Chemotherapy PDF

Chemotherapy Chemoptherapeutic agents are divided into A) Antimicrobial agents (Antibacterial, antiviral and antifungal) B) Antiparasitic and antiprotozoal agents) C) Antineoplastic Antibacterial Chemotherapy Classification of Antibacterial Drugs A. Classification acco...

Chemotherapy Chemoptherapeutic agents are divided into A) Antimicrobial agents (Antibacterial, antiviral and antifungal) B) Antiparasitic and antiprotozoal agents) C) Antineoplastic Antibacterial Chemotherapy Classification of Antibacterial Drugs A. Classification according to effect on bacteria:· Bactericidal: kill the microorganisms & eradicate the infection with no need for the body defense mechanisms e.g.penicillins & aminoglycosides. Bacteriostatic: stop growth of microorganisms with the need for the body defense mechanisms to eradicate the infection e.g. tetracyclines & chloramphenicol. N.B.:A bactericidal drug should not be combined with a bacteriostatic agent (The bacteriostatic drug will inhibit the growth of the bacteria abolishing the action of the bactericidal one which acts only on rapidly growing or dividing organisms). B. According to the spectrum against bacteria A. Drugs are mostly effective against gram-positive organism as Penicillin G and beta-lactamase-resistant pencillin, vancomycin, macrolides. B. Drugs are mostly effective against gram-negative organisms as aminoglycosides i.e Narrow spectrum Chemotherapeutic agents C. Drugs are mostly effective against both gram-positive and gram negative organism. i.e Broad spectrum Drugs such as tetracycline and chloramphenicol affect a wide variety of microbial species and are referred to as broad spectrum antibiotics C- According to the mechanism of action 1. Inhibitors of cell wall synthesis. e.g Penicillin,Cephalosporine vancomycin and bacitracin 2. Inhibitor of protein synthesis e.g chloroamphinicol, tetracyclines, erythromycin and clindamycin 3. Inhibitor of metabolic pathway. A metabolite is a component necessary for bacteria’s metabolism to function properly. E. g Sulphonamides/ Trimethoprim 4. Inhibition of Nucleic acid synthesis e.g Rifampin. 5. Drugs that disturb cell membrane Antibiotic pharmacodynamics categories I. Concentration-Dependent antibiotics with post antibiotic effect (PAE): Bactericidal effect depends on drug conc (increased effect with increased conc).Optimum effect is achieved with conc. 10 times MIC.· Trough drug conc. may fall below MIC during dosing interval without loss of efficacy as bacterial regrowth is inhibited by the PAE→↓resistance N.B. Maximize drug,Conc,·Large infrequent,doses are superior,to small frequent,doses, EX: Gentamycin – Ciprofloxacin- Azithromycin · II. Time- Dependent antibiotics with Minimal/no PAE: Bactericidal effect depends on the duration that the drug level exceeds MIC'. Concentrations should be maintained at 2 to 4 times MIC throughout the dosing interval as bacterial re-growth starts very soon after trough falls below MIC since drug has no PAE. N.B. Maximize duration,of exposure to drug, Small frequent doses,& iv infusions are,superior to large,infrequent doses EX: Vancomycin- Cephalosporins- Penicillins – Erythromycin III.Time-Dependent Antibiotics with enhanced PAE:., ·Drugs have both time -dependent & concentration - dependent effects. V. COMBINATIONS OF ANTIBIOTIC DRUGS. Indications Includes 1- Mixed bacterial infections. 2.Therapy of severe infections in which a specific cause is unknown. 3. Enhancement of antibacterial activity in the treatment of a specific infection e.g enterococal endocarditis pencillin-aminoglycoside combination produces a synergistic effect and has been recommended 4. Prevention of emergence of resistant microorganisms. In treatment of tuberculosis concomitant use of two or more active drugs, greatly improves cure rates by preventing the development of resistance. 5. Decrease the dose –related toxicity by using reduced doses of one or both drugs. 6- This strategy reduces the possibility of superinfection. Synergism 1-Block the sequential steps of a metabolic pathway by two drugs sulfonamide and trimethoprim. The simultaneous use of both drugs for complete inhibitions of growth than either component alone 2- Clavulanic acid or sulbactam inhibit beta-lactamase or pencillinase can protect ampcillin or amoxiciin from inactivation by beta-lactamase producing enzyme Disadvantages of drug combinations 1- Antagonism of antibacterial effect may results when the batericidal and bacteriostatic are given concurrently. 2- Increased coast 3- Increased incidence of adverse effects when we use two or more drugs.  Inhibitors of Cell Wall Synthesis Selective toxicity Unique to bacteria, cell wall is not found in mammalian cells..  PENICILLINS History Chemistery Members of this family of antibiotics differ from each other due to groups attached to β-lactam ring. These differences include: Spectrum. Stability to gastric acidity.- Susceptibility to bacterial β-lactamase. Mechanism of action  Bactericidal -time‐dependent The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation), Cell lysis can then occur, and these drugs are therefore bactericidal  Activation of Autolysins  Not active against bacteria lacking cell wall …. Which ones are?  Penicillins are effective against rapidly growing organisms that synthesize a peptidoglycan cell wall.  Three mechanisms are involved :  Penicillin‐binding proteins (PBPs): proteins which are important in cell wall synthesis and maintenance of morphology  mutations in PBPs can lead to bacterial resistance, e.g. MRSA.  Inhibition of transpeptidase: are PBPs that catalyze transpeptidation.  Production of autolysins: autolysins are secreted by bacteria (e.g. G+ve cocci) that contribute to normal remodelling of the cell wall. Penicillins leave the degrading effect of autolysins unopposed  further damage of cell wall Resistance Natural resistance to the penicillins lack a peptidoglycan cell wall (for example, Mycoplasma) or cell walls that are impermeable to the drugs (outer membrane and efflux pumps). β‐Lactamase activity ‐‐‐‐ Major cause of resistance Acquired resistance to the penicillins Mutation of PBPs ‐‐‐ of lower affinity to penicillins Preparations of Penicillins 1.Natural Penicillins: Penicillin G (benzyl penecillin) and Penicillin V Narrow spectrum (Gram +ve cocci & bacilli) & Gram-ve cocci. Penicillin G is less stable to acid (so given parenterally). Inactivated by β-lactamase Penicillin V is acid-stable (so can be given orally). 2. Long acting penicillins, e.g. benzathine penicillin-procaine penicillin· Insoluble salts of Penicillin G → allow slow drug absorption with long duration of action (penicillin G is short acting; 6 hours) Procaine penicillin: given every 12 hours. Benzathine penicillin: given once/ month.(IM) 3. Anti-Staph Penicillins (B-lactamse resistance penecillin): e.g.oxacillin,cloxacillin,flucloxacillin& nafcillin. Stable to gastric acidity. Stable to β-lactamase. Methicillin is the 1st preparation in this group. It is not used now due to its nephrotoxicity Flumox ??? MRSA??? 4. Broad-spetram penicllins,e& ampicllin &amoxicllins Broad-spectrum (as natural penicillins but are more effective against gram- negative bacilli ). Stable to gastric acidity. Inactivated by β-lactamase???? Ampicillin is the drug of choice for the gram-positive bacillus. These agents are also widely used in the treatment of respiratory infections, Amoxicillin is employed prophylactically by dentists for patients with abnormal heart valves who are to undergo extensive oral surgery. Advantages of Amoxicillin over Ampicillin: Better absorption (almost completely absorbed). Higher plasma level. Less GIT disturbances & diarrhea. Talampicillin / Pivampicillin?? β-Lactamase inhibitor Tazobactam- sulbactam- clavulanic acid Formulation with a {β-Lactamase inhibitor, such as clavulanic acid or sulbactam, protects amoxicillin or ampicillin, respectively, from enzymatic hydrolysis, and extends their antimicrobial spectrum. 5. Antipseudomonal penicillins, e.g. ticarcillin & carbenicillin. Broad-spectrum including Pseudomonas & many Gram-ve bacilli Unstable to gastric acidity (so given parenterally). Inactivated by β-lactamase. expensive Penicillins and aminoglycosides: The antibacterial effects of all the β -Iactam antibiotics are synergistic with the aminoglycosides. Although the combination is employed clinically, these drug types should never be placed in the same infusion fluid, because on prolonged contact, the positively charged aminoglycosides form an inactive complex with the negatively charged penicillins. Not given in the same site Routes of Administration: Depend on stability to gastric acidity & severity of infection: 1. Oral: in moderate infection and acid-stable preparations: e.g. Penicillin V & ampicillin 2.Parenteral (IV or IM) in severe infections or acid-unstable preparations. ·Penicillin G is preferred in severe infections with susceptible organisms. Ticarcillin& carbenicillin are also given parenterally. ·Depot IM preparations: procaine penicilin (given/12-24 h),benzathine penicillin (long- acting given monthly as prophylactic against Rh.fever). Pharmacokinetics Absorption· Most preparations are incompletely absorbed orally, e.g. ampicillin. Distribution Penicillins can cross placenta.( non teratogenic)· Cross BBB when inflamed in case of meningitis. Excretion· Renal elimination. Probenecid inhibits renal tubular secretion of penicillin by competing with it for acid secretory mechanism. Thus, it prolongs penicillin action. Nafciliiin excreted by bile Therapeutic Uses 1. Streptococcal infections: ·Acute throat infections, wound sepsis ·Bacterial endocarditis: penicillin is given plus aminoglycoside)(facilitate penetration of aminoglycosides by interfering with bacterial cell wall synthesis →synergistic bactericidal effect). Separate IV bolus injection with time interval to avoid interaction 2. Staphylococcal infections. ???? 3 Pneumococcal infections. 4. Syphilis & gonorrhea. 5.Meningococcal meningitis: penicillin G or ampicíllin IV plus chloramphenicol. 6. Typhoid & paratyphoid fever: amoxicillin & ampicillin. 7.Prophylaxis against: a. Rheumatic fever: benzathine penicillin(1.2 million units/mon) b. Bacterial endocarditis (plus an aminoglycoside). E. Adverse reactions (one of the safest antibiotic) 1-Hypersensitivity: ( most important). rashes to angioedema and anaphylaxis. Cross"allergic reactions occur among the β"lactam antibiotics. 2- Diarrhea: This effect, which is caused by a disruption of the normal balance of intestinal microorganisms, is a common problem. It occurs to a greater extent with those agents that are incompletely absorbed and broad spectrum. (ampicillin) 3. Nephritis: All penicillins, but particularly methicillin, have the potential to cause acute interstitial nephritis. 4- Neurotoxicity: The penicillins are irritating to neuronal tissue and can provoke seizures if injected intrathecally or if very high blood levels are reached. Epileptic patients are especially at risk. (procane penecillin) 5-Platelet dysfunction: It is generally a concern when treating patients predisposed to hemorrhage or those receiving anticoagulants. (ticarcillin) 6- Cation toxicity: Penicillins are generally administered as the sodium or potassium salt. K+ in penicillin G →hyperkalemia Carbenicillin Na+ → ↑BP.