Chemotherapeutic Agents

Transcription

1 Chemotherapeutic Agents

2 The cell is the basic structure of all living organisms. The cell membrane features specifi c receptor sites that allow interaction with various chemicals, histocompatibility proteins that allow for self-identifi cation, and channels or pores that allow for the passage of substances into and out of the cell.

3 The cytoplasm of the cell contains various organelles that are important for cellular function. The mitochondria produce energy for the cell; the endoplasmic reticulum contains ribosomes that produce proteins; the Golgi apparatus packages proteins; and lysosomes contain proteindissolving enzymes that are important for digestion and the recycling of organisms in nature.

4 All cells progress through a cell cycle, which allows them to reproduce. Each cell goes through a resting phase (G0); a gathering phase (G1), when the components needed for cell division are collected by the cell; a synthesizing phase (S), when DNA and other components are produced; a fi nal gathering phase (G2), when the last substances needed for division are collected and produced; and an M phase, when actual cell division occurs, producing two identical daughter cells.

5 The cell is composed of a nucleus, which contains genetic material and controls the production of proteins by the cell; a cell membrane, which separates the inside of the cell from the outside environment; and a cytoplasm, which contains various organelles important to cell function. The cell membrane functions as a fl uid barrier made of lipids and proteins. The arrangement of the lipoprotein membrane controls what enters and leaves the cell. Proteins on the cell membrane surface can act either as receptor sites for specifi c substances or as histocompatibility markers that identify the cell as a selfcell (i.e., a cell belonging to that individual).

6 Channels or pores in the cell membrane allow for easier movement of specifi c substances needed by the cell for normal functioning. Mitochondria are rod-shaped organelles that produce energy in the form of ATP for use by cells. Ribosomes are sites of protein production within the cell cytoplasm. The specifi c proteins produced by a cell are determined by the genetic material within the cell nucleus. The Golgi apparatus packages particular substances for removal from the cell (e.g., neurotransmitters, hormones).

7 Lysosomes are packets of digestive enzymes located in the cell cytoplasm. These enzymes are responsible for destroying injured or nonfunctioning parts of the cell and for promoting cellular disintegration when the cell dies. Endocytosis is the process of moving substances into a cell by extending the cell membrane around the substance and engulfi ng it. Pinocytosis refers to the engulfing of necessary materials, and phagocytosis refers to the engulfi ng and destroying of bacteria or other proteins by white blood cells.

8 Exocytosis is the process of removing substances from a cell by moving them toward the cell membrane and then changing the cell membrane to allow passage of the substance out of the cell. Cells maintain homeostasis by regulating the movement of solutes and water into and out of the cell. Diffusion, which does not require energy, is the movement of solutes from a region of high concentration to a region of lower concentration across a concentration gradient. Osmosis, which, like diffusion, does not require energy, is the movement of water from an area low in solutes to an area high in solutes. Osmosis exerts a pressure against the cell membrane that is called osmotic pressure.

9 Active transport, an energy-requiring process, is the movement of particular substances against a concentration gradient. Active transport is important in maintaining cell homeostasis. Cells replicate at differing rates, depending on the genetic programming of the cell. All cells go through a life cycle consisting of the following phases: G0, the resting phase; G1, which involves the production of proteins for DNA synthesis; S, which involves the synthesis of DNA; G2, which involves manufacture of the materials needed for mitotic spindle production; and M, the mitotic phase, in which the cell splits to form two identical daughter cells. Chemotherapeutic drugs act on cells to cause cell death or alteration. All properties of the drug that affect cells should be considered when administering a chemotherapeutic agent.

10 ANTI-INFECTIVE DRUGS

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12 Therapeutic Actions Some anti-infectives interfere with biosynthesis of the pathogen cell wall. Because bacterial cells have a slightly different composition than human cells, this is an effective way to destroy the bacteria without interfering with the host. The penicillins work in this way.

13 Therapeutic Actions 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 trimethoprimsulfamethoxazole (a combination drug frequently used to treat urinary tract infections) work in this way.

14 Therapeutic Actions 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 work in this way.

15 Therapeutic Actions Some anti-infectives interfere with DNA synthesis in the cell, leading to inability to divide and cell death. The fluoroquinolones work in this way.

16 Therapeutic Actions 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.

17 Acquiring Resistance Producing an enzyme that deactivates the antimicrobial drug. For example, some strains of bacteria that were once controlled by penicillin now produce an enzyme called penicillinase, which inactivates penicillin before it can affect the bacteria. This occurrence led to the development of new drugs that are resistant to penicillinase.

18 Acquiring Resistance Changing cellular permeability to prevent the drug from entering the cell or altering transport systems to exclude the drug from active transport into the cell. Altering binding sites on the membranes or ribosomes, which then no longer accept the drug. Producing a chemical that acts as an antagonist to the drug.

19 The goal of anti-infective therapy is the reduction of the invading organisms to a point at which the human immune response can take care of the infection. Anti-infectives can act to destroy an infective pathogen (bactericidal) or to prevent the pathogen from reproducing (bacteriostatic). Anti-infectives can have a small group of pathogens against which they are effective (narrow spectrum), or they can be effective against many pathogens (broad spectrum).

20 Resistance of a pathogen to an anti-infective agent can be natural (the pathogen does not use the process on which the anti-infective works) or acquired (the pathogen develops a process to oppose the antiinfective agent). The emergence of resistant strains is a serious public health problem. Health care providers need to be alert to preventing the emergence of resistant strains by not using antibiotics inappropriately, assuring that the antiinfective is taken at a high enough dose for a long enough period of time, and avoiding the use of newer, powerful anti-infectives if other drugs would be just as effective.

21 Anti-infectives are drugs designed to act on foreign organisms that have invaded and infected the human host with selective toxicity, which means that they affect biological systems or structures found in the invading organisms but not in the host. Anti-infectives include antibiotics, antivirals, antifungals, antiprotozoals, and anthelmintic agents. The goal of anti-infective therapy is interference with the normal function of invading organisms to prevent them from reproducing and promotion of cell death without negative effects on the host cells. The infection should be eradicated with the least toxicity to the host and the least likelihood for development of resistance.

22 Anti-infectives can work by altering the cell membrane of the pathogen, by interfering with protein synthesis, or by interfering with the ability of the pathogen to obtain needed nutrients. Anti-infectives also work to kill invading organisms or to prevent them from reproducing, thus depleting the size of the invasion to one that can be dealt with by the human immune system. Pathogens can develop resistance to the effects of antiinfectives over time when (1) mutant organisms that do not respond to the anti-infective become the majority of the pathogen population or (2) the pathogen develops enzymes to block the anti-infectives or alternative routes to obtain nutrients or maintain the cell membrane.

23 An important aspect of clinical care involving antiinfective agents is preventing or delaying the development of resistance. This can be done by ensuring that the particular anti-infective agent is the drug of choice for the specific pathogen involved and that it is given in high enough doses for sufficiently long periods to rid the body of the pathogen. Culture and sensitivity testing of a suspected infection ensures that the correct drug is being used to treat the infection effectively. Culture and sensitivity testing should be performed before an anti-infective agent is prescribed.

24 Anti-infectives can have several adverse effects on the human host, including renal toxicity, multiple GI effects, neurotoxicity, hypersensitivity reactions, and superinfections. Some anti-infectives are used as a means of prophylaxis when patients expect to be in situations that will expose them to a known pathogen, such as travel to an area where malaria is endemic, or oral or invasive GI surgery in a person who is susceptible to subacute bacterial endocarditis.

25 ANTIBIOTICS

26 Learning Objectives 1. Explain how an antibiotic is selected for use in a particular clinical situation. 2. Describe therapeutic actions, indications, pharmacokinetics, contraindications, most common adverse reactions, and important drug drug interactions associated with each of the classes of antibiotics. 3. Discuss use of antibiotics as they are used across the lifespan. 4. Compare and contrast prototype drugs for each class of antibiotics with other drugs in that class. 5. Outline nursing considerations for patients receiving each class of antibiotic.

27 Glossary of Key Terms 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

28 Glossary of Key Terms 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

29 Antibiotics are made in three ways: - by living microorganisms, - by synthetic manufacture, - genetic engineering. Antibiotics may either be - bacteriostatic (preventing the growth of bacteria) - bactericidal (killing bacteria directly), Although several antibiotics are both bactericidal and bacteriostatic, depending on the concentration of the particular drug.

30 Major Classes Of Antibiotics Aminoglycosides Carbapenems Cephalosporins Fluoroquinolones Penicillins And Penicillinaseresistant Drugs Sulfonamides Tetracyclines Disease-specific Antimycobacterials: Antitubercular And Leprostatic Antibiotics That Do Not Fit Into The Large Antibiotic Classes Include: Ketolides Lincosamides Lipoglycopeptides, Macrolides Monobactams.

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33 BACTERIA AND ANTIBIOTICS Bacteria can invade the human body through many routes. Once the bacteria invade the body, the human immune response is activated, and signs and symptoms of an infection occur as the body tries to rid itself of the foreign cells. Fever, lethargy, slow-wave sleep induction, and the classic signs of inflammation (e.g., redness, swelling, heat and pain).

34 The goal of antibiotic therapy is to decrease the population of invading bacteria to a point at which the human immune system can effectively deal with the invader. To determine which antibiotic will effectively interfere with the specific proteins or enzyme systems for treatment of a specific infection, the causative organism must be identified through a culture. Sensitivity testing is also done to determine the antibiotic to which that particular organism is most sensitive (e.g., which antibiotic best kills or controls the bacteria).

35 Gram-positive bacteria are commonly associated with infections of the respiratory tract and soft tissues. An example of a gram-positive bacterium is Streptococcus pneumoniae, a common cause of pneumonia. Gram-negative bacteria are frequently associated with infections of the genitourinary (GU) or GI tract. An example of a gram-negative bacterium is Escherichia coli, a common cause of cystitis.

36 The goal of antibiotic therapy is to reduce the population of invading bacteria to a size that the human immune response can deal with. Bacteria can be classified as gram-positive (frequently found in respiratory infections) or gram-negative (frequently found in GI and GU infections). They can also be classified as anaerobic (not needing oxygen) or aerobic (dependent on oxygen). 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.

37 Effect Of The Site Of Infection On Therapy The blood-brain barrier Adequate levels of an antibiotic must reach the site of infection for the invading microorganisms to be effectively eradicated. Capillaries with varying degrees of permeability carry drugs to the body tissues.

38 Natural barriers to drug delivery are created by the structures of the capillaries of some tissues (prostate, the vitreous body of the eye, and the central nervous system (CNS)). Of particular significance are the capillaries in the brain, which help to create and maintain the blood-brain barrier. This barrier can be demonstrated by injecting dyes into laboratory animals.

39 The penetration and concentration of an antibacterial agent in the CSF is particularly influenced by the following: 1. Lipid solubility of the drug: All compounds without a specific transporter must pass intracellularly from the blood to the CSF. The lipid solubility of a drug therefore determines its ability to penetrate the brain. Lipid-soluble drugs, such as chloramphenicol and metronidazole, have significant penetration into the CNS. In contrast, β-lactam antibiotics, such as penicillin, are ionized at physiologic ph and have low solubility in lipids. They therefore have limited penetration under normal circumstances. In infections such as meningitis in which the brain becomes inflamed, the barrier does not function as effectively, and local permeability is increased. Some β-lactam antibiotics can then enter the CSF in therapeutic amounts 2. Molecular weight of the drug: A compound with a low molecular weight has an enhanced ability to cross the blood-brain barrier, whereas compounds with a high molecular weight (for example, vancomycin) penetrate poorly, even in the presence of meningeal infl ammation. 3. Protein binding of the drug: A high degree of protein binding of a drug in the serum restricts its entry into the CSF. Therefore, the amount of free (unbound) drug in serum, rather than the total amount of drug present, is important for CSF penetration.

40 AMINOGLYCOSIDES

41 The aminoglycosides are a group of powerful antibiotics used to treat serious infections caused by gram-negative aerobic bacilli. Aminoglycosides include amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kantrex), neomycin (Mycifradin), streptomycin (generic), and tobramycin (TOBI, Tobrex).

42 Therapeutic Actions and Indications Bactericidal They inhibit protein synthesis in susceptible strains of gram-negative bacteria. They irreversibly bind to a unit of the bacteria ribosomes, leading to misreading of the genetic code and cell death. used to treat serious infections caused by susceptible strains of gram negative bacteria, including Pseudomonas aeruginosa, E. coli, Proteus species, the Klebsiella Enterobacter Serratia group, Citrobacter species, and Staphylococcus species such as Staphylococcus aureus. indicated for the treatment of serious infections that are susceptible to penicillin when penicillin is contraindicated can be used in severe infections before culture and sensitivity tests have been completed.

43 Pharmacokinetics The aminoglycosides are poorly absorbed from the GI tract but rapidly absorbed after intramuscular (IM) injection, reaching peak levels within 1 hour. These drugs have an average half-life of 2 to 3 hours. They are widely distributed throughout the body, cross the placenta and enter breast milk, and are excreted unchanged in the urine

44 Key Points Aminoglycosides inhibit protein synthesis in susceptible strains of gram-negative bacteria. These drugs are reserved for use in serious infections because of potentially serious adverse effects. Monitor for ototoxicity, renal toxicity, GI disturbances, bone marrow depression, and superinfections.