New Mansoura University Pharmacology III-Lecture (1) PDF

New Mansoura University Faculty of Pharmacy Pharm D Program __________________________________________________________ _________________ pharmacology-iii & Biostatistics Introduction to Chemotherapy &...

New Mansoura University Faculty of Pharmacy Pharm D Program __________________________________________________________ _________________ pharmacology-iii & Biostatistics Introduction to Chemotherapy & Cell Wall Inhibitors Lecture(1)  Course Objectives By the completion of this course, the student should be able to describe mechanisms of action (pharmacodynamics), pharmacokinetics, prototypic examples, side effects, contraindications and therapeutic applications of diverse chemotherapeutic treatments used in infections (antibacterials, antifungals, antivirals) and cancers (alkylating agents, antimetabolites, antimitotics, hormonal therapies and tyrosine kinase inhibitors). Introduction to chemotherapy Antimycobacterials Cell wall inhibitors Antivirals Protein synthesis inhibitors Antifungals Qinolones Anticancer drugs Folic acid antagonists Immunosuppressants Urinary tract antiseptics  Chemotherapy Chemotherapeutic agents are intended to eliminate foreign organisms (antimicrobials) or abnormal (cancer) cells (anticancer drugs) from healthy tissues of the patient. An essential property of all chemotherapeutic drugs is selective toxicity; deleterious actions directed a ga i n s t t h e t a r g e t c e l l s w i t h o u t comparable effects on the tissue of the host.  Identification of the Infecting Organism & Determination of Antimicrobial Susceptibility Bacteriostatic versus Bactericidal Drugs Minimum Inhibitory Concentration (MIC) & Minimum Bactericidal Concentration (MBC)  Chemotherapeutic Spectra The clinically important bacteria have been organized into eight groups based on gram stain, morphology, and biochemical or other characteristics. A. Narrow-spectrum antibiotics Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a narrow spectrum. For example, isoniazid is active only against Mycobacterium tuberculosis. B. Extended-spectrum antibiotics Extended spectrum 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. C. Broad-spectrum antibiotics Drugs such as tetracycline, fluoroquinolones and carbapenems affect a wide variety of microbial species and are referred to as broad-spectrum antibiotics. Administration of broad-spectrum antibiotics can drastically alter the nature of the normal bacterial flora and precipitate a superinfection. Chemotherapeutic Spectra  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. Some organisms are inherently resistant to an antibiotic. For example, most gram-negative organisms are inherently resistant to vancomycin. However, microbial species that are normally responsive to a particular drug may develop more virulent or resistant strains through spontaneous mutation or acquired resistance and selection. Some of these strains may even become resistant to more than one antibiotic. Drug Resistance  Complications of Antibiotic Therapy A. Hypersensitivity: Hypersensitivity or immune reactions to antimicrobial drugs or their metabolic products frequently occur. For example, the penicillins, despite their almost absolute selective microbial toxicity, can cause serious hypersensitivity problems, ranging from urticaria (hives) to anaphylactic shock. Some reactions may be related to the rate of infusion, such as “Red man syndrome” seen with rapid infusion of vancomycin.  Complications of Antibiotic Therapy B. Direct toxicity: High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host. For example, aminoglycosides can cause ototoxicity by interfering with membrane function in the auditory hair cells. Chloramphenicol can have a direct toxic effect on mitochondria, leading to bone marrow suppression. Fluoroquinolones can have effects on cartilage and tendons, and tetracyclines have direct effects on bones. A number of antibiotics can cause photosensitivity.  Complications of Antibiotic Therapy C. Superinfections: Drug therapy, particularly with broad-spectrum antimicrobials or combinations of agents, can lead to alterations of the normal microbial flora of the upper respiratory, oral, intestinal, and genitourinary tracts, permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. These infections usually require secondary treatments using specific anti-infective agents.  Cell Wall Inhibitors Some antimicrobial drugs selectively interfere with synthesis of the bacterial cell wall—a structure that mammalian cells do not possess. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links.  Penicillins The basic structure of penicillins consists of a core four-membered β-lactam ring, which is attached to a thiazolidine ring and an R side chain. Members of this family differ from one another in the R substituent attached to the 6- aminopenicillanic acid residue. The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, cross-hypersensitivity, and susceptibility to bacterial degradative enzymes (β-lactamases).  Penicillins v Mechanism of action Penicillins interfere with the last step of bacterial cell wall synthesis, which is the cross-linking of adjacent peptidoglycan strands by a process known as transpeptidation. Since penicillins structurally resemble the terminal portion of the peptidoglycan strand, they compete for and bind to enzymes called penicillin-binding proteins (PBPs), which catalyze transpeptidase and facilitate cross-linking of the cell wall. The result is the formation of a weakened cell wall and ultimately cell death. For this reason, penicillins are regarded as bactericidal and work in a time-dependent fashion. Another mechanism; production and activation of autolysin.  Penicillins v Antibacterial spectrum The antibacterial spectrum of the various penicillins is determined, in part, by their ability 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, and hydrophobicity of the particular β-lactam 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 lipopolysaccharide membrane surrounding the cell wall that presents a barrier to the water-soluble penicillins. However, gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry. Classification of Penicillins  Penicillins v Antibacterial spectrum 1. Natural penicillins Penicillin G (benzylpenicillin) and penicillin V (phenoxymethylpenicillin) are obtained from fermentations of the fungus Penicillium chrysogenum. Penicillin G has activity against a variety of gram-positive organisms, gram-negative organisms, and spirochetes. The potency of penicillin G is five to ten times greater than that of penicillin V against both Neisseria spp. and certain anaerobes. Most streptococci are very sensitive to penicillin G, but penicillin- resistant viridans streptococci and Streptococcus pneumoniae isolates are emerging. The vast majority of Staphylococcus aureus (greater than 90%) are now penicillinase producing and therefore resistant to penicillin G. v Antibacterial spectrum Penicillins 1. Natural penicillins D e s p i te w i d e s p re a d u s e a n d i n c re a s i n g resistance in many types of bacteria, penicillin remains the drug of choice for the treatment of gas gangrene (Clostridium perfringens) and syphilis (Treponema pallidum). Penicillin V, only available in oral formulation, has a spectrum similar to that of penicillin G, but it is not used for treatment of severe infections because of its limited oral absorption. Penicillin V is more acid stable than is penicillin G and is the oral agent employed in the treatment of less severe infections.  Penicillins v Antibacterial spectrum 2. Semisynthetic penicillins Ampicillin and amoxicillin (also known as aminopenicillins or extended-spectrum penicillins) are created by chemically attaching different R groups to the 6-aminopenicillanic acid nucleus. Addition of R groups extends the gram-negative antimicrobial activity of aminopenicillins to include Haemophilus influenzae, Escherichia coli, and Proteus mirabilis. Ampicillin (with or without the addition of gentamicin) is the drug of choice for the gram-positive bacillus Listeria monocytogenes and susceptible enterococcal species. These extended-spectrum agents are also widely used in the treatment of respiratory infections. Amoxicillin is employed prophylactically by dentists in high-risk patients for the prevention of bacterial endocarditis. v Antibacterial spectrum Penicillins 2. Semisynthetic penicillins These drugs are coformulated with β-lactamase inhibitors, such as clavulanic acid or sulbactam, to combat infections caused by β-lactamase–producing organisms. For example, without the β-lactamase inhibitor, methicillin-sensitive Staphylococcus aureus (MSSA) is resistant to ampicillin and amoxicillin. Resistance in the form of plasmid-mediated penicillinases is a major clinical problem, which limits use of aminopenicillins with some gram-negative organisms.  Penicillins v Antibacterial spectrum 3. Antistaphylococcal penicillins Methicillin, nafcillin, oxacillin, and dicloxacillin are β-lactamase (penicillinase)-resistant penicillins. Their use is restricted to the treatment of infections caused by penicillinase-producing staphylococci, including MSSA. Methicillin-resistant Staphylococcus aureus (MRSA) is currently a source of serious community and nosocomial (hospital-acquired) infections and is resistant to most commercially available β- lactam antibiotics. The penicillinase-resistant penicillins have minimal to no activity against gram-negative infections.  Penicillins v Antibacterial spectrum 4. Antipseudomonal penicillin Piperacillin is also referred to as an antipseudomonal penicillin because of its activity against Pseudomonas aeruginosa. Formulation of piperacillin with tazobactam extends the antimicrobial spectrum to include penicillinase-producing organisms (for example, most Enterobacteriaceae and Bacteroides species). Stability of the penicillins to acid or the action of penicillinase  Penicillins v Resistance Ø Survival of bacteria in the presence of β-lactam antibiotics occurs due to the following: 1. β-Lactamase production 2. Decreased permeability to the drug – An excellent example of a pathogen lacking high permeability porins is Pseudomonas aeruginosa. – The presence of an efflux pump, which actively removes antibiotics from the site of action, can also reduce the amount of intracellular drug (for example, Klebsiella pneumoniae). 3. Altered PBPs – Modified PBPs have a lower affinity for β-lactam antibiotics (This explains MRSA resistance to most commercially available β-lactams).  Penicillins v Pharmacokinetics 1. Administration The route of administration of a β-lactam antibiotic is determined by the stability of the drug to gastric acid and by the severity of the infection. 2. Routes of administration The combination of ampicillin with sulbactam, piperacillin with tazobactam, and the antistaphylococcal penicillins nafcillin and oxacillin must be administered intravenously (IV) or intramuscularly (IM). Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations. Others are effective by the oral, IV, or IM routes. 3. Depot forms Procaine penicillin G and benzathine penicillin G (long acting; 3-4 weeks) are administered IM and serve as depot forms. They are slowly absorbed into the circulation and persist at low levels over a long time period.  Penicillins v Pharmacokinetics 4. Absorption The acidic environment within the intestinal tract is unfavorable for the absorption of penicillins. In the case of penicillin V, only one-third of an oral dose is absorbed under the best of conditions. Food decreases the absorption of the penicillinase-resistant penicillin dicloxacillin because as gastric emptying time increases, the drug is destroyed by stomach acid. Therefore, it should be taken on an empty stomach. Conversely, amoxicillin is stable in acid and is readily absorbed from the gastrointestinal (GI) tract. v Pharmacokinetics Penicillins 5. Distribution The β-lactam antibiotics distribute well throughout the body. All the penicillins cross the placental barrier, but none have been shown to have teratogenic effects. However, penetration into bone or cerebrospinal fluid (CSF) is insufficient for therapy unless these sites are inflamed. Note: Inflamed meninges are more permeable to the penicillins, resulting in an increased ratio of the drug in the CSF compared to the serum. Penicillin levels in the prostate are insufficient to be effective against infections. v Pharmacokinetics Penicillins 6. Metabolism Host metabolism of the β-lactam antibiotics is usually insignificant, but some metabolism of penicillin G may occur in patients with impaired renal function. Nafcillin and oxacillin are exceptions to the rule and are primarily metabolized in the liver. 7. Excretion The primary route of excretion is through the kidney. Patients with impaired renal function must have dosage regimens adjusted. Because nafcillin and oxacillin are primarily metabolized in the liver, they do not require dose adjustment for renal insufficiency. Probenecid inhibits the secretion of penicillins by competing for active tubular secretion and, thus, can increase blood levels. The penicillins are also excreted in breast milk.  Penicillins v Adverse reactions Ø Penicillins are among the safest drugs. However, adverse reactions may occur. 1. Hypersensitivity Approximately 10% of patients self-report allergy to penicillin. Reactions range from rashes to angioedema (marked swelling of the lips, tongue, and periorbital area) and anaphylaxis. Cross-allergic reactions occur among the β-lactam antibiotics. To determine whether treatment with a β-lactam is safe when an allergy is noted, patient history regarding severity of previous reaction is essential. 2. Diarrhea Diarrhea is a common problem that is caused by a disruption of the normal balance of intestinal microorganisms. It occurs to a greater extent with those agents that are incompletely absorbed and have an extended antibacterial spectrum. Pseudomembranous colitis from Clostridium difficile and other organisms may occur with penicillin use. v Adverse reactions Penicillins 3. Nephritis Penicillins, particularly methicillin, have the potential to cause acute interstitial nephritis. Note: Methicillin is therefore no longer used clinically. 4. Neurotoxicity The penicillins are irritating to neuronal tissue, and they can provoke seizures if injected intrathecally or if very high blood levels are reached. Epileptic patients are particularly at risk due to the ability of penicillins to cause GABAergic inhibition. 5. Hematologic toxicities Decreased coagulation may be observed with high doses of piperacillin and nafcillin (and, to some extent, with penicillin G). Cytopenias have been associated with therapy of greater than 2 weeks, and therefore, blood counts should be monitored weekly for such patients. Q1: Which of the following is the primary mechanism of action of penicillin? A) Inhibition of protein synthesis B) Disruption of cell membrane function C) Inhibition of bacterial cell wall synthesis D) Inhibition of DNA gyrase Q2: Which of the following bacteria is most likely to be resistant to penicillin due to the production of beta-lactamase? A) Staphylococcus aureus B) Streptococcus pyogenes C) Clostridium tetani D) Bacillus anthracis Q3: Penicillin G is administered primarily via which route due to its instability in the acidic environment of the stomach? A) Oral B) Intramuscular C) Subcutaneous D) Inhalational Q4: Which of the following adverse effects is most commonly associated with penicillin use? A) Hepatotoxicity B) Nephrotoxicity C) Hypersensitivity reactions D) Hemolytic anemia Q5: Which of the following types of penicillin is effective against Pseudomonas aeruginosa? A) Penicillin V B) Ampicillin C) Amoxicillin D) Piperacillin Q6: Which of the following penicillins is classified as a narrow- spectrum, penicillinase-resistant antibiotic? A) Amoxicillin B) Methicillin C) Ticarcillin D) Penicillin G Q7: Which of the following is the primary reason for combining penicillin with a beta-lactamase inhibitor (e.g., clavulanic acid)? A) To reduce the cost of treatment B) To enhance absorption C) To increase the spectrum of activity against beta-lactamase- producing bacteria D) To prevent gastrointestinal side effects Q8: Which of the following is a common indication for penicillin use? A) Viral infections like the common cold B) Fungal infections like candidiasis C) Bacterial infections such as syphilis D) Parasitic infections like malaria Q9: What is the main reason penicillin is less effective against gram-negative bacteria compared to gram-positive bacteria? A) Gram-negative bacteria lack a cell wall B) Gram-negative bacteria have an outer membrane that limits drug entry C) Gram-positive bacteria produce more beta-lactamase D) Penicillin is rapidly metabolized in gram-negative bacteria Q10: Which of the following drugs should be avoided in patients with a known penicillin allergy due to potential cross-reactivity? A) Cephalexin B) Erythromycin C) Ciprofloxacin D) Vancomycin thank you