PM 716 Pharmacology I - Tetracyclines Slides PDF

PM 716 Pharmacology I Chapter 44 Protein Synthesis Inhibitors RMRocco PhD PM716 C44 PSI 1  Antibiotics (PSI Part I) (1) Protein Synthesis Inhibitors tetracyclines(5) all end in “cycline” macrolides (3) all end in “mycin”...

PM 716 Pharmacology I Chapter 44 Protein Synthesis Inhibitors RMRocco PhD PM716 C44 PSI 1  Antibiotics (PSI Part I) (1) Protein Synthesis Inhibitors tetracyclines(5) all end in “cycline” macrolides (3) all end in “mycin” erythromycin clarithromycin azithromycin ketolides (1) the only “telithro” telithromycin chloramphenicol (1) only one of its kind PM716 C44 PSI 2  Protein Synthesis Transcription: DNA-dependent RNA synthesis Translation: RNA-dependent protein synthesis. Most of the drugs discussed in lectures are Translation inhibitors. PM716 C44 PSI 3  Translation Inhibitors Three phases of Translation: (1) Initiation of the peptide chain (2) Elongation of the peptide chain (3) Termination of the peptide chain PM716 C44 PSI 4  (1) Initiation 30S ribosomal subunit of mRNA binds with formyl methionyl-tRNA to form an initiation complex. The codon initiation signal is AUG in mRNA which recognizes the anticodon fMet tRNA. PM716 C44 PSI 5  (2) Elongation Major Target of Antibiotics Amino acyl tRNA on the P site of the ribosome is released from the linkage of tRNA to join amino acyl tRNA by actions of peptidyl transferase. Translocation moves ribosome along the mRNA (5’ to 3’ terminus direction). PM716 C44 PSI 6  (3) Termination Polypeptide chain termination initiated by UAA, UAG or UGA with hydrolysis of peptide and release of the newly formed polypeptide. PM716 C44 PSI 7 Chapter 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones PM716 C44 PSI 8 © The McGraw-Hill Companies, Inc,  Actions of Antibiotics Inhibit 30S ribosomal subunit through (a) Prevent mRNA from attaching (b) Impair movement of mRNA (c) Block amino acyl acceptor site. PM716 C44 PSI 9 Protein Synthesis TRANSCRIPTION: RNA polymerase reads the DNA code and synthesizes mRNA. mRNA = series of codons (3 nucleotides) = 1 amino acid PM716 C44 PSI 10 Protein Synthesis TRANSLATION: Ribosome binds to start codon (AUG) of mRNA. tRNA with attached amino acid binds to proper codon in mRNA forming complementary base pairs with the tRNA anticodon. One tRNA for each of the 20 amino acids. Ribosome moves along mRNA adding amino acids to growing polypeptide chain. PM716 C44 PSI 11  Tetracyclines demeclocycline doxycycline minocycline tetracycline tigecycline PM716 C44 PSI 12  Tetracycline 1. Structure/Source: 1946 Streptomyces various species, including semisynthetic. chlortetracycline, oxytetracycline, demeclocycline, methacycline, doxycycline, minocycline PM716 C44 PSI 13 Tetracyclines 2. Mechanism of Action: bind to the 30S subunit of bacterial ribosome blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. PM716 C44 PSI 14  Tetracyclines 3. Pharmacokinetics: absorption varies by type from 30 to 100% F, absorption impaired by Ca++ ions, forms chelation product which blocks absorption, do not take po with dairy products. Main excretion is renal which requires dosage adjustments based on CC (except for doxycycline, the drug of choice in renal failure). PM716 C44 PSI 15  Tetracyclines 4. Antimicrobial Activity: Broad spectrum bacteriostatic active against gram pos, gram neg, anaerobes, rickettsiae, chlamydiae. Mycoplasmas. All in this class have same antimicrobial activity but resistance may determine usage. PM716 C44 PSI 16  Tetracyclines 5. Clinical Uses: Drugs of choice for Mycoplasma pneumoniae, chlamydiae, rickettsiae, some spirochetes. Used in combination to treat Helicobacter pylori. Used to treat acne. Many applications abandoned because of resistance. PM716 C44 PSI 17  Tetracyclines 6. Adverse Effects and ADRs: Drugs bind to calcium deposited in teeth and bones. PM716 C44 PSI 18 Tetracyclines Binding to calcium in bone is irreversible. 3500 year old mummy bones shown to have tetracyline rings in the long bones. Tetracyline dosing used to measure bone growth. PM716 C44 PSI 19  Tetracyclines Highly fluorescent molecules. Photosensitization reactions are common after exposure to sun and UV light. Ex 390-425 nm Tet Em 525 - 560 nm PM716 C44 PSI 20  Tetracyclines 7. Mechanisms of Resistance: 1. Decreased intracellular accumulation due to impaired influx or increased efflux (active transport pump). 2. Mutation expression of proteins that block tetracycline binding to ribosome subunit. 3. Mutation expression of enzyme that degrades drug. PM716 C44 PSI 21  Tetracyclines Clinical uses limited in lower extremity infections to mostly doxycycline and minocycline. Uses also include MRSA infections Doxycycline (po) used for Lyme disease. For use with staph and strep infections in patients with penicillin allergies. PM716 C44 PSI 22  Macrolides 1. Structure/ Source: Erythromycin; azithromycin; clarithromycin. From Streptomyces erythreus (1952) and semisynthetic (AZ, CL). Named for macrolide ring in structure. PM716 C44 PSI 23 Macrolides 2. Mechanism of Action: Binds to 50S ribosomal RNA and blocks aminoacyl translocation reactions and blocks the formation of initiation complexes. PM716 C44 PSI 24  Macrolides 3. Pharmacokinetics: Stomach acid destroys and enteric coating must be used. Excretion is mostly bile, adjustment for renal failure not required. Dose po or iv. 4. Antimicrobial Activity: Gram pos pneumococci, streptococci, staphylococci, corynebacteria, mycoplasma, legionella, Chlamydia, Helicobacter, listeria. Some gram Neg, neisseria. PM716 C44 PSI 25  Macrolides 5. Clinical Uses: Drug of choice for diphtheria, corynebacterial sepsis, chlamydial infections, community acquired pneumonia, legionella. Substitute for penicillin when allergy is present. Prevent endocarditis during dental procedures. PM716 C44 PSI 26  Macrolides 6. Adverse Effects and ADRs: Hypersensitivity hepatitis (fever, jaundice, impaired liver function), allergic rashes. Metabolites of erythromycin inhibit some CYP enzymes and this causes rises in Cp of some drugs. PM716 C44 PSI 27 Erythromycin First macrolide antibiotic introduced over 50 years ago. Available iv, po, topical. Dosage adjustment usually not required for decreased CC. DOSE: po up to 500 mg four times a day. PM716 C44 PSI 28  Legionella pneumophila (Legionnair’s Disease) American Legion Convention at a hotel in Philadelphia in the summer of 1976. 4 000 in attendance, 200 develop cough and low fever, 30 passed into a coma and died. L. pneumophila identified as causative agent in 1977. Resistant to most antibiotics at the time. PM716 C44 PSI 29  L. pneumophila Rare Gram neg soil bacterium that is isolated from most human contact. Inhibited by Ca++ which is found almost all culture media. Human-Induced Environmental Disease: artificial environment created new niche for microbial growth and human contact. PM716 C44 PSI 30 L. pneumophila Organism grows in natural waters including air- conditioning cooling-tower waters. Grows 25 to 43o C Takes 3-7 days in vitro in special media to grow in the lab Up to 18 000 cases in US/year Treat with iv Erythromycin (all generations of Pen, Ceph and aminoglycocides are ineffective). PM716 C44 PSI 31 L. pneumophila Organism grew in cooling water in the hotel’s air conditioner. Water used to keep machinery of AC from overheating. At the time cooling water was kept in troughs open to the air. Water was aerosolized by nearby ventilation fans and bacteria blown through the hotel ventilation system, PM716 C44 PSI 32  L. pneumophila Treatment Macrolides: erythromycin (10 days) azithromycin clarithromycon Tetracyline: doxycycline PM716 C44 PSI 33 Azithromycin Most Gram Pos pathogens (staph and strep) Limited Gram Neg acitvity. Unique dosing form: “Z-Pak®” PM716 C44 PSI 34  Azithromycin Pharmacokinetics 500 mg (2 x 250 mg tablets) on Day 1 250 mg (1 x 250 mg tablet) on Days 2 -5 N =12 volunteers Day 1 Day 5 Cp max ng/mL 410 240 AUC ng. h/mL 2600 2100 PM716 C44 PSI 35  Azithromycin Dosing Day 1 2 x 500 mg po dose Day 2 -5 1 x 250 mg po dose/day (for up to four days). Once a day dosing improves patient compliance. PM716 C44 PSI 36  Ketolide 1. Structure/Source: Telithromycin only one approved. Derived from erythromycin (semisynthetic). 2. Mechanism of Action: same as macrolides PM716 C44 PSI 37  Ketolides 3. Pharmacokinetics: same as macrolides. 4. Antimicrobial Activity: same as macrolides 5. Clinical Uses: Used for macrolide-resistant strains. Modified structure makes them poor substrates for the efflux pump and higher affinity for binding site on ribosome subunit. PM716 C44 PSI 38  Ketolides 6. Adverse Effects and ADRs: similar to macrolides 7. Mechanism of Resistance: tbd, new drug. PM716 C44 PSI 39  Ketolides Telithromycin Dose: once a day po Drug mostly eliminated mostly in bile and urine NOTE: Drug inhibits CYP3A4 enzyme. PM716 C44 PSI 40 Chloramphenicol 1. Structure/Source: Streptomyces venezuelae 1947 soil sample from Venezuela 2. Mechanism of Action: reversible binding to 50S subunit of bacterial ribosome. Inhibits peptidyl transferase step. PM716 C44 PSI 41  Chloramphenicol No other antibiotic has been discovered with similar structure. Effective po and parenterally. Readily crosses BB and placental barriers. Major toxic side effects (bone marrow suppression) has limited its use. PM716 C44 PSI 42  Chloramphenicol 3. Pharmacokinetics: po tablets, 1 g po dose produces Cp levels of 10 - 15 ug/mL. Large Vd with distribution into CNS equal to plasma levels. Inactivation to metabolites by Phase II in liver. Renal disease does not require CC correction (90% inactive metabolites excreted) but liver disease does. PM716 C44 PSI 43  Chloramphenicol 4. Antimicrobial Activity: bacteriostatic broad spectrum against aerobic and anaerobic gram pos and gram neg. 5. Clinical Uses: resistance and toxicity limits usefulness. Used when penicillins contraindicated due to allergy or for rickettsial infections (Rocky Mt spotted fever) in children where tetracyclines can not be used. PM716 C44 PSI 44  Chloramphenicol 6. Adverse Effects and ADRs: Bone marrow suppression of red cell production after 1-2 weeks dosing. Aplastic anemia (idiosyncratic) Aplastic anemia in 1/24 000 to 1/40 000 patients who receive the drug. Inhibits different CYP450s and prolongs t1/2 of other drugs. PM716 C44 PSI 45  Chloramphenicol 7. Mechanisms of Resistance: mutations that cause organism to be less permeable to the drug. Mutation selection for production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug. PM716 C44 PSI 46  Chloramphenicol Gray Baby Syndrome Infants with decreased RBCs, cyanosis, and cardiovascular collapse. Premature neonates are deficient in hepatic glucuronosyltransferase which is responsible for inactivation (biotrans- formation) of this drug into inactive metabolites. PM716 C44 PSI 47  Antibiotics (PSI Part II) lincosamides (1) clindamycin aminoglycosides (10) streptogramins (1) streptogramin A + B oxazolidinones (1) linezolid PM716 C44 PSI 48  Lincosamides 1. Structure/Source: Clindamycin only one. Streptomyces lincolnensis. 2. Mechanism of Action: Bind to 50S subunit, identical to erythromycin and other macrolides. PM716 C44 PSI 49  Lincosamides 3. Pharmacokinetics: po or iv. Fairly high Vd with penetration into most tissues. No dosage adjustment for renal failure required. 4. Antimicrobial Activity: Gram pos and neg. Streptococci, staphylococci, pneumococci. PM716 C44 PSI 50  Spectrum of Activity Clindamycin (Cleocin®) Most Gram Pos organisms (Staph and Strep) Most anaerobes (Bacteroides but up to ~ 20% are resistant). PM716 C44 PSI 51  Lincosamides 5. Clinical Uses: Severe anaerobic infection caused by bacteroides and other anaerobes. 6. Adverse Effects and ADRs: Skin rashes, impaired liver function, antibiotic- associated colitis due to C. difficile, often fatal. Treat with metronidazole. PM716 C44 PSI 52  Clindamycin Most often reported ADR is diarrhea in up to 20% of patients on this drug. Diarrhea resolves after drug is stopped. DOSE: 600 - 900 mg q8h iv or im or 150 - 300 mg three times a day po. No dosage adjustment required for reduced CC because drug is hepatic cleared. Hepatic failure requires dosage adjustment. PM716 C44 PSI 53  Lincosamides 7. Mechanism of Resistance: confers cross resistance to macrolides. 1. Mutation in ribosomal receptor binding site. 2. Enzymatic inactivation of drug 3. Mutation alteration of receptor by induced methylase. PM716 C44 PSI 54  Clindamycin Clinical uses in lower extremity infections: Staph infection in patients allergic to penicillin drugs Oral therapy for mild diabetic ulcerations. Combined with Gram Neg antibiotic in severe diabetic ulcerations. Osteomyelitis due to staph because of good penetration into bone. PM716 C44 PSI 55  Streptogramins Quinupristin-dalfopristin Combination of two streptogramins Same mechanisms as clindamycin IV dosing; elimination fecal Can be used for vanco resistant strains of E faecium PM716 C44 PSI 56  Linezolid An oxazolidinone antibiotic Gram pos staph, strep, enterococci, and Gram pos rods Drug is mostly bacteriostatic Binds 50s ribosome, inhibits protein synthesis Used often for vancomycin resistant infection Given po or iv, does not interact with CYP 450 enzymes. PM716 C44 PSI 57  Case Study 19-year old female with 2-week history of vaginal discharge. Patient is sexually active with multiple partners sometimes with unprotected sex. Treat empirically for gonococcal and chlamydial cervicitis pending results back from C&S. Patient may be pregnant. PM716 C44 PSI 58  Case Study Tetracylcine or a macrolide for chlamydal infection. Doxycycline po or azithromycin po preferred choices. Do not use teracyclines in pregnancy, use azithromycin. PM716 C44 PSI 59