Antibiotics (Pencillin) 2 أ. م . د. وحدة اليوزبكي Head of Department of Pharmacology- College of Medicine- University of Mosul-2014 Antibiotics (Pencillin) 2

Objectives At end of this lecture, the students will be able to: 1- State the chemical structure and mechanism of action of Penicillin. 2- Enumerate the classes of Penicillin. 3- State the clinically important features of each individual class of penicillin (Its pharmacokinetic properties, antibacterial activities, clinical uses and side effects). 4- List the differences between different classes of penicillin. - At a level accepted to the quality assurance standards for the College of Medicine/ University of Mosul.

Chemistry of Pencillin - All penicillin, have the basic structure shown in Fig. : Thiazolidine (A) is attacked to a beta lactum ring (B) that carries the secondary group RNH. - Variation of the side chain produced a number of penicillin with improved activity against gram negative bacteria compared to penicillin G.

Chemistry of Pencillin Notes: - The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes (B-lactamases). - The structure integrity of the 6 amino pencillanic acid nucleus is essential for biologic activity of these compounds. - If the beta lactam ring is enzymatically cleaved by bacterial beta lactimase, the resulting product is pencilloic acid, which lack the antibacterial activity.

Mechanism of action of Penicillin - Penicillin prevent cell wall synthesis by inhibiting the enzymes called penicillin binding proteins (PBP) which present in the bacterial cell membrane and are involved in the formation of the peptidoglycan layer of the cell wall (which protects the bacteria from its environment), so in this case the bacteria incapable of withstanding the osmotic gradient between its interior and its environment , so the cell of bacteria swells and ruptures. - Penicillin thus are bactericidal & are effective only against multiplying organism because resting organism are not making new cell.

Classification of Penicillin 1. Natural Penicillin: - Benzylpenicillin = Penicillin G - Phenoxymethylpenicillin = Penicillin V 2. Penicillinase Resistant Penicillin: (antistaphylococcal) - Methicillin, Oxacillin, Nafcillin, Cloxacillin, and Dicloxacillin. 3. Extended Spectrum Penicillins (Aminopenicillins) Ampicillin, Amoxicillin, and Bacampicillin.

4. Broad Spectrum Penicillins (Anti-pseudomonal) a.Carboxypenicillins: Carbenicillin, Ticarcillin. b. Ureidopenicillins: Piperacillin, azlocillin. 5. B-Lactamase inhibitor combinations: Amoxicillin-Clavulanic acid (Augmentin), Ampicillin-Sulbactam, Ticarcillin-Clavulanic acid (Timentin), Piperacillin-Tazobactam.

Classification (Types) of Penicillin 1. Natural Penicillin: - Benzylpenicillin = Penicillin G - Phenoxymethylpenicillin = Penicillin V

Penicillin G (Benzyl penicillin) - It is destroyed by gastric acid so given paretrally. - Easily destroyed by Beta-lactamase. - High activity against gram positive organisms (cocci & bacilli) and gram negative cocci. - Low activity against gram negative Bacilli.

Note: - Benzyl penicillin is excreted by kidney, with about 80% being actively secreted by renal tubules (20% filtered by glomeruli), which can be blocked by probencid eg. That can be given with penicillin to decrease its excretion & increase availability of penicillin to reduce the frequency of injection for small children or for single dose therapy as in gonorrhea.

Clinical uses of Benzyl penicillin

Pharmaceutical preparations of Benzyl penicillin 1. Penicillin G injections. 2. Procaine Penicillin injections. 3. Benzathine Penicillin injections (long acting given as injection every month), used in the prophylaxis against repeated strep. infection (tonsillitis and its complication , the rheumatic fever).

Penicillin V (Phenoxymethyl Penicillin) - It is acid stable, so given orally. - It has a spectrum similar to Penicillin G but less activity. - It is indicated in mild to moderate infections due to streptococci so used mostly for the treatment of tonsillitis, Otitis media & for prophylaxis of strep. & peumococcal infection.

2- Extended (Broad) spectrum Penicillin (Ampicillin & Amoxicillin) - Have an antibacterial spectrum similar to that of Penicillin G, but are more effective against G-ve bacilli. - Their antibacterial activity extended to include a number of gram negative bacteria including : E. coli, Proteus mirabilis, Haemophilus influenzae, Shigella and Salmonella.

Extended (Broad) spectrum Penicillin 1- Ampicillin: - It is acid stable, moderately absorbed. Given orally. - Oral dose 250 mg- 1gm 6-8h or IM or IV 500mg 4-6 h. - Approximately 1/3 of a dose appear unchanged in the urine. The drug is concentrated in the bile.

Side Effects of Ampicillin 1- Diarrhea: Incidence is 12% > Amoxicillin. 2-Clostridium difficile diarrhea (Pseudomembranous colitis). Notes: Ampicillin & Amoxicillin are the commonest antibiotic associated with diarrhea, although it is related to the frequency of their use rather to their innate risk of causing the disease. 3- Macular rash resembling Measles. usually unaccompanied by other signs of allergy. These rashes are very common in patients with disease of lymphoid system, notably infectious mononucleosis & lymphoid leukemia.

Extended (Broad) spectrum Penicillin 2- Amoxicillin: - It is structural analogue of Ampicillin, but differ in: a- Better absorbed from gut. b- Better absorbed especially after food. (same dose achieve double plasma conc.) c- Diarrhea less frequent < Ampicillin. d- Oral dose 250mg 8 hourly.

Extended (Broad) spectrum Penicillin 3- Piv ampicillin & Bac ampicillin: They are esters of penicillin given orally. Absorption is complete. Little side effects (Low incidence of diarrhea). Absorption is not effected by food.

3- Penicillinase Resistant Penicillins (Antistaphylococcal Penicillin) - The most important agents: Cloxacillin, Dicloxacillin, Fluxocillin (absorbed better from GIT than cloxacillin & may produce cholestatic jaundice), Oxacillin, Nafcillin. - Methicillin is rarely used, because of its toxicity (acute interstitial nephritis),

Penicillinase Resistant Penicillins (Antistaphylococcal Penicillin) - These agents not affected by B-lactamase Enz. because they pocess acyl side chain which protect the penicillin from destruction by B-lactamase. - The use is restricted to the treatment of infections caused by pencillinase producing staphylococci, including skin infections (impetigo), abscesses, Pneumonias, Prosthetic joint, endocarditis, meningitis and bone infections (Osteomylitis).

4- Antipseudomonal Penicillin a- Carboxy penicillin: Ticarcillin & Carbencillin : - These agents pocess activity similar to that of broad spectrum penicillin but extend to G- antibacterial activity including pseudomonas aeroginosa & Indole +ve proteus species.

Carboxy penicillin: Ticarcillin & Carbencillin - Both these drugs used parentrally. They are also affected by B-lactamase Enz. - The disadvantage of these agents in that, they are available as Disodium salt, each 1gm release 5.4 mmol of Na. So should not be given to patients with hypertension or cardiac or renal failure.

Antipseudomonal Penicillin b- Uredopenicillin: Azlocillin, Piperacillin - They are used parenterally. -These agents differ from carboxy penicillin by: 1- Greater activity against pseudomonas aeroginosa 2- Present as Monosodium salt , each 1gm release 2mmol of Na. 3- They cause less accumulation in patient with renal failure because about 25% of the dose is excreted with bile into GIT with feceses.

Clinical uses of Antipseudomonal penicillin 1. Serious P. Aeruginosa infections . 2. Mixed infections 3. Complicated UTIs. 4. Prostatitis. 5. Surgical prophylaxis

5. B-Lactamase inhibitor combinations The commercially available are: - Amoxicillin-Clavulanic acid (Augmentin), - Ampicillin-Sulbactam. - Ticarcillin-Clavulanic acid (Timentin), - Piperacillin-Tazobactam. - These compounds act as inhibitors of the bacterial B-lactamase.

B-Lactamase inhibitor combinations - Prevent the hydrolysis of the B-lactam ring, either by enzymatic cleavage with a B-lactamase (penicillinase) enzyme or by acid, that destroys the antimicrobial activity of a B-lactam antibiotic. - B-Lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam, contain a B-lactam ring but, by themselves, do not have significant antibacterial activity. Instead, they bind to and inactivate B-lactamases enzymes, thereby protecting the antibiotics that are normally substrates for these enzymes such as penicillin from degradation and so expand the utility of these drugs. - The B-lactamase inhibitors are therefore formulated in combination with B-lactamase sensitive antibiotics.

B-Lactamase inhibitor combinations - They are used for the treatment of infections due to B-lactamase producing bacteria (resistant infections) such as: H.influanzae, Staphylococcous aureous, E.coli, Klebsiella species Proteus mirabilis (but not pseudomonas aeroginosa).

Clinical uses of B-Lactamase inhibitor combinations The diseases treated include: Respiratory tract infections. Skin and soft tissue infections. UTIs. Intra-abdominal infections. Endocarditis. Septicemia. Bone and joint infections.

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