Antimicrobials PDF

## Antimicrobials ### Quinolones - Can damage growing cartilage and cause arthropathy - Contraindicated under the age of 18 years and in pregnant women and in lactating women because it's secreted in milk - Tendinitis that can lead to tendon rupture ### Tuberculosis - Infectious disease caused...

## Antimicrobials ### Quinolones - Can damage growing cartilage and cause arthropathy - Contraindicated under the age of 18 years and in pregnant women and in lactating women because it's secreted in milk - Tendinitis that can lead to tendon rupture ### Tuberculosis - Infectious disease caused by the mycobacterium tuberculosis - Primarily involves the lungs but may attack most of the organs of the body - Clinical features include fever, anorexia, hemoptysis, cough, sputum, weight loss, anemia, sweating at night and enlarged lymph nodes - Leads to tubercle formation, necrosis and fibrosis of lung ### Antimucobacterial drugs #### First Line or Standard Drugs 1. Isoniazid (INH) 2. Rifampicin 3. Ethambutol 4. Streptomycin 5. Pyrazinamide #### Second line or Reserve Drugs - Used when the first line drugs fail to produce a response or if the microorganisms are resistant to those drugs 1. Ciprofloxacin 2. Ofloxacin 3. Amikacin 4. Cycloserine 5. Ethionamide 6. Para-aminosalicylic acid 7. Capreomycin 8. Rifabutin *Note*: The anti-tuberculosis drugs are given in combination to prevent bacterial resistance to the drugs ### Isoniazid ( INH) #### Mode of Action - Inhibits synthesis of mycolic acids which are essential components of mycobacterial cell walls #### Pharmacokinetics - **Absorption**: Absorbed orally, absorption is impaired if taken with food, particularly carbohydrates or antacids. Given before breakfast in an empty stomach. Serum and CSF levels are about the same. - **Metabolism and excretion**: Metabolized by acetylation in the liver. Metabolites and a small amount of unchanged drug are excreted in urine. - **Dosage adjustment**: Required in hepatic insufficiency but not in renal failure. - **Indication**: Tuberculosis. #### Side Effects - Hypersensitivity reactions: Skin rashes and fever - Direct toxicity: Hepatitis (INH-induced hepatitis is the most frequent major side effect of INH, the risk increases with age, during pregnancy and postpartum period. Manifests as jaundice, right hypochondrial pain and raised liver enzymes) Peripheral neuritis (results from Pyridoxine deficiency produced by isoniazid which increases its excretion, predisposing factors are malnutrition, diabetes, uremia, alcoholism and AIDS Peripheral neuritis or neuropathy presents as paresthesias, deficiency is corrected by Pyridoxine supplementation) ### Rifampicin #### Mode of Action - Inhibits DNA-dependent RNA polymerase enzyme of myobacteria leading to suppression of RNA synthesis #### Antibacterial Spectrum 1. Mycobacterium tuberculosis 2. Mycobacterium leprae 3. Prophylaxis of meningitis due to meningococci or H. influenzae 4. Leprosy 5. Prophylactically for meningitis caused by meningococci or H. influenzae #### Pharmacokinetics - Absorption is adequate after oral administration and excreted mainly through the liver into bile. Undergoes enterohepatic circulation, with the bulk excreted as deacylated metabolite in feces, and a small amount in urine. - Dose adjustment in renal failure is not required. - Adequate CSF concentration is achieved in the presence of meningeal inflammation only. #### Side Effects - Nausea, vomiting, rash and fever are most common - Rifampicin gives harmless, orange color to urine, sweat, tears and contact lenses - Cholestatic jaundice, hepatitis - Drug interactions: Increases elimination of anticoagulants, anticonvulsants and oral contraceptives by inducing hepatic enzymes. Therefore oral contraceptives are not reliable. Ketoconazole reduces rifampicin concentration. ### Ethambutol #### Mode of Action - Inhibits RNA synthesis. Its principal value is inhibition of growth of mutants which are resistant to INH and rifampicin. #### Pharmacokinetics - Well absorbed after oral administration. About 20% of the drug is excreted in feces and 50% in urine in an unchanged form. Dose adjustment is required in renal failure. It crosses only inflamed meninges. #### Adverse Effects - Retrobulbar neuritis: Causing loss of visual acuity and loss of ability to discriminate between red and green color. Therefore contraindicated in children because visual assessment is not possible for side effects. ### Pyrazinamide #### Mode of Action - Unknown. #### Adverse Effects - Liver damage - GIT disturbances eg nausea, vomiting - Allergic skin rashes - Gout ### Streptomycin #### Mode of Action - Acts directly on ribosome to inhibit protein synthesis by binding with 30s ribosomal sub unit. #### Adverse Effects - Hypersensitivity reactions - Vestibular nerve damage - Nephrotoxicity - Superinfection ### Ethionamide #### Mode of Action - Inhibits protein synthesis in the tubercle bacilli. It is metabolized by the liver. #### Adverse Effects - Allergic reactions - GIT disturbances - Toxic hepatitis - Depression and deafness - Visual disturbances - Acne ### Cycloserine - Inhibits bacterial cell wall synthesis. - Metabolized in the liver and excreted through the kidneys. Dose adjustment is required in renal failure. - Side effects include peripheral neuropathy and exacerbation of epileptic seizures. ### Dosage of Antituberculous Drugs | Drug | Dosage | |---|---| | INH | 5-10mg/kg | | Rifampicin | 10-20mg/kg | | Ethambutol | 15-25mg/kg | | Pyrazinamide | 20-35mg/kg | | Pyridoxine (Vit. B6) | 10mg/day | ### Prescription - Antituberculous drugs are prescribed according to the weight of the patient. Following are the commonly used prescriptions for adults. **Above 50 kg** | Drug | Dosage | Frequency | |---|---|---| | Tab. INH | 100mg | 3 OD | | Tab. Rifampicin | 600mg | 1 OD | | Tab. Ethambutol | 400mg | 3 OD | | Tab. Pyrazinamide | 500mg | 3 OD | | Tab. Pyridoxine | 50mg | 1 OD | **Below 50 kg** | Drug | Dosage | Frequency | |---|---|---| | Tab. INH | 100mg | 2 OD | | Tab. Rifampicin | 450mg | 1 OD | | Tab. Ethambutol | 400mg | According to weight | | Tab. Pyrazinamide | 500mg | According to weight | | Tab. Pyridoxine | 50mg | 1 OD | ### Important Viva Questions 1. What are the drugs used in the treatment of tuberculosis? 2. What is the drug of choice in tuberculosis? 3. What are the side effects of rifampicin? 4. Why do we combine two or more drugs in the treatment of tuberculosis? 5. What are the side effects of ethambutol? 6. What is the mode of action of isoniazid and rifampicin? ### Leprosy - Disease caused by mycobacterium leprae - Causes characteristic lesions in the skin and the peripheral nerves ### Drugs Used in Leprosy 1. Sulphones: eg. Dapson, acedapsone 2. Phenazine: eg. Clofazimine 3. Anti-tubercular drugs: eg. Rifampicin, thiacetazone, ethionamide, streptomycin 4. Others: eg. Thiambutosine, amithiozone ### Dapson - **Mode of action:** Competitively inhibits the utilization of PABA for synthesis of folic acid, an essential step for DNA synthesis. Therefore, it inhibits DNA synthesis in microorganisms. - **Adverse effects:** Anemia, methemoglobinemia, hemolytic anemia, in G-6-P dehydrogenase deficiency, anorexia, nausea, and vomiting. ### Clofazimine - **Mod of action:** Inhibits template function of DNA - **Adverse effects:** Discolouration of skin, GIT disorders. ### Amithiozone - Used as an alternate to dapsone - When used alone for long time, resistance develops - **Side effects:** Hepatic damage, GIT disturbances and bone marrow depression ### Important Viva Questions 1. Name the drugs used in leprosy 2. What are the side effects of dapsone? 3. What is the mechanism of actions of dapsone? 4. What are the side effects of rifampicin? ### Antifungal Drugs #### Classification - **Systemic antifungal drugs for systemic infections:** - Amphotericin-B - Flucytosine - Azoles: eg. Ketoconazole, itraconazole, fluconazole - **Systemic antifungal drugs for mucocutaneous infections:** - Griseofulvin - Terbinafine - **Topical antifungal therapy:** - Nystatin - Topical azoles: eg. Clotrimazole, miconazole and ketoconazole #### Polyenes - **Amphotericin-B:** Drug of choice for systemic fungal infection. Amphotericin B, nystatin and natamycin are called polyenes and have the same mode of action. - **Mode of Action:** Act as antimicrobial agents by inhibiting cell membrane function. Polyenes bind to the ergosterol present in fungal cell membrane and disturb the permeability and transport characteristics of the membrane. This results in leakage of ions and small molecules from the cell leading to irreversible damage. - **Note:** Bacteria are not destroyed by polyenes because they lack ergosterol that is essential for attachment to the cell membrane. - **Pharmacokinetics:** Administered intravenously. It can be given intrathecally in meningitis due to fungi. It crosses the placenta and its metabolites are excreted through kidney and bile, therefore, no dose adjustment is required in hepatic or renal insufficiency. - **Indications:** The only antibiotic available for serious systemic fungal infections.Topically in candida lesions. - **Side effects:** Fever, chills, headache and nausea, vomiting on I/V administration. Renal failure (very important side effect), Hypotension and hypokalemia, Anemia due to suppression of RBC production, Hypersensitivity reactions including anaphylaxis, Thrombophlebitis - **Contra indications:** Renal failure, Pregnancy. - **Nystatin:** Mode of action, structure and chemistry are similar to amphotericin B. - **Pharmacokinetics:** Used topically. Absorption from GI tract is negligible. Never used parenterally. - **Indications:** Localized candidiasis of vagina, mouth, skin and GIT. It is administered as an oral agent (swish and swallow) for the treatment of oral candidiasis. - **Side effects:** Side effects are rare because there is no absorption, sometimes nausea and vomiting occur. #### Imidazoles - Ketoconazole - Fluconazole - Itraconazole - **Mode of action:** Act as antimicrobial by inhibiting the cell membrane function. They damage the cytoplasmic membrane and cell walls of fungi by inhibiting the biosynthesis of ergosterol in them. ### Ketoconazole (Nizoral) - **Pharmacokinetics:** Administered orally. It is better absorbed in the acidic medium of stomach, coca-cola is acidic and improves absorption of ketoconazole. Food, antacids, cimetidine and rifampicin impair absorption. Metabolism is by the liver and excretion through bile. - **Indications:** - Candidiasis of skin, mucosa and genital tract - Systemic fungal infections eg. histoplasmosis, coccidiomycosis and blastomycosis - **Adverse effects:** - GI disturbances - Antiandrogenic effects like impotence, decreased libido -Hepatotoxicity -Drug interactions: By inhibiting hepatic cytochrome P-450 ketoconazole increase the levels and cause toxicity of cyclosporine, phenytoin, antihistamines, warfarin. ### Fluconazole (Diflucan) - **Fluconazole** has some advantages over Ketoconazole, such as there is no antiandrogenic effect, CSF penetration is excellent. It is the drug of choice for cryptococcus neoformans, candidasis, and coccidiomycosis. It is given orally or intravenously. - **Side effects** are nausea, vomiting, rashes. No endocrine effects but it also inhibits cytochrome P-450. Hepatitis is rare. ### Drugs for Superficial Fungal Infections #### Griseofulvin (Griseovin) - **Mode of action:** It combines with the mitotic spindles and causes the destruction of microtubules thus inhibiting fungal mitosis, growth and multiplication. ### Miconazole (Daktarin), Clotrimazole (Canesten) - Miconazole, clotrimazole, and econazole are topically active imidazole drugs. Miconazole and clotrimazole are available in cream or lotion for and as vaginal cream or suppositories for vulvovaginal candidiasis. Local side effects may be itching, erythema or irritation. ### Antiprotozoal Drugs #### Malaria - Disease caused by protozoa *Plasmodium* transmitted to the human by the bite of a female *Anopheles* mosquito. - Characterized by fever with rigor, anemia and splenomegaly. ##### Life Cycle 1. When an infected *Anopheles* mosquito bites a person the *sporozoites* present in the saliva enter the blood stream. 2. *Sporozoites* invade the liver, where they grow to form *merozoites*. This stage is known as *pre-erythrocytic stage*. In the liver, the *sporozoites* multiply to form *Schizont*. The *schizonts* rupture and release *merozoites* into the blood. These merozoites infect red blood cells and undergo further multiplication. The red blood cell stage is responsible for the symptoms of malaria. *Trophozoites* are active, feeding stages. *Schizonts* are the dividing parasite, which infect new red blood cells. *Gametocytes* are sexual stages which develop from the schizonts, they are picked by a mosquito during a blood meal. #### Important Viva Questions 1. What is malaria? 2. What are the symptoms of malaria? 3. What are the drugs used in the treatment of malaria? 4. What are the side effects of chloroquine? 5. What is the mode of action of artemisinin?