Pharmacology II - Protein Synthesis Inhibitors II PDF

Pharmacology II PROTEIN SYNTHESIS INHIBITORS II Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  3 TETRACYCLINES Consi...

Pharmacology II PROTEIN SYNTHESIS INHIBITORS II Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  3 TETRACYCLINES Consist of four fused rings with a system of conjugated double bonds. Substitutions on these rings are responsible for variation in the drugs’ individual pharmacokinetics, which cause small differences in their clinical efficacy.  4 Mechanism of action Tetracycline are transported into susceptible organisms by passive diffusion and an energy-dependent transport protein mechanism (unique to the bacterial inner cytoplasmic membrane). ‫…يجري التحميل‬ Binds REVERSIBLY to the 30S subunit, thereby blocking tRNA to the mRNA- ribosome complex. Tetracycline  5 Antimicrobial Activity Bacteriostatic Broad-spectrum including anaerobes, rickettsiae, chlamydiae, mycoplasmas, spirochetes Commonly used to treat acne and Chlamydia infections (doxycycline). tetracycline-resistant strains may be susceptible to doxycycline, minocycline, and tigecycline, all of which are poor substrates for the efflux pump that mediates resistance.  6 Resistance Main issues: Production of an efflux pump and ribosomal protection Resistance to one tetracycline ≠ resistance to all tetracyclines ‫…يجري التحميل‬ Daniel N. Wilson, 2014 (Nature)  12 Clinical Uses Treat Mycoplasma pneumoniae, chlamydiae, legionella, rickettsiae and some spirochetes. First line for vibrio cholera (resistance has appeared during epidemics). Tetracyclines remain effective in most chlamydial infections, including sexually transmitted diseases (Not for gonorrhea due to emergence of resistance). Tetracycline + aminoglycoside (plague, tularemia, and brucellosis).  15 Adverse Reactions Gastric discomfort: Nausea, vomiting, and diarrhea (most common reasons for tetracycline discontinuation) (Superinfection- overgrowth of clostridium difficile; candida in the vagina) Effects on calcified tissues: Deposition in the bone and primary dentition occurs during the calcification process in growing children (discoloration and hypoplasia of teeth and a temporary stunting of growth). Hepatotoxicity: Rarely except for high doses (particularly in pregnant women) and pre-existing hepatic dysfunction or renal impairment.  15 Adverse Reactions Phototoxicity: Severe sunburn who are exposed to sun or ultraviolet rays (more frequently with tetracycline and demeclocycline). Vestibular dysfunction: Dizziness, vertigo, and tinnitus may occur particularly with minocycline. Doxycycline may also cause vestibular dysfunction. Pseudotumor cerebri: Benign, intracranial hypertension characterized by headache and blurred vision may occur rarely in adults. Contraindications: Should not be used in pregnant or breast-feeding women or in children (< 8 years old).  21 Thank you Antibiotics!  15 GLYCYLCYCLINES Tigecycline (approved in 2005) Mechanism of action bacteriostatic Bind reversibly to 30S ribosomal subunit. Antibacterial spectrum Broad-spectrum includes MRSA, multidrug-resistant ESBL–producing ‫…يجري التحميل‬ streptococci, vancomycin-resistant enterococci (VRE), gram-negative, Acinetobacter baumannii and many anaerobic. Resistance - overexpression of efflux pumps. Adverse effect: Significant nausea and vomiting Acute pancreatitis ↑ liver enzymes and serum creatinine Photosensitivity, pseudotumor cerebri, teeth discoloration, and fetal harm.  7 Pharmacokinetics Absorption: Adequately absorbed (oral) Dairy products or substances that contain divalent and trivalent cations (Mg2+, Al3+ or Fe2+) decreases absorption, particularly for tetracycline (Why?) Both doxycycline and minocycline are available as oral and IV form. Distribution: Well penetration into body fluids. Concentrate in the bile, liver, kidney, gingival fluid and skin. Only minocycline and doxycycline achieve therapeutic levels in CSF. Minocycline achieves high levels in saliva and tears to eliminate carrier status of N. meningitidis Cross placental barrier (concentrate in foetal bones and dentition).  10 Pharmacokinetics Elimination: Tetracycline and doxycycline are not hepatically metabolized. Tetracycline is primarily eliminated unchanged in the urine, whereas minocycline undergoes hepatic metabolism and is eliminated to a lesser extent via the kidney. Doxycycline is preferred for renal impairment patient (primarily eliminated via bile into the faeces).  14 Clinical Uses Tetracyclines formerly were used for a variety of common infections, including bacterial gastroenteritis, pneumonia (other than mycoplasmal or chlamydial pneumonia), and urinar trac infections. y t However, many strains of bacteria causing these infections now are resistant, and other agents have largely supplanted tetracyclines. Demeclocycline inhibits the action of antidiuretic hormone in the renal tubule and has been used in the treatment of inappropriate secretion of antidiuretic hormone or similar peptides by certain tumors.