Pharmacology (3) Lecture Slides PDF

Pharmacology (3) 0201433 ‫عراقة وجودة‬ Tradition and Quality Dr. Osama Abusara Faculty of Pharmacy Al-Zaytoonah University of Jordan Lippincott® Illustrated Reviews – Pharmacology / 7th Edition Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 1 Pha...

Pharmacology (3) 0201433 ‫عراقة وجودة‬ Tradition and Quality Dr. Osama Abusara Faculty of Pharmacy Al-Zaytoonah University of Jordan Lippincott® Illustrated Reviews – Pharmacology / 7th Edition Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 1 Pharmacology (3) – Topics 1. Antimicrobial Drugs a) b) c) d) Antibacterial Drugs Antifungal Drugs Antiviral Drugs Antiparasitic Drugs 2. Anticancer Drugs 3. Thyroid Hormones 4. Estrogens and Androgens Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 2 Chapter 28 Principles of Antimicrobial Therapy Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 3 Principles of Antimicrobial Therapy Overview: • Antimicrobial therapy takes advantage of the biochemical differences that exist between microorganisms and human beings…..Resulting in selective toxicity • Selective toxicity is relative rather than absolute Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 4 Principles of Antimicrobial Therapy Selection of the most appropriate antimicrobial agent: 1. The identity of the organism (Gram stain, sample culture, DNA, RNA, antigens) 2. The susceptibility of the organism to a particular agent (bacteriostatic versus bactericidal drugs / MIC and MBC) 3. The site of infection (CNS, GIT, lungs, ..etc.) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 5 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 6 Principles of Antimicrobial Therapy The structure of capillaries of some tissues, such as prostate, testes, placenta, the vitreous body of the eye, and the central nervous system (CNS), act as natural barriers to drug delivery. Capillaries in the brain - help to create and maintain BBB. Hence, penetration and concentration of antimicrobial agent depends on: • Lipid solubility of the drug (chloramphenicol and metronidazole vs βlactams) (Effect of meningitis on permeability?) • Molecular weight of the drug (vancomycin – high MW?) • Protein binding of the drug Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 7 Principles of Antimicrobial Therapy Selection of the most appropriate antimicrobial agent: 4. Patient factors: • Immune system (Immunocompetent vs immunocompromised) • Renal dysfunction • Hepatic dysfunction • Poor perfusion • Age (renal and hepatic elimination processes) • Pregnancy and lactation Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 8 Principles of Antimicrobial Therapy Selection of the most appropriate antimicrobial agent: 5. The safety and efficacy of the agent 6. The cost of the therapy …….. some patients (critically ill) require empiric therapy Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 9 Principles of Antimicrobial Therapy Route of drug administration: • Oral, parenteral, and/or topical administration Determinants of rational dosing: • Based on PD and PK (ADME) of antimicrobial agents • Properties that have a significant influence on the frequency of dosing are: 1. Concentration-dependent killing 2. Time-dependent killing 3. Postantibiotic effect (PAE) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 10 Principles of Antimicrobial Therapy • Properties that have a significant influence on the frequency of dosing are: 1. Concentration-dependent killing e.g. aminoglycosides and daptomycin • Rate of bacterial killing increases as the concentration of antibiotic increases from 4- to 64-fold the MIC of the drug for the infecting organism • Administered as once-a-day bolus infusion - achieves high peak levels, favoring rapid killing of the infecting pathogen. Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 11 Principles of Antimicrobial Therapy • Properties that have a significant influence on the frequency of dosing are: 2. Time-dependent killing e.g. β-lactams, macrolides, clindamycin • Clinical efficacy of these antimicrobials is best predicted by the percentage of time that blood concentrations of a drug remain above the MIC. • e.g. penicillins blood levels greater than the MIC for 50% of the time provide the most clinical efficacy Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 12 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 13 Principles of Antimicrobial Therapy • Properties that have a significant influence on the frequency of dosing are: 3. Postantibiotic effect (PAE) e.g. aminoglycosides and fluoroquinolones • Persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC. • Often require only one dose per day Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 14 Principles of Antimicrobial Therapy • Chemotherapeutic Spectra: 1. Narrow-spectrum antimicrobial drugs 2. Extended- / Broad-spectrum antimicrobial drugs • Combinations of antimicrobial drugs Therapeutically advisable to treat patients with a single agent that is most specific to the infecting organism - reduces the possibility of superinfections, decreases the emergence of resistant organisms, and minimizes toxicity……….However, combinations of antimicrobial drugs are required in some situations. Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 15 Principles of Antimicrobial Therapy • Combinations of antimicrobial drugs • Advantages • Synergism - the combination is more effective than either of the drugs used separately e.g. in the treatment of TB or infection with unknown origin • Disadvantages • A drug interfering with the activity of other drug (bactericidal + bacteriostatic drugs?) • Risk of selection pressure and the development of antibiotic resistance by giving unnecessary combination therapy Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 16 Principles of Antimicrobial Therapy • Drug resistance • Bacteria (or other microorganisms) are considered resistant to an antibiotic (or antimicrobial drugs) if the maximal level of that drug that can be tolerated by the host does not halt their growth. • Causes: 1. Naturally inherent resistance 2. Acquired resistance Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 17 Principles of Antimicrobial Therapy • Drug resistance • Causes: 2. Acquired resistance • Genetic alterations leading to drug resistance • Altered expression of proteins in drug-resistant organisms 1. 2. 3. Modification of target sites Decreased accumulation (porins and efflux pump) Enzymatic inactivation: β-lactamases (penicillins, cephalosporins, and related drugs); acetyltransferases (chloramphenicol or aminoglycosides); esterases (macrolides). Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 18 Principles of Antimicrobial Therapy • Prophylactic use of antibiotics • Certain clinical situations - require the use of antibiotics for the prevention rather than for the treatment of infections • Used when benefits outweigh the potential risks (due to resistance and superinfections) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 19 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 20 Chapter 29 Cell Wall Inhibitors (Antibacterial Drugs) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 21 Cell Wall Inhibitors • Antimicrobial drugs interfering with bacterial cell wall synthesis a) b) c) d) Penicillins Cephalosporins Carbapenems Monobactams β-Lactam Antibiotics • Bacterial cell wall is composed of peptidoglycan strands (polymer of glycan units joined to each other by peptide cross-links) • To be highly effective – require actively proliferating cells Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 22 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 23 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 24 Cell Wall Inhibitors / Penicillins Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 25 Cell Wall Inhibitors / Penicillins • Penicillins ➢MOA: • Terminal portion (amino acids) of peptidoglycan strand binds to penicillinbinding proteins (PBPs) enzymes – catalyze transpeptidase and facilitate cross-linking of cell wall – rigid cell wall • Penicillins resemble the terminal portion of the peptidoglycan strand – compete for and bind to PBPs • Interfere with transpeptidation process • Weakened cell wall – cell death • Bactericidal Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 26 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 27 Cell Wall Inhibitors / Penicillins • Penicillins ➢Antibacterial spectrum: 1. Natural penicillins (fermentations of fungus) • Penicillin G (parenteral) / Penicillin V (oral) • Both of similar spectrum (G +ve, G –ve, spirochetes, anaerobic organisms) – but increasing resistance (due to β-lactamases [penicillinases] production) in many types of bacteria • Drug of choice – gas gangrene (Clostridium perfringens) and syphilis (Treponema pallidum) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 28 Cell Wall Inhibitors / Penicillins • Penicillins ➢Antibacterial spectrum: 2. Semisynthetic penicillins • Ampicillin / Amoxicillin (aminopenicillins or extended-spectrum penecillins) • Extended G –ve antimicrobial activity • Uses: respiratory infections / prophylactically by dentists in high-risk patients for the prevention of bacterial endocarditis • Resistance – due to penicillinases • Used in combination with β-lactamase inhibitors: clavulanic acid or sulbactam Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 29 Cell Wall Inhibitors / Penicillins • Penicillins ➢Antibacterial spectrum: 3. Antistaphylococcal penicillins • Methicillin / Nafcillin / Oxacillin • β-lactamase (penicillinases)-resistant penicillins • Use: restricted to the treatment of infections caused penicillinaseproducing staphylococci (G +ve) including MSSA / little or no activity against G –ve infections • Resistance – MRSA (source of serious community and nosocomial infections – resistant to most β-lactam antibiotics Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 30 Cell Wall Inhibitors / Penicillins • Penicillins ➢Antibacterial spectrum: 4. Antipseudomonal penicillins • Piperacillin – antipseudomonal penicillin due to activity against Pseudomonas aeruginosa (but act on other G –ve bacteria) • Resistance – due to penicillinases • With tazobactam (β-lactamase inhibitor) – extends its spectrum to include penicillinase-producing organisms (Enterobacteriaceae and Bacteroides species) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 31 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 32 Cell Wall Inhibitors / Penicillins • Penicillins ➢Resistance: 1. β-Lactamase production • Hydrolyzes cyclic amide bond • Produced by bacteria or acquired • Secreted extracellularly – G +ve / in periplasmic space – G -ve Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 33 Cell Wall Inhibitors / Penicillins • Penicillins ➢Resistance: 2. Decreased permeability to the drug • Decreased penetration to reach PBPs / membranes, porins, efflux pumps • G +ve not of a much concern • G –ve: complex cell wall + porins • Pseudomonas aeruginosa lacks high permeability porins • Klebsiella pneumoniae has efflux pumps Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 34 Cell Wall Inhibitors / Penicillins • Penicillins ➢Resistance: 3. Altered PBPs • Modified PBPs have low affinity to β-lactam antibiotics – e.g. MRSA Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 35 Cell Wall Inhibitors / Penicillins • Penicillins ➢PK: 1. Administration • Oral / Parenteral (IM, IV) • Depot forms: Procaine penicillin G and benzathine penicillin G – IM – slowly absorbed – long period of time Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 36 Cell Wall Inhibitors / Penicillins • Penicillins ➢PK: 2. Absorption • Not all of them are absorbed orally due to their instability on stomach acids • Penicillin V – poor oral bioavailability • Dicloxacillin – empty stomach • Amoxicillin – stable in acid / readily absorbed from GI tract Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 37 Cell Wall Inhibitors / Penicillins • Penicillins ➢PK: 3. Distribution • Distributed well throughout the body • Cross placental barrier – no teratogenic effects • Insufficient bone and CSF penetration – except during inflammation • Prostate – insufficient levels 4. Metabolism • Insignificant (penicillin G metabolism may occur in patients with impaired renal function • Nafcillin + oxacillin – metabolized in liver Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 38 Cell Wall Inhibitors / Penicillins • Penicillins ➢PK: 5. Excretion • Primary route – kidneys (via organic acid [tubular] secretory system + glomerular filtration – dose adjustments? • Nafcillin and oxacillin – liver • Breast milk Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 39 Cell Wall Inhibitors / Penicillins • Penicillins ➢Adverse reactions: 1. Hypersensitivity (rashes to angioedema and anaphylaxis) / cross-allergic reactions among the β-lactam antibiotics 2. Diarrhea (interfering with normal microbial flora / pseudomembranous colitis from Clostridium difficile) 3. Nephritis (methicillin) 4. Neurotoxicity (seizures / GABAergic inhibition) 5. Hematologic toxicities (decreased coagulation by piperacillin, nafcillin, and penicillin G / cytopenias with prolonged therapy) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 40 Cell Wall Inhibitors / Cephalosporins affect antibacterial activity affect PK properties Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 41 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢MOA: • Same as Penicillins ➢Resistance: • Hydrolysis of beta-lactam ring by β-lactamases (some may be induced by 2nd and 3rd generation cephalosporins) • Reduced affinity to PBPs Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 42 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢Antibacterial spectrum: ▪ 1st, 2nd, 3rd, 4th, and advanced generation (based on bacterial susceptibility and resistance to β-lactamases) 1. First generation • Cephalexin (oral) – pharyngitis / cefadroxil (oral) / cefazolin (parenteral) – longer duration of action • Penicillin G substituents • Act on G +ve and G -ve • Resistant to staphylococcal penicillinase, act against MSSA • Bacterial resistance – as penicillin Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 43 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢Antibacterial spectrum: 2. Second generation • Cefuroxime axetil (oral) • Cefuroxime sodium (parenteral) – longer half-life than similar agents, crosses BBB, for community-acquired bronchitis or pneumonia in elderly or immunocompromised patients • Cephamycins (cefotetan and cefoxitin) – G -ve anaerobes (not 1st line) • Greater activity on G –ve compared to 1st generation, such as H. influenzae, Klebsiella species, Proteus species, E. coli, and Moraxella catarrhalis • Weaker activity on G +ve compared to 1st generation, act against MSSA Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 44 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢Antibacterial spectrum: 3. Third generation • Cefdinir and cefixime (oral) / Cefotaxime, Ceftazidime, and Ceftriaxone (parenteral) • Cefotaxime – penetrates well into the CSF, drug of choice for the treatment of meningitis • Ceftazidime – only drug in this group against Pseudomonas aeruginosa • Ceftriaxone – longest half-life of all cephalosporins (6-8 hrs), high levels in blood and CSF, drug of choice for the treatment of meningitis, good penetration into bone, used for penicillin-resistant Neisseria gonorrhoeae (genital, anal, pharyngeal) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 45 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢Antibacterial spectrum: 3. Third generation • Less potent than 1st generation on MSSA • Enhanced activity against G –ve bacilli, including β-lactamase producing strains of H. influenzae and Nesseria gonorrhoea • Must be used with cautious – due to resistance and C. difficile infection • Act against G +ve and G -ve Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 46 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢Antibacterial spectrum: 4. Fourth generation • Cefepime (parenterally) • Active against P. aeruginosa • Wide antibacterial coverage (as 3rd generation), against also streptococci and staphylococci (methicillin susceptible) • Greater stability against β-lactamases Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 47 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢Antibacterial spectrum: 5. Advanced generation • Ceftaroline (parenterally) • Only β-lactam active against MRSA • Active against MRSA and penicillin-resistant Streptococcus pneumoniae? • Used for the treatment of complicated skin and skin structure infections and community-acquired pneumonia • Broad G +ve spectrum / G –ve as 3rd generation • Other bacteria are resistant, such as P. aeruginosa Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 48 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢PK: 1. Administration • Oral / Parenteral (IM, IV) 2. Distribution • Distribute very well into body fluids • CSF infections – ceftriaxone and cefotaxime / neonatal and childhood meningitis caused by H. influenzae • Cefazolin – surgical prophylaxis due to its good tissue and fluid penetration + activity against penicillinase-producing S. aureus Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 49 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢PK: 3. Elimination • Tubular secretion and/or glomerular filtration • Ceftriaxone – excreted through the bile into the feces Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 50 Cell Wall Inhibitors / Cephalosporins • Cephalosporins ➢Adverse reactions: • Well-tolerated as penicillins • Allergic reactions: cross-reactivity between penicillin and cephalosporins around 3% to 5% and is determined by similarity in the side chain • Highest rate of allergic cross-sensitivity between penicillin and 1st generation cephalosporins • Avoided or used in caution in individuals with penicillin allergy Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 51 Cell Wall Inhibitors / Carbapenems Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 52 Cell Wall Inhibitors / Carbapenems • Carbapenems • Imipenem / Meropenem / Doripenem / Ertapenem (its coverage not like others) ➢MOA: • Same as Penicillins • Broad spectrum; β-lactamase-producing G +ve and G –ve organisms, anaerobes, and P. aeruginosa ➢Resistance: • Resist hydrolysis by most β-lactamases – but not the metallo-β-lactamases Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 53 Cell Wall Inhibitors / Carbapenems • Carbapenems ➢PK: • All administered parenterally (IV) • Excreted by glomerular filtration • Penetrates well into body tissues and fluids including CSF when meninges are inflamed (meropenem can reach therapeutic levels without inflammation) • Imipenem hydrolyzed by dehydropeptidase in brush border of proximal renal tubule – coadministered with cilastatin – prolongs imipenem’s activity – other carbapenems don’t require coadministration Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 54 Cell Wall Inhibitors / Carbapenems • Carbapenems ➢Adverse effects: • • • • Imipenem/cilastatin = NVD Eosinophilia and neutropenia Seizures – imipenem Cross-reactivity rate between them and penicillin is less than 1% - used cautiously with penicillin-allergic patients Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 55 Cell Wall Inhibitors / Monobactams Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 56 Cell Wall Inhibitors / Monobactams • Monobactams • Aztreonam • MOA same as Penicillins • Active against only G –ve bacteria including Enterobacteriaceae and P. aeruginosa / no activity against G +ve or anaerobes • Excreted through kidneys • Administered IV or IM • May cause phlebitis, skin rash, and occasionally abnormal liver function tests • Little cross-reactivity with other β-lactams – safe in patients who are allergic to penicillins, cephalosporins, or carbapenems Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 57 Cell Wall Inhibitors ➢β-Lactamase inhibitors • Examples: • Amoxicillin + clavulanic acid / (oral) • Ceftolozone (3rd generation cephalosporin) + tazobactam / (IV) • Ceftazidime (3rd generation cephalosporin) + avibactam / (IV) • Meropenem + vaborbactam / (IV) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 58 Other Cell Wall Inhibitors ➢Vancomycin • Active against aerobic and anaerobic G +ve bacteria / including MRSA, MRSE, Enterococcus species, and Clostridium difficile • Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide – disrupts cross-linking – cell death • Commonly used in patients with skin and soft tissue infections, infective endocarditis, and nosocomial pneumonia • IV or Oral / poor oral absorption – limited for the management of Clostridium difficile infections • Adverse effects: nephrotoxicity, infusion-related toxicity, ototoxicity Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 59 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 60 Resistance to vancomycin: D-Ala-D-Ala is changed to D-Ala-D-Lactate Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 61 Other Cell Wall Inhibitors ➢Bacitracin • Active against G +ve bacteria • Interfere with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall • Highly nephrotoxic – administered only topically ➢Fosfomycin • Active against G +ve and G –ve bacteria • Inhibits the cytoplasmic enzyme enolpyruvate transferase – required for the formation N -acetylmuramic acid (component of bacterial cell wall – peptidoglycan) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 62 Cell Membrane Active Drugs ➢Polymixins: Polymixin B and colistin (Polymixin E) • Active against G -ve bacteria • Bind to phospholipids on bacterial cell membrane – detergent-like effect – leakage – cell death • Nephrotoxic and neurotoxic – salvage therapy for patients with multi-drug resistant infections • Polymixin B – parenteral, ophthalmic, otic, topical • Colistin – IV or inhalation Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 63 Cell Membrane Active Drugs ➢Daptomycin • Spectrum as Vancomycin / active against vancomycin-resistant strains • Parenterally Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 64 Chapter 30 Protein Synthesis Inhibitors (Antibacterial Drugs) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 65 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 66 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 67 Protein Synthesis Inhibitors / Tetracyclines • Tetracyclines Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 68 Protein Synthesis Inhibitors / Tetracyclines • Tetracyclines ➢MOA: • Broad-spectrum bacteriostatic antibiotics • Enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport (inner cytoplasmic membrane) • Binds reversibly to 30S subunit of bacterial ribosome Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 69 Protein Synthesis Inhibitors / Tetracyclines • Tetracyclines ➢Antibacterial Spectrum: • Broad-spectrum bacteriostatic antibiotics • G +ve, G –ve, protozoa, spirochetes, mycobacteria • Commonly used for the treatment of acne and Chlamydia infections ➢Resistance: • Increased efflux or impaired influx • Production of proteins that interfere with tetracycline binding to the ribosome • Enzymatic inactivation Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 70 Protein Synthesis Inhibitors / Tetracyclines • Tetracyclines ➢PK: • Absorption • Adequately absorbed after oral absorption. Doxycycline and minocycline – oral and IV • Avoid administration with dairy products or substances with divalent and trivalent cations (tetracycline on empty stomach) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 71 Protein Synthesis Inhibitors / Tetracyclines • Tetracyclines ➢PK: • Distribution • Concentrate well into most body fluids, bile, liver, kidney • Bind to tissues undergoing calcification – pediatrics/children? • Cross placental barrier and concentrate in fetal bones and dentition • Only minocycline and doxycycline achieve therapeutic level in CSF • Elimination • Tetracycline – unchanged in urine • Minocycline – undergoes hepatic metabolism + lesser extent via kidney • Doxycycline – primarily eliminated via the bile into the feces Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 72 Protein Synthesis Inhibitors / Tetracyclines • Tetracyclines ➢Adverse effects: • GI disturbances – minimized with food or fluids • Deposition of drug in bones and teeth – pediatrics/children? • Hepatoxicity • Phototoxicity (sunburn); particularly with tetracycline and demeclocycline – wear adequate sun protection • Vestibular dysfunction; particularly with minocycline • (Rare) Benign intracranial HTN – headache, blurred vision • Contraindicated in pregnant, breast-feeding women, or children less than 8 years of age Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 73 Protein Synthesis Inhibitors / Glycylcyclines • Glycylcyclines (e.g. Tigecycline) ➢ MOA: • Same as tetracyclines ➢ Spectrum: • Broad-spectrum / MRSA, VRE, anerobic organisms, multi-drug resistant streptococci, extended-spectrum β-lactamase-producing G –ve bacteria / inactive against Pseudomonas ➢ Resistance: • Via efflux pumps (was developed to overcome tetracycline resistant organisms ➢ PK: • IV / high volume of distribution / low plasma concentrations / eliminated by biliary-fecal route ➢ Adverse effect: • Same as tetracyclines / N and V / elevations of liver enzymes and serum creatinine / decrease clearance of warfarin / used when alternatives doesn’t work Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 74 Protein Synthesis Inhibitors / Aminoglycosides • Aminoglycosides Streptomycin Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan Other Aminoglycosides 75 Protein Synthesis Inhibitors / Aminoglycosides • Aminoglycosides ➢ MOA: • Bactericidal • Used for the treatment of serious infections caused by aerobic G –ve bacilli • Diffuse through porins, then into cytoplasm via oxygen-dependent active transport • Bind to 30S ribosomal subunit – interfere with assembly of the functional ribosomal apparatus and/or causing 30S subunit of the completed ribosome to misread the genetic code • Concentration-dependent bactericidal activity • Exhibit PAE Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 76 Protein Synthesis Inhibitors / Aminoglycosides • Aminoglycosides ➢Spectrum: • Aerobic G –ve bacilli including those that are multi-drug resistant, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter species • Cell wall active drug + aminoglycosides = enhanced transport / synergism // G +ve? • UTIs ➢Resistance: • Efflux pumps / Impaired entry - decreased uptake • Enzymes: modification (transferase) or inactivation (by adenylylation, acetylation, or phosphorylation) / No cross resistance / Amikacin is the least vulnerable to enzymes among them Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 77 Protein Synthesis Inhibitors / Aminoglycosides • Aminoglycosides ➢PK: • Absorption • Highly polar and polycationic – parenterally (neomycin – highly nephrotoxic parenterally – topically or orally) others available topically • Distribution • Cross placental barrier / accumulate in fetal plasma and amniotic fluid • Tissue concentrations may be subtherapeutic and penetration to most body fluids is minimal – hydrophilicity • CNS infections – intrathecal or intraventricular route Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 78 Protein Synthesis Inhibitors / Aminoglycosides • Aminoglycosides ➢PK: • Elimination • Mostly excreted unchanged in the urine • Neomycin – excreted unchanged in feces ➢Adverse effects: • Ototoxicity (vestibular and auditory) / patients receiving concomitant ototoxic drugs (e.g. loop diuretics, cisplatin) are at risk / deafness may be irreversible in fetuses • Nephrotoxicity – ranging from mild, reversible renal impairment to severe, potentially irreversible, acute tubular necrosis Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 79 Protein Synthesis Inhibitors / Aminoglycosides • Aminoglycosides ➢Adverse effects: • Neuromuscular paralysis / from high doses infused over short period concurrent administration with neuromuscular blockers – reversed by prompt administration of calcium gluconate or neostigmine • Allergic reactions – contact dermatitis (from neomycin) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 80 Protein Synthesis Inhibitors / Macrolides • Macrolides Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 81 Protein Synthesis Inhibitors / Macrolides • Macrolides ➢MOA: • Bacteriostatic (bactericidal at high doses) • Bind irreversibly to 50S subunit – inhibiting translocation / may affect transpeptidation • Binding site – identical or in close proximity to clindamycin and chloramphenicol Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 82 Protein Synthesis Inhibitors / Macrolides • Macrolides ➢Antibacterial Spectrum: • Erythromycin = against many of the same organisms as penicillin G • Clarithromycin = as erythromycin + Haemophilus influenzae + intracellular pathogens (Chlamydia, Legionella, Moraxella, Uroplasma species, and Helicobacter pylori) • Azithromycin = less active than erythromycin against streptococci and staphylococci, but far more active against respiratory pathogens, such as H. influenzae and Moraxella • Telithromycin (a ketolide) = similar to azithromycin, but also act on macrolide-resistant organisms Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 83 Protein Synthesis Inhibitors / Macrolides • Macrolides ➢Resistance: • Reduced permeability or active efflux • Decreased affinity of the 50S ribosomal subunit due to methylation of binding site (G +ve) • Presence of plasmid-associated esterases that hydrolyze macrolides (G –ve as Enterobacteriaceae) ❖High resistance against erythromycin ❖Cross resistance – clarithromycin and azithromycin Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 84 Protein Synthesis Inhibitors / Macrolides • Macrolides ➢PK: • Absorption: • Erythromycin base is destroyed by gastric acid (enteric-coated tablets or esterified forms) • Clarithromycin + azithromycin – stable in stomach acid – readily absorbed • All have adequate oral absorption • Erythromycin + azithromycin – empty stomach • Absorption of clarithromycin increase with food • Erythromycin and azithromycin – available as IV Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 85 Protein Synthesis Inhibitors / Macrolides • Macrolides ➢PK: • Distribution: • All do not penetrate the CNS • All concentrate in liver • Azithromycin has the largest volume of distribution (half-life may reach 68hrs) • Excretion: • Erythromycin + azithromycin – excreted in the bile as active drug with their metabolites (erythromycin undergoes also hepatic metabolism) • Clarithromycin – hepatically metabolized, active drug and metabolites excreted mainly in urine Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 86 Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 87 Protein Synthesis Inhibitors / Macrolides • Macrolides ➢Adverse effects: • GI upset (especially with erythromycin – others are well-tolerated) / high doses of erythromycin stimulate smooth muscle contractions – movement of gastric contents to the duodenum – treatment of gastroparesis or postoperative ileus • Jaundice (estolate form of erythromycin and others) • Ototoxicity (high doses of erythromycin / azithromycin – irreversible sensorineural hearing loss) • QTc prolongation – caution with arrhythmic patients • Drug interaction – erythromycin + clarithromycin inhibit cytochrome P450 enzymes – accumulation of drugs (statins, warfarin, antiepileptics) Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 88 Protein Synthesis Inhibitors / Chloramphenicol • Chloramphenicol • Broad-spectrum antibiotic – restricted to life-threatening infections for which no alternatives exist Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 89 Protein Synthesis Inhibitors / Chloramphenicol • Chloramphenicol ➢MOA: • Reversibly binds to bacterial 50S ribosomal subunit – inhibits peptidyl transferase • Act on mammalian mitochondrial ribosomes (similar to those of bacteria) – protein and ATP synthesis may be inhibited at high chloramphenicol conc. – bone marrow toxicity Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 90 Protein Synthesis Inhibitors / Chloramphenicol • Chloramphenicol ➢Antibacterial Spectrum: • Bacteriostatic broad-spectrum (may exert bactericidal activity depending on dose and organism) • Against chlamydiae, rickettsiae, spirochestes, and anaerobes. • Aerobic and anaerobic G +ve and G –ve organisms ➢Resistance: • Enzymatic inactivation • Decreased ability to penetrate the organism / ribosomal binding site alterations Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 91 Protein Synthesis Inhibitors / Chloramphenicol • Chloramphenicol ➢PK: • Widely distributed throughout the body + in the CSF • Administered IV • Undergoes hepatic metabolism – inactive glucuronide metabolite (eliminated in urine) • Secreted in breast milk Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 92 Protein Synthesis Inhibitors / Chloramphenicol • Chloramphenicol ➢Adverse effects: • Anemias: dose-related anemia, hemolytic anemia (G6PD deficiency), and aplastic anemia • Gray baby syndrome: neonates have low capacity to glucuronidate drug + underdeveloped renal function – accumulation – interfering with mammalian mitochondrial ribosomes causing poor feeding, depressed breathing, CV collapse, cyanosis, and death. Adults taking high doses may have same effect. • Drug interactions: inhibit hepatic mixed-function oxidase – warfarin and phenytoin accumulation Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 93 Protein Synthesis Inhibitors / Linezolid • Oxazolidinones (e.g. Linezolid) ➢MOA: • Binds to bacterial 23S ribosomal RNA of the 50S subunit – inhibiting the formation of the 70S initiation complex • Bacteriostatic (cidal on streptococci) • Against resistant G +ve bacteria (MRSA, VRE, penicillin-resistant streptococci) • Alternative to daptomycin for infections caused by VRE Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 94 Protein Synthesis Inhibitors / Linezolid • Oxazolidinones (e.g. Linezolid) ➢Resistance: • Reduced binding to target site ➢PK: • Oral and IV • Distribute widely throughout the body • Metabolized via oxidation to 2 inactive metabolites • Excreted by renal and nonrenal routes Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 95 Protein Synthesis Inhibitors / Linezolid • Oxazolidinones (e.g. Linezolid) ➢Adverse effects: • GI upset, NVD, headache, rash • Thrombocytopenia • Has nonselective monoamine oxidase (MAO) activity – serotonin syndrome with large quantities of tyramine-containing food, SSRI, or MAO inhibitors reversible • Irreversible neuropathies or blindness – if used more than 28 days Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 96 Protein Synthesis Inhibitors / Streptogramins • Streptogramins (e.g. Quinupristin/dalfopristin – 30:70) ➢MOA: • Each binds to separate site on the 50S bacterial ribosome • Dalfopristin disrupts elongation by interfering with the addition of new amino acids to the peptide chain • Quinupristin prevents elongation similar to the macrolides and causes release of incomplete peptide chains • Synergism – bactericidal + long PAE ➢Antibacterial spectrum: • Severe infections caused by VRE in the absence of other therapeutic options Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 97 Protein Synthesis Inhibitors / Streptogramins • Streptogramins (e.g. Quinupristin/dalfopristin – 30:70) ➢Resistance: • Enzymatic processes: (some cases - bactericidal to bacteriostatic) • Target site methylation (interfere with quinupristin binding) • Plasmid-associated acetyltransferase inactivates dalfopristin • Efflux pumps ➢PK: • IV • Doesn’t achieve therapeutic concentrations in CSF • Hepatic metabolism – excretion in feces Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 98 Protein Synthesis Inhibitors / Streptogramins • Streptogramins (e.g. Quinupristin/dalfopristin – 30:70) ➢Adverse effects: • Venous irritation • Hyperbilirubinemia • Arthralgia and myalgia – high doses • Inhibit cytochrome P450 CYP3A4 isoenzymes – drug-drug interactions Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 99 Protein Synthesis Inhibitors / Clindamycin • • • • • • • • • Clindamycin Chlorine-substituted derivative of lincomycin MOA same as macrolides Resistance mechanisms as macrolides To treat infections caused G +ve, such as MRSA, streptococcus, and anaerobic bacteria (treatment of skin and soft-tissue infections) Oral and IV Distributes well to all body fluids but poor entry into CSF Extensive oxidative metabolism to active and inactive metabolites – excreted into bile and urine C. difficile is resistant – treatment with vancomycin or metronidazole Dr. Osama Abusara / Pharmacology (3) / Faculty of Pharmacy / Al-Zaytoonah University of Jordan 100