Antimicrobial drugs

1. Kharkiv National Medical UniversityDepartment of Pharmacology and Medical Prescription assistant Gordiychuk D. Antimicrobial drugs I. Antiseptics and disinfectants. II. Sulfonamides.

2. Plan of lecture • I. Antiseptics and disinfectants. • II. Sulfonamides. • III. Combined sulfa drugs. • IV. Antimicrobials with different chemical structure.

3. Medicines with an antimicrobial activity are divided into two groups:1 – non-selective antimicrobial agents, causes most destructive effect on the majority of microorganisms (antiseptics and disinfectants).2 - selective antimicrobial drugs (chemotherapeutic agents).

4. ANTICEPTICS are disinfecting agents with sufficiently low toxicity for host cells that they can be used directly on skin, mucous membranes or wounds. ANTISEPSIS - it is the use of chemicals to destroymost pathogenic organisms on animate surfaces.

5. Antiseptic drugs are used in: The treatment of skin infections Prevention of infections in cuts and wounds Cleaning the skin area of surgery from microorganisms Profilaxy and treatment of infections in mucosal areas such as mouth, nose and vagina that are open to environment As a scrub for surgeans and the medical personnel

6. Disinfection DISINFECTANTSare chemical agents that inhibit or kill microorganisms (surgical apparatus, periphery of the patient, and the objects used by the patient). Disinfection It is the application of chemicals to destroy most pathogenic organisms on inanimate surfaces. Can be accomplished by application of chemical agents, use of physical agents (ionizing radiation) dry or moist heat, superheated steam(autoclave, 120̊ C). NB! Draw a sharp line between antiseptics and disinfectants is not always possible, because many substances used in low concentrations as antiseptics, and higher - for disinfection.

7. Requirements for antiseptics and disinfectants. • Must have a broad spectrum of action; • Rapid onset of action; • Should have a small latency period; • Should have a high activity; • Must be chemically resistant; • High availability and low cost; • Lack of local irritant or allergic effects on tissues; • Minimal absorption from the place of their application; • Low toxicity.

8. ORIGINS OF ANTISEPTICS Joseph Lister (1827 - 1912) • Realised that deaths from operations mostly occurred from infection contracted during the operation as a result of unclean practices. • He started using Carbolic acid (phenol) during operations to maintain aseptic conditions with significant improvements. • Like Semmelweiss he initially encountered opposition, but use of his methods by the Germans during the Franco-Prussian war in 1870 provided his major breakthrough and over the next 10 years, the practise of aseptic surgery became accepted.

9. Antimicrobials could be • narrow-spectrum - effective only against a limited variety of pathogens or broad-spectrum, affecting many different types of pathogens. • bactericidal if they kill the susceptible bacteria or bacteriostatic if they inhibit the growth of bacteria

10. THE PATHOGENS THAT CAN BE TRANSMITTED Human Immunodeficiency Virus (HIV) Herpes Simplex Virus types 1 and 2 Hepatitis B Virus (HBV) Streptococci Staphylococci Mycobacterium tuberculosis Cytomegalovirus Some upper respiratory tract viruses Disinfectants and antiseptics may be contaminated by resistant spores, Pseudomonas aeruginosa Serretia marcesnes and may transmit infection.

11. Sources of antiseptics • Early antiseptics were probably vegetable extracts • Many spices contain antibacterial agents • Essential oils extracted from plants often have antibacterial properties • Lister used carbolic acid which chemically is a solution of phenol • Phenol was originally extracted from coal tar. • Coal tar preparations are still used today in therapeutic soaps and shampoos. • To characterize the antimicrobial activity of the antiseptic agents used phenol ratio which indicates action force of the antimicrobial agent in comparison with the phenol, the difference between antiseptics and disinfectants, the objectives of their application.

12. I. Inorganic substances 1. Halogens: Iodine (2%, 3%, 5% alcochol solution) Iodinolum Ioddicerinum Povidon-Iod (Betadinum) Iodophorm Lugol’s solution Chloramine B Chlorhexidine bigluconate Pantocidum (Halazone) 2.Oxidizing agents: Hydrogen peroxide Potassium permanganate 3.Acids and alkalis: Boric acid Salicylic acid Solution of ammonia 4. Metallic salts: Hydrargyri dichloridum Hydrargyri amidochloridum Silver nitrate Copper sulfate Zinc sulfate Zinc oxide Classification of Antiseptics and Disinfectants (according chemical structure)

13. II. Organic substances 1. Aldehydes: Formaldehyde (Formalinum) Glutaraldehide Hexamethylentetraminum (Methenamine) 2. Alcochols: Spiritus aethylicus (Ethyl alcohol) 3. Phenol derivatives: Phenol (Phenolum purum, Carbolic acid) Cresol (Tricresolum) Resorcinol Thymol Benzylbenzoat 4. Dyes: Methylenum blue Brilliant green (Viride nitens) Etacridin lactate 5. Detergents: Aethonium Decamethoxin Roccal Dimexid 6. Tar, resins, products of petroleum: Pix liquida Betulae (Birch tar) Ichthyolum Liniment by Vishnevsky 7. Nitrofuran derivatives: Nitrofurasone (Furacilinum) 8. Antiseptics from medicinal plants: Chlorophyliptum Novoimaninum Classification cont.

14. Halogens Chlorine • Discovered in 1774 by a Swede, C.W. Scheele • It is a pale green, toxic, reactive gas • It is a powerful irritant and toxin • Used as a gas warfare agent in WWI • very nasty, inflicting lifelong damage on those who survived • The damaged lungs were possibly a factor in the 1918 flu pandemic • Solution of chlorine in water is both a powerful bleach and disinfectant • Semmelweis had used chloride of lime as an antiseptic

15. Halogens The mechanism of antimicrobial action • Denaturation of proteins of the protoplasm of microbial cells by reacting with the amino group of the proteins, displacing hydrogen. • Denatured protein loses its activity. NB!!! In the presence of organic substances halogen’s antimicrobial effectdecreases.

16. Iodines • Iodine - active bactericidal element. • At a dilution of 1: 20 000 - kill vegetative forms of bacteria for 1 min. • Alcoholic solution of Iodine 5% (5 g of Iodine, KI -2g, ethyl alcohol 95% -100ml) • An irritant and a distraction action • INDICATIONS: Disinfection of the surgical field, disinfection of wounds, the surgeon's hands, in myositis, neuralgia. • Iodine is partially absorbed into the blood from the skin and exhibits resorptive effects, especially in children. • SIDE EFFECT: Chemical burns, dermatitis.

17. Iodine cont. • LUGOL'S SOLUTION (Iodine-1 part, 2 part -KI, water-17 part) • INDICATION: Mucus lubrication in pharyngitis and laryngitis. • IODDICERINE (Iodine, dimethyl sulfoxide, glycerol) • Fungicidal, antimicrobial, antiviral, antinecrotic, antioxidant effects. NB!!!The most active Iodine preparation!!! • Doesn’t irritate tissue, does not cause pain reaction, deeply penetrates into the tissue. • INDICATION: Inflammatory infection (purulent wounds, infectious ulcers, sore throats, tonsillitis, pulpitis, otitis, pyoderma, erosion of the mucous membranes, mastitis, candidiasis, inflammatory diseases of the genital organs). • Topically in the form of tampons, napkins, irrigation, washing.

18. Halogens (Chlorine disinfectants) CHLORINE - active bactericidal element is active in the undissociated form of HOCl when Cl dissolved in water at neutral and acidic pH. • Bleach - not less than 32% of free Cl. Antimicrobial action - fast, but not for long. • INDICATIONS: 0.2-0.5% sol. for the disinfection of premises, infective patients discharge (pus, sputum, urine, feces). • Corrosive to metals. CHLORAMINE B - 25-29% active Cl. • INDICATION: eye wash, hand disinfection, douching (0.25-0.5%), treatment of purulent wounds, burns, pustular skin diseases (0.5-2%). Disinfection of premises, health products and non-metallic tools . • Deodorizing properties. • 4-8mg CHLORAMINE B is able to sterilize 1 liter of water for 15-60 min. (Pantocid), if the water contains a lot of organic substances.

19. Halogens CHLORHEXIDINE BIGLUCONATE (Bisdiguanidine derivative). • Has the properties of chlorine and detergent compounds. • Capable of damaging the plasma membrane of microorganisms. • Strong antibacterial and fungicidal action. • Bactericidal activity against GR+, Gr- bacterias, active against Treponema, gonococci, trichomonas, Proteus. INDICATIONS: disinfection of the surgical area, the surgeon's hands, tools, burn surfaces, septic processes, prevention of sexually transmitted diseases. In the form of a tabl. - in infectious and inflammatory diseases of the mouth and throat. 0.2% solution inhibits the formation of plaque and effective in treating gingivitis. SIDE EFFECTS:Dry hands, itchy skin, dermatitis. • !!!Can not be used in conjunction with IODINE!!! • CHLORHEXIDINE is often used as an active ingredient in mouthwash pastes to reduce dental plaque and oral bacteria. • It have an immediate bactericidal action and a prolonged bacteriostatic action due to adsorption onto the pellicle-coated enamel surface.

20. Oxidizing agents • HYDROGEN PEROXIDE • It is available as 30% and 3% solution. More common 3% solutions is used. • H2O2 = 2H + O2 It is decomposed with release of molecular form of oxygen that is responsible for antimicrobial effect. • Releasing oxygen makes foam that cleans and deodorizes putrid wounds and ulcers. • Catalases present in tissues speeds decomposition and foaming of hydrogen peroxide. • Hydrogen peroxide is used in treatment of infected wounds and to stop small bleeding.

21. Hydrogen peroxide Indications: - rinsing the mouth and throat, for the treatment of wounds that are infected with anaerobic microflora. Concentrated solutions (20-30%) is indicated for the treatment of warts, lichen planus. Side effects: - burn mucosa. Not used in deep wounds, and not introduced into a body cavity - may cause embolism.

22. Potassium permanganate • 2KMnO4 + H2O = 2KOH + 2MnO2 + 3O2 It liberates oxygen in atomic form. • Highly water soluble, used in 1:4000-1:10000 solution. • Higher concentrations cause burns and blistering. • It promotes rusting. Clinical uses: • Gargling, douching, irrigating cavities, urethra and wounds. • Stomach wash in alkaloid poisoning. • In a 2-5% solution is used for burns, bites of mosquitoes and snakes, for quick healing of wounds. • Disinfection of water.

23. Heavy metal compounds • Their mechanism of action is the blocking of SH-groups, carboxyl and amino groups of proteins and enzymes of microorganisms. • Metal ions are formed by dissociation of the salts, interaction with these active biosubstrates functional groups cause their denaturation. • At a deeper penetration of the substance in the tissue causes irritated cells and nerve endings effect, and the extreme manifestation of a cauterizing effect of metal salts. • (Pb, ... Al, Zn, Cu, Ag, ... Hg) In such sequence an increases antimicrobial activity. As antiseptics most active are metal salts on the right side of the row.

24. Heavy metal cont. • With prolonged use of salts of heavy metals can be cytotoxic effect due to the inhibition of thiol enzymes in the tissues. • Symptoms of poisoning with salts of heavy metals: a chemical burn of GIT mucosa, the weakening of cardiac activity, collapse, kidney and liver damage. • In cases of poisoning: gastric lavage with water, tea solution with activated carbon, Unithiol. Inside: milk, raw eggs, Unithiol or Tetacin calcium, Sodium thiosulfate. Symptomatic treatment: cardiac glycosides, sympathomimetics, plasma expanders, vasoconstrictors, narcotic analgesics.

25. Acids and alkalis • Acids: BORIC ACID, SALICYLIC -Shift the pH to the acid side → protein denaturation of microbial cell protoplasm. Since proteins of the skin and mucous membranes forming dense, insoluble albuminates, that is providing anti-microbial, anti-inflammatory, anti-fungal effects. • In high concentrations cauterize tissue (coagulative necrosis )! • Boric acid: used for washing and rinsing of the mucous membranes of the mouth, diaper rash, acute and chronic otitis media, colitis, pyoderma, pediculosis. • Side effect:It penetrates through the skin and mucous membranes, especially in children,cumulates. With long-term use in patients with impairedrenal function develops acute and chronic poisoning (nausea,vomiting, diarrhea, skin rashes, confusionconsciousness, convulsions, oliguria, sometimes shock. • Salicylic acid:Weak antiseptic, irritant, low concentrations (1-3%) –keratoplastic, in high (5% -10%) - keratolytic effect. • Indications:Oily seborrhea, acne, eczema, psoriasis, ichthyosis, warts, corns, etc.

26. Alkalis NAHCO3, SODIUM TETRABORATE, SOL. OF AMMONIA. • NaHCO3, sodium tetraborate - melted mucin, a softening effect. Inflammatory exudate pH shifts to the alkaline side reduces the manifestations of inflammation. • 10% ammonia solution exhibits antiseptic effect, manifests cleaning properties, dissolves fat. Given these properties, it is suggested for washing hands before surgery (25 ml solution of ammonia diluted in 5 liters of water). • Inhalation to stimulate the respiratory center.

27. Organic antiseptics Group of (aromatic) phenol, resorcinol, thimol, tar, ichthiol, benzylbenzoate. • Phenol (carbolic acid):3-5% solution for disinfection of furniture, household items, hospital linen, patients discharge. • 0.25-1% - sometimes in skin diseases accompanied by itching. • 0.1-0.5% - conservation of serum and suppository. • Readily absorbed through intact skin and mucous membranes, causing intoxication (short-term stimulation of the CNS, respiratory depression and cardiac activity, decrease in body temperature, damage of parenchymal organs).

28. ORGANIC COMPOUNDS  Phenols Resorcinol • In small doses has keratoplastic property in the more annoying - keratolytic. • Used for the treatment of skin diseases (eczema, seborrhea), fungal infections (2-5% solutions, 5-20% ointment, paste). Birch tar • Has: antimicrobial, keratoplastic, keratolytic and irritant effect. • Is used to treat a number of skin diseases and scabies. • Is one of the components of balsamic liniment of Vishnevskiy.

29. Group of aldehydes and alcohols FORMALDEHYDE SOLUTION, LISOFORM, ETHYL ALCOHOL, HEXAMETHYLENETETRAMINE (METHENAMINE) Formaldehyde solution (Formalin) • Has antimicrobial (vegetative forms and spores) and deodorizing effects. • MECHANISM OF ACTION: dehydration of microbial cells protoplasm proteins causing its destruction. • Is used as a disinfectant and deodorant, skin treatment with sweating (0.5-1%), disinfection of tools (0.5%). For the preservation of anatomical objects.

30. Aldehydes and alcohols (Formaldehyde cont.) • If inhaled formaldehyde - tearing, coughing, shortness of breath, agitation. • In oral poisoning - pain in the mouth, behind the sternum, in epigastric region, hematemesis, thirst, loss of consciousness, cyanosis, coma. • Emergency in poisoning:Inhalation of water vapor, oxygen saturation, gastric lavage 2.3% sol. of Ammonium chloride. • Inward enter: 2-3 tbsp. of activated carbon, 100 ml of 30% solution of magnesium sulfate. • In severe poisoning - forced diuresis, s/c 1 ml - 0.1% solution of Atropine sulfate, Promedol, inward - Codeine in tabl.

31. ETHYL ALCOHOL • Bactericidal activity starts with alcohol 20% and increases with concentration. On the spore form does not affect. • High concentrations of alcohol in the protein environment form dense protein aggregates. • 70% - it is more deeply penetrates into the deeper layers of the epidermis of the skin, sebaceous and sweat glands, provides a high antiseptic effect (antimicrobial strength of 70% is equal to 3% phenol sol.). • Application: disinfection of hands and operating field (70%). • Sterilization of surgical instruments (90-96%). • Disinfection of the skin before injection (70%). • Alcohol compresses for children (20%), adults (40%). • For the preparation of medicaments.

32. Group of dyes ETHACRIDINE LACTATE (RIVANOL), BRILLIANT GREEN, METHYLENE BLUE • Antimicrobial activity of this group falls In the protein environment • The most sensitive Gr + bacteria, cocci.

33. ETHACRIDINE LACTATE (RIVANOL): - used in surgery, gynecology, urology, ophthalmology, dermatology. For washing of fresh and infected wounds,cavities (pleura, peritoneum), bladder, uterus. BRILLIANT GREEN (1-2% WATER AND ALCOHOL SOL.): - for the treatment of skin with scratches, pyoderma, blepharitis, and others. METHYLENE BLUE: - used internally for urinary tract infections (cystitis, urethritis). -I/V 1% sol. 50-100 ml in case of poisoning with hydrocyanic acid or salts(in large doses translates hemoglobin to methemoglobin which comes into contact with a non-toxic form of cyanide complex cyanmethemoglobin). - When administered I/V in small doses (0.1-0.15 ml/kg 1% sol.) contrary methylene blue restores methemoglobin in the hemoglobin (with nitrite poisoning, aniline, and others.)

34. Nitrofuran derivatives(FURACILLIN, FURAZOLIDONE) • Spectrum of action: Gr-, Gr + bacteria (staphylococci, streptococci, dysentery bacillus, intestinal coli, Salmonella paratyphi, the causative agent of gas gangrene, etc.) and protozoa (Trichomonas, Giardia). • Pharmacodynamic: influenced microbes reductase, there is a restoration of the nitro group and their transformation into toxic products for cells (inhibition of the respiratory chain, the destruction of the microbial wall). • In the presence of pus does not lose effectiveness. • Apply for external treatment of wounds, skin, mucous membranes, wash serous and joint cavities, otitis media, conjunctivitis and others. Eye diseases and orally for the treatment of bacterial dysentery.

35. Detergents • Detergents - are substances with a high surface activity. • Show antiseptic and cleansing action. • Distinguish anionic and cationic detergents. • Anionic detergents include ordinary soaps (sodium or potassium salts of fatty acids). • As antiseptics mainly used cationic surfactants: Benzalkonium chloride, cetylpyridinium chloride, miramistim. • Benzalkonium chloride has antibacterial, antiprotozoal and spermicidal action (spermicidal effect develops in two stages: first - the destruction of the flagellum, and then - the gap of the sperm head, which makes it impossible to fertilization). • Used for treatment of skin, mucous membranes, wounds, rinsing the bladder, urethra, and for contraception in women.

36. Miramistim: • Antiseptic, antiviral, antibacterial agent • Gr-, Gr +, anaerobes, fungi. • Reduces the resistance of bacteria and fungi to antibiotics. Application:used as a 0.01% solution as an antiseptic in dental practice for the treatment of infected wounds, burns, infections of upper respiratory tract, urogenital system, stimulates local non-specific immunity, accelerates regeneration. Cetylpyridinium chloride in the composition of the drug "Tserigel" is used for hand washing before surgery.

37. SULFONAMIDES

39. Sulfonamides • Sulfa drugs (SA) - synthetic chemotherapeutic agents, which are derivatives of sulfanilamide, or amides of sulfonic acid. Common properties of SA: - Sulfa nucleus; - Mechanism of action; - Spectrum of antibacterial action. The first preparation of SA: Red Streptocid (1935).

40. I. Preparations with the resorptive (system) action which are well absorbed in the intestine, creating high concentrations in the blood and other tissues: 1.short-acting drugs (t1/2 less than 10 hours are applied 3-4 times per day, sometimes even 4-6 times a day in an amount of 4-6 g/day): - Sulfadimezin; - Ethazol; - Norsulfazol; - Urosulfan. Classification of SA

41. Classification of SA cont. 2. drugs with intermediate action (t 1/2 = 10 -24 hours): • - Sulfazin; • - Sulfamethoxazole. 3. long-acting (t 1/2 = 24-28 hours): • - Sulfadimetoxin; • - Sulfapiridazin; • - Sulfamonomethoxine. 4. extremely long-acting (t 1/2 of 48 hours): • - Sulfalen.

42. Classification of SA II. Preparations of the intestinal action, which are slowly and incompletely absorbed from the GIT, they are use for the treatment of intestinal infections(t 1/2 <10 hours). • - Ftalazol; • - Sulgin; • - Ftazin; III. SA for topical application (readily soluble in water and is used topically in the eye drops for the prevention and treatment of gonococcal eye disease in newborns, as well as for the treatment of conjunctivitis, blepharitis, corneal ulcers and other pathologies of the eye). • -Sulfacil-sodium.

43. Mechanism of action • Certain microbes require paraaminobenzoic acid (PABA) to synthesize dihydrofolic acid which is required to produce purines and ultimately nucleic acids. • Sulfonamides, chemical analogs of PABA, are competitive inhibitors ofdihydropteroate synthase. • Sulfonamides therefore are reversible inhibitors of folic acid synthesis and bacteriostatic not bacteriocidal.

44. Mechanism of action

45. Conditions necessary for the manifestation of the antibacterial action of the SA: • - microorganisms can use SA instead of PABA in the case when the concentration of the drug in tissues in 2000-5000 times higher than the concentration of PABA; • - SA efficiency sharply decreases in the presence of pus, blood and tissue breakdown products due to the PABA high concentration in these products; • - SA have antimicrobial action only against those microorganisms which are themselves synthesized DHFA; • - In SA resistant microorganisms observed increased synthesis of PABA; • - The use of the SA in low concentrations contributes to the formation of resistant strains of microorganisms and leads to inefficiency of the SA.

46. SA antimicrobial spectrum • Currently used SA have broad spectrum, they inhibit gram-positive and gram-negative bacteria:Streptococcus pneumoniae, beta-haemolytic streptococci,E. coli, Klebciella, Shigella, Salmonella, Enterobacter, Gonococci, Meningococci and Pneumococci; • Nocardia, • Chlamidia, • Protozoa (toxoplasma and malarial plasmodia).

47. SA pharmacokinetics • Absorption. Slightly in the stomach and mainly in the small intestine. Within 30 minutes after the administration of the SA are found in urine. The bioavailability is 70-90%. • Biotransport. Reversibly binds to serum albumin, an agent which is directly proportional to the degree of hydrophobicity of the molecule of the drug. SA can displace from its association another protein drugs, particularly NSAIDs and endogenous substances (bilirubin). • Distribution. Pass through the blood-tissue, placenta and blood-brain barriers. Also passes into breast milk.

48. SA pharmacokinetics (cont.) • Biotransformation. Phase I reactions - acetylation, hydrogen substitution in the group NH2-acetic acid residue, thereby forming acetylated derivatives which do not have antimicrobial activity in an acidic medium and form crystals that disrupts the function of the kidney (crystalluria). Reaction Phase II – formation of double binding with glucuronic acid. • Excretion. Advantageously, urine, saliva, to a lesser extent and intestinal contents, but also breast milk. Are displayed in the form of metabolites and unchanged.

49. Clinical uses of SA • Infections of urinary tract • GIT infections • Respiratory tract infection • Pharingitis, gingivitis • Chlamidial infections • Wounds, burns • Toxoplasmosis • Malaria • For systemic treatment cotrimoxazole is more often used nowadays • Sufonamides are used for prevention of infections.

50. Side effects of sulfonamides - occur in 3 - 5% of patients and more frequently in children and the elderly. Complications due to overdose, and patients with hypersensitivity to the SA. • The central nervous system: nausea, vomiting, dizziness, headache (central genesis), depression, increased fatigue. 2.Blood: leukopenia, thrombocytopenia, agranulocytosis, methemoglobinemia, hemolytic anemia. 3. Kidneys: oliguria, proteinuria, hematuria, crystalluria. 4. Allergic reactions: fever, itching, rash, pain in the joints. Prevention of crystalluria: • - Drink plenty of liquids (3-5 liters per day); • - drink alkaline mineral water or milk during SA using. Contraindications: Toxic and allergic reactions to drugs.