteria and contain a macrocyclic lactone ring. Erythromycin was the first macrolide discovered in 1952.
- Macrolides work by attaching to the 50S subunit of bacterial ribosomes and inhibiting protein synthesis. They are bacteriostatic and have selectivity for bacterial over mammalian cells.
- Common macrolides include erythromycin, clarithromycin, roxithromycin, and azithromycin. They are effective against many gram-positive bacteria and some gram-negatives. Azithromycin has the broadest spectrum of activity.
This document discusses macrolide antibiotics, including their structure, examples (erythromycin, azithromycin), mechanism of action, spectrum of activity, resistance, pharmacokinetics, adverse effects, drug interactions, and contraindications. Macrolides bind to the bacterial ribosome and inhibit protein synthesis, generally being bacteriostatic. Their spectrum includes many gram-positive bacteria and some intracellular pathogens. Resistance can occur via efflux pumps or ribosomal mutations. Adverse effects include gastrointestinal issues and ototoxicity. Macrolides can interact with drugs metabolized by CYP450 enzymes.
Topical corticosteroids are powerful anti-inflammatory drugs that are classified based on their potency from mild to very potent. More potent corticosteroids are associated with greater risk of side effects. They work by preventing the formation of inflammatory molecules. Their absorption and effect can be enhanced by certain vehicle formulations, occlusion, damaged skin barriers, and other factors. Guidelines recommend restricting very potent corticosteroid use to small areas for short periods to reduce risk of side effects like skin atrophy.
Dapsone is an antibacterial drug used to treat leprosy, dermatitis herpetiformis, and other conditions. It works by inhibiting bacterial synthesis of dihydrofolic acid. Common side effects include nausea, headache, and rash. Severe side effects include methemoglobinemia and blood disorders. Dapsone is generally taken once daily but the dosage varies depending on the condition being treated and patient age. It can interact with other medications in ways that affect absorption or increase the risk of side effects.
This document discusses various classes of antibiotics - polyenes and polypeptides. It provides details about Amphotericin B, Nystatin, Hamycin in the polyene class and Bacitracin, Polymyxin-B, Colistin/Polymyxin-E, and Dactinomycin/Actinomycin-D in the polypeptide class. It describes their origins, mechanisms of action, therapeutic uses, dosages and adverse effects.
The drugs included in the presentation are Methotrexate, Cyclosporine, Azathioprine, Cyclophosphamide, Mycophenolate mofetil and Intravenous Immunoglobulin.
It is useful mainly for dermatologists.
The document summarizes quinolones and fluoroquinolones. Quinolones are a family of synthetic broad-spectrum antibacterial drugs that prevent bacterial DNA from duplicating. Fluoroquinolones are derived from quinolones and have an even broader spectrum. They are classified into generations based on their spectrum, with later generations having increased gram-positive and atypical coverage. Fluoroquinolones are generally well-absorbed, penetrate tissues deeply, and have few drug interactions or side effects, making them preferred drugs. However, their overuse has led to increasing antimicrobial resistance.
This document discusses macrolide antibiotics. It begins by introducing macrolides as a class of antibiotics characterized by a macrocyclic lactone ring to which sugars are attached. It then focuses on individual macrolides including erythromycin, clarithromycin, azithromycin, roxithromycin, and spiramycin. The document discusses the mechanism of action, spectrum of activity, resistance, pharmacokinetics, uses, interactions, and adverse effects of macrolide antibiotics.
1) Aminoglycosides are polybasic amino groups linked glycosidically to aminosugar compounds. They are highly water soluble and excreted unchanged in urine.
2) They are bactericidal, inhibiting protein synthesis by binding to the 30S/50S interface of bacterial ribosomes. This causes misreading of mRNA and nonfunctional protein formation.
3) Common adverse effects include ototoxicity (hearing loss) and nephrotoxicity. Individual drugs vary in their specific toxicities.
Methotrexate is an antifolate drug that inhibits dihydrofolate reductase (DHFR), blocking the production of nucleotides needed for DNA synthesis. It is used to treat cancers like acute lymphoblastic leukemia as well as autoimmune diseases like rheumatoid arthritis. Methotrexate is transported into cells and polyglutamated, increasing its intracellular activity and half-life. It causes cell death by inhibiting DNA synthesis and inducing strand breaks. Resistance can develop through reduced polyglutamation, increased DHFR levels, or drug efflux pumps. The cytotoxic effects of methotrexate are S-phase specific and depend on drug concentration and duration of exposure.
Apremilast is a small molecule inhibitor of phosphodiesterase 4 approved for treatment of moderate to severe plaque psoriasis and active psoriatic arthritis. It works by downregulating inflammatory immune mediators. Pharmacokinetically, it has good oral bioavailability and undergoes extensive metabolism. Clinical trials showed apremilast improved signs and symptoms of psoriasis and psoriatic arthritis over both short and long term use. The most common side effects are diarrhea, upper respiratory tract infection, and nausea. Apremilast is approved in Europe and the US for patients with psoriasis or psoriatic arthritis with inadequate response or intolerance to other systemic therapies.
This document discusses antiprotozoal drugs used to treat various protozoal infections. It covers drugs used to treat trypanosomiasis, giardiasis, trichomoniasis, and toxoplasmosis. For each infection, it describes the causative protozoa, clinical features, and treatment recommendations including first-line and alternative drug options along with their mechanisms of action, pharmacokinetics, therapeutic uses, dosing, and toxicity profiles. Key drugs discussed include metronidazole, tinidazole, secnidazole, nifurtimox, benznidazole, suramin, pentamidine, melarsoprol, and enflornithine
1. The document discusses drug therapy for Hansen's disease (leprosy), including the historical use of dapsone and the current multidrug therapy (MDT) regimen.
2. MDT combines dapsone, rifampicin, and clofazimine to treat multibacillary leprosy, reducing the treatment duration and risk of resistance. Paucibacillary leprosy is treated with rifampicin, dapsone, and a shorter course of 6 months.
3. Leprosy reactions include Type 1 (reversal reaction) treated with corticosteroids and Type 2 (Erythema Nodosum Leprosum) initially treated with cort
The document discusses two types of adverse cutaneous drug reactions: drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). DRESS is characterized by a skin eruption, hematologic abnormalities like eosinophilia, and internal organ involvement. It has a delayed onset and can cause long-term complications. AGEP presents with sudden onset of fever and a pustular rash, but does not involve internal organs. Both can be life-threatening but typically resolve after stopping the culprit drug.
This document summarizes anti-tubercular and anti-leprotic drugs. It discusses the classification, mechanism of action, pharmacokinetics, resistance, and adverse effects of first and second-line anti-tubercular drugs like isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin. It also discusses anti-leprotic drugs like dapsone, clofazimine, rifampicin, and others. Dapsone is the oldest, cheapest, and most commonly used anti-leprotic, but can cause haemolytic anemia in G-6-PD deficient individuals.
1. Acetaminophen is an effective over-the-counter analgesic with few side effects at recommended doses but can cause liver damage in high doses, especially with alcohol use.
2. Antiepileptic drugs and certain antidepressants are used as adjuvant analgesics for neuropathic pain conditions by various mechanisms such as blocking sodium channels, enhancing GABA, or inhibiting glutamate.
3. Gabapentin, pregabalin, and some antidepressants are first-line treatments for neuropathic pain and are generally well-tolerated but require gradual titration to effective doses to reduce side effects like drowsiness.
The document discusses various types of anticancer drugs including alkylating agents like cisplatin and cyclophosphamide, antimetabolites like methotrexate and 5-fluorouracil, and targeted drugs. It describes their mechanisms of action, toxicities, and common uses in treating cancers like breast cancer, leukemia, lymphoma, and others. The goal of cancer chemotherapy is to cure cancer when possible or induce remission, but the drugs can also be used for palliation to reduce tumor size and prolong life when the cancer is not curable.
Immunomodulators can stimulate or suppress the immune system. There are several classes of immunomodulators including glucocorticoids, calcineurin inhibitors, antiproliferatives, and biologicals. Glucocorticoids have broad anti-inflammatory effects and work by binding to receptors that regulate gene transcription. Calcineurin inhibitors like tacrolimus and cyclosporine inhibit T cell activation. Antiproliferatives such as azathioprine, mycophenolate mofetil, and methotrexate inhibit lymphocyte proliferation. Biologicals include monoclonal antibodies that target specific molecules. Immunomodulators are used to prevent transplant rejection and treat autoimmune disorders but can have side
This document discusses topical corticosteroids (TCS). It begins by describing the discovery and structure of corticosteroids. It then covers the pharmacokinetics of TCS, noting they are distributed in the skin and absorbed systemically before being metabolized in the liver. The potency of a TCS preparation depends on its structure, vehicle, and skin condition. The document outlines the anti-inflammatory, antiproliferative, and atrophogenic mechanisms of action of TCS. It concludes by listing common indications and side effects of TCS.
This document summarizes information about the drug dapsone, including:
1. Dapsone was invented in the early 20th century and is commonly used to treat leprosy in combination with other drugs.
2. It is absorbed after oral administration and metabolized in the liver. Common side effects include anemia, nausea, and rashes.
3. Analytical methods like HPLC and spectroscopy can be used to detect and quantify dapsone in samples.
- Macrolides are a class of antibiotics that are produced by Streptomyces bacteria and contain a macrocyclic lactone ring. Erythromycin was the first macrolide discovered in 1952.
- Macrolides work by attaching to the 50S subunit of bacterial ribosomes and inhibiting protein synthesis. They are bacteriostatic and have selectivity for bacterial over mammalian cells.
- Common macrolides include erythromycin, clarithromycin, roxithromycin, and azithromycin. They are effective against many gram-positive bacteria and some gram-negatives. Azithromycin has the broadest spectrum of activity.
This document discusses macrolide antibiotics, including their structure, examples (erythromycin, azithromycin), mechanism of action, spectrum of activity, resistance, pharmacokinetics, adverse effects, drug interactions, and contraindications. Macrolides bind to the bacterial ribosome and inhibit protein synthesis, generally being bacteriostatic. Their spectrum includes many gram-positive bacteria and some intracellular pathogens. Resistance can occur via efflux pumps or ribosomal mutations. Adverse effects include gastrointestinal issues and ototoxicity. Macrolides can interact with drugs metabolized by CYP450 enzymes.
Topical corticosteroids are powerful anti-inflammatory drugs that are classified based on their potency from mild to very potent. More potent corticosteroids are associated with greater risk of side effects. They work by preventing the formation of inflammatory molecules. Their absorption and effect can be enhanced by certain vehicle formulations, occlusion, damaged skin barriers, and other factors. Guidelines recommend restricting very potent corticosteroid use to small areas for short periods to reduce risk of side effects like skin atrophy.
Dapsone is an antibacterial drug used to treat leprosy, dermatitis herpetiformis, and other conditions. It works by inhibiting bacterial synthesis of dihydrofolic acid. Common side effects include nausea, headache, and rash. Severe side effects include methemoglobinemia and blood disorders. Dapsone is generally taken once daily but the dosage varies depending on the condition being treated and patient age. It can interact with other medications in ways that affect absorption or increase the risk of side effects.
This document discusses various classes of antibiotics - polyenes and polypeptides. It provides details about Amphotericin B, Nystatin, Hamycin in the polyene class and Bacitracin, Polymyxin-B, Colistin/Polymyxin-E, and Dactinomycin/Actinomycin-D in the polypeptide class. It describes their origins, mechanisms of action, therapeutic uses, dosages and adverse effects.
The drugs included in the presentation are Methotrexate, Cyclosporine, Azathioprine, Cyclophosphamide, Mycophenolate mofetil and Intravenous Immunoglobulin.
It is useful mainly for dermatologists.
The document summarizes quinolones and fluoroquinolones. Quinolones are a family of synthetic broad-spectrum antibacterial drugs that prevent bacterial DNA from duplicating. Fluoroquinolones are derived from quinolones and have an even broader spectrum. They are classified into generations based on their spectrum, with later generations having increased gram-positive and atypical coverage. Fluoroquinolones are generally well-absorbed, penetrate tissues deeply, and have few drug interactions or side effects, making them preferred drugs. However, their overuse has led to increasing antimicrobial resistance.
This document discusses macrolide antibiotics. It begins by introducing macrolides as a class of antibiotics characterized by a macrocyclic lactone ring to which sugars are attached. It then focuses on individual macrolides including erythromycin, clarithromycin, azithromycin, roxithromycin, and spiramycin. The document discusses the mechanism of action, spectrum of activity, resistance, pharmacokinetics, uses, interactions, and adverse effects of macrolide antibiotics.
1) Aminoglycosides are polybasic amino groups linked glycosidically to aminosugar compounds. They are highly water soluble and excreted unchanged in urine.
2) They are bactericidal, inhibiting protein synthesis by binding to the 30S/50S interface of bacterial ribosomes. This causes misreading of mRNA and nonfunctional protein formation.
3) Common adverse effects include ototoxicity (hearing loss) and nephrotoxicity. Individual drugs vary in their specific toxicities.
Methotrexate is an antifolate drug that inhibits dihydrofolate reductase (DHFR), blocking the production of nucleotides needed for DNA synthesis. It is used to treat cancers like acute lymphoblastic leukemia as well as autoimmune diseases like rheumatoid arthritis. Methotrexate is transported into cells and polyglutamated, increasing its intracellular activity and half-life. It causes cell death by inhibiting DNA synthesis and inducing strand breaks. Resistance can develop through reduced polyglutamation, increased DHFR levels, or drug efflux pumps. The cytotoxic effects of methotrexate are S-phase specific and depend on drug concentration and duration of exposure.
Apremilast is a small molecule inhibitor of phosphodiesterase 4 approved for treatment of moderate to severe plaque psoriasis and active psoriatic arthritis. It works by downregulating inflammatory immune mediators. Pharmacokinetically, it has good oral bioavailability and undergoes extensive metabolism. Clinical trials showed apremilast improved signs and symptoms of psoriasis and psoriatic arthritis over both short and long term use. The most common side effects are diarrhea, upper respiratory tract infection, and nausea. Apremilast is approved in Europe and the US for patients with psoriasis or psoriatic arthritis with inadequate response or intolerance to other systemic therapies.
This document discusses antiprotozoal drugs used to treat various protozoal infections. It covers drugs used to treat trypanosomiasis, giardiasis, trichomoniasis, and toxoplasmosis. For each infection, it describes the causative protozoa, clinical features, and treatment recommendations including first-line and alternative drug options along with their mechanisms of action, pharmacokinetics, therapeutic uses, dosing, and toxicity profiles. Key drugs discussed include metronidazole, tinidazole, secnidazole, nifurtimox, benznidazole, suramin, pentamidine, melarsoprol, and enflornithine
1. The document discusses drug therapy for Hansen's disease (leprosy), including the historical use of dapsone and the current multidrug therapy (MDT) regimen.
2. MDT combines dapsone, rifampicin, and clofazimine to treat multibacillary leprosy, reducing the treatment duration and risk of resistance. Paucibacillary leprosy is treated with rifampicin, dapsone, and a shorter course of 6 months.
3. Leprosy reactions include Type 1 (reversal reaction) treated with corticosteroids and Type 2 (Erythema Nodosum Leprosum) initially treated with cort
The document discusses two types of adverse cutaneous drug reactions: drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). DRESS is characterized by a skin eruption, hematologic abnormalities like eosinophilia, and internal organ involvement. It has a delayed onset and can cause long-term complications. AGEP presents with sudden onset of fever and a pustular rash, but does not involve internal organs. Both can be life-threatening but typically resolve after stopping the culprit drug.
This document summarizes anti-tubercular and anti-leprotic drugs. It discusses the classification, mechanism of action, pharmacokinetics, resistance, and adverse effects of first and second-line anti-tubercular drugs like isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin. It also discusses anti-leprotic drugs like dapsone, clofazimine, rifampicin, and others. Dapsone is the oldest, cheapest, and most commonly used anti-leprotic, but can cause haemolytic anemia in G-6-PD deficient individuals.
1. Acetaminophen is an effective over-the-counter analgesic with few side effects at recommended doses but can cause liver damage in high doses, especially with alcohol use.
2. Antiepileptic drugs and certain antidepressants are used as adjuvant analgesics for neuropathic pain conditions by various mechanisms such as blocking sodium channels, enhancing GABA, or inhibiting glutamate.
3. Gabapentin, pregabalin, and some antidepressants are first-line treatments for neuropathic pain and are generally well-tolerated but require gradual titration to effective doses to reduce side effects like drowsiness.
The document discusses various types of anticancer drugs including alkylating agents like cisplatin and cyclophosphamide, antimetabolites like methotrexate and 5-fluorouracil, and targeted drugs. It describes their mechanisms of action, toxicities, and common uses in treating cancers like breast cancer, leukemia, lymphoma, and others. The goal of cancer chemotherapy is to cure cancer when possible or induce remission, but the drugs can also be used for palliation to reduce tumor size and prolong life when the cancer is not curable.
Immunomodulators can stimulate or suppress the immune system. There are several classes of immunomodulators including glucocorticoids, calcineurin inhibitors, antiproliferatives, and biologicals. Glucocorticoids have broad anti-inflammatory effects and work by binding to receptors that regulate gene transcription. Calcineurin inhibitors like tacrolimus and cyclosporine inhibit T cell activation. Antiproliferatives such as azathioprine, mycophenolate mofetil, and methotrexate inhibit lymphocyte proliferation. Biologicals include monoclonal antibodies that target specific molecules. Immunomodulators are used to prevent transplant rejection and treat autoimmune disorders but can have side
This document discusses mechanisms of action, types, doses, side effects, indications, and contraindications of immunomodulators and management of organ transplant rejection. It begins by defining immunosuppressants and immunostimulants. It then describes several classes of immunosuppressants including calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors like sirolimus, antiproliferative agents, corticosteroids, cytotoxic drugs, and biological agents. For each drug or class, the document discusses mechanisms of action, pharmacokinetics, clinical uses, and adverse effects. The overall purpose is to provide medical students information on immunomodulators used to prevent organ transplant rejection and treat
Kidney transplantation is the most effective therapy for end-stage renal disease. The transplanted organ can come from a live or deceased donor. Immunosuppressive medications are used to prevent rejection and include corticosteroids, calcineurin inhibitors, mTOR inhibitors, and antimetabolites. Common post-transplant complications include acute rejection, infections like cytomegalovirus, and chronic allograft dysfunction.
This document discusses various classes of immunosuppressant drugs used to prevent rejection of transplanted organs or treat autoimmune diseases. It describes glucocorticoids, calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors like sirolimus and everolimus, antiproliferative agents, biological agents targeting cytokines like TNF inhibitors, monoclonal antibodies, adhesion molecule inhibitors, and tolerogens. Specific drugs are discussed within each class along with their mechanisms of action, pharmacokinetics, and adverse effects.
This document provides information on various types of anti-cancer drugs, including their mechanisms of action, uses, and side effects. It discusses alkylating agents, antimetabolites, natural products/taxanes, antibiotics, platinum compounds, and drugs that alter the hormonal milieu. It also classifies anti-cancer drugs according to how they directly act on cells and their mechanism of action. Key drugs discussed include chlorambucil, cyclophosphamide, busulfan, methotrexate, fluorouracil, doxorubicin, paclitaxel, etoposide, and hydroxyurea.
DMARDs are used to decrease pain, inflammation, and prevent joint damage in rheumatoid arthritis. They work by limiting inflammation early in the disease course before structural damage occurs. The traditional DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, while biologic DMARDs target cytokines like TNF-α. Methotrexate is usually the first choice due to its efficacy and safety profile. DMARD therapy should be started aggressively within 3 months of diagnosis to prevent long-term disability. Combination therapy and treatment adherence are important to control symptoms and progression of rheumatoid arthritis.
The document summarizes various immunosuppressant drugs used to prevent rejection of organ transplants. It discusses calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors sirolimus and everolimus, antiproliferative drugs, glucocorticoids, and biological agents. Cyclosporine inhibits T-cell activation by blocking calcineurin. Tacrolimus is more potent than cyclosporine. Sirolimus inhibits T-cell proliferation by blocking mTOR. Other drugs discussed include azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, chlorambucil, prednisone, infliximab,
This document discusses renal transplantation, including its history, immunosuppression medications and regimens, complications, and follow up care. It notes that the first successful kidney transplant was performed in 1954. Modern immunosuppression involves the use of corticosteroids, calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors like sirolimus, and antimetabolites to prevent rejection while managing side effects. Common complications include infection, acute rejection, chronic allograft dysfunction, and malignancy. Patients require lifelong follow up including routine blood and urine tests and management of any complications.
Rheumatoid arthritis is an autoimmune disorder that causes chronic inflammation of the joints. It can affect many tissues and organs but principally attacks the joints, causing swelling and pain and potentially resulting in damage to cartilage and bones. Disease-modifying antirheumatic drugs are commonly used treatments and include immunosuppressants like methotrexate as well as biologic agents that target inflammatory cytokines like TNF-alpha. Corticosteroids may also be used as adjuvant therapy to reduce inflammation.
This document discusses chemotherapy and its use in treating cancer. It begins by defining chemotherapy as using chemical agents that are selectively toxic to cancer cells. The objectives of chemotherapy are to maximize cancer cell death, cure the patient if possible, control tumor growth if a cure is not possible, and extend lifespan and quality of life. It then describes how chemotherapy works by targeting cells that are actively dividing, explains the cell cycle and how different drugs work at specific phases, and classifies common chemotherapy drugs like alkylating agents and antimetabolites. Side effects of chemotherapy like bone marrow suppression and nausea are also summarized.
Chemotherapy and rdiotherapy by heena mehtamehtaheena
This document discusses chemotherapy and its use in treating cancer. It begins by defining chemotherapy as using chemical agents that are selectively toxic to cancer cells. The objectives of chemotherapy are to maximize cancer cell death, cure the patient if possible, control tumor growth if a cure is not possible, and extend lifespan and quality of life. It then explains how chemotherapy works by targeting cells that are actively dividing, specifically during the S and M phases of the cell cycle. The document classifies chemotherapy drugs and discusses their mechanisms of action and side effects, focusing on alkylating agents and anti-metabolites.
This document summarizes several types of immunosuppressant drugs used to inhibit immune responses for organ transplantation and autoimmune diseases. It describes calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors like sirolimus, antiproliferative drugs like azathioprine and mycophenolate mofetil, glucocorticoids like prednisone, and biological agents like TNFα inhibitors and IL-2 receptor antagonists. It provides details on the mechanisms of action, pharmacokinetics, adverse effects and uses of these major immunosuppressive drug classes and examples like cyclosporine, tacrolimus and sirolimus.
This document discusses disease modifying anti-rheumatic drugs (DMARDs) used to treat rheumatoid arthritis. It describes two main categories of DMARDs - synthetic DMARDs like methotrexate, sulfasalazine, and hydroxychloroquine, and biological DMARDs that target specific proteins in the immune system like TNF inhibitors etanercept and infliximab. It provides details on the mechanisms of action, dosages, and side effects of various DMARDs commonly used as first-line and subsequent options for treating rheumatoid arthritis.
Therapeutic drug monitoring for immunosuppressive agents ( organ transplants)pavithra vinayak
Therapeutic drug monitoring (TDM) is used to measure drug concentrations in body fluids to aid in managing drug therapy for diseases. TDM is integral for immunosuppressive drugs used after organ transplants as they have a narrow therapeutic index and concentrations vary between individuals. Common immunosuppressive drugs monitored include cyclosporine, tacrolimus, sirolimus, and mycophenolic acid. Monitoring is important as supratherapeutic and subtherapeutic concentrations of these drugs can have serious negative health outcomes for transplant recipients. Factors like metabolism, drug interactions, and individual pharmacokinetics require close monitoring to optimize efficacy and safety.
Malignant diseases account for many deaths in developed countries. Cancer chemotherapy aims to palliate symptoms, induce remission, and possibly cure. There are several classes of anticancer drugs including alkylating agents, antimetabolites, and antibiotics. Alkylating agents like cyclophosphamide work by alkylating DNA and inhibiting cell replication. Antimetabolites like fluorouracil interfere with DNA synthesis by blocking thymidylate synthetase. New drugs undergo long testing including pre-clinical and four phases of clinical trials to evaluate safety, efficacy, and appropriate dosage before approval.
This document discusses cytotoxic drugs used in chemotherapy. It begins by defining cytotoxic agents as drugs that destroy or inhibit the growth of malignant cells. It then provides details on various classes of cytotoxic drugs including alkylating agents, platinum coordination complexes, antimetabolites, topoisomerase inhibitors, antibiotics, and targeted therapies. For each drug class and individual drugs, it describes mechanisms of action, indications, dosages, administration routes, metabolism, toxicities and resistance mechanisms. The document provides an in-depth review of cytotoxic chemotherapy agents.
The document discusses immunosuppression in renal transplant patients. It explains that immunosuppression involves reducing the immune system's activation to prevent rejection of transplanted organs. Several immunosuppressive drug classes and agents are described, including corticosteroids, calcineurin inhibitors, mTOR inhibitors, antiproliferatives, and antibodies. The principles of immunosuppressive treatment include starting suppression before immunogen exposure, using multiple low-dose drugs to minimize toxicity risks from over-immunosuppression. Induction therapy provides potent initial suppression while maintenance therapy prevents long-term rejection.
Similar to Cytotoxic agents used in dermatology (20)
Gene therapy involves introducing genetic material into cells to treat or prevent disease. It has the potential to cure genetic disorders by correcting the underlying genetic defect. There are two main types - somatic gene therapy, which affects only targeted cells and is safer, and germline gene therapy which can permanently alter the genes and be passed to offspring. Recent advances include FDA-approved CAR-T immunotherapies for cancer and the first gene therapy approved for an inherited retinal disease. Challenges remain regarding delivery methods, safety, and ethical issues.
This document discusses stereoisomers in pharmacology. It begins with an introduction to stereochemistry and the three types of isomers - constitutional, configurational, and conformational. It then discusses the history of isomerism, chirality, enantiomers, and nomenclature systems. The document outlines important differences between single enantiomers and racemic mixtures in terms of pharmacokinetic and pharmacodynamic properties. It provides several examples to illustrate these differences. Finally, the document concludes that increasing availability of single-enantiomer drugs can provide safer, better tolerated, and more efficacious treatments compared to racemic mixtures.
Recent advances in the treatment of diabetes mellituschandiniyrao
Recent advances in the treatment of diabetes mellitus include newer drug classes and delivery methods. Newer drug classes target the incretin system through GLP-1 agonists and DPP-4 inhibitors, sodium-glucose transporters with SGLT2 inhibitors, and amylin signaling with pramlintide. Improved insulin formulations include long-acting insulins glargine and degludec. Novel delivery methods involve insulin pumps for continuous subcutaneous delivery and inhaled formulations. Emerging therapies aim to preserve beta cell function through stem cell technology, anti-CD3 antibodies, and gene therapies.
- GABA is the major inhibitory neurotransmitter in the mammalian brain. It acts through GABAA, GABAB, and GABAC receptors.
- GABAA receptors are ligand-gated chloride channels modulated by drugs like benzodiazepines, barbiturates, and general anesthetics. GABAB receptors are G-protein coupled receptors that inhibit neurotransmitter release and hyperpolarize neurons.
- Drugs that enhance GABAergic transmission through GABAA receptors like benzodiazepines are used as sedatives, anxiolytics, and anticonvulsants. The GABAB agonist baclofen is used as a muscle relaxant for spastic
- Biosimilars are biologic medical products that are similar but not identical copies of original biologic drugs. They are developed when the patent expires on the original product.
- Regulatory agencies have stringent approval criteria for biosimilars to demonstrate similar quality, safety and efficacy as the reference product. Clinical trials must show comparable pharmacokinetics, pharmacodynamics and immunogenicity.
- While biosimilars increase access and lower costs, they are not generic copies and have unique safety profiles. Automatic substitution is not appropriate and unique nonproprietary names and labeling is required to facilitate pharmacovigilance.
Nitric oxide (NO) is an important signalling molecule in the body that regulates many physiological processes. It is synthesized by nitric oxide synthase enzymes from L-arginine and oxygen. NO signals through activation of soluble guanylate cyclase and production of cyclic GMP. It has diverse effects in the cardiovascular, immune, and nervous systems and is involved in processes like vasodilation, neurotransmission, and inflammation. Both insufficient and excessive NO production can contribute to disease.
This document discusses newer drug delivery systems that provide targeted and sustained drug release. It begins by introducing drug delivery systems and their basic parameters of route of entry and dosage form. It then discusses the need for multidisciplinary approaches to drug delivery due to slow progress treating severe diseases. Newer systems aim for targeted delivery and sustained release formulations. These systems increase efficacy, provide site-specific delivery, decrease toxicity and side effects, and improve convenience and patient compliance. The document goes on to describe various drug delivery systems including carrier-based, transdermal, mucoadhesive, and osmotically-controlled systems. It provides examples of specific drug delivery carriers, formulations, and medical devices. In general, these newer systems provide improvements
This document discusses neuroactive steroids, which are steroids synthesized in the brain or other endocrine glands that rapidly alter neuronal excitability through interaction with receptors. They can have inhibitory or excitatory effects and are involved in many neurological and psychiatric conditions. Neuroactive steroids are also implicated in sex differences in brain disorder susceptibility. While their roles are increasingly understood, key questions remain regarding their regulatory mechanisms and impact on specific brain conditions and gender differences. Further research is needed to clarify their molecular mechanisms of action and therapeutic potential.
The document discusses the transmitters and receptors of the autonomic nervous system (ANS). It covers the main transmitters - acetylcholine (ACh) and norepinephrine (NE). It describes the synthesis, storage, and release of ACh at cholinergic synapses and its transmission via nicotinic and muscarinic receptors. It also discusses the synthesis and metabolism of NE, its transmission via alpha and beta adrenergic receptors, and the mechanisms of cholinergic and adrenergic receptor signal transduction. Additionally, it covers neuromodulation via pre-synaptic and post-synaptic mechanisms and examples such as autoinhibition of noradrenergic nerve terminals.
Review on various families of drug transporters in our body, their functions & drugs acting through them & drug interactions involving these transporters
This document summarizes the treatment of hypertension. It discusses various classes of antihypertensive drugs including those acting on the renin-angiotensin-aldosterone system like ACE inhibitors, ARBs, and aldosterone antagonists. It also discusses calcium channel blockers, diuretics, beta blockers, and other miscellaneous drugs. Combination drug therapy and treatment of resistant hypertension is also covered. Lifestyle modifications including diet, exercise, weight loss, and limiting alcohol are recommended as first-line treatment.
This document provides a history of anesthesia, alkaloids, antibiotics, and cardiovascular drugs. It discusses key discoveries and scientists such as:
- Discovery of nitrous oxide, ether, and other inhaled anesthetics for pain relief during surgery in the 18th-19th centuries.
- Isolation of important alkaloids from plants including quinine, atropine, pilocarpine, and curare.
- Milestones in antibiotic discovery including prontosil, penicillin, and streptomycin and their impact on treating bacterial infections.
- Key events in insulin discovery and treatment of diabetes, as well as isolation of corticosteroids and thyroxine hormones.
This document provides a history of pharmacology from ancient civilizations to modern times. It discusses:
1) Early use of herbal remedies and natural substances in ancient India, China, Egypt, and Greece with no scientific basis.
2) Developments in the 17th-19th centuries including the establishment of pharmacology as a science based on experimentation and observation.
3) Pioneers in pharmacology like Magendie, Bernard, and Abel who established the field through experimental studies of drugs like curare, strychnine, and epinephrine.
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Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
• Pitfalls and pivots needed to use AI effectively in public health
• Evidence-based strategies to address health misinformation effectively
• Building trust with communities online and offline
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Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
3. Introduction
Cytotoxic drugs (Anti-neoplastics) –
Drugs that contain chemicals toxic to cells,
preventing their replication or growth inhibit or
prevent the function of cells
Primary role - Cancer Rx
3
4. Others –
Rheumatoid diseases, steroid-resistant
muscle conditions, severe dermatologic diseases
Many normal cells are damaged along
with cancer cells.
Myelosuppression, mucosal irritation,
carcinogenesis, teratogenesis etc
4
7. Alkylating agents
Act independently of the cell cycle
Direct damage to DNA
- Alkylation:
(N7) guanine in DNA: main target
↓
Cross linking, Abnormal base pairing
7
8. Bifunctional agents:
Intra- & interchain cross-linking
↓
Interferes with replication
& transcription
↓
Cell death
(Apoptosis)
8
9. Cyclophosphamide
Derived from nitrogen mustard (Mechlorethamine).
1st synthesized in 1957
Effective cytotoxic & immunosuppressive
agent - Antineoplastic
Highest T.I.
9
10. 10
• Dermat –
Immunosuppressive &
“steroid-sparing’ agent.
Oral & IV preparations
• Cytotoxic effects
independent of the
cell cycle.
11. Cyclophosphamide
B cells > T Cells
Suppressor T cells > Helper T cells
(Rx of Advanced cutaneous T cell lymphoma & as
Immunosuppressant)
Resistance
- ↓ cellular penetration
- improved DNA repair
- ↑ drug metabolism.
11
13. Therapeutic guidelines -
• AntiCa dose: 100mg/𝒎 𝟐/day oral
500mg/𝒎 𝟐
/day IV
• Dermatological dose
- 2-3 mg/kg/day in divided doses,
4-6 wk delay in onset of action.
• IV pulse therapy:
- 0.5-1 g along with Dexamethasone(100mg)
- very severe or refractory Pemphigus .
(fewer A/E than daily oral dosing)
13
14. Adverse effects
Haemorrhagic cystitis & Bladder Ca –
• 5-41% of patients
• Metabolite responsible – Acrolein
• Rx: MESNA
- conjugates acrolein in the bladder & ↓ irritation.
- Orally or IV.
- prolonged or high-dose Rx with Cyclophosphamide
- ↑ fluid intake
• Unchecked bladder toxicity Bladder Ca
14
20. A/E of Alkylating agents
1. Bone marrow suppression
• Dose-limiting a/e
• Leukopenia &/or thrombocytopenia
(Less common with Cyclophosphamide)
• Opportunistic infections
(P.jiroveci, fungal infs,
reactivation of Hep B)
20
21. 2. Carcinogenesis
• Non Hodgkin’s Lymphoma, leukemia & SCC
• Cyclophosphamide - high doses for long
durations
• Chlorambucil - lower doses & for shorter
duration
3. Gastrointestinal
• Mucosal toxicity Nausea, Vomiting
• Rx: Ondansetron & Dexamethasone.
21
23. Contraindications -
Absolute –
1) Drug allergy
2) Depressed bone marrow function
3) Pregnancy & lactation
Relative –
1) Active infection
2) Impaired hepatic & renal function
3) Seizure/Mood disorder (Chlorambucil)
23
24. Antimetabolites
Drugs that interfere with >/=1 enzymes or
their reactions necessary for DNA synthesis.
Act as substitutes to actual metabolites used in
normal metabolism
Inhibit cell division @ S phase of cell cycle
24
28. TG -
Starting dose - 5-7.5mg/wk
(max of 15mg/wk)
↑ gradually to 10-25mg/wk if needed
2 methods of weekly administration:
28
Once wkly regimen
(10-25mg)
3 divided doses/wk
(2.5mg each orally
over a 24 hr period)
• Max – 30mg/wk
32. 5-Fluorouracil (5-FU)
• 1st demonstrated in 1950.
Since then - IV chemotherapeutic agent in Rx
of various Ca.
• 1963 – Used as topical agent
(20% FU used to treat extensive Actinic
keratosis.
• Structure –
analogue of Uracil.
32
38. PK -
• Well absorbed orally
• Metabolized to 6-mp
• Inactivation – Xanthine oxidase
(dose ↓ when given with allopurinol)
TG –
• Starting dose: 1-2 mg/kg/day.
• Started early (requires 6-8 wks for effect)
38
39. D/I -
Others:
XO inhibitors: Allopurinol
(most important)
ACEIs
Folate antagonists
• ↑ myelosuppressive action of Azathioprine.
39
55. References -
1) Comprehensive Dermatologic Drug Therapy –
Stephanie E. Wolverton
2) Pharmacological Basis of Therapeutics –
Goodman & Gilman
3) Basic & Clinical Pharmacology –
Katzung & Trevor
3) Rang & Dale’s Pharmacology
55
Editor's Notes
Cytotoxic drugs (sometimes known as antineoplastics) describe a group of medicines that contain chemicals which are toxic to cells, preventing their replication or growth, thereby inhibit or prevent the function of cells
Cytotoxic drugs are primarily used to treat cancer, frequently as part of a chemotherapy regime. (Cytotoxic drugs can prevent the rapid growth and division of cancer cells) Recently, their uses have expanded to treat certain skin conditions (e.g., psoriasis), rheumatoid and juvenile rheumatoid arthritis, and steroid-resistant muscle conditions.
these medications are used in severe dermatologic diseases, in which previously corticosteroids were the only effective treatment available. Cytotoxic drugs have the potential to improve survival and to decrease morbidity, by reducing the requirement for corticosteroid therapy.
They can also affect the growth of other quick dividing cells in the body, like hair follicles and the lining of the digestive system. As a result of the treatment, many normal cells are damaged along with the cancer cells.
In dermatology cytotoxic agents are used to treat severe &/or refractory skin diseases – recalcitrant psoriasis, mycosis fungoides, connective tissue disease, vasculitis, immunobullous disorders & neutrophilic dermatoses, to name a few.
When treating severe skin disease, these agents are typically used at immunomodulatory doses. The clinician must be aware of the risks of carcinogenesis, teratorgenesis & myelosuppression with increased potential of infection with these agents.
These CAs can damage rapidly dividing normal cells, this depresses both cellular as well as humoral immunity; this can be both beneficial as well as harmful; beneficial in Rx of various AIDs,
Harmful bcos likely to depress bone marrow, impair healing and depress growth , cause hair loss & GI disturbances. On prolonged use - depression of gametogenesis (particularly in men), leading to sterility, and an increased risk of acute non-lymphocytic leukaemia and other malignancies.
Cas may be divided into 2 general classes –
Antimetabolites
Alkylating agents.
Cytotoxic agents & cell cycle
Cas modulate the behavior of cells through inhibition of growth & development. Knowledge of ‘cell cycle’ is necessary to understand the mechanism of action of mny of these drugs.
(pic)
In brief the cell cycle begins with the G1 phase, which is directed towards preparing the cell for DNA synthesis.
The subsequent S phase is devoted to DNA synthesis. At the end of S phase. G2 phase or interphase occurs, f/b M phase of actual cell division. Some cells of the body may enter a G0 (resting) phase of indeterminate length, awaiting a stimulus or conditions upon which to re-enter the cell cycle.
Alkylating agents
Exert their effect by direct damage to DNA, usually through physicochemical interactions such as alkylation by forming covalent bonds with the nucleophilic centres of DNA. Leads to DNA cross linking, abnormal base pair formation, imidazole ring cleavage ultimately leading to cell death.
These agents act independently of the cell cycle. The nitrogen at position 7 (N7) of guanine, being strongly nucleophilic, is probably the main molecular target for alkylation in DNA, other bases are also alkylated albeit to lesser degrees.
Most of the cytotoxic anticancer alkylating agents are bifunctional, can cause intra- or interchain cross-linking (Fig. 55.3). This interferes not only with transcription, but also with replication cell death (apoptosis) which is probably the critical effect of anticancer alkylating agents. This forms a basis for their therapeutic and toxic properties
Cyclophosphamide
Is an alkylating agent derived from nitrogen mustard (mechlorethamine*). Was 1st synthesized by Arnold & Bourseaux in 1957. the most commonly used alkylating agent as it has the highest T.I. Effective cytotoxic & immunosuppressive agent.
While in oncology C is used as an antineoplastic agent, in dermatology it is used as an immunosuppressive & “steroid-sparing’ agent. Both oral & iv prepns of C are used in Dermat.
* Mechlorethamine was the first clinically used nitrogen mustard. Rarely used in clinical practise.
MOA
Cytotoxic effects are independent of the cell cycle.
. The primary metabolites of C are responsible for (a carbonium ion being the reactive intermediate)
C has greater effect on B Ls than T Ls & a greater effect on suppressor T cells than helper T cells. (1 of its uses – Rx of advanced cut T cell lymphoma & can also be used as an immunosuppressant)
Resistance to C may occur d/t decreased cellular penetration, improved DNA repair or increased drug metabolism.
PK –
Usually given orally Cyclophosphamide is well absorbed orally, has high B.A. (~75%). Maximal concentrations in plasma are achieved 1 hour after oral administration & plasma T1/2 is ~7hrs
It is inactive until metabolized in the liver by P450 enzyme Cyt P-450 system, the prodrug is converted to 4-hydroxyC which exists in equilibrium with Aldophosphamide. Both 4-HC & A readily diffuse into cells, where A is cleaved intracellulary to phosphoramide mustard, an active metabolite which is responsible for antitumor effects while acrolein causes hemorrhagic cystitis often seen during therapy with cyclophosphamide. A can also be converted to an inactive metabolite –carboxyphosphamide & C is excreted in the urine mainly in this form (30-60%), only <20% of unmetabolized drug is excreted in urine.
The usual oral dosage is 2-3 mg/kg/day in divided doses, there is often a 4-6 wk delay in onset of action.
Another form of cyclophosphamide administration is iv pulse therapy of 0.5-1 g along with dexamethasone.27 This combination regimen is indicated in cases of very severe pemphigus or those cases refractory to usual therapy. May be a/w fewer a/e than daily oral dosing.
The cyclophosphamide-dexamethasone pulse therapy regimen would be implemented with intervals of 21 or 28 days. On the first day sequential cyclophosphamide-dexamethasone pulses are done. On the second and third days, only dexamethasone is used. Cyclophosphamide (1000mg or 10-15 mg/kg) is diluted in 500ml of GS5%, infusing it in 3 to 4 hours. Dexamethasone 100mg (2ml ampoule with 25 mg - 4 ampoules) is diluted in 250 ml of GS5%, infusing it in 3 to 4 hours.
pulse therapy with cyclophosphamide guarantees better results than daily doses of the drug, and it also reduces the occurrence of side effects.(Dexa is known to increase the met of Cy)
A/E
H’gic cystitis & bladder Ca –
Bladder toxicity is probably the single most widely recognized consequence of C use (5-41% of pts Rx with C). Metabolite responsible – acrolein
Can be prevented by administering a scavenging thiol agent MESNA (sodium-2-mercaptoethane sulfonate). Acts by conjugating acrolein in the bladder & reduces irritation. Admin orally or iv.
MESNA is typically recommended for those taking oral C for prolonged periods &/or at a particularly high dose.
In addition increased fluid intake can also reduce bladder comlications.
Unchecked bladder toxicity can markedly increase the risk of TCC of bladder. May arise many yrs, or even decades after Rx & continued monitoring of lower urinary tract is indicated in all patients who have used the drug.
D/I
Chlorambucil
another alkylating agent also derived from N mustard. In derma Cl is used more rarely than C
MOA –
Same as that of C: cell-cycle indepedent alkylating agent that exerts its effects through direct damage to DNA via cross-linking.
PK-
Given orally, with 87% B.A., but food reduces its b.a. by 10-20%. Highly protein-bound to alb (99%), has plasma T1/2 of approx. 1.5 hrs.
Although the drug is metabolized by the liver, unlike C it doesn’t require activation in the liver, but more importantly the drug metabolism doesn’t yield acrolein & no risk of h’gic cystitis. (adv over C)
Therapeutic guidelines –
Supplied as 2mg tab.
Recommended dose: 0.05-0.2 mg/kg daily. For cut ds doses usually remains near the lower end of this range. Typically inductive doses range from 4-10 mg/day, & maintenance doses are often 2-4 mg/day od. Results are usually expected with 3-6 wks of continued use.
C
1. Bone marrow suppression –
Can cause acute myelosuppression with resultant leukopenia &/or thrombocytopenia (latter is less with C than other drugs)
Dose-limiting a/e immunosuppression – can be reversible @ usual doses, but opportunistic infs can occur (P.jiroveci, fungal infs, reactivation of Hep B)
Because of these 2 a/e C is used only in the most severe, recalcitrant dermatologcal ds.
2. Carcinogenesis –
In +n to risk of bladder Ca, C is also a/w devp of other Ca – NHL, leukemia & SCC. Following exposure to high doses for extended durations. However when used for Rx of most skin disorders there is probably a lesser risk d/t use of lesser doses & shorter courses.
3. GI –
M/c – N & V (can affect 70-90% of users). d/t mucosal toxicity. May require co-admn of ondansetron & dexamethasone. Addition of aprepitant mat provide even better anti-emetic action.
[Box 17-8]
4. Effects on skin –
Alopecia (usually reversible, can be permanent
..
Rarely urticarial & SJS.
5. Finally, all alkylating agents have toxic effects on the male and female reproductive systems, causing an often permanent amenorrhea, particularly in perimenopausal women, and an irreversible azoospermia in men.
Cl
A/E –
Gen a/e –
Altho Cl is relatively less toxic form of N. mustard, common a/e are similar to those of C – N & V, azoospermia, amenorrhoea, pul fibrosis, seizures, derma s/e & hepatotoxicity. In particular, the epileptogenic potential & mood alterations attributed to Cl are significant.
Carcinogenesis –
Admn of Cl particularly in transplant pts, Ca pts & pts with significant conn t. ds, a/w increased risk of secondary malignancies, particularly leukemia & SCC. Even seen with lower doses & for shorter duration of Rx as in dermatological ds. Therfore approp pt counselling & consent is indicated.
C
C/I (table)
Antimetabolites
Antimetabolites are drugs that interfere with one or more enzymes or their reactions that are necessary for DNA synthesis. They affect DNA synthesis by acting as a substitute to the actual metabolites that would be used in the normal metabolism (for example antifolates interfere with the use of folic acid). Thus they are more active during the S phase
Classifn –
Ams commonly used in derma –
Mtx, Aza, mycophenolate mofetil, top 5-FU, thioguanine & HU
Methotrexate
Folate antagonist & anti-folate, is the most commonly used antimetabolite in derma.
In the 1940s, during tests to determine the effect of folic acid on acute leukemia in children, the antifolate (methotrexate) was synthesized. It was later approved by the FDA as an oncologic drug in 1953.
Structurally Mtx is a chemical analogue of FA (consists of 3 elements - …)
MOA –
Potent comp antagonist of DHFR enz.
Folates are actively taken up into cells by folate transport system, where they are converted to polyglutamates. In order to act as coenzymes, folates must be reduced to tetrahydrofolate (FH4). This two-step reaction is catalysed by dihydrofolate reductase, which converts the substrate first to dihydrofolate (FH2), then to FH4 (Fig. 55.6). FH4 functions as an essential co-factor in the synthesis of purines, pyridines DNA. Methotrexate has a higher affinity than FH2 for dihydrofolate reductase and thus inhibits the enzyme (Fig. 55.6), depleting intracellular FH4.
Thus the overall effect of MTX is inhibition of cell division, specifically in the S phase of cell cycle. This is the basis for its immunosuppressive & cytotoxic effects. However its anti-inflammatory effect is not known to be d/t inhibition of DHFR. It is predom mediated by adenosine
PK-
Methotrexate is usually given orally (as it is readily absorbed from GIT) but but larger doses are absorbed incompletely and are routinely administered intravenously, can also be given intramuscularly or intrathecally
The drug has low lipid solubility and thus does not readily cross the blood–brain barrier. It is, however, actively taken up into cells and is metabolised to polyglutamate derivatives, which are retained in the cell for weeks (or even months in some cases)
Renal excretion is the main route of elimination; Up to 90% of a given dose is excreted unchanged in the urine within 48 hours.
Metabolism of methotrexate in humans usually is minimal. After high doses, however, metabolites are readily detectable; these include 7-hydroxy-methotrexate, which is potentially nephrotoxic. Therefore dose-adjustment is required in pts with renal insuffieciency.
The biologic effects of MTX can be reversed by administration of the reduced folate leucovorin (5-formyltetrahydrofolate) or by l-leucovorin, which is the active enantiomer. Leucovorin rescue (100mg/m2) is used in conjunction with highdose MTX therapy to rescue normal cells from undue toxicity
Therapeutic guidelines –
A usual starting dose of Mtx Rx is 5-7.5mg/wk (max of 15mg/wk) this dosage may be increased gradually to 10-25mg/wk if needed.
There are 2 methods of weekly administration: once wkly regimen (10-25mg) or 3 divided doses (2.5mg each) orally over a 24 hr period each wk. total weekly dose should not exceed 30mg. In gen, patients with psoriasis are able to achieve benefits at 10-15 mg/wk.
When max benefit is reached mtx may be tapered by 2.5mg/wk. in c/o im mtx
D/I –
Methotrexate should never be co-administered with trimethoprim–sulfamethoxazole, probenecid, salicylates, or other drugs that can compete with it for protein binding and thereby raise plasma concentrations to levels that may result in bone marrow suppression.
5-FU
Another anti-metabolite. 1st demo in 1950, since then widely used as an IV chemotherapeutic agent in Rx of various Ca. its use as top agent began in 1963 when 20% FU was used to treat pts with extensive Actinic keratosis.
Str – it’s a strl analogue of uracil with a fluorine atom at the C5 position instead of H.
MOA –
5-Fluorouracil (5-FU) is inactive in its parent form, converted to its active metabolite 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) by a series of enz reactions(ribosylation & phosphorylation). It forms a covalent bond with thymidylate synthetase & hence prevents conversion of DUMP to DTMP, thereby inhibiting DNA synthesis (like Mtx), also its metabolites are misincorporated into RNA & disrupt RNA synthesis as well.
PK-
5-FU is administered parenterally, because absorption after oral ingestion of the drug is unpredictable and incomplete.
However in dermat ds – top application preferred, bcos of 15-75x greater degree of sys absorption.
Intralesional inj of 5-FU have also been used for sm ds – keratoacanthomas, warts etc
Metabolism – after it enters skin 5-FU is converted to several active metabolites (FdUMP, FdUTP, FUTP). A key enzyme in the metabolic pathway is dihydropyrimidine DH (DPD) which converts 5-FU to dihydrofluorouracil (DHFU).
Therapeutic guidelines –
Available as 1, 2 & 5% solutions (applied twice daily) & 0.5, 1 & 5% creams (applied od). Treatment duration: 2-8 wks.
Azathioprine
Azathioprine (IMURAN, others) is a purine antimetabolite. It is an imidazolyl derivative of 6-mercaptopurine,
Azathioprine was first introduced as an immunosuppressive agent in 1961, helping to make allogeneic kidney transplantation possible.
During 1960s-1970s it became the DOC for organ transplantation. Apart from immunosuppression it has also got anti-inflammatory properties.
In dermatological practice it is used off-label as a steroid-sparing agent for auto-immune & inflammatory dermatoses.
MOA-
A metabolized to 6-thioguanine metabolites which are structurally similar to endo purines (adenine & guanine). Exact mech by which these purine analogs lead to immunosuppression & anti-inflammatory effects is not known. However d/t strl similarity 6-thioguanine may get incorporated into DNA & RNA inhibiting purine synthesis & cell division. Also A is known to depress T-cell mediated function & B-cell mediated Ab production which is of central importance in immunobullous dermatoses.
PK-
Azathioprine is well absorbed from the gastrointestinal tract, The t1/2 of azathioprine is ~10 minutes, while that of its metabolite, 6-mercaptopurine, is ~1 hour.
metabolized primarily to mercaptopurine. Xanthine oxidase converts much of the active material to 6-thiouric acid prior to excretion in the urine
Since much of the drug’s inactivation depends on xanthine oxidase, patients who are also receiving allopurinol (see Chapters 36 and 54) for control of hyperuricemia should have the dose of azathioprine reduced to onefourth to one-third the usual amount to prevent excessive toxicity
Therapeutic guidelines –
The usual starting dosage is 1-2 mg/kg/day. Because it generally takes 6-8 weeks to achieve therapeutic effect, azathioprine often is started early in the course of disease management.
D/I –
Most imp d/I occurs between A & allopurinol.
Other drugs which increase myelosuppressive property of Az –
Mycophenolate mofetil
Is a semisynthetic derivative of Mycophenolic acid which is a product obtained from the fungus Penicillium
An antimetabolite
Str-
2-morpholinoethyl ester of mycophenolic acid (MPA).
MOA –
Basically a purine synthesis inhibitor. MMF is a prodrug that is rapidly hydrolyzed to the active drug, MPA, a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), an important enzyme in the de novo pathway of guanine nucleotide synthesis. B and T lymphocytes are highly dependent on this pathway for cell proliferation. Therefore MMF inhibits proliferation of T & B Ls, & reduced the production of cytotoxic T cells.
PK-
Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid. Approx 97% of MPA is bound to alb.
MPA is then inactivated by glucuronidation. T1/2 - ~16-18 hrs. Elimination – urine as inactive glucuronide.
Therapeutic guidelines-
MMF is used increasingly to Rx inflamm & AIDs in derma in dosages ranging from 1-2g/day orally.
Hydroxyurea
Was 1st synthesized by Dressler & Stein in 1869. over time it has been used to treat a variety of conditions m/cly heatological malignancies & SCA. In derma, HU is used mainly in psoriasis.
MOA-
.
Impairs DNA synthesis through inhibition of ribonucleotide diP reductase, an enz that reduces nucleotides to deoxynucleotides. This limits the supply of DNA bases available for synthesis, thereby resulting in strand breakage & cell death.
HU is also a radiation sensitizer, preventing cells from repairing damage d/t ultraviolet or ionizing radiation.
Lastly through hypomethylation HU alters gene expression. It is though that this effect may lead to improved differentiation in psoriatic skin.
HU is most effective in cells with a high proliferation index, as it acts upon cells entering S phase of the cell cycle, preferentially concentrated within leucocytes
TG –
Available as 500mg capsules. Typical dose range from 1-2g daily, usually as divided dose of 20-30mg/kg daily. Doses above 2g daily – toxic.
Older patients & those with renal impairment should receive starting doses of only 500mg/day.
MTX
A/E –
Hepatotoxicity –
Seen with long-term Rx – as in psoriasis & RA. Cumulative doses at or above 4.0 kg have been considered risky for Htoxicity.
2) Hematological effects – Pancytopenia presents with greatest potential for loss of life d/t Mtx, common with rheumat Rx, far fewer reports in dermat pts.
3) Carcinogenesis – incidences lymphomas, esp with use of Mtx in collagen vascular ds.
4) GI – N,V,D & ulcerative stomatitis. Presence of severe D with US requires cessation of Mtx Rx.
5) Reproductive effects –
Mtx has long been considered a potent teratogen & abortifacient. Women of child bearing age who take mtx should use reliable birth control.
6) Renal – high dose Rx (50-250mg/m2) renal toxicity secondary to pptn of mtx in renal tubules.
7) Pul toxicity – rarely, acute pneumonitis. Can occur with extremely small doses, life threatening if mtx is not stopped.
5-FU
A/E –
M/c ones localized to areas of Rx & include erythema, irritation, burning pain, pruritis, hypo-/hyperpigmentation. Also allergic contact dermatitis has been reported.
Sys a/e are extremely rare with top appln. However there is a single case report of life threatening toxicity in a patient treated with top 5% FU (who was found to have defcy of the key enz in metabolism of 5-FU, DPD)
Az
A/E –
Immunosuppression - The major side effect of azathioprine is bone marrow suppression, including leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon)
2) carcinogenesis- (related to immunosuppression)
The m/c malignancies a/w A in dermatological set up are – lymphoproliferative & SCCs.
3) Infections – d/t immunosuppression
Typically seen with high doses, or those on multiple immunosuppressive agents (eg organ transplant pts)
Eg. Herpes v, HPV, scabies etc.
4) HS synd
5) GI – NVD, rarely pancreatitis.
6) Hepatic – chronic admn of A has been a/w uncommon but life threatening hepatic damage. LFT monitoring mandatory
7) Teratogenicity
MMF
A/E –
The principal toxicities of MMF are gastrointestinal and hematologic. These include leukopenia, pure red cell aplasia, diarrhea, and vomiting. There also is an increased incidence of some infections, especially sepsis associated with cytomegalovirus; progressive multifocal leukoencephalopathy also has been reported in conjunction with the administration of MMF.
HU
A/E –
Myelosuppression-
m/c
Mild megaloblastic changes, frank anemia, leukopenia
2) Cut a/e-
Dermatomyositis-like eruption, lichenoid drug eruption resembling chronic GVHD, leg ulcers, limited & reversible alopecia.
C/I-
A: P (D), DA
R: cardiopul, hemat, hep, renal, inf