Pharma Group 1 (Chemotherapeutic Drugs).pdf

CHEMOTHERAPEUTIC DRUGS (PATIENT DRUGS) GROUP 1  Content Topics for discussion 01 Introduction to Cell Physiology 02 Anti-Infective Agents 03 Antiviral Agents 04 Antifungal Agents 05 Antiprotozoal Agents 06 Anthelmintic Agents 07 Antin...

CHEMOTHERAPEUTIC DRUGS (PATIENT DRUGS) GROUP 1  Content Topics for discussion 01 Introduction to Cell Physiology 02 Anti-Infective Agents 03 Antiviral Agents 04 Antifungal Agents 05 Antiprotozoal Agents 06 Anthelmintic Agents 07 Antineoplasctic Agents INTRODUCTION TO CELL PHYSIOLOGY Learning Objectives: 01 Identify the parts of the human cell. 02 Describe the role of each organelle. 03 Explain the unique properties of the cell membrane. 04 Describe processes for moving things across the cell membrane. 05 Outline the cell cycle and its phases. INTRODUCTION Chemotherapeutic drugs target both invading organisms (like bacteria, viruses, and fungi) and abnormal cells (such as cancer cells). They work by altering cellular functions, disrupting cellular integrity, or preventing cell reproduction, leading to cell death. However, these drugs often lack complete selectivity, which means they can also affect normal, healthy cells in addition to their targets.  INTRODUCTION TO CELL PHYSIOLOGY THE CELL The cell is the basic structural unit of the body. The cells that make up living organisms, which are arranged into tissues and organs, all have the same basic structure. Each cell has a nucleus, a cell membrane, and cytoplasm, which contains a variety of organelles  INTRODUCTION TO CELL PHYSIOLOGY Cell Nucleus Each cell is “programmed” by the genes, or sequences of DNA, that allow for cell division, produce specific proteins that allow the cell to carry out its functions, and maintain cell homeostasis or stability. The nucleus -is the part of a cell that contains all genetic material necessary for cell reproduction and for the regulation of cellular production of proteins.  INTRODUCTION TO CELL PHYSIOLOGY small spherical mass, called the nucleolus, is located within the nucleus. Within this mass are dense fibers and proteins that will eventually become ribosomes, the sites of protein synthesis within the cell. Genes are responsible for the formation of messenger RNA and transcription RNA, which are involved in production of the proteins unique to the cell. The DNA necessary for cell division is found on long strains called chromatin. These structures line up and enlarge during the process of cell division.  INTRODUCTION TO CELL PHYSIOLOGY Receptor sites are very important in the functioning of neurons, muscle cells, endocrine glands, and other cell types, and they play a very important role in clinical pharmacology Channels Channels or pores within the cell membrane are made by proteins in the cell wall that allow the passage of small substances in or out of the cell.  INTRODUCTION TO CELL PHYSIOLOGY Cytoplasm The cell cytoplasm lies within the cell membrane and outside the nucleus and is the site of activities of cellular metabolism and special cellular functions. The cytoplasm contains many organelles, which are structures with specific functions such as producing proteins and energy. The organelles within the cytoplasm include the mitochondria, the endoplasmic reticulum, free ribosomes, the Golgi apparatus, and the lysosomes. INTRODUCTION TO CELL PHYSIOLOGY INTRODUCTION TO CELL PHYSIOLOGY INTRODUCTION TO CELL PHYSIOLOGY INTRODUCTION TO CELL PHYSIOLOGY INTRODUCTION TO CELL PHYSIOLOGY  INTRODUCTION TO CELL PHYSIOLOGY Homeostasis The main goal of a cell is to maintain homeostasis, which means keeping the cytoplasm stable within the cell membrane. Each cell uses a series of active and passive transport systems to achieve homeostasis; the exact system used depends on the type of cell and its reactions with the immediate environment INTRODUCTION TO CELL PHYSIOLOGY INTRODUCTION TO CELL PHYSIOLOGY INTRODUCTION TO CELL PHYSIOLOGY INTRODUCTION TO CELL PHYSIOLOGY  is a general term that encompasses antibacterials, antibiotics, antifungals, antiprotozoans and antivirals. - are drugs capable of acting against infection, by inhibiting the spread or by killing the infectious agent Anti-infective agents are drugs designed to target foreign organisms that have invaded and infected the body of a human host. Although anti-infective agents target foreign organisms infecting the body of a human host, they do not possess selective toxicity. Selective toxicity is the property of certain chemicals to destroy one form of life without harming another. which is the ability to affect certain proteins or enzyme systems used only by the infecting organism but not by human cells. Because all living cells are somewhat similar, however, no anti-infective drug has yet been developed that does not affect the host. The following chapters discuss specific agents used to treat particular infections: -antibiotics for bacterial infections; -antivirals; antifungals; -antiprotozoals for infections caused by specific protozoa, including malaria; and anthelmintics for infections caused by worms.  Therapeutic Actions Anti-infective agents may act on the cells of invading organisms in several different ways. The goal is interference with the normal function of the invading organism to prevent it from reproducing and to cause cell death without affecting host cells. Some anti-infectives prevent the cells of the invading organism from using substances essential to their growth and development, leading to an inability to divide and eventually to cell death. The sulfonamides, the antimycobacterial drugs, and trimethoprim-sulfamethoxazole (a combination drug frequently used to treat urinary tract infections) work in this way. Many anti-infectives interfere with the steps involved in protein synthesis, a function necessary to maintain the cell and allow for cell division. The aminoglycosides, the macrolides, and chloramphenicol (see the section on adverse effects for a box on chloramphenicol) work in this way. Some anti-infectives interfere with DNA synthesis in the cell, leading to inability to divide and cell death. The fl uoroquinolones work in this way. Other anti-infectives alter the permeability of the cell membrane to allow essential cellular components to leak out, causing cell death. Some antibiotics, antifungals, and antiprotozoal drugs work in this manner. Mechanisms of Action: Cell Wall Biosynthesis: E.g., Penicillins Nutrient Utilization: E.g., Sulfonamides Protein Synthesis Interference: E.g., Aminoglycosides, Macrolides DNA Synthesis Inhibition: E.g., Fluoroquinolones Cell Membrane Permeability: E.g., Some antibiotics and antifungals Some anti-infectives are so active against the infective microorganisms that they actually cause the death of the cells they affect. These drugs are said to be BACTERICIDAL. Some anti-infectives are not as aggressive against invading organisms; they interfere with the ability of the cells to reproduce or divide. These drugs are said to be bacteriostatic Spectrum of Activity: Narrow Spectrum: Specific microorganisms Broad Spectrum: Wide range of microorganisms Bactericidal vs. Bacteriostatic: Bactericidal: Kills pathogens Bacteriostatic: Inhibits reproduction  Human Immune Response It is difficult to treat any infections in such patients for two reasons: (1) Anti-infective drugs cannot totally eliminate the pathogen without causing severe toxicity in the host, (2) these patients do not have the immune response in place to deal with even a few invading organisms.  Resistance -Resistance can be natural or acquired, -Refers to the ability over time to adapt to an anti-infective drug andproduce cells that are no longer affected by a particular drug. -Strategies to combat resistance include appropriate use of antimicrobials, proper dosing, and avoiding unnecessary prescriptions.  Acquired Resistance: Acquired resistance occurs when bacteria, viruses, or cancer cells develop the ability to survive and proliferate despite the presence of drugs or treatments that were previously effective. This can result from genetic mutations, environmental pressures, or exposure to sub- lethal doses of the therapeutic agent. For example, bacteria can acquire resistance to antibiotics through mutation or by obtaining resistance genes from other bacteria via horizontal gene transfer.  Prophylaxis Sometimes it is clinically useful to use anti-infectives as a means of prophylaxis to prevent infections before they occur. For example, when patients anticipate traveling to an area where malaria is endemic, they may begin taking antimalarial drugs before the journey and periodically during the trip. *When these patients are at high risk for developing one of these infections they may use prophylactic antibiotic therapy as a precaution when undergoing certain invasive procedures, including dental work  Adverse Reactions Common side effects include kidney and liver damage, gastrointestinal and nervous system toxicity, and hypersensitivity reactions. aerobic - bacteria that depend on oxygen for survival anaerobic - bacteria that survive without oxygen, which are often seen when blood flow is cut off to an area of the body antibiotic - chemical that is able to inhibit the growth of specific bacteria or cause the death of susceptible bacteria gram-negative - bacteria that accept a negative stain and are frequently associated with infections of the genitourinary or GI tract gram-positive - bacteria that take a positive stain and are frequently associated with infections of the respiratory tract and soft tissues Synergistic - drugs that work together to increase drug effectiveness  Many new bacteria appear each year, and researchers are challenged to develop new antibiotics—chemicals that inhibit specific bacteria—to deal with each new threat. Antibiotics are made in three ways: by living microorganisms, by synthetic manufacture, and, in some cases, through genetic engineering. Antibiotics may either be: bacteriostatic (preventing the growth of bacteria) or bactericidal (killing bacteria directly)  Bacteria invade the human body through respiratory, gastrointestinal (GI), and skin routes. The immune response activates, causing fever, lethargy, slow-wave sleep induction, and inflammation (redness, swelling, heat, and pain). The goal of antibiotic therapy is to decrease the population of invading bacteria so the human immune system can effectively deal with the invader. Identifying the causative organism through a culture and performing sensitivity testing determines which antibiotic will best kill or control the bacteria. Culture and sensitivity testing ensures that the correct antibiotic is chosen for each infection, a practice that may help to decrease the number of emerging resistant-strain bacteria. Gram-positive bacteria those whose cell wall retains a stain known as Gram’s stain or resists decolorization with alcohol during culture and sensitivity testing. commonly associated with infections of the respiratory tract and soft tissues. Example : Streptococcus pneumoniae, a common cause of pneumonia. Gram-negative bacteria those whose cell walls lose a stain or are decolorized by alcohol. frequently associated with infections of the genitourinary (GU) or GI tract. Example: Escherichia coli, a common cause of cystitis Aerobic bacteria depend on oxygen for survival, whereas anaerobic bacteria (e.g., those bacteria associated with gangrene) do not use oxygen.  Bacteria have survived for hundreds of years because they can adapt to their environment. They do this by altering their cell wall or enzyme systems to become resistant to (e.g., protect themselves from) unfavorable conditions or situations. The longer an antibiotic has been in use, the greater is the chance that the bacteria will develop into a resistant strain. AMINOGLYCOSIDES a group of powerful antibiotics used to treat serious infections caused by gram- negative aerobic bacilli are bactericidal include amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kantrex), neomycin (Mycifradin), streptomycin (generic), and tobramycin (TOBI, Tobrex).  AMINOGLYCOSIDES Therapeutic Actions and Indications inhibit protein synthesis in susceptible strains of gram- negative bacteria. irreversibly bind to a unit of the bacteria ribosomes, leading to misreading of the genetic code and cell death Targeted Bacteria: Indication: Pseudomonas aeruginosa treatment of serious infections that E. coli are susceptible to penicillin when Proteus species penicillin is contraindicated Klebsiella-Enterobacter- can be used in severe infections Serratia group before culture and sensitivity tests Citrobacter species have been completed Staphylococcus species (e.g., Staphylococcus aureus)  AMINOGLYCOSIDES Pharmacokinetics poorly absorbed from the GI tract but rapidly absorbed after intramuscular (IM) injection, reaching peak levels within 1 hour have an average half-life of 2 to 3 hours widely distributed throughout the body, cross the placenta and enter breast milk, and are excreted unchanged in the urine Amikacin is available for short-term IM or intravenous (IV) use. Gentamicin is available in many forms: ophthalmic, topical, IV, intrathecal, impregnated beads on surgical wire, and liposomal injection. Kanamycin is available in parenteral forms. Neomycin is available in topical and oral forms. Streptomycin is only available for IM use. Tobramycin is used for short-term IM or IV treatment and is also available in an ophthalmic form and as a nebulizer solution.  AMINOGLYCOSIDES Contraindications and Cautions Aminoglycosides are contraindicated in the following conditions: known allergy to any of the aminoglycosides renal or hepatic disease preexisting hearing loss active infection with herpes or mycobacterial infections myasthenia gravis or parkinsonism, and lactation Caution is necessary when these agents are administered during pregnancy. It is necessary to test urine function frequently when these drugs are used because they depend on the kidney for excretion and are toxic to the kidney.  AMINOGLYCOSIDES ADVERSE EFFECTS Serious Adverse Effects: Gastrointestinal (GI) Effects: Black Box Warning: Nausea, vomiting, diarrhea, weight loss, Ototoxicity and nephrotoxicity stomatitis, hepatic toxicity Central Nervous System (CNS) Effects: Cardiac Effects: Ototoxicity (irreversible deafness) Palpitations, Hypotension, Hypertension Vestibular paralysis (auditory nerve Hypersensitivity Reactions: effects) Purpura Confusion, depression, disorientation Rash Numbness, tingling, and weakness Urticaria (nerve effects) Exfoliative dermatitis Renal Toxicity: Direct damage to the glomerulus. Bone Marrow Depression  CARBAPENEMS are a relatively new class of broad-spectrum antibiotics effective against gram-positive and gram-negative bacteria Some carbapenems include: Doripenem (Doribax), Ertapenem (Invanz), Imipenem–cilastatin (Primaxin), and Meropenem (Merrem IV) Meropenem has limited use because of the severe risk for potentially fatal GI toxicities.  CARBAPENEMS Therapeutic Actions and Indications are bactericidal, they inhibit cell membrane synthesis in susceptible bacteria, leading to cell death. indicated for treating serious intra-abdominal, urinary tract, skin and skin structure, bone and joint, and gynecological infections. These drugs are used to treat serious infections caused by susceptible strains of: S. pneumoniae, Eubacterium lentum, Streptococcus agalactiae, Haemophilus influenzae, Bacteroides fragilis, Porphyromonas Moraxella catarrhalis, Bacteroides distasonis, asaccharolytica, S. aureus, Bacteroides ovatus, Prevotella bivia, and other Streptococcus pyogenes, Bacteroides thetaiotamicron, susceptible bacteria. E. coli, Bacteroides uniformis, Peptostreptococcus, Proteus mirabilis, Klebsiella pneumoniae, P. aeruginosa, Clostridium clostridiiforme, Acinetobacter baumannii,  CARBAPENEMS Pharmacokinetics rapidly absorbed if given IM and reach peak levels at the end of the infusion if given IV. Carbapenems are excreted unchanged in the urine and have an average half-life of 1 to 4 hours. Doripenem given IV every 8 hours by a 1-hour IV infusion for 5 to 14 days. Ertapenem can be given IV or IM once a day for 5 to 14 days, depending on the infection. Imipenem–cilastatin can be given IV or IM approved for use in children. Meropenem given IV over 1 hour, every 8 hours for 5 to 14 days.  CARBAPENEMS Contraindications and Cautions Carbapenems are contraindicated in the following conditions: known allergy to any of the carbanems or beta-lactams; seizure disorders, meningitis, and lactation Use caution during pregnancy and test urine function regularly when these drugs. Ertapenem is not recommended for use in patients younger than 18 years of age. Meropenem is associated with the development of pseudomembranous colitis and should be used with caution in patients with infl ammatory bowel disorders.  CARBAPENEMS ADVERSE EFFECTS Adverse Effects of Carbapenems Gastrointestinal (GI) Effects: Central Nervous System (CNS) Effects: Pseudomembranous colitis Headache Clostridium difficile diarrhea Dizziness Nausea and vomiting Altered mental state Risk of serious dehydration and Seizures (especially when combined electrolyte imbalances with other drugs) Potential for new serious infections Superinfections  CEPHALOSPORINS first introduced in the 1960s. similar to the penicillin’s in structure and in activity First-generation cephalosporins are largely effective against: same gram-positive bacteria that are affected by penicillin G gram-negative bacteria P. mirabilis, E. coli, and K. pneumoniae Drugs: cefadroxil (generic), cefazolin (Zolicef), and cephalexin (Keflex)  CEPHALOSPORINS Second-generation cephalosporins are effective against: the previously mentioned strains, H. infl uenzae, Enterobacter aerogenes, and Neisseria Second-generation drugs are less effective against gram-positive bacteria, these include: cefaclor (Ceclor), cefoxitin (generic), cefprozil (generic), and cefuroxime (Zinacef)  CEPHALOSPORINS Third-generation cephalosporins, which are effective against all of the previously mentioned strains, are relatively weak against gram- positive bacteria but are more potent against the gram-negative bacilli, as well as against Serratia marcescens. Drugs: cefdinir (Omnicef), cefotaxime (Claforan), cefpodoxime (Vantin), ceftazidime (Ceptaz, Tazicef), ceftibuten (Cedax), ceftizoxime (Cefi zox), and ceftriaxone (Rocephin)  CEPHALOSPORINS Fourth-generation cephalosporins are in development. It includes: cefepime (Maxipime) cefditoren (Spectracef) ceftaroline (Tefl aro)  CEPHALOSPORINS Therapeutic Actions and Indications Both bactericidal and bacteriostatic, depending on dose and drug. Interfere with bacterial cell wall synthesis, causing cell walls to weaken and burst. Treat infections caused by susceptible bacteria. Choice of cephalosporin depends on bacterial sensitivity, route of administration, and cost.  CEPHALOSPORINS Pharmacokinetics well absorbed from the GI tract: the first-generation drugs cefadroxil and cephalexin; the second-generation drugs cefaclor, cefprozil, and cefuroxime; the third-generation drugs cefdinir, cefpodoxime, and ceftibuten; and the fourth-generation drugs cefditoren and cefepime. absorbed well after IM injection or IV administration primarily metabolized in the liver and excreted in the urine.  CEPHALOSPORINS ADVERSE EFFECTS Gastrointestinal (GI) Effects: Central Nervous System (CNS) Effects: nausea headache vomiting dizziness diarrhea lethargy anorexia paresthesias abdominal pain flatulence Pseudomembranous colitis Nephrotoxicity - particularly to those who have a predisposing renal insufficiency  FLUOROQUINOLONES relatively new synthetic class of antibiotics with a broad spectrum of activity includes: ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin (Avelox), norfloxacin (Noroxin), and ofloxacin (Floxin, Ocuflox).  FLUOROQUINOLONES Therapeutic Actions and Indications Enter bacterial cells by passive diffusion. Interfere with DNA enzymes essential for bacterial growth and reproduction. Cause cell death by damaging bacterial DNA. Indications: Specific Uses: Treat infections by susceptible Ciprofloxacin: Broad spectrum of gram-negative bacteria (e.g., E. gram-negative bacteria. coli, P. mirabilis, K. pneumoniae, Approved for anthrax prevention etc.). (2001) in germ warfare exposure. Commonly used for urinary tract, Effective against typhoid fever. respiratory tract, and skin infections.  FLUOROQUINOLONES Pharmacokinetics absorbed from the GI tract, metabolized in the liver, and excreted in the urine and feces. Ciprofloxacin is available in injectable, oral, and topical forms. Gemifloxacin, lomefl oxacin, Moxifloxacin are oral agents Levofloxacin is available in oral and IV forms. Norfloxacin is only available in an oral form. Ofloxacin can be given IV or orally and is also available as an ophthalmic agent for treatment of ocular infections caused by susceptible bacteria.  FLUOROQUINOLONES Contraindications and Cautions Fluoroquinolones are contraindicated in patients with: pregnant or lactating patients allergy to any fluoroquinolone Use with caution in the presence of renal dysfunction and seizures.  FLUOROQUINOLONES ADVERSE EFFECTS These drugs are generally associated with relatively mild adverse reactions. Most common are headache, dizziness, insomnia, and depression. Gastrointestinal (GI) Effects: nausea, Immunological effects include vomiting, bone marrow depression, other diarrhea, adverse effects include fever, dry mouth, and rash, and photosensitivity. possibly to stimulation of the chemoreceptor trigger zone in the CNS. PENICILLINS AND PENICILLINASERESISTANT ANTIBIOTICS first antibiotic introduced for clinical use by Sir Alexander Fleming Penicillins include: penicillin G benzathine (Bicillin, Permapen) penicillin G potassium (Pfi zerpen) penicillin G procaine (Wycillin) penicillin V (Veetids) amoxicillin (Amoxil, Trimox) ampicillin (Principen)  PENICILLINS AND PENICILLINASERESISTANT ANTIBIOTICS Therapeutic Actions and Indications Bactericidal effects by interfering with bacterial cell wall synthesis during division. Prevent bacteria from biosynthesizing the cell wall framework. Weakened cell walls lead to swelling and bursting due to osmotic pressure. Selective toxicity: human cells are not affected. Indications: Rat-bite fever. Streptococcal infections: Pharyngitis, Diphtheria. tonsillitis, scarlet fever, endocarditis. Anthrax. Pneumococcal infections. Syphilis. Staphylococcal infections. Uncomplicated gonococcal infections. Fusospirochetal infections. High doses: Meningococcal meningitis  PENICILLINS AND PENICILLINASERESISTANT ANTIBIOTICS Pharmacokinetics Absorption: Excretion: Rapidly absorbed from the GI tract. Excreted unchanged in the Reach peak levels in 1 hour. urine. Sensitive to gastric acid; should be Renal function is crucial for taken on an empty stomach. safe use. Breast Milk: Penicillin enter breast milk. Can cause adverse reactions in nursing infants. PENICILLINS AND PENICILLINASERESISTANT ANTIBIOTICS Contraindications and Cautions Contraindications: Allergy to penicillin or cephalosporins or other allergens. Penicillin Sensitivity Tests: Available if allergy history is unclear. Use with Caution: In patients with renal disease (lowered doses needed). Pregnancy and Lactation: Limited use during pregnancy and lactation. Risk of diarrhea and superinfections in the infant. Culture and Sensitivity Tests: Essential to ensure the causative organism is sensitive to the penicillin selected. Important due to the emergence of resistant bacterial strains.  PENICILLINS AND PENICILLINASERESISTANT ANTIBIOTICS ADVERSE EFFECTS Gastrointestinal (GI) Effects: Superinfections: Nausea Yeast infections Vomiting Related to loss of bacteria Diarrhea from the normal flora Abdominal pain Hypersensitivity Reactions: Glossitis Rash Stomatitis Fever Gastritis Wheezing Sore mouth Anaphylaxis (with repeated Furry tongue exposure, can progress to Injection Site Effects: anaphylactic shock and Pain death) Inflammation  SULFONAMIDES or sulfa drugs, are drugs that inhibit folic acid synthesis. Sulfonamides include sulfadiazine (generic), sulfasalazine (Azulfi dine), and cotrimoxazole (Septra, Bactrim).  SULFONAMIDES Therapeutic Actions and Indications Block paraaminobenzoic acid to prevent synthesis of folic acid in susceptible bacteria. Bacteria synthesize their own folates for RNA and DNA production. Target Bacteria: Indications: Gram-negative and UTIs gram-positive bacteria Trachoma (a leading cause of blindness) such as Chlamydia Nocardiosis (causes pneumonias, brain trachomatis, Nocardia, abscesses, and inflammation) H. influenzae, E. coli, Sexually transmitted diseases and P. mirabilis. Sulfasalazine: Treatment of ulcerative colitis and rheumatoid arthritis  SULFONAMIDES Pharmacokinetics Teratogenic and distributed into breast milk. Given orally and are absorbed from the GI tract. It is metabolized in the liver and excreted in the urine. Sulfadiazine: Sulfasalazine: Slowly absorbed from the GI tract. Contains sulfapyridine and Peak levels in 3 to 6 hours. aminosalicylic acids. Released in the colon for anti- Cotrimoxazole: inflammatory effects. Combination of sulfamethoxazole Rapidly absorbed from the GI tract. and trimethoprim. Peak levels in 2 to 6 hours. Rapidly absorbed from the GI tract. Half-life of 5 to 10 hours. Peak levels in 2 hours. Used for rheumatoid arthritis in Half-life of 7 to 12 hours. delayed-release form.  SULFONAMIDES Contraindications and Cautions Contraindications: Known allergy to sulfonamides, sulfonylureas, or thiazide diuretics (cross-sensitivities). During pregnancy (risk of birth defects and kernicterus). During lactation (risk of kernicterus, diarrhea, and rash in the infant). Cautions: Use with caution in patients with renal disease or a history of kidney stones (possibility of increased toxic effects).  SULFONAMIDES ADVERSE EFFECTS Gastrointestinal (GI) Effects: Central Nervous System Renal Effects: Nausea (CNS) Effects: Crystalluria Vomiting Headache Hematuria Diarrhea Dizziness Proteinuria Abdominal pain Vertigo Anorexia Ataxia Bone Marrow Stomatitis Convulsions Depression Hepatic injury Depression Dermatological Effects: Hypersensitivity Reactions: Photosensitivity A wide range of reactions Rash may occur. Related to direct effects on dermal cells.  TETRACYCLINES developed as semisynthetic antibiotics based on the structure of a common soil mold. Researchers have developed newer tetracyclines to increase absorption and tissue penetration Tetracyclines include tetracycline (Sumycin), demeclocycline (Declomycin), doxycycline (Doryx, Periostat), and minocycline (Minocin).  TETRACYCLINES Therapeutic Actions and Indications work by inhibiting protein synthesis in a wide range of bacteria, leading to the inability of the bacteria to multiply. Tetracyclines are indicated for treatment of infections caused by: Rickettsiae, Bacteroides species, Klebsiella species, Mycoplasma pneumoniae, Vibrio comma, Diplococcus Borrelia recurrentis, Vibrio fetus, pneumoniae H. infl uenzae, Brucella species, S. aureus Haemophilus ducreyi, E. coli, Pasteurella pestis, E. aerogenes, Pasteurella tularensis, Shigella species, Bartonella bacilliformis, Acinetobacter calcoaceticus,  TETRACYCLINES Therapeutic Actions and Indications against agents that cause psittacosis, ornithosis, lymphogranuloma venereum, and granuloma inguinale; when penicillin is contraindicated in susceptible infections; and for treatment of acne and uncomplicated GI infections  TETRACYCLINES Pharmacokinetics Tetracyclines are absorbed adequately, but not completely, from the GI tract. Their absorption is affectedby food, iron, calcium, and other drugs in the stomach. Tetracyclines are concentrated in the liver and excreted unchanged in the urine, with half-lives ranging from 12 to 25 hours. Tetracycline is available in oral and topical forms, in addition to being available as an ophthalmic agent.  TETRACYCLINES Contraindications and Cautions Tetracyclines are contraindicated in patients with: allergy to tetracyclines or to tartrazine during pregnancy and lactation Tetracyclines should be used with caution in children younger than 8 years of age and in patients with hepatic or renal dysfunction  TETRACYCLINES ADVERSE EFFECTS The major adverse effects of tetracycline therapy involve: Direct irritation of the GI tract and include nausea, vomiting, diarrhea, abdominal pain, glossitis, and dysphagia. Skeletal effects involve damage to the teeth and bones. Dermatological effects include photosensitivity and rash. Superinfections, including yeast infections.  ANTIMYCOBACTERIALS Mycobacteria, including pathogens causing tuberculosis and leprosy, are classified as "acid-fast" due to their ability to retain a stain despite destaining agents. They have a protective mycolic acid coat, allowing them to resist many disinfectants and survive long periods. These slow-growing bacteria often require prolonged treatment for eradication.  ANTIMYCOBACTERIALS Mycobacterium tuberculosis causes tuberculosis, a major global cause of death from infectious disease. Tuberculosis is resurging due to increased immune compromise and resistant strains. Mycobacterium leprae causes leprosy (Hansen’s disease), characterized by disfiguring skin lesions and respiratory tract damage. It is infectious and affects individuals with susceptible skin or respiratory tracts. Mycobacterium avium-intracellulare causes mycobacterial avium complex, particularly in AIDS patients or those severely immunocompromised. Rifabutin (Mycobutin), initially an antituberculosis drug, is highly effective against this strain.  ANTITUBERCULOSIS DRUGS Tuberculosis can lead to serious damage in the lungs, the GU tract, bones, and the meninges. The treatment must be continued for 6 months to 2 years due to the slow growth of M. tuberculosis. Using combination therapy helps decrease the emergence of resistant strains and affects the bacteria at various phases during their long and slow life cycle. First-line Drugs: Used in combinations of two or more agents until bacterial conversion occurs or maximum improvement is seen. First-line drugs include: Isoniazid (Nydrazid) Rifampin (Rifadin) Pyrazinamide (generic) Ethambutol (Myambutol) Streptomycin (generic) Rifapentine (Priftin)  ANTITUBERCULOSIS DRUGS Second-line Drugs: Used if the patient cannot take one or more first-line drugs or if the disease progresses due to resistant strains. Second-line drugs include: Ethionamide (Trecator-SC) Capreomycin (Capastat) Cycloserine (Seromycin) Rifabutin (Mycobutin)  LEPROSTATIC DRUGS The antibiotic used to treat leprosy is dapsone (generic), which has been the mainstay of leprosy treatment for many years, although resistant strains are emerging. Inhibits folate synthesis in susceptible bacteria Also used to treat P. carinii pneumonia in AIDS patients and for a variety of infection, as well as for brown recluse spider bites  LEPROSTATIC DRUGS Therapeutic Actions and Indications Antimycobacterial agents typically target bacterial DNA and/or RNA, preventing growth and causing bacterial death. Isoniazid (INH) specifically disrupts the mycolic acid coat of the bacterium. While these agents can be effective against other susceptible bacteria, they are primarily used to treat tuberculosis or leprosy. Combination therapy with antituberculosis drugs is essential to target bacteria at different stages and reduce the emergence of resistant strains  LEPROSTATIC DRUGS Pharmacokinetics generally well absorbed from the GI tract given orally, are metabolizedin the liver and excreted in the urine; they cross the placenta and enter breast milk, placing the fetus or child at risk for adverse reactions  LEPROSTATIC DRUGS Contraindications and Cautions Contraindications for antimycobacterials include: Known allergy to these agents Severe renal or hepatic failure (interferes with metabolism or excretion) Severe CNS dysfunction (could be exacerbated by the drug) Pregnancy (possible adverse effects on the fetus) If necessary during pregnancy, combination of isoniazid, ethambutol, and rifampin is considered the safest.  LEPROSTATIC DRUGS ADVERSE EFFECTS CNS effects include neuritis, dizziness, headache, malaise, drowsiness, and hallucinations, related to direct effects on neurons. GI tract irritation causes nausea, vomiting, anorexia, stomach upset, and abdominal pain. Rifampin, rifabutin, and rifapentine cause discoloration of body fluids (urine, sweat, tears) which can stain clothing and contact lenses. There is a possibility of hypersensitivity reactions.  OTHER ANTIBIOTICS There are other antibiotics that do not fit into the large antibiotic classes These drugs—the ketolides, lincosamides, lipoglycopeptides, macrolides, and monobactams— work in unique ways and are effective against specific bacteria  KETOLIDES The ketolide class of antibiotics was first introduced in 2004. At this time, telithromycin (Ketek) is the only approved drug in the class.  KETOLIDES Therapeutic Actions and Indications Ketolides block protein synthesis, leading to cell death. Telithromycin binds to specific ribosome subunits, causing cell death in susceptible bacteria. Effective against: S. pneumoniae (including multidrug-resistant strains) H. influenzae M. catarrhalis Chlamydophila pneumoniae M. pneumoniae Approved for treating mild to moderate community- acquired pneumonia.  KETOLIDES Pharmacokinetics Available as an oral drug only. Rapidly absorbed through the GI tract, reaching peak levels in 1 hour. Widely distributed, crosses the placenta, and passes into breast milk. Metabolized in the liver with a half-life of 10 hours. Excreted in urine and feces.  KETOLIDES Contraindications and Cautions Contraindicated with: Known allergy to any component of the drug or to macrolide antibiotics Known congenital prolonged QT interval, bradycardia, or any proarrhythmic condition such as hypokalemia Concurrent use of pimozide, cardiac antiarrhythmics, simvastatin, atorvastatin, or lovastatin Myasthenia gravis (black box warning due to risk of potentially fatal respiratory failure) Contraindicated with: Renal or hepatic impairment Pregnant and lactating patients Perform culture and sensitivity testing to ensure appropriate use.  KETOLIDES ADVERSE EFFECTS Toxic effects on the GI tract: nausea, vomiting, taste alterations, and potential for pseudomembranous colitis. Common superinfections related to the loss of normal flora bacteria. Serious hypersensitivity reactions, including anaphylaxis.  LINCOSAMIDES Similar to macrolides but more toxic Examples: Clindamycin (Cleocin) and lincomycin (Lincocin)  LINCOSAMIDES Therapeutic Actions and Indications React at almost the same site in bacterial protein synthesis Effective against the same strains of bacteria Used for severe infections when a less-toxic antibiotic cannot be used  LINCOSAMIDES Pharmacokinetics Rapidly absorbed from the GI tract or from IM injections Metabolized in the liver, excreted in urine and feces Cross the placenta and enter breast milk Clindamycin: Half-life: 2 to 3 hours Available in parenteral, oral, topical, and vaginal forms Lincomycin: Half-life: 5 hours Can be given orally, IM, or IV  LINCOSAMIDES Contraindications and Cautions Use with caution in patients with hepatic or renal impairment Use during pregnancy and lactation only if the benefit outweighs the risk to the fetus or neonate  LINCOSAMIDES ADVERSE EFFECTS Severe GI reactions, including fatal pseudomembranous colitis Other toxic effects: pain, skin infections, bone marrow depression Limit usefulness but may be the drug of choice for serious infections caused by susceptible bacteria.  LIPOGLYCOPEPTIDES The lipoglycopeptides class of antibiotics was first introduced in 2010. At this time, televancin (Vibativ) is the only approved drug in the class.  LIPOGLYCOPEPTIDES Therapeutic Actions and Indications Semisynthetic derivatives of vancomycin Inhibit bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptidoglycans Bind to the bacterial membrane and disrupt the membrane barrier function, causing bacterial cell death Effective against: S. aureus (including methicillin-susceptible and methicillin- resistant isolates) S. pyogenes S. agalactiae Streptococcus anginosus Enterococcus faecalis (vancomycin-susceptible isolates only) Approved for treating complicated skin and skin-structure infections in adults  LIPOGLYCOPEPTIDES Pharmacokinetics Available as an IV drug only Rapidly absorbed with peak levels at the end of the infusion Widely distributed, may cross the placenta, and may pass into breast milk Site of metabolism is not known Half-life: 8 to 9 hours Excreted in urine  LIPOGLYCOPEPTIDES Contraindications and Cautions Contraindicated with known allergy to any component of the drug and with pregnant and lactating patients due to potential toxic effects on the fetus or infant Black Box Warning: Serious fetal risk Perform culture and sensitivity testing to ensure appropriate use  LIPOGLYCOPEPTIDES ADVERSE EFFECTS Largely secondary to toxic effects on the GI tract: Nausea Vomiting Taste alterations Diarrhea Loss of appetite Risk of C. difficile diarrhea Nephrotoxicity reported Foamy urine, which patients should be alerted to Risk of prolonged QTc interval Transfusion reaction called red man syndrome (flushing, sweating, hypotension) can occur with rapid infusion Infusion site reactions with pain and redness reported  MACROLIDES The macrolides are antibiotics that interfere with protein synthesis in susceptible bacteria. Macrolides include erythromycin (Ery-Tab, Eryc, and others), azithromycin (Zithromax), clarithromycin (Biaxin), and dirithromycin (Dynabac).  MACROLIDES Therapeutic Actions and Indications Macrolides: bactericidal or bacteriostatic by binding to bacterial cell membrane and changing protein function Indicated for: Acute infections: S. pneumoniae, M. pneumoniae, Listeria monocytogenes, Legionella pneumophila Group A beta-hemolytic streptococci infections Pelvic inflammatory disease: N. gonorrhoeae Upper respiratory tract infections: H. influenzae (with sulfonamides) Infections: Corynebacterium diphtheriae, Corynebacterium minutissimum (with antitoxin) Intestinal amebiasis Infections: C. trachomatis Maybe used as Prophylaxis for endocarditis before dental procedures in high-risk patients with valvular heart disease allergic to penicillin Topical use for ocular infections, acne vulgaris, minor skin abrasions, and skin infections  MACROLIDES Pharmacokinetics Widely distributed, cross the placenta, enter breast milk Absorbed in the GI tract Erythromycin: Metabolized in the liver, excreted in bile to feces Half-life: 1.6 hours Azithromycin: Excreted unchanged in urine Half-life: 68 hours Clarithromycin: Excreted unchanged in urine Half-life: 3 to 7 hours Dirithromycin: Converted to erythromycylamine in intestinal wall Excreted through feces Half-life: 2 to 36 hours  MACROLIDES Contraindications and Cautions Contraindicated in patients with known allergy to any macrolide Ocular preparations contraindicated for viral, fungal, or mycobacterial eye infections Use with caution in: Hepatic dysfunction Renal disease Lactating women (can cause diarrhea and superinfections in infant) Pregnant women (use only if benefit outweighs risk)  MACROLIDES ADVERSE EFFECTS Most frequent: GI tract effects (abdominal cramping, anorexia, diarrhea, vomiting, pseudomembranous colitis) Neurological symptoms: confusion, abnormal thinking, uncontrollable emotions Hypersensitivity reactions: rash to anaphylaxis Superinfections related to loss of normal flora  MONOBACTAM ANTIBIOTIC The only monobactam antibiotic currently available for use is aztreonam (Azactam)  MONOBACTAM ANTIBIOTIC Therapeutic Actions and Indications Unique structure with little cross-resistance Effective against gram-negative enterobacteria No effect on gram-positive or anaerobic bacteria Disrupts bacterial cell wall synthesis, causing leakage of cellular contents and cell death Indicated for treating: Urinary tract infections Skin infections Intra-abdominal infections Gynecological infections Septicemia caused by susceptible bacteria (E. coli, Enterobacter, Serratia, Proteus, Salmonella, Providencia, Pseudomonas, Citrobacter, Haemophilus, Neisseria, Klebsiella)  MONOBACTAM ANTIBIOTIC Pharmacokinetics Available for IV and IM use only Peak effect levels in 1 to 1.5 hours Half-life: 1.5 to 2 hours Excreted unchanged in urine Crosses the placenta and enters breast milk  MONOBACTAM ANTIBIOTIC Contraindications and Cautions Contraindicated with known allergy to aztreonam Use with caution in patients with: History of acute allergic reaction to penicillins or cephalosporins (possibility of cross-reactivity) Renal or hepatic dysfunction (could interfere with clearance and excretion) Pregnant and lactating women (potential adverse effects on fetus or neonate)  MONOBACTAM ANTIBIOTIC ADVERSE EFFECTS Relatively mild Local GI effects: nausea, GI upset, vomiting, diarrhea Hepatic enzyme elevations related to direct drug effects on the liver Other effects: inflammation, phlebitis, discomfort at injection sites Potential for allergic response, including anaphylaxis ANTIVIRAL AGENTS KEY TERMS KEY TERMS  Viruses cause a variety of conditions, ranging from warts, to the common cold and “flu,” to diseases such as chickenpox and measles. A single virus particle is composed of a piece of DNA or RNA inside a protein coat. Viruses that respond to some antiviral therapy include influenza A and some respiratory viruses, herpes viruses, cytomegalovirus (CMV), HIV) AIDS, hepatitis B, hepatitis C, and some viruses that cause warts and certain eye infections. Agents for INFLUENZA A and RESPIRATORY VIRUSES Amantadine (Symmetrel) Oseltamivir (Tamiflu) Ribavirin (Virazole) Rimantadine (Flumadine) Zanamivir Pharmacokinetics Amantadine is slowly absorbed from the gastrointestinal (GI) tract, reaching peak levels in 4 hours. Excretion occurs unchanged through the urine, with a half-life of 15 hours. Oseltamivir is readily absorbed from the GI tract, extensively metabolized in the urine, and excreted in the urine with a half-life of 6 to 10 hours. Pharmacokinetics Ribavirin, an inhaled drug, is slowly absorbed through the respiratory tract. It is metabolized at the cellular level and is excreted in the feces and urine with a half-life of 9.5 hours. Pharmacokinetics Rimantadine is absorbed from the GI tract with peak levels achieved in 6 hours. This drug is extensively metabolized in the liver and excreted in the urine. Pharmacokinetics Zanamivir must be delivered by a Diskhaler device, which comes with every prescription of zanamivir. It is absorbed through the respiratory tract and excreted unchanged in the urine with a half-life of 2.5 to 5.1 hours. Adverse Effect light-headedness dizziness insomia nausea orothostatic hypotension urinary retention Agents for HERPES and CYTOMEGALOVIRUS Acyclovir (Zovirax) Cidofovir (Vestide) Famciclovir (Famvir) Foscarnet (Foscavir) Ganciclovir (Cytovene) Valacyclovir (Valtrex) Valganciclovir (Valcyte) Pharmacokinetics Acyclovir, which can be given orally and parenterally or applied topically, reaches peak levels within 1 hour and has a half-life of 2.5 to 5 hours. It is excreted unchanged in the urine. It crosses into breast milk, which exposes the neonate to high levels of the drug. Pharmacokinetics Cidofovir, which is given by intravenous (IV) infusion, reaches peak levels at the end of the infusion and in studies was cleared from the system within 15 minutes after the infusion. It is excreted unchanged in the urine and must be given with probenecid to increase renal clearance of the drug. The dose must be decreased according to renal function and creatinine clearance; renal function tests must be done before each dose and the dose planned accordingly. Pharmacokinetics Famciclovir, an oral drug, is well absorbed from the GI tract, reaching peak levels in 2 to 3 hours. Famciclovir is metabolized in the liver and excreted in the urine and feces. It has a half-life of 2 hours and is known to cross the placenta. Pharmacokinetics Foscarnet is available in IV form only. It reaches peak levels at the end of the infusion and has a half- life of 4 hours. About 90% of foscarnet is excreted unchanged in the urine, making it highly toxic to the kidneys. Use caution and at reduced dose in patients with renal impairment. Pharmacokinetics Ganciclovir is available in IV and oral forms. It has a slow onset and reaches peak levels at 1 hour if given IV and 2 to 4 hours if given orally. This drug is primarily excreted unchanged in the feces with some urinary excre tion, with a half-life of 2 to 4 hours. Pharmacokinetics Valacyclovir is an oral agent and is rapidly absorbed from the GI tract and metabolized in the liver to acyclovir. Excretion occurs through the urine, so caution should be used in patients with renal impairment. Pharmacokinetics Valganciclovir is the oral prodrug, that is, it is immediately converted to ganciclovir once it is in the body. It is rapidly absorbed and reaches peak levels in 3 hours. It is primarily excreted unchanged in the feces with some urinary excretion, with a half-life of 2.5 to 3 hours. Adverse Effect nausea vomiting headache depression parethesias neuropathy rash , inflammation occurs at IV sites hair loss renal dysfuntion and renal failure Agents for HIV and AIDS The types of antiviral agents that are used to treat HIV infections are the nonnucleoside and NRTIs, the protease inhibitors, and three newer classes of drugs—the fusion inhibitors, CCR5 coreceptor antagonists, and integrase inhibitors Nonnucleoside Reverse Transcriptase Inhibitors Pharmacokinetics Delavirdine is rapidly absorbed from the GI tract, with peak levels occurring within 1 hour. Delavirdine is extensively metabolized by the cytochrome P450 system in the liver and is excreted through the urine. Pharmacokinetics Efavirenz is absorbed rapidly from the GI tract, reaching peak levels in 3 to 5 hours. Efavirenz is metabolized in the liver by the cytochrome P450 system and is excreted in the urine and feces with a half-life of 52 to 76 hours. Pharmacokinetics Etravirine is rapidly absorbed from the GI tract, reaching peak levels in 2.5 to 4 hours. Etravirine is metabolized in the liver by the cytochrome P450 system and is excreted in feces and urine with a half-life of 21 to 61 hours. Pharmacokinetics Nevirapine is recommended for use in adults and children older than 2 months. After rapid GI absorption with a peak effect occurring at 4 hours, nevirapine is metabolized by the cytochrome P450 system in the liver. Excretion is through the urine with a half-life of 45 hours. Box 10.4 provides information about theemergence of resistance to certain reverse transcriptase inhibitor combinations. Pharmacokinetics Rilpivirine (Edurant) is the newest drug in this class. It is rapidly absorbed from the GI tract, reaching peak levels in 4 to 5 hours. It is metabolized in the liver and excreted in feces and urine with a half-life of 50 hours. Adverse Effect GI related: drymouth constipation diarrhea nausea abdominal pain dyspepsoa diziness blurry vision headache flu-like syndrome Nucleoside Reverse Transcriptase Inhibitors Pharmacokinetics Abacavir is an oral drug that is rapidly absorbed from the GI tract. It is metabolized in the liver and excreted in feces and urine with a half-life of 1 to 2 hours. Pharmacokinetics Didanosine is rapidly destroyed in an acid environment and therefore must be taken in a buffered form. It reaches peak levels in 15 to 75 minutes. Didanosine undergoes intracellular metabolism with a half-life of 8 to 24 hours. It is excreted in the urine. Pharmacokinetics Emtricitabine has the advantage of being a one-capsule-a-day therapy. Emtricitabine has a rapid onset and peaks in 1 to 2 hours. It has a half-life of 10 hours, and after being metabolized in the liver is excreted in the urine and feces. Dose needs to be reduced in patients with renal impairment. It has been associated with severe and even fatal hepatomegaly with steatosis, afatty degeneration of the liver. Pharmacokinetics Lamivudine is rapidly absorbed from the GI tract and is excreted primarily unchanged in the urine. It peaks within 4 hours and has a half-life of 5 to 7 hours. Because excretion depends on renal function, dose reduction is recommended in the presence of renal impairment. The drug is available as an oral solution, Epivir- HBV, it is also recommended for the treatment of chronic hepatitis B. Pharmacokinetics Stavudine is rapidly absorbed from the GI tract, reaching peak levels in 1 hour. Most of the drug is excreted unchanged in the urine, making it important to reduce dose and monitor patients carefully in the presence of renal dysfunction. It can be used for adults and children and is only available in an extended-release form, allowing for once-a-day dosing. Pharmacokinetics Tenofovir is a newer drug that affects the virus at slightly different point in replication—a nucleotide that becomes a nucleoside. It is used only in combination with other antiretroviral agents. It is rapidly absorbed from the GI tract, reaching peak levels in 45 to 75 minutes. Its metabolism is not known, but it is excreted in the urine. Pharmacokinetics Zidovudine was one of the fi rst drugs found to be effective in the treatment of AIDS. It is rapidly absorbed from the GI tract, with peak levels occurring within 30 to 75 minutes. Zidovudine is metabolized in the liver and excreted in the urine, with a half-life of 1 hour. Adverse Effect Serious-to-fatal hypersensitivity Chills Rash Fatigue GI upset Flu-like symptoms Didanosine- Serious pancreatitis, hepatomegaly, and neurological problems Emtricitabine has been associated with severe and even fatal hepatomegaly with steatosis. Severe hepatomegaly with steatosis has been reported with tenofovir Severe bone marrow suppression has occurred with zidovudine. Protease Inhibitors Pharmacokinetics Atazanavir (Reyataz) is rapidly absorbed from the GI tract and can be taken with food. After metabolism in the liver, it is excreted in the urine and feces with a half-life of 6.5 to 7.9 hours. It is not recommended for patients with severe hepatic impairment; for those with moderate hepatic impairment, the dose should be reduced. Pharmacokinetics Darunavir (Prezista) is well absorbed from the GI tract, reaching peak levels in 2.5 to 4 hours. It is metabolized in the liver and excreted in the urine and feces with a half-life of 15 hours. It is not recommended for patients with severe hepatic impairment. Pharmacokinetics Fosamprenavir (Lexiva) is rapidly absorbed after oral administration, reaching peak levels in 1.5 to 4 hours. It is metabolized in the liver and excreted in urine and feces. Pharmacokinetics Indinavir is rapidly absorbed from the GI tract, reaching peak levels in 0.8 hour. Indinavir is metabolized in the liver by the cytochrome P450 system. It is excreted in the urine with a half- life of 1.8 hours. Patients with hepatic or renal impairment are at risk for increased toxic effects, necessitating a reduction in dose. Pharmacokinetics Lopinavir (Kaletra) is used as a fixed combination drug that combines lopinavir and ritonavir. The ritonavir inhibits the metabolism of lopinavir, leading to increased lopinavir serum levels and effectiveness. It is readily absorbed from theGI tract, reaching peak levels in 3 to 4 hours, and undergoes extensive hepatic metabolism by the cytochrome P450 system. Lopinavir is excreted in urine and feces. Pharmacokinetics Tipranavir wa (Aptivus) s approved in 2005 for the treatment of HIV infection in adults in combination with 200 mg of ritonavir. It is taken orally with food, two 250-mg capsules each day with the ritonavir. It is slowly absorbed, reaching peak levels in 2.9 hours. It is metabolized in the liver with a half-life of 4.8 to 6 hours; excretion is through urine and feces. Pharmacokinetics Nelfinavir( Viracept) is well absorbed from the GI tract, reaching peak levels in 2 to 4 hours. Nelfi navir is metabolized in the liver using the cytochrome P450 CY3A system, and caution must be used in patients with any hepatic dysfunction. It is primarily excreted in the feces, with a half-life of 3.5 to 5 hours. Because there is little renal excretion, this is considered a good drug for patients with renal impairment. Pharmacokinetics Ritonavir (Norvir)is rapidly absorbed from the GI tract, reaching peak levels in 2 to 4 hours. Ritonavir undergoes extensive metabolism in the liver and is excreted in feces and urine. Pharmacokinetics Saquinavir (Fortovase) is slowly absorbed from the GI tract and is metabolized in the liver by the cytochrome P450 mediator, so it must be used cautiously in the presence of hepatic dysfunction. It is primarily excreted in the feces with a short half-life. Adverse Effect GI effects nausea vomitting diarrhea anorexia changes in liver funtion rashes pruritus potentially fatal Steven_Johnson Fusion Inhibitors Pharmacokinetics Enfuvirtide is given by subcutaneous injection and peaks in effect in 4 to 8 hours. After metabolism in the liver, it is recycled in the tissues and not excreted. The half-life of enfuvirtide is 3.2 to 4.4 hours. CCR% Coreceptor Antagonist Pharmacokinetics Maraviroc (Selzentry) is a CCR5 coreceptor antagonist. It blocks the receptor site on the cell membrane to which the HIV virus needs to interact to enter the cell. Maraviroc is rapidly absorbed from the GI tract,metabolized in the liver, and excreted primarily through the feces. It has a half-life of 14 to 18 hours. Integrase Inhibitor Pharmacokinetics Raltegravir inhibits the activity of the virus-specifi c enzyme integrase, an encoded enzyme needed for viral replication. Raltegravir is rapidly absorbed from the GI tract and metabolized in the liver.It has a half-life of 3 hours and is excreted primarily in the feces.  Anti-Hepatitis B Agents Hepatitis B is a serious-to-potentially fatal viral infection of the liver. Adefovir (Hepsera) Entecavir (Baraclude) Telbivudine (Tyzeka)  Pharmacokinetics Adefovir has a half-life of 7.5 and effects occurring in 0.5 to 4hours. Entecavir has a half-life of 128 to 149 hours and effects occurring in 0.5 to 1.5 hours. Telbivudine has a half-life of 40 to 49 hours and effects occurring in 1 to 4 hours.  Adverse Effects headache dizziness nausea diarrhea elevated liver enzymes severe hepatomegaly with steatosis renal impairment lactic acidosis  Anti-Hepatitis C Agents People can get HCV in a number of ways, including: exposure to blood that is infected with the virus, being born to a mother with HCV, sharing a needle, having sex with an infected person, sharing personal items such as a razor or toothbrush with someone who is infected with the virus, or from unsterilized tattoo or piercing tools. Boceprevie (Victrelis) Telaprevir (Incivek)  Adverse Effects headache nausea diarrhea fatigue bone marrow supression severe skin reactions  Locally Active Antiviral Agents Docosanol (Abreva) Ganciclovir (Vitrasert) Imiquimod (Aldara) Penciclovir (Denavir) Trifluridine (Viroptic) The adverse effects most commonly reported are local burning, stinging, and discomfort. ANTIPROTOZOAL ANTIPROTOZOAL AGENTS Key Terms amebiasis - amebic dysentery, which is caused by intestinal invasion of the trophozoite stage of the protozoan Entamoeba histolytica Anopheles mosquito - type of mosquito that is essential to the life cycle of Plasmodium; injects the protozoa into humans for further maturation cinchonism - syndrome of quinine toxicity characterized by nausea, vomiting, tinnitus, and vertigo giardiasis - protozoal intestinal infection that causes severe diarrhea and epigastric distress; may lead to serious malnutrition leishmaniasis: skin, mucous membrane, or visceral infection caused by a protozoan passed to humans by the bites of sand flies Key Terms malaria - protozoal infection with Plasmodium, characterized by cyclic fever and chills as the parasite is released from ruptured red blood cells; causes serious liver, CNS, heart, and lung damage Plasmodium - a protozoan that causes malaria in humans; its life cycle includes the Anopheles mosquito, which injects protozoa into humans Pneumocystis jiroveci pneumonia - opportunistic infection that occurs when the immune system is depressed; a frequent cause of pneumonia in patients with AIDS and in those who are receiving immunosuppressive therapy trichomoniasis - infestation with a protozoan that causes vaginitis in women but no signs or symptoms in men Key Terms protozoa - single-celled organisms that pass through several stages in their life cycle, including at least one phase as a human parasite; found in areas of poor sanitation and hygiene and crowded living conditions trophozoite - a developing stage of a parasite, which uses the host for essential nutrients needed for growth trypanosomiasis: African sleeping sickness, which is caused by a protozoan that inflames the CNS and is spread to humans by the bite of the tsetse fly; also, Chagas' disease, which causes a serious cardiomyopathy after the bite of the house fly Protozoal infections, caused by single-celled organisms that pass through several stages, including at least one phase as a human parasite, are common in several parts of the world. These infections are prevalent in tropical areas where many people suffer multiple infestations simultaneously. Protozoal infections are relatively rare in the United States but can occur in individuals returning from trips to Africa, Asia, or South America. Protozoa thrive in tropical climates but can survive and reproduce in crowded and unsanitary conditions elsewhere. The chapter focuses on protozoal infections caused by insect bites (malaria, trypanosomiasis, leishmaniasis) and those resulting from ingestion or contact with the organism (amebiasis, giardiasis, trichomoniasis).  MALARIA parasitic disease that has killed hundreds of millions of people and even changed the course of history remains endemic in many parts of the world Method of Transmission: bite of a female Anopheles mosquito  MALARIA Four protozoal parasites, all in the genus Plasmodium, have been identified as causes of malaria: Plasmodium falciparum Plasmodium malariae Most dangerous, causes an acute, Endemic in many tropical countries, rapidly fulminating disease with high causes mild signs and symptoms fever, severe hypotension, swelling locally but can cause more acute and reddening of the limbs, loss of disease in travelers. red blood cells, and potentially death. Plasmodium vivax Plasmodium ovale Causes a milder form of the disease, Rarely seen and seems to be in the seldom resulting in death. process of being eradicated. The Life Cycle of Plasmodium The life cycle of Plasmodium involves both the Anopheles mosquito and the human host. When a mosquito bites an infected human, it sucks blood infested with gametocytes (male and female forms of Plasmodium). These gametocytes mate in the mosquito’s stomach, producing a zygote that forms sporozoites, which migrate to the mosquito’s salivary glands. The mosquito injects thousands of sporozoites into the next person it bites. In humans, sporozoites travel through the bloodstream to the liver and other tissues, invading cells. Inside human cells, the organisms undergo asexual division and reproduction, forming schizonts.  The Life Cycle of Plasmodium Schizonts grow and multiply, producing merozoites that burst from cells, invade red blood cells, and continue dividing until causing red blood cells to burst. The cycle of chills and fever from red blood cell rupture occurs about every 72 hours. With P. vivax and P. malariae, this cycle may continue for a long period, with dormant tissue schizonts causing resurgence of the acute cycle for years in untreated patients. With P. falciparum, no prolonged relapses occur; the first attack can destroy many red blood cells, clog capillaries, interrupt circulation to vital organs, and lead to death.  ANTIMALARIALS Antimalarial drugs are usually given in combination to attack Plasmodium at various stages of its life cycle. This approach can prevent the acute malarial reaction in infected individuals Antimalarial drugs: Schizonticidal - acting against the red-blood-cell phase Gametocytocidal - acting against gametocytes Sporontocidal - acting against parasites developing in the mosquito or acting against tissue schizonts as prophylactic or antirelapse agents ANTIMALARIALS Quinine (Qualaquin) was the first effective antimalarial drug and is now available for uncomplicated malaria. Other antimalarials include: chloroquine (Aralen Phosphate), mefloquine (Lariam), primaquine (generic), and pyrimethamine (Daraprim)  ANTIMALARIALS Therapeutic Actions and Indications Chloroquine is the mainstay of antimalarial therapy. Enters human red blood cells and changes metabolic pathways necessary for Plasmodium reproduction. Directly toxic to parasites by decreasing their ability to synthesize DNA, blocking reproduction Resistance to chloroquine is developing; the CDC recommends combination therapy with certain antibiotics for resistant strains.  ANTIMALARIALS Therapeutic Actions and Indications Mechanism of Actions are as follows: Mefloquine Pyrimethamine Increases acidity of plasmodial food Used in combination therapy, blocks vacuoles, causing cell rupture and use of folic acid in protein synthesis by death. Plasmodium. Used in malarial prevention and Leads to inability to reproduce and cell treatment. death. Quinine Primaquine Inhibits nucleic acid synthesis, Disrupts Plasmodium mitochondria, protein synthesis, and glycolysis in P. causing death of gametocytes and falciparum. exoerythrocytic forms. Used to treat uncomplicated Prevents reproduction of other malaria, effective in regions with forms. chloroquine resistance.  ANTIMALARIALS Pharmacokinetics Chloroquine Primaquine Readily absorbed from the GI tract, peak Readily absorbed, metabolized in the liver. serum levels in 1 to 6 hours. Excreted primarily in urine. Concentrated in liver, spleen, kidney, and Safety during pregnancy not established. brain. Excreted slowly in urine, primarily Pyrimethamine unchanged. Readily absorbed from GI tract, peak levels in 2 to 6 hours. Mefloquine Metabolized in liver, half-life of 4 days. Mixture of molecules absorbed, Maintains suppressive concentrations for metabolized, and excreted at different about 2 weeks. rates. Quinine Terminal half-life of 13 to 24 days. Rapidly absorbed from GI tract, Metabolized in liver; caution in patients peak serum levels in 1 to 3 hours. with hepatic dysfunction. Metabolized in liver, half-life of 4 to 6 hours. Excreted in urine.  ANTIMALARIALS Contraindications and Cautions Contradictions: Caution: Known patient allergy to any Patients with retinal disease or damage, antimalarial drugs. as these drugs can affect vision and the Liver disease or alcoholism retina. Lactation Patients with psoriasis or porphyria due Pregnancy to potential skin damage. Patients with damage to mucous membranes Genetic enzyme differences in various groups can predispose them to adverse effects associated with these drugs.  ANTIMALARIALS ADVERSE EFFECTS Gastrointestinal (GI) Effects: Central Nervous System Immune Reaction Nausea (CNS) Effects: Effects: Vomiting Headache Crystalluria Dyspepsia Dizziness Hematuria Anorexia Hepatic Dysfunction Proteinuria Dermatological Effects: Visual changes: Pruritus possible blindness from Rash retinal damage Hair Loss Cinchonism Ototoxicity Nausea, vomiting, tinnitus, and vertigo with high related to nerve levels of quinine or primaquine. damage  OTHER PROTOZOAL INFECTIONS Amebiasis or amebic dysentery, is caused by Entamoeba histolytica. E. histolytica has two stages: cystic (dormant) and trophozoite (active in the large intestine). Transmitted through cysts in fecal matter, contaminating water and food. Cysts are ingested, becoming trophozoites in the intestine, penetrating the colon wall, and spreading through the body (liver, lungs, heart, brain). Symptoms range from mild to severe diarrhea; severe cases can lead to death. Some individuals are carriers, symptomless but passing cysts in stool  OTHER PROTOZOAL INFECTIONS Leishmaniasis Caused by a protozoan transmitted by sand flies. The protozoan, a promastigote, infects and divides inside macrophages, forming amastigotes that cause serious lesions in skin, viscera, or mucous membranes. Trypanosomiasis Caused by Trypanosoma species. African sleeping sickness: Caused by Trypanosoma brucei gambiense, transmitted by the tsetse fly. Invades CNS, causing lethargy, prolonged sleep, and potentially death. Chagas’ disease: Caused by Trypanosoma cruzi, transmitted by the common housefly. Causes severe cardiomyopathy, leading to death and disabilities.  OTHER PROTOZOAL INFECTIONS Trichomoniasis Giardiasis Caused by Trichomonas vaginalis, Caused by Giardia lamblia, the most leading to vaginitis. Spread through common intestinal parasite in the U.S. sexual intercourse by asymptomatic Cysts are transmitted through men, causing vaginal inflammation, contaminated water or food, causing itching, burning, and discharge in diarrhea, foul-smelling stool, and women. possible epigastric distress, weight loss, and malnutrition. Pneumocystis jiroveci Pneumonia Caused by Pneumocystis jiroveci, typically asymptomatic but can cause severe pneumonia in immunocompromised individuals (e.g., AIDS patients, those on immunosuppressants, elderly)  OTHER ANTIPROTOZOAL AGENTS Drugs for Protozoan Infections Malarial drugs chloroquine for extraintestinal amebiasis, pyrimethamine for toxoplasmosis tetracyclines aminoglycosides Antiprotozoal drugs like atovaquone (Mepron), metronidazole (Flagyl, MetroGel, Noritate), nitazoxanide (Alinia), pentamidine (Pentam 300, NebuPent), and tinidazole (Tindamax) OTHER ANTIPROTOZOAL AGENTS Therapeutic Actions and Indications Inhibit DNA synthesis in protozoa, interfering with reproduction and causing cell death. Indicated for infections by susceptible protozoa.  OTHER ANTIPROTOZOAL AGENTS Pharmacokinetics Atovaquone Nitazoxanide Slowly absorbed, highly protein- : Peak levels in 1-4 hours, half-life of bound, half-life of 67-76 hours, 8-12 hours, metabolized liver, excreted in feces excreted in urine and feces Metronidazole Pentamidine Peak levels in 1-2 hours, half-life of Absorbed through lungs, traces in 8-15 hours, metabolized in liver, urine for up to 6 weeks. excreted in urine. Tinidazole Peak levels in 60-90 minutes, half-life of 12-14 hours, excreted in urine. OTHER ANTIPROTOZOAL AGENTS Contraindications and Cautions Contraindicated in known allergy, pregnancy, CNS disease, hepatic disease, candidiasis, and lactation. Caution in renal dysfunction (tinidazole) and children (pentamidine).  OTHER ANTIPROTOZOAL AGENTS ADVERSE EFFECTS Gastrointestinal (GI) Effects: Central Nervous System (CNS) Effects: Nausea Headache Vomiting Dizziness Diarrhea Ataxia Unpleasant Taste loss of coordination Cramps peripheral neuropathy Liver function changes Superinfections Disruption of normal flora ANFUNGAL AGENTS  An infection caused by a fungus is called a mycosis. Fungi differ from bacteria in that the fungus has a rigid cell wall that is made up of chitin and various polysaccharides and a cell membrane that contains ergosterol. SYSTEMIC ANTIFUNGALS The drugs used to treat systemic fungal infections can be toxic to the host and are not to be used indiscriminately. AZOLE ANTIFUNGALS The drugs used to treat systemic fungal infections can be toxic to the host and are not to be used indiscriminately. Fluconazole (Diflucan) Itraconazole (Sporanox) Ketoconazole (Nizoral) Posaconazole (Noxafil) Terbinafine (Lamisil) Voriconazole (Vfend) Ketoconazole orally available as a shampoo and a cream aborbed rapidly from the Gi tract peak levels ocurring within 1 to 3 hours metabolized in the liver excreted through the feces hepatic toxicity endocrine or fertility problems Fluconazole orally and IV peak levels within 1 to 2 hours excreted through urine caution on patient with liver or renal impairment Posaconazole orally rapin onset f action peaks within 3 to 5 hours metabolized in the liver excreted in the feces Terbinafine orally absorbed from Gi tract half-life of 36 hours metabolized in the liver excreted in the urine Voriconazole peak levels in 1 to 2 hours (orally) at the onset of infusion if given IV Adverse Effect liver toxicity effects on a fetus or nursing baby should not be used to pregnant women  ECHINOCANDIN ANTIFUNGALS The echinocandins work by inhibiting glucan synthesis. Anidulafungin Caspofungin Micacfungin Anidulafungin daily IV infusion for atleast 14 dyas rapid onset of action metabolized by degradation has a half-life of 40 to 50 hours excrete in the feces may cross the placenta nad enter breast milk it can be tooxic to the liver Caspofungin IV metabolized in the liver half-lives of 9 to 11 hours then 6 to hours, then 40-50 hours sxcreted through urine can be toxic to liver embrytoxic in animals Micafungin IV drug rapid onset hal-life of 14-17 hours excreted in the urine potential for adverse reaction in the fetus or the neonate  Adverse Effect hepatic toxicity hypersensitivity reactions bone marrow supression Other Antifungal Agents Amphotericin B (Abelcet, AmBisome, Amphotec) IV half-life of 24 hours and then a 15-day half- life excreted in the urine used cautiously druing pregnancy Other Antifungal Agents Flucystosine IV absorbed from GI tract peak levels ocurring in 2 hours half-life to 2,4 to 48 hours excreted in the urine used cautiously during pregnancy Other Antifungal Agents Griseofluvin orally peak levels around 4 hours half-life of 24 hours metabolized in the liver excreted in the urine Nystatin not absorbed in Gi tract  Adverse Effect toxic effects on the liver and kidney bone marrow supresson rash and dermatological changes TOPICAL ANITUNGALS Fungi that cause these mycoses are called dermatophytes. Butoconazole (Gynazole) Clotrimazole (Lotrimin, Mycelex) Econazole (Spectazole) Ketoconazole (Extina, Nizoral, Xolegel) Miconazole (Fungoid, Lotrimin AF, Monistat) Oxiconazole (Oxistat) Sertaconazole Nitrate (Ertaczo) Sulconazole (Exelderm) Terbinafine (Lamisil) Terconazole (Teazol) Ticonazole TOPICAL ANITUNGALS Butenafine (Mentax) Ciclopirox (Loprox, Penlac Nail Lacquer) Gentian Violet (Generic) NAftfinr (Naftin) Tolnaftate (Aftate, Tinacitin) Undecylenic Acid (Cruex, Desenex, Pedi-Dri, Fungoid AF) Econazole local burning and irritation Gentian violet stain skin and clothing toxic when absorbed Naftine, Oxiconazole and Sertaconazole should not be used for longer than 4 weeks Sulconazole should not be used for longer than 6 weeks Terbinafine should not be used longer than 4 weeks. Anthelmintic Agents  Anthelmintic Agents Helminthic infections, caused by worm infestations in the gastrointestinal tract or other tissues, affect about 1 billion people globally. These infections are most common in tropical areas but can also be found in regions like the United States and Canada. With extensive global travel, it's not uncommon for travelers to contract these infections abroad and bring them back home, potentially spreading them further. The two main types of helminths that infect humans are: nematodes (roundworms) and platyhelminths (flatworms),  Many worms that infect humans reside only in the intestinal tract. Treating these infections requires Anthelmintic Drugs Preventing reinfection or spread involves: Thorough hand washing after using the toilet. Frequent laundering of bed linens and underwear in hot, chlorine-treated water. Disinfecting toilets and bathroom areas after each use, and Maintaining good personal hygiene to wash away eggs.  Infections by Nematodes Nematodes, or roundworms, include pinworms, whipworms, threadworms, Ascaris, and hookworms, causing diseases ranging from mild to potentially fatal. Pinworms - are commonly transmitted by ingesting eggs through contact with contaminated surfaces or inhaling airborne eggs. They reside in the intestine, causing mainly perianal or vaginal itching. Pinworm infection is the most common helminthic infection among school-aged children. Whipworms- are transmitted by ingesting eggs found in soil. They attach to the colon wall, causing colitis and bloody diarrhea. Severe infestations can lead to prolapse of the intestinal wall and anemia due to blood loss. Threadworm Infestation - transmitted through larvae in soil, can cause significant damage. They burrow into the small intestine wall, lay eggs that hatch into larvae, and invade various body tissues, including the lungs, liver, and heart. Severe cases can result in pneumonia or abscesses in the lungs or liver, potentially leading to death. Ascaris Infections - is the most prevalent helminthic infection worldwide, often occurring in areas with poor sanitation. Eggs are ingested with contaminated food, hatch in the small intestine, migrate to the lungs causing respiratory symptoms, and then return to the intestine to mature. Severe cases can lead to intestinal obstruction Hookworm Infections - Hookworms hatch in soil, and the larvae penetrate human skin, enter the bloodstream, and reach the intestine within a week. They attach to the small intestine, sucking blood and causing severe anemia, weakness, fatigue, and malabsorption issues. Treatment includes addressing anemia and fluid and electrolyte disturbances.  Infections Caused by Platyhelminths Platyhelminths, or flatworms, include cestodes (tapeworms) that live in the human intestine and flukes (schistosomes) that invade other tissues Cestodes - are segmented flatworms that enter the body through undercooked meat or fish. They can grow several yards long, causing abdominal discomfort, distention, and weight loss. Infected patients often need psychological support due to the distress of excreting parts of the tapeworm or having it exit through the mouth or nose.  Tissue-Invading Worm Infections These worms invade the body outside the intestinal tract, causing significant tissue damage and being more difficult to treat. Trichinosis - is caused by ingesting larvae of the roundworm Trichinella spiralis in undercooked pork. The larvae penetrate the intestinal mucosa, enter the bloodstream, and spread throughout the body, potentially causing inflammatory reactions in skeletal and cardiac muscles, and the brain. Prevention includes freezing pork, monitoring pig feed, and properly cooking pork Filariasis - involves worm embryos (filariae) entering the body through insect bites, overwhelming the lymphatic system, and causing massive inflammatory reactions, leading to severe swelling known as elephantiasis. Schistosomiasis - is caused by a fluke carried by snails, common in parts of Africa, Asia, South America, and the Caribbean. Symptoms include a pruritic rash (swimmer's itch), fever, chills, headache, abdominal pain, diarrhea, and potentially liver and spleen enlargement, and CNS and cardiac ischemia.  Drug Therapy Across the Lifespan: CHILDREN Culture of the suspected worm is important before beginning any drug therapy. More toxic drugs, such as albendazole, ivermectin, and praziquantel, should be avoided in children. Mebendazole, the most commonly used anthelmintic, comes in a chewable tablet, making it convenient for children. ADULTS Adults may be repulsed by the idea of a worm infestation and reluctant to discuss lifestyle adjustments and treatment plans. Pregnant and nursing women should avoid these drugs unless the benefits clearly outweigh the potential risks to the fetus or neonate. In severe cases, some drugs may be used with informed consent about potential risks. OLDER ADULTS Older patients may be more susceptible to central nervous system and GI effects of these drugs, requiring dose adjustments. Hydration and nutritional status should be monitore d carefully.  Pharmacokinetics of Anthelmintic Agents Mebendazole Praziquantel Ivermectin Form: Chewable tablet Dosage: Taken in a series of three oral Absorption: Readily absorbed Course: Typical 3-day course, can be doses at 4- to 6-hour intervals from the GI tract repeated in 3 weeks if needed Absorption: Rapidly absorbed from the Peak Plasma Levels: About 4 Absorption: Very little absorbed GI tract hours systemically Peak Plasma Levels: Within 1 to 3 hours Metabolism: Completely Metabolism: Not metabolized in the body Metabolism: Metabolized in the liver metabolized in the liver Excretion: Mostly in feces, small amount Half-Life: 0.8 to 1.5 hours Half-Life: 16 hours in urine Excretion: Primarily through urine Excretion: Through feces Adverse Effects: Few due to minimal systemic absorption Albendazole Pyrantel Absorption: Poorly absorbed from Absorption: Poorly absorbed the GI tract Excretion: Mostly unchanged in Peak Plasma Levels: About 5 hours feces, small amount in urine Metabolism: Metabolized in the liver Excretion: Primarily in urine  Contraindications and Cautions Contraindications: Allergy: Known allergy to any anthelmintic drugs to prevent hypersensitivity reactions. Lactation: These drugs can enter breast milk and be toxic to the infant; breastfeeding should be avoided while using these drugs. Pregnancy: Most anthelmintics are contraindicated due to potential fetal abnormalities or death; women of childbearing age should use barrier contraceptives while taking these drugs. Pyrantel: Safety not established for children younger than 2 years. Albendazole: Should be used only after identifying the causative worm due to potential adverse liver effects, which can be problematic if the patient has liver involvement. Cautions: Use caution in patients with renal or hepatic disease that interferes with the metabolism or excretion of systemically absorbed drugs. Caution in cases of severe diarrhea and malnourishment, which can alter the drug's effects on the intestine and existing helminths Adverse Effects: Non-systemically absorbed drugs (Mebendazole and Pyrantel): May cause abdominal discomfort, diarrhea, or pain but are generally well tolerated. Systemically absorbed drugs: Can cause headache, dizziness, fever, shaking, chills, malaise (immune reaction to worm death), rash, pruritus, and hair loss. Albendazole: Associated with renal failure and severe bone marrow depression, requiring careful monitoring. Clinically Important Drug-Drug Interactions: Albendazole's effects may increase if combined with dexamethasone, praziquantel, or cimetidine. These combinations should be avoided if possible, and patients should be monitored closely for adverse effects if these combinations are necessary. Chemotherapy and Antineoplastic Agents  Chemotherapy and Antineoplastic Agents Chemotherapy Often associated with cancer treatment, involves drugs that target and kill or alter human cells, particularly antineoplastic agents designed to combat neoplasms (cancers). Action of Antineoplastic Drugs Aim to target abnormal cancer cells more than normal cells, but normal cells can also be affected. This area of pharmacology includes drugs that use the immune system to fight cancer cells. Cancer Overview Prevalence: Second leading cause of death in the U.S., affecting individuals of any age. Treatment can be prolonged and debilitating with numerous complications. Origin and Development: Begins with a single abnormal cell that divides, forming a tumor (neoplasm) with characteristics different from original tissue. Cancer cells exhibit: Anaplasia: Loss of cellular differentiation and organization, losing normal function. Autonomy: Growth without usual regulatory control, leading to tumor formation. Metastasis: Cancer cells can spread from the original site to other body areas, forming new tumors where conditions favor growth. Cancer Cell Behavior and Immune Response Angiogenesis: Abnormal cancer cells release enzymes that generate blood vessels to supply oxygen and nutrients, aiding their growth. Impact on Host Cells: Cancer cells deprive host cells of energy and nutrients and block normal lymph and vascular vessels, leading to loss of normal cellular function. Immune System Response: T Cells: Recognize and destroy abnormal cells. Antibodies: Form in response to abnormal cell proteins. Interferons and Tissue Necrosis Factor: Assist in eliminating abnormal cells. Immune System Overwhelm: As the neoplasm grows, it may become too large for the immune system to manage effectively, threatening the host's life. Causes of Cancer: Genetic Predisposition: Some cancers, like breast cancer, have genetic links. Viral Infections and Irritation: Constant cell turnover and viral infections can lead to cancer. Stress: Suppresses the immune system, increasing the risk of cell mutations. Environmental Factors: Exposure to carcinogenic chemicals in air, water, or ground increases risk. Lifestyle Choices: Pipe smoking can lead to tongue and mouth cancers due to continuous cell damage and replacement. Types of Cancer: Solid Tumors - Originate in body organs. Carcinomas - Originate in epithelial cells (e.g., breast, bronchial tubes, skin). Sarcomas - Originate in mesenchymal (connective) tissue (e.g., bone, muscles). Hematological Malignancies - Affect blood-forming organs (bone marrow, lymphatic system) and disrupt blood cell production and regulation. Antineoplastic Drugs Cell kill theory. A set percentage of cells is killed after each dose of chemotherapy. The percentage killed is dependent upon the drug therapy. In this example, each course of chemotherapy kills 90% of cells in a cancerous tumor. After the fifth course of chemotherapy in this example, a one cell tumor remains; the patient's system would destroy this malignant cell.  Dormant malignant cells can remain inactive for long periods and re-emerge, making them hard to destroy. Antineoplastic agents are given over time to target cancer cells as they come out of dormancy Common adverse effects include nausea, vomiting, hair and skin changes, and bone marrow suppression. Antineoplastic drugs can affect fertility and are contraindicated during pregnancy due to fetal risks. Patients must undergo regular hematological monitoring and understand the need for repeated chemotherapy sessions. Drug therapy across the lifespan Children: Combination therapy is essential for treating pediatric cancers to eliminate mutant cells, and dose double-checking is crucial; close attention to hydration, nutritional status, and support for social, emotional, and intellectual needs is needed, with careful monitoring and adjustment of bone marrow activity. Adults: Address body image changes such as hair loss and GI complaints, provide emotional support and networking, and avoid antineoplastic drugs during pregnancy and nursing while using barrier contraceptives for women of childbearing age. Older Adults: Monitor for CNS and GI effects, regularly test renal and hepatic function with dose adjustments as needed, and prevent infection and injury by protecting immunosuppressed patients, monitoring blood counts, and arranging for rest or dose modifications. Alkylating Agents: These non-cell cycle specific drugs target both dividing and resting cells, making them effective for slow-growing cancers. Key examples include altretamine, bendamustine, busulfan, carboplatin, cisplatin, and cyclophosphamide. Therapeutic Actions and Indications: Alkylating agents cause cytotoxic effects by binding with cellular DNA. They are effective for treating slow-growing cancers, including lymphomas, leukemias, myelomas, ovarian, testicular, breast, and some pancreatic cancer Pharmacokinetics Alkylating agents vary in absorption, have uncertain tissue distribution, are often metabolized in the liver via cytochrome P450 systems, are excreted in urine, and should be used cautiously with other hepatotoxic or nephrotoxic drugs, as well as those metabolized by the liver.s Contraindications and Cautions Alkylating agents are contraindicated during pregnancy and lactation due to severe effects on the fetus and neonate, and should be used with caution in individuals with known allergies, bone marrow suppression, or suppressed renal or hepatic function, which may require dose adjustments Adverse Effects Adverse Effects of Alkylating Agents: Common effects include bone marrow suppression (leukopenia, thrombocytopenia, anemia), gastrointestinal issues (nausea, vomiting, diarrhea), hepatic and renal toxicity, alopecia, and increased uric acid levels. Cytoprotective drugs like amifostine and mesna may mitigate some effects, and allopurinol or rasburicase can manage elevated uric acid levels Drug-Drug Interactions for Alkylating Agents Use caution when combining with other hepatotoxic or nephrotoxic drugs, as they can exacerbate liver or kidney toxicity, and hepatotoxic alkylating agents may impair the metabolism and efficacy of other liver-metabolized drugs. ANTIMETABOLITES These drugs mimic natural metabolites needed for cell growth and division. Key antimetabolites include capecitabine, cladribine, clofarabine, cytarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, and thioguanine Therapeutic Actions and Indications Antimetabolites block DNA production by mimicking essential metabolites, inhibiting enzymes like thymidylate synthetase, DNA polymerase, or folic acid reductase. They are S phase-specific and effective against rapidly dividing cells, used in treating leukemias and some GI and basal cell cancers, often in combination therapy due to resistance development Pharmacokinetics Methotrexate is well-absorbed from the GI tract, excreted unchanged in urine, and crosses the blood-brain barrier. Other antimetabolites like cytarabine and gemcitabine are poorly absorbed orally, requiring parenteral administration, metabolized in the liver, and excreted in urine. Mercaptopurine and thioguanine are slowly absorbed from the GI tract and similarly processe d. Contraindications and Cautions Antimetabolites are contraindicated during pregnancy and lactation due to severe risks to the fetus and neonate. Use with caution in individuals with allergies, bone marrow suppression, renal or hepatic dysfunction (which may require dose adjustments), and GI ulcerations or diseases (which may be worsened by these drugs). Adverse effects Adverse effects are frequently encountered with the use of the antimetabolites. To counteract the effects of treatment with one antimetabolite-methotrexate- the drug leucovorin or its isomer levoleucovorin is some- times given. Clinically Important Drug-Drug Interactions Antimetabolites that cause hepatic or renal toxicity should be used cautiously with other hepatotoxic or nephrotoxic drugs. Liver-toxic drugs may also affect the metabolism or action of liver-metabolized drugs, such as oral anticoagulants Antineoplastic antibiotics - are toxic to rapidly dividing cells, are used in cancer treatment. They include: Bleomycin (Blenoxane) Dactinomycin (Cosmegen) Daunorubicin (DaunoXome) Doxorubicin (Adriamycin, Doxil) Epirubicin (Ellence) Idarubicin (Idamycin) Mitomycin (Mutamycin) Mitoxantrone (Novantrone) Valrubicin (Valstar) Therapeutic Actions and Indications Antineoplastic antibiotics disrupt DNA synthesis either by breaking DNA links or inserting between DNA base pairs, causing cell death. They are used to treat cancers but can have serious side effects on rapidly dividing cells like those in the bone marrow, GI tract, and skin, limiting their use in debilitated patients or those with preexisting conditions Pharmacokinetics Antineoplastic antibotics are poorly absorbed from the GI tract and are administered IV. They are metabolized in the liver and excreted in the urine, with some having very long half-lives. Daunorubicin and doxorubicin do not cross the blood-brain barrier but accum