Drugs acting on ribosome

ByDr. Mohamed Abd Almoneim Attia

TETRACYCLINES Examples :tetracycline, oxytetracyclin, and doxycyclin.Antibacterial spectrumTetracyclines display broad-spectrum activity and are effective against: 1-Most gram-positive, many gram-negative bacteria and anaerobic bacteria.2-Rickettsia, Coxiella, Mycoplasma and Chlamydia, Brucella. 3-Spirochetes, Actinomycines, Protozoa.4-Helico bacter pylori. Mechanism of action1-Tetracyclines bind to the 30S ribosome preventing the addition of amino acids to the growing peptide chain. 2-They chelate some cations necessary for enzymatic action in bacteria e.g. Ca, Mg and Mn.

Pharmacokinetic :Absorption: These antibiotics are partially absorbed from the stomach and upper gastrointestinal tract and the amounts remaining may alter bacterial flora leading to super infection. Calcium (milk and Ca. antacids), magnesium (Mg hydroxide), aluminum hydroxide and iron interfere with their absorption since they form insoluble chelates with tetracyclines. Food did not impair absorption of doxycyclin. Because absorption of doxycycline is rapid and complete ,it has weak effect on intestinal flora.Distribution: Tetracyclines are distributed throughout body tissues and fluids. Doxycycline is the most lipid-soluble, while oxytetracycline is the least lipid soluble. The tetracyclines penetrate the uninflamed meninges and cross the placental barrier. It is concentrated in the liver and bile. Because of their chelating properties with calcium they tend to be deposited in growing bones and teeth causing yellow discoloration.

Metabolism and excretion: Tetracyclines are metabolized in the liver and are concentrated and excreted in the bile then reabsorbed. Doxycycline is excreted primarily in feces (not renal excretion). The other tetracyclines are eliminated primarily in the urine by glomerular filtration.

Therapeutic uses The use of tetracyclines became limited because of other safe and bactericidal antibiotics, the appearance of tetracycline- resistant strains as well as their various adverse effects. 1-Mycoplasma pneumoniae although other agents may be equally effective. 2-The tetracyclines are still the drugs of choice for the treatment and prophlaxsis of cholera . 3-Combination regimen to treat gastric and duodenal ulcer disease caused by helicobacter pylori.

4-Tetracyclines are clinically effective in acne . Minocycline and doxycycline are superior in treatment of acne. They act by decreasing fatty acids of sebum.

5- Diseases caused by Rickettsia (Typhus) and Coxiella.

6- Granuloma inguinale and relapsing fever.

7- The chlamydial diseases (trachoma, lymphogranuloma venereum).

8- Nonspecific urethritis and mixed bacterial infection of respiratory tract e.g. sinusits, bronchitis.

9-They are also effective in the treatment of brucellosis and infections caused by pasteurella (plague).

10Tetracyclines are second choice in other diseases resistant to penicillins and in patients sensitive to penicillins e.g. syphilis, chancroid, gonorrhea, actinomycosis, anthrax and shigellosis.

11-Bacillary and amoebic dysentery as adjuvant therapy (Oxetetracycline is the most active one, it acts indirectly by modifying the intestinal flora necessary for amoebae to survive in bowel lumen).

12-Tetracycline in combination with quinine may be an alternative treatment of plasmodium falciparum malaria when resistance has developed to fancidar. 13-Local applications of tetracycline e.g. eye ointment for treatment of eye infections.

Adverse effects1-Gastrointestinal disturbance: nausea, vomiting, epigastric burning and hyperacidity This can be prevented by giving tetracycline after meals. Antacids may help but avoid those containing Al, Mg and milk because they chelate tetracycline preventing its absorption.

Diarrhea may occur secondry to tetracycline treatment due to:The irritative effect of tetracycline on GIT (leading to frequant fluid stools which do not contain blood or leucocytes). Superinfection of bowel (see before)e.g.Pseudomembranous colitis caused by the overgrowth and production of toxins by clostridium difficile (which is cytotoxic to mucosa leading to ulcer, severe diarrhoea, fever, shreds of mucosa in stools with large number of neutrophils. Diarrhea in these cases could be treated by vancomycin orally or metronidazole with stopping of the causative agent).

2-Disorders of epithelial surfaces e.g. sore throat, sore tongue, black hairy tongue, perioral soreness. The cause is decreased synthesis of Vit. B12 and mild superinfection.

3-Yellow staining of both the deciduous and permanent teeth and dental enamel hypoplasia (increased susceptibility to caries, as well as retardation of bone growth) because of their chelating properties with calcium.This can occur if tetracyclines are administered after the fourth month of gestation or if they are given to children less than 8 years of age, this is a further reason for avoiding their use during pregnancy. Doxycycline is less likely to cause tooth discoloration 4-Hepatotoxicity and pancreatic damage occurs infrequently but may be fatal if it is given during pregnancy, with large dose IV and in presence of renal dysfunction.

5-Photosensitivity observed as abnormal sunburn reaction, is particularly associated with doxycycline administration 6-Fanconi-like syndrome occurs with out-dated tetracyclines. 7-Teratogenesis, when administered early in pregnancy. 8-Hypersensitivity reactions.

Contraindications1-Hypersensitivity to tetracyclines.2-Severe hepatic disease.3-Concomitant administration of total parenteral nutrition as it leads to decreased utilization of amino acids for protein synthesis.4-It should be avoided in patients with peptic ulcer, renal disease, children (less than 8 years of age), pregnancy and lactation.

Interactions1-Avoid simultaneous ingestion of dairy products (milk & cheese), antacids,2-Laxative or iron containing products with tetracyclines because of chelating action of tetracyclines.3-Avoid doxycyclin in alcoholic patients because ethanol causes induction of hepatic enzymes leading to decrease serum level of antibiotic.4-With oral anti-coagulants, tetracyclines decrease vitamin K synthesis in intestinal lumen leading to potentiation of anti-coagulant effect.

CHLORAMPHENICOL Mechanism of action Chloramphenicol inhibits protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. Antibacterial spectrum Chloramphenicol is a broad-spectrum antibiotic. As with tetracyclines, it is effective against gram-positive and gram-negative bacteria, including Salmonella, Rickettsia, Mycoplasma and Chlamydia. Chloramphenicol is also effective against most anaerobic bacteria, including Bacteroides fragilis.

Pharmacokinetic properties Absorption: Chloramphenicol is rapidly and completely absorbed from the gastrointestinal tract and not affected by food ingestion or metal ions. Since absorption is rapid and complete after oral administration, there is less alteration of bacterial flora with less susceptability to superinfection. Distribution: Chloramphenicol penetrates body fluids and tissues well. The drug penetrates the brain and CSF with high concentration and crosses the placental barrier.

Metabolism and excretion: Renal elimination is by tubular secretion of metabolite and glomerular filtration of active drug. Therapeutic usesThe serious and potentially fatal nature of chloramphenicol-induced bone marrow suppression restricts its use to a few life-threatening infections in which the benefits outweigh the risks. 1-It was the drug of choice in typhoid fever, but now other safe and more effective drugs are used e.g. ciprofloxacin and amoxycillin. 2-It is a good choice for the treatment of pyogenic meningitis (Since effective CSF levels are obtained), particularly that caused by Haemophilas influenza. Although the 3rd generation cephalosporins are peferred. 3-In treating other invasive infections caused by H. influenzae, such as arthritis, osteomyelitis and epiglottis 4-Treatment of serious anaerobic infections of brain caused by penicillin- resistant bacteria, such as B-fragilis. 5-Rickettsial disease: Chloramphenicol is an alternative to tetracycline. 6-Topical treatment of both ear and eye infections.

Adverse effects 1-Toxic bone marrow depression: The bone marrow depression is dose related. It is recognized as anemia, thrombocytopenia or leukopenia (agranulocytosis). It is reversible on discontinuation of the chloramphenicol. Treatment of agranulocytosis:1-Stop the drug.2-Fresh blood transfusion.3-Cortisone to inhibit reaction.4-Penicillin to eradicate streptococcal infection in the throat.5-Bone marrow stimulants e.g. growth factor (G-CSF), vitamin B complex, adenine sulphate, pentose nucleotide.

2-Gray baby syndrome: It occurs in newborn infants with large doses, especially those born prematurely. It is due to immature hepatic conjugating mechanism and in adequate renal excretion which leads to high levels of chloramphenicol. This syndrome is characterized by abdominal distention, vomiting, progressive cyanosis, irregular respiration, hypothermia, flaccid paralysis and vasomotor collapse. Mortality is high (40%). 3-Gastrointestinal disturbance: nausea, vomiting, diarrhea and glossitis. 4-Superinfection: It usually occurs after 5 –10 days. 5-Hypersensitivity reactions: skin rashes, fever, angioedema (not frequent). 6-Optic neuritis and encephalopathy: (rare).Drug InteractionsChloramphenicol inhibits the activity of the liver microsomal enzymes and thus enhances the activity of drugs, such as dicoumarol, diphenylhydantoin and tolbutamide which are normally degraded by these enzymes.

BACITRACIN, VANCOMYCINS, POLYMYXINS AND SODIUM FUSIDATE (MINOR ANTIBIOTICS) They are relatively toxic drugs and have only limited use in chemotherapy. It is usually used topically.BACITRACINMechanism of action Bacitracin prevents cell wall synthesis.Antimicrobial spectrumBacitracin inhibits gram-positive cocci and a few gram-negative organisms. Therapeutic usesit is mainly used topically alone or in combination with other antibiotics (Notably polymyxin-B and neomycin) or hydrocortisone (as anti-inflammatory) in the form of creams, ointments and aerosol preparations.

Adverse effects : nephrotoxicity.

VANCOMYCINMechanism of action Vancomycin inhibits cell wall synthesis. Antimicrobial spectrumIt has a narrow-spectrum activity (only against gram-positive bacteria). Therapeutic uses It is mainly used in:1-Vancomycin is also the drug of choice in patients in whom pseudomembranous colitis (antibiotic associated colitis) has developed 2-Methicillin-resistant Staphylococcus aureus infections 3-Other infections due to susceptible organisms e.g. streptococci, bacillus anthracis, corynebacterium diphtheria, clostridium tetani and difficile.

Adverse effects1-The major adverse effect associated with vancomycin therapy is ototoxicity.2-"Red neck syndrome": More commonly, the intravenous infusion of vancomycin can result in the occurrence of chills, fever and a maculopapular skin rash often involving the head and upper thorax due to histamine release.

THE POLYMYXINSpolymyxin B and colistin (polymyxin E) are used in the treatment bacterial diseases. Antimicrobial spectrumThe polymyxins are active against facultative gram-negative bacteria and P. aeruginosa and coliform organisms in particular.

Therapeutic uses 1-In combination with neomycin, polymyxin B is used as a bladder irrigant to reduce the risk of catheter- associated infections.2-Polymyxin B also is applied topically in combination with other antibiotics for infections of skin, eye or ear.

Adverse effects1- Nephrotoxicity.2-Neurotoxicity. recognized by perioral paresthesia, numbness, weakness, ataxia and blurred vision.3-These drugs precipitate respiratory arrest (due to Neuromuscular blocking effect) especially both in patients given muscle relaxants during anesthesia and in persons suffering from myasthenia gravis.

SODIUM FUSIDATE (Fucidin)It inhibits protein synthesis by binding to 50 S ribosomal subunit. It is active against gram-positive bacteria and some gram-negative diplococci Good penetration into bone and pus.

Thank you