Tet Pharm

DR. M. OWAIS ISMAIL DEPARTMENT OF PHARMACOLOGY & THERAPEUTICS

ZIAUDDIN UNIVERSITY

ANTIMCROBIALS Protein Synthesis inhibitors in Bacteria Target is bacterial ribosome Attached to 30s or 50s unit Interferes with translation Bacteriostatic except aminoglycosides

PROTEIN SYNTHESIS

PROTEIN SYNTHESIS

Protein Synthesis

√ Blockade of initiation.

√ Blockade of further Translation √ Incorporation of incorrect amino acids

Inhibitors of Protein Synthesis in Bacteria Aminoglycosides (30S) Tetracyclines (30S) Chloramphenicol Macrolides Clindamycin Streptogramins

(50S) (50S) (50S) (50S)

ANTIMCROBIALS Protein Synthesis inhibitors in Bacteria

Target is bacterial ribosome Attached to 30s unit Interferes with translation Bacteriostatic

antibiotics with similar structure and activity. 1948, Chlortetracycline ------ Streptomyces aureofasciens 1950 Oxytetracycline ----------- Stretomyceus rimosus. Chlortetracycline is Dehalogenated to give Tetracycline Demethylated to give demeclocycline. OTHER SYNTHETIC TETRACYCLINES Doxycycline, Minocycline Methacyclines.

CLASS. Short acting. Chlortetracycline Tetracycline, Oxytetracycline Intermediate acting Demeclocycline, Methacycline Long Acting Doxycycline, Minocycline

Half life

6-8 hrs

12 hrs

16-18 hrs

MOA Bind to 30s ribosomal subunit, blocking binding of aminoacyl tRNA to the acceptor site Addition of amino acids to the growing peptide is prevented.

Properties Bacteriostatic Crystalline amphoteric Low water solubility Transport passive diffusion Oxygen dependent process

RESISTANCE Natural Transport system crucial Oxygen dependent Induced Acquired resistance Plasmid borne  I/C concentration due to  influx or ↑ efflux. Enzymatic inactivation Impaired entry Alteration in the porins proteins production interfere with the binding of drugs to target site.

PK profile ORAL ABSORPTION. A portion remains in the gut modifying the gut flora.

Absorption is impaired by

Chlortetracycline

Tetracycline, Oxy, 60-70% Demeclocycline and Methacycline 95Doxycycline 100% Minocycline

-Food, - Dairy products and Antacids -Divalent ions Ca++, Mg++, Fe++ and Al+++. -Alkaline pH.

30%

PK profile Protein binding is 40-80% Distributed to all tissues and body fluids except CSF Cross placenta and excreted in Milk Minocycline secreted in saliva and tears. Excreted in Bile (Recycled) and Urine 10-50%. Upto 40% excreted in feces. Doxycyline is not renally eliminated. No dosage adjustment is necessary in renal failure.

Narrow MARGIN OF SAFETY Effects Bones and teeth Liver Kidney Ear

Not used as first line drug usually

SPECTRUM Broad spectrum bacteriostatic g +ve, g-ve Mycoplasma, Chlymidiae, Ricketsia. Helicobacter Pylori. Vibrio cholera. Brucella Entamoeba, Plasmodium falciparum.

THERAPEUTIC USES Infections commonly indicated Skin and soft tissue (Acne, wound infections), GIT (AGE) RTI (Pneumonia) UTI Non tuberculous M.B infections STD Plague, Tuleremia 

Malaria Amebiasis

ADVERSE REACTIONS (NUMEROUS) HYPERSENSITY REACTIONS. G.I.T.  NVD,  Modify flora: anal pruritis, candidiases,  Pseudomembranous enteroclitis with shock and death  Discolor teeth in children,  Phototoxicity,  Vestibular toxicity (minocycline)  Renal toxicity  Hepatic toxicity

MACROLIDES Target is bacterial ribosome Attached to 50s unit Interferes with translation Bacteriostatic usually Bactericidal at high conc.

Erythromycin Clarithromycin Ezithromycin Roxithromycin Telithromycin (ketolide)

Clarithro and Ezithro are synthetic derivative of Erythromycin

MACROLIDES So named because they contain a many-membered lactone ring to which are attached one or more deoxy sugars

MOA Bind to 50s ribosomal subunit, blocking transfer of amino acid from incoming charged tRNA to the acceptor site

inhibiting translocation of peptidyltRNA Block of initiation complex

Properties Bacteriostatic, Have lactone ring Poor water solubility More active in alkaline pH good absorbed from small intestine; well distribute to body tissues poor penetration in CNS can cross the placenta Destroyed by gastric acid

First-pass metabolism reduces bioavailability Drug food interactions Food delays absorption. Oral and IV small amount excreted in urine Ezithromycin better absorption on empty stomach

RESISTANCE • Reduced cellular permeability or enhancement of efflux 2. Production of enzymes that hydrolyze macrolides (Estrases) Enterobacteriaceae 3. Change in ribosomal binding site properties.

PK profile ABSORPTION

small intestine;

Inactivated by gastric acids Food delays absorption. Oral or I/V. Clarithromycin is absorbed rapidly from the GIT First-pass metabolism reduces bioavailability to 50% - 55%. Distributes widely to body tissues, except CSF.

PK profile Distributes widely to all tissues, except CSF and ear Significant concentrations in breast milk(50% of serum). Cross the placental barrier, ( 5% to 20%). Protein binding is approximately 70% to 90%.

ELIMINATION. ORAL: 2% to 5% excreted in active form in the urine; I/V : 12% to 15% _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Concentrated in the liver and appears in active form in bile. The plasma elimination half-life of erythromycin is 1.6 hours Clarithromycin also is eliminated by renal and nonrenal mechanisms, metabolized in the liver to several metabolites, the 14-hydroxy metabolite being the most significant because of the amount produced and its important biological activity. The exact biodisposition of azithromycin still is under study.

EXCRETION Erythromycin Hepatic metabolism (CYP3A) Some biliary secretion Azithromycin Feces as unchanged drug Prolonged half-life (68 hrs) Given for only 5 days Clarithromycin Unchanged in urine (30%) and feces

SPECTRUM USES:

&

CLINICAL

Mycoplasma pneumoniae. Legionnaires' Disease. Chlamydia Infections Diphtheria. Pertussis. Streptococcal Infections. Staphylococcal Infections. Campylobacter Infections. Tetanus. Syphilis. Gonorrhea. Atypical Mycobacterial Infections. Toxoplasmosis H. pylori infection

G +ve G -ve

UNTOWARD EFFECTS. 1.ALLERGIC REACTIONS Fever, Eosinophilia, Skin eruptions, Cholestatic hepatitis (hypersensitivity to estolate) 2.G.I.T Epigastric distress Abdominal cramps, Nausea, vomiting, and diarrhea. 3. Intravenous infusion may result on thrombophlebitis 4. C.V.S: Cardiac arrythmias, 5.Transient auditory impairment.

DRUG INTERACTIONS. Inhibits cytochrome P450-mediated metabolism Potentiates the effect of following drugs ASTEMIZOLE, CARBAMAZAPINE, CORTICOSTEROIDS, CYCLOSPORINE, DIGOXIN, ERGOT ALKALOIDS, TERFENADINE, THEOPHYLLINE, TRIAZOLAM, VALPROATE, WARFARIN,

Rx Erythromycin 500 mg * PO * TID ( 5 days) Simvaststin 10 mg * PO * OD

Rx Clarithromycin 250 mg * PO * BID ( 7 days) Theophylline 225 mg * PO * OD

ANTIMCROBIALS Protein Synthesis inhibitors in Bacteria

Target is bacterial ribosome Attached to 50s unit Interferes with translation Bacteriostatic

MOA (same as erythro) Bind to 50s ribosomal subunit, blocking transfer of amino acid from incoming charged tRNA to the acceptor site Block of initiation complex

Chlorine substitutive derivative of licomycin Obtained from streptomyces Lincomycin--- toxic --- no longer used

RESISTANCE Mutation of ribosomal receptor site Enzymatic inactivation Altered structure of ribosome

PK profile Dose = 10 - 20mg/kg/d 90% protein bound ½ life = 2.5 hrs Widely distributed to all body tissues given oral or IV Less absorption from GIT Dosage = TID Level achieved in most tissues are high Metabolized in liver Accumulated in liver and kidney excreted via urine and bile Can cross placenta

SPECTRUM BROAD SPECTRUM BACTERIOSTATIC AEORBIC AND ANAEROBIC ORGANISMS Strepto Staph Enterococci Bacteroide fragilis Cl. defficile

ADVERSE EFFECTS NVD Skin rash Nephrotoxicity Hepatotoxicity Neutropenia Psoudomembranous colitis