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pharmacology chemotherapy - Leaderboard
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| Isoniazid mechanism | Isoniazid (INH) is a structural congener of pyridoxine. Its mechanism of action involves inhibition of the synthesis of mycolic acids, essential parts of mycobacterial cell walls. It is a prodrug that is activated by a mycobacterial catalase-peroxidase (KatG). It inhibits enoyl acyl carrier protein reductase (InhA) and a β-ketoacyl-ACP synthase (KasA) within the unique Type II fatty acid synthase system for mycolic acids. INH is bactericidal for actively growing tubercle bacilli, but is less effective against dormant organisms. |
| Isoniazid resistance | Resistance can emerge rapidly if the drug is used alone. High-level resistance is associated with deletion in the katG gene that codes for a catalase-peroxidase involved in the bioactivation of INH. Low-level resistance occurs via deletions in the inhA gene that encodes the target enzyme, an acyl carrier protein reductase. Cross-resistance does not occur between isoniazid and other antitubercular drugs. |
| Inh pharmacokinetics | INH is taken orally and penetrates cells to act on intracellular mycobacteria. The liver metabolism of INH is by acetylation and is under genetic control. Patients may be fast or slow inactivators of the drug. It enters CSF. Absorption is impaired if isoniazid is taken with food, particularly carbohydrates, or with aluminum-containing antacids. Infected tissue tends to retain the drug longer. Isoniazid undergoes N acetylation and hydrolysis, resulting in inactive products. INH halflife in fast acetylators is 60–90 min; in slow acetylators it may be 3–4 h. Fast acetylators may require higher dosage than slow acetylators for equivalent therapeutic effects. |
| Clinical use inh | INH is the single most important drug used in tuberculosis It is a component of most drug combination regimens. In the treatment of latent infection (formerly known as prophylaxis), skin test converters and for close contacts of patients with active disease, INH is given as the sole drug. |
| Inh toxicity | Neurotoxic effects i.e peripheral neuritis, restlessness, muscle twitching, and insomnia.These effects are due to pyridoxine defeciency and can be fixed by giving pyridoxine (25–50 mg/d orally). INH is hepatotoxic and may cause abnormal liver function tests, jaundice, and hepatitis. Hepatotoxicity is rare in children.It has been suggested that this is caused by a toxic metabolite of monoacetylhydrazine , formed during the metabolism of isoniazid. The incidence increases among patients with increasing age, among patients who also take rifampin, or among those who drink alcohol daily. INH may inhibit the hepatic metabolism of drugs (eg, carbamazepine, phenytoin, warfarin). Slow acetylators are particularly at risk. Hemolysis has occurred in patients with glucose-6-phosphate dehydrogenase (G6PDH) deficiency. A lupus-like syndrome has also been reported, rashes and fever, optic neuritis |
| Rifampin mechanism | Rifampin, a derivative of rifamycin, is bactericidal against M tuberculosis. The drug inhibits DNA-dependent RNA polymerase (encoded by the rpo gene) in M tuberculosis and many other microorganisms. It has broader spectrum than isoniazid Rifampin blocks transcription by interacting with the β subunit of bacterial, but not human, DNAdependent RNA polymerase and inhibiting mRNA synthesis Resistance via changes in drug sensitivity of the polymerase often emerges rapidly if the drug is used alone. |
| Rifampin pharmacokinetics | Rifampin is given orally it is distributed to most body tissues, including the central nervous system even without inflammation it is present in csf The drug undergoes enterohepatic cycling and is partially metabolized in the liver. Both free drug and metabolites, which are orange-colored, are eliminated mainly in the feces. |
| Uses of rifampin | Rifampin is almost always used in combination with other drugs for tuberculosis rifampin can be used as the sole drug in treatment of latent tuberculosis in INH-intolerant patients or in close contacts of patients with INH-resistant strains of the organism. In leprosy, rifampin given monthly delays the emergence of resistance to dapsone. |
| Rifampin toxicity | Rifampin commonly causes light-chain proteinuria and may impair antibody responses. skin rashes, thrombocytopenia,nephritis, and liver dysfunction nausea vomiting hepatitis and liver failure rare but shouldnt be used for elderly and alcoholics increased incidence with isoniazid If given less than twice weekly, rifampin may cause a flu-like syndrome and anemia, fever, chills, and myalgias, acute renal failure, hemolytic anemia, and shock. Rifampin strongly induces liver drug-metabolizing enzymes and enhances the elimination rate of many drugs, including anticonvulsants, contraceptive steroids, cyclosporine, ketoconazole, methadone, terbinafine, and warfarin. |
| Ethambutol mechanism | It inhibits arabinosyltransferases (encoded by the embCAB operon) involved in the synthesis of arabinogalactan, a component of mycobacterial cell walls. Resistance occurs rapidly via mutations in the emb gene if the drug is used alone. it is bacteriostatic Resistance is not a serious problem if the drug is employed with other antitubercular agents. |
| Ethambutol pharmacokinetics | The drug is well absorbed orally and distributed to most tissues, including the CNS. A large fraction is eliminated unchanged in the urine. Dose reduction is necessary in renal impairment. |
| Uses of ethambutol | The main use of ethambutol is in tuberculosis,and it is always given in combination with other drugs. |
| Ethambutol adverse effects | The most common adverse effects are dose-dependent visual disturbances, including decreased visual acuity, red-green color blindness, optic neuritis, and possible retinal damage (from prolonged use at high doses). Most of these effects regress when the drug is stopped. Other adverse effects include headache, confusion,hyperuricemia and peripheral neuritis. increased urate levels |
| Pyrazinamide mechanism | The mechanism of action of pyrazinamide is not known; however, it has bacteriostatic action that appears to require metabolic conversion via pyrazinamidases (encoded by the pncA gene) present in M tuberculosis. Resistance occurs via mutations in the gene that encodes enzymes involved in the bioactivation of pyrazinamide and by increased expression of drug efflux systems. This develops rapidly when the drug is used alone, but there is minimal cross-resistance with other antimycobacterial drugs. Some resistant strains lack the pyrazinamidase. Pyrazinamide is active against tubercle bacilli in the acidic environment of lysosomes, and macrophages. |
| Pharmacokinetics pyrazinamide | Pyrazinamide is absorbed orally and penetrates most body tissues, including the CNS. The drug is partly metabolized to pyrazinoic acid which is its active form, and both parent molecule and metabolite are excreted in the urine. The plasma half-life of pyrazinamide is increased in hepatic or renal failure |
| Clinical use pyrazinamide | Combined use of pyrazinamide with other antituberculous drugs is an important factor in the success of shortcourse treatment regimens. |
| Toxicity pyrazinamide | Approximately 40% of patients develop nongouty polyarthralgia urate accumulation leads to gout hyperurecemia one in 5 people experience liver dysfunction Other adverse effects are myalgia, gastrointestinal irritation, maculopapular rash, hepatic dysfunction, porphyria, and photosensitivity reactions. Pyrazinamide should be avoided in pregnancy. |
| Streptomycin | Streptomycin is used principally in drug combinations for the treatment of life-threatening tuberculous disease, including meningitis, miliary dissemination, and severe organ tuberculosis. |
| Anikacin | Amikacin is a second line drug indicated for the treatment of tuberculosis suspected to be caused by streptomycin-resistant or multidrugresistant mycobacterial strains. To avoid emergence of resistance, amikacin should always be used in combination drug regimens. |
| Ciprafloxacin and ofloxacin | Ciprofloxacin and ofloxacin are often active against strains of M tuberculosis resistant to first-line agents. They are second line drugs. The fluoroquinolones should always be used in combination regimens with two or more other active agents. |
| Ethionamide | Ethionamide is a congener of INH, but cross-resistance does not occur. Ethionamide can inhibit acetylation of isoniazid It is effective after oral administration and is widely distributed including the CSF Adverse effects that limit its use include gastric irritation, hepatotoxicity, peripheral neuropathies, and optic neuritis. Supplementation with vitamin B6 (pyridoxine) may lessen the severity of the neurologic side effects. |
| P aminosalicylic acid | P-Aminosalicylic acid (PAS) is rarely used because primary resistance is common. In addition, its toxicity includes gastrointestinal irritation, peptic ulceration, hypersensitivity reactions, and effects on kidney, liver, and thyroid function. |
| Drugs not in use | Other drugs of limited use because of their toxicity include capreomycin (ototoxicity, renal dysfunction) and cycloserine which inhibits synthesis of d-alanine(peripheral neuropathy, CNS dysfunction). |
| Standard regimen | For empiric treatment of pulmonary TB (in most areas of <4% INH resistance), an initial 3-drug regimen of INH, rifampin, and pyrazinamide is recommended. If the organisms are fully susceptible (and the patient is HIV-negative), pyrazinamide can be discontinued after 2 month and treatment continued for a further 4 month with a 2-drug regimen. ethambutol can be given with 3 drugs too |
| Alternative regimen | Alternative regimens in cases of fully susceptible organisms include INH + rifampin for 9 month, or INH + ethambutol for 18 month. Intermittent (2 or 3 × weekly) high-dose 4-drug regimens are also effective. |
| Resistance in regimen | If resistance to INH is higher than 4%, the initial drug regimen should include ethambutol or streptomycin. Tuberculosis resistant only to INH (the most common form of resistance) can be treated for 6 month with a regimen of rifampin + pyrazinamide + ethambutol or streptomycin. Multidrug-resistant organisms (resistant to both INH and rifampin) should be treated with 3 or more drugs to which the organism is susceptible for a period of more than 18 month, including 12 mo after sputum cultures become negative. |
| Tuberculosis test | Diagnostic testing for tuberculosis can be accomplished via the standard tuberculin skin test with purified protein derivative (PPD) or by an interferon-gamma release assay (IGRA) blood test, Quantiferon-TB Gold, approved by the FDA in 2005. The advantages that the blood test offers is that it requires only a single test visit, and it is less susceptible to false positive results due to BCG vaccination or to infection with mycobacteria other than Mycobacterium tuberculosis. |
| First line drugs | Ethambutol MYAMBUTOL Isoniazid (INH) NYDRAZID, OTHERS Pyrazinamide Rifamycins RIFADIN |
| 2nd line drugs | Aminoglycosides Aminosalicylic acid PASER Capreomycin CAPASTAT SULFATE Cycloserine SEROMYCIN Ethionamide TRECATOR Fluoroquinolones Macrolides |
| Antibacterial spectrum isoniazid | For bacilli in the stationary phase, isoniazid is bacteriostatic, but for rapidly dividing organisms, it is bactericidal. It is effective against intracellular bacteria. Isoniazid is specific for treatment of M. tuberculosis, although Mycobacterium kansasii(an organism that causes three percent of the clinical illness known as tuberculosis) may be susceptible at higher drug levels. |
| Rifamycins include | Rifampin, rifabutin and rifapentine |
| Antimicrobial spectrum rifampin | Rifampin is bactericidal for both intracellular and extracellular mycobacteria, including M. tuberculosis, and atypical mycobacteria, such as M. kansasii. It is used against many gram-positive and gram-negative organisms it may be used with vancomycin for infections due to resistant staphylococci (methicillin-resistant Staphylococcus aureus [MRSA] strains) or pneumococci (penicillin-resistant Streptococcus pneumoniae [PRSP] strains). Other uses of rifampin include the meningococcal and staphylococcal carrier states. it is used prophylactically for individuals exposed to meningitis caused by meningococci or Haemophilus influenzae. |
| Resistance rifampin | Resistance to rifampin can be caused by a mutation in the affinity of the bacterial DNA-dependent RNA polymerase for the drug, or by decreased permeability. |
| Rifabutin | It is a derivative of rifampin, is the preferred drug for use in tuberculosis-infected patients with (HIV), who are concomitantly treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors, because it is a less potent inducer of cytochrome P450 enzymes. Rifabutin has adverse effects similar to those of rifampin, but can also cause uveitis, skin hyperpigmentation, and neutropenia. |
| Rifapentine | It has activity comparable to that of rifampin but has a longer half-life than rifampin and rifabutin, which permits weekly dosing. However, for the intensive phase(initial 2 months) of the short-course therapy for tuberculosis, rifapentine is given twice weekly. In the subsequent phase, rifapentine is dosed once per week for 4 months. To avoid resistance issues, rifapentine should not be used alone but, rather, be included in a three to four-drug regimen. |
| Rifamixin | It is not properly absorbed from git and used for travelers diarrhea |
| Fluoroquinolones | The fluoroquinolones, specifically, ciprofloxacin, moxifloxacin and levofloxacin have an important place in the treatment of multidrug-resistant tuberculosis. Some atypical strains of mycobacteria are also susceptible |
| Macrolides | The macrolides, such as azithromycin and clarithromycin, are part of the regimen that includes ethambutol and rifabutin used for the treatment of infections by M. avium-intracellulare complex. Azithromycin is preferred for HIV-infected patients because it is least likely to interfere with the metabolism of antiretroviral drugs. |
| Clinical use and toxicity | Oral acyclovir is commonly used for the treatment of mucocutaneous and genital herpes lesions and for prophylaxis in AIDS and in other immunocompromised patients (eg, those undergoing organ transplantation). The oral drug is well tolerated but may cause (GI) distress and headache. Intravenous administration is used for severe herpes disease, including encephalitis, and for neonatal HSV infection. Toxic effects with parenteral administration include delirium, tremor, seizures, hypotension, and nephrotoxicity.It is given intravenous (IV), oral, or topical route. [Note: The efficacy of topical applications is doubtful.] The drug distributes (CSF). Acyclovir is partially metabolized to an inactive product. Excretion into the urine occurs both by glomerular filtration and by tubular secretion Acyclovir accumulates in patients with renal failure. local irritation may occur from topical application; headache, diarrhea, nausea, and vomiting may result after oral administration. Transient renal dysfunction may occur at high doses or in a dehydrated patient receiving the drug Altered or deficient thymidine kinase and DNA polymerases have been found in some resistant viral strains and are most commonly isolated from immunocompromised patients.Cross-resistance to the other agents in this family occurs. [Note: Cytomegalovirus (CMV) is resistant, because it lacks a specific viral thymidine kinase.] |
| Valacyclovir | Valacyclovir is a prodrug converted to acyclovir by hepatic metabolism after oral administration and reaches plasma leveles 3–5 times greater than those achieved by acyclovir. Valcyclovir has a longer duration of action than acyclovir. it has greater bioavailability and at high doses or in a dehydrated patient receiving the drug IV. High-dose valacyclovir can cause GI problems and thrombotic thrombocytopenic purpura in patients with AIDS. |
| Peniclover | Penciclovir undergoes activation by viral thymidine kinase, and the triphosphate form inhibits DNA polymerase but does not cause chain termination is an acyclic guanosine nucleoside derivative that is active against HSV-1, HSV-2, and VZV. Penciclovir is only administered topically It is monophosphorylated by viral thymidine kinase, and cellular enzymes form the nucleoside triphosphate, which inhibits HSV DNA polymerase. Penciclovir triphosphate has an intracellular half-life 20 to 30-fold longer than does acyclovir triphosphate. Penciclovir is negligibly absorbed upon topical application and is well tolerated. Both pain and healing are shortened by approximately half a day in duration |
| Famiclovir | Famciclovir is a prodrug converted to penciclovir by first-pass metabolism in the liver. Used orally in genital herpes and for herpes zoster, None of the acyclovir congeners has activity against TK– strains of HSV. another acyclic analog of 2’-deoxyguanosine, is a prodrug that is metabolized to the active penciclovir. The antiviral spectrum is similar to that of ganciclovir, but it is presently approved only for treatment of acute herpes zoster. The drug is effective orally Adverse eff ects include headaches and nausea. Studies in experimental animals have shown an increased incidence of mammary adenocarcinomas and testicular toxicity. |
| Docosanol | Docosanol is an aliphatic alcohol that inhibits fusion between the HSV envelope and plasma membranes. It prevents viral entry and subsequent replication. Used topically docosanol shortens healing time. |
| Ganciclover | Ganciclovir, a guanine derivative, is triphosphorylated to form a nucleotide that inhibits DNA polymerases of cytomegalovirus (CMV), and HSV and causes chain termination. The first phosphorylation step is catalyzed by virus-specific enzymes in both CMV-infected and HSV-infected cells. CMV resistance mechanisms involve mutations in the genes that code for the activating viral phosphotransferase and the viral DNA polymerase. Thymidine kinase-deficient HSV strains are resistant to ganciclovir.that has 8 to 20 times greater activity against CMV, which is the only viral infection for which it is approved. It is currently available for treatment of CMV retinitis in immunocompromised patients and for CMV prophylaxis in transplant patients.Like acyclovir, ganciclovir is activated through conversion to the nucleoside triphosphate by viral and cellular enzymes, with the actual pathway depending on the virus. CMV is deficient in thymidine kinase and, therefore, forms the triphosphate by another route. The nucleotide competitively inhibits viral DNA polymerase and can be incorporated into the DNA, thereby decreasing the rateof chain elongation. |
| Ganciclover pharmacokinetics | Ganciclovir is usually given intravenously and penetrates the eye and the central nervous system (CNS). The drug undergoes renal elimination in direct proportion to creatinine clearance. Oral bioavailability is less than 10%. An intraocular implant form of ganciclovir can be used in CMV retinitis. Valganciclovir, a prodrug of ganciclovir, has high oral bioavailability and has decreased the use of intravenous forms of ganciclovir (and also of intravenous cidofovir and foscarnet) in end-organ CMV disease. |
| Ganciclover uses and toxicity | Ganciclovir is used for the prophylaxis and treatment of CMV retinitis and other CMV infections in immunocompromised patients. Systemic toxic effects include leukopenia, thrombocytopenia, mucositis, hepatic dysfunction, and seizures. The drug may cause severe neutropenia when used with zidovudine or other myelosuppressive agents. valganciclovir has high oral bioavailability, because rapid hydrolysis in the intestine and liver after oral administration leads to high levels of ganciclovir. adverse effects include severe, dose-dependent neutropenia. Note: Combined treatment with zidovudine, azathioprine, or mycophenolate mofetil can result in additive neutropenia.] Ganciclovir is carcinogenic as well as embryotoxic and teratogenic in experimental animals. Resistant CMV strains have been detected that have lower levels of ganciclovir triphosphate. |
| Cidofovir | Cidofovir is activated exclusively by host cell kinases and the active diphosphate, which inhibits DNA polymerases of HSV, CMV, adenovirus, and papillomavirus (HPV). Because phosphorylation does not require viral kinase, cidofovir is active against many acyclovir and ganciclovirresistant strains. Resistance is due to mutations in the DNA polymerase gene. The drug is given intravenously and undergoes renal elimination. Dosage should be adjusted in proportion to creatinine clearance and full hydration maintained. Slow elimination of the active intracellular metabolite permits prolonged dosage intervals and eliminates the permanent venous access used for ganciclovir therapy. Cidofovir is available for IV, intravitreal (injection into the eye’s vitreous humor between the lens and the retina), and topical administration. |
| Uses and toxicity cidofovir | Cidofovir is effective in CMV retinitis, in mucocutaneous HSV infections, including those resistant to acyclovir, and in genital warts. Nephrotoxicity is the major dose-limiting toxicity of cidofovir, additive with other nephrotoxic drugs including amphotericin B and aminoglycoside antibiotics. probenacid must be given |
| Foscarnet | Foscarnet is a phosphonoformate derivative that does not require phosphorylation for antiviral activity. Although it is not an antimetabolite, foscarnet inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase. Resistance involves point mutations in the DNA polymerase gene. Foscarnet is given intravenously and penetrates well into tissues, including the CNS. The drug undergoes renal elimination in direct proportion to creatinine clearance. It is used for acyclovir-resistant HSV and herpes zoster infections. Foscarnet works by reversibly inhibiting viral DNA and RNA polymerases, thereby interfering with viral DNA and RNA synthesis. Mutation of the polymerase structure is responsible for resistant viruses. [Note: Cross-resistance between foscarnet and ganciclovir or acyclovir is uncommon.] Foscarnet is poorly absorbed orally and must be injected IV. It must also be given frequently to avoid relapse when plasma levels fall. It is dispersed throughout the body and greater than 10 percent enters the bone matrix, from which it slowly leaves. The parent drug is eliminated by glomerular filtration andtubular secretion into the urine |
| Uses and toxicities foscarnet | The drug is an alternative for prophylaxis and treatment of CMV infections, including CMV retinitis, and has activity against ganciclovir-resistant strains of this virus. Foscarnet inhibits herpes DNA polymerase in acyclovir-resistant strains that are thymidine kinase–deficient and may suppress such resistant herpetic infections in patients with AIDS. Adverse effects are severe and include nephrotoxicity (30% incidence) with disturbances in electrolyte balance (especially hypocalcemia), genitourinary ulceration, and CNS effects(headache, hallucinations, seizures).Adverse effects include nephrotoxicity, anemia, nausea, and fever. Due to chelation with divalent cations, hypocalcemia and hypomagnesemia are also seen. In addition, hypokalemia, hypo- and hyperphosphatemia, seizures, and arrhythmias have been reported. |
| Vibardine | Vidarabine is an adenine analog and has activity against HSV, VZV, and CMV. Its use for systemic infections is limited by rapid metabolic inactivation and marked toxic potential. Vidarabine is used topically for herpes keratitis but has no effect on genital lesions. Toxic effects with systemic use include GI irritation, paresthesias, tremor, convulsions, and hepatic dysfunction. Vidarabine is teratogenic in animals. (arabinofuranosyl adenine, ara-A, adenine arabinoside) is one of the most effective of the nucleoside analogs. However, it has been supplanted clinically by acyclovir, which is more efficacious and safe. Although vidarabine is active against HSV-1, HSV-2, and VZV, its use is limited to treatment of immunocompromised patients with herpetic and vaccinial keratitis and in HSV keratoconjunctivitis. [Note: Vidarabine is only available as an ophthalmic ointment.] Vidarabine, an adenosine analog, is converted in the cell to its 5’-triphosphate analog (ara-ATP), which is postulated to inhibit viral DNA synthesis. Some resistant HSV mutants have been detected that have altered polymerase. |
| Idoxuridine and trifluridine | These pyrimidine analogs are used topically in herpes keratitis (HSV-1). They are too toxic for systemic use. |
| Fomivirsen | Fomivirsen is an antisense oligonucleotide that binds to mRNA of CMV, inhibiting early protein synthesis. The drug is injected intravitreally for treatment of CMV retinitis. Concurrent systemic anti-CMV therapy is recommended to protect against extraocular and contralateral retinal CMV disease. Fomiversin causes iritis, vitreitis, increased intraocular pressure and changes in vision It is an antisense oligonucleotide directed against CMV mRNA. Its use is limited to those who cannot tolerate or have failed other therapies for CMV retinitis. A 2 to 4-week hiatus after discontinuing cidofovir is desirable to reduce toxicity. The drug is administered intravitreally. The common adverse effects include iritis, vitritis, and changes in vision. |
| Amantidine and rimantidine mechanism | Amantadine and rimantadine inhibit an early step in replication of the influenza A (but not influenza B) virus. They prevent “uncoating” by binding to a proton channel. This protein functions as a proton ion channel required at the onset of infection to permit acidification of the virus core, which in turn activates viral RNA transcriptase. Adamantine resistant influenza A virus mutants are now common. For example, these drugs are 70 to 90 percent effective in preventing infection if treatment is begun at the time of, or prior to, exposure to the virus. Also, both drugs reduce the duration and severity of systemic symptoms if started within the first 48 hours after exposure to the virusBoth drugs are well absorbed orally. Amantadine dipenetrates into the (CNS), whereas rimantadine does not cross the blood-brain barrier to the same extent. Amantadine is not extensively metabolized. It is excreted into the urine and may accumulate to toxic levels in patients with renal failure. |
| Rimantidine amantidine use and toxicity | These drugs are prophylactic against influenza A virus infection and can reduce the duration of symptoms if given within 48 h after contact.However, adamantine-resistant influenza A virus mutants including H3N2 strains causing seasonal influenza in the United States have increased dramatically in the last 2–3 yr. The H1N1 strain responsible for the recent pandemic that contain genes derived from both avian and porcine influenza viruses is also resistant to the adamantines. Fortunately, there is minimal cross-resistance to the neuraminidase inhibitors. Neither impairs the immune response to influenza A vaccine, and either can be administered as a supplement to vaccination, thus providing protection until antibody response occurs (usually 2 weeks in healthy adults). Treatment is particularly useful in high-risk patients who have not been vaccinated and during epidemics. [Note: Amantadine is also effective in the treatment of some cases of Parkinson disease.] Toxic effects of these agents include GI irritation, dizziness, ataxia, and slurred speech. Rimantadine’s activity is no greater than that of amantadine, but it has a longer half-life and requires no dosage adjustment in renal failure.The side effects of amantadine are mainly associated with the CNS. Minor neurologic symptoms include insomnia,dizziness, and ataxia. More serious side effects have been reported(for example, hallucinations and seizures). The drug should be employed cautiously in patients with psychiatric problems, cerebral atherosclerosis, renal impairment, or epilepsy. Rimantadine causes fewer CNS reactions, because it does not efficiently cross the blood-brain barrier. Both drugs cause GI intolerance.Amantadine and rimantadine should be used with caution in pregnant and nursing mothers, because they have been found to be embryotoxic and teratogenic in rats. |
| Neuraminidase uses | These drugs are inhibitors of neuraminidases produced by influenza A and B and are currently active against both H3N2 and H1N1 strains. These viral enzymes cleave sialic acid residues from viral proteins and surface proteins of infected cells. They function to promote virion release and to prevent clumping of newly released virions. By interfering with these actions, neuraminidase inhibitors impede viral spread. Decreased susceptibility to the drugs is associated with mutations in viral neuraminidase, but worldwide resistance remains rare. Unlike the adamantane analogs, oseltamivir and zanamivir are effective against both Type A and Type B influenza viruses. They do not interfere with the immune response to influenza A vaccine. Administered prior to exposure, neuraminidase inhibitors prevent infection, and, when administered within the first 24 to 48 hours after the onset of infection, they have a modest effect on the intensity and duration of symptoms.Influenza viruses employ a specific neuraminidase that is inserted into the host cell membrane for the purpose of releasing newly formed virions. Oseltamivir and zanamivir are transition-state analogs of the sialic acid substrate and serve as inhibitors of the enzyme activity. Oseltamivir is an orally active prodrug that is rapidly hydrolyzed by the liver to its active form. Zanamivir, on the other hand, is not active orally and is either inhaled or administered intranasally. Both drugs are eliminated unchanged in the urine |
| Oseltamivir and zanamivir uses and toxicity | Oseltamivir is a prodrug used orally, activated in the gut and the liver. Zanamivir is administered intranasally. Both drugs decrease the time to alleviation of influenza symptoms and are more effective if used within 24 h after onset of symptoms. Taken prophylactically, oseltamivir significantly decreases the incidence of influenza. GI symptoms may occur with oseltamivir; zanamivir may cause cough and throat discomfort and has induced bronchospasm in asthmatic patients. |
| Viral hepatitis drugs | Interferon-α (IFN-α), lamivudine, adefovir dipivoxil, entacavir, telbivudine, tenofovir, ribavirin, and sofosbuvir |
| Interferon mechanism | IFN-α is a cytokine that acts through host cell surface receptors increasing the activity of Janus kinases (JAKS). These enzymes phosphorylate signal transducers and activators of transcription (STATS) to increase the formation of antiviral proteins. The selective antiviral action of IFN-α is primarily due to activation of a host cell ribonuclease that preferentially degrades viral mRNA. IFN-α also promotes formation of natural killer cells that destroy infected liver cells. |
| Interferon toxicity | Toxic effects of IFN-α include GI irritation, a flu-like syndrome, neutropenia, profound fatigue and myalgia, alopecia, reversible hearing loss, thyroid dysfunction, mental confusion, and severe depression. Contraindications include pregnancy.fever cgill fatigue weight loss somnolence Interferon interferes with hepatic drug metabolism, and toxic accumulations of theophylline have been reported.Interferon may also potentiate the myelosuppression caused by other bone marrow–depressing agents such as zidovudine. |
| Uses of interferon | Interferon-α is used in chronic HBV as an individual agent or in combination with other drugs. When used in combinations with ribavirin, the progression of acute HCV infection to chronic HCV is reduced. Pegylated IFN-α together with ribavirin is superior to standard forms of IFN-α in chronic HCV. Other uses of IFN-α include treatment of Kaposi’s sarcoma, papillomatosis, and topically for genital warts. is a family of naturally occurring, inducible glycoproteins that interfere with the ability of viruses to infect cells. Although interferon inhibits the growth of many viruses in vitro, its activity in vivo against viruses has been disappointing. The interferons are synthesized by recombinant DNA technology. At least three types of interferons exist, α, β, and γ interferon-α-2b, has been approved for treatment of hepatitis B and C In so-called “pegylated” formulations, bis-monomethoxy polyethylene glycol has been covalently attached to either interferon-α-2a or -α-2b to increase the size of the molecule. The larger molecular size delays absorption from the injection site, lengthens the duration of action of the drug, and also decreases its clearance. it may be administered intralesionally, subcutaneously, or intravenously. Cellular uptake and metabolism by the liver and kidney account for the disappearance of interferon from the plasma. Negligible renal elimination occurs. |
| Pharmacokinetics interferon | There are several forms of IFN-α with minor differences in amino acid composition. Absorption from intramuscular or subcutaneous injection is slow; elimination of IFN-α is mainly via proteolytic hydrolysis in the kidney. Conventional forms of IFN-α are usually administered daily or 3 times a week. Pegylated forms of IFN-α conjugated to polyethylene glycol can be administered once a week. |
| Adefovir and dipivoxil | Adefovir dipivoxil is the prodrug of adefovir, which competitively inhibits HBV DNA polymerase and results in chain termination after incorporation into the viral DNA. Adefovir has good oral bioavailability Dose reductions are required in renal dysfunction. Adefovir suppresses HBV replication and improves liver histology and fibrosis. However, serum HBV DNA reappears after cessation of therapy. Adefovir has activity against lamivudine-resistant strains of HBV. Nephrotoxicity is dose-limiting. Lactic acidosis and severe hepatomegaly with steatosis may also occur. Adefovir dipivoxil is a nucleotide analog that is phosphorylated to adefovir diphosphate , which is then incorporated into viral DNA. This leads to termination of further DNA synthesis and prevents viral replication. Adefovir is administered once a day and is excreted in urine, with 45 percent as the active compound. Clearance is influenced by renal function. Both decreased viral load and improved liver function have occurred in patients treated with adefovir. As with other agents, discontinuation of adefovir results in severe exacerbation of hepatitis in about 25 percent of patients. Adefovir does not seem to have significant drug interactions. The drug should be used cautiously in patients with existing renal dysfunction. |
| Entecavir | Entecavir inhibits HBV DNA polymerase. Effective orally, the drug undergoes renal elimination in part via active tubular secretion. Clinical efficacy is similar to that of lamivudine and there is cross-resistance between the 2 drugs. The drug causes headache, dizziness, fatigue, and nausea. It is a guanosine analog approved for the treatment of HBV infections. Following intracellular phosphorylation to the triphosphate, it competes with the natural substrate, deoxyguanosine triphosphate, for viral reverse transcriptase. Entecavir has been shown to be effective against lamivudine-resistant strains of HBV. Liver inflammation and scarring are improved. Entecavir need only be given once a day. Entecavir undergoes both glomerular filtration and tubular secretion. Very little, if any, drug is metabolized. Renal function must be assessed periodically, and drugs that have renal toxicity should be avoided. Patients should be monitored closely for several months after discontinuation of therapy because of the possibility of severe hepatitis. |
| Lamivudine | This nucleoside inhibitor of HIV reverse transcriptase is active in chronic HBV infection. Lamivudine has a longer intracellular half-life in HBV-infected cells than in HIV-infected cells and thus can be used in lower doses for hepatitis than for HIV infection. Used as monotherapy, lamivudine rapidly suppresses HBV replication and is remarkably nontoxic. This cytosine analog is an inhibitor of both hepatitis B virus (HBV) DNA polymerase and human immunodeficiency virus (HIV) reverse transcriptase. must be phosphorylated by host cellular enzymes to the triphosphate (active) form. This compound competitively inhibits HBV DNA polymerase at concentrations that have negligible effects on host DNA polymerase. As with many nucleotide analogs, the intracellular half-life of the triphosphate is many hours longer than its plasma half-life. Chronic treatment is associated with decreased plasma HBV DNA levels, improved biochemical markers, and reduced hepatic inflammation. Lamivudine is well absorbed orally and is widely distributed. Its plasma half-life is about 9 hours. Seventy percent is excreted unchanged in urine. Dose reductions are necessary when there is moderate renal insufficiency (creatinine clearance less than 50 mL/min). Lamivudine is well tolerated, with rare occurrences of headache and dizziness. |
| Ribavirin | Ribavirin inhibits the replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza, respiratory syncytial virus (RSV), paramyxoviruses, HCV, and HIV. Although the precise antiviral mechanism of ribavirin is not known, the drug inhibits guanosine triphosphate formation, prevents capping of viral mRNA, and can block RNAdependent RNA polymerases. Ribavirin is effective orally (avoid antacids) and is also available in intravenous and aerosol forms.It is eliminated by the kidney, necessitating dose reductions in renal dysfunction. Ribavirin is used adjunctively with IFN-α in chronic HCV infection in patients with compensated liver disease.Monotherapy with ribavirin alone is not effective. Early intravenous administration of ribavirin decreases mortality in viral hemorrhagic fevers.Despite its alleged activity against RSV it is still recommended by some authorities in immunocompromised children.Ribavirin is also effective in chronic hepatitis C infections when used in combination with interferon-α. Ribavirin may reduce the mortality and viremia of Lassa fever. The drug is first converted to the 5’-phosphate derivatives, the major product being the compound ribavirin-triphosphate, which exerts its antiviral action by inhibiting guanosine triphosphate formation, preventing viral messenger RNA (mRNA) capping, and blocking RNA-dependent RNA polymerase.[Note: Rhinoviruses and enteroviruses, which contain preformed mRNA and do not need to synthesize mRNA in the host cell to initiate an infection, are relatively resistant to the action of ribavirin.] Ribavirin is effective orally and intravenously.Absorption is increased if the drug is taken with a fatty meal. An aerosol is used in certain respiratory viral conditions such as the treatment of RSV infection.NO CNS |
| Ribavirin toxicity | Systemic use results in dose-dependent hemolytic anemia. Aerosol ribavirin may cause conjunctival and bronchial irritation. Ribavirin is a known human teratogen, absolutely contraindicated in pregnancy.Side effects reported for oral or parenteral use of ribavirin have included dose-dependent transient anemia. Elevated bilirubin has been reported. |
| Other drugs used for viral hepatitis | Telbivudine, a nucleoside analog, is phosphorylated by cellular kinases to the triphosphate form, which inhibits HBV DNA polymerase.The drug is at least as effective as lamivudine in chronic HBV infections and is similar in terms of its safety profile. Tenofovir, an antiretroviral drug, is also approved for chronic HBV infection and is active against lamivudine- and entecavir-resistant strains. Sofosbuvir inhibits RNA polymerase in HCV, alone or in combination with interferon or ribavirin and achieves very high cure rates (90–95%). Boceprevir is a protease inhibitor in HCV and is used in combination with ribavirin. |
| Respiratory virus infection | Amantadine, Oseltamivir ,Ribavirin , REBETOL, RIBAPAK,rIBASPHERE,Rimantadine Zanamivir |
| Hepatic viral drugs | Adefovir Entecavir Interferon Lamivudine Telbivudine Tenofovir |
| Herpes virus | Acyclovir Cidofovir Famciclovir Fomivirsen Foscarnet Ganciclovir Penciclovir Valacyclovir Valganciclovir Vidarabine |
| Reverse transcriptase inhibitors | Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zalcitabine Zidovudine |
| Hepatitis treatment | Chronic hepatitis B may be treated with peginterferon-α-2a, which is injected subcutaneously once weekly. [Note: Interferon-α-2b injected intramuscularly or subcutaneously three times weekly is also useful in the treatment of hepatitis B, but peginteferon-α-2a has similar or slightly better efficacy.] Oral therapy includes lamivudine, adefovir, entecavir, tenofovir, or telbivudine. Combination therapy of an interferon plus lamivudine is no more effective than monotherapy with lamivudine. Patients with acquired immunodeficiency syndrome (AIDS) who are co-infected with hepatitis B are usually poor responders to interferon therapy. In the treatment of chronic hepatitis C, the preferred treatment is the combination of peginterferon-α-2a or peginterferon-α-2b plus ribavirin, which is more effective than the combination of standard interferons and ribavirin. |
| Telbivudine | It is a thymidine analog that can be used in the treatment of HBV. Unlike lamivudine and adefovir, telbivudine is not active against HIV or other viruses. The drug is phosphorylated intracellularly to the triphosphate, which can either compete with endogenous thymidine triphosphate for incorporation into DNA or else be incorporated into viral DNA, where it serves to terminate further elongation of the DNA chain. The drug is administered orally, once a day, with or without food. Telbivudine is eliminated by glomerular fi ltration as the unchanged drug, and no metabolites have been detected. The dose must be adjusted in renal failure. The combination of telbivudine with lamivudine has been no more eff ective than telbivudine alone. |
| Acyclovir mechanism | (acycloguanosine) is the prototypic antiherpetic therapeutic agent. It has a greater specificity than vidarabine against herpesviruses. Herpes simplex virus (HSV) Types 1 and 2, varicella-zoster virus (VZV), and some Epstein-Barr virus–mediated infections are sensitive to acyclovir. It is the treatment of choice in HSV encephalitis and is more efficacious than vidarabine at increasing the rate of survival. The most common use of acyclovir is in therapy for genital herpes infections. It is also given prophylactically to seropositive patients before bone marrow and after heart transplants to protect such individuals during posttransplant immunosuppressive treatments. It is monophosphorylated in the cell by the herpes virus–encoded enzyme, thymidine kinase Therefore, virus-infected cells are most susceptible. The monophosphate analog is converted to the di- and triphosphate forms by the host cells. Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase and is itself incorporated into the viral DNA, causing premature DNA-chain termination Irreversible binding of the acyclovir-containing template primer to viral DNA polymerase inactivates the enzyme. The drug is less effective against the host enzyme. Because of its short half-life, oral administration requires multiple daily doses of acyclovir.Renal excretion is the major route of elimination of acyclovir |
| Appropriate hiv combination | 1) avoiding the use of two agents of the same nucleoside analog 2) avoiding overlapping toxicities and genotypic and phenotypic characteristics of the virus 3) patient factors, such as disease symptoms and concurrent illnesses 4) impact of drug interactions 5)ease of adherence to a frequently complex administration regimen. |
| Hiv infection treatment | The current recommendation for primary therapy is to administer two NRTIs with either a protease inhibitor, an NNRTI, or an integrase inhibitor |
| Mechanism of nrti | NRTIs are analogs of native ribosides (nucleosides or nucleotides containing ribose), which all lack a 3’-hydroxyl group. Once they enter cells, they are phosphorylated by a variety of cellular enzymes to the corresponding triphosphate analog, which is preferentially incorporated into the viral DNA by virus reverse transcriptase. Because the 3’-hydroxyl group is not present, a 3’-5’ phosphodiester bond between an incoming nucleoside triphosphate and the growing DNA chain cannot be formed, and DNA chain elongation is terminated. Affinities of the drugs for many host cell DNA polymerases are lower than they are for HIV reverse transcriptase, mitochondrial DNA polymerase γ appears to be susceptible at therapeutic concentrations. |
| Nrti toxicity | The NRTIs are primarily renally excreted, and all require dosage adjustment in renal insufficiency except abacavir, which is metabolized by alcohol dehydrogenase and glucuronyl transferase. Dosage adjustment is required when the creatinine clearance drops below 50 mL/min. 3. Adverse effects: inhibition of the mitochondrial DNA polymerase in certain tissues.the dideoxynucleosides, such as zalcitabine, didanosine, and stavudine, have a greater affinity for the mitochondrial DNA polymerase, leading to peripheral neuropathy, pancreatitis, and lipoatrophy. When more than one NRTI is given, care is taken not to have overlapping toxicities. All of the NRTIs have been associated with a potentially fatal liver toxicity characterized by lactic acidosis and hepatomegaly with steatosis. zidovudine and tenofovir have drug interactions |
| Resistance nrti | NRTI resistance is well characterized, and the most common mutation is the mutation at viral codon 184, which confers a high degree of resistance to lamivudine and emtricitabine but, more importantly, restores sensitivity to zidovudine and tenofovir. Because cross-resistance and antagonism occur between agents of the same analog class (thymidine, cytosine, guanosine, and adenosine), concomitant use of agents in the same class is contraindicated (for example, zidovudine plus stavudine). |
| Zidovudine | The first agent available for treatment of HIV infection is the pyrimidine analog, 3’-azido-3’-deoxythymidine (AZT). to prevent prenatal infection in pregnancy. It is also used for prophylaxis in individuals exposed to HIV infection. The drug is well absorbed after oral administration. If taken with food, peak levels may be lower, but the total amount of drug absorbed is not affected. Penetration across the blood-brain barrier is excellent, and the drug has a half-life of 1 hour. The intracellular half-life, is approximately 3 hours. Most of the AZT is glucuronidated by the liver and then excreted in the urine. In spite of its seeming specificity, AZT is toxic to bone marrow. Headaches are also common. The toxicity of AZT is potentiated if glucuronidation is decreased by co-administration of drugs like probenecid, acetaminophen, lorazepam, indomethacin, and cimetidine. They should be avoided or used with caution in patients receiving AZT. Both stavudine and ribavirin are activated by the same intracellular pathways and should not be given with AZT.Dosage reduction is necessary in uremic patients and those with cirrhosis. The primary toxicity of zidovudine is bone marrow suppression (additive with other immunosuppressive drugs) leading to anemia and neutropenia, which may require transfusions. GI distress, thrombocytopenia, headaches, myalgia, acute cholestatic hepatitis, agitation, and insomnia may also occur. Drugs that may increase plasma levels of zidovudine include azole antifungals and protease inhibitors. Rifampin increases the clearance of zidovudine. |
| Stavudine | Stavudine is an analog of thymidine, in which a double bond joins the 2’ and 3’ = carbons of the sugar. Stavudine is a strong inhibitor of cellular enzymes such as the β and γ DNA polymerases, thus reducing mitochondrial DNA synthesis and resulting in toxicity. The drug is almost completely absorbed on oral ingestion and is not affected by food. Stavudine penetrates the blood-brain barrier. About half of the parent drug can be accounted for in the urine. Renal impairment interferes with clearance. The major and most common clinical toxicity is peripheral neuropathy along with lipoatrophy and hyperlipidemia. Peripheral neuropathy is dose-limiting and increased with coadministration of didanosine or zalcitabine. Lactic acidosis with hepatic steatosis occurs more frequently with stavudine than with other NRTIs. |
| Didanosine | The second drug approved to treat HIV-1 infection was didanosine (dideoxyinosine, ddI), which is missing both the 2’- and 3’-hydroxyl groups. Upon entry into the host cell, ddI is biotransformed into dideoxyadenosine triphosphate (ddATP) through a series of reactions that involve phosphorylation of the ddI, amination to dideoxyadenosine monophosphate, and further phosphorylation. Like AZT, the resulting ddATP is incorporated into the DNA chain, causing termination of chain elongation. Due to its acid lability, absorption is best if ddI is taken in the fasting state. The drug penetrates into the CSF but to a lesser extent than does AZT. About 55 percent of the parent drug appears in the urine Pancreatitis, which may be fatal, is a major toxicity of ddI treatment and requires monitoring of serum amylase. The dose-limiting toxicity of ddI is peripheral neuropathy. Because of its similar adverse effect profile, concurrent use of stavudine is not recommended.diarrhoea hepatic dysfunction hyperurecemia cns effects alcoholic patients and those with hypertriglyceridemia reduced by food and chelating |
| Tenofovir | Is the first approved drug that is a nucleotide analog, namely, an acyclic nucleoside phosphonate analog of adenosine 5’-monophosphate. It is converted by cellular enzymes to the diphosphate, which is the inhibitor of HIV reverse transcriptase. Cross-resistance with other NRTIs may occur, but some AZT-resistant strains retain susceptibility to tenofovir. Tenofovir has a long half-life, allowing once-daily dosing. Most of the drug is recovered unchanged in the urine, and elimination is by filtration and active secretion. Serum creatinine must be monitored and doses adjusted in renal insuffi ciency. GI complaints are frequent and include nausea, diarrhea, and bloating Tenofovir is the only NRTI with signifi cant antiretroviral drug interactions. Tenofovir increases the concentrations of ddI to the point that ddI dosage reductions are required if the two are given together. However, these two agents are no longer recommended for combined use. Tenofovir decreases the concentrations of atazanavir such that atazanavir must be boosted with ritonavir if given with tenofovir to maintain eff ective atazanavir concentrations Tenofovir also has activity against HBV Adverse effects include GI distress, asthenia, and headache; rare cases of acute renal failure and Fanconi’s syndrome have been reported. |
| Lamivudine | Lamivudine is approved for treatment of HIV in combination with AZT, but it should not be used with other cytosine analogs due to antagonism. Lamivudine terminates the synthesis of the proviral DNA chain, and it inhibits the reverse transcriptase of both HIV and HBV. However, it does not affect mitochondrial DNA synthesis or bone marrow precursor cells. It has good bioavailability on oral administration, depends on the kidney for excretion, and is well tolerated.Lamivudine is 80% bioavailable insomnia fatigue gi |
| Emitracitabine | Emtricitabine a fluoro-derivative of lamivudine,inhibits both HIV and HBV reverse transcriptase. In a small clinical trial, it was shown to be at least as effective as lamivudine in the treatment of HIV-infected individuals. Emtricitabine is orally active, with a mean bioavailability of 93 percent. Plasma half-life is about 10 hours, whereas it has a long intracellular half-life of 39 hours. Emtricitabine is eliminated essentially unchanged in urine. It does not affect cytochrome P450 (CYP450) isozymes and has no signifi cant interactions with other drugs. Headache, diarrhea, nausea, and rash are its most common adverse effects. Emtricitabine causes hyperpigmentation of the soles and palms, and it has been associated with lactic acidosis, fatty liver, and hepatomegaly. Withdrawal of emtricitabine in HBV-infected patients may result in worsening of the hepatitis.renal elimination l in the oral solution, the drug is contraindicated in pregnancy and young children and in patients with hepatic or renal dysfunction. Common adverse effects of the drug include asthenia, GI distress, headache |
| Zalcitabine | It was the first cytosine analog developed. However, due to severe toxicity, it was removed from the market.Zalcitabine has a high oral bioavailability. Dosage adjustment is needed in patients with renal insufficiency and nephrotoxic drugs (eg, amphotericin B, aminoglycosides) increase toxic potential. Dose-limiting peripheral neuropathy is the major adverse effect of ddC. Pancreatitis, esophageal ulceration, stomatitis, and arthralgias may also occur. |
| Abacavir | It is a guanosine analog. There may be some cross-resistance with strains resistant to AZT and lamivudine. Abacavir is well absorbed orally, and metabolites appear in the urine Most of the drug is metabolized by non-CYP450–dependent reactions. A carboxylic acid derivative and a glucuronidated form have been identified. Common side effects include GI disturbances, headache, and dizziness. Approximately 5 percent of patients exhibit the “hypersensitivity reaction,” which is usually characterized by drug fever, plus one or more of the following symptoms of rash, GI symptoms, malaise, and respiratory distress Sensitized individuals should never be re-challenged because of rapidly appearing, severe reactions that lead to death. There is a newly approved HLA genetic test available to screen patients for the potential of this reaction. an intracellular half-life of 12–24 h |
| Nnrti | NNRTIs are highly selective, noncompetitive inhibitors of HIV-1 reverse transcriptase. They bind to HIV reverse transcriptase at a site adjacent to the active site, inducing a conformational change that results in enzyme inhibition. They do not require activation by cellular enzymes. Their major advantage is their lack of effect on the host blood-forming elements and their lack of cross-resistance with NRTIs. These drugs, however, do have common characteristics that include cross-resistance within the NNRTI class, drug interactions, and a high incidence of hypersensitivity reactions, including rash.There is no cross-resistance with NRTIs. Resistance from mutations in the pol gene occurs very rapidly if these agents are used as monotherapy. |
| Nevirapine | Is used in combination with other antiretroviral drugs for the treatment of HIV-1 infections in adults and children. Due to potential severe hepatotoxicity, nevirapine should not be initiated in women with CD4+ T-cell counts greater than 250 cells/mm3 or in men with CD4+ T cell counts greater than 400 cells/mm3. Nevirapine is well absorbed orally, and its absorption is not affected by food and antacids. The lipophilic nature of nevirapine accounts for its entrance into the fetus and mother’s milk and for its distribution, including the CNS. Nevirapine is dependent upon metabolism for elimination, and most of the drug is excreted in urine as the glucuronide of hydroxylated metabolites Nevirapine is an inducer of the CYP3A4 family of CYP450 drug-metabolizing enzymes. Nevirapine increases the metabolism of protease inhibitors, but most combinations do not require dosage adjustment. Nevirapine increases the metabolism of a number of drugs, such as oral contraceptives, ketoconazole, methadone, metronidazole, quinidine, theophylline, and warfarin. The most frequently observed side effects are rash, fever, headache, and elevated serum transaminases and fatal hepatotoxicity. Severe dermatologic eff ects have been encountered, including StevensJohnson syndrome and toxic epidermal necrolysis. A 14-day titration period at half the dose is mandatory to reduce the risk of serious epidermal reactions and hepatotoxicity.Hypersensitivity reactions with nevirapine include a rash, which occurs in 15–20% of patients, especially female.Nevirapine blood levels are increased by cimetidine and macrolide antibiotics and decreased by enzyme inducers such as rifampin. |
| Delavirdine | Delavirdine is not recommended in us it is rapidly absorbed after oral administration and is unaffected by the presence of food. Delavirdine is extensively metabolized, and very little is excreted as the parent compound. Fecal and urinary excretion each account for approximately half the elimination. Delavirdine is an inhibitor of CYP450–mediated drug metabolism, including that of protease inhibitors. Fluoxetine and ketoconazole increase plasma levels of delavirdine, whereas phenytoin, phenobarbital, and carbamazepine result in substantial decreases in plasma levels of delavirdine. Rash is the most common side effect of delavirdine.Delaviridine increases plasma levels of several benzodiazepines, nifedipine, protease inhibitors, quinidine, and warfarin. Delavirdine causes skin rash in up to 20% of patients, and the drug should be avoided in pregnancy because it is teratogenic in animals.Conversely, the blood levels of delavirdine are increased by azole antifungals and macrolide antibiotics. |
| Efavirinez | Efavirenz treatment results in increases in CD4+ cell counts and a decrease in viral load comparable to that achieved by protease inhibitors when used in combination with NRTIs. Therefore, it is the preferred NNRTI on the DHHS guidelines. Following oral administration, efavirenz is well distributed, including to the CNS. It should be administered on an empty stomach to reduce adverse CNS effects. Most of the drug is bound to plasma albumin (99 percent) at therapeutic doses. A halflife of more than 40 hours accounts for its recommended once-aday dosing. Efavirenz is extensively metabolized to inactive products. Efavirenz is a potent inducer of CYP450 enzymes and, therefore, may reduce the concentrations of drugs that are substrates of the CYP450. Most adverse effects are tolerable and are associated with the CNS, including dizziness, headache, vivid dreams, and loss of concentration.,skin,rash Nearly half of the patients experience these complaints, which usually resolve within a few weeks. Rash is the other most common side effect, with an incidence of approximately 25 percent. Severe, life-threatening reactions are rare. Efavirenz should be avoided in pregnant women. |
| Etravirine | Is the first second-generation NNRTI. It is active against many of the strains of HIV that are resistant to the first-generation NNRTIs. HIV strains with the common K103N resistance mutation to the first generation of NNRTIs are fully susceptible to etravirine. Following oral administration, etravirine is well distributed, and bioavailability is enhanced when taken with a high-fat meal. Although it has a half-life of approximately 40 hours, it is indicated for twice-daily dosing. Etravirine is extensively metabolized to inactive products. Because etravirine is a potent inducer of CYP450, the doses of CYP450 substrates may need to be increased when given with etravirine. Rash is the most common side effect.nausea, and diarrhea it is pregnancy category B. Etravirine is indicated for HIV treatment–experienced, multidrug-resistant adult patients who have evidence of ongoing viral replication.Elevations in serum cholesterol, triglycerides, and transaminase levels may occur. Etravirine is a substrate as well as an inducer of CYP3A4 and also inhibits CYP2C9 and CYP2C19 and may be involved in significant drug interactions. |
| Hiv protease inhibitor | All of the drugs in this group are reversible inhibitors of the HIV aspartyl protease, which is the viral enzyme responsible for cleavage of the viral polyprotein into a number of essential enzymes (reverse transcriptase, protease, and integrase) and several structural proteins. The protease inhibitors exhibit at least a thousandfold greater affinity for HIV-1 and HIV-2 enzymes than they have for comparable human proteases, such as renin and cathepsin D/E. This accounts for their selective toxicity. The inhibition prevents maturation of the viral particles and results in the production of noninfectious virions. Treatment of antiretroviral naïve patients (those who have never had HIV therapy) with a protease inhibitor and two NRTIs results in a decrease in the plasma viral load to undetectable levels in 60 to 95 percent of patients. Treatment failures under these conditions are most likely due to a lack of patient adherence. |
| Metabolism hiv protease inhibitors | Most protease inhibitors have poor oral bioavailability. High-fat meals substantially increase the bioavailability of some, such as nelfinavir and saquinavir, whereas the bioavailability of indinavir is decreased, and others are essentially unaffected. All are substrates for the CYP3A4 isozyme of CYP450, and individual protease inhibitors are also metabolized by other P450 isozymes. Metabolism is extensive, and very little of the protease inhibitors are excreted unchanged in urine. Dosage adjustments are unnecessary in renal impairment. Distribution into some tissues may be affected because protease inhibitors are substrates for the P-glycoprotein multidrug efflux pump. The presence of this pump in endothelial cells of capillaries in the brain may limit protease inhibitor access to the CNS. The HIV protease inhibitors are all substantially bound to plasma proteins, specifically α1-acid glycoprotein. This may be clinically important, because the concentration of α1-acid glycoprotein increases in response to trauma and surgery. |
| Adverse effects hiv protease inhibitors | Protease inhibitors commonly cause paresthesias, nausea, vomiting, and diarrhea Disturbances in glucose and lipid metabolism also occur, including diabetes, hypertriglyceridemia, and hypercholesterolemia. Chronic administration results in fat redistribution, including loss of fat from the extremities, fat accumulation in the abdomen and the base of the neck (“buffalo hump”), and breast enlargement. These physical changes may indicate to others that an individual is HIV infected.Drug interactions are a common problem for all protease inhibitors, because they are not only substrates but also potent inhibitors of CYP isozymes. The inhibitory potency of the compounds lies between that of ritonavir, the most potent, and that of saquinavir, the least potent Drugs that rely on metabolism for their termination of action may accumulate to toxic levels. Examples of potentially dangerous interactions from drugs that are contraindicated with protease inhibitors include rhabdomyolysis from simvastatin or lovastatin, excessive sedation from midazolam or triazolam, and respiratory depression from fentanyl Other drug interactions that require dosage modification and cautious use include warfarin, sildenafi l, and phenytoin inducers of CYP isozymes may result in the lowering of protease inhibitor plasma concentrations to suboptimal levels, contributing to treatment failures. Thus, drugs such as rifampin and St. John’s wort are also contraindicated with protease inhibitors. Meticulous attention must be paid to all of these detrimental interactions.A peripheral neuropathy, skin rash, and hyperbilirubinemia. Prolongation of the QTc interval may occur at high doses. Unlike most PIs, atazanavir does not appear to be associated with dyslipidemias, fat deposition, or a metabolic syndrome. However, it is a potent inhibitor of CYP3A4 and CYP2C9. |
| Resistance hiv protease inhibitors | Resistance occurs as an accumulation of stepwise mutations of the protease gene. Initial mutations result in decreased ability of the virus to replicate, but as the mutations accumulate, virions with high levels of resistance to the protease emerges. Suboptimal concentrations result in the more rapid appearance of resistant strains. |
| Ritonavir | It is no longer used as a single protease inhibitor but, instead, is used as a pharmacokinetic enhancer or "booster” of other protease inhibitors. Ritonavir is a potent inhibitor of CYP3A, and concomitant ritonavir administration (at low doses) increases the bioavailability of the second protease inhibitor, often allowing for longer dosing intervals. The resulting higher Cmin levels of the “boosted" protease inhibitors also help to prevent the development of resistance. Therefore, “boosted" protease inhibitors are preferred agents in the DHHS treatment guidelines. Metabolism and biliary excretion are the primary methods of elimination. Ritonavir has a half-life of 3 to 5 hours. Because it is primarily an inhibitor of CYP450 isozymes, numerous drug interactions have been identifi ed. Nausea, vomiting, diarrhea,headache, and circumoral paresthesias are among the more common adverse effects.elevations of hepatic aminotransferases and triglycerides in the plasma also occur. Drugs that increase the activity of the cytochrome P450 isoform CYP3A4 (anticonvulsants, rifamycins) reduce serum levels of ritonavir, and drugs that inhibit this enzyme (azole antifungals, cimetidine, erythromycin) elevate serum levels of the antiviral drug. Ritonavir inhibits the metabolism of a wide range of drugs, including erythromycin, dronabinol, ketoconazole, prednisone, rifampin, and saquinavir. Subtherapeutic doses of ritonavir inhibit the CYP3A-mediated metabolism of other protease inhibitors (eg, indinavir, lopinavir, saquinavir); this is the rationale for PI combinations that include ritonavir because it permits the use of lower doses of the other protease inhibitor. |
| Saquinavir | To maximize bioavailability, saquinavir is always given along with a low dose of ritonavir. High-fat meals also enhance absorption. Elimination of saquinavir is primarily by metabolism, followed by biliary excretion. Its half-life is 7 to 12 hours, requiring twice daily doses. Drugs that enhance the metabolism of saquinavir, such as rifampin, rifabutin, nevirapine, efavirenz, and other enzyme inducers, should be avoided if possible. The most common adverse effects of saquinavir treatment include headache, fatigue, dyspepsia rhinitis diarrhea, nausea, and other GI disturbances. Increased levels of hepatic aminotransferases have been noted, particularly in patients with concurrent viral hepatitis B or C infections.Original formulations of saquinavir had low and erratic oral bioavailability. Reformulation for once-daily dosing in combination with low-dose ritonavir has improved efficacy with decreased GI side effects. The drug undergoes extensive first-pass metabolism and functions as both a substrate and inhibitor of CYP3A4.Saquinavir plasma levels are increased by azole antifungals, clarithromycin, grapefruit juice, indinavir, and ritonavir. Drugs that induce CYP3A4 decrease plasma levels of saquinavir. |
| Indinavir | It is well absorbed orally and, of all the protease inhibitors, is the least protein bound, at 60 percent. Acidic gastric conditions are necessary for absorption. Absorption is decreased when administered with meals, although a light, low-fat snack is permissible. Ritonavir overcomes this problem and also permits twice-a-day dosing. Metabolism and hepatic clearance account for elimination of indinavir. The dosage should, therefore, be reduced in the presence of hepatic insufficiency. Indinavir has the shortest half-life of the protease inhibitors, at 1.8 hours. It is well tolerated, with the usual GI symptoms and headache predominating. Indinavir characteristically causes nephrolithiasis and hyperbilirubinemia. Adequate hydration is important to reduce the incidence of kidney stone formation, and patients should drink at least 1.5 L of water per day. Fat redistribution is particularly troublesome with this drug.nausea, diarrhea, thrombocytopenia, To reduce renal damage, it is important to maintain good hydration. Insulin resistance may be more common with indinavir than other PIs. Indinavir is a substrate for and an inhibitor of the cytochrome P450 isoform CYP3A4 and is implicated in drug interactions. Serum levels of indinavir are increased by azole antifungals and decreased by rifamycins. Indinavir increases the serum levels of antihistamines, benzodiazepines, and rifampin. |