Drugs That Cause DNA Synthesis Inhibition PDF

DRUGS THAT CAUSE DNA SYNTHESIS INHIBITION Anti-Folate Drugs Thomas A. Panavelil, Ph.D., M.B.A. Folate Synthesis Inhibitors: Targetsbacteraonly folate cantlesynthesized byEukaryotes Sulfonamides: antibacterial & antiprotozoal Folate Reduct...

DRUGS THAT CAUSE DNA SYNTHESIS INHIBITION Anti-Folate Drugs Thomas A. Panavelil, Ph.D., M.B.A. Folate Synthesis Inhibitors: Targetsbacteraonly folate cantlesynthesized byEukaryotes Sulfonamides: antibacterial & antiprotozoal Folate Reduction Inhibitors: THFproductionfromSolar CanimpactHostneed tobecouseay aboutwhatisused Trimethoprim: antibacterial Pyrimethamine antiprotozoal Proguanil: antiprotozoal Combinational: Broad spectrum Co-trimoxazole (sulfamethoxazole-trimethoprim, TMP-SMX): Antibacterial Sulfadoxine plus Pyrimethamine: Antiprotozoal used intreatment  Folate synthesis inhibitors 1 Sulfamethoxazole (Gantanol)) anti Sulfisoxazole (Gantrisin) beeteralandanlrp.eu Sulfacytine I (Renoquid) Sulfadiazine Sulfamethizole (Thiosulfil) Mafenide (Sulfamylon Topical) Burnprophylaxis 1 I Sulfadoxine Sulfasalazine 1 (Azulfidine) sulitawithanfiinflamitaryforu.ee Sulfacetamide I 1 Silver sulfadiazine (Silvadene topical) Structure of sulfonamides and PABA mixed with come my Folate reduction inhibitors: Trimethoprim (Proloprim, Trimpex) Antibacterial Pyrimethamine (Daraprim) Antiprotozoal Proguanil Antiprotozoal Folate synthesis and reduction combinations: Trimethoprim-Sulfamethoxazole called Co- trimoxazole (TMP-SMZ or TMP-SMX ,Bactrim, Septra). Pyrimethamine-Sulfadoxine (Fansidar) Chemistry: Sulfonamides are derivatives of sulfanilamide (p- aminobenzene-sulfonamide). Most of them are insoluble in water, but sodium salts are soluble. The important structural parameters for antimicrobial action are sulfur directly linked to benzene and the para- amino group. Substitutions made in the amide group (- SO2NH2) with heterocyclic aromatic nuclei yield highly potent compounds. Antimicrobial spectra: Sulfonamides have a wide range of antimicrobial activity and they treat many gram-positive and gram-negative bacteria. The usefulness of sulfa drugs in the treatment against many organisms has diminished due to development of resistance.  Mechanism of action Sulfonamides and trimethoprim act as antimetabolites. Sulfonamides are structural analogues and competitive antagonists and para-aminobenzoic acid (PABA) and thus prevent the normal bacterial utilization of PABA for the synthesis of folic acid (Folic acid co-enzymes are required in the synthesis of purines and pyrimidines). Sulfonamides inhibit dihydro-pteroate synthase, the “bacterial enzyme” responsible for the incorporation of PABA in to dihydropteroic acid, the immediate precursor of the folic acid. MOA  Synergists of sulfonamide Trimethoprim is an analogue of dihydrofolic acid. It is a potent and selective inhibitor for the enzyme dihydrofolate reductase which reduces dihydrofolate to tetrahydrofolate (this reduced form of folate is used in one carbon transfers involving purine and pyrimidine synthesis). Bacterial enzyme is about 4 to 5 orders of magnitude sensitive than mammalian enzyme to the inhibition by trimethoprim and therefore reasonably selective against bacteria. The combination administration of a sulfonamide and trimethoprim causes a sequential block of folic acid synthesis. This sequential block results in a bactericidal action.  Resistance Bacterial resistance to sulfonamides originates by random mutation and selection or transfer of resistance by plasmids. Such resistance is persistent and irreversible. Resistance is caused by: Plasmid mediated or random mutations of the enzyme dihydro-pteroate synthase An increased capacity to destroy or inactivate the drug. Alternate pathways to synthesize essential metabolites. An increase production of the substrate (some resistant Staphylococci can synthesize 70 times as much PABA as the susceptible parent strains). Decreased uptake due to reduction in permeability.  Pharmacokinetics and Classification Sulfonamides are classified into three major groups. A) oral absorbable, B) oral non-absorbable and C) topical D) Parenteral Popuse Sulfonamides are distributed throughout all tissues of the body. They easily enter and are present in unbound form in pleural, synovial, peritoneal and ocular fluids. Individual sulfonamides: The sulfonamides may be short-acting (sulfisoxazole and sulfamethizole half-life 5-6 hours), intermediate- acting (sulfamethoxazole and sulfadiazine with serum half-life of 10-11 hours) and long-acting (sulfadoxine has serum half life of 100 to 230 hours). Sulfisoxazole (Gantrisin): Rapidly absorbed and rapidly excreted. It is highly soluble with low renal toxicity and low incidence of crystalluria. They are bound extensively to plasma proteins. Sulfisoxazole diolamine is for topical use in the eye. Sulfisoxazole-Phenazopyridine combination (Azo Gantrisin) is a urinary tract antiseptic and analgesic. Urine becomes orange red due to phenazopyridine. In children with otitis media, sulfisoxazole acetyl is marketed in combination with erythromycin as Pediazole, Eryzole or Pediagen. Redeactris notselloftenduetoresistance Sulfamethoxazole (Gantanol): Compared to sulfisoxazole, its rate of absorption and urinary excretion are slower. Half-life of sulfamethoxazole in babies in their first 10 days is much longer than in children and adults. Sulfamethoxazole crystalluria due to insoluble acetylated drug is common. It is also marketed with phenazopyridine as UTI antiseptic and analgesic (Azo Gantanol). With trimethoprim it is marketed as co- trimoxazole (see below). Combouse withTMP verycomon  Sulfadiazine Given orally, it is rapidly absorbed from the GI tract and peak concentration reaches within 3-6 hours. see Therapeutic concentrations are attained in CSF with 4 hours after a single oral dose. It is excreted by the kidneys as free and acetylated forms. Drug interactions: Sulfadiazene is known to increase the action of warfarin through displacement of warfarin from serum albumin binding sites. Administration of alkali accelerates the renal clearance. Used in prolonged infections Sulfasalazine (Azulfidine): They are poorly absorbed in the GI tract. It is used in ulcerative colitis and regional enteritis, but relapses are very common. samActivity Sulfasalazine is preferred over corticosteroids for treatment of patients ill with ulcerative colitis. how It is also used in cases of granulomatous colitis.  Topical sulfonamides Neomycin hasreplacedsulfacetamale Sulfacetamide (Isoptocetamide, Sulamyd sodium): It is used extensively in ophthalmic infections. Even very high aqueous concentrations are non-irritating to the eye therefore is an advantage to use against susceptible organisms. notcommonlyused Silver sulfadiazine (Silvadene): Topically used to reduce microbial colonization. It should not be used in established deep infection. Burning, rash and itching are adverse effects. Used extensively for the prevention of infection of burns Triple combination: Sulfabenzamide, sulfacetamide, and sulfathiazole are used together to treat bacterial vaginosis caused by Hemophilus (Gardnerella) vaginalis (as Sultrin, Dayto Sulf, Gyne-sulf, Triple Sulfa and Trysul). Mafenide (Sulfamylon): Effective in the prevention of colonization of burns. Not used in deep infection. Candida superinfection may be a problem. Adverse reactions include intense pain at sites of application and allergic reactions.  Long-acting sulfonamides (Sulfadoxine) used in Reff Acting plasmodium Half-life 7-9 days. In combination with pyrimethamine (Fansidar), it is used for the prophylaxis and treatment of Mefloquine resistant Plasmodium falciparum. Oral Trimethoprim-sulfamethoxazole (TMP-SMZ): Effective in Pneumocystis jirovecii pneumonia (initially classified as a protozoa and in 1988 reclassifies as yeast), Shigellosis, systemic salmonella infections (caused by ampicillin- and chloramphenicol resistant organisms. Effective in complicated UTI infections, ear infections, prostatitis, some non-tuberculous mycobacterial infections. adf.LI fEfIimegmratns Effective in treatment of both urinary tract infections and bacterial prostatitis due to beta-lactamase producing Escherichia coli. 1 apr Trimethoprim (a weak base) concentrates in prostatic fluid and in vaginal fluid, which are more acidic than plasma. Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs. Effective against respiratory pathogens like Hemophillus species, Moraxella catarrhalis (normal flora of upper respiratory tract, but in immune compromised patients causes infections), and Klebsiella pneumoniae (facultative gram-negative rod) and not Mycoplasma, making it alternative to beta-lactam antibiotics for upper respiratory infection and community acquired pneumonia. Strains of E. coli and penicillin resistant pneumococci have been found to have resistance to trimethoprim-sulfamethoxazole. Also used in methicillin resistant Staph. aureus infections. First line in UTI withcypro andfirstlinein Prostatites  I.V. trimethoprim-sulfamethoxazole Used in the management of severe P. jirovecii pneumonia, in AIDS patients. Also useful in gram-negative bacterial sepsis including that caused by multi-drug resistant drug species such as Enterobacter and Serratia. Also in Shigellosis, typhoid fever and UTI when patient cannot take the drug by mouth. Oral Pyrimethamine with Sulfonamide 9 dates Used in the treatment of Leishmaniasis (Leishmania donovani, parasitic protozoa) and toxoplasmosis (Toxoplasma gondii, a protozoa). In falciparum malaria the combination Pyrimethamine and Sulfadoxine (Fansidar) has been used especially in Mefloquine resistant strains. Sulfadoxine has a half-life of 7-9 days. Due to Steven Johnson syndrome, the prophylactic use is only in high-risk cases.II era many sulfa Patients drugallergic Proguanil & Atovaquone Oxphosinhibitor The activity of proguanil is due to its active metabolite cycloguanil. Cycloguanil selectively inhibits the bifunctional dihydrofolate reductase- thymidylate synthetase enzyme of plasmodia. Proguanil is used in combination with atovaquone (as Malarone) in prevention and treating malaria. Atovaquone is a plasmodial mitochondrial oxidative phosphorylation inhibitor.  Adverse reactions Hypersensitivity (drug fever, reactions, eosinophilia) is common. Dermatitis, Steven-Johnson syndrome, polyarteritis etc. Signs of serious adverse drug Artrymfumetnf reactions such as Steven-Johnson syndrome preclude a patient from being given the drug again in the future. GI: Nausea, vomiting, diarrhea etc. due to local irritation of the intestine. Mild hepatic dysfunction. Hematological: Rarely granulocytopenia, thrombocytopenia and aplastic anemia. G6PDH deficient patients may develop acute hemolytic anemia. Nephrologic: precipitation in urine in acidic pH resulting in crystalluria and hematuria. Synopsis of major diseases TMP-SMZ treat UTIs: Chronic and recurrent. Bacterial respiratory infections: Acute otitis media, chronic bronchitis and maxillary sinusitis. GI infections: Shigellosis, second-line drug for typhoid fever, and management of carriers of these strains Infections by Pneumocystis jirovecii: High dose therapy in patients with AIDS. Lower doses given prophylactically in AIDS patients to prevent pneumonia. Rash, leukopenia and hepatitis are problems. For Prophylaxis in neutropenic patients (P. jirovecii)  Other uses Used against a wide range of gram-positive and gram- negative organisms, Chlamydia, Nocardia and Protozoa etc. Ocular (Chlamydia trachoma): Sulfacetamide topical Nocardiosis (gram-positive actinomycete): Sulfadiazine Burns : Mafenide, Ag sulfadiazine Ulcerative colitis: Oral Sulfasalazine Nocardiosis: caused by Nocardia (filamentous gram- positive non-motile bacteria) with primary pulmonary lesions with or without hematogenous spread to deep viscera and CNS.  Malaria: Malarone contains proguanil (along with atovaquone), a plasmodial folate reductase inhibitor. longactzeneededwithspecificproteaseInhibitor  Miscellaneous: Brucellosis (gm-negative, intracellular, attacks reticuloendothelial system) etc.