抗生素药理学（英文ppt） pharmacology of the antibiotics课件

Pharmacology of the Antibiotics,PAUL E. MANAIG,M.D.,The anti-infective drugs,Anti-infective agents are drugs that are designed to act selectively on foreign organisms that have invaded and infected the body,The anti-infective drugs,Anti-infective drugs - range from Antibacterials Antifungals Antiprotozoals Antihelminthics Antivirals Antimycobacterial,General Mechanisms of Action of anti-infective agents,The mechanisms are: Inhibition the biosynthesis of bacterial cell WALL Inhibition of protein synthesis Some change the cell membrane permeability Some inhibit DNA synthesis,Examples,Spectrum of Activity of Anti-infectives,Narrow spectrum Broad-spectrum,Spectrum of Activity of Anti-infectives,Narrow spectrum anti-infectives affect only a few bacterial types The early penicillin drugs are examples.,Spectrum of Activity of Anti-infectives,Broad-spectrum anti-infectives affect many bacteria. Meropenem is an example. Because narrow spectrum antibiotics are selective, they are more active against single organisms than the broad spectrum antibiotics.,Spectrum of Activity of Anti-infectives,Anti-infective agents can also be: Bacteriostatic Erythromycin, tetracyclines, clindamycin, chloramphenicol, spectinomycin, sulfonamides,Bactericidal - Penicillins, Cephalosphorins, Metronidazole, Aminoglycosides, Vancomycin, Polymyxin,Spectrum of Activity of Anti-infectives,Anti-infectives that interfere with the ability of the cell to reproduce/replicate without killing them are called BACTERIOSTATIC drugs. Tetracycline is an example.,Spectrum of Activity of Anti-infectives,Antibiotics that can aggressively cause bacterial death are called BACTERICIDAL. These properties (-cidal and static) can also depend on the antibiotic concentration in the blood. (e.g. Erythromycin and Clindamycin may be bactericidal at higher blood levels),Factors That Determine the Likehood Of a microorganism Causing an Infection:,Virulence of the microorganism Number of the microorganism present Resistance of the host,Potentially Periodontopathic Bacteria:,Adult peiodontitis - Bacteriodes gingivalis - B. intermedius - Fusobacterium nucleatum - Veillonella parvula - Actinomyces (naestundii, israelli, viscosus) Localized Juvenile Periodontitis - Actinobacillus actinomycetemcomitans - Capnocytophaga sp.,Streptococcus mutans causing dental caries ( most common dental infection) treatment of choice: local physical removal of microbial plaque on a regular basis( good oral hygiene),Antimicrobial use in dentistry,I. Prophylaxis treatment For Infective Endocarditis: Prophylaxis for dental, oral, upper respiratory tract or esophageal procedures: (Gram positive organisms) Oral: Amoxycillin 2 g orally 1 hr before procedure; children 50mg/kg orally 1 hr before procedure Penicillin allergy: Clindamycin 600mg orally 1hr before procedure or Cephalexin 2 g orally 1 hr before procedure Parenteral: Ampicillin 2 g IM or IV 30 min before procedure II. Prophylaxis for Gastrointestinal and Genitourinary Procedures:(Gram-negative procedures) Parenteral: Ampicillin 2 g IV plus Gentamicin 1.5 mg/kg IM or IV (not to exceed 80mg) 30 min before procedure; followed by ampicillin 1 g IV 6 hr later Penicillin Allergy: Vancomycin 1 g IV infused slowly over 1 hr plus Gentamycin 1.5 mg/kg IM or IV ( not to exceed 80 mg) 1 hr before procedure,Common Side effects,Common Adverse Reactions to Anti-infective Therapy,The most common adverse effects are due to the direct action of the drugs in the following organ system- Neuro, nephro and GI system,Common Adverse Reactions to Anti-infective Therapy,Nephrotoxicity Antibiotics that are metabolized and excreted in the kidney most frequently cause kidney damage,Common Adverse Reactions to Anti-infective Therapy,2. Gastro-intestinal toxicity Direct toxic effect to the cells of the GI tract can cause nausea, vomiting, stomach pain and diarrhea. Some drugs are toxic to liver cells and can cause hepatitis or liver failure.,Common Adverse Reactions to Anti-infective Therapy,3. CNS toxicity When drugs can pass through the brain barrier and accumulate in the nervous tissues, they can interfere with neuronal function.,Common Adverse Reactions to Anti-infective Therapy,4. Hypersensitivity Most protein antibiotics can induce the bodys immune system to produce allergic responses. Drugs are considered foreign substances and when taken by the individual, it encounters the bodys immune cells.,Common Adverse Reactions to Anti-infective Therapy,5. Super-infections Opportunistic infections that develop during the course of antibiotic therapy are called SUPERINFECTIONS.,The Penicillins,The PENICILLINS,Narrow spectrum penicillins Penicillin G Penicillin V Broad Spectrum Penicillins (aminopenicillin) Amoxicillin Ampicillin Bacampicillin Penicillinase-resistant Penicillin (anti-staphyloccocal penicillins) Cloxacillin Nafcillin Methicillin Dicloxacillin Oxacillin Extended-Spectrum penicillins (Anti-pseudomonal penicillins) Carbenicillin Mezlocillin Piperacillin Ticacillin Beta-lactamase inhibitors Clavulanic acid Sulbactam Tazobactam,Penicillin,Penicillin is a beta-lactam drug, with a beta-lactam ring. The group of penicillins is called beta lactam antibiotics.,Penicillin,The action of Penicillins The penicillin and penicillinase-resistant penicillins produce BACTERICIDAL effects by interfering with the ability of susceptible bacteria from biosynthesizing the framework of the cell wall.,Penicillin,The bacterium will have weakened cell wall, will swell and then burst from the osmotic pressure within the cell.,Penicillin,Pharmacokinetics: Amoxicillin is well absorbed in the GIT. This in NOT affected by food intake!,Penicillin,Therapeutic Indications of penicillin The penicillins are indicated for the treatment of streptococcal infections Syphilis Tetanus,Adverse Effects of Penicillins,GI system effects- the major adverse effects of penicillin therapy involve the GIT. Nausea, vomiting, diarrhea, abdominal pain, glossitis, stomatitis, gastritis, sore mouth and furry tongue. The reason for some of these effects (superinfection) is associated with the loss of bacterial flora.,Adverse Effects of Penicillins,Hypersensitivity reactions- rashes, pruritus, fever and urticaria These indicate mild allergic reaction. Wheezing and diarrhea may also occur. Anaphylaxis can also happen leading to shock or death. It occurs in 5-10% of those receiving penicillins. Pain and inflammation on injection sites,the cephalosporins,THE CEPHALOSPORINS,The cephalosporins also belong to the beta-lactam group of antibiotics,THE CEPHALOSPORINS,First Generation cephalosporin Second generation cephalosporin Third Generation cephalosporin Fourth generation cephalosporin,THE CEPHALOSPORINS,First Generation cephalosporins- are largely effective against the same gram-positive organisms affected by penicillin. Second generation cephalosporins- are effective against those strains as well as Haemophilus influenza, Entreobacter aerogenes and Nesseria sp. These drugs are less effective against gram positive bacteria,THE CEPHALOSPORINS,Third Generation cephlosporins- are relatively weak against gram-positive bacteria but more potent against gram-negative bacteria, to include Serratia marcescens. Fourth generation cephalosporins- are developed to fight against the resistant gram-negative bacteria. The first drug is cefepime.,First generation cephalosporins cefadroxil Cefazolin Cephalexin Cephalotin Cephapirin Cephadrine Second Generation cephalosporins Cefaclor Cefamandole Cefonizind Cefotetan Cefoxitin Cefmetazole Cefprozil Cefuroxime Third Generation Cephaosporins Cefnidir Cefixime Cefoperazone Cefotaxime Cefpodoxime Ceftazidime Ceftibuten Moxalactam Fourth Generation Cephalosporin Cefepime,generations,Cephalosporin,The mechanism of action The cephalosporins are primarily BACTERICIDAL. They interfere with the cell-wall building ability of bacteria when they divide. They prevent the bacteria from biosynthesizing the framework of their cell wall. The weakened cell wall will swell and burst causing cell death.,Cephalosporin,Pharmacokinetics Only a few cephalosporins are administered orally, most are administered parenterally. Their half-lives are short and they are excreted mainly in the urine. Contraindications and Precautions The drugs are contraindicated in patients with known allergies to cephalosporins and penicillins.,Cephalosporin,Adverse Effects GI system- Nausea, vomiting, diarrhea, anorexia, abdominal pain and flatulence are common effects. CNS headache, dizziness, lethargy and paresthesias have been reported. Renal system- nephrotoxicity in individuals with pre-existing renal disease Hypersensitivity,Cephalosporin,Drug-Drug interactions ALCOHOL- many patients experience a disulfiram-like reactions when taken with some specific cephlosporins ( cefamandole, cefoperazone or moxalactam). The patient may experience flushing, headache, nausea, vomiting and muscular cramps. This may occur even up to 72 hours of cephalosporin discontinuance.,aminoglycosides,The Aminoglycosides,The following are the aminoglycosides 1. Gentamycin 2. Tobramycin 3. Amikacin 4. Netilmicin 5. Kanamycin,The Aminoglycosides,Mechanism of action These are BACTERICIDAL. They inhibit protein synthesis in susceptible strains of gram-negative bacteria, leading to loss of functional integrity of the bacterial cell membrane, which causes cell death.,The Aminoglycosides,Therapeutic Use of the Aminoglycosides These drugs are used to treat serious infections caused by gram-NEGATIVE bacteria. These drugs are contraindicated in known allergies to aminoglycosides, in patients with renal failure, hepatic disease, pre-existing hearing loss, myasthenia gravis, Parkinsons, pregnancy and lactation.,The Aminoglycosides,Adverse Effects of Aminoglycosides CNS- irreversible deafness, vestibular paralysis, confusion, depression, disorientation, numbness, tingling and weakness related to drug effects. Kidney- renal toxicity, which may progress to renal failure caused by the direct toxicity of the aminoglycosides. Hema- bone marrow depression resulting from direct drug effect may lead to immune suppression and super-infection. Ototoxicity,The Aminoglycosides,Adverse Effects of Aminoglycosides GI system- nausea, vomiting, diarrhea, weight loss, stomatitis and hepatic toxicity Skin effects- photosensitivity, purpura, rash, urticaria and exfoliative dermatitis Cardiac- palpitations, hypotension or hypertension,The Aminoglycosides,Drug to drug interactions Diuretics- increased incidence of ototoxicity, nephrotoxicity and neurotoxicity. Anesthetics and Neuromusular blockers- increased neuromuscular blockage and paralysis may be possible Penicillin- synergistic action,The Macrolides,The macrolides are Azithromycin Clarithromycin Dirithromycin Erythromycin,The Macrolides,Mechanism of Action of the Macrolides They exert their effect by binding to the bacterial cell ribosomes and changing or altering protein production/function This will lead to impaired cell metabolism and division.,The Macrolides,Pharmacokinetics Erythromycin is destroyed by the gastric juice, which is why slats are added to stabilize the drug. Food does not interfere with the absorption of the macrolides.,The Macrolides,Therapeutic Use of Macrolides These are indicated for the treatment of the following conditions: Steptococcal infection, Mycoplasma infection, Listeria infection and group A beta hemolytic strep infection.,The Macrolides,Contraindications and Precautions in the Use of Macrolides These agents are contraindicated in the presence of known allergy to any macrolide, because cross-sensitivity occurs. Caution should be used in patients with hepatic dysfunction that could alter the metabolism of the drug; in lactating women because of drug excretion in breast milk and in pregnant women because potential adverse effects on the developing fetus.,The Macrolides,Adverse Effects of Macrolides GI system- abdominal cramping, anorexia, diarrhea, vomiting and pseudomembranous colitis. HEPATOTOXICITY can occur if the drug is taken in high doses with other hepatotoxic drugs. CNS- confusion, abnormal thinking and uncontrollable emotions. Hypersensitivity reactions,The Lincosamides,These agents are similar to the Macrolides but are more toxic. Clindamycin lincomycin,The Lincosamides,Pharmacodynamics: The Mechanism of Action of Lincosamides These agents penetrate the cell membrane and bind to the ribosome in the bacterial cytoplasm to prevent the protein production,The Lincosamides,Side effects and Adverse Reactions GIT- GI irritation, nausea, vomiting and stomatitis Allergic reactions Drug Interactions Lincomycin and clindamycin are incompatible with aminophyline, phenytoin, barbiturates and ampicillin.,The Tetracyclines,These agents were first isolated from Streptomyces aureofaciens The following are the tetracyclines Short-acting tetracyclines tetracycline oxytetracycline Intermediate acting tetracyclines demeclocycline methacycline Long acting tetracyclines doxycycline minocycline,The Tetracyclines,Pharmacodynamics The tetracyclines inhibit protein synthesis in susceptible bacteria leading to the inability of the bacteria to multiply.,The Tetracyclines,Contraindications and Precautions in the use of Tetracyclines It is not recommended for use in pregnancy and lactation because the drug can affect the bones and teeth, causing permanent discoloration and sometimes arrest of growth. Tetracyclines are also avoided in children less than 8 (eight) years of age because of the potential damage to the bones and permanent discoloration of the teeth.,The Tetracyclines,Adverse Effects of the Tetracycline GI system- nausea, vomiting, diarrhea, abdominal pain, glossitis and dysphagia. Fatal hepatotoxicity related to tetracyclines irritating effect on the liver cells has been reported. Musculoskletal- Tetracyclines have an affinity for teeth and bones; they accumulate there, leading to weakening of the bone/teeth and permanent staining and pitting. Skin- photosensitivity and rash are expected. Less frequent- bone marrow depression, hypersensitivity, super infections, pain and hypertension,The Tetracyclines,Drug-Drug Interactions Penicillin- if taken with tetracyclines, will decrease the effectiveness of penicillin. Oral contraceptives- if taken with tetracycline, will have decreased effectiveness. Digoxin- digoxin toxicity rises when tetracyclines are used together,The Tetracyclines,Drug-Food Interaction Dairy products- can complex with tetracycline and render unabsorbable. Tetracyclines should then be given on an EMPTY stomach 1 hour before meals or 2-3 hours after any meal or other medications.,The Fluoroquinolones,The fluoroquinolones are broad-spectrum antibiotics. They are usually manufactured synthetically and are associated with mild adverse reactions. The examples are: 1. Nalidixic acid 2. ciprofloxacin 3. ofloxacin 4. norfloxacin 5.Levfofloxacin 6.Sparfloxacin,The Fluoroquinolones,Pharmacodynamics: Mechanism of action of the Fluoroquinolones These agents enter the bacterial cell by diffusion through cell channel. Once inside they interfere with the action of DNA enzymes (DNA gyrase) necessary for the growth and reproduction of the bacteria. This will lead to cell death.,The Fluoroquinolones,Contraindications and Precautions Pregnancy and lactation are also contraindications. These agents are found to cause significant damage to the cartilages such that they are given cautiously to growing children and adolescents less than 18 years of age,The Fluoroquinolones,Adverse Effects of the Fluoroquinolones CNS- dizziness, insomnia, headache, and depression related to possible effects on the CNS membrane. GI system- nausea, vomiting, diarrhea and dry mouth related to the direct effect on the GIT Hema- bone marrow depression related to the direct effect of the drug on the cells of the bone marrow that rapidly turn over. Other effects- skin reactions, rash, fever and photosensitivity,Sulfonamides,The following are the sulfonamides: 1. Sulfazalazine 2. Sulfamethoxazole 3. Sulfadiazine 4. Sulfixoxazole,Sulfonamides,Pharmacodynamics The sulfa drugs competitively block the para-amino benzoic acid to prevent the synthesis of folic acid in susceptible bacteria that synthesize their own folates for the production of RNA and DNA.,Sulfonamides,Contraindications and precautions These agents are contraindicated to patients with known allergy to sulfa drugs, sulfonylureas and thiazide diuretics because they share similar structures. It is not recommended for use in pregnancy because it can cross the placenta and cause birth defects and kernicterus. Lactating women who take these drugs will excrete them in the breast milk potentially causing kernicterus, diarrhea and rash in the newborn.,Sulfonamides,Adverse Effects of the Sulfonamides GI system- nausea, vomiting, diarrhea, abdominal pain, anorexia,