Lecture 2 By Prof. Dr. Mohammed Fahmy Pharmacology-3 Lecture 2 By Prof. Dr. Mohammed Fahmy

Antibiotics Chemical substances produced by various species of organisms that are capable of killing or inhibiting the growth of other microbes or cells

Classification of bacteria 1- Gram-positive e.g., Staphylococcus & Streptococcus Many peptidoglycan layers Stain blue 2- Gram-negative e.g., E. coli & Salmonella Few peptidoglycan layers Stain red

Classification of antibacterial drugs A- According to spectrum 1- Narrow spectrum e.g., Penicillin G & V Effective against Gram +ve or Gram –ve 2- Broad spectrum e.g., Ampicillin & Amoxicillin Effective against Gram +ve and Gram –ve

B- According to effect on bacteria 1- Bacteriostatic Inhibit growth e.g., Tetracycline & Chloramphenicol 2- Bactericidal Kill bacteria e.g., Penicillins & Cephalosporins

C- According to mechanism of action 1- Cell wall synthesis inhibitors e.g., Penicillins & Cephalosporins 2- Cell membrane synthesis inhibitors e.g., Daptomycin & Polymixin B

3- Protein synthesis inhibitors e.g., Aminoglycosides & Tetracyclines 4- Nucleic acid synthesis inhibitors e.g., Quinolones & Rifampicin 5- Folic acid synthesis inhibitors e.g., Sulfonamides & Trimethoprim

Inhibitors of bacterial cell wall synthesis Beta-lactam antibiotics Other antibiotics Penicillins Vancomycin Cephalosporins Bacitracin Carbapenems Monobactams

Penicllins Discovered by Alexander Fleming in 1928 Obtained naturally from penicillum mold and synthetically Contain beta lactam ring which is essential for antibacterial activity

Mechanism of action 1- Bactericidal 2- Bind to specific penicillin binding protein (PBP): Inhibit transpeptidase enzyme responsible for cross-linking of peptidoglycan cell wall synthesis Activate autolytic enzyme (autolysin) Lysis of cell wall 3- Selectivity Human cells have no peptidoglycan cell wall

Preparation of penicillins 1- Benzyl penicillin (Penicillin G) Natural penicillin The spectrum of activity includes most Gram-positive cocci Has the following disadvantages: - Destroyed by gastric acidity and must be given parenterally

- Inactivated by beta lactamase (not effective in β-lactamase secreting organisms e.g., S. aureus) - Narrow spectrum (not effective against Gram negative bacilli e.g., E. coli) - Short duration of action (6 hrs)

2- Long acting penicillins G e. g 2- Long acting penicillins G e.g., Procaine penicillin G Benzathine penicillin G (Durapen) - Used in suspension form - Given I.M. only never I.V. 3- Phenoxymethyl penicillin (Penicillin V, Ospen) - Natural penicillin - Acid stable (given orally)

4- Methicillin - Beta lactamase resistant - Effective against S. aureus - Not used due to its nephrotoxicity 5- Acid & beta lactamase resistant penicillins e.g., Oxacillin, Cloxacillin and Nafcillin Effective against S. aureus

6- Broad spectrum penicillins e.g., Ampicillin & Amoxicillin (Hiconcil) - Effective against Gram +ve & Gram –ve - Not effective against Pseudomons & Klibsiella Advantages of Amoxicillin over ampicillin Better absorbed orally and not affected by food

Longer duration of action (8 hrs) Less GIT disturbances & diarrhea 7- Extended spectrum penicillins e.g., Carbenicillin & Piperacillin - Broad spectrum + effective against Pseudomons & Klebsiella ِ - Acid sensitive (Given parenterally)

Resistance to penicillins 1- Inactivation by beta-lactamases 2- Modification of PBPs can decrease penetration of the antibiotic through the outer cell membrane 3- The presence of an efflux pump can reduce the amount of intracellular drug

Pharmacokinetics of penicillins 1- Absorption Absorption of most oral penicillins (except amoxicillin) is impaired by food Should be given 1-2 hours before or after meals 2- Distribution Widely distributed all over the body Pass placenta, but not teratogenic Cross BBB when inflammed as in case of meningitis

3- Metabolism Metabolized by the liver to penicillanic acid, penicillamine and penicilloic acid (allergenic metabolites) 4- Excretion Most penicillins are excreted by the kidneys Nafcillin is excreted mainly in bile Probenecid blocks the active tubular secretion of penicillin, thus elevating its blood level

Therapeutic uses of penicillins 1- Streptococcal infections e.g., Tonsilitis, Otitis media & Sinusitis 2- Pneumococcal infections e.g., Pneumonia 3- Staphylococcal infections e.g., Abscess 4- Meningococcal infections e.g., Meningitis

6- Diphtheria, tetanus and gas gangrene 7- Urinary tract infections 5- Gonorrhea and syphilis 6- Diphtheria, tetanus and gas gangrene 7- Urinary tract infections 8- Typhoid and paratyphoid fever 9- Prophylaxis of streptococcal infection in rheumatic fever

Side effects of penicillins 1- Hypersensitivity reactions Occur in 20% of patients Produced by degradation products especially penicilloic acid Induce urticaria, angioedema and anaphylactic shock Treated by adrenaline, cortisol and antihistaminic

2- Diarrhea due to superinfection, especially after oral ampicillin 3- Convulsions may occur after intrathecal injection of penicillin 4- Nephritis with methicillin 5- Platelet dysfunction with carbenicillin

Beta-lactamase (penicillinase) inhibitors Examples: Clavulinic acid, Sulbactam and Tazobactam They protect penicillins from inactivation by β-lactamases secreted by some bacteria e.g., S. aureus & E. coli They have no antibacterial activity

(Augmentin, E-Moxclav, Hibiotic) Preparations: 1- Clavulinic acid + Amoxicillin (Oral) (Augmentin, E-Moxclav, Hibiotic)

2- Sulbactam + Ampicillin (Oral, IM & IV) (Unasyn) 3- Tazobactam + Piperacillin (IV) (Tazocin)

Cephalosporins Isolated from cephalosporium fungus Similar to penicillin in structure and mode of action More resistant to β-lactamase than penicillin

Classification 1- First generation Examples: Cephalexin (Keflex), Cephadroxil (Duracef), Cephradin (Velosef) Active mainly against Gram +ve cocci Active on some Gram –ve bacilli Resistant to β-lactamase enzyme Do not pass BBB (Not effective in meningitis)

2- Second generation Examples: Cefaclor (Ceclor), Cefamandole (Mandol), Cefuroxime (Zinacef, Zinnat) Less active on Gram +ve than 1st generation More active on Gram –ve than 1st generation More resistant to β-lactamase than 1st generation Do not pass BBB except cefuroxime

3-Third generation Examples: Cefotaxime (Claforan), Ceftriaxone (Rociphen), Cefoperazone (Cefobid), Ceftazidine (Fortum) Less active on Gram +ve than 2nd generation More active on Gram -ve than 2nd generation More resistant to β-lactamase than 2nd generation Pass BBB (useful in meningitis)

4- Fourth generation Examples: Cefepime (Maxipime), Cefpirome (Cefrom) Similar to 3rd generation but highly resistant to β-lactamase

Therapeutic uses 1- Urinary tract infections, especially in pregnancy 2- Pneumonia 3- Septicemia 4- Meningitis 5- Sinusitis

Can be prevented by vitamin K Adverse effects 1- Allergy and cross allergy with penicillin (10%) 2- Diarrhea and superinfections 3- Bleeding with Cefamandole and cefoperazone Can be prevented by vitamin K 4- Severe pain after IM injection