Medical Pharmacology Topics
| Preliminary Outline |
| Bacteriostatic
Antibiotics |
The bacteriostatic antibiotics include the macrolides, tetracyclines, aminoglycosides and other agents like chloramphemnicol and clindamycin. They inhibit bacterial protein synthesis by acting on bacterial ribosomal units. In addition to the bacteriostatic activity, each drug class has other characteristic mechanisms:
Macrolides
The macrolides are bacteriostatic agents that accumulate in gram-positive bacteria, and include azithromycin and erythromycin.They are indicated to treat atypical pneumonias caused by Mycoplasma pneumoniae and Legionella pneumoniae. Other patogens like Streptococcus pneumonia, H. influenzae and M. avium readily develop resistance by either increasing drug eflux from bacterial cells or by altering drug binding targets.
Azithromycin is also indicated to treat H. influenzae, bronchitis and Chlamydia. Antiacids containing magnesium or aluminum may lower peak serum levels of azithromycin, and food will decrease absorption of the oral dose (also available IV). Hepatic impairment may interfere with azithromycin elimination.
Erythromycin is also indicated to treat otitis media in combination with sulfisoxazole. It may cause cardiac arrhythmias and QT prolongation, and blocks the metabolism of carbamazepine, digoxin, theophilline and warfarin. Erythromycin is contraindicated in patients with hepatic impairment or taking potentially hepatotoxic drugs, and may cause cholestatic jaundice.
The macrolides concentrate in tissue and inflammatory cells, but CNS levels are too low to be effective. They are metabolized in the liver and excreted primarily in bile. May cause stomach cramps, nausea, vomiting and diarrhea by overstimulation of the GI muscles. Chloramphenicol and clindamycin antagonize the antibiotic effect of macrolides.
Tetracyclines
The tetracyclines like doxycycline are bacteriostatic agents that are pumped into bacterial cells, creating a hiogh differential concentration. They are indicated to treat Rickettsia, Chlamydia, Mycoplasma, Lyme disease, relapsing fever, and selected gram-positive and gram-negative bacteria. Plasmid-mediated resistance is common, leading to either reduced accumulation of drug in bacteril cells or ribosomal-protecting enzymes.
The tetracyclines are contraindicated in children less than 9 years old and pregnant women because they interfere with bone and teeth development. They are also contraindicated in patients with renal impairment. Milk, antiacids, drugs or supplements containing calcium, iron or magnesium block absorption of tetracyclines. Most have poor lipid solubility and oral absorption is decreased by food, except doxycyline and a few others. While most are renally excreted, doxycycle is excreted mostly by the liver and by diffusion into the vowel lumen.
Tetracyclines antagonize the antibiotic effects of penicillins. The GI effects are due to changes in bacterial flora. Candida of the mouth, bowel or vagina may occur, as well as photosensitivity and dizziness.
Aminoglycosides and Aminocyclitols
The aminoglycosides and aminocyclitols block bacterial protein synthesis by binding to the 30s/50s ribosomal subunits. They block the action of the normal initiation complex, promote misreading of codons and disintegration of polyribosomes. Unlike other bacterioastatic agents, they are also bactericidal. Since they are heavily charged, entry into cells is energy dependent.
The aminoglycosides include amikacin, gentamycin, kanamycin, netilmycin, streptomycin, neomycin and paromomycin. The only amynociclitol in use is spectinomycin. These agents are indicated against gram-negative aerobic bacteria like E. coli, Enterobacter, Proteus and Klessiella. Anmikacin, gentamicin, netlmicin and tobramycin are active against Ps. aeruginosa. They are also used against gram-positive aerobic bacteria like Strep. viridans, Strep. agatactae and Enterococus. Aminoglycosides are used in combination with beta-lactams to treat serious gram-positive infections. Streptomycin is indicated against M. tuberculosis and spectinomycin against N. gonorrhea.
The aminoglycosides and spectinomycin are not asbsorbed orally, thus are administered IV or IM. They are not lipid soluble, thus will distribute to fluids. Specific pump mechanisms concentrate these drugs in renal tubular cells and hair cells of the inner ear. There is minimal metabolism of these agents and they are eliminated almost exclusively by the kidneys. Neonates and the elderly eliminate aminoglycosides more slowly, while cystic fibrosis or burn patients eliminate them faster than normal. The dosing protocol of aminoglycosides is based upon ideal body weight and creatinine clearance.
The aminoglycosides cause dose-dependent ototoxicity (may be permanent), renal toxicity and neuromuscular blockade due to atypical absortion. The combination of a single excretion route, high individual variability of elimination and dose-dependent toxicity demands use with extreame caution. They are contraindicated in patients with impaired renal function, eight cranial nerve impairment, parkinsonism, myastenia gravis or botulism in infants. Aminoglycosides interact with other ototoxic or nephrotoxic drugs, inhalation anesthetics, neuromuscular blockers and beta-lactam antibiotics. The beta-lactams and aminoglycosides inactivate each other in sdolution but act synergistically when used sequentially.
Chloramphenicol and Clindamycin
Other bacteriostatic antibiotics include chloramphenicol and clindamycin. Chloramphenicol is inactivated by bacterial acetyltransferase and is contraindicated when safer drugs are available because it also affects mitochondrial protein synthesis in host cells. It is indicated to treat H. influenzae, Salmonella, Ricketsia, Chlamydia and anaerobic absesses, especially in the brain, or meningitis.
Chloramphenicol will cause reversible bone marrow supression (dose-related), aplastic anemia (rare and fatal, not dose related, may occur weeks or months after therapy), and gray baby syndrome. It inhibits P450 irreversibly thus interfering with the metabolism of many drugs, and antagonizes the antibiotic effects of erythromycin and clindamycin.
Chloramphenicol is well absorbed orally and distributes well, reaching therapeutic concentrations in the CNS. It is metabolized in the liver mostly by glucuronidation (not well developed in babies, thus the gray baby syndrome), but also by acetylation and dehalogenation. Metabolites and uncharged drug are excreted in the urine.
Clindamycin passively enters bateria and concentrates in macrophages. The main indication for clindamycin is treatment of anaerobic bacteria or sites, like bone and abdomen. Other indications are against gram-positive bateria and Pneumocystis carinni (in combination with primaquine).
Clindamycin is well absorbed orally and distributes in high concentration to many fluids and tissues, including bone, although CNS concentrations are insufficient for therapy. Hepatic metabolism accounts for 85% of the eliminatred dose. It may cause diarrhea, antibiotic associated colitis and pseudomembramous colitis, and may interact with anesthetics, neuromuscular blockers (enhance block), antidiarrheals (block absorption), and will antagonize the antibiotic effects of chloramphenicol and the macrolides.
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Macrolides
Azithromycin