Protein synthesis Inhibitors

Dr. Hanaa Mohamed Khalaf

MINIA UNIVERSITY MINIA UNIVERSITY MINIA UNIVERSITY MINIA UNIVERSITY

Drug examples:

Tetracyclines, Aminoglycosides Chloramphenicol Macrolides Streptogramins.

All are bacteriostatic, except aminoglycosides bactericidal

Aminoglycosides

Aminoglycosides

Bactericidal by inhibiting bacterial protein synthesis

Only active against aerobes because an oxygen dependent system is

required to transport the molecules into the cell. Synergism with cell wall inhibitors is seen because they increase the

permeability of the cell.

Members:

Gentamicin Tobramycin

Amikacin Netilmicin

Kanamycin Streptomycin

Neomycin.

Mechanism of action

Aminoglycosides diffuse passively through aqueous channels (formed by porin proteins) in the outer membrane of gram-negative bacteria to enter the peri-plasmic space.

Transported actively (oxygen is required) across the

cytoplasmic membrane to reach cytoplasm.

Aminoglycosides inside the cell bind to 30S ribosomal subunit and interfere with protein synthesis by causing interference with the initiation of protein synthesis, misreading of the mRNA template and incorporation of incorrect amino acids in growing polypeptide chains.

Antimicrobial activity

Active against aerobic gram-negative bacteria Bacterial killing is concentration-dependent Have a post-antibiotic effect Toxicity is “time dependant” Duration of post antibiotic effect is concentration dependent. These properties probably account for the efficacy of once-daily dosing regimens of aminoglycosides.

Mechanisms of resistance

Impaired drug entry,uptake Alteration or deletion of binding sites Production of inactivating enzymes (transferase enzymes)

Pharmacokinetics Absorption Very poorly absorbed orally. Gentamicin oral absorption increased in case of ulcers or IBD. Intoxication occur when applied topically for long periods particularly if

there is renal insufficiency. Distribution Aminoglycosides do not penetrate into most cells negligible plasma albumin binding. Nephrotoxicity and ototoxicity (due to high concentrations in renal cortex

and inner ear) Elimination mainly unchanged in urine (ADJUSTE DOSE in renal impairment.!!!!)

Adverse effects

Dose dependant and time dependant Ototoxicity (only reversible. If noted early; increased with

concomitant use of loop diuretics vancomycin and cisplatin Nephrotoxicity (reversible) Neuromuscular blockade Peripheral neuritis Optic nerve dysfunction N.B. used with caution during pregnancy and only for strong clinical indications in the absence of suitable alternatives.

Clinical uses Treatment of infection caused by gram-negative enteric

bacteria. Used in combination with Beta-lactam antibiotic to extend the

spectrum as in endocarditis. They have synergestic effects. Streptomycin used in TB, brucellosis, plague, tularemia. Gentamycin and neomycin can be used topically in skin

infection. Neomycin can be used orally in GIT infection, preoperative,

hepatic coma.

Tetracyclines

Mechanism of action Enter bacterial cell by passive diffusion and active transport. Bind reversibly to 30S ribosomal subunit Inhibit binding of tRNA to its binding site, inhibit protein

synthesis Spectrum Bateriostatic broad spectrum against gram-positive and gram-

negative Resistance : Impaired influx or increased efflux ribosome protection due to production of proteins that interfere

with tetracycline binding and enzymatic inactivation

Members Short acting (t1/2 6-8 hr): oxytetracycline. Intermediate acting (t1/2 12 hr): demeclocycline. Long acting (t1/2 16-18 hr): doxycycline &

minocycline. Very long acting (t1/2 36 hr): tigecycline.

Pharmacokinetics: Absorption Good oral absorption (Doxycycline 95%, minocycline 100%) Distribution All tissues including CNS, placenta, milk, so, may affect the

development of tooth and bone in growing child. Elimination Both renal and hepatic except Doxycycline and tigecycline

which are eliminated by non-renal mechanisms, so both drugs can be used safely in renal impairment.

Drug interactions Pharmacokinetic interactions Absorption: Inhibited by dairy foods, calcium, Al and Fe Metabolism: Induced by (carbamazepine, phenytoin,

barbiturates, chronic alcohol) Pharmacodynamic interactions Antagonistic effect with bactericidal-Penicillin

Clinical uses: Drug of choice in infection caused by mycoplasma pneumoniae, chlamydiae, richettsiae, and some spirochetes. Rikettsial infections Mycoplasma infection Chlamydia infection: conjuctivitis, trachome, urethritis Brucellosis, cholera Eradication of nasopharyngeal meningococcal carrier state e.g.

by minocycline Tigecycline (i.v. only) for treatment of skin and intra-

abdominal infections.

Adverse effects:

GIT: the most common adverse effect

Bone and teeth: discoloration, abnormal growth (not used in

young children and pregnant or nursing mother).

Liver: increase liver enzymes and fatal hepatotoxicity

Hypersensitivity

Others as renal necrosis, phlebitis, photosensitivity, tinnitus,

vertigo

Chloramphenicol

Mechanism of Action Penetrates bacterial cells, probably by facilitated diffusion. Binding reversibly to the 50S ribosomal subunit (near the

binding site for the macrolide antibiotics and clindamycin, so they are competitive inhibitors to each other).

Prevents binding of the amino acid to the acceptor site on the 50S ribosomal subunit, and peptide bond formation is inhibited.

Chloramphenicol also can inhibit mitochondr ial protein synthesis in mammalian cells (high doses)

Antimicrobial Actions a broad spectrum of antimicrobial activity against aerobic and

anaerobic gram positive and gram negative organisms. Chloramphenicol is bacteriostatic against most species,

although it may be bactericidal against H. influenzae, Neisseria meningitidis, and S. pneumoniae.

Resistance Inactivating enzymes (acetyltransferase) Decreased permeability of bacterial membrane. Mutation in binding site (Ribosomal mutation).

Pharmacokinetics Absorption: rapid oral absorption Distibution: widely distributed in the body, including CNS,

bile, milk, and placental fluid. About 50% is bound to plasma proteins; such binding is reduced in cirrhotic patients and in neonates (Dose adjustment).

Metabolism: Hepatic metabolism to the inactive glucuronide. (Dose adjustment).

Elimination: metabolites are excreted in urine (only 10% excreted unchanged).

Significant variability in the metabolism and excretion of chloramphenicol in neonates, infants, and children necessitates monitoring of plasma drug concentrations

Therapeutic uses: Chloramphenicol is only used for treatment of life-

threatening infections (e.g., meningitis, rickettsial infections) in patients who cannot take safer alternatives.

Typhoid fever (replaced by third generation cephalosporins and quinolons)

Bacterial meningitis (replaced by third generation cephalosporins)

Rickettsial Diseases (tetracyclins is preferred) Anaerobic or mixed infection

Used topically in eye infection

Adverse effects: 1) Hematological: Dose-related toxicity Idiosyncratic response 2) Gray baby syndrome (Neonate or premature baby) Due to: Insufficient metabolizing enzymes In adequate renal excretion 3) GIT: Nausea and vomiting, unpleasant taste, diarrhea, 4) Hypersensitivity 5) Others …blurring of vision and digital paresthesias.

Drug Interactions Chloramphenicol inhibits hepatic cytochrome P450 isozymes prolongs half-lives of drugs (warfarin, dicumarol), oral hypoglycemic (tolbutamide, chlorpropamide), CNS drugs (phenytoin) and antiretroviral protease inhibitors (rifabutin).

Other drugs may alter the elimination of chloramphenicol. Concurrent administration of phenobarbital or rifampin, which potently induces CYPs, shortens the half-life of the antibiotic and may result in sub-therapeutic drug concentrations.

Macrolides

Mechanism of Action Bacteriostatic agents (bactericidal to some species in high

concentrations) inhibit protein synthesis by binding to 50S ribosomal subunits, leading to inhibition of protein synthesis.

Antimicrobial activity Mainly against gram positive organisms, in addition to

Mycoplasma, legionella, Chlamydia trachomatis. Resistance due to: Reduced permeability or drug efflux Enzymes modify ribosomal target decreasing binding Hydrolysis by hydrolyzing enzymes Cross-resistance between macrolide and compounds with

similar mechanism of action such as Clindamycin and Streptogamins

Members:

Erythromycin

Azithromycin

Clarithromycin

Spiramycin

Roxithromycin

Erythromycin Pharmacokinetics Absorption: incompletely but adequately absorbed from upper small intestine (inactivated by gastric acid,administered as enteric-coated ) . Distribution: Distributed widely except to the CNS. Elimination: Excreted in an active form in the bile and lost in feces. Hepatic biliary disease affects its elimination. Partial reabsorption occurs through the enterohepatic

circulation and inactive metabolites are excreted into urine. Only 5% is excreted in the active form in the kidney (dose

adjustment is not necessary for renal failure).

Clinical uses Corynbacterial infections Chlamydial infections Pertussis. Erythromycin is the drug of choice Mycoplasma pneumoniae infection It is used as an alternative to in penicillin-allergic individual Adverse Reactions GIT: (acts as motilin receptor agonist);most common reason

for discontinuing oral erythromycin Liver Toxicity: Cholestatic hepatitis Others: Hypersensitivity reactions; and transient auditory

impairment after large parenteral doses.

Drug interaction Enzyme inhibitor: Erythromycin metabolites can inhibit

cytochrome P 450 enzymes and thus increase the serum concentration of Theophylline, oral anticoagulants, cyclosporine & Methylprednisolone

Erythromycin increases serum concentration of oral digoxin by

increasing its bioavailability

Clarithromycin as erythromycin except: Antibacterial activity: More active against Mycobacterium

avium, active against M leprae and toxoplasma gondii Pharmacokinetics: Acid stability and oral absorption

increased by food. Eliminated by renal and non-renal routes (20 -40% excreted unchanged) and dose adjustment is required in renal impairment.

Adverse effects: Less frequent GIT adverse Clinical uses: Alternative to erythromycin.

Azithromycin unique pharmacokinetic: extensive tissue distribution and high

drug concentrations within cells concentrations in tissue or secretions

Biliary excretion is the major route of elimination. Elimination half-life, 40 to 68 hr, extensive tissue

sequestration and binding administered once daily for short time.

No drug interaction as of erythromycin and clarithromycin It is used in combination with amoxicillin and proton pump

inhibitors in treatment of Helicobacter pylori associated with peptic ulcer.

Clindamycin

Clinical uses anaerobic infection caused especially by B. fragilis Used in combination with aminoglycosides in treatment of

intraabdominal infection Used in combination with pyrimethamine in treatment of some

infections affecting AIDS-patients (e.g toxoplasmosis). Adverse reactions 1- GIT: Diarrhea, Psudomembraneous colitis 2- Skin rashes rarely Steven-Johnson syndrome 3- Cholestatic hepatitis

Streptogramins

Quinupristin-Dalfopristin (30:70) (Synercid)

Mechanism of Action Quinupristin and dalfopristin are protein synthesis inhibitors that bind

the 50S ribosomal subunit at two different sites and act synergistically as bactericidal

Antibacterial Activity Act on gram-positive cocci Active against organisms responsible for atypical pneumonia, M.

pneumoniae, Legionella spp., and Chlamydia pneumoniae.

Pharmacokinetics Quinupristin/dalfopristin is administered only by intravenous infusion over

at least 1 hour Hepatic metabolism by conjugation is the principal means of clearance for

both compounds, with 80% of an administered dose eliminated by biliary excretion. Dose adjustment is reguired in hepatic patients.

Therapeutic Uses 1- Treatment of vancomycin-resistant strains of Enterococcus faecium but not E. facecalis, which is intrinsically resistant probably because of an efflux-type resistant mechanism. 2- Treatment of infections caused by methicillin-susceptible and resistant strains of S. aureus or S. pyogenes. Side Effects The most common side effects are infusion-related events, such as pain

and phlebitis at the infusion site and arthralgias and myalgias

Linezolid

Mechanism of Action It binds to unique binding site, P site located on 23 ribosomal subunit of 50S

ribosomal subunit, resulting in prevention of ribosome complex that initiates protein synthesis.

Antibacterial Activity Linezolid is active against gram-positive organisms. It is also active against

strains that are resistant to other antibiotics [e.g. penicillin-resistant strains of S. pneumoniae; methicillin-resistant organisms, and vancomycin-resistant strains of enterococci].

Therapeutic Uses (it should be reserved for treatment of infection caused by multidrug-resistant gram positive bacteria) Adverse reactions Blood: Thrombocytopenia (the most common, 3%), anemia, leucopenia,

pancytopenia. Others side effects: Gastrointestinal complaints, headache, rash.

Tuberculosis (TB) Chemotherapy

TB is caused by infection with Mycobacterium tuberculosis, M. bovis and M africanum.

It is the number one cause of death from infectious disease worldwide. Multidrug-resistant TB is a growing problem in many parts of the world. Drugs used in treatment of TB include: First line drugs (more effective and less toxic): 1- Isoniazide (INH) 2- Rifampin 3- Ethambutol 4- Pyrazinamide 5- Streptomycin

Second line drugs

Aminosalicylic acid (GIT irritation, hypersensitivity)

Ethionamide (gastric irritation, neurological and hepatological toxicities)

Capreomycin (ototoxicity and nephrotoxicity)

Cycloserine (CNS toxicity)

Others (ciprofloxacin, amikacin)

Note: Second line drugs (used only in case of resistance to first line drugs because they are less effective and more toxic).

Isoniazid Isoniazid is bacteriostatic for "resting" bacilli, but is bactericidal for rapidly

dividing microorganisms. Mechanism of action Inhibit the biosynthesis of mycolic acids that form part of the

mycobacterial cell wall. Mycolic acids are unique to mycobacteria, explaining the high degree of

selectivity of the antimicrobial activity of isoniazid. Pharmacokinetics Absorption Readily absorbed either orally or parenterally. Ditribution Diffuses readily into all body fluids and cells Elimination It is metabolized in the liver by acetylation and hydrolysis.

Isoniazid Therapeutic Uses

Isoniazid is still the most important drug worldwide for the treatment of all types of tuberculosis in combination with other drugs (should never used alone).

Prophylaxis of TB (can be used alone) Adverse effects Hepatitis Neurological effects (peripheral neuritis due to pyridoxine deficiency,

convulsions, psychotic disorders) Agranulocytosis, eosinophilia, thrombocytopenia, anemia). Drug interaction Isoniazide can reduce the metabolism of phenytoin increasing its blood level and toxicity.

Rifampin Mechanism of action: It is bactericidal broad spectrum antibiotic acting by inhibition of RNA synthesis in bacteria by inhibiting RNA-polymerase. Adverse effects: The most common are rash , fever and nausea and vomiting Drug interaction Rifampin potently induces some CYP450 enzymes Therapeutic uses Treatment of TB in combination with other drugs Chemoprophylaxis in meningococcal meningitis Some cases of Staph. Infections.

Ethambutol It is a bacteriostatic agent acting by exactly unknown mechanism but may

be through inhibition of myocolic acid incorporation into cell wall of the mycobacteria.

Adverse effects Optic neuritis: dose dependant; reversible and manifested by decreased

color perception, reduced visual acuity. Hyperuricemia: due to decreased renal excretion of uric acid Others (GIT upset, headache, hallucination) Ethambutol is not recommended for children under 5 years of age