Antileprotic drugs

Antileprotic drugs

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  Leprosy or Hansen’sDisease • Leprosy is caused mainly by Mycobacterium leprae, a rod shaped bacillus that is an obligate intracellular (only grows inside of certain human and animal cells) bacterium. • Means Living culture media is required for growth of this bacterium eg of culture media- Rat- Whole animal (Like virus and Reckettsia) • It is a Gram positive bacteria. • M. lepraeis termed an "acid fast" bacterium. When special stains ( eg. The Ziehl-Neelsen stain) are used for microscopic analysis, it stains red on a blue background due to mycolic acid content in its cell walls. • The bacteria take an extremely long time to reproduce inside of cells (about 12-14 days as compared to minutes to hours for most bacteria) • The bacteria grow very well in the body's macrophages (a type of immune system cell) and Schwann cells (cells that cover and protect nerve axons). M. leprae is genetically related to M. tuberculosis (the type of bacteria that cause tuberculosis) and other mycobacteria that infect humans. Note- Artificial culture media- M. lepraeis do not show growth. This character is different in it from other bacteria.
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  Risk factors forleprosy • People at highest risk are those who live in the areas where leprosy is endemic (parts of India, China, Japan, Nepal, Egypt, and other areas) and especially those people in constant physical contact with infected people. • There is some evidence that genetic defects in the immune system may cause certain people to be more likely to become infected (region q25 on chromosome 6). • People who handle certain animals that are known to carry the bacteria (for example, armadillos, African chimpanzee, sooty mangabey, and cynomolgus macaque) are at risk of getting the bacteria from the animals, especially if they do not wear gloves while handling the animals.
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  Transmission  Droplets andother secretions can contain the bacteria that cause Hansen’s disease.  Disease can spread from person to person when someone with the disease coughs or sneezes. This can release droplets into the air. Symptoms of Leprosy Leprosy primarily affects the skin and the nerves outside the brain and spinal cord, called the peripheral nerves. It may also strike the eyes and the thin tissue lining the inside of the nose. The main symptom of leprosy is disfiguring skin sores, lumps, or bumps that do not go away after several weeks or months. The skin sores are pale-colored. Nerve damage can lead to: Loss of feeling in the arms and legs Muscle weakness It usually takes about 3 to 5 years for symptoms to appear after coming into contact with the leprosy-causing bacteria. Some people do not develop symptoms until 20 years later. The time between contact with the bacteria and the appearance of symptoms is called the incubation period. Leprosy's long incubation period makes it very difficult for doctors to determine when and where a person with leprosy got infected.
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  Type of Leprosy •A mild, less severe form of leprosy. • People with this type have only one or a few patches of flat, pale-colored skin (paucibacillary leprosy). • The affected area of skin may feel numb because of nerve damage underneath. • Tuberculoid leprosy is less contagious than other forms. Treatment depend on the type of leprosy. Tuberculoide Lepromatous •A more severe form of the disease. It has widespread skin bumps and rashes (multibacillary leprosy), numbness, and muscle weakness. •The nose, kidneys, and male reproductive organs may also be affected. •It is more contagious than tuberculoid leprosy. People with this type of leprosy have symptoms of both the tuberculoid and lepromatous forms. Borderline
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  Diagnostic test • Skinbiopsy -Docter remove a small sample of the abnormal skin and send it to a lab to be examined. • Skin smear test • Result of test-In paucibacillary leprosy, no bacteria will be detected. In contrast, bacteria are expected to be found on a skin smear test from a person with multibacillary leprosy.
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  Anti leprosy drugs AAntileprosy drugs is a drug that interferes with proliferation of the bacterium that causes leprosy Sulfone • Dapsone (Primary Antileprotic Drugs) Phenazine dye • Clofazimine Antibiotics • Minocycline, • Ofloxacin Anti-TB drugs • Rifampine • Ethionamide
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  SULFONE Dapsone IUPAC Name- 4-[(4-aminobenzene)sulfonyl]aniline Dapsone, alsoknown as diaminodiphenyl sulfone (DDS),is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. Dapsone is the most widely used sulfone for the long-term therapy of leprosy. Although the sulfones are highly effective against most strains of M. leprae, a small number of organisms, especially those found in lepromatous leprosy patients, are less susceptible and can persist for many years, resulting in relapse. Before the introduction of current multidrug regimens, resistance rates were as high as 20% with dapsone monotherapy. MOA The sulfones are structural analogues of PABA and are competitive inhibitors of folic acid synthesis. Sulfones are bacteriostatic and are used only in the treatment of leprosy.
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  • Sulfones, suchas dapsone are well absorbed orally and are widely distributed throughout body fluids and tissues. • Peak concentrations of dapsone are reached within 1 to 3 hours of oral administration and have a half-life of 21 to 44 hours; about 50% of administered dapsone is bound to serum proteins. • The sulfones tend to remain in the skin, muscle, kidney, and liver up to 3 weeks after therapy is stopped. The concentration in inflamed skin is 10 to 15 times higher than that found in normal skin. • The sulfones are retained in the circulation for a long time (12–35 days) because of hepatobiliary drug recirculation. The sulfones metabolism by acetylation in the liver, and 70 to 80% of drug is excreted in the urine as metabolites. Pharmacokinetic Dapsone, combined with other antileprotic agents like rifampicin and clofazimine, is used in the treatment of both multibacillary and paucibacillary M. leprae infections. Note- sulfoxone (Diasone) is other Sulphone that use as Anti leprotic USE
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  Within a fewweeks of therapy some patients may develop acute skin lesions described as sulfone syndrome ordapsone dermatitis. Some rare side effects include fever, pruritus, paresthesia, reversible neuropathy, and hepatotoxicity. Adverse effects Phototoxicity- patient should avoid direct sun light exposure Acute Haemolytic anaemia - especially in those with (G-6-PD) glucose- 6-phosphate dehydrogenase deficiency (Genetic defect). NOTE- This enzyme protect RBC from oxidizing agents NOTE- Dapsone is contraindicated in = Severely anemic person Hb<7 Methemoglobinemia
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  Allergic reaction orlepra Reaction • During the course of leprosy, immunologically mediated episodes of acute or subacute inflammation known as reactions may occur in up to 25% of patients with paucibacillary leprosy and as much as 40% in multibacillary leprosy. • Clinical indications of a reaction are nerve pain, loss of sensation and loss of function. The reactions may rapidly cause severe and irreversible nerve damage and must always be treated promptly. If a patient does not respond to lepra reaction treatment within 4 weeks or patient condition deteriorates at any time during lepra reaction treatment, send that patient immediately to the nearest specialist centre. • During a lepra reaction, do not interrupt leprosy multidrug therapy. Treatment with multidrug therapy reduces the frequency and severity of lepra reactions. LEPRA REACTIONS TYPE 1 Lepra Reactions TYPE 2 Lepra Reactions
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  Type 1 leprareactions or reversal reactions • Type 1 lepra reactions or reversal reactions are associated with the development of M. leprae antigenic determinants. • They are delayed hypersensitivity reactions and may occur in both paucibacillary leprosy and multibacillary leprosy. • In type 1 lepra reactions, there is a high risk of permanent damage to the peripheral nerve trunks. • If the reaction is mild and there is no evidence of neuritis (pain, loss of sensation or function), the reaction should be treated with analgesics, such as acetylsalicylic acid or paracetamol. • However, if there is nerve involvement, treat type 1 reactions with analgesics and corticosteroids, such as oral prednisolone. The usual course begins with 40 - 60 mg daily (up to a maximum of 1 mg/kg), and the reaction is generally controlled within a few days. The dose is then gradually reduced weekly or fortnightly and eventually stopped. Most reversal reactions and neuritis can be treated successfully under field conditions with a standard 12-week course of prednisolone but some authorities claim that corticosteroids need to be continued for much longer periods of time.
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  Type 2 leprareactions (erythema nodosum leprosum) • Type 2 lepra reactions (erythema nodosum leprosum), are associated with circulation and tissue deposition of immune complexes. • They are an antibody response or immune complex response to M. leprae antigenic determinants which occur only in multibacillary leprosy. • Therapy for type 2 reactions may include analgesics, such as acetylsalicylic acid or paracetamol, and corticosteroids, such as oral prednisolone. • In patients with severe type 2 reactions, who do not respond to corticosteroids or in whom corticosteroids are contraindicated, clofazimine at high doses or thalidomide may be used under close medical supervision. • Clofazimine often requires 4-6 weeks before an effect is seen, and therefore must never be used as the sole drug for treatment of severe type 2 reactions. However, it may be useful for reducing or withdrawing corticosteroids from patients who have become dependent on corticosteroids. • The clofazimine dose for treatment of severe type 2 reactions is 300 mg daily, which should be given in 3 doses of 100 mg each. The total duration of this high dose of clofazimine should not exceed 12 months. • Thalidomide should be avoided in women of childbearing age since it is a proven teratogen. If this is not possible, it is imperative that pregnancy is excluded before this treatment is initiated. Effective contraception must be used during the 4 weeks preceding and following treatment as well as during the treatment period. Should pregnancy occur despite these precautions, there is a high risk of severe malformation of the fetus.
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  Phenazine dye (Clofazimine) •Clofazimine is a weakly bactericidal dye (Red color dye) that has activity against M. leprae. It is not primary drug to treat leprosy. • Clofazimine is given to treat sulfone-resistant leprosy or to patients who are intolerant to sulfones. IUPAC Name N,5-bis(4-chlorophenyl)-3-(propan-2- ylimino)-3,5-dihydrophenazin-2-amine
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  • This isa major advantage of clofazimine over other antileprosy drugs is • Ulcerative lesions caused by Mycobacterium ulcerans respond well to clofazimine. • It also has some activity against M. tuberculosis and can be used as last resort therapy for the treatment of MDR (Multi Drug Therapy) tuberculosis. • May involve binding with mycobacterial DNA – and interfer its templet functions • It also Increase generation of Reactive oxidants from Neutrophils and exerts an antiinflammatory effect and prevents erythema nodosum leprosum, which can interrupt treatment with dapsone. Mechanism of action USE
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  • The mostdisturbing adverse reaction to clofazimine is a red-brown discoloration of the skin, especially in light-skinned persons. • A rare but serious adverse reaction is acute abdominal pain significant enough to warrant exploratory laparotomy or exploratory . • Other infrequent side effects include splenic infarction, bowel obstruction, paralytic ileus, and upper GI bleeding. Adverse Effect • Its oral absorption is quite variable, with 9 to 70% of the drug eliminated in the feces. • Clofazimine achieves significant concentrations in tissues, including the phagocytic cells; it has a plasma half-life of 70 days. • It is primarily excreted in bile, with less than 1% excretion in urine. Pharmacokinetic