introduction to Chemotherapy -1.pdf

Introduction to Chemotherapy Dr. Najla’a Kasim Mohammed Al-Shibany Assistant Professor of Pharmacology HUCOM  The term “chemotherapy” include: 1. Antimicrobial agents: Chemicals that kill or stop the growth & multiplication of infective mi...

Introduction to Chemotherapy Dr. Najla’a Kasim Mohammed Al-Shibany Assistant Professor of Pharmacology HUCOM  The term “chemotherapy” include: 1. Antimicrobial agents: Chemicals that kill or stop the growth & multiplication of infective microbes (bacteria, viruses, fungi and parasites). 2. Antineoplastic (anticancer) agents. Traditionally, the term antibiotic was used to refer to substances produced by microorganisms that suppress the growth of other MO, while antibacterial was used to describe not only natural antibiotics produced by microorganisms but also drugs synthesized in the laboratory. 2 Classification of Antibacterial Agents 1. According to their effect on the bacteria. 2. According to the antibacterial spectrum. 3. According to the mode of action. 3 a) According to their effect on the bacteria 1. Bactericidal: 2. Bacteriostatic: Kill the micro- Stop growth of m.o.→ organisms →No the body defense need for the body mechanisms are defense needed to eradicate mechanisms to the infection. eradicate the e.g. tetracyclines & infection chloramphenicol. e.g. penicillins & aminoglycosides. 4 5  b) According to the antibacterial spectrum 1. Broad spectrum agents:  Kill or stop the growth of wide range of m.o.  Effective against both gm +ve & gm–ve bacteria. Examples: tetracyclines & chloramphenicol. 2. Narrow spectrum agents:  Kill or stop the growth of only limited range of m. o.  Penicillin G/ erythromycin (act mostly against gm+ve bacteria). 6  Aminoglycosides (act against gm–ve bacteria). 3. Extended-spectrum antibiotics:  It is the term applied to antibiotics that are modified to be effective against gram-positive organisms and also against a significant number of gram-negative bacteria.  For example, ampicillin is considered to have an extended spectrum because it acts against gram-positive and some gram-negative bacteria. 7  Chemotherapeutic Spectra 8 c) According to the mode of action: 9  1) Inhibitors of Bacterial Cell Wall Synthesis In most bacteria, a cell wall surrounds the cell like a rigid shell that protects against noxious outside influences and prevents rupture of the plasma membrane from a high internal osmotic pressure. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. Any drug impairs the structure or synthesis of this peptidoglycan will lead to damage of the membrane & consequently cell lysis (bactericidal 10 effect). 11  Composition of Gram-Positive and Gram- Negative Bacterial Envelopes Gram-positive bacteria are particularly susceptible.  Antibacterial spectrum:  Is determined, in part, by the ability of the drug molecules to cross the bacterial peptidoglycan cell wall to reach the PBPs in the periplasmic space.  Factors determining PBP susceptibility to these antibiotics include size, charge, & hydrophobicity of the antibiotic.  In general, gram-positive microorganisms have cell walls that are easily traversed by penicillins, and, therefore, in the absence of resistance, they are susceptible to these drugs.  Gram-negative microorganisms have an outer lipopoly- saccharide membrane surrounding the cell wall that presents a barrier to the water-soluble β-lactam antibiotic. However, they have proteins inserted in the 13 lipopolysaccharide layer that act as water-filled channels  Inhibitors of cell wall synthesis are suitable antibacter-ial agents because animal cells (including human cells) lack a cell wall. To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms. They have little or no effect on bacteria that are not growing and dividing. (Should not be used with static??) Examples:  β-Lactam antibiotics (penicillins & cephalosporins)  Vancomycin. 14 2) Inhibitors of Cell Membrane Function Some antibacterial drugs produce their effects by disrupting cell membrane function. Examples:  Polymyxin  Amphotericin B 15  3) Inhibitors of Protein Synthesis A number of antibiotics exert their antimicrobial effects by targeting bacterial ribosomes and inhibiting bacterial protein synthesis. Examples: Aminoglycosides Tetracycline Chloramphenicol Erythromycin. 16  Aminoglycosides, tetracyclines, and glycylcyclines bind to the 30S ribosomal subunit; all others bind to sites on the 50S subunit. Depending on the drug class and the bacteria, these agents may result in either bactericidal or bacteriostatic effects. In general, the aminoglycosides are bactericidal, while the others are bacteriostatic with a few exceptions for several specific bacteria. Bacterial ribosomes differ structurally from mammalian cytoplasmic ribosomes and are composed of 30S and 50S subunits (mammalian ribosomes have 40S and 60S subunits). Selective toxicity. 17 4) Inhibitors of Bacterial Nucleic Acid Synthesis Some antibiotics exert their antimicrobial effects by inhibiting bacterial deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) synthesis. DNA synthesis is important for cell division and proliferation. RNA has an important role in protein synthesis (cell growth and regulation of cell function). Examples: Quinolones, Rifampin. 18 5) Inhibitors of Metabolic Pathways Some antibacterial drugs produce their effects by blocking specific metabolic steps that are essential for the growth and replication of the m. o. Ex: folate antagonists (sulfonamides & trimethoprim ). Selective toxicity (Human derive folic acid 19 from diet)  Selective Toxicity The drug kills or stop growth of the infective agents without damaging the host. This selective toxicity is possible due to difference in structure or metabolism between the pathogen & the host. Drug with selective toxicity caused greater harm to the infective microbes than to host. 20  DRUG RESISTANCE Bacteria are considered resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not halt bacterial growth. Microbial resistant may be inherited or acquired. Acquired antibiotic resistance requires the temporary or permanent gain or alteration of bacterial genetic information. Resistance develops due to the ability of DNA to undergo spontaneous mutation or to move from one organism to another. 21 Causes of Resistance to Antimicrobial Agents 1. Reduced entrance of the drug into the pathogen. 2. Enhanced export of antibiotic by efflux pumps. 3. Release of microbial enzymes that destroy the antibiotic. 4. Reduced affinity of the drug to altered target structure in the microbe. 5. Development of alternative metabolic pathway to those inhibited by the antibiotic. 6. Metabolically inactive microorganisms are resistant to antimicrobials. 22  Inappropriate use of antimicrobials is leading to increased antimicrobial resistance (AMR). AMR is one of the world’s most serious public health problems resulting in prolonged illness and hospitalization, which are costly. 23  Factors Leading to Increase in Antimicrobial Resistance (AMR) 1. Overuse, misuse, and irrational use by doctors. 2. Noncompliance to prescribed regimen, self- medication, and use of leftover antibiotics by patients. 3. Use of antibiotics in animal husbandry, aquaculture, and agriculture. 4. Poor infection control in healthcare settings: It leads to spread of outbreaks and transmission of resistant organisms among patients. 5. Poor hygiene and sanitation. 6. Absence of new antibiotics being discovered. 24  Lippincott Illustrated Reviews: Pharmacology (South Asian Edition) 2019 Principles of Antimicrobial Therapy (chapter 28) SELECTION OF ANTIMICROBIAL AGENTS. DETERMINANTS OF RATIONAL DOSING. COMBINATIONS OF ANTIMICROBIAL DRUGS. 25  Factors to Consider When Selecting Antimicrobial Agents for Therapy in Patients Identification of the infecting organism (C&S, vs Empiric antimicrobial therapy) site of infection (BBB) Patient factors (Immune system, Renal dysfunction, Hepatic dysfunction, Poor perfusion, Age, Pregnancy and lactation, Risk factors for multidrug-resistant organisms, Safety of the agent Cost of therapy 26 IV. DETERMINANTS OF RATIONAL DOSING Rational dosing of antimicrobial agents is based on pharmacodynamics (the relationship of drug concentrations to antimicrobial effects) and pharmacokinetic properties (the absorption, distribution, metabolism, and elimination of the drug). Three important properties that have a significant influence on the frequency of dosing are concentration-dependent killing, time-dependent (concentration-independent) killing, and postantibiotic effect (PAE). 27 VI. COMBINATIONS OF ANTIMICROBIAL DRUGS It is therapeutically advisable to treat patients with a single agent that is most specific to the infecting organism. This strategy reduces the possibility of superinfections, decreases the emergence of resistant organisms, and minimizes toxicity. However, in some situations, combinations of antimicrobial drugs are advantageous or even required. A. Advantages of drug combinations Certain combinations of antibiotics, such as β- lactams and aminoglycosides, show 28 Thanks 29  Factors to Consider When Selecting Antimicrobial Agents for Therapy in Patients Drug-Bacteria (Antibacterial spectrum, mechanism of action, selective toxicity, susceptibility of infecting microorganism, time-dependent and concentration- dependent killing effects, postantibiotic effect, need for bactericidal versus bacteriostatic agent, bacterial resistance). Host-Bacteria (Necessity for an antimicrobial agent, identification of the pathogen, host defense system, empiric, definitive and prophylactic therapy, combination therapy). Drug-Host (Pharmacokinetic factors (absorption, distribution, metabolism, elimination), age, adverse effects, allergy history, genetic or metabolic abnormalities). 30 31  Drugs Targeting Bacterial DNA Sulfonamides and trimethoprim Fluoroquinolones Nitrofurans Nitroimidazoles 32