Penicillins (ANTIBIOTICS)

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Penicillins

PenicillinsDr. Arham ShabbirPharm.D, M.Phil. Pharmacology, Ph.D. Pharmacology(U.H.S)Professor (Pharmacology)Lahore Pharmacy College ofLahore Medical & Dental College

StructureA thiazolidine ring which is attached to -lactam ring6- aminopenicillanic acid nucleus is essential for activityIf the -lactam ring is enzymatically cleaved by bacterial -lactamases, the resulting product, penicilloic acid lacks antibacterial activity

ClassificationNatual penicillinsPenicillin G (Benzyl penicillin)Penicillin V has a spectrum similar to that of penicillin G, but it is not used for treatment of bacteremia because of its poor absorption, narrow spectrum and need for dosing four times.Anti staphylococcal penicillinsThe semi synthetic penicillins Methicillin, nafcillin, oxacillin, and dicloxacillin are penicillinase resistant penicillins. Because of its toxicity (interstitial nephritis), methicillin is not used clinically except to identify resistant strains of S. aureus. Methicillin resistant Staphylococcus aureus (MRSA) is currently a source of serious community and nosocomial (hospital-acquired) infections and is resistant to all commercially available -lactam antibiotics, including antistaphylococcal penicillins. This organism is usually susceptible to Vancomycin.

The penicillinase-resistant penicillins have no activity versus gram-negative infections.However, for infections caused by methicillin susceptible strains of staphylococci these are considered the drugs of choice.Extended spectrum penicillinsAmpicillin and Amoxicillin have an antibacterial spectrum similar to that of penicillin G but are more effective against gram-negative bacilli. Therefore, they are referred to as extended-spectrum penicillinsResistance to these antibiotics is now a major clinical problem because of inactivation by plasmid mediated penicillinases.Formulation with a -lactamase inhibitor, such as clavulanic acid or sulbactam, protects amoxicillin or ampicillin, respectively, from enzymatic hydrolysis and extends their antimicrobial spectrumSynergistic effect with aminoglycosides

Anti pseudomonal penicillins

Carbenicillin, ticarcillin, and piperacillin are called antipseudomonal penicillins because of their activity against P. aeruginosaThese drugs have activity against several gram-negative rods, including Pseudomonas, Enterobacter, and in some cases Klebsiella species.susceptible to penicillinases and are often used in combination with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance their activity.Synergism with aminoglycosides

Mechanism of actionThe transpeptidation reaction in Staphylococcus aureus that is inhibited by -lactam antibiotics. The cell wall of gram-positive bacteria is made up of long peptidoglycan polymer chains consisting of the alternating N-acetylglucosamine (G) and N-acetylmuramic acid (M) with pentapeptide side chains linked (in S. aureus) by pentaglycine bridges. The exact composition of the side chains varies among species. The diagram illustrates small segments of two such polymer chains and their amino acid side chains. These linear polymers must be cross-linked by transpeptidation of the side chains at the points indicated by the asterisk to achieve the strength necessary for cell viability.UDP-acetylmuramyl-L-Ala-D-Glu-L-Lys-D-Ala-D-Ala sequence is also called as Park nucelotide, formerly called as Park peptide

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Penicillin binding proteins (PBPs) catalyze the transpeptidase reaction that removes the terminal alanine to form a cross link with a nearby peptide.This gives cell wall its structural rigidity- lactam antibiotics are structural analogs of the D-ala-D-ala substrate.This substrate is bound by PBP at active siteWhen a - lactam is attached PBP, transpeptidation reaction is blocked which leads to inhibition of peptidoglycan synthesis and the cell diesExact mechanism of bacterial cell death is unknown but involvement of autolysins activation and destabilization of bacterial membrane against high internal osmotic pressure is suggested.

ResistanceInactivation of antibiotic with -lactamaseModification of target PBPsImpaired penetration of drug to target PBPsPresence of efflux pump-lactamase production is the most common mechanism of resistanceSome -lactamase hydrolyze penicillins but not cephalosporins e.g. those produced by E. coli, S. aureus.Whereas, those produced by P. aeruginosa and enterobacter hydrolyze both.Carbapenems are highly resistant to hydrolysis by penicillinases and cephalosporinases but are hydrolyzed by metallo--lactamase.

PharmacokineticsAbsorption differs for different penicillins, depending upon their acid stability and protein binding.Methicillin is acid labileGastrointestinal absorption of nafcillin is erraticBoth are not suitable for oral administration.Amoxicillin, ampicillin and dicloxacillin are acid stable and relatively well absorbedAbsorption of most oral penicillins are impaired by food (except amoxicillin), therefore, should be administered 1-2 hrs before meal.Absorption through IV route is preferred due to local irritation and pain produced by IM injection of large doses.

Penicillins are usually excreted by kidney through urine and small amounts are excreted by other routesThose penicillins which are excreted through kidney, dose must be adjusted according to renal function e.g. normal half life of Penicillin G is usually 30 min and in renal failure it may increase upto 10 hours.Nafcillin is primarily cleared by biliary excretionOxacillin, dicloxacillin and cloxacillin are cleared by both kidney and biliary excretion.No dose adjustments are required for these drugs in renal failure.

Adverse reactionsPenicillins are remarkably non toxic1- Hypersensitivity reactionsDue to penicilloic acid (metabolite of penicillin)From skin rash to anaphylactic shock (includes fever, nephritis, pruritis, urticaria, joint swelling etc.)Methicillin cause interstitial nephritis while nafcillin causes neutropeniaIncidence of allergic reaction in small children is negligible2-GIT disturbancesDue to over growth of G+ organisms or by direct irritationNausea, vomiting, diarrheaPseudomembranous colitis (Inflammation of colon)Ampicillin (rare).

MOA: Penicillin causes normal flora to alter. When an antibiotic kills competing bacteria in the intestine, the remaining bacteria will have less competition for space and nutrition. The net effect is to permit more extensive growth than normal of certain bacteria. E.g. C. difficile.Vaginal candidiasis can also occur.3- SeizuresPenicillin G causes seizures if given intra-thecal in patients especially with renal failure patients. They also can cause confusion and psychosis (neurotoxicity). MOA: Most widely accepted theory involves binding to GABA receptors which are involved in inhibitory neurotransmissionBenzodiazepines and Barbiturates are used as treatmentCessation of seizure activity has been reported 12-72 hrs after therapy is discontinued. The epilepticogenic activity may be due to -lactam ring

Treatment / Anti-dotAllergy is treated by Anti-histamineDesensitization can be accomplished with gradually increasing doses of penicillinAnaphylactic shock is treated by Adrenaline and corticosteroids.MOA: Vasodilation (Fall in BP) and bronchoconstriction are important symptoms of anaphylactic shock, whereas, adrenaline causes vasoconstriction and bronchodilation.Corticosteroids have anti-inflammatory effectsPenicillins and carbapenems are both neurotoxic. Dose adjustment in renal failure is key strategy to avoid neurotoxicity.

Contraindications / drug interactionsCaptopril (capotein) Increase potassium level.Spironolactone (Aldactone) K+ sparing diureticsK+ suppliments (KCl).Especially with those penicillins which are available in potassium salts. Hyperkalemia can generate arrhythmia in cardiac patients.Sodium salts should be avoided in hypertensive patients.Ticarcillin and carbencillin have antiplatelet aggregation effect. Be careful when administering Streptokinase, warfarin, heparin, clopidogrel etc to patients who are already taking these penicillins.

Penicillins inhibit the excretion of methotrexate (anti-cancer) due to which toxic effects of methotrexate occur, such as, bone marrow depression.Probencid is a uricosuric agent. It increases the concentration of penicillin and inhibit its excretion.Penicillins decrease the effectiveness of estrogens in contraceptive pills.Dose of penicillins should be increased in immunocompromised patients.Should not be taken with acidic juices and should be administered with full glass of water.

Patient historyAllergyHypertensive (having low salt diet)Impaired renal functionGIT problemsTendency to bleed