Pharmacology of Semi synthetic Penicillins

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Here I have discussed various penicillins like acid resistant, beta lactamase resistant penicillins, Beta lactamase inhibitor penicillins, broad spectrum penicillins

1. Beta Lactam Antibiotics Mr. Vijay Kevlani

2. SEMI-SYNTHETIC PENICILLINS

3. Semisynthetic penicillins are produced by chemically combining specific side chains (in place of benzyl side chain of PnG) or by incorporating specific precursors in the mould cultures. Thus, procaine penicillin and benzathine penicillin are salts of PnG and not semisynthetic penicillins .

4. The aim of producing semisynthetic penicillins has been to overcome the shortcomings of PnG , which are : Poor oral efficacy 2. Susceptibility to penicillinase 3. Narrow spectrum of activity. 4. Hypersensitivity reactions ( this has not been overcome in any preparation ). In addition, some B-lactamase inhibitors have been developed which themselves are not antibacterial, but augment the activity of penicillins against B-lactamase producing organisms

5. ACID-RESISTANT ALTERNATIVE TO PENICILLIN-G Phenoxymethyl penicillin (Penicillin V) It differs from PnG only in that it is acid stable . Oral absorption is better; peak blood level is reached in I hour and plasma t½ is 3 0-60 min . The antibacterial spectrum of penicillin V is identical to PnG , but it is about l/5 as active against Neisseria, other gram negative bacteria and anaerobes.

6. It cannot be depended upon for more serious infections and is occasionally used for streptococcal pharyngitis, sinuitis , otitis media, prophylaxis of rheumatic fever (when an oral drug has to be selected), less serious pneumococcal infections and trench mouth.

7. PENICILLINASE-RESISTANT PENICILLINS These congeners have side chains that protect the B-lactam ring from attack by staphylococcal penicillinase . However , this also partially protects the bacteria from the B lactam ring: Non-penicillinase producing organisms are less sensitive to these drugs than to PnG .

8. Their only indication is infections caused by penicillinase producing Staphylococci. Which are not methicillin resistant as well. Utility of these penicillins has markedly declined, because methicillin resistant Staph. aureus ' (MRSA ) have become universally prevalent .

9. EXTENDED SPECTRUM PENICILLINS These semisynthetic penicillins are in addition active against a variety of gram-negative bacilli because of improved ability to penetrate through their celI membrane. However , they are susceptible to several B-lactamases.

10. Amino penicillins This group includes ampicillin , its prodrug bacampicill in, and amoxicillin . Ampicillin lt is active against all organisms sensitive to PnG . In addition, non-B-lactamase producing strains of many gram- negative bacilli , e.g. H. influenzae , E. coli, Proteus, Salmonella, Shigella and Helicobacter pylori are inhibited .

11. However, due to widespread use , many of these have developed resistance; usefulness of this antibiotic has decreased considerably. Ampicillin is more active than PnG for Strep. viridans , enterococci and Listeria; Equally active for pneumococci , gonococci and meningococci , But penicillin- resistant strains are resistant to ampicillin as well.

12. Pharmacokinetics Ampicillin is not degraded by gastric acid; oral absorption is incomplete but adequate . Food interferes with absorption . It is partly excreted in bile and reabsorbed-enterohepatic circulation occurs. However , primary channel of excretion is kidney, but tubular secretion is slower than for PnG ; plasma t½ is l hr.

13. Uses Respiratory Tract Infection Urinary Tract Infection Meningitis Gonorrhea Typhoid Dysentry Cholecystitis Subacture Bacterial Endocarditis H.Pyroli Septicemia

14. Adverse effects Diarrhea is frequent after oral administration. Ampicillin is incompletely absorbed- the unabsorbed drug irritates the lower intestines as well as causes marked alteration of bacterial flora . It produces a high incidence (up to 10%) of rashes, especially in patients with AIDS, TB virus infections or lymphatic leukaemia .

15. Concurrent administration of allopurinol also increases the incidence of rashes. Patients with a history of immediate type of hypersensitivity to PnG should not be given ampicillin as well .

16. Interactions Hydrocortisone inactivates ampicillin if mixed in the i.v. solution. By inhibiting colonic flora, it may interfere with de-conjugation and enterohepatic cycling of oral contraceptives resulting in failure of oral contraception . Probenecid retards renal excretion of ampicillin.

17. Amoxicillin It is a close congener of ampicillin similar to it in all respects except : • Oral absorption is better; food does not interfere with absorption; higher and more sustained blood levels are produced . Amoxicillin given 3 times a day is equivalent to ampicillin given 4 times a day. • Incidence of diarrhea is lower.

18. • It is less active against Shigella and H. infiuenzae . • It is more active against relatively penicillin resistant Strep. pneumoniae. Many physicians now prefer amoxicillin over ampicillin for bronchitis , urinary infections, SABE and gonorrhoea . It is a component of most triple drug H. pylori eradication regimens

19. 2. Carboxypenicillins Carbenicillin The special feature of this penicillin congener is its activity against Pseudomonas aeruginorn and indole positive Proteus which are not inhibited by PnG or amino penicillins . It is less active against Salmonella, E. coli and Enterobacrer , while Klebslella and gram-positive cocci are unaffected by it.

20. Carbenicillin is not penicillinase-resistant. It is inactive orally and is excreted rapidly in urine (t½ I hr ). It is used as sodium salt in a dose of 1-2 g i.m . or 1-5 g i.v. every 4-6 hours. At the higher doses, enough Na may be administered to cause fluid retention and CHF in patients with borderline renal or cardiac function. High doses have also caused bleeding by interfering with platelet function.

21. Ticarcillin It is the second carboxypenicill in, similar in properties to carbenicillin , but is more active and produces fewer adverse effects . Its combination with clavulanic acid extends efficacy to cover B-lactamase producing strains. For the treatment of serious Pseudomonas infections it is often used a long with gentamicin.

22. Ureidopenicillins Piperacillin This antipseudomonal penicillin is about 8 times more active than carbenicillin . In addition, it has good activity against Klebsiella , many Enterobacteriaceae and some Bacteroides .

23. Piperacillin is frequently employed for treating serious gram-negative infections in neutropenic/immunocompromised or burn patients . Elimination t½ is I hr. It is combined with tazobactam to cover B-lactamase producing strains. Concurrent use of gentamicin or tobramycin is advised.

24. BETA-LACTAMASE INHIBITORS B-lactamases are a family of enzymes produced by many gram-positive and gram-negative bacteria that inactivate B-lactam antibiotics by opening the B-lactam ring. Different B-lactamases differ in their substrate affinities . Three inhibitors of this enzyme clavulanic acid, sulbactam and tazobactam are available for clinical use only in combination with specific penicillins

25. Clavulanic acid Obtained from Streptomyces clavuligerus , it has a B-lactam ring but no/weak antibacterial activity of its own. It inhibits a wide variety of B lactamases produced by both gram-positive and gram-negative bacteria . Clavulanic acid is a ' progressive' inhibitor, because binding with B-lactamase is reversible initially, but becomes covalent later- inhibition increases with time.

26. Called a 'suicide' inhibitor, it gets inactivated after binding to the enzyme . Clavulanate permeates the outer layers of the cell wall of gram-negative bacteria and inhibits the periplasmically located B-lactamase . Pharmacokinetics Clavulanic acid has rapid oral absorption and a bioavailability of 60%. It can also be injected. The elimination t½ o f 1 hr and tissue distribution matches amoxicillin, with which it is combined (called coamoxiclav ).

27. However, clavulanate is eliminated mainly by glomerular filtration Moreover , it is largely hydrolysed and decarboxylated before excretion. Uses : Addition of clavulanic acid re-establishes the activity of amoxicillin against B-lactamase producing resistant Staph. aureus (but not MRSA that have altered PBPs), H. inf / uenzae , N. gonorrhoeae, E. coli, Proteus, Klebsiella , Salmonella and Shigella .

28. Though Bact. fragilis and Branhamella catarrhalis are not responsive to amoxicillin alone, they are inhibited by the combination. Coamoxiclav is indicated for empirical therapy of: • Skin and soft tissue infections , intra-abdominal and gynaecological sepsis, urinary, biliary and respiratory tract infections: especially for hospital acquired infections . •

29. Adverse effects are the same as for amoxicillin alone; but g. i . tolerance is poorer- especially in children. Other adverse effects are stomatitis/vaginitis and rashes. Some cases of hepatic injury have been reported with the combination.

30. T hank Y O U