Pharmacology of Penicillin bsc nurs.pptx

This ppt explains the pharmacology of penicillin, further classification of penicillin, penicillin G, V, superinfection, and also explained topic principle of microbiology and everything you need to understand about pharmacokinetics and pharmacodynamics related to penicillin.

1. Pharmacology of Penicillin

2. Objectives / learning objectives General principles for use of antimicrobial agents Types of antimicrobial agents Antibiotics definition mechanism of actin of Anti-microbial agents Narrow v/s broad spectrum antimicrobials Bactericidal or Bacteriostatic anti microbial agents

3. Objectives / learning outcomes Limitations of anti-microbial agents Who are at risk of developing super infection Factors affecting effects of antimicrobial agents

4. General principles for use of antimicrobial drugs/agents Antimicrobial agents are those drugs that treat, prevent infections caused by micro-organisms(bacteria, fungi, parasites, viruses)

5. What are antibiotics in real ?? These are the substances that are produced by microorganisms that selectively suppresses the growth or kills the other organisms at low concentration

6. Examples- penicillin ,cephalosporin (derived from fungi) Derived from bacteria- polymycin B, colistin and bartracin. Actinomycetes derived from other sources such as aminoglycosides, macrolides,tetracyclines

7. Mechanism of action Follows a variety of mechanism of action Such as

8. May inhibit the cell wall

9. Damage to cell membrane to cause leakage of cellular content

10. May inhibit the protein synthesis

11. Interference with the DNA replication

12. Interference of cellular metabolism

13. Spectrum of antimicrobial agent Narrow spectrum Broad spectrum

14. Narrow spectrum Inhibits specific group of micro-organisms Example penicillin G, streptomycin, erythromycin,etc. Broad spectrum Possess activity against many groups of microorganisms. Example chloramphenicol, tetracycline.

15. Bacteriostatic or bactericidal antimicrobial agents??

16. Bacteriostatic Anti microbial agents Inhibits the growth and replication of bacteria w/o causing immediate death Interferes with protein synthesis, DNA replication, cell wall synthesis . Prevents multiplication of bacteria Example tetracycline

17. Bactericidal agents Bactericidal –directly kills bacteria Disrupts essential functions Cell death (necrosis) Complete eradication of bacteria Example- penicillin, vancomycin.

18. Important note In high conc. Bacteriostatic can act as bactericidal agents.

19. Limitations of anti microbial agents Allergic rxns Toxicity Super infection Drug resistance

20. Allergic reactions All forms of penicillin can cause allergy but anaphylaxis is more common following parenteral route than oral route. topical penicillin is highly sensitizing and therefore banned ( can cause high risk of developing surgery when comes in contact) hence direct contact must be avoided.

21. Toxicity

22. Super infection Super-infection also known as suprainfection. It is the addition or appearance of a new infection resulting from the use of microbes. Broad spectrum microbes destroys the normal flora of the body.

23. Who are at risk for developing super infection?? On corticosteroids Having diabetes mellitus On immunodepressants.

24. Drug resistance Some bacteria develops resistance by production of penicillase enzyme (beta-lactamase) By destroying beta lactamase ring in the drug Acts on both gram positive ad gram negative bacteria

25. Video antimirobial resiatnce

26. Other mechanism of drug resistance in bacteria It is by targeting those enzymes that have love affinity towards penicillin

27. Avoid drug resistance by Prolonged use Avoiding antibiotics for viral diarrhea, seasonal flu and cold. Using narrow spectrum over broad-spectrum Broad spectrum- critically ill patient. Preferring topical over oral and systemic over parenteral Using antibiotics acc to guidelines

28. Factors affecting selection of antimicrobial agent Patient related Microbe related Drug related

29. Patient related Age( toxicity) Renal and hepatic status Pregnancy Immunity(immunodepressant used by pt.) History of drug allergy individualization- therapeutic principle

30. Microbe related Guess microbe (area/site/prevalance) Microbial identification Culture and sensitivity test(most suitable anti microbial agent) Resistance pattern

31. Drug related Drug efficacy Spectrum Route of administration (oral greatly preferred over parenteral) Adverse effects (less adverse effects) Risks/ benefits- therapeutic principle Cheap/ cost effective

32. Antibiotics especially beta lactam rings

33. Learning objectives/ objectives Definition of bacteria Structure of bacteria Cell wall gram positive and gram negative Beta-lactam antibiotics Penicillin Structure of pencillin History of penicillin Mass production Value of penicillin Why study penicillin? Structure of penicillin Mechanism of action Classification of penicillin

34. Definition of bacteria Unicellular , free-living ,prokaryotic organism Very small in size Genetic material is DNA, RNA Some are disease causing known as pathogenic bacteria Lack well defined nucleus Relatively simpler organization than eukaryotes

35. Classification of penicillin Natural penicillin spectrum Pharmacokinetics Preparation Uses Averse effects manifestation of allergy/ hypersenstivity on body

36. Semisynthetic penicillin Acid – resistant Penicillase resistant Aminopenicillin Antipseudomonal penicillins

37. Structure of Bacteria

38. Cell wall Gram positive 90%PETIDOGLYCAN Techionic acid provides rigidity Several layers of peptidoglycan 15-50nm thick Outer membrane absent Less lipid content Gram staining procedures- Retains the crystal violet dye= appears purple in color Gram negative 5-10% PEPTIDOGLYCAN Major portion of cell wall made up of lipoproteins and outer membrane 10nm thick Single layer peptidoglycan Lipid content is high Outer membrane is present Gram staining procedures- don’t retain the crystal dye= appears pink in color

39. Diagram of cell wall (positive and negative)

40. Beta- Lactam A ntibiotics Antibiotics that have beta lactam ring in their cell wall are known as beta- lactam antibiotics Example are pencillin,cephalosporin,monobactams, carbapenems

41. Penicillins Sir alexander fleming discovered penicillin – 1928 From Penicillium notatum Available for therapeutic use-in 1941 Now obtained from the fungus Penicillium chrysogenum

42. Structure of penicillin

43. History of penicillin Alexander Fleming at  St. Mary's Hospital  in London (now part of  Imperial College ) was the first to show that  Penicillium rubens  had antibacterial properties he observed that fungal contamination of a bacterial culture ( Staphylococcus aureus ) appeared to kill the bacteria. this observation with a new experiment on 28 September 1928. [78]  He published his experiment in 1929, and called the antibacterial substance (the fungal extract) penicillin.

44. Sample of  penicillium  mould presented by Alexander Fleming to Douglas Macleod, 1935

45. [79]  Fleming expressed initial optimism that penicillin would be a useful antiseptic, because of its high potency and minimal toxicity in comparison to other antiseptics of the day, and noted its laboratory value in the isolation of  Bacillus influenzae  (now called  Haemophilus influenzae )

46. In 1930 , Cecil George Paine, a  pathologist  at the  Royal Infirmary  in  Sheffield , successfully treated  ophthalmia neonatorum , a gonococcal infection in infants, with penicillin (fungal extract) on November 25, 1930.

47. The first successful use of pure penicillin was in 1942 when Fleming cured Harry Lambert of an infection of the nervous system (streptococcal  meningitis ) which would otherwise have been fatal By that time the Oxford team could produce only a small amount. Florey willingly gave the only available sample to Fleming. Lambert showed improvement from the very next day of the treatment, and was completely cured within a week . [90][91]   Fleming published his clinical trial in  The Lancet  in 1943. [7]   Following the medical breakthrough the British  War Cabinet  set up the Penicillin Committee on 5 April 1943 that led to projects for  mass production . [92][93]

48. Mass Production As the medical application was established , the Oxford team found that it was impossible to produce usable amounts in their laboratory Failing to persuade the British government, Florey and Heatley travelled to the US in June 1941 with their mould samples in order to interest the US government for large-scale production. [94]

49. . [95]   Mass culture of the mould and search for better moulds immediately followed . [94] On March 14, 1942, the first patient was treated for streptococcal sepsis with US-made penicillin produced by  Merck & Co. [ 96] [96]   Half of the total supply produced at the time was used on that one patient, Anne Miller . [97] In July 1943, the  to War Production Board  drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe. [ 99]  The results of fermentation research on  corn steep liquor  at the NRRL allowed the United States to produce 2.3 million doses in time for the  invasion of Normandy  in the spring of 1944.

50.    Large-scale production resulted from the development of a deep-tank fermentation plant by  chemical engineer   Margaret Hutchinson Rousseau . [102]  As a direct result of the war and the War Production Board, by June 1945, over 646 billion units per year were being produced. [99] During  World War II , penicillin made a major difference in the number of deaths and amputations caused by infected wounds among  Allied  forces, saving an estimated 12%–15% of lives . [104]  Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid  renal clearance  of the drug , necessitating frequent dosing . Methods for mass production of penicillin were patented by  Andrew Jackson Moyer  in 1945. [ 105][106][107]   Florey had not patented penicillin , having been advised by Sir  Henry Dale  that doing so would be unethical

51. Value of penicillin Penicillin is actively excreted, and about 80% of a penicillin dose is cleared from the body within three to four hours of administration . Indeed, during the early penicillin era, the drug was so scarce and so highly valued that it became common to collect the urine from patients being treated , so that the penicillin in the urine could be isolated and reused . [108]   This was not a satisfactory solution, so researchers looked for a way to slow penicillin excretion

52. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for excretion, such that the transporter would preferentially excrete the competing molecule and the penicillin would be retained. The  uricosuric   agent  probenecid  proved to be suitable . When probenecid and penicillin are administered together, probenecid competitively inhibits the excretion of penicillin, increasing penicillin's concentration and prolonging its activity. Eventually, the advent of mass-production techniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined [108]   Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins. [ 109]

53. Penicillin Fact file After World War II , Australia was the first country to make the drug available for civilian use. In the U.S., penicillin was made available to the general public on March 15, 1945 . [110] Fleming, Florey, and Chain shared the 1945 Nobel Prize in Physiology or Medicine for the development of penicillin .

54. Horward Walt florey

55. Why study pharma of penicillin?? It is the most important groups of antibiotics that’s why we will study penicillin in this presentation.

56. Structure of penicillin Made up of thiazolidine ring+beta-lactum + side chains Provides specific antibacterial properties and pharmacokinetics Additionally provides properties to diff. penicillin

57. Video At youtube

58. Mechanism of action (moa) Inhibits the synthesis of bacterial cell wall in bacteria

59. Important point Nurse must have a drug history from the patient before injecting penicillin Incidence is higher in atopic patients( Atopy refers to the genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema). Atopy is typically associated with heightened immune responses to common allergens, especially inhaled allergens and food allergens. ) A scratch test or intradermal sensitivity test with2-10 units should be done Even if it is negative it does not rules out the chances of patient having a penicillin allergy Penicillin must be given cautiously and a syringe loaded with ADR should be kept ready

60. Classification of penicillin Natural penicillin Semi-synthetic penicillin Extended spectrum penicillin

61. Natural penicillin Penicillin G Semi-synthetic penicillin 1. acid-resistant- penicillin V 2.penicillase resistant – nafcillin,methicillin 3 .aminopenicillins - ampicillin, bacampicillin, amoxicillin 4 . anti-pseudomonal penicillin- are further of two types Carboxy penicillins and ureidopenicillins

62. A.) Natural Penicillin AKA Penicillin G Benzyl penicillin

63. Spectrum of action Narrow spectrum antibiotic Anti-bacterial drug Largely active on gram positive microbes

64. Such as streptococci, C. diphtheria On few gram negative microorganisms such as N. gonorrhea and N. meningitidis Staphylococcus and some strains of gonococcus have become resistant to penicillin G.

65. Pharmacokinetics Penicillin G destroyed by gastric juice( hence given 2 hours) after food Rapidly absorbed into the bloodstream after IM injection Distributed widely into the body( doesn’t cross BBB but in presence of inflammation therapeutic conc. Is attained in CSF)

66. But enters in the CSF in case of meningeal inflammation Largely excreted through kidney (unchanged) Renal excretion is decreased by drug probenecid which blocks its renal tubular secretion, thus increasing its duration of action

67. Preparation of penicillin Sodium penicillin G aka crystalline penicillin- IM/IV Repository penicillin G aka Long acting Penicillin- given IM Only Benzathine Penicillin G – IM every 2 to 3 weeks Fortified proclaine penicillin G

68. Uses of Penicillin G (and book pj ) Streptococcal infections- pharyngitis, laryingitis,otitis media,rhemuatic fever, scarlet fever. Syphilis - procaine penicillin G 1.2 MU*10 Days for treating early signs 0f penicillin Pneumococcal infections : pneumonia, meningitis and otitis media treated with PnG if the strain is susceptible to it.

69. Diphtheria- 1-2 MU of procaine Pn G given for 10 days. Antitoxin is also given Acute necrotising ulcerative gingivitis : PnG given along with metronidazole for this indication Endocarditis prophylaxis : before dental or surgical procedures to prevent endocarditis in high risk individuals

70. Manifestation of allergic and hypersensitivity reactions Skin rash Itching Urticaria Angioedema Bronchospasm serum thickness Rare anaphylactic shock

71. Due to cross sensitivity patient may be allergic to the drugs of this class Therefore drug history is very important to elicit the possibility of allergy To do it inter dermal skin test I also done before administering to the patient.

72. Other adverse effects Local- pain, infection,thromophelebitis on IV site CNS - large doses of PnG ay cause confusion, muscle twitching,convulsions ad coma. Suprainfections - are rare beacsue penicillin is narrow spectrum of activity.

73. Adverse effect Allergic and hypersensitivity reactions Hematological effects Super infections

74. Disadvantages of PnG Narrow spectrum of activity Not effective orally Susceptible to penicillase Risk of hypersensitivity That is why semi-synthetic drugs were developed to overcome these disadvantages.

75. B.)Semi-synthetic penicillin Developed by changing the structure of side chains of Pn G They are advantageous over penicillin G because they are less susceptible to penicillase enzyme Have broader spectrum of action or oral efficacy

76. Penicillin V(aka phenoxymethyl penicillin) Can be given orally Generally used in mild streptococcal infections pharyngitis, sinusitis and trench mouth. Dose; 250-500 mg 6hrly

77. B1.) Acid resistant penicillin Penicillin V – is an acid resistant penicillin An alternate to penicillin G Similar spectrum of action Similar clinical indication Dose- 250-500mg QID.

78. B2.) Penicillase resistant penicillin Aka antistaphylococcal penicillin these are the drugs which are resistant to action of penicillase enzyme However they are less effective to other microorganisms than PnG Penicillase enzyme produced by Staphylococcus aureus Under this- methicillin and cloxacillin and dicloxacillin

79. Methicillin - destroyed by gastric juice that is why given parentally Cloxacillin is given orally Nafcillin is highly resistant to penicillase But useful against non-penicillase producing organisms Given parenterally cause of its unreliable absorption from the gut.

80. Methicillin This drug is no longer preferred Cause of widespread resistance to this drug in staphylococcus aureus bacteria Such bacteria are known as methicillin resistant staphylococcus aureus (MRSA) Also produces nephrotoxicity .

81. Cloxacillin and dicloxacillin Are penicillase and acid resistant Only used for penicillase producing staphylococcus aureus bacteria and not for other indications of penicillin G. Dose- 0.25-0.5mg orally/IV/IM QID.

82. Uses Are drugs of choices for infections with penicillase producing staphylococci Methicillin resistant strains have now emerged and treated with vancomycin

83. C.) Extended spectrum penicillin Also inhibits some gram negative bacteria in addition to gram-positive ones However not resistant to penicillase. Aminopenicillin include drugs such as apicillin, bacampicillin and amoxicillin.

84. 1.) Aminopenicillin Is a gastric acid resistant drug which inhibits Penicillin G susceptible microorganisms Are orally effective but are sensitive to beta lactamase It also inhibits gram – ve microbes such as H influenza ,E coli , proteus , salmonella, shigella and H. pylori and gram positive bacterias too. However some resistant has developed in these microbes too.

85. Ampicillin Well absorbed orally Food interferes with absorption Excreted mainly via kidneys Adverse effects- Diarrhoea( if not absorbed irritates the gut lining) most commo effect ofampicillin Skin rashes

86. USES: For treatment of cholecystitis ( high conc ability in gall bladder) UTI RTI( sinusitis, otitis media) Meningitis Intra-abdominal infections Gonorrhea Necrotizing ulcerative gingivitis Septicemia Prophylaxis for sub acute bacterial endocarditis

87. Adverse effect Frequently causes diarrhea( irritation produced by unabsorbed drug) Skin rashes Can also produce allergic or hypersensitive reactions

88. Dose 0.5-2 gram oral/IV/IM , 4 times a day

89. Drug interaction It produces inhibition of intestinal microflaura Hinders de conjugation of estrogen and progesterone present in oral contraceptives Decreasing their blood levels and causing failure or oral contraception.

90. Drug interaction Co-administration of ampicillin and probenecid. Higher blood levels of ampicillin due to blockage of renal tubular secretions of ampicillin by probenoid .

91. 2.) Bacampicillin Similar to ampicillin, an ester of ampicillin It is a prodrug (that is why better absorbed hence diarrhoea is less common) and longer acting than ampicillin But completely absorbed by GIT and hence lesser incidence of diarrhea Dose – 400-800 mg BD.

92. 3.) Amoxicillin Another aminopenicillin which is similar to ampicillin Commonly used clinically because of the advantage of having better oral absorption less frequency of drug intake Less incidence of diarrhoea. Indications are same as ampicillin Also a component of H. pylori therapy

93. Uses Similar indication as in ampicillin like UTI, RTI. Amoxicillin is used in various regimens to eradicate H. pylori. Have advantage over ampicillin over many.

94. Dose 0.25-1 g TDS.

95. Amoxicillin Is better and different from ampicillin Better absorbed orally Food doesn’t interfere wth absorption Diarrhoea is less common( cause amoxicillin is well absorbed) Amoxicillin is given thrice in a day but ampicillin is given four times a day

96. D.) Anti pseudomonal penicillins

97. Carboxy penicillins Ticarcilin and carbenicillin are carboxy penicillins that are active against pseudomonas and proteus Acts on gram – ve microbes too Not penicillase resistant Hence given in combination with beta- lactamase inhibitor( clauvulanic acid) for inhibiting beta- lactamase producing strains.

98. Uses- Used in case of pseudomonas and proteus infection----- burn patients Septicemia UTI

99. Carboxypenicillins

100. Carbenicillin Acts on proteus and pseudomonas aeruginosa too… It is less preffered than ticarcillin for these indications Because its tendency to produce salt and water retention causes consequent congestive heart failure Dose- 3 g IM/IV QID. Or 2-5 gm 6 hrlyIM /IV

101. Ticarcillin Have a better effect over pseudomonas aeruginosa than carbenicillin Combined effect with aminoglycosides for synergistic effect over the psedomonas aeruginosa May be given IM/IV Used in severe UTI’s against p. aeruginosa All of them are sensitive to penicillase

102. Adverse effect of antipseudomonal penicillin Carbenicillin is used as a salt and in higher doses this sodium excess can cause edema And CCF May cause bleeding due to abnormal platelet aggregation

103. Ureidopenicillins Have a wider antibacterial range than ticarcillin are effective against many gram negative organisms moreover their sodium content is low Hence they almost replaced carboxypenicillins Another anti pseudomonal penicillin With its properties also has a good enterobacteriaceae Used for treatment of serious gram-negative infections in seriously ill immunocompromised or burnt patients .

104. Azlocillin,mezlocillin and piperacillin are all administered as IV. When combined with Beta lactamase inhibitor , piperacillin can be considered to have a broadest antibiotic spectrum among penicillins It can cross BBB therefore is useful in Meningitis Piperacillin is advised in severe pseudomonal infection.

105. It is combined with tazabactum(beta lactamase inhibitor) to extend its spectrum of action to beta – lactamase producing strains of bacteria also. Dose- 100-150mg/kg/day in 3 divided doses or 3-4 gm 4-6 hrly .