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April 21/Monday pharmacology/sheet #16 Eman B. Alhamad We will continue talking about the chemotherapy , getting more in the details ..Antibacterial Agents - we are going to follow a classification of these agents according to their mechanisms of action for example some of them work by inhibiting the cell wall synthesis like penicillin , others use another mechanism of action .- within this classification we are going to sub divide the drugs according to their chemical structures .- what the doctor wants from us to focus on is how do these drugs work, their indications and side effects .- don't focus on the relation of the chemical structure of the drugs with their mechanisms of action .-what is really important to focus on is the mechanisms of resistance against these drugs by the bacteria itself.……………………………………………………………………………………………………………………………………………………………….Starting with a group of antibacterial agents which is The Beta-Lactams which includes : * Penicillins * Cephalosporins * Carbapenems * Carbacephems * Monobactams* also VancomycinThis group of drugs share the same chemical structure which is the Beta-lactam ring , and they work by inhibiting the synthesis of the bacterial cell wall . they differ from each other just by the R-group that is associated with the side chain as a type of modification and this may alter the drug more acidic or more basic thus governs it's absorption and excretion . ex. Some modifications make the drug stays longer and less excreted , some modifications let the drug to be orally taken instead of being given by injection . *( gram +ve )bacteria have such a thick wall (many layers ) composed of peptidoglycans .* ( gram –ve) bacteria have very thin wall of peptidoglycans ,but has a cell membrane to compensate .- you may think that gram +ve bacteria are more resistant to antibacterial drugs but the truth that gram –ve bacteria are more resistant because of its' cell membrane components ( lipids, proteins..) that can compensate the absence of thick peptidoglycan layers within the cell wall . - the beta-lactam ring of the drug has an important role to do in developing the resistance against the drug by the bacteria, because this ring binds to the cell wall of the bacteria and destroys it . so the bacteria will find a way to resist this binding thus rendering the drug inactive … how bacteria resist the binding of the ring with the bacterial cell wall ?- by making proteins called Beta-lactamases which destroy the beta-lactam ring of the drug preventing any further binding . so mainly these drugs are effective only during the phase of growing and division of the bacteria not during the other stages of the bacterial life . - Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity to bind penicillin. They are a normal constituent of many bacteria; beta- lactam ring binds to PBPs, which are essential for catalyzing a number of reactions involved in the process of synthesizing cross-linked peptidoglycan ( cross link two layers of P.G ) and mediating the removal of? alanine? from the precursor of peptidoglycan . - SO the conclusion that Penicillin-binding proteins or transpeptidases 'another name' are the targets of penicillin and other beta-lactam drugs . ...........................................................................................................................................................We said the bacteria develop a resistance a against the antibiotic by different mechanisms which they are : The production of beta-lactamases enzymes that destroy the beta-lactam ring and inactivate the drug .A mutation that alters the binding site of beta-lactame ring with Penicillin-binding proteins ( modification of the target ) .In relation to (gram –ve bacteria) we have two different forms of resistance :Modifications on porins ( that they work as channels through the cell wall allowing the passage of penicillin and other molecules inside of the bacteria ) . this modification may be by down regulation of porins ( reduced in number ) or by inactivating them .Special protein structures are active pumps that pump out the unibacterial agent if it has already entered the periplasmic membrane .1 and 2 >> general mechanisms present in all bacteria . 3 >> concerning mainly gram negative bacteria . ………………………………………………………………………………………………………………………………………………………..In general , the Indications for antibacterials include:? Treating bacterial infections , and the best drug to choose for treating a certain infection is determined according to the culture and sensitivity testing .for example : a patient with sore throat and the doctor suspects he has a bacterial infection what the doctor does is taking a swab from the patient and culture it in the lab then test the efficiency of untibacterial agents against the infection by the sensitivity test to decide the best / most suitable agent to be used . ? Prophylaxis: To prevent the occurrence of infections in some patients with certain conditions like AIDS , Cancer , surgery e.g. gastro-intestinal surgery.- joint replacement- meningitis contacts . – surgical/ dental procedures in patients with artificial heart valves or heart valve lesions >>> Patients with infective endocarditis by staphylococcus bacteria they have infection on the heart valves , they can be treated from the infection and become better . But , if you as a dentist do some dental procedures like dental surgery , some bacteria can gain access to the blood stream through the oral cavity and then reinfect the valves of the heart !!- so YOU SHOULD give untibacterial agents as a prophylactic step to any patient with a history of -infective endocarditis , or prosthetic valves , or congenital heart valves lesions to prevent the reinfection due to your dental procedure . ………………………………………………………………………………………………………………………………………………………………….. Classification * Penicillins – Natural penicillins * PenG, PenVK, Benzathine Pen, Procaine Pen – Aminopenicillins * Ampicillin, Amoxicillin – Anti-Staph penicillins * Oxacillin, Dicloxacillin – Anti-Pseudomonal * Ticarcillin * [Ureido] Piperacillin ……………………………………………………………………………………………………………………………………………………………………. Penicillin G- could be used IM, IV - preferable to be given IV injection - it is quickly absorbed and excreted , so we have a modification on penicillin G to make the drug staying longer period of time in the body by addition of benzyl group converting it to Benzathine Pencillin . it is givin mainly by intramuscular injection . - Procaine Pencillin G >> it is developed because penicillin G drug is very painful and irritating to the patient at the site of injection , so procaine has an anesthetic agent to decrease the pain ( given IM ) .- generally 90% of penicillin G is eliminated rapidly through the kidneys during just ( 3 – 4 ) hrs , so there is an agent added to penicillin G which is Probencid to increase half life and serum concentration of penicillin G . - Probencid is used in the treatment of gout diseases to enhance the excretion of uric acid outside the body by working on certain excretion channels on the kidney tubules , these excretion channels are also used to excrete penicillin G outside the body .. so the probencid compete penicillin on these channels preventing it from being excreted thus staying for a longer period of time inside the body . Probencid compete penicillin at the site of excretion >> uric acid get excreted by the channels >> inhibiting the excretion of penicillin >> increasing the half life of penicillin .- penicillin G is used for treating gram +ve infections mainly . also gram –ve cocci infections for a lesser extent but NOT gram –ve rods . - penicillin G is used commonly in treating syphilis . ……………………………………………………………………………………………………………………………………………………………….Penicillin VK- very old -orally administered - used in minor infections like minor pharyngitis -now there are better choices such as ampicillin and amoxicillin - usually food interfers with absorption of orally taken penicillin , so all types of orally taken penicillins are needed to be taken 1 – 2 hrz before or after a meal , except for ( Amoxicillin) which can be taken on empty stomach . - in dentistry it is very commonly used in periapical infections- in dental practice >> it is used as prophylaxis for enterococcal infections , to prevent reinfection with patients for example with a history of infective endocarditis …. Given orally one hour prior to the dental operation. -very safe during pregnancy ……………………………………………………………………………………………………………………………………………………………….Side effects of penicillin In general some patients show sensitivity to penicillin not necessarily to be as a form of anaphylactic shock ! Just it starts with itching , fever .. people who have sensitivity to penicillin may have also sensitivity towards others beta-lactam drugs such as cephalosporins this is what we call ' cross sensitivity ' Patients who show mild and minor sensitivity to penicillin ( rash,fever) we can give them cephalosporins instead of penicillin as a second choice of drugs , we don't conseder these patients allergic enogh that they would have cross sensitivity with cephalosporins . But if they show major sensitivity ( anaphylactic shock) to penicillin , you will be more scared about giving him cephalosporins as a second choice . you should think to give them a drug from another different group of untibacterial agents . ……………………………………………………………………………………………………………………………………………………………..Oxacillin and Dicloxicillin- They aren’t excreted completely through the kidneys .- they stay in the body for a long period of time .- they are excreted equally through the kidneys and biliary tracts .- so because of that it is safe to give it to patients who have renal problems with no need to adjust the dose for them , while because penicillin is mainly excreted through the kidneys when it is given to patients with renal problems the dose should be adjusted according to the Creatinine levels . - Oxacillin is the drug of choice to treat Methicillin-sensitive Staphylococcus aureus(MSSA) , it's better than Vancomycin in treating this kind of infection . -for Dicloxicillin it's given orally , it differs from oxacillin that it's better to be given on empty stomach because it's absorption is interfered by food . ………………………………………………………………………………………………………………………………………………………………………………Ampicillin/Amoxicillin- it is the drug of choice to treat Listeria monocytogenes and in Enterococcus Dental Prophylaxis. ( the first drug of choice in dental infections ) - Amox 1 gram orally given 1 hour prior to appointment .- Amoclan or Augmentin ( they are trade names) >> which combines amoxicillin with Clavulanic Acid (Amox/Clav). This combination renders the drug to cover broader spectrum of microorganisms including (Methicillin-sensitive Staphylococcus aureus MSSA ) and ( upper respiratory infection ) and most( anaerobes) .- it is suitable for dental cases in which streptococcus present and some anaerobes .-usually the patient will suffer from side effects associated with Augmentin like diarrhea ( GI side effects ) .- it should be kept in the refrigerator because at the room tempreture it's gonna be degraded and loses its activity.………………………………………………………………………………………………………………………………………………………………Piperacillin- it is given for treating Pseudomonas .- usually given with other types of agents to cover broader spectrum of microorganisms .…………………………………………………………………………………………………………………………………………………………………. Sulbactam - another agent which is combined with penicillin , it is very similar to Clavulanic Acid . it is combined with penicillin in a drug called Unasyn (Amp/Sulbactam) .- suitable for broad spectrum ( gram +ve , gram –ve , anaerobs ) .- it is the best drug of choice for treatment of mixed infection ( E.coli, Proteus, anaerobes when Pseudomonas is not implicated ) . -sulbactam alone is considered also as untibacterial agent , not as clavulanic acid . so sulbactam alone is very active against Acinetobacter species ( a Gram negative bacteria) .………………………………………………………………………………………………………………………………………………………………NOTES :the doctor doesn’t expect from us to memorize all the species of bacteria in the slides , except the types she mentions in the lectures for few certain types of drugs . The doses which are only mentioned in the lectures are included concerning the prophylaxis doses in dental practice . ……………………………………………………………………………………………………………………………………………………………Tazobactam - is usually administred with high Piperacillin in adrug called Zosyn (Pip/Tazo).- it is the broadest spectrum penicillin .. it's not commonly used in Jordan - it covers gram negative rods , whereas a lot of penicillins don't cover gram negative rods rather they may cover gram negative cocci . GOOD LUCK ................
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