Mechanism of Protein synthesis

Formation of the Initiation Complex

Joining of 50S Ribosomal Subunit

Protein Elongation

Termination of Translation

Aminoglycoside

Aminoglycosides

• Streptomycin – 1944• Actinomycetes – Streptomyces griseus• Bactericidal antibiotics• Interfere with protein synthesis• Used to treat aerobic Gram –ve bacteria • Resemble each other in MOA, pharmacokinetic

therapeutic and toxic properties• Relatively low margin of safety • Exhibit ototoxicity and nephrotoxicity

Aminoglycosides

• Systemic– Streptomycin– Gentamicin– Kanamycin – Amikacin– Sisomicin – Tobramycin– Netilimicin

• Topical – Neomycin – Framycetin

Mechanism of action

• Initially they penetrate bacterial cell wall, to reach periplasmic space through porin channels (passive diffusion)

• Further transport across cytoplasmic membrane takes place by active transport by proton pump; an oxygen-dependent process

Mechanism of Action

• Bind 30S ribosomal subunits and interfere the initiation complex

• Induce misreading of genetic code on mRNA

• Breakup of polysomes into monosomes

Post antibiotic effect

• Aminoglycosides exhibit concentration dependent killing.

• They also possess significant Post-antibiotic effect.

• Single daily dosing at least as effective as and no more toxic than multiple dosing.

Mechanism of resistance

• Synthesis of plasmid mediated bacterial transferase enzyme: Inactivate aminoglycosides

• ↓ transport into bacterial cytosol • Deletion/alteration of receptor protein on 30 S

ribosomal unit by mutation: prevents attachment

Antibacterial spectrum

• Primarily against Gm –ve aerobic bacilli – Proteus, pseudomonas – E.Coli,enterobacter – Klebsiella– Shigella

• Only few Gm +ve cocci: – staph aureus, strepto viridans

• Not effective against Gm +ve bacilli, Gm-ve cocci and anaerobes

Pharmacokinetics

• Highly polar basic drugs: poor oral BA• Administered parenterally or applied locally • Poorly distributed and poorly protein bound• Do not undergo any significant metabolism• Nearly all IV dose is excreted unchanged in

urine • Dose adjustment is needed in renal

insufficiency

Pharmacokinetics

Clinical uses • Gram –ve bacillary infection

– Septicaemia, pelvic & abdominal sepsis• Bacterial endocarditis –

– enterococcal, streptococcal or staphylococcal infection of heart valves

• Pneumonias, Tuberculosis• Tularemia• Plague, Brucellosis• Topical – Neomycin, Framycetin.• Infections of conjunctiva or external ear• To sterilize the bowel of patients who receive

immunosuppressive therapy, before surgery & in hepatic coma

Shared toxicities

• Ototoxicity – Vestibular damage – Cochlear damage

• Nephrotoxicity • Neuromuscular blockade• Skin rash

Ototoxicity

• Impairment of VIII cranial nerve function• May be irreversible • Cochlear damage

– Hearing loss and tinnitus – More with neomycin , amikacin and kanamycin

• Vestibular damage– Vertigo, ataxia, loss of balance – More with Streptomycin, gentamycin

• Tobramycin has both types of toxicity • Netilimycin claimed to have low ototoxicity

Nephrotoxicity

• Gentamicin, amikacin and tobramycin are more toxic than streptomycin

• Responsible for 10-15% of all renal failure cases

• Reversible if drug promptly discontinued • ↓ GFR, ↑ sr creatinine • ↓clearance of antibiotic → ↑ ototoxicity

Neuromuscular blockade

• Cause N-M junction blockade by – Displacing Ca2+ from NM junction– By blocking post synaptic NM receptors– Inhibiting Ach release from motor nerve

• Neomycin & streptomycin: more propensity• Tobramycin least likely to produce it• Myasthenic weakness ↑by these drugs

Streptomycin

• Ribosomal resistance develops fast• Limited usefulness as single agent • Plague, tularemia and brucellosis

– In combination with tetracycline • SABE: due to Streptococcus Viridans & faecalis

– With penicillin but gentamicin preferred • Reserve first line drug for tuberculosis used

only in combination

Chloramphenicol

• An antibiotic produced by Streptomyces venezuelae, an organism first isolated in 1947 from a soil sample collected in Venezuela.

Mechanism of Action

• Chloramphenicol inhibits protein synthesis in bacteria and, to a lesser extent, in eukaryotic cells. The drug readily penetrates bacterial cells, probably by facilitated diffusion.

• Chloramphenicol acts primarily by binding reversibly to the 50 S ribosomal subunit. Although binding of tRNA at the codon recognition site on the 30 S ribosomal subunit is thus undisturbed, the drug appears to prevent the binding of the amino-acid-containing end of the aminoacyl tRNA to the acceptor site on the 50 S ribosomal subunit. The interaction between peptidyltransferase and its amino acid substrate cannot occur, and peptide bond formation is inhibited

• Chloramphenicol also can inhibit mitochondrial protein synthesis in mammalian cells, perhaps because mitochondrial ribosomes resemble bacterial ribosomes (both are 70 S) more than they do the 80 S cytoplasmic ribosomes of mammalian cells.

Pharmacokinetics:

• Chloramphenicol is available for oral administration in two forms: the active drug itself and the inactive prodrug, chloramphenicol palmitate (which is used to prepare an oral suspension).

• Hydrolysis of the ester bond of chloramphenicol palmitate is accomplished rapidly and almost completely by pancreatic lipases in the duodenum under normal physiologic conditions.

Absorption

• Chloramphenicol then is absorbed from the gastrointestinal tract

• peak concentrations of 10 to 13 g/ml occur within 2 to 3 hours after the administration of a 1-g dose.

• In patients with gastrointestinal disease or in newborns, the bioavailability is greater for chloramphenicol than for chloramphenicol palmitate, probably because of the incomplete hydrolysis of the latter

Absorption cont.

• The hydrolysis of chloramphenicol succinate may be due to esterases of the liver, kidneys, and lungs.

Absorption cont.

• Chloramphenicol succinate itself is rapidly cleared from plasma by the kidneys.

• This renal clearance of the prodrug may affect the overall bioavailability of chloramphenicol, because up to 20% to 30% of the dose may be excreted prior to hydrolysis.

• Poor renal function in the neonate and other states of renal insufficiency result in increased plasma concentrations of chloramphenicol succinate

Distribution

• Chloramphenicol is well distributed in all body fluids and readily reaches therapeutic concentrations in CSF, where values are approximately 60% of those in plasma (range, 45% to 99%).

• Chloramphenicol is present in bile, is secreted into milk, and readily traverses the placental barrier. It also penetrates into the aqueous humor after subconjunctival injection.

Fate and Excretion• The half-life of chloramphenicol has been correlated

with plasma bilirubin concentrations. • About 50% of chloramphenicol is bound to plasma

proteins. • The half-life of the active drug (4 hours) is not

significantly changed in patients with renal failure• The major route of elimination of chloramphenicol is

hepatic metabolism to the inactive glucuronide. • Over a 24-hour period, 75% to 90% of an orally

administered dose is excreted; about 5% to 10% is in the biologically active form.

Adverse effects cont. Hematologic Toxicity

• The most important adverse effect of chloramphenicol is on the bone marrow.

• Chloramphenicol affects the hematopoietic system aplastic anemia, fatal pancytopenia,

• Leukopenia , thrombocytopenia.

Reversible bone marrow suppression

• A second, and dose-related, toxic hematologic effect of chloramphenicol is a common and predictable (but reversible) erythroid suppression of the bone marrow.

• probably due to inhibitory action of the drug on mitochondrial protein synthesis.

• It occurs regularly when plasma concentrations are 25 g/ml or higher and is observed with the use of large doses of chloramphenicol, prolonged treatment, or both.

Gray baby syndrome

• Fatal chloramphenicol toxicity may develop in neonates, especially premature babies, when they are exposed to excessive doses of the drug.

• The manifestations in the first 24 hours are vomiting, refusal to suck, irregular and rapid respiration, abdominal distention, periods of cyanosis, and passage of loose, green stools. Soon they become flaccid, turn an ashen-gray color, and become hypothermic

Hypersensitivity Reactions

• Although relatively uncommon, macular or vesicular skin rashes occur as a result of hypersensitivity to chloramphenicol.

• Angioedema is a rare complication. Jarisch-Herxheimer reactions have been observed shortly after institution of chloramphenicol therapy for syphilis, brucellosis, and typhoid fever.

Therapeutic Uses

• Chloramphenicol has a wide range activity that includes gram+, gram-, aerobic and anaerobic bacteria

• Typhoid Fever• Bacterial Meningitis• Anaerobic Infections• Rickettsial Diseases• Brucellosis

Tetracycline

CONTENTS

• Introduction• Classification and there structures• Mechanism of action• Structure Activity Relationship• Spectrum of activity• Toxicity and uses

INTRODUCTION

• Tetracyclines is a group of antibotic that include tetracycline.

• Tetracyclines are obtained by fermentation from Streptomyces spp. Or by chemical transformation of natural products.

• They are derivatives of an octahydro- naphthacene,a hydrocarbon system that comprises four annulated six member rings.

CLASSIFICATION

TETRACYCLINES

SHORT ACTING:•Tetracycline

•Oxytetracycline

INTERMEDIATE ACTING:

•Demeclocycline•Lymecycline

LONG ACTING:•Doxycycline•Minocycline

Mechanism of Action

• Tetracyclines are specific inhibitors of bacterial protein synthesis. They bind to the 30S ribosomal subunit and thereby prevent the binding of aminoacyl tRNA to the mRNA ribosome complex.

• Tetracyclines also inhibit protein synthesis in the host ,but are less likely to reach the concentration required because eukaryotic cells do not have a tetracycline uptake mechanism.

Spectrum of activity

• Tetracyclines are broad spectrum antibiotics, active against wide range of Gram-positive and Gram-negative bacteria, spirochetes, mycoplasm, rickettsiae, and chalmydiae.

Toxicity of tetracycline• Use of this medication for prolonged or repeated

periods may result in oral thrush or a new yeast infection (oral or vaginal fungal infection).

• Nausea, vomiting, diarrhea, loss of appetite, mouth sores, black hairy tongue, sore throat, dizziness, headache, or rectal discomfort may occur.

• This antibiotic treats only bacterial infections. It will not work for viral infections (e.g.,common cold, flu). Unnecessary use or overuse of any antibiotic can lead to its decreased effectiveness.

Uses of tetracycline

• Tetracycline is used to treat a wide variety of infections, including acne. It is an antibiotic that works by stopping the growth of bacteria.– Used in treatment of infections like septicemia,

endocarditis , meningitis.

Macrolides

• Belong to the Polypetide class of natural Belong to the Polypetide class of natural products.products.

• A group of antibiotics consisting of a A group of antibiotics consisting of a macrolide macrolide ringring

• A large lactone ring to which one or more deoxy sugars, A large lactone ring to which one or more deoxy sugars, are attached.are attached.

• The lactone ring can be either 14, 15 or 16 memberedThe lactone ring can be either 14, 15 or 16 membered.

• Naturally-occurring macrolide derived from Naturally-occurring macrolide derived from Streptomyces erythreusStreptomyces erythreus

• Problems with erythromycinProblems with erythromycin• Acid labileAcid labile• Narrow spectrumNarrow spectrum• Poor GI tolerance Poor GI tolerance • Short elimination half-lifeShort elimination half-life

Structural derivatives

Clarithromycin and AzithromycinClarithromycin and Azithromycin• Broader spectrum of activityBroader spectrum of activity• Improved PK properties – Improved PK properties –

» Better bioavailabilityBetter bioavailability» Better tissue penetrationBetter tissue penetration» Prolonged half-livesProlonged half-lives

• Improved tolerabilityImproved tolerability

• Inhibits protein synthesis by reversibly binding to Inhibits protein synthesis by reversibly binding to the the 50S50S ribosomal subunit ribosomal subunit

– Suppression of RNA-dependent protein synthesis Suppression of RNA-dependent protein synthesis by by inhibition of translocation of mRNAinhibition of translocation of mRNA

• Typically Typically bacteriostaticbacteriostatic activity activity• BactericidalBactericidal at high concentrations against very at high concentrations against very

susceptible organismssusceptible organisms

Gram-Positive AerobesGram-Positive Aerobes : : Erythromycin & clarithromycin display the best activity Erythromycin & clarithromycin display the best activity

(Clarithro>Erythro>Azithro)(Clarithro>Erythro>Azithro)• Methicillin-susceptible Methicillin-susceptible Staphylococcus aureusStaphylococcus aureus• Streptococcus pneumoniae Streptococcus pneumoniae –resistance is developing–resistance is developing• Group and viridans streptococciGroup and viridans streptococci• Bacillus spBacillus sp.. • Corynebacterium sp.Corynebacterium sp.

Gram-Negative AerobesGram-Negative Aerobes – Newer macrolides with – Newer macrolides with enhanced activity enhanced activity (Azithro>Clarithro>Erythro)(Azithro>Clarithro>Erythro)

• H. influenzae (not erythro), H. influenzae (not erythro), • M. catarrhalis, M. catarrhalis, • Neisseria sp.Neisseria sp.• Do NOT have activity against any Do NOT have activity against any EnterobacteriaceaeEnterobacteriaceae

Macrolide Spectrum of Activity

AnaerobesAnaerobes – Upper airway anaerobes – Upper airway anaerobesAtypical BacteriaAtypical Bacteria – All have excellent activity – All have excellent activity

• Legionella pneumophila - DOCLegionella pneumophila - DOC• Chlamydia sp.Chlamydia sp.• Mycoplasma sp.Mycoplasma sp.• Ureaplasma Ureaplasma

Macrolide Spectrum of Activity

Other Bacteria –• Mycobacterium aviumMycobacterium avium complex complex

(MAC – only A and C), (MAC – only A and C), • Treponema pallidum, Treponema pallidum, • CampylobacterCampylobacter• Borrelia, BordetellaBorrelia, Bordetella• BrucellaBrucella• PasteurellaPasteurella

AbsorptionAbsorptionErythromycinErythromycin – variable absorption, food may – variable absorption, food may

decrease the absorption decrease the absorption – Base: destroyed by gastric acid; enteric coatedBase: destroyed by gastric acid; enteric coated– Esters and ester salts: more acid stableEsters and ester salts: more acid stable

ClarithromycinClarithromycin – acid stable and well-absorbed – acid stable and well-absorbed regardless of presence of foodregardless of presence of food

AzithromycinAzithromycin –acid stable; food decreases absorption –acid stable; food decreases absorption of capsulesof capsules

DistributionDistribution Extensive tissue and cellular distributionExtensive tissue and cellular distribution

clarithromycin and azithromycin with clarithromycin and azithromycin with extensiveextensive penetration penetration

Minimal CSF penetration Minimal CSF penetration

– Gastrointestinal – up to 33 %Nausea, vomiting, diarrhea, dyspepsiaGastic pain, crampsMost common with erythro; less with new agents

– Cholestatic hepatitis - rare > 1 to 2 weeks of erythromycin estolate

– Thrombophlebitis – IV Erythro and AzithroDilution of dose; slow administration

– Other: Ototoxicity (high dose erythro ); QTc prolongation; Allergy

Erythromycin and Clarithromycin ONLY– are inhibitors of cytochrome p450 system in the liver; may increase concentrations of:

Theophylline Digoxin, DisopyramideCarbamazepine Valproic acidCyclosporine Terfenadine, AstemizolePhenytoin CisaprideWarfarin Ergot alkaloids

• ENT infections , Tonsillitis, URTIENT infections , Tonsillitis, URTI• Mycoplasma pneumonie infectionsMycoplasma pneumonie infections• Legionnaires DiseaseLegionnaires Disease• Chlamydial infections (any macrolides)Chlamydial infections (any macrolides)• Diphtheria (erythromycin)Diphtheria (erythromycin)• Pertussis (erythromycin)Pertussis (erythromycin)

• Strep/Staph Infections; alternatives in patients Strep/Staph Infections; alternatives in patients allergic to Penicillinallergic to Penicillin

• Prophylaxis against endocarditis in dental Prophylaxis against endocarditis in dental proceduresprocedures

• Campylobacter/ Helicobacter Infections :Campylobacter/ Helicobacter Infections :clarithroclarithro• Tetanus: in patients allergic to PenicillinTetanus: in patients allergic to Penicillin• Mycobacterial Infections: Mycobacterial Infections: Clathri / Azithro Clathri / Azithro Ist choice Ist choice

“Drug of Choice” for Mycoplasma pneumoniaeLegionella pneumophila Chlamydia pneumoniae, C. trachomatisBordetella pertussis (whooping cough)C. diphtheriae

Esters of erythromycinEsters of erythromycin -sterate/estolate/ethylsuccinate are resistant to inactivation.