Download Free Medical SULFONAMIDES PowerPoint Presentation

SULFONAMIDES PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Check out this medical presentation on Pharmacology, which is titled "Sulfonamides", to know about Sulfonamides (sulphonamides), a group of man-made (synthetic) medicines that contain the sulfonamide chemical group.

Tags : Pharmacology, Sulfonamides, sulphonamides, synthetic, medicines

Published on : Jul 18, 2021 | Views : 2944 | Downloads : 6

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

SULFONAMIDES Assoc. Prof. Iv. Lambev (itlambev@mail.bg) G. Domagk (1895–1964), bacteriologist and pathologist discovered the first sulfonamide in 1935. Nobel prize for Physiology and Medicine in 1939.
Slide 2-

Mechanism of action Unlike man, most bacteria cannot utilize external folic acid, a nutrient which is essential for growth, and they have to synthesize it from para-aminobenzoic acid (PABA). Sulfonamides are struc- turally similar to PABA and inhibit the enzyme dihydrofolate synthetase in the biosynthetic pathway for folic acid. High concentrations of PABA antagonize the effectiveness of sulfonamides.
Slide 3-

PABA Sulfanilamide
Slide 4-

ppt slide no 4 content not found
Slide 5-

ppt slide no 5 content not found
Slide 6-

Spectrum of activity Sulfonamides have a bacteriostatic action on a wide range of Gram-positive and Gram- negative microorganisms and also are active against toxoplasma, nocardia species, and chlamydia. Sulfonamides alone are usually reserved for the treatment of nocardiosis and toxоplasmosis.
Slide 7-

Resistance is common and due to the production of dihydrofolate synthetase with reduced affinity for binding of sulfonamides, and is transmitted in Gram-negative bacteria by plasmids. Resistant strains of Staphylococcus aureus can synthesize more PABA than normal.
Slide 8-

Pharmacokinetics Most sulfonamides are well absorbed orally. They are widely distributed in the body and cross the BBB and placenta. Sulfonamides are metabolized in the liver, initially by acetylation which shows genetic polymorphism. The acetylated product has no antimicrobial actions but retains toxic potential.
Slide 9-

A large number of parent drugs and N-acetyl metabolites are excreted by the kidney.
Slide 10-

Unwanted effects Hypersensitivity reactions include rashes, vasculitis, Stevens-Johnson syndrome. Haemolysis in patients with glucose-6- phoshate-dehydrogenase deficiency. Crystalluria is a potential problem with overdose of these drugs or with acid urine. Sulfonamides compete for bilirubin binding sites on albumin and can cause kernicterus in neonates.
Slide 11-

Lyell syndrome after oral intake of Co-trimoxazole Stevens–Johnson syndrome after oral intake of Co-trimoxazole (Color Atlas and Synopsis of Clinical Dermatology, 1999)
Slide 12-

Clcr
Slide 13-

t1/2 8–16 h: - sulfamethoxazolе - sulfametrolе t1/2 > 16 h: - sulfadimethoxinе - sulfalen DRUG PREPARATIONS
Slide 14-

collyrium 20% 10 ml Sulfacetamidе Sulfadicramide For local treatment of bacterial conjunctivitis
Slide 15-

Low GI abssorption (30%) - Sulfaguanidinе in GI infections
Slide 16-

Sulfasalazinе (Salazopyrin®) colitis ulcerosa
Slide 17-

Biseptol® - tab. 480 mg Trimezol® - tab. 480 mg 960 mg/12 h 7–10 days Co-trimoxazolе (BAN) Sulfamethoxazole/Trimethoprim:
Slide 18-

Co-trimoxazolе (BAN)
Slide 19-

PABA DHF synthetase DHFA DHF reductase THFA Purines Sulfamethoxazole (-) Trimethoprim (-) Trimethoprim inhibits dihydrofolate reductase which converts dihydrofolate to tetrahydrofolate:
Slide 20-

The bacterial enzyme is inhibited at 50 000 times lower concentrations than the mammalian equivalent. The combination of trimethoprim with the sulfonamide sulfamethoxazole (known as co-trimoxazole – BAN) acts synergistically to prevent folate synthesis by bacteria. However, resistance to the sulfamethoxazole component, and the incidence of unwanted effects limit the value of this combination.
Slide 21-

Trimethoprim has a wide spectrum of activity against Gram-positive and Gram- negative bacteria. The combination with sulfamethoxazole is also effective against Proteus and Pneumocystis carinii (this is now its major indication). Trimethoprim and sufamethoxazole are well absorbed from the gut. Their t1/2 is about 11 h. Trimethoprim is excreted unchanged by the kidney. Co-trimoxazole is availble for p.o. and i.v. use.
Slide 22-

Adverse effects Nausea, vomiting, and diarrhoea, which are usually mild. Skin rashes. Folate deficiency leading to megaloblastic changes in the bone marrow is rare except in patients with depleted folate stores. Marrow depression with agranulocytosis.
Slide 23-

Basic antitubercular drugs Synthetic drugs (p.o.): Isoniazid, Ethambutol, Pyrazinamide, Ethionamide Antibiotics: Rifampicin (p.o.), Rifamycin (i.v. infusion), Rifabutin; Streptomycin Drugs for treatment of leprosy p.o.: Rifampicin, Clofazimine, Dapsone ANTIMYCOBACTERIAL DRUGS
Slide 24-

ANTITUBERCULAR DRUGS First line drugs: Isoniazid Rifampicin Ethambutol Pyrazinamide Streptomycin These drugs are use routinely. They have high antitubercular efficacy, and low toxicity.
Slide 25-

Second line drugs Antibiotics: Aminoglycosides: Kanamycin, Amikacin Other rifamicins: Rifabutin, Pifapentine Some macrolides: Azithromycin, Clarithromycin Other antibiotics: Capreomycin, Cycloserine Synthetic drugs: Fluoroquinolones: Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxacin Ethionamide, Para-aminosalicylic acid Linezolid These drugs are no more effective than the first-line agents. Their toxicities are often more serious. They are active against atypical strains of mycobacteria.
Slide 26-

ppt slide no 26 content not found
Slide 27-

 Isoniazid (5 mg/kg/24 h p.o. ) inhibits production of long-chain mycolic acids which are unique to the cell wall of mycobacteria species. It is bacterio- cidal against dividing microorganisms. Resistance is due to random mutation. It can be troublesome in the developing countries.
Slide 28-

Oral absorption of isoniazid is good, but reduced by food. It diffuses well into the body tissues, including the CSF, and pene- trates into macrophages so that it is effe- ctive against intracellular tubercle bacilli. Isoniazid undergoes genetically controlled polymorphic acetylation in the liver. A high percentage of fast acetylators being found in Japanese and Eskimo populations. In European populations 40–50% are rapid acetylators.
Slide 29-

Unwanted effects of isoniazid Nausea and vomiting. Peripheral neuropathy in high doses. This can be prevented by prophylactic oral use of pyridoxine (vit. B6). High risk patients are with diabetes, alcoholism, chronic renal failure, malnutrition. Hepatotoxicity. Systemic lupus erythematosus-like syndrome.
Slide 30-

(B6)
Slide 31-

 Ethambutol impairs synthesis of the cell wall of mycobacteria. It is primarily bacteriostatic. Its oral bioavailability is 77%. Only a small amount is metabo- lized and most is eliminated unchanged by the kidney. Unwanted effects: Headache, dizziness Optic neuritis (dose-related, but usually reversible).  Pyrazinamide has a bactericidal effect.
Slide 32-

This semisynthetically modiﬁed antibiotic product of Streptomyces mediterranei has been an important component of the treatment of tuberculosis in humans. Rifampicin acts by inhibiting RNA polymerase, which catalyzes the transcription of DNA to RNA. Rifampicin is bactericidal and has a wide spectrum: ● Brucella, Staphiloccocus spp. ● Gram-positive and Gram-negative anaerobic bacteria are inhibited at low concentrations, including Bacteroides fragilis. ● Chlamydia and Rickettsia are susceptible. ● Mycobacterium tuberculosis. ● Mycobacterium leprae.  Rifampicin (Rifampin – USAN)
Slide 33-

ppt slide no 33 content not found
Slide 34-

Absorption from the gut is almost complete, but is delayed by food. Peak plasma levels reach 3 h after a single oral dose of 600 mg. The t1/2 is 3 h. About 85-90% of the drug is protein bound in plasma but rifampicin penetrates well into most tissues, cavities, and exuda- tes. It is metabolized by deacetylation and is excreted mainly in the bile. The drug and its metabolite undergo prolonged enterohepatic recirculation.
Slide 35-

Rifampicin
Slide 36-

Unwanted effects of rifampicin Sometimes influenza-like symptoms, flushing, rashes. Hepatotoxicity, usually only producing a transient rise of transaminases in plasma. Induction of drug-metabolizing enzymes in the liver. Important interactions include those with oral contraceptives, phenytoin, warfarin, and sulphonylureas. Urine and tears become pink/red which may be a useful guide to compliance.
Slide 37-

 Streptomycin is an aminoglycoside antibiotic. Its antibacterial activity is due to its binding to the 30S subunit of the bacterial ribosome and inhibiting of protein synthesis. It has a wide spectrum of anti- bacterial activity but it is primarily used to treat mycobacterial infections (i.m.). The main problems are eighth nerve toxi- city (vestibulotoxicity more than deaf- ness), nephrotoxicity, allergic reactions, resistance.
Slide 38-

DRUG TREATMENT OF TUBERCULOSIS Mycobacterium tuberculosis readily deve- lops resistance to monotherapy. Three or four drugs are used for the first 2 months, and then the treatment is continued with 2 drugs for a further 4–7 months.
Slide 39-

A standard regimen in the UK includes rifampicin and isoniazid for 6 months with ethambutol and pyrazinamide for the first 2 months only.
Slide 40-

PRINCIPLES OF RATIONAL ANTIBACTERIAL CHEMOTHERAPY (Adapted from Laurence et al., 1997 & others)
Slide 41-

The following principles, many of which apply to drug therapy in general, are a guide to good clinical practice with antimicrobial agents. (1) Make a diagnosis precisely: – defining the site of action; – defining the microorganism(s) responsible and their sensitivity to drugs; – biological samples for laboratory must be taken before treatment is begun.
Slide 42-

(2) Aims of therapy The goal of antibacterial therapy is to help the body eliminate infectious organisms without toxicity to the host. It is important to recognize that the natural defense mechanisms of a patient are of primary importance in preventing and controlling infection. Examples of natural defenses against bacterial invasion are: ● the mucociliary escalator in the respiratory tract ● the ﬂushing effect of urination ● the normal ﬂora in the GIT. All such mechanisms can be affected by disease or therapeutic interventions.
Slide 43-

Once microbial invasion occurs, various host responses serve to combat the invading organisms, including: ● the inﬂammatory response ● cellular migration and phagocytosis ● the complement system ● antibody production. The difﬁculty of controlling infections in immunocom- promised patients emphasizes that antibacterial therapy is most effective when it supplements endogenous defense mechanisms rather than when acting as the sole means of control.
Slide 44-

(3) Consider factors affecting the success of antibacterial therapy Bacterial susceptibility Various factors need to be considered in susceptibility testing. The minimum inhibitory concentration (MIC) is the concentration of drug that must be attained at the infection site to achieve inhibition of bacterial replication. In general, if bacteria are not susceptible to a drug in vitro they will be resistant in vivo. Distribution to the site of infection To be effective, an antibacterial agent must be distributed to the site of infection and come into contact with the infecting organism in adequate concentrations of the active drug form.
Slide 45-

Bacteria that locate intracellularly (Bartonella, Brucella, Chlamydoia, Mycobacterium, Rickettsia) will not be affected by antibacterial agents that remain in the extracellular space. Staphylococcus is facultatively intracellular and may sometimes resist treatment because of intracellular survival. Drugs that accumulate in leukocytes and other cells include ﬂuoroquinolones, lincosamides, sulfonaides and macrolides but aminoglycosides and β-lactams do not achieve effective intracellular concentrations.
Slide 46-

An infectious/inﬂammatory process often adversely affects the distribution of a drug in vivo. An exception is inﬂammation of the meninges (meningitis), which reduces the normal barrier between blood and CSF, so that antibacterial agents that normally cannot cross this barrier reach the CSF. This breakdown of barriers by inﬂammation does not occur to an appreciable extent with the blood–prostate barrier and blood–bronchus barrier. Effective antibacterial concentrations may not be achieved in poorly vascularized tissues, e.g. the extremities during shock, sequestered bone fragments or heart valves.
Slide 47-

(4) Remove barriers to cure (e.g. lack of free drainage of abscesses, obstruction in the urinary or respiratory tracts). (5) Decide whether therapy is necessary. As a general rule, acute infections require chemotherapy whilst chronic infections may not. Chronic abscess or empyema respond poorly. Even some acute infections such as gastroenteritis are better managed symptomatically than by antimicrobials.
Slide 48-

(6) Choose the most suitable route of administration of antibacterial drug(s) Often there is a choice of routes of administration, although some drugs (such as aminoglycosides) must be given parenterally if systemic activity is desired. Other factors inﬂuencing route selection include the characteristics of the disease being treated, likely treatment duration, the patient’s temperament and owner’s capability.
Slide 49-

● Topical administration is valuable for disorders of eye and ear and some skin or gut infections. High drug concentration may be achieved locally in this way and some drugs too toxic for routine systemic administration (bacitracin, neomycin, polymyxins) can be useful topically. ● Oral administration is adequate in most infections and is usually preferable for home treatment. Some owners ﬁnd it easier to administer drugs orally with food but the potential ADRs of ingesta on systemic drug availability should be considered.
Slide 50-

If in doubt, administration on an empty stomach (no food for 1–2 h before and after dosing) is recommended, as the most common outcome of drug–ingesta interactions is impaired systemic drug availability. ● Parenteral administration is not routinely advantageous but can be useful for fractious, unconscious or vomiting patients, or those with oral/pharyngeal/esophageal pain or dysfunction.
Slide 51-

(7) Select the best drugs. This involves consideration of: – specificity (the antimicrobial activity of a drug must cover the infecting organisms); – pharmacokinetic factors (the chosen drug must reach the site of infection (e.g. by crossing BBB); – the patients (who may previously had allergic reactions to antimicrobials or whose routes of drug elimination may be impaired, e.g. by renal disease).
Slide 52-

In some infections the choice of antimicro- bials follows automatically from the clinic- cal diagnosis because the causative organ- nism is always the same, and is virtually always sensitive to the same drug, e.g. segmental pneumonia in a young person which is almost always caused by S. pneu- monia (benzylpenicillin), some haemolytic streptococcal infections, e.g. scarlet fever and erysipelas (benzylpenicillin), typhus (tetracycline), leprosy, lues.
Slide 53-

In the other cases the infecting organism is identified by the clinical diagnosis, but no assumption can be made as to its sensitivity to any one antimicrobial, e.g. tuberculosis. In the most cases the infecting organism is not identified by the clinical diagnosis, e.g. in urinary tract infections, meningitis, etc. In the last two categories the choice of antimicrobial drug may be guided by: – knowledge of the likely pathogens – simple staining and sensitivity tests.
Slide 54-

8. Compliance As with all drug therapy, antibacterials will not be effective unless administered correctly to the patient. It is very important for the successful treatment to keep a compliance from patients.
Slide 55-

(9) Indications for combination therapy: – to avoid the development of resistance in chronic infections (e.g. FIV, HIV, tuberculosis). – to broaden the antibacterial spectrum: a) in a known mixed infection; b) unusual pathogens, including Mycobacterium, Rhodococcus and fungi. c) if the microorganism cannot be predicted (septicemia complicating neutropenia); – to obtain potentation (e.g. penicillin plus gentamicin for enterococcal endocarditis)
Slide 56-

(10) Antimicrobial therapy and pregnancy PRC B have: Azithromycine Erythromycine Penicillins Most cephalosporines or lactation
Slide 57-

ppt slide no 57 content not found
Slide 58-

(11) Administer the drug in optimum dose and frequency – Inadequate dose may encourage the development of microbial resistance. – Intermittent dosing is preffered to continual infusion. – Plasma concentration monitoring can be applied to optimize therapy with aminoglyco- sides, fluoroquinolones, cephalosporins, etc. in patients with kidney disease.
Slide 59-

(12) Continue therapy until apparent cure has been achieved. – Most acute infections are treated for 5 to 10 days. There are many exceptions to this, such as typhoid fever, tuberculo- sis, and infective endocarditis, in which relapse is possible long after apparent clinical cure and so the drugs are continued for a long time, determined by clinical experience.
Slide 60-

(13) Test for cure. In some infections, microbio- logical proof of cure is desirable because disappearance of symptoms and signs occurs before the microorganisms are eradicated, e.g. urinary tract infections (examinations must be done after withdrawal of chemotherapy). (14) Prophylactic chemotherapy for surgical and dental procedures should be of very limited duration. It should be started at the time of surgery to reduce the risk of producing resistant microorganisms.
Slide 61-

(15) Remeber that the most important carriers of cross infections are your 10 fingers.