General Pharmacology 4 PDF

Anti- Infective Agents Anti-infective agents treat infection by suppressing or destroying the causative microorganisms – bacteria, mycobacteria, fungi, protozoa, or viruses, Antimicrobial agents are synthetic chemical substances that can kill or suppress the growth of microorganisms. Antibiotics ar...

Anti- Infective Agents Anti-infective agents treat infection by suppressing or destroying the causative microorganisms – bacteria, mycobacteria, fungi, protozoa, or viruses, Antimicrobial agents are synthetic chemical substances that can kill or suppress the growth of microorganisms. Antibiotics are soluble compound that are derived from certain microorganisms and that inhibit the growth of other microorganisms  Community-Acquired Versus Nosocomial Infections Infections are often categorized as community acquired or hospital acquired (nosocomial). Because the microbial environments differ, the two types of infections often have different etiologies and require different antimicrobial drugs. As a general rule, community-acquired infections are less severe and easier to treat. Nosocomial infections may be more severe and difficult to manage because they often result from drug-resistant microorganisms and occur in people whose resistance to disease is impaired. Drug-resistant strains of staphylococci, Pseudomonas, and Proteus are common causes of nosocomial infections.  Antibiotic-Resistant Microorganisms Contributing factors include Widespread use of antimicrobial drugs, especially broad-spectrum agents. Interrupted or inadequate antimicrobial treatment of infections. Type of bacteria. Type of infection. Condition of the host. Location or setting.Rational Use of Antimicrobial Drugs Avoid the use of broad-spectrum antibacterial drugs to treat trivial or viral infections; use narrow-spectrum agents when likely to be effective. Give antibacterial drugs only when a significant bacterial infection is diagnosed or strongly suspected or when there is an established indication for prophylaxis. These drugs are ineffective and should not be used to treat viral infections. Minimize antimicrobial drug therapy for fever unless other clinical manifestations or laboratory data indicate infection. Use the drugs along with other interventions to decrease microbial proliferation, such as universal precautions, medical isolation techniques, frequent and thorough handwashing, and preoperative skin and bowel cleansing. Follow recommendations of the Centers for Disease Control and Prevention for prevention and treatment of infections, especially those caused by drug-resistant organisms (eg, gonorrhea, penicillin- resistant streptococcal infections, methicillin-resistant staphylococcal infections, vancomycin-resistant enterococcal infections, and MDR- TB). Consult infectious disease physicians, infection control nurses, and infectious disease pharmacists about local patterns of drug-resistant organisms and treatment of complicated infections.  Initial, empiric therapy Because most laboratory tests to definitively identify causative organisms and to determine susceptibility to antibiotics require 48 to 72 hours, the physician usually prescribes for immediate administration a drug that is likely to be effective. This empiric therapy is based on an informed estimate of the most likely pathogen, given the client’s signs and symptoms and apparent site of infection. A single broad-spectrum antibiotic or a combination of drugs is often chosen. Culture and susceptibility studies Anti-infective agent should be :used only when A significant infection has been diagnosed or is strongly suspected. An established indication for prophylactic therapy exists.  Antimicrobial drugs are classified as either bacteriostatic or bactericidal. Bacteriostatic drugs arrest the growth and replication of bacteria, thus limiting the spread of infection while the body’s immune system attacks, immobilizes, and eliminates the pathogens. Bactericidal agent kills bacteria and the total number of viable organism decreases. This classification may be too simplistic because it is possible for an antibiotic to be bacteriostatic for one organism and cidal for another, e.g. chloramphenicol is static against gram negative rods and cidal against Pneumococci. Antimicrobial drugs are also classified in ac cording to their sites of action.  Chemotherapeutic Spectra The chemotherapeutic spectrum of a particular drug refers to the species of organisms affected by the drug. Narrow spectrum: chemotherapeutic agent acting only on a single or a limited group of microorganisms, e.g isoniazid is active only against Mycobacteria. Extended spectrum: chemotherapeutic effective against gram-positive organisms and also against a significant number of gram-negative bacteria. E.g. amppicillin. Broad spectrum: chemotherapeutic affect a wide variety of microbial species, e.g. tetracycline and chloramphenicol. Agents Used for the Treatment of Bacterial InfectionsI- inhibitors of cell wall synthesis  Beta-Lactam Antibiotics Penicillin (Penicilline G and V, Ampicillin, Amoxicillin, Pivampicillin) There are four groups of penicillins: natural penicillins, penicillinase-resistant penicillins, aminopenicillins, and the extended-spectrum penicillins. they inhibit the synthesis of bacterial cell walls and are considered bactericidal. They are used in gram- positive coccal (streptococcal and staphylococcal) infections, treatment of pneumococcal infections, otitis media, in gram-negative coccal (meningococcal, gonococcal) infections, syphilis. Penicillin G is susceptible to inactivation by β-lactamases enzymes, which hydrolyzes the β-lactam ring. Penicillin V is more acid stable than penicillin G often employed in the treatment of oral infection. Amoxicillin is broad- spectrum penicillin used in sinusitis otitis media, UTI, meningitis.  Methicillin, ticarcillin, carbencillin, mezlocillin, piperacillin must be administered intravenously or intramuscularly. Penicillin V, ampicillin amoxicillin are available as oral preparation. Adverse effects: hypersensitivity reactions, G.I upset diarrhea, platelet dysfunction. Nephrotoxicity. superinfection results.  Signs and Symptoms of Hypersensitivity to Penicillin Skin rash Urticaria (hives) Sneezing Wheezing Pruritus (itching) Bronchospasm (spasm of the bronchi) Laryngospasm (spasm of the larynx) Angioedema (also called angioneurotic edema)—swelling of the skin and mucous membranes, especially around and in the mouth and throat Hypotension—can progress to shock Signs and symptoms resembling serum sickness—chills, fever, edema, joint and muscle pain, and malaise  Lactamase Inhibitor Combinations Augmentin—combination of amoxicillin and clavulanic acid Timentin—combination of ticarcillin and clavulanic acid Unasyn—combination of ampicillin and sulbactam Zosyn—combination of piperacillin and tazobactam  B. Cephalosporin's The cephalosporin are β-lactam antibiotics that are closely related both structurally and functionally to the penicillin. They are classified as first, second or third generation, largely on the basis of bacterial susceptibility patterns and resistance to β-lactamases. Cephalosporin used in skin infections, osteomyelitis, pneumococcal pneumonia, respiratory and UTI. Adverse effects: a, renal damage, bleeding because anti-vitamin K effects, superinfections. gastrointestinal disturbances, such as nausea, vomiting, and diarrhea. Hypersensitivity (allergic) reactions may occur with administration of the cephalosporins and range from mild to life threatening. Mild hypersensitivity reactions include pruritus, urticaria, and skin rashes. More serious hypersensitivity reactions include Stevens- Johnson syndrome (fever, cough, muscular aches andpains, headache, and the appearance of lesions on the skin, mucous membranes, and eyes), hepatic and renal dysfunction, aplastic anemia (anemia due to deficient red blood cell production), and epidermal necrolysis (death of the epidermal layer of the skin). A cross-sensitivity reaction because of the close relation of the cephalosporins to penicillin, a patient allergic to penicillin also may be allergic to the cephalosporins. Other adverse reactions that may be seen with administration of the cephalosporins are headache, dizziness, nephrotoxicity (damage to the kidneys by a toxic substance), malaise, heartburn, and fever. Intramuscular (IM) administration often results in pain, tenderness, and inflammation at the injection site. Intravenous (IV) administration has resulted in thrombophlebitis and phlebitis. Therapy with cephalosporins may result in a bacterial or fungal superinfection. Diarrhea may be an indication of pseudomembranous colitis, which is one type of bacterial superinfection. C. Other agents affecting the cell wall Vancomycin. Used in life-threatening infection. Adverse effect includes fever, chills, flushing (“red man syndrome”) and shock, which result due to histamine release caused by rapid infusion, hearing loss. Bacitracin. It is active against a wide variety of gram-positive organisms. Its use is restricted to topical application because of its potential for nephrotoxicity.  II. Protein Synthesis Inhibitors A number of antibiotics exert their antimicrobial effects by targeting the bacterial ribosome, which has components that differ structurally from those of the mammalian ribosome.  Tetracyclines (Tetracycline,.1 Doxycycline, Demeclocycline,.Minocycline) As broad-spectrum antibiotics they are useful As broad-spectrum antibiotics they are useful in the treatment of the following conditions, rickettsial infections (rickettsial box, Rocky Mountain spotted fever) chlamydial infections (trachoma) bacillary infection (cholera) venereal infection (gonorrhea, syphilis) amebiasis. Tetracyclines are also used in situations in which penicillin is contraindicated, in the treatment of intestinal amebiasis, and in some skin and soft tissue infections. Tetracycline in combination with metronidazole and bismuth subsalicylate is useful in treating Helicobacter pylori (a bacteria in the stomach that can cause peptic ulcer).  Adverse effect hypersensitivity reactions, G.I irritation, hepatic dysfunction, phototoxicity, superinfections. A photosensitivity (phototoxic) reaction may be seen with this group of drugs, manifested by an exaggerated sunburn reaction when the skin is exposed to sunlight even for brief periods. The tetracyclines are not given to children younger than 9 years of age unless their use is absolutely necessary because these drugs may cause permanent yellowgray- brown discoloration of the teeth. The use of the tetracyclines, especially prolonged or repeated therapy, may result in bacterial or fungal overgrowth of nonsusceptible organisms. Antacids containing aluminum, zinc, magnesium, or bismuth salts, or foods high in calcium impair absorption of the tetracyclines. When the tetracyclines are administered with oral anticoagulants, an increase in the effects of the anticoagulant may occur. When tetracyclines are administered to women using oral contraceptives, a decrease in the effect of the oral contraceptive may be seen. This may result in breakthrough bleeding or pregnancy. When digoxin is administered with the tetracyclines there is an increased risk for digitalis toxicity. The effects of this could last for months after tetracycline administration is discontinued. Tetracyclines may reduce insulin requirements. Blood glucose levels should be monitored frequently during tetracycline therapy.  Aminoglycosides (Streptomycin,.2 Neomycin, Tobramycin, Nitilmicin, Gentamycin, Amikacin) Aminoglycosides that are derived from Streptomyces have “mycin” suffixes, whereas those from Micromonospora end in “micin.” Aminoglycosides used in bacterial endocaditis, brucellosis and used primarily in the treatment of infections caused by gram-negative microorganisms. Because the oral aminoglycosides are poorly absorbed, they are useful to suppressing gastrointestinal bacteria. The oral aminoglycosides kanamycin (Kantrex) and neomycin (Mycifradin) are used preoperatively to reduce the number of bacteria normally present in the intestine (bowel prep). used orally in the management of hepatic coma. In this disorder, liver failure results in an elevation of blood ammonia levels. By reducing the number of ammoniaforming bacteria in the intestines, blood ammonia levels may be lowered, thereby temporarily reducing some of the symptoms associated with this disorder. The aminoglycosides are capable of causing nephrotoxicity and ototoxicity). Signs and symptoms of nephrotoxicity may include protein in the urine (proteinuria), hematuria increase in the blood urea nitrogen level, decrease in urine output, and an increase in the serum creatinine concentration. Nephrotoxicity is usually reversible once the drug is discontinued. Signs and symptoms of ototoxicity include tinnitus, dizziness, roaring in the ears, vertigo, and a mild to severe loss of hearing. If hearing loss occurs, it is most often permanent. Neurotoxicity may also be seen with the administration of the aminoglycosides. Signs and symptoms of neurotoxicity include numbness, skin tingling, circumoral (around the mouth) paresthesia, peripheral paresthesia, tremors, muscle twitching, convulsions, muscle weakness, and neuromuscular blockade (acute muscular paralysis and apnea).  Macrolides (Erythromycin,.3 Clarithromycin, Azithromycin) The macrolides are bacteriostatic or bactericidal in susceptible bacteria. The drugs act by binding to cell membranes and causing changes in protein function. Erythromycin base is destroyed by gastric acid; thus either enteric-coated tablets or esterified forms are administered. They are useful for patients who are allergic to penicillin, pneumonia. Most of the adverse reactions seen with the administration of azithromycin and clarithromycin are related to the gastrointestinal tract and include nausea, vomiting, diarrhea, and abdominal pain. Abdominal cramping, nausea, vomiting, diarrhea, and allergic reactions superinfection, transient deafness, have been reported with the administration of erythromycin. However, there appears to be a low incidence of adverse reactions associated with normal oral doses of erythromycin. As with almost all antibacterial drugs, pseudomembranous colitis may occur ranging in severity from mild to life threatening.  Lincosamides.4 The lincosamides act by inhibiting protein synthesis in susceptible bacteria, causing death. These antibiotics are effective in the treatment of infections caused by a wide range of gram- negative and grampositive microorganisms. The lincosamides are used for the more serious infections. In serious infections they may be used in conjunction with other antibiotics. In addition, the drugs are used to treat acne vulgaris and skin infections, in conjunction with sulfonamides to treat upper respiratory infections caused by Hemophilus influenzae, and as prophylaxis before dental or other procedures. Abdominal pain, esophagitis, nausea, vomiting, diarrhea, skin rash, and blood dyscrasias may be seen with the use of the lincosamides. These drugs also can cause pseudomembranous colitis, which may range from mild to very severe. Discontinuing the drug may relieve mild symptoms of pseudomembranous colitis. It is important to use these drugs with caution in patients with a history of gastrointestinal disorders, renal disease, or liver impairment. The neuromuscular blocking action of the lincosamides poses a danger to patients with myasthenia gravis (an autoimmune disease manifested by extreme weakness and exhaustion of the muscles)..Chloramphenicol.5 Chloramphenicol has wide spectrum antimicrobial activity. Chloramphenicol the drug of choice for typhoid fever, bacterial meningitis, most anaerobic infections respond to chloramphenicol. This is a potentially dangerous drug, and therefore its use is limited to serious infections when less potentially dangerous drugs are ineffective or contraindicated. Serious and sometimes fatal blood dyscrasias (pathologic condition of blood; disorder of cellular elements of blood) are the chief adverse reaction seen with the administration of chloramphenicol. In addition to blood dyscrasias, superinfection, hypersensitivity reactions, nausea, vomiting, and headache may be seen. It is recommended that patients receiving oral chloramphenicol be hospitalized so that patient observation and frequent blood studies can be performed during treatment with this other adverse effects: bone marrow depression resulting in pancytopenia, cyanosis, and green stool..  Folate Antagonists Folic acid coenzymes are required for the synthesis of purines and pyrimidines (precursors of RNA and DNA) and other compounds required for cellular growth and replication. In the absence of folic acid synthesis cells cannot grow or divide. The sulfa drugs are inhibitors of folic acid synthesis. All sulfonamides in clinical use are synthetic structural analogs of p- aminobenzoic acid (PABA). Many bacteria must rely on their ability to synthesize folate from PABA, pteridine and glutamate.  Sulfonamides (Trimethoprim + Sulfamethazole) Derivative of sulfonamide, these agent are the first drugs to prevent and cure human bacterial infection successfully. Although their current usefulness is limited by the introduction of more effective antibiotics and the emergence of resistant bacterial strains, they are used to treat acute uncomplicated urinary tract infections, Nocardiosis. Adverse effects: dermatitis, agranulocytosis  II. Quinolones and Urinary Tract Antiseptics The fluoroquinolones exert their bactericidal effect by interfering with an enzyme (DNA gyrase) needed by bacteria for the synthesis of DNA. This interference prevents cell reproduction, leading to death of the bacteria. The fluoroquinolones are used in the treatment of infections caused by susceptible microorganisms. The fluoroquinolones are effective in the treatment of infections caused by gram-positive and gram-negative microorganisms. They are primarily used in the treatment of susceptible microorganisms in lower respiratory infections, infections of the skin, urinary tract infections, and sexually transmitted diseases. Ciprofloxacin, norfloxacin, and ofloxacin are available in ophthalmic forms for infections in the eyes. Bacterial or fungal superinfections and pseudomembranous colitis may occur with the use of both of these drugs. The administration of any drug may result in a hypersensitivity reaction, which can range from mild to severe and in some cases can be life threatening. Mild hypersensitivity reactions may only require discontinuing the drug, whereas the more serious reactions require immediate treatment. The more common adverse effects seen with the administration of these drugs include nausea, diarrhea, headache, abdominal pain or discomfort, and dizziness. A more serious adverse reaction seen with the administration of the fluoroquinolones, especially lomefloxacin and sparfloxacin, is a photosensitivity reaction. This is manifested by an exaggerated sunburn reaction when the skin is exposed to the ultraviolet rays of sunlight or sunlamps.  Antimycobacterial Drug Tuberculosis is a major health problem throughout the world, infecting more than 8 million individuals each year. It is the world’s leading cause of death from infectious disease. Individuals living in crowded conditions, those with compromised immune systems, and individuals with debilitative conditions are especially susceptible to tuberculosis. The mycobacteria are classified on the basis of their staining properties. They are difficult to stain because of the presence of an outer coat of mycolic acid, once stained the hold the stain even in the presence of destaining agents such as acid. Thus they are referred to as “acid-fast” Mycobaterium tuberculosis, one of a number of mycobacteria. Treating tuberculosis as well as other mycobacterial infections presents therapeutic problems. The organism grows slowly, and thus the disease may have to be treated for up to 2 years, especially if it is caused by resistant organism. Because strains of the organism resistant to particular agent emerge during treatment, multiple drug therapy is employed to delay or prevent their emergence. Isoniazid, Rifampin, Pyrazinamide, Ethambutol, and Streptomycin. Are the principal or so-called “first line” drug because of their efficacy and acceptable degree of toxicity. However today, because of poor patient compliance and other factors, the number of multidrug- resistant organisms has risen. Therefore, although treatment regimens vary in duration and in agents employed, they always include a minimum of two drugs, preferably both cidal. Alternate second line drugs include Aminosalicylic acid, Ethoionamide, and Cycloserine.  Isoniazid Isoniazid often referred to as INH, is believed to target the enzyme responsible for assembly of mycolic acids into the outer layer of the mycobacteria, it is bactericidal. Isoniazid is specific for treatment of tuberculosis. Individual in close contact with the tuberculosis patient especially children are given isoniazid as prophylaxis. Adverse effects: peripheral neuritis as paresthesia, which can be corrected by pyridoxine (vitamin B6) supplementation, hepatotoxicity, and drug interaction.  Rifampin Rifampin has a broader antimicrobial activity than isoniazid and has found application in the treatment of other bacterial infection. It is never given as a single agent in the treatment of active tuberculosis. Adverse effects include nausea and vomiting, rash, and fever.  Chemotherapy of Leprosy Leprosy is a chronic, communicable disease spread by prolonged, intimate contact with an infected person. Peripheral nerves are affected, and skin involvement is present. Lesions may be confined to a few isolated areas or may be fairly widespread over the entire body. Treatment with the leprostatic drugs provides a good prospect for controlling the disease and preventing complications. Leprosy, also referred to as Hansen’s disease, is caused by the bacterium Mycobacterium leprae. Although rare in colder climates, this disease may be seen in tropical and subtropical zones. Dapsone and clofazimine (Lamprene) are the two drugs currently used to treat leprosy. The leprostatic drugs are listed in the  CLOFAZIMINE Clofazimine is primarily bactericidal against M. leprae. The exact mode of action of this drug is unknown, used to treat leprosy. Clofazimine may cause pigmentation of the skin, abdominal pain, diarrhea, nausea, and vomiting. Clofazimine is used cautiously in patients with gastrointestinal disorders, diarrhea, and during pregnancy (Pregnancy Category C) and lactation. If clofazimine is used during pregnancy, the infant may be born with pigmented skin.  DAPSONE Dapsone is bactericidal and bacteriostatic against M. leprae. The drug is used to treat leprosy. Dapsone may also be used in the treatment of dermatitis herpetiformis, a chronic, inflammatory skin disease. Administration of dapsone may result in hemolysis (destruction of red blood cells), nausea, vomiting, anorexia, and blurred vision. Dapsone is used with caution in patients with anemia, severe cardiopulmonary disease, hepatic dysfunction, and during pregnancy (Pregnancy Category C). Dapsone is contraindicated during lactation. Substantial amounts of dapsone are excreted in breast milk and can cause hemolytic reactions in neonates.  III. Anti Fungal Drugs Infection diseases caused by fungi are called mycoses and are often chronic in nature. The fungal infections that are most difficult to treat are the systemic mycoses, which are often life threatening. Fungal infections are generally resistant to antibiotics used in the treatment of bacterial infections. Conversely, bacteria are resistant to the antifungal agents. Fungal infections range from superficial skin infections to life-threatening systemic infections. Systemic fungal infections are serious infections that occur when fungi gain entrance into the interior of the body. Antifungal drugs may be fungicidal (able to destroy fungi) or fungistatic (able to slow or retard the multiplication of fungi). Amphotericin B (Fungizone IV), miconazole (Monistat), nystatin (Mycostatin), and ketoconazole (Nizoral) are thought to have an effect on the cell membrane of the fungus, resulting in a fungicidal or fungistatic effect. The fungicidal or fungistatic effect of these drugs appears to be related to their concentration in body tissues. Fluconazole (Diflucan) has fungistatic activity that appears to result from the depletion of sterols (a group of substances related to fats) in the fungus cells.  Amphotericin B is a broad-spectrum antifungal agent, is the most effective drug available for systemic fungal infections, used to treat life-threatening fungal infections in patients with impaired defense mechanisms (e.g cancer chemotherapy and AIDS patients), should be used in hospital. Adverse effects: hypersensitivity, fever, decrease renal function anemia.  Flucytosin is fungistatic. Adverse effects include G.I. distress, hepatic dysfunction.  Ketoconazole, Fluconazole effective against oropharyngyeal and esophageal candidiasis. Should not be used with amphotercin B together. Adverse effects: G.I. distress, hepatic dysfunction, and drug interaction.  Drugs for superficial mycotic.infections Griseofullvin useful for treating mycotic diseases of the skin, hair, nail such as tinea capitis, its given orally topical use has little effects. Adverse effects not generally clinical problem although include G.I. distress, hepatic dysfunction. Nystatin is a fungistatic and fungicidal used to treat Candida infections of the skin, mucous membranes and intestinal track. Adverse affects G.I disturbances Miconazole a topical agent used to treat ringworm and other skin infections  IV. Antiprotozoal Drugs Protozoal infections are common among people in underdeveloped tropical and suptropical where sanitary condition, hygienic practices, and control of the vectors of transmission are inadequate.  VI. Antiviral Drugs Viruses are obligate intracellular parasites that require the active participation of the metabolic processes of the invaded cell to survive. Because viruses lack independent metabolic activity and can replicate only with living host cells, antiviral agents tend to injure host as well as viral cells Amantadine and Rimantadine Used as prophylaxis for influenza. Adverse effects: confusion, insomnia, dizziness, and hallucination  Ribavirin Ribavirin used in influenza A and B, respiratory syncytial virus, adverse effects: transient anemia, it’s contraindicated in pregnancy.  Acyclovir Acyclovir used in herpes simplex infections, the most common use is in herpes genitals infections. Adverse affects rash, diarrhea, and renal dysfunction.  Ganciclovir same as Acyclovir  Trifluridin Trifluridin has replaced the earlier drug, Idoxuridine, to treat herpes keratitis as ophthalmic solution or ointment..Vidarabine Vidarabine used to treat herpes simplex infections. Adverse effect: G.I and CNS disturbances.Zidovudine AZT The only clinical use for AZT is in the treatment of patients infected with HIV. Adverse effect: toxic to bone marrow, headaches. Anticancer Drugs (oncology) More than one million new cancers diagnosed each year. Less than a quarter of these patients will be cured solely by surgery and/or local radiation. Most of the remainder will receive systemic chemotherapy at some time during their illness. The term cancer is used to describe many disease processes with the common characteristics of uncontrolled cell growth, invasiveness, and metastasis, as well as numerous etiologies, clinical manifestations, and treatments. One theory of carcinogenesis involves abnormal genes and cells, in which cancer may be caused by mutation of genes (abnormal structural changes in cellular genetic material), abnormal activation of genes that regulate cell growth and mitosis, or lack of tumor suppressor genes. The abnormal genes, called oncogenes, are mutations of normal growth- regulating genes called protooncogenes, which are present in all body cells. Normally, proto- oncogenes are active for a brief period in the cell reproductive cycle. When exposed to carcinogens and genetically altered to oncogenes, however, they may operate continuously and cause abnormal, disordered, and unregulated cell growth..Warning signs of cancer Change in bowel or bladder habits A sore that does not heal Unusual bleeding or discharge Thickening or lump in the breast Indigestion or difficulty swallowing Obvious change in a wart or mole Nagging cough or hoarseness Antineoplastic drugs are used in the treatment of malignant diseases (cancer). These drugs can be used for cure, control, or palliative (relief of symptoms) therapy. The term chemotherapy is often used to refer to therapy with antineoplastic drugs. Many antineoplastic drugs are available to treat malignancies, include the alkylating drugs, antibiotics, antimetabolites, hormones, mitotic inhibitors, and selected miscellaneous drugs.  General Characteristics Most drugs kill malignant cells by interfering with cell replication, with the supply and use of nutrients (eg, amino acids, purines, pyrimidines), or with the genetic materials in the cell nucleus (DNA or RNA). The drugs act during the cell’s reproductive cycle. Some, called cell cycle specific, act mainly during specific phases such as DNA synthesis or formation of the mitotic spindle. Others act during any phase of the cell cycle and are called cell cycle nonspecific. Cytotoxic drugs are most active against rapidly dividing cells, both normal and malignant. Commonly damaged normal cells are those of the bone marrow, the lining of the gastrointestinal tract, and the hair follicles. Each drug dose kills a specific percentage of cells. To achieve a cure, all malignant cells must be killed or reduced to a small number that can be killed by the person’s immune system. Antineoplastic drugs may induce drug-resistant malignant cells. Mechanisms may include inhibiting drug uptake or activation, increasing the rate of drug inactivation, pumping the drug out of the cell before it can act, increasing cellular repair of DNA damaged by the drugs, or altering metabolic pathways and target enzymes of the drugs. Mutant cells also may emerge. Most cytotoxic antineoplastic drugs are potential teratogens. Most antineoplastic drugs are given orally or intravenously (IV); some are given topically, intrathecally, or by instillation into a body cavity. A few drugs are available in liposomal preparations.  :Principles of treatment Cytotoxic drugs are usually given in intermittent high-dose treatments over long periods. The smaller the mass of tumor treated the better the result because small tumors have less resting cells which are insensitive to chemotherapy. Suppression of the bone marrow is very common, as cytotoxic drugs have to be given at the maximum tolerated dose.  Most common side effect of :cytotoxic drug is Extravasation (some IV cytotoxic drugs leak into extravascular compartment leading to local tissue necrosis) e.g. Doxrubicin, Vinblastin, Epirubicin, and vincristine. The extravasation treated by stopping infusion immediately, removing the needle, elevating the limb, keeping the area cool, applying 1% hydrocortisone cream twice daily, and finally consulting an expert. Nausea and vomiting Alopecia reversible hair loss most cytotoxic drug cause alopecia patient should be warn before starting therapy, ice-cold water caps may decrease the loss of hair. Bone marrow suppression: cytotoxic drug causes decrease WBC, platelets and RBC which lead to increase chance of infection. Blood count must be checked prior to each treatment. Hyperuricaemia: accumulation of uric acid crystal in the urinary tract. Patient should be adequately hydrated. Reproductive function most cytotoxic drug are teratogenic and shouldn't be administered during pregnancy.  Immunopharmacology Immunology is the science that concerned with the specific mechanisms by which living tissues react to foreign biological materials (including invading microorganisms) so that resistance or immunity develops. The integrity of the defense system of the host, and its ability to react to and overcome invasion by microorganisms, is of vital importance for the survival of the individual. Immunity refers to the ability of the body to identify and resist microorganisms that are potentially harmful. This ability enables the body to fight or prevent infectious disease and inhibit tissue and organ damage. The immune system is not confined to any one part of the body. Immune stem cells, formed in the bone marrow, may remain in the bone marrow until maturation or migrate to different body sites for maturation. After maturation, most immune cells circulate into the body and exert specific effects. The immune system has two distinct, but overlapping, mechanisms with which to fight invading organisms: Cell-mediated defenses (cellular immunity) Antibody-mediated defenses (humoral immunity)  Immunosuppressive Agent in Organ Transplantation Organ transplantation is the replacement of a diseased vital organ with a viable organ from a living or cadaver donor. Solid organ transplantation has become the therapy of choice for many patients with end-organ failure (i.e., heart, liver, lung, and kidney disease). However, it generally requires immunosuppression to overcome the immunologic barrier between donor and recipient, except in syngenic (i.e., twins) or autologous transplantation. Type of graft rejection according :to the time course Hyperacute rejection: immediate destruction (within minutes or hours) of transplanted organ by preformed antibody or complement system. Today, this is extremely rare. There is no treatment available. Acute rejection: occur within few days to several months after transplantation. This rejection can be reversible by steroids or antibody therapy such as muromonoab-CD3 or antihymocyte globulin. Chronic rejection: occurs several months to several years after transplantation. There is no treatment available.  Calcineurin Inhibitor Cyclosporine (Sandimmune Neoral®, Sandimmune®, or Gengraf®) Cyclosporin binds intracellular receptor, cyclophiline, inhibiting T-cell activation in the early stage of immune response to foreign antigen such as a graft. Side effects. Nephrotoxicity is the major side effect. Neurotoxicity and hepatotoxicity are also common. Tacrolimus (Prograf®) It is very similar to cyclosporin  Antimetabolites Azathioprin (Imuran®) Azathioprin converted to 6-mercaptopurine in the body and is a non-specific purin synthesis inhibitor. It interferes with DNA and RNA synthesis so that it may reduce both cell- mediated and humoral immune responses. Side effects include bone marrow suppression (leukopenia, thrombocytopenia) Mycophenolate moftil (cellCept®) It is very similar to Azathioprin.  Methotrexate This agent is used mainly in autoimmune disease and preventing graft versus host disease in bone marrow transplant. It inhibits DNA and protein synthesis. Side effect very similar to Azathioprin, in addition to diarrhea and mucositis.  Alkylating Agent Cyclophosphamide Cyclophosphamide is the alkylating agent mainly used for BMT patients. it is converted to active metabolite, phosphoramide mustard in the liver, which inhibits the cross-linking of DNA, leading to cell death. Side effects include bone marrow suppression (leukopenia, thrombocytopenia). In addition, nausea, vomiting, and diarrhea.  Antibody Products Muromonab CD3 (Orthoclone OKT3®) Muromonab CD3 is the first therapeutic mouse monoclonal antibody produced for use in human. Muromonab CD3 bound to T-cells so they lose the antigen recognition function and connote initiate rejection process. Side effect. With the first few doses, the patient develop severe flu-like symptoms such as fever, chills, nausea, vomiting, and headache leukopenia. Antithymocyte globulin (Atgam®) Antithymocyte globulin is a purified polyclonal immunoglobulin from horses, which bind to the human T-cells. However it may have cross reactivity against the red blood cells, platelets, and granulocytes. Side effect fever, chills, nausea, vomiting, and headache leukopenia. Daclizumab (Zenapax®) Daclizumab is a molecularly engineered humanized immunoglobulin that preventing T-cell activation and proliferation. Based on result of clinical trials, nonspecific safety monitoring is required with Daclizumab. Basiliximab (Simulect®) Basiliximab is a chimeric (murine/human) monoclonal antibody produced by recombinant DNA technology, it prevent T-lymphocyte activation, thus preventing acute rejections. Based on result of clinical trials, no cytokine release syndrome have been noticed.  Corticosteroids Prednisone and Methylprednisone are the major corticosteroids products used for transplant patients. Corticosteroids have multiple pharmacological effects in various cells. Corticosteroids bind with intercellular glucocorticoid receptors, which results in altering DNA and RNA translation. As a result corticosteroids cause rapid and profound drop in circulating T-lymphocytes. They have potent anti-inflammatory effects by inhibiting arachidonic acid release and macrophage phagocytosis. Side effect. In long term, corticosteroids cause more troubling side effects. They include psychological disturbance ( euphoria, depression) adrenal axis suppression, hypertension, sodium and water retention, myopathy, impaired wound healing, increased appetite, osteoporosis, hyperglycemia, and cataracts.