PROTEIN SYNTHESIS INHIBITORS

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INTRODUCTION.

• A number of antibiotics exert their antimicrobial effects by targeting the bacterial ribosome which has components that differ structurally from those of the mammalian cytoplasmic ribosome.
• In general, the bacterial ribosome is smaller (70S) than the mammalian ribosome (80S) and is composed of 50S and 30S subunits.

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• The mammalian mitochondrial ribosome, however, more closely resembles the bacterial ribosome.
• Drugs that interact with the bacterial target usually spare the host cells.
• High levels of drugs such as chloramphenicol and the tetracyclines may cause toxic effects as a result of interaction with the host mitochondrial ribosomes.

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Classification of protein synthesis inhibitors

TETRACYCLINES …..

• Demeclocycline
• Doxycycline
• Minocycline
• Tetracycline

GLYCYLCYCLINES

• Tigecycline

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AMINOGLYCOSIDES………

• Amikacin
• Gentamycin
• Neomycin
• Streptomycin
• Tobramycin

MACROLIDES/KETOLIDES

• Azithromycin
• Clarithromycin
• Erythromycin
• Telithromycin

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CHLORAMPHENICOL…..

CLINDAMYCIN

QUINUPRISTIN/DALFOPRISTIN

LINEZOLID

TETRACYCLINES

• Consists of four fused rings with a system of conjugated double bonds.
• Substitution on these rings are responsible for variation in the drugs’ individual pharmacokinetics.

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MECH OF ACTION.

• Entry of these agents into susceptible organisms is mediated both by passive diffusion and by an energy-dependant transport protein mechanism unique to the bacterial inner cytoplasmic membrane.
• Nonresistant strains concentrate the tetracyclines intracellularly.

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• The drug binds reversibly to the 30S subunit of the bacterial ribosome, thereby blocking access of the amino acyl-tRNA to the mRNA-ribosome complex at the acceptor site.
• By this mechanism, bacterial protein synthesis is inhibited.

ANTIBACTERIAL SPECTRUM

• Tetracyclines are bacteriostatic and broad spectrum antibiotics active against gram positive and gram negative bacteria.

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• Tetracyclines can be used in the mgt of……

Chlamydial infections

• Chlamydia tracomatis is the major cause of sexually transmitted disease in the united states.
• It causes nongonococcal urethritis and pelvic inflammatory disease and lymphogranuloma venereum.

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• Chlamydia psittaci causes psittacosis which usually takes the form of pneumonia. Other clinical forms include hepatitis, myocarditis and coma.
• Doxycycline or azithromycin is used to treat chlamydial infections.

Mycoplasma pneumonia

• Mycoplasma pneumoniae is a common cause of pneumonia in young adults and in people who live in close confines such as in mil camps

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• Treatment leads to a shorter duration of fever, cough and malaise.
• Treatment with macrolides is also effective.

Lyme disease

• This is a spirochetal infection caused by Borrelia burgdorferi. The disease is transmitted by the bite of infected ticks.
• Infection results in skin lesions, headache, and fever, followed by meningoencephalitis and eventually arthritis.

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• A single 200mg dose of doxycycline. Given within 72hrs after a tick bite can prevent a development of the disease.

Rocky mountain spotted fever

• This disease, caused by Rickettsia rickettsi is characterized fever, chills and aches in bones and joints.
• Response to tetracyclines is prompt if the drug is started early in the disease process.

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Cholera

• Cholera is caused by Vibrio cholerae ingested as part of fecally contaminated food or water.
• The organism multiplies in the gastrointestinal tract, where it secretes an enterotoxin that produces diarrhea.
• Treatment includes doxycycline, which reduces the number of intestinal vibrios and fluid replacement.

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RESISTANCE

• There is widespread resistance to the tetracyclines hence their limited clinical use.
• The inability of the organisms to accumulate the drug produces resistance.
• This is accomplished by Mg++ dependent, active efflux of the drug, mediated by the plasmid-encoded resistance protein, TetA.

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• Other mechanisms include enzymatic inactivation of the drug and production of bacterial proteins that prevent tetracyclines from binding to the ribosome.
• Organisms resistant to one tetracycline is resistant to all.
• The majority of penicillinase producing staphyllococci are now insensitive to tetracyclines.

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PHARMACOKINETICS

ABSORPTION

• All tetracyclines are adequately but incompletely absorbed after oral ingestion.
• Taking TCNs with dairy foods in the diet decreases absorption due to the formation of nonabsorbable chelates of the TCNs with calcium ions.

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• Nonabsorbable chelates are also formed with other divalent and trivalent cations (Mg2+, Al3+ and Iron preparations.)
• Note that this presents a problem if a patient self-treats the epigastric upsets caused by TCN ingestion with antacids.
• Doxycycline and minocycline are almost totally absorbed on oral administration.
• Currently Doxycycline is the preferred tetracycline for parenteral administration.

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DISTRIBUTION

• TCNs concentrate in the liver, kidney, spleen and the skin and they bind to tissues undergoing calcification e.g teeth and bones or to tumors that have a high calcium content e.g gastric carcinoma.
• Penetration into most body fluids is adequate including the CSF although levels in the CSF are insufficient for therapeutic efficacy, except for minocycline.

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• Minocycline enters the brain in the absence of inflammation and also appears in tears and saliva.
• Although useful in eradicating the meningococcal carrier state. Minocycline is not effective forCNS infections.
• All TCNs cross the placental barrier and concentrate in fetal bones and dentition.

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FATE

• All TCNs concentrate in the liver, where they are in part metabolized and conjugated to form soluble glucuronides.
• The parent drug and its metabolites are secreted into the bile.
• Most TCNs are reabsorbed in the intestine via the enterohepatic circulation and enter the urine by glomerular filtration.

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• Obstruction of the bile duct and hepatic or renal dysfunction can increase their half lives.
• Unlike other TCNs, doxycycline can be employed for treating infections in renally compromised patients because it is preferentially excreted via the bile into the feces
• TCNs are also excreted in breast milk.

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ADVERSE EFFECTS

GASTRIC DISCOMFORT

• Epigastric distress commonly results from irritation of the gastric mucosa and is often responsible for noncompliance in patients treated with these drugs.
• The discomfort can be controlled if the drug is taken with foods other than dairy products.

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EFFECTS ON CALCIFIED TISSUES

• Deposition in the bone and primary dentition occurs during calcification in growing children.
• This causes discoloration and hypoplasia of the teeth and temporary staunting of growth.

FATAL HEPATOTOXICITY

• This side effect has been known to occur in pregnant women who received high doses of TCNs, especially if they were experiencing pyelonephritis.

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PHOTOTOXICITY

• Phototoxicity, such as severe sunburn, occurs when a patient receiving a TCN is exposed to sun or ultraviolet rays.
• This toxicity is encountered most frequently with tetracyclines, doxycyclines and demeclocycline.

VESTIBULAR PROBLEMS

• These side effects e.g dizziness, nausea and vomiting occur particularly with minocycline

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with concentrates in the endolymp of the ear and affects function.

• Doxycycline may also cause vestibular effects.

PSEUDOTUMOR CEREBRI

• Benign, intracranial hypertension characterized by headache and blurred vision may occur rarely in adults.
• Although discontinuation of the drug reverses this condition.

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SUPERINFECTIONS

• Overgrowths of candida e.g in the vagina or resistant staphylococci (in the intestine) may occur.
• Pseudomembranous colitis due to an overgrowth of clostridium difficile has also been reported

CONTRAINDICATIONS

• Renally impaired patients should not be treated with any TCNs except doxycycline.

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• Accumulation of TCNs may aggravate preexisting azotemia(a higher than normal level of urea or other nitrogen containing compds in the blood) by interferring with protein synthesis, thus promoting amino acid degredation.
• The TCNs should not be employed in pregnant or breast feeding women or in children less than 8years of age.

1�GLYCYLCYCLINES

Tigecycline

• This is the first available member of a new class of antimicrobial agents called glycylcyclines.
• It is a derivative of minocycline and structurally similar to the TCNs and has a broad-spectrum activity against multi-resistant gram-positive pathogens, some gram-negative organisms and anaerobic organisms.

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• Tigecycline is indicated for treatment of complicated skin and soft tissue infections as well as complicated intra-abdominal infections.

Mechanism of action

• Tigecycline exhibits bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting protein translation.

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ANTIBACTERIAL SPECTRUM

• Tigecycline exhibits expanded broad spectrum activity that includes methicillin-resistant staphylococci, multidrug-resistant streptococcus pneumoniae and other susceptible strains of streptococcal species, vancomycin-resistant enterococci, extended-spectrum beta-lactamase producing gram-negative bacteria, Acinetobacter baumanii and many anaerobic organisms.

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• Tigecycline is not active against Proteus, Providencia and Pseudomonas species.

RESISTANCE

• Tigecycline was developed to overcome the recent emergence of tetracycline class-resistant organisms that utilize efflux and ribosomal protection to infer resistance.

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PHARMACOKINETICS

• Tigecycline is extensively distributed throughout plasma and body tissue.
• It does not undergo significant liver metabolism, but it is primarily eliminated via biliary/fecal excretion.
• No dose adjustment is necessary for patients who are renally impaired.
• Dose adjustment is needed in severe hepatic dysfunction. (available for parenteral use)

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ADVERSE EFFECTS

• Similar to those of TCNs.

DRUG INTERACTIONS

• Tigecycline is not metabolized by cytochrome P450 liver enzymes therefore it will not be affected by medications that induce or inhibit these enzymes.
• Tigecycline does not affect prothrombin time significantly, it has been found to inhibit

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the clearance of warfarin.

• Therefore, it is recommended that anticoagulation be monitored closely when tigecycline is coadministered with warfarin.
• However, another method of contraception is suggested when tigecycline and oral contraceptives are coadministered, because the oral contraceptives may become less effective.

1�AMINOGLYCOSIDES

• Aminoglycoside antibiotics had been the mainstays for treatment of serious infections due to aerobic gram-negative bacilli.
• Because their use is associated with serious toxicities, they have been replaced to some extent by safer antibiotics, such as the third and fourth generation cephalosporins, the fluoroquinolones and the carbapenims.

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• All members of this family are believed to inhibit bacterial protein synthesis.

MECHANISM OF ACTION

• Aminoglycosides diffuse through porin channels on the outer membranes of the microorganisms.
• With the aid of oxygen dependent transport system, the drug is carried to bind with 30S ribosomal subunit prior to ribosome formation.

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• There it interferes with assembly of the functional ribosomal apparatus and can cause the 30S subunit of the completed ribosome to misread the genetic code.
• Polysomes become depleted, because the aminoglycosides interrupt the process of polysome disaggregation and assembly.
• Aminoglycosides synergize with beta-lactam antibiotics because of the latter’s action on cell wall synthesis, which enhances diffusion

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Of the aminoglycosides into the bacterium.

ANTIBACTERIAL SPECTRUM

• Aminoglycosides are effective in the empirical treatment of infections suspected of being due to aerobic gram-negative bacilli, including Pseudomonas aeruginosa.
• For additive or synergistic effect, aminoglycisides are often combined with a beta- lactam antibiotic, or vancomycin or a drug active against anaerobic bacteria.

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• All aminoglycosides are bactericidal.
• The exact mechanism of their lethality is unknown because other other antibiotics that affect protein synthesis are generally bacteriostatic.
• The aminoglycosides are effective only against aerobic organisms because strict anaerobes lack the oxygen-requiring transport system.

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• Commonly used aminoglycosides incude, Amikacin, Gentamicin, Tobramycin, Streptomycin, Kanamycin, Neomycin.

RESISTANCE CAN BE CAUSED BY :

• Decreased uptake of drug when the oxygen-dependent transport system for aminoglycosides or purin channels are absent
• Plasmid- associated synthesis of enzymes e.g acetyl transferases, nucleotidyltransferases and phosphotransferases that modify and

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and inactivate aminoglycoside antibiotics.

• Each of these enzymes has its own aminoglycoside specificity, therefore cross resistance is not an invariable rule.
• Amikacin is less vulnerable to these enzymes than are the other antibiotics of this group.

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PHARMACOKINETICS

ADMINISTRATION.

• The highly polar, polycationic structure of the aminoglycosides prevent adequate absorption after oral administration.
• Therefore, all aminoglycosides except Neomycin must be given parenterally to achieve serum levels.

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• The severe nephrotoxicity associated with neomycin precludes parenteral administration and its current use is limited to topical application for skin infections, oral administration to prepare the bowel prior to surgery.

DISTRIBUTION

• All aminoglycosides have similar pharmacokinetic properties.

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• Levels achieved in most tissues are low, and penetration into most body fluids is variable.
• Concentrations in CSF are inadequate, even when the meninges are inflamed.
• Except for neomycin, the aminoglycosides may be administered intrathecally or intraventricularly.
• High concentrations accumulate in the renal cortex and in the endolymph and perilymph of the inner ear which may account for their

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• Nephrotoxic and ototoxic potential.
• All aminoglycosides cross the placental barrier and may accumulate in the fetal plasma and amniotic fluid.

FATE

• Metabolism of aminoglycosides does not occur in the host.
• All are rapidly excreted into the urine, predominantly by glomerular filtration.

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• Accumulation occurs in patients with renal failure and requires dose modification.

ADVERSE EFFECTS

OTOTOXICITY

• The antibiotic accumulates in the endolymph and perilymph of the inner ear, and toxicity correlates with the number of destroyed hair cells in the organ of corti.

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• Deafness may be irreversible and has been known to affect fetuses in utero.
• Patients simultaneously receiving another ototoxic drug, such as cisplatin or the loop diuretics, furosemide, bumetanide or ethacrynic acid, are particularly at risk.
• Vertigo and loss of balance especially in patients receiving streptomycin may also occur, because these drugs affect the vestibular apparatus.

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NEPHROTOXICITY

• Retention of the aminoglycosides by the proximal tubular cells disrupts calcium mediated transport processes, and this results in kidney damage ranging from mild, reversible renal impairment to severe, acute tubular necrosis, which can be irreversible.

NEUROMUSCULAR PARALYSIS

• This side effect most often occurs after direct

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Intraperitoneal or intrapleural application of large doses of aminoglycosides.

• The mechanism responsible is a decrease in both the release of acetylcholine from prejunctional nerve endings and the sensitivity of the postsynaptic site.
• Patients with myasthenia gravis are particularly at risk.
• Prompt administration of calcium gluconate or neostigmine can reverse the block.

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ALLERGIC REACTIONS

• Contact dermatitis is a common reaction to topically applied neomycin.

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1�CHLORAMPHENICOL

• Chloramphenicol is active against a wide range of gram-positive and gram-negative organisms.
• However because of its toxicity, its use is restricted to life-threatening infections for which no alternatives exist.

MECH OF ACTION.

• The drug binds to the bacterial 50S ribosomal subunit and inhibit protein synthesis at the peptidyltransferase reaction.

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• Because of the similarity of mammalian mitochondrial ribosomes to those of bacteria, protein synthesis in these organelles may be inhibited at high circulating chloramphenicol levels, producing bone marrow toxicity.

ANTIMICROBIAL SPECTRUM

• Chloramphenicol, a broad spectrum antibiotic, is active not only against bacteria but also against other organisms, such as rickettsiae.

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• Pseudomonas aeruginosa is not affected nor are the chlamydiae.
• Chloramphenicol has excellent activity against anerobes.
• The drug is either bactericidal or bacteriostatic, depending on the organism.

RESISTANCE

• Resistance is conferred by the presence of acetyl coenzyme A transferase.

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• This enzyme inactivates chloramphenicol.
• Another mechanism for resistance is associated with an inability of the antibiotic to penetrate the organism.
• This change in permeability may be the basis of multidrug resistance.

PHARMACOKINETICS

• CMN may be administered either intravenously or orally.

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• It is completely absorbed via the oral route because of its lipophilic nature, and is widely distributed throughout the body.
• It readily enters the normal CSF.
• The drug inhibits the hepatic mixed- function oxidases.
• Excretion of the drug depends on its conversion in the liver to glucuronide which is then secreted by the renal tubule.

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• CMN is also secreted into breast milk.

ADVERSE EFFECTS

The clinical use of CMN is limited to life-threatening infections because of the serious adverse effects associated with its administration.

In addition to gastrointestinal upsets, overgrowth of candida albicans may appear on mucous membranes.

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ANEMIAS

• Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate dehydrogynase.
• Other types of anemia occuring as a side effect of CMN include reversible anemia, which is apparently dose-related and occurs concomitantly with therapy and aplastic anemia which although rare is idiosyncratic and are usually fatal.

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• Aplastic anemia is independent of dose and may occur after therapy has ceased.

GRAY BABY SYNDROME

• This adverse effect occurs in neonates if the dosage regimen of CMN is not properly adjusted.
• Neonates have a low capacity to glucuronylate the antibiotic and they have underdeveloped renal function.

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• Therefore, neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes.
• This leads to poor feeding, depressed breathing, cardiovascular collapse, cyanosis(hence the term” gray baby”) and death.
• Adults who have received very high doses of the drug can also exhibit this toxicity.

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INTERACTIONS

• CMN is able to inhibit some of the hepatic mixed-function oxidases and thus blocks the metabolism of such drugs as warfarin, phenytoin, tolbutamide and chlorpropamide, thereby elevating their concentrations and potentiating their effects.