ANTI-LEPROTIC AGENTS
ANTI-LEPROTIC AGENTS
INTRODUCTION:
Leprosy, also known as Hansen disease is an infectious disease that causes severe, disfiguring skin sores and nerve damage in the arms and legs. The disease has been around since ancient times often surrounded by terrifying, negative stigmas and tales of leprosy patient being shunned as outcasts.
Mycobacterium leprae, the causative agent of leprosy, was discovered by G.H. Armauer Hansen in Norway in 1873, making it the first bacterium to be identified as causing disease in human
Today, about 180,000 people worldwide are infected with leprosy, according to the WHO, most of them in Africa and Asia. About 200 people are diagnosed with leprosy in the US; every year, mostly in the south, California, Hawaii and some US territories.
GENERAL OVERVIEW
Causative agent: M. leprae (a slow-growing type of bacteria)
M. lepromatosis (newly-identified mycobacterium)
ROUTES OF TRANSMISSION
Skin
Nasal mucosa via the upper respiratory tract
INCUBATION PERIOD
Maximum incubation period reported is as short as few weeks, and maximum is as long as 30years.
CLASSIFICATION
For therapeutic purposes, it is divided into 2 groups of 5 types:
PATHOPHYSIOLOGY
Onset of leprosy is insidious. It affects nerves, skin and eyes. It may also affect mucosa (mouth, nose, and pharynx), testes, kidney, voluntary/smooth muscles, reticulo-endothelial system and vascular endothelium.
Bacilli enter the body usually through respiratory system. It has low pathogenicity, only a small proportion of infected people develop signs of the disease. After entering the body, the bacilli migrate towards the neural tissue and enter the Schwann cells and endothelial cells of blood vessels.
After enteringthe Schwann cells/macrophage; fate of the bacterium depends on the resistance of the infected individual towards the infecting organism. Bacilli start multiplying slowly (about 12-14 days for one bacterium to divide into two) within the cells, get liberated from the destroyed cells and enter other unaffected cells. Till this stage, person remains free from signs and symptoms of leprosy.
As the bacilli multiply, bacteria load increases in the body and infection by the immunological system. Lymphocytes and histocytes (macrophages) inside the infected tissue. At this stage clinical manifestation of nerves with impairment of sensation of sensation and/or skin patches. If it is not diagnosed and treated in the early stage, further progress of the disease is determined by the strength of the patient’s immune response.
Specific and effective cell mediated immunity (CMI) provides protection to a person against leprosy. When specific CMI is effective in eliminating/controlling the infection in the body, lesions heal spontaneously or it produces Paucibacillary (PB) type of leprosy. If CMI is deficient; the disease spread uncontrolled and produces multibacillary (MB) leprosy with multiple system involvement. Sometimes, the immune response is abruptly altered, either following treatment (MDT) or due to improvement of immunological response, which results in the inflammation of skin/or nerves and even other tissues, called as leprosy reaction (type 1&2).
SIGNS AND SYMPTOMS
Skin lesions – macule, patch, papules, plaques or nodules
Nasal mucosa resulting in – nasal congestion
- Anosmia (inability to smell)
- Perforation of nasal septum
- Saddle nose deformity
- Involvement of nerves – impairment of nerve function
- Pain and tenderness in the course of a nerve
- Swelling in the cause of a nerve
Commonly affected peripheral nerves:
- Trigeminal nerve – conjunctival sensation
- Ulnar nerve – adduction of little finger
- Lateral popliteal nerve – foot drop
- Posterior tibial nerve – clawing of toes
TREATMENT
A multidrug treatment regimen (MDT) is recommended for leprosy because resistance to the primary drug used has become common in the past twenty years.
Dapsone is the primary drug indicated for treatment of leprosy and it is almost always accompanied by at least one of other medication.
It works by preventing the formation of folic acid thereby inhibiting the organism’s replication.
Two of the common additional drugs are Rifampicin and Clofazimine.
DAPSONE: - It is bacteriostatic
- It inhibits synthesis of folic acid, which is responsible for the growth and multiplication of M. leprae.
- Dapsone (Avlosulfon) 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 MDT regimens, resistance is as high as 20% with Dapsone therapy.
Dapsone is well absorbed orally and is widely distributed throughout body fluids and tissues.
Peak concentration is within 1 - 3hrs of oral administration.
Half-life of 21 – 44hrs, about 50% of administered Dapsone is bound to serum proteins.
They tend to remain in the skin, muscle, kidney and lives up to 3weeks after therapy is stopped
They are retained in circulation for a long time (12 – 35days)
70 – 80% excreted in urine as metabolites.
Acedapsone is a derivative of Dapsone that has little activity against M. leprae but is converted to a active Dapsone metabolites.
It is a long-acting intramuscular respiratory form of Dapsone with a half-life of 46days.
Sulfones can produce non-haemolytic anaemia, methemoglobineamia and sometimes acute haemolytic anaemia
Some patients may develop acute skin lesions described as Sulfone Syndrome or Dapsone dermatitis. Some rare side effects include fever, pruritis, parasthesia, reversible neuropathy and hepato-toxicity.
CLOFAZIMINE:
Weakly bactericidal dye that has some activity against M. leprae.
Precise MOA is unknown, but may involve mycobacterial DNA binding.
Oral absorption is quite variable, 9 – 7% eliminated in faeces.
Has significant concentration in tissues, including phagocytic cells, has a plasma half-life of 70days.
Primarily excreted in bile, 1% in urine.
Used in treatment of sulfone-resistant leprosy in patients that are intolerant to sulfones.
It also exerts an anti-inflammatory effects and prevents erythema nodosumleprosum which can interrupt treatment with Dapsone.
Ulcerative lesions caused by M. ulcerans responds well to Clofazimine.
Also some activity against M. tuberculosis
Adverse reaction - Red brown distribution of the skin
- Acute abdominal pain that may warrant laparotomy or laparoscopy
- Splenic infarction
- Bowel obstruction
- Paralytic ileus
- GI bleeding
RIFAMPICIN:
Lipid soluble
Antibiotic that inhibits RNA synthesis in a broad-range of microbial pathogens.
Well absorbed orally, and a peak serum concentration is usually within 2 – 4hrs.
Drug absorption is impaired when given concurrently with aminosalicylic acid or if immediately after a meal.
Widely distributed throughout the body.
Therapeutic levels are achieved in all body fluids including CSF.
Rifampicin is capable of inducing its own metabolism, so its half-life can be reduced to 2hrs within a week of continued therapy
Most of the drug is excreted into the GIT and small amount in the urine.
Moderate dose adjustment is required in patients with underlying liver disease.
Adverse effects: - GI disturbances – nausea, vomiting, headache
- Hepatitis is a major side effect
- Hypersensitivity reactions such as pruritis, cutaneous vasculitis, thrombocytopenia
- Harmless red-coloured urine, faeces, saliva, sweat, tears.
DAPSONE (Avlosulfon)
Therapeutic category: Antibiotic, leprostatic, bacteriostatic
MOA: Inhibits folic acid biosynthesis in susceptible organisms
Indication: Paucibacillary (PB) or multibacillary (MB) leprosy
Contra-indication: Hypersensitivity to sulfones, severe anaemia.
Dosage: PBleprosy (in combination with Rifampicin).
Adult – 100mg.Children 10–14yrs, 50mg daily for 6 months
MB leprosy (in combination with Rifampicin and Clofazimine)
Adult – 100mg. Children 10 -14yrs 50mg daily for 12 months
Side effects: Haemolytic and methemoglobineamia, Dapsone syndrome
Hypersensitivity reaction: rash, fever, jaundice, GI irritation, tachycardia, headache, nervousness, insomnia, blurred vision.
Nursing consideration: Frequent blood test in early treatment
Watch out for symptoms of hypersensitivity
Discontinue or reduce dose if WBC count; Hb, RBC is low.
Nursing mothers should be advised to report cyanosis in infants.
CLOFAZIMINE (Lamperene)
Therapeutic category: Antibiotic, leprostatic,
MOA: Inhibits DNA binding
Indication: MB leprosy, type 2 lepra reactions
Contra-indication: Pregnancy
Dosage: MB (in combination with Dapsone and Rifampicin)
Adult – 50mgdaily. Children 10 -14yrs 50mg on alternate days/150mg once in a month for 12 months for 12 months
Type 2lepra reaction; 200mg – 300mg daily in 2/3 DD for max. 3months.
Side effects: Discoloration of skin, hair, cornea, conjunctiva, tears, sweat, sputum, faeces
Nursing consideration:
RIFAMPICIN
Therapeutic category:Antibiotic, leprostatic
MOA:Inhibits RNA synthesis in bacteria preventing replication
Indication: Paucibacillary (PB)
leprosy, Tuberculosis, meningitis
Contra-indication:Hypersensitivity to rifampicin, jaundice.
Dosage: PBleprosy (in combination with Dapsone).
Adult – 600mg once a month. Children 10 -14yrs 450mg once a month for 12 months
Side effects: Severe GI disturbances, anorexia, nausea, vomiting and diarrhoea
Headache, drowsiness, rashes, fever, influenza-like syndrome, collapse shock
Nursing consideration:
INTRODUCTION:
Leprosy, also known as Hansen disease is an infectious disease that causes severe, disfiguring skin sores and nerve damage in the arms and legs. The disease has been around since ancient times often surrounded by terrifying, negative stigmas and tales of leprosy patient being shunned as outcasts.
Mycobacterium leprae, the causative agent of leprosy, was discovered by G.H. Armauer Hansen in Norway in 1873, making it the first bacterium to be identified as causing disease in human
Today, about 180,000 people worldwide are infected with leprosy, according to the WHO, most of them in Africa and Asia. About 200 people are diagnosed with leprosy in the US; every year, mostly in the south, California, Hawaii and some US territories.
GENERAL OVERVIEW
Causative agent: M. leprae (a slow-growing type of bacteria)
M. lepromatosis (newly-identified mycobacterium)
ROUTES OF TRANSMISSION
Skin
Nasal mucosa via the upper respiratory tract
INCUBATION PERIOD
Maximum incubation period reported is as short as few weeks, and maximum is as long as 30years.
CLASSIFICATION
For therapeutic purposes, it is divided into 2 groups of 5 types:
- Paucibacillary (Tuberculoid polar leprosy (TT), Borderline Tuberculoid (BT) )
- Multibacillary (Midborderline (BB), Borderline Lepromatous (BL), Lepromatous polar leprosy (LL) )
- Tuberculoid: A mild less severe form of leprosy. People with this type have only one or few patches of flat, pale-coloured skin (Paucibacillary leprosy). The affected area of skin may feel numb because of nerve damage underneath. It is less contagious than other forms.
- 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 organ will also be affected.
- Borderline: people with this type of leprosy have symptoms of both the Tuberculoid and Lepromatous forms.
PATHOPHYSIOLOGY
Onset of leprosy is insidious. It affects nerves, skin and eyes. It may also affect mucosa (mouth, nose, and pharynx), testes, kidney, voluntary/smooth muscles, reticulo-endothelial system and vascular endothelium.
Bacilli enter the body usually through respiratory system. It has low pathogenicity, only a small proportion of infected people develop signs of the disease. After entering the body, the bacilli migrate towards the neural tissue and enter the Schwann cells and endothelial cells of blood vessels.
After enteringthe Schwann cells/macrophage; fate of the bacterium depends on the resistance of the infected individual towards the infecting organism. Bacilli start multiplying slowly (about 12-14 days for one bacterium to divide into two) within the cells, get liberated from the destroyed cells and enter other unaffected cells. Till this stage, person remains free from signs and symptoms of leprosy.
As the bacilli multiply, bacteria load increases in the body and infection by the immunological system. Lymphocytes and histocytes (macrophages) inside the infected tissue. At this stage clinical manifestation of nerves with impairment of sensation of sensation and/or skin patches. If it is not diagnosed and treated in the early stage, further progress of the disease is determined by the strength of the patient’s immune response.
Specific and effective cell mediated immunity (CMI) provides protection to a person against leprosy. When specific CMI is effective in eliminating/controlling the infection in the body, lesions heal spontaneously or it produces Paucibacillary (PB) type of leprosy. If CMI is deficient; the disease spread uncontrolled and produces multibacillary (MB) leprosy with multiple system involvement. Sometimes, the immune response is abruptly altered, either following treatment (MDT) or due to improvement of immunological response, which results in the inflammation of skin/or nerves and even other tissues, called as leprosy reaction (type 1&2).
SIGNS AND SYMPTOMS
Skin lesions – macule, patch, papules, plaques or nodules
Nasal mucosa resulting in – nasal congestion
- Anosmia (inability to smell)
- Perforation of nasal septum
- Saddle nose deformity
- Involvement of nerves – impairment of nerve function
- Pain and tenderness in the course of a nerve
- Swelling in the cause of a nerve
Commonly affected peripheral nerves:
- Trigeminal nerve – conjunctival sensation
- Ulnar nerve – adduction of little finger
- Lateral popliteal nerve – foot drop
- Posterior tibial nerve – clawing of toes
TREATMENT
A multidrug treatment regimen (MDT) is recommended for leprosy because resistance to the primary drug used has become common in the past twenty years.
Dapsone is the primary drug indicated for treatment of leprosy and it is almost always accompanied by at least one of other medication.
It works by preventing the formation of folic acid thereby inhibiting the organism’s replication.
Two of the common additional drugs are Rifampicin and Clofazimine.
DAPSONE: - It is bacteriostatic
- It inhibits synthesis of folic acid, which is responsible for the growth and multiplication of M. leprae.
- Dapsone (Avlosulfon) 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 MDT regimens, resistance is as high as 20% with Dapsone therapy.
Dapsone is well absorbed orally and is widely distributed throughout body fluids and tissues.
Peak concentration is within 1 - 3hrs of oral administration.
Half-life of 21 – 44hrs, about 50% of administered Dapsone is bound to serum proteins.
They tend to remain in the skin, muscle, kidney and lives up to 3weeks after therapy is stopped
They are retained in circulation for a long time (12 – 35days)
70 – 80% excreted in urine as metabolites.
Acedapsone is a derivative of Dapsone that has little activity against M. leprae but is converted to a active Dapsone metabolites.
It is a long-acting intramuscular respiratory form of Dapsone with a half-life of 46days.
Sulfones can produce non-haemolytic anaemia, methemoglobineamia and sometimes acute haemolytic anaemia
Some patients may develop acute skin lesions described as Sulfone Syndrome or Dapsone dermatitis. Some rare side effects include fever, pruritis, parasthesia, reversible neuropathy and hepato-toxicity.
CLOFAZIMINE:
Weakly bactericidal dye that has some activity against M. leprae.
Precise MOA is unknown, but may involve mycobacterial DNA binding.
Oral absorption is quite variable, 9 – 7% eliminated in faeces.
Has significant concentration in tissues, including phagocytic cells, has a plasma half-life of 70days.
Primarily excreted in bile, 1% in urine.
Used in treatment of sulfone-resistant leprosy in patients that are intolerant to sulfones.
It also exerts an anti-inflammatory effects and prevents erythema nodosumleprosum which can interrupt treatment with Dapsone.
Ulcerative lesions caused by M. ulcerans responds well to Clofazimine.
Also some activity against M. tuberculosis
Adverse reaction - Red brown distribution of the skin
- Acute abdominal pain that may warrant laparotomy or laparoscopy
- Splenic infarction
- Bowel obstruction
- Paralytic ileus
- GI bleeding
RIFAMPICIN:
Lipid soluble
Antibiotic that inhibits RNA synthesis in a broad-range of microbial pathogens.
Well absorbed orally, and a peak serum concentration is usually within 2 – 4hrs.
Drug absorption is impaired when given concurrently with aminosalicylic acid or if immediately after a meal.
Widely distributed throughout the body.
Therapeutic levels are achieved in all body fluids including CSF.
Rifampicin is capable of inducing its own metabolism, so its half-life can be reduced to 2hrs within a week of continued therapy
Most of the drug is excreted into the GIT and small amount in the urine.
Moderate dose adjustment is required in patients with underlying liver disease.
Adverse effects: - GI disturbances – nausea, vomiting, headache
- Hepatitis is a major side effect
- Hypersensitivity reactions such as pruritis, cutaneous vasculitis, thrombocytopenia
- Harmless red-coloured urine, faeces, saliva, sweat, tears.
DAPSONE (Avlosulfon)
Therapeutic category: Antibiotic, leprostatic, bacteriostatic
MOA: Inhibits folic acid biosynthesis in susceptible organisms
Indication: Paucibacillary (PB) or multibacillary (MB) leprosy
Contra-indication: Hypersensitivity to sulfones, severe anaemia.
Dosage: PBleprosy (in combination with Rifampicin).
Adult – 100mg.Children 10–14yrs, 50mg daily for 6 months
MB leprosy (in combination with Rifampicin and Clofazimine)
Adult – 100mg. Children 10 -14yrs 50mg daily for 12 months
Side effects: Haemolytic and methemoglobineamia, Dapsone syndrome
Hypersensitivity reaction: rash, fever, jaundice, GI irritation, tachycardia, headache, nervousness, insomnia, blurred vision.
Nursing consideration: Frequent blood test in early treatment
Watch out for symptoms of hypersensitivity
Discontinue or reduce dose if WBC count; Hb, RBC is low.
Nursing mothers should be advised to report cyanosis in infants.
CLOFAZIMINE (Lamperene)
Therapeutic category: Antibiotic, leprostatic,
MOA: Inhibits DNA binding
Indication: MB leprosy, type 2 lepra reactions
Contra-indication: Pregnancy
Dosage: MB (in combination with Dapsone and Rifampicin)
Adult – 50mgdaily. Children 10 -14yrs 50mg on alternate days/150mg once in a month for 12 months for 12 months
Type 2lepra reaction; 200mg – 300mg daily in 2/3 DD for max. 3months.
Side effects: Discoloration of skin, hair, cornea, conjunctiva, tears, sweat, sputum, faeces
- GI disturbances; nausea, vomiting, diarrhoea
- Weight loss, GI bleeding
Nursing consideration:
- Advise patient to take drug with meal
- Use cautiously in GI dysfunction
- Warn patient about discoloration
- Advise patient to apply skin oil or cream to help reverse skin dryness
- Do not administer to pregnant woman
RIFAMPICIN
Therapeutic category:Antibiotic, leprostatic
MOA:Inhibits RNA synthesis in bacteria preventing replication
Indication: Paucibacillary (PB)
leprosy, Tuberculosis, meningitis
Contra-indication:Hypersensitivity to rifampicin, jaundice.
Dosage: PBleprosy (in combination with Dapsone).
Adult – 600mg once a month. Children 10 -14yrs 450mg once a month for 12 months
Side effects: Severe GI disturbances, anorexia, nausea, vomiting and diarrhoea
Headache, drowsiness, rashes, fever, influenza-like syndrome, collapse shock
Nursing consideration:
- Advice patient about discoloration of urine, tears, sweatT
- ake 1hr before or 2hrs after meal on an empty stomach
- Watch out for hypersensitivity
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