ANTIVIRAL ANTIFUNGAL ANTIPROTOSOAL ANTISPIROCHETES AGENTS (Remantadinum, Interferonum, Acyclovirum, Idoxoridinum, Laferonum, Azidotimidinum, Biiochinolum, Metronidaasolum, Emetinihydrochloridum, Chingaminum, Chiniofonum, Tinidasolum, Furasolidonum, aminochinolum).
ANTIHELMINTICS (Levamisolum (Decaris), Pirantelum, Piperasiniadipinas, Naphtamonum, Piriviniipaomas, Mebendasolum (Vermox), Fenasalum, Dytrasinum, Chloxilum, Antimonilinatriumtartras, Praziqantelum.
ANTINEOPLASTICAGENTS (Dopanum, Sarcolisinum, Chlorbutinum, Cyclophosphanum, Myelosanum, Cyclophosphamidum, Metotrexatum, Phtoruracilum, Mercaptopurinum, Vincristinum, Vinblastinum, Colhaminum, Doxorubicinihydrochloridum, Dactinomicinum, Fosfestrolum, Prednisolonum, Tamoxifenum, Propes, Asparginase).
Common pharmacology
Antiviral agents
Antiviral Agents: Introduction
Viruses are obligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell.
Consequently, to be effective, antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell. As a corollary, nonselective
inhibitors of virus replication may interfere with host cell function and produce toxicity. The search for chemicals that inhibit virus-specific functions is currently one of the most active areas of pharmacologic investigation. Research in antiviral chemotherapy began in the early 1950s, when the search for anticancer drugs generated several new compounds capable of inhibiting viral DNA synthesis. The two firstgeneration antivirals, 5-iododeoxyuridine and trifluorothymidine, had poor specificity (ie, they inhibited host cellular as well as viral DNA) that rendered them too toxic for systemic use. However, both are effective when used topically for the treatment of herpes keratitis. Recent research has focused on the identification of agents with greater selectivity, in vivo stability, and lack of toxicity. Selective antiretroviral agents that inhibit a critical HIV-1 enzyme such as 3TC: Lamivudine
cella-zoster virus
Agents to Treat Herpes Simplex Virus (HSV) & Varicella Zoster Virus (VZV) Infections Three oral agents are licensed for the treatment of HSV and VZV infections: acyclovir, valacyclovir, and famciclovir. They have similar mechanisms of action and similar indications for clinical use; all are well tolerated.
Acyclovir, licensed first, has been the most extensively studied; in addition, it is the only anti-HSV agent available for intravenous use in the United States. Neither valacyclovir nor famciclovir have been fully evaluated in pediatric patients; thus, they are not indicated for the treatment of varicella infection.
Acyclovir
Acyclovir is an acyclic guanosine derivative with clinical activity against HSV-1, HSV-2, and VZV. In vitro activity against Epstein-Barr virus, cytomegalovirus, and human herpesvirus-6 is present but comparatively weaker.
Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by the virus-specified thymidine kinase and then to the di- and triphosphate compounds by the host’s cellular enzymes. Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated and accumulates only in infected cells. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: competitive inhibition with deoxyGTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex; and chain termination following incorporation into the viral DNA.
Pharmacokinetics
The bioavailability of oral acyclovir is 15–20% and is unaffected by food. Peak serum concentrations of approximately 1 g/mL after a 200 mg oral dose and 1.5–2 g/mL after an 800 mg dose are reached 1.5–2 hours after dosing. Peak serum concentrations are 10 g/mL and 20 g/mL after intravenous infusions (over 1 hour) of 5 mg/kg and 10 mg/kg, respectively. Topical formulations produce local concentrations that may exceed 10 g/mL in herpetic lesions, but systemic concentrations are undetectable.
Acyclovir is cleared primarily by glomerular filtration and tubular secretion. The half-life is approximately 3 hours in patients with normal renal function and 20 hours in patients with anuria.
Acyclovir is readily cleared by hemodialysis but not by peritoneal dialysis. Acyclovir diffuses into most tissues and body fluids to produce concentrations that are 50–100% of those in serum. Cerebrospinal fluid concentrations are 50% of serum values.
Clinical Uses
Oral acyclovir has multiple uses. In primary genital herpes, oral acyclovir shortens by approximately 5 days the duration of symptoms, the time of viral shedding, and the time to resolution of lesions; in recurrent genital herpes, the time course is shortened by 1–2 days.
Treatment of primary genital herpes does not alter the frequency or severity of recurrent outbreaks. Long-term chronic suppression of genital herpes with oral acyclovir decreases the frequency both of symptomatic recurrences and of asymptomatic viral shedding in patients with frequent recurrences, thus decreasing sexual transmission. However, outbreaks may resume upon discontinuation of suppressive acyclovir. In recurrent herpes labialis, oral acyclovir reduces the mean duration of pain but not the time to healing. Oral acyclovir decreases the total number of lesions and duration of varicella (if begun within 24 hours after the onset of rash) and cutaneous zoster (if begun within 72 hours). However, because VZV is less susceptible to acyclovir than HSV, higher doses are required. A meta-analysis suggested that acyclovir was superior to placebo in reducing the duration of “zoster-associated pain,” a continuous variable combining acute and chronic pain. When given prophylactically to patients undergoing organ transplantation, oral acyclovir (200 mg every 8 hours or 800 mg every 12 hours) or intravenous acyclovir (5 mg/kg every 8 hours) prevents reactivation of HSV infection. The benefit of acyclovir for prevention of CMV infections in transplant patients is controversial.
Adverse Reactions
Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported. Intravenous infusion may be associated with reversible tremors, delirium, seizures); however, these renal dysfunction due to crystalline nephropathy or neurologic toxicity (eg, are uncommon with adequate hydration and avoidance of rapid infusion rates. Chronic daily suppressive use of acyclovir for more than 10 years has not been associated with untoward effects.
High doses of acyclovir cause testicular atrophy in rats, but there has beeo evidence of teratogenicity to date in a cumulative registry and no effect on sperm production was demonstrated in a placebo-controlled trial of patients receiving daily chronic acyclovir.
Valacyclovir
Valacyclovir is the L-valyl ester of acyclovir. It is rapidly converted to acyclovir after oral administration, resulting in serum levels three to five times greater than those achieved with oral acyclovir and approximating those resulting from intravenous acyclovir administration. Oral bioavailability is about 48%. As with acyclovir, uses of valacyclovir include treatment of first atacks or recurrences of genital herpes, suppression of frequently recurrent genital herpes, treatment of herpes zoster infection, and, recently, as a 1-day treatment for orolabial herpes.
Valacyclovir has also been shown to be effective in preventing cytomegalovirus disease after organ transplantation when compared with placebo. In general, comparative studies have shown similar or slightly improved efficacy of valacyclovir versus acyclovir for all indications; furthermore, valacyclovir therapy was associated with a shorter duration of zoster-associated pain than acyclovir in one study, as well as a lower frequency of postherpetic neuralgia. Once-daily dosing of valacyclovir (500 mg) as chronic suppression in persons with recurrent genital herpes has recently been shown to markedly decrease the risk of sexual transmission. Valacyclovir is generally well tolerated, although nausea, diarrhea, and headache may occur. AIDS patients receiving high-dosage valacyclovir chronically (ie, 8 g/d) had an increased incidence of gastrointestinal intolerance as well as thrombotic microangiopathies such as thrombotic thrombocytopenic purpura and hemolyticuremic syndrome. In transplant patients receiving valacyclovir (8 g/d), non-dose-limiting confusion and hallucinations were the most frequent side effects.
Famciclovir
Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic guanosine analog (Figure 49–2). After oral administration, famciclovir is rapidly converted by first-pass metabolism to penciclovir, which shares many features with acyclovir. It is active in vitro against HSV-1, HSV- 2, VZV, EBV, and HBV. Activation by phosphorylation is catalyzed by the virus-specified thymidine kinase in infected cells, followed by competitive inhibition of the viral DNA polymerase to block DNA synthesis. Unlike acyclovir, penciclovir does not cause chain termination. Penciclovir triphosphate has lower affinity for the viral DNA polymerase than acyclovir triphosphate, but it achieves higher intracellular concentrations and has a more prolonged intracellular effect in experimental systems. The most commonly encountered clinical mutants of HSV are thymidine kinase-deficient and are cross-resistant to acyclovir and famciclovir.
Pharmacokinetics
The bioavailability of penciclovir from orally administered famciclovir is 70%; less than 20% is plasma protein-bound. A peak serum concentration of 2 g/mL is achieved following a 250 mg oral dose. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-infected cells, 20 hours in HSV-2-infected cells, and 7 hours in VZV-infected cells in vitro. Penciclovir is excreted primarily in the urine.
Clinical Uses
Oral famciclovir is effective for the treatment of first and recurrent genital herpes attacks and for chronic daily suppression. It is also used to treat acute herpes zoster (shingles). In controlled trials in immunocompetent patients with zoster, famciclovir was similar to acyclovir in rates of cutaneous healing but was associated with a shorter duration of postherpetic neuralgia.
Comparison of famciclovir to valacyclovir for treatment of herpes zoster in immunocompetent patients showed similar rates of cutaneous healing and pain resolution. However, neither drug decreased the incidence of postherpetic neuralgia.
Adverse Reactions
Oral famciclovir is generally well tolerated, although headache, diarrhea, and nausea may occur. As with acyclovir, testicular toxicity has been demonstrated in animals receiving repeated doses. However, men receiving daily famciclovir (250 mg every 12 hours) had no changes in sperm morphology or motility. The incidence of mammary adenocarcinoma was also increased in female rats receiving famciclovir for 2 years.
AIDS TREATMENT
A large and increasing number of antiretroviral agents are currently available for treatment of HIV- 1-infected patients. When to initiate therapy is controversial, but it is clear that monotherapy with any one agent should be avoided because of the need for maximal potency to durably inhibit virus replication and to avoid premature development of resistance. A combination of agents (highly active antiretroviral therapy; HAART) is usually effective in reducing plasma HIV RNA levels and in gradually increasing CD4 cell counts, particularly in antiretroviral-naïve patients. Also important in selection of agents is optimization of adherence, tolerability, and convenience. Given that many patients will ultimately experience at least one treatment failure, close monitoring of viral load and CD4 cell counts is critical to trigger appropriate changes in therapy. The judicious use of drug resistance testing should be considered in selecting an alternative regimen for a patient who is not responding to therapy.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase and can also be incorporated into the growing viral DNA chain to cause termination. Each requires intracytoplasmic activation as a result of phosphorylation by cellular enzymes to the triphosphate form. Most have activity against HIV-2 as well as HIV-1. Lactic acidemia and severe hepatomegaly with steatosis have been reported with the use of NRTI agents, alone or in combination with other antiretroviral drugs. Obesity, prolonged nucleoside exposure, and risk factors for liver disease have been described as factors that increase risk for lactic acidemia; however, cases have also been reported in patients with no known risk factors.
NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic or lactic acidosis of unknown cause. Given their similar mechanism of action, it is probable that these cautions should be applied to treatment with nucleotide inhibitors as well (see Nucleotide Inhibitors).
Zidovudine
As the first licensed antiretroviral agent, zidovudine has been well studied. Zidovudine has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytopenia. In pregnancy, a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation (100 mg five times a day), intravenous zidovudine during labor (2 mg/kg over 1 hour, then 1 mg/kg/h by continuous infusion), and zidovudine syrup to the neonate from As with other NRTI agents, resistance may limit clinical efficacy. High-level zidovudine resistance is generally seen in strains with three or more of the five most common mutations: M41L, D67N, K70R, T215F, and K219Q. However, the emergence of certain mutations that confer decreased susceptibility to one drug (eg, L74V in the case of didanosine and M184V in the case of lamivudine) seems to enhance susceptibility in previously zidovudine-resistant strains.
Withdrawal ofzidovudine exposure may permit the reversion of zidovudine-resistant HIV-1 isolates to the susceptible wild-type phenotype.
The most common adverse effect of zidovudine is myelosuppression, resulting in anemia or neutropenia. Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. Less frequent side effects include thrombocytopenia, hyperpigmentation of the nails, and myopathy. Very high doses can cause anxiety, confusion, and tremulousness. Zidovudine causes vaginal neoplasms in mice; however, no humn cases of genital neoplasms have been reported to date. Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin, methadone, fluconazole, atovaquone, valproic acid, and lamivudine, either through inhibition of first-pass metabolism or through decreased clearance.
Zidovudine may decrease phenytoin levels, and this warrants monitoring of serum phenytoin levels in epileptic patients taking both agents. Hematologic toxicity may be increased during coadministration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents. (See Treatment of HIV-Infected Individuals: Importance of Pharmacokinetic Knowledge.)
Didanosine
Didanosine (ddI) is a synthetic analog of deoxyadenosine. At acid pH, hydrolysis of the glycosidic bond between the sugar and the base moieties of ddI will inactivate the compound.
Resistance to didanosine, due typically to mutation at codon 74 (L74V), may partially restore susceptibility to zidovudine but may confer cross-resistance to abacavir, zalcitabine, and lamivudine. High-level resistance (> 100-fold decreased susceptibility) has not been reported to date.
The major clinical toxicity associated with didanosine therapy is dose-dependent pancreatitis. Other risk factors for pancreatitis (eg, alcoholism, hypertriglyceridemia) are relative contraindications to administration of didanosine, and other drugs with the potential to cause pancreatitis should be avoided. Other reported adverse effects include painful peripheral distal neuropathy, diarrhea, hepatitis, esophageal ulceration, cardiomyopathy, and central nervous system toxicity (headache, irritability, insomnia). Asymptomatic hyperuricemia may precipitate attacks of gout in susceptible individuals. Reports of retinal changes and optic neuritis in patients receiving didanosine— particularly in adults receiving high doses and in children—indicate the utility of periodic retinal examinations.
Fluoroquinolones and tetracyclines should be administered at least 2 hours before or after didanosine in order to avoid decreased antibiotic plasma concentrations due to chelation. Coadministration with ganciclovir results in an increased AUC of didanosine and a decreased AUC of ganciclovir, while coadministration with methadone results in decreased didanosine serum levels.
Lamivudine
Lamivudine (3TC) is a cytosine analog (Figure 49–4) with in vitro activity against HIV-1 that is synergistic with a variety of antiretroviral nucleoside analogs—including zidovudine and stavudine—against both zidovudine-sensitive and zidovudine-resistant HIV-1 strains. Oral bioavailability exceeds 80% and is not food-dependent. Peak serum levels after standard doses are 1.5 ± 0.5 g/mL, and protein binding is less than 36%. In children, the mean CSF:plasma ratio of lamivudine was 0.2. Mean elimination half-life is 2.5 hours, while the intracellular half-life of the active 5′-triphosphate metabolite in HIV-1-infected cell lines is 10.5–15.5 hours. The majority of lamivudine is eliminated unchanged in the urine, and the dose should be reduced in patients with renal insufficiency or low body weight No supplemental doses are required after routine hemodialysis. Lamivudine therapy rapidly selects—both in vitro and in vivo—for M184V-resistant mutants of HIV, which show high-level resistance to lamivudine and a reduction in susceptibility to abacavir, didanosine, and zalcitabine.
Potential side effects are headache, insomnia, fatigue, and gastrointestinal discomfort, though these are typically mild. Lamivudine’s AUC increases when it is coadministered with trimethoprimsulfamethoxazole. Peak levels of zidovudine increase when the drug is administered with lamivudine, though this effect is not felt to have clinical significance.
Stavudine
The thymidine analog stavudine (D4T) (Figure 49–4) has high oral bioavailability (86%) that is not food-dependent. The plasma half-life is 1.22 hours; the intracellular half-life is 3.5 hours; and mean cerebrospinal fluid concentrations are 55% of those of plasma. Plasma protein binding is negligible. Excretion is by active tubular secretion and glomerular filtration. The dosage of stavudine should be reduced in patients with renal insufficiency, in those receiving hemodialysis, and for low bodyweight.
Since zidovudine may reduce the phosphorylation of stavudine, these two drugs should generally not be used together.
Abacavir
In contrast to earlier NRTIs, abacavir is a guanosine analog. It is well absorbed following oral administration (83%), is unaffected by food, and is about 50% bound to plasma proteins. In singledose studies, the elimination half-life was 1.5 hours. Cerebrospinal fluid levels are approximately one-third those of plasma. The drug is metabolized by alcohol dehydrogenase and glucuronosyltransferase to inactive metabolites that are eliminated primarily in the urine. High-level resistance to abacavir appears to require at least two or three concomitant mutations (eg, M184V, L74V), and for that reason it tends to develop slowly. Although cross-resistance to lamivudine, didanosine, and zalcitabine has been noted in vitro in recombinant strains with abacavir-associated mutations, the clinical significance is unknown.
Hypersensitivity reactions, occasionally fatal, have been reported in 2–5% of patients receiving abacavir. Symptoms, which generally occur within the first 6 weeks of therapy, involve multiple organ systems and include fever, malaise, and gastrointestinal complaints. Skin rash may or may not be present. Laboratory abnormalities such as mildly elevated serum aminotransferase or creatine kinase levels are not specific for this reaction. Although the syndrome tends to resolve quickly with discontinuation of medication, rechallenge with abacavir following discontinuation results in return of symptoms within hours and may be fatal. Other adverse events may include rash, nausea and vomiting, diarrhea, headache, and fatigue. Adverse effects that appear to be infrequent include pancreatitis, hyperglycemia, and hypertriglyceridemia. Clinically significant adverse drug interactions have not been reported to date, though coadministration of alcohol and abacavir may result in an increase in abacavir’s AUC.
Nucleotide Inhibitors
Tenofovir
Tenofovir disoproxilfumarate is a prodrug that is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine. Like the NRTIs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. The oral bioavailability of tenofovir from tenofovir disopoxilfumarate, a water-soluble diester prodrug of the active ingredient tenofovir, in fasted patients is approximately 25%. Oral bioavailability is increased if the drug is ingested following a high-fat meal (increased AUC by
about 40%); therefore, taking the drug along with a meal is recommended. Maximum serum concentrations are achieved in about 1 hour after taking the medication. Elimination occurs by a combination of glomerular filtration and active tubular secretion. However, only 70–80% of the dose is recovered in the urine, allowing for the possibility of hepatic metabolism as well as alteration in hepatic insufficiency; the latter has not been studied.
Tenofovir is indicated for use in combination with other antiretroviral agents. Initial studies demonstrated potent HIV-1 suppression in treatment-experienced adults with evidence of viral replication despite ongoing antiretroviral therapy; similar benefit in antiretroviral-naive patients has yet to be demonstrated. The once-daily dosing regimen of tenofovir lends added convenience.
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
The NNRTIs bind directly to a site on the HIV-1 reverse transcriptase, resulting in blockade of RNA- and DNA-dependent DNA polymerase activities. The binding site is near to but distinct from that of the NRTIs. Unlike the latter group of agents, the NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active. Resistance to an NNRTI is generally rapid with monotherapy and is associated with the K103N mutation as well as the less critical Y181C/I mutation; cross-resistance among this class of agents, although observed in vitro, is of unknown clinical significance. There is no cross-resistance between the NNRTIs and the NRTIs or the protease inhibitors.
A syndrome of drug hypersensitivity has been described in patients receiving NNRTIs as well as in those receiving amprenavir or abacavir. Serious rashes, including Stevens-Johnson syndrome, have occurred.
Nevirapine
The oral bioavailability of nevirapine is excellent (> 90%) and is not food-dependent. The drug is highly lipophilic, approximately 60% protein-bound, and achieves cerebrospinal fluid levels that are 45% of those in plasma. It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites and then excreted, primarily in the urine.
Nevirapine is typically used as a component of a combination antiretroviral regimen. In addition, a single dose of nevirapine (200 mg) has recently been shown to be effective in the prevention of transmission of HIV from mother to newborn when administered to women at the onset of labor and followed by a 2-mg/kg oral dose given to the neonate within 3 days after delivery.
Severe and life-threatening skin rashes have occurred during nevirapine therapy, including Stevens- Johnson syndrome and toxic epidermal necrolysis. Nevirapine therapy should be immediately discontinued in patients with severe rash and in those with rash accompanied by constitutional symptoms. Rash occurs in approximately 17% of patients, most typically in the first 4–8 weeks of therapy, and is dose-limiting in about 7% of patients. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the frequency of rash. Fulminant hepatitis may occur in association with rash and fever, typically within the first 6 weeks of initiation of therapy, or may occur without a concomitant rash. Therefore, serial monitoring of liver function tests is strongly recommended. Other frequently reported adverse effects associated with nevirapine therapy are fever, nausea, headache, and somnolence.
Delavirdine
Delavirdine has an oral bioavailability of about 85%, but this is reduced by antacids. It is extensively bound (about 98%) to plasma proteins. Cerebrospinal fluid levels average only 0.4% of the corresponding plasma concentrations, representing about 20% of the fractioot bound to plasma proteins. Caution should be used when administering delavirdine to patients with hepatic insufficiency because clinical experience in this situation is limited. Skin rash occurs in about 18% of patients receiving delavirdine; it typically occurs during the first month of therapy and does not preclude rechallenge. However, severe rash such as erythema multiforme and Stevens-Johnson syndrome have rarely been reported. Other adverse effects may include headache, fatigue, nausea, diarrhea, and increased serum aminotransferase levels.
Efavirenz
Efavirenz can be given once daily because of its long half-life (40–55 hours). It is moderately well absorbed following oral administration (45%), and bioavailability is increased to about 65% following a high-fat meal. Peak plasma concentrations are seen 3–5 hours after administration of daily doses; steady state plasma concentrations are reached in 6–10 days. Efavirenz is principally metabolized by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites; the remainder is eliminated in the feces as unchanged drug. It is highly bound to albumin (> 99%).
Cerebrospinal fluid levels range from 0.3% to 1.2% of plasma levels; these are approximately three times higher than the free fraction of efavirenz in the plasma. Because there is limited experience to date, caution is advised with use in patients with hepatic impairment.
The principal adverse effects of efavirenz involve the central nervous system (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria); these may occur in up to 50% of patients. They tend to occur during the first days of therapy and may resolve while medication is continued; administration at bedtime may be helpful. However, psychiatric symptoms may be severe. Skin rash has also been reported early in therapy in up to 28% of patients, is usually mild to moderate, and typically resolves despite continuation. Other potential adverse reactions include nausea and vomiting, diarrhea, crystalluria, elevated liver enzymes, and an increase in total serum cholesterol by 10–20%. High rates of fetal abnormalities occurred in pregnant monkeys exposed to efavirenz in doses roughly equivalent to the human dosage of 600 mg/d. Therefore, pregnancy should be avoided in women receiving efavirenz.
Protease Inhibitors
During the later stages of the HIV growth cycle, the Gag and Gag-Pol gene products are translated into polyproteins and then become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core.
Saquinavir
In its original formulation as a hard gel capsule (saquinavir-H; Invirase), oral saquinavir was poorly bioavailable (about 4% in the fed state). It was therefore largely replaced in clinical use by a soft gel capsule formulation (saquinavir-S; Fortovase), in which absorption was increased approximately threefold. However, reformulation of saquinavir-H for once-daily dosing in combination with lowdose ritonavir (see Ritonavir) has both improved antiviral efficacy and decreased the gastrointestinal side effects typically associated with saquinavir-S. Moreover, coadministration of saquinavir-H with ritonavir results in blood levels of saquinavir similar to those associated with saquinavir-S, thus capitalizing on the pharmacokinetic interaction of the two agents.
Ritonavir
The most common adverse effects of ritonavir are gastrointestinal disturbances, paresthesias (circumoral and peripheral), elevated serum aminotransferase levels, altered taste, and hypertriglyceridemia. Nausea, vomiting, and abdominal pain typically occur during the first few weeks of therapy, and patients should be told to expect them. Slow dose escalation over 4–5 days is recommended to decrease the frequency of dose-limiting side effects. Liver adenomas and carcinomas have been induced in male mice receiving ritonavir; no similar effects have been observed to date in humans.
Ease of administration is limited by ritonavir’s numerous drug interactions. Ritonavir is both a substrate and an inhibitor of CYP3A4; as such, coadministration with agents heavily metabolized by CYP3A must be approached with the same precautions discussed above. In addition, since ritonavir is an inhibitor of the CYP3A4 isoenzyme, concurrent administration with other PIs results in increased plasma levels of the latter drugs; these interactions have been exploited to permit more convenient dosing.
Lopinavir/Ritonavir
Several studies have shown enhanced efficacy or improved tolerability of two protease inhibitors administered together. Lopinavir 100/ritonavir 400 is a licensed combination in which subtherapeutic doses of ritonavir inhibit the CYP3A-mediated metabolism of lopinavir, thereby resulting in increased exposure to lopinavir.
Fusion Inhibitors
Enfuvirtide
Enfuvirtide (formerly called T-20) is a newly approved antiretroviral agent of a novel class, ie, a fusion inhibitor that blocks entry into the cell. Enfuvirtide, a synthetic 36-amino-acid peptide, binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.
Resistance to enfuvirtide can occur, and the frequency and mechanisms of this phenomenon are currently being investigated. However, enfuvirtide completely lacks cross-resistance to the other currently approved antiretroviral drug classes. The drug is administered subcutaneously in combination with other antiretroviral agents in treatment-experienced patients with persistent HIV-1 replication despite ongoing therapy. Protein binding is high (92%), and metabolism appears to be by proteolytic hydrolysis without involvement of the cytochrome p450 system. Elimination half-life is 3.8 hours, and time to peak concentration is 8 hours. The most common side effects associated with enfuvirtide therapy are local injection site reactions. Hypersensitivity reactions may occur, are of varying severity, and may recur on rechallenge. Eosinophilia has also beeoted. No interactions have been identified that would require alteration of other antiretroviral drugs.
Interferon Alfa
Interferons are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving synthesis of both RNA and protein. They appear to function by binding to specific membrane receptors on the cell surface and initiating a series of intracellular events that include enzyme induction, suppression of cell proliferation, immunomodulatory activities, and inhibition of virus replication.
They are classified according to the cell type from which they were derived, and each of the three immunologically distinct major classes of human interferons has unique physicochemical characteristics and different producer cells, inducers, and biologic effects.
Interferon alfa preparations are available for treatment of both HBV and HCV virus infections. Interferon alfa-2b is the only preparation licensed for treatment of HBV infection and for acute hepatitis C. Interferon alfa-2b leads to loss of HBeAg, normalization of serum aminotransferases, and sustained histologic improvement in approximately one-third of patients with chronic hepatitis B, thus reducing the risk of progressive liver disease.
In acute hepatitis C, the rate of clearance of the virus without therapy is estimated to be 15–30%. No therapy has yet been proved effective in the treatment of acute hepatitis C; however, a recent study suggested that interferon alfa-2b, in doses higher than those used for treatment of chronic hepatitis C, resulted in a sustained rate of clearance of 98%.
Several interferon alfa preparations are available for the treatment of patients with chronic hepatitis C infection, including interferon alfa-2a, interferon alfa-2b, interferon alfacon-2, pegylated interferon alfa-2a, and pegylated interferon alfa-2b, as described below. Factors associated with a favorable response to therapy include HCV genotype 2 or 3, absence of cirrhosis on liver biopsy, and low pretreatment HCV RNA levels. For all agents, combination therapy with oral ribavirin in patients with chronic hepatitis C is more effective than monotherapy with either interferon or ribavirin alone, increasing the percentage of previously untreated patients with a sustained virologic response from approximately 16% to approximately 40%. Therefore, monotherapy is recommended only in patients who cannot tolerate ribavirin. The time to maximal response may range from 24 weeks to 48 weeks of therapy.
Pegylated Interferon Alfa
Pegylated interferon alfa-2a (peginterferon alfa-2a) and pegylated interferon alfa-2b (peginterferon alfa-2b) have recently been introduced for the treatment of patients with chronic hepatitis C infection. In these agents, a linear or branched polyethylene glycol (PEG) moiety is attached to interferon by a covalent bond. Reduced clearance and sustained absorption results in an increased half-life and steadier drug concentrations, allowing for less frequent dosing.
In comparison with the nonpegylated interferon alfa compounds, the pegylated products have substantially longer terminal half-lives and slower clearance. Maximum serum concentrations occur between 15 hours and 44 hours after dosing and are sustained for up to 48–72 hours.
Anti-Influenza Agents
Amantadine & Rimantadine
Amantadine (1-aminoadamantane hydrochloride) and its -methyl derivative, rimantadine, are cyclic amines that inhibit uncoating of the viral RNA of influenza A within infected host cells, thus preventing its replication. Rimantadine is four to ten times more active than amantadine in vitro.
Steady state peak plasma levels in healthy young adults average 0.5—0.8 g/mL for amantadine; elderly persons require only one half of the weight-adjusted dose for young adults to achieve equivalent trough plasma levels of 0.3 g/mL. While amantadine is excreted unmetabolized in the urine, rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion. Dose reductions are required for both agents in the elderly, in renal insufficiency, and for rimantadine in patients with marked hepatic insufficiency. No supplemental doses of either agent are required after hemodialysis. Plasma half-life is 12–18 hours for amantadine and 24–36 hours for rimantadine.
Both amantadine and rimantadine, in doses of 100 mg twice daily or 200 mg once daily, are approximately 70–90% protective in the prevention of clinical illness by influenza A. The effectiveness of postexposure prophylaxis is inconsistent. When begun within 1–2 days after the onset of clinical symptoms of influenza, both drugs reduce the duration of fever and systemic complaints by 1–2 days.
The most common adverse effects are gastrointestinal intolerance and central nervous system complaints (eg, nervousness, difficulty in concentrating, lightheadedness); the latter are less frequent with rimantadine than with amantadine. The central nervous system toxicity of amantadine may be increased with concomitant antihistamines, anticholinergic drugs, hydrochlorothiazide, and trimethoprim-sulfamethoxazole. Serious neurotoxic reactions, occasionally fatal, may occur in association with high amantadine plasma concentrations (1–5 g/mL).
Acute amantadine overdose is associated with anticholinergic effects. Amantadine is teratogenic and embrytoxic in rodents, and birth defects have been reported after exposure during pregnancy.
Zanamivir & Oseltamivir
Neuraminidase is an essential viral glycoprotein for virus replication and release. The neuraminidase inhibitors zanamivir and oseltamivir have recently been approved for the treatment of acute uncomplicated influenza infection. When a 5-day course of therapy is initiated within 36– 48 hours after the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults. Unlike amantadine and rimantidine, zanamivir and oseltamivir have activity against both influenza A and influenza B. Zanamivir is administered via oral inhaler. The compound displays poor oral bioavailability, limited plasma protein binding, rapid renal clearance, and absence of significant metabolism. Nasal and throat discomfort may occur—as well as bronchospasm in patients with reactive airway disease.
Potential side effects include nausea and vomiting, which may be decreased by administration with food. Decreased susceptibility to zanamivir and oseltamivir in vitro is associated with mutations in viral neuraminidase or hemagglutinin. A resistant virus was recovered from an immunocompromised patient who had received zanamivir for 2 weeks. However, the incidence and clinical significance of resistance are not yet known.
Antifungal Agents
Antifungal Agents: Introduction
Human fungal infections have increased dramatically in incidence and severity in recent years, due mainly to advances in surgery, cancer treatment, and critical care accompanied by increases in the use of broad-spectrum antimicrobials and the HIV epidemic. These changes have resulted in increased numbers of patients at risk for fungal infections.
Pharmacotherapy of fungal disease has been revolutionized by the introduction of the relatively nontoxic oral azole drugs and the echinocandins. Combination therapy is being reconsidered, and new formulations of old agents are becoming available. Unfortunately, the appearance of azoleresistant organisms, as well as the rise in the number of patients at risk for mycotic infections, has created new challenges. The antifungal drugs presently available fall into several categories: systemic drugs (oral or parenteral) for systemic infections, oral drugs for mucocutaneous infections, and topical drugs for mucocutaneous infections.
Systemic Antifungal Drugs for Systemic Infections
Amphotericin B
Amphotericin A and B are antifungal antibiotics produced by Streptomyces nodosus. Amphotericin A is not in clinical use.
Chemistry Amphotericin B is an amphoteric polyene macrolide (polyene = containing many double bonds;
macrolide = containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water, and is therefore prepared as a colloidal suspension of amphotericin B and sodium desoxycholate for intravenous injection. Several new formulations have been developed in which amphotericin B is packaged in a lipid-associated delivery system.
Pharmacokinetics
Amphotericin B is poorly absorbed from the gastrointestinal tract. Oral amphotericin B is thus effective only on fungi within the lumen of the tract and cannot be used for treatment of systemic disease. The intravenous injection of 0.6 mg/kg/d of amphotericin B results in average blood levels of 0.3–1 g/mL; the drug is more than 90% bound by serum proteins. While it is mostly metabolized, some amphotericin B is excreted slowly in the urine over a period of several days. The serum t1/2 is approximately 15 days. Hepatic impairment, renal impairment, and dialysis have little impact on drug concentrations and therefore no dose adjustment is required. The drug is widely distributed in most tissues, but only 2–3% of the blood level is reached in cerebrospinal fluid, thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis.
Mechanism of Action
Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. Ergosterol, a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol. Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin B-associated pores in the cell membrane. As suggested by its chemistry, amphotericin B combines avidly with lipids (ergosterol) along the double bond-rich side of its structure and associates with water molecules along the hydroxyl-rich side. This amphipathic characteristic facilitates pore formation by multiple amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death. Some binding to human membrane sterols does occur, probably accounting for the drug’s prominent toxicity.
Resistance to amphotericin B occurs if ergosterol binding is impaired, either by decreasing the membrane concentration of ergosterol or by modifying the sterol target molecule to reduce its affinity for the drug.
Adverse Effects
The toxicity of amphotericin B can be divided into two broad categories: immediate reactions, related to the infusion of the drug, and those occurring more slowly.
Infusion-Related Toxicity
These reactions are nearly universal and consist of fever, chills, muscle spasms, vomiting, headache, and hypotension. They can be ameliorated by slowing the infusion rate or decreasing the daily dose. Premedication with antipyretics, antihistamines, meperidine, or corticosteroids can be helpful. When starting therapy, many clinicians administer a test dose of 1 mg intravenously to gauge the severity of the reaction. This can serve as a guide to an initial dosing regimen and
premedication strategy.
Slower Toxicity
Renal damage is the most significant toxic reaction. Renal impairment occurs iearly all patients treated with clinically significant doses of amphotericin. The degree of azotemia is variable and often stabilizes during therapy, but can be serious enough to necessitate dialysis. A reversible component is associated with decreased renal perfusion and represents a form of prerenal renal failure. An irreversible component results from renal tubular injury and subsequent dysfunction. The irreversible form of amphotericiephrotoxicity usually occurs in the setting of prolonged administration (>
Abnormalities of liver function tests are occasionally seen, as is a varying degree of anemia due to reduced erythropoietin production by damaged renal tubular cells. After intrathecal therapy with amphotericin, seizures and a chemical arachnoiditis may develop, often with serious neurologic sequelae.
Antifungal Activity
Amphotericin B remains the antifungal agent with the broadest spectrum of action. It has activity against the clinically significant yeasts, including Candida albicans and Cryptococcus neoformans; the organisms causing endemic mycoses, including Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis; and the pathogenic molds, such as Aspergillus fumigatus and mucor. Some fungal organisms such as Candida lusitaniae and Pseudallescheria boydii display intrinsic amphotericin B resistance.
Clinical Use
Azoles
Azoles are synthetic compounds that can be classified as either imidazoles or triazoles according to the number of nitrogen atoms in the five-membered azole ring as indicated below. The imidazoles consist of ketoconazole, miconazole, and clotrimazole (Figure 48–1). The latter two drugs are now used only in topical therapy. The triazoles include itraconazole, fluconazole, and voriconazole.
Pharmacology
Mechanism of Action
The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. The specificity of azole drugs results from greater affinity for fungal than for human cytochrome P450 enzymes. Imidazoles exhibit a lesser degree of specificity than the triazoles, accounting for their higher incidence of drug interactions and side effects. Resistance to azoles occurs via multiple mechanisms. Once rare, increasing numbers of resistant strains are being reported, suggesting that increasing use of these agents for prophylaxis and therapy may be selecting for clinical drug resistance in certain settings.
Clinical Use
The spectrum of action of these medications is quite broad, ranging from many candida species, Cryptococcus neoformans, the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes, and, in the case of itraconazole and voriconazole, even aspergillus infections. They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as Pseudallescheria boydii.
Adverse Effects
As a group, the azoles are relatively nontoxic. The most common adverse reaction is relatively minor gastrointestinal upset. All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis. Adverse effects specific to individual agents are discussed below.
Drug Interactions
All azole drugs affect the mammalian cytochrome P450 system of enzymes to some extent, and consequently they are prone to drug interactions. The most significant reactions are indicated below.
Systemic Antifungal Drugs for Mucocutaneous Infections
Griseofulvin
Griseofulvin is a very insoluble fungistatic drug derived from a species of penicillium. It is administered in a microcrystalline form at a dosage of 1 g/d. Absorption is improved when it is given with fatty foods. Griseofulvin’s mechanism of action at the cellular level is unclear, but it is deposited in newly forming skin where it binds to keratin, protecting the skin from new infection. Since its action is to prevent infection of these new skin structures, it must be administered for 2–6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. Nail infections may require therapy for months to allow regrowth of the new protected nail and is often followed by relapse. Adverse effects include an allergic syndrome much like serum sickness, hepatitis, and drug interactions with warfarin and phenobarbital. Griseofulvin has been largely replaced by newer antifungal medications such as itraconazole and terbinafine.
Terbinafine
Terbinafine is a synthetic allylamine that is available in an oral formulation and is used at a dosage of 250 mg/d. It is used in the treatment of dermatophytoses, especially onychomycosis. Like griseofulvin, it is a keratophilic medication, but unlike griseofulvin, it is fungicidal. Like the azole drugs, it interferes with ergosterol biosynthesis, but rather than interacting with the P450 system, terbinafine inhibits the fungal enzyme squalene epoxidase. This leads to the accumulation of the sterol squalene, which is toxic to the organism.
One tablet given daily for 12 weeks achieves a cure rate of up to 90% for onychomycosis and is more effective than griseofulvin or itraconazole. Adverse effects are rare, consisting primarily of gastrointestinal upset and headache. Terbinafine does not seem to affect the P450 system and has demonstrated no significant drug interactions to date.
Nystatin
Nystatin is a polyene macrolide much like amphotericin B. It is too toxic for parenteral administration and is only used topically. It is currently available in creams, ointments, suppositories, and other forms for application to skin and mucous membranes. Nystatin is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract. As a result, it has little toxicity, though oral use is often limited by the unpleasant taste.
Nystatin is active against most candida species and is most commonly used for suppression of local candidal infections. Some common indications include oropharyngeal thrush, vaginal candidiasis, and intertriginous candidal infections.
Topical Azoles
The two azoles most commonly used topically are clotrimazole and miconazole; several others are available. Both are available over-the-counter and are often used for vulvovaginal candidiasis. Oral clotrimazole troches are available for treatment of oral thrush and are a pleasant-tasting alternative to nystatin. In cream form, both agents are useful for dermatophytic infections, including tinea corporis, tinea pedis, and tinea cruris. Absorption is negligible, and adverse effects are rare. Topical and shampoo forms of ketoconazole are also available and useful in the treatment of seborrheic dermatitis and pityriasis versicolor. Several other azoles are available for topical use.
Antiprotozoal Drugs
Treatment of Malaria
Four species of plasmodium cause human malaria: Plasmodium falciparum, P vivax, P malariae, and P ovale. Although all may cause significant illness, P falciparum is responsible for nearly all serious complications and deaths. Drug resistance is an important therapeutic problem, most notably with P falciparum.
Parasite Life Cycle
An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection. Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness. Repeated cycles of infection can lead to the infection of many erythrocytes and serious disease. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.
In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure these infections. In P vivax and P ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most drugs, and subsequent relapses can therefore occur after therapy directed against erythrocytic parasites. Eradication of both erythrocytic and hepatic parasites is required to cure these infections.
Drug Classification
Several classes of antimalarial drugs are available. Drugs that eliminate developing or dormant liver forms are called tissue schizonticides; those that act on erythrocytic parasites are blood schizonticides;
and those that kill sexual stages and prevent transmission to mosquitoes are gametocides. No one available agent can reliably effect a radical cure, ie, eliminate both hepatic and erythrocytic stages. Few available agents are causal prophylactic drugs, ie, capable of preventing erythrocytic infection. However, all effective chemoprophylactic agents kill erythrocytic parasites before they grow sufficiently iumber to cause clinical disease.
Treatment of Amebiasis
Amebiasis is infection with Entamoeba histolytica. This agent can cause asymptomatic intestinal infection, mild to moderate colitis, severe intestinal infection (dysentery), ameboma, liver abscess, and other extraintestinal infections.
Treatment of Specific Forms of Amebiasis
Asymptomatic Intestinal Infection
Asymptomatic carriers generally are not treated in endemic areas but ionendemic areas they are treated with a luminal amebicide. A tissue amebicidal drug is unnecessary. Standard luminal amebicides are diloxanide furoate, iodoquinol, and paromomycin. Each drug eradicates carriage in about 80–90% of patients with a single course of treatment. Therapy with a luminal amebicide is also required in the treatment of all other forms of amebiasis.
Amebic Colitis
Metronidazole plus a luminal amebicide is the treatment of choice for colitis and dysentery. Tetracyclines and erythromycin are alternative drugs for moderate colitis but are not effective against extraintestinal disease. Dehydroemetine or emetine can also be used, but these agents are best avoided (when possible) because of their toxicity.
Extraintestinal Infections
The treatment of choice is metronidazole plus a luminal amebicide. A 10-day course of metronidazole cures over 95% of uncomplicated liver abscesses. For unusual cases where initial chloroquine to a repeat course of metronidazole
Metronidazole
Metronidazole, a nitroimidazole (Figure 53–2), is the drug of choice for the treatment of extraluminal amebiasis. It kills trophozoites but not cysts of E histolytica and effectively eradicates intestinal and extraintestinal tissue infections.
Chemistry & Pharmacokinetics
Oral metronidazole is readily absorbed and permeates all tissues by simple diffusion. Intracellular concentrations rapidly approach extracellular levels. Peak plasma concentrations are reached in 1–3 hours. Protein binding is low (< 20%), and the half-life of the unchanged drug is 7.5 hours. The drug and its metabolites are excreted mainly in the urine. Plasma clearance of metronidazole isdecreased in patients with impaired liver function.
Mechanism of Action
The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity.
Clinical Uses
Amebiasis
Metronidazole is the drug of choice for the treatment of all tissue infections with E histolytica. It is not reliably effective against luminal parasites and so must be used with a luminal amebicide to ensure eradication of the infection. Tinidazole, a related nitroimidazole, appears to have similar activity and a better toxicity profile than metronidazole, but it is not available in the USA.
Giardiasis
Metronidazole is the treatment of choice for giardiasis. The dosage for giardiasis is much lower— and the drug thus better tolerated—than that for amebiasis. Efficacy after a single treatment is about 90%. Tinidazole is equally effective.
Trichomoniasis
Metronidazole is the treatment of choice. A single dose of
Adverse Effects & Cautions
Nausea, headache, dry mouth, or a metallic taste in the mouth occurs commonly. Infrequent adverse effects include vomiting, diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria, dark urine, vertigo, paresthesias, and neutropenia. Taking the drug with meals lessens gastrointestinal irritation. Pancreatitis and severe central nervous system toxicity (ataxia, encephalopathy, seizures) are rare.
Metronidazole has a disulfiram-like effect, so that nausea and vomiting can occur if alcohol is ingested during therapy. The drug should be used with caution in patients with central nervous system disease. Intravenous infusions have rarely caused seizures or peripheral neuropathy. The dosage should be adjusted for patients with severe liver or renal disease.
Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, while cimetidine may decrease plasma clearance. Lithium toxicity may occur when the drug is used with metronidazole.
Metronidazole and its metabolites are mutagenic in bacteria. Chronic administration of large doses led to tumorigenicity in mice. Data on teratogenicity are inconsistent. Metronidazole is thus best avoided in pregnant or nursing women, though congenital abnormalities have not clearly been associated with use in humans.
African Trypanosomiasis (Sleeping Sickness)
Pentamidine has been used since 1940 as an alternative to suramin for the early hemolymphatic stage of disease caused by Trypanosoma brucei (especially T brucei gambiense). The drug can also be used with suramin. Pentamidine should not be used to treat late trypanosomiasis with central nervous system involvement. A number of dosing regimens have been described, generally providing 2–4 mg/kg daily or on alternate days for a total of 10–15 doses. Pentamidine has also been used for chemoprophylaxis against African trypanosomiasis, with dosing of 4 mg/kg every 3– 6 months.
Anthelmintic Drugs
Clinacal Pharmacology of the Anthelminthic Drugs: Introduction. In general, parasites should be identified before treatment is started.
Diethylcarbamazine Citrate
Diethylcarbamazine is a drug of choice in the treatment of filariasis, loiasis, and tropical eosinophilia. It has been replaced by ivermectin for the treatment of onchocerciasis.
Chemistry & Pharmacokinetics
Diethylcarbamazine, a synthetic piperazine derivative, is marketed as a citrate salt. It is rapidly absorbed from the gastrointestinal tract; after a 0.5 mg/kg dose, peak plasma levels are reached within 1–2 hours. The plasma half-life is 2–3 hours in the presence of acidic urine but about 10 hours if the urine is alkaline. The drug rapidly equilibrates with all tissues except fat. It is excreted, principally in the urine, as unchanged drug and the N-oxide metabolite. Dosage may have to be
reduced in patients with persistent urinary alkalosis or renal impairment.
Anthelmintic Actions
Diethylcarbamazine immobilizes microfilariae and alters their surface structure, displacing them from tissues and making them more susceptible to destruction by host defense mechanisms. The mode of action against adult worms is unknown.
Clinical Uses
Diethylcarbamazine is the drug of choice for treatment of infections with these parasites because of its efficacy and lack of serious toxicity. Microfilariae of all species are rapidly killed; adult parasites are killed more slowly, often requiring several courses of treatment. The drug is highly effective against adult L loa. The extent to which W bancrofti and B malayi adults are killed is not known, but after appropriate therapy microfilariae do not reappear in the majority of patients.
These infections are treated for 2 or (for L loa) 3 weeks, with initial low doses to reduce the incidence of allergic reactions to dying microfilariae. This regimen is 50 mg (1 mg/kg in children) on day 1, three 50 mg doses on day 2, three 100 mg doses (2 mg/kg in children) on day 3, and then 2 mg/kg three times per day to complete the 2–3 week course.
Antihistamines may be given for the first few days of therapy to limit allergic reactions, and corticosteroids should be started and doses of diethylcarbamazine lowered or interrupted if severe reactions occur. Cures may require several courses of treatment.
Diethylcarbamazine may also be used for chemoprophylaxis (300 mg weekly or 300 mg on 3 successive days each month for loiasis; 50 mg monthly for bancroftian and Malayan filariasis).
Other Uses
For tropical eosinophilia, diethylcarbamazine is given orally at a dosage of 2 mg/kg three times daily for 7 days. Diethylcarbamazine is effective in Mansonella streptocerca infections, since it kills both adults and microfilariae. Limited information suggests that the drug is not effective, however, against adult Mansonella ozzardi or M perstans and that it has limited activity against microfilariae of these parasites. An important application of diethylcarbamazine has been its use for mass treatment of W bancrofti infections to reduce transmission. Weekly or monthly administration regimens have been studied; and, most recently, yearly treatment (with or without ivermectin) markedly reduced reservoirs of infection in Papua New Guinea.
Adverse Reactions, Contraindications, & Cautions
Reactions to diethylcarbamazine, which are generally mild and transient, include headache, malaise, anorexia, weakness, nausea, vomiting, and dizziness. Adverse effects also occur as a result of the release of proteins from dying microfilariae or adult worms. Reactions are particularly severe with onchocerciasis, but diethylcarbamazine is generally no longer used for this infection, as ivermectin is equally efficacious and less toxic. Reactions to dying microfilariae are usually mild in W bancrofti, more intense in B malayi, and occasionally severe in L loa infections. Reactions include fever, malaise, papular rash, headache, gastrointestinal symptoms, cough, chest pain, and muscle or joint pain. Leukocytosis is common. Eosinophilia may increase with treatment. Proteinuria may also occur. Symptoms are most likely to occur in patients with heavy loads of microfilariae. Retinal hemorrhages and, rarely, encephalopathy have been described.
Between the third and twelfth days of treatment, local reactions may occur in the vicinity of dying adult or immature worms. These include lymphangitis with localized swellings in W bancrofti and B malayi, small wheals in the skin in L loa, and flat papules in M streptocerca infections. Patients with attacks of lymphangitis due to W bancrofti or B malayi should be treated during a quiescent period between attacks.
Caution is advised when using diethylcarbamazine in patients with hypertension or renal disease.
Mebendazole
Mebendazole is a synthetic benzimidazole (compare with albendazole) that has a wide spectrum of anthelmintic activity and a low incidence of adverse effects.
Chemistry & Pharmacokinetics
Less than 10% of orally administered mebendazole is absorbed. The absorbed drug is protein-bound (> 90%), rapidly converted to inactive metabolites (primarily during its first pass in the liver), and has a half-life of 2–6 hours. It is excreted mostly in the urine, principally as decarboxylated derivatives. In addition, a portion of absorbed drug and its derivatives are excreted in the bile. Absorption is increased if the drug is ingested with a fatty meal.
Anthelmintic Actions
Mebendazole probably acts by inhibiting microtubule synthesis; the parent drug appears to be the active form. Efficacy of the drug varies with gastrointestinal transit time, with intensity of infection, and perhaps with the strain of parasite. The drug kills hookworm, ascaris, and trichuris eggs.
Clinical Uses
In the USA, mebendazole has been approved for use in ascariasis, trichuriasis, and hookworm and pinworm infection. It can be taken before or after meals; the tablets should be chewed before swallowing. For pinworm infection, the dose is 100 mg once, repeated at 2 weeks. For ascariasis, trichuriasis, hookworm, and trichostrongylus infections, a dosage of 100 mg twice daily for 3 days is used for adults and for children over 2 years of age. Cure rates are 90–100% for pinworm infections, ascariasis, and trichuriasis. Cure rates are lower for hookworm infections, but a marked reduction in the worm burden occurs in those not cured. For intestinal capillariasis, mebendazole is used at a dosage of 400 mg/d in divided doses for 21 or more days. In trichinosis, limited reports suggest efficacy against adult worms in the intestinal tract and tissue larvae. Treatment is three times daily, with fatty foods, at 200–400 mg per dose for 3 days and then 400–500 mg per dose for 10 days. Corticosteroids should be coadministered for severe infections.
Adverse Reactions, Contraindications, & Cautions
Short-term mebendazole therapy for intestinal nematodes is nearly free of adverse effects. Mild nausea, vomiting, diarrhea, and abdominal pain have been reported infrequently. Rare side effects, usually with high-dose therapy, are hypersensitivity reactions (rash, urticaria), agranulocytosis, alopecia, and elevation of liver enzymes.
Mebendazole is teratogenic in animals and therefore contraindicated in pregnancy. It should be used with caution in children under 2 years of age because of limited experience and rare reports of convulsions in this age group. Plasma levels may be decreased by concomitant use of carbamazepine or phenytoin and increased by cimetidine. Mebendazole should be used with caution in those with cirrhosis.
Metrifonate (Trichlorfon)
Metrifonate is a safe, low-cost alternative drug for the treatment of Schistosoma haematobium infections. It is not active against S mansoni or S japonicum. It is not available in the USA.
Chemistry & Pharmacokinetics
Metrifonate, an organophosphate compound, is rapidly absorbed after oral administration. Following the standard oral dose, peak blood levels are reached in 1–2 hours; the half-life is about 1.5 hours. Clearance appears to be through nonenzymatic transformation to dichlorvos, its active metabolite. Metrifonate and dichlorvos are well distributed to the tissues and are completely eliminated in 24–48 hours.
Anthelmintic Actions
The mode of action is thought to be related to cholinesterase inhibition. This inhibition temporarily paralyzes the adult worms, resulting in their shift from the bladder venous plexus to small arterioles of the lungs, where they are trapped, encased by the immune system, and die. The drug is not effective against S haematobium eggs; live eggs continue to pass in the urine for several months after all adult worms have been killed.
Clinical Uses
In the treatment of S haematobium, a single oral dose of 7.5–10 mg/kg is given three times at 14- day intervals. Cure rates on this schedule are 44–93%, with marked reductions in egg counts in those not cured. Metrifonate was also effective as a prophylactic agent when given monthly to children in a highly endemic area, and it has been used in mass treatment programs. In mixed infections with S haematobium and S mansoni, metrifonate has been successfully combined with oxamniquine.
Adverse Reactions, Contraindications, & Cautions
Some studies note mild and transient cholinergic symptoms, including nausea and vomiting, diarrhea, abdominal pain, bronchospasm, headache, sweating, fatigue, weakness, dizziness, and vertigo. These symptoms may begin within 30 minutes and persist up to 12 hours. Metrifonate should not be used after recent exposure to insecticides or drugs that might potentiate cholinesterase inhibition. Metrifonate is contraindicated in pregnancy.
Praziquantel
Praziquantel is effective in the treatment of schistosome infections of all species and most other trematode and cestode infections, including cysticercosis. The drug’s safety and effectiveness as a single oral dose have also made it useful in mass treatment of several infections.
Chemistry & Pharmacokinetics
Praziquantel is a synthetic isoquinoline-pyrazine derivative. It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum concentrations are reached 1–3 hours after a therapeutic dose. Cerebrospinal fluid concentrations of praziquantel reach 14–20% of the drug’s plasma concentration. About 80% of the drug is bound to plasma proteins. Most of the drug is rapidly metabolized to inactive mono- and polyhydroxylated products after a first pass in the liver. The half-life is 0.8–1.5 hours. Excretion is mainly via the kidneys (60–80%) and bile (15– 35%). Plasma concentrations of praziquantel increase when the drug is taken with a highcarbohydrate meal or with cimetidine; bioavailability is markedly reduced with some antiepileptics (phenytoin, carbamazepine) or with corticosteroids.
Anthelmintic Actions
Praziquantel appears to increase the permeability of trematode and cestode cell membranes to calcium, resulting in paralysis, dislodgement, and death. In schistosome infections of experimental animals, praziquantel is effective against adult worms and immature stages and it has a prophylactic effect against cercarial infection.
Clinical Uses
Praziquantel tablets are taken with liquid after a meal; they should be swallowed without chewing because their bitter taste can induce retching and vomiting.
Pyrantel Pamoate
Pyrantel pamoate is a broad-spectrum anthelmintic highly effective for the treatment of pinworm, ascaris, and Trichostrongylus orientalis infections. It is moderately effective against both species of hookworm. It is not effective in trichuriasis or strongyloidiasis. Oxantel pamoate, an analog of pyrantel not available in the USA, has been used successfully in the treatment of trichuriasis; the two drugs have been combined for their broad-spectrum anthelmintic activity.
Chemistry & Pharmacokinetics
Pyrantel pamoate is a tetrahydropyrimidine derivative. It is poorly absorbed from the gastrointestinal tract and active mainly against luminal organisms. Peak plasma levels are reached in 1–3 hours. Over half of the administered dose is recovered unchanged in the feces.
Anthelmintic Actions
Pyrantel is effective against mature and immature forms of susceptible helminths within the intestinal tract but not against migratory stages in the tissues or against ova. The drug is a neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinesterase; this results in paralysis, which is followed by expulsion of worms.
Clinical Uses
The standard dose is 11 mg (base)/kg (maximum,
For ascariasis, a single dose yields cure rates of 85–100%. Treatment should be repeated if eggs are found 2 weeks after treatment. For hookworm infections, a single dose is effective against light infections; but for heavy infections, especially with N americanus, a 3-day course is necessary to reach 90% cure rates. A course of treatment can be repeated in 2 weeks.
Adverse Reactions, Contraindications, & Cautions
Adverse effects are infrequent, mild, and transient. They include nausea, vomiting, diarrhea, abdominal cramps, dizziness, drowsiness, headache, insomnia, rash, fever, and weakness. Pyrantel should be used with caution in patients with liver dysfunction, since low, transient aminotransferase elevations have beeoted in a small number of patients. Experience with the drug in pregnant women and children under age 2 years is limited.
Antineoplastic agents
Cancer is basically a disease of cells characterized by a shift in the control mechanisms that govern cell proliferation and differentiation.
Cells that have undergone neoplastic transformation usually express cell surface antigens that may be of normal fetal type, may display other signs of apparent immaturity, and may exhibit qualitative or quantitative chromosomal abnormalities, including various translocations and the appearance of amplified gene sequences. Such cells proliferate excessively and form local tumors that can compress or invade adjacent normal structures. A small subpopulation of cells within the tumor can be described as tumor stem cells. They retain the ability to undergo repeated cycles of proliferation as well as to migrate to distant sites in the body to colonize various organs in the process called metastasis. Such tumor stem cells thus can express clonogenic or colony-forming capability. Tumor stem cells often have chromosome abnormalities reflecting their genetic instability, which leads to progressive selection of subclones that can survive more readily in the multicellular environment of the host. Quantitative abnormalities in various metabolic pathways and cellular components accompany this neoplastic progression. The invasive and metastatic processes as well as a series of metabolic abnormalities resulting from the cancer cause illness and eventual death of the patient unless the neoplasm can be eradicated with treatment.
Importance of Cell Cycle Kinetics
Information on cell and population kinetics of cancer cells explains, in part, the limited effectiveness of most available anticancer drugs. A schematic summary of cell cycle kinetics is presented in Figure 55–2. This information is relevant to the mode of action, indications, and scheduling of cell cycle-specific (CCS) and cell cycle-nonspecific (CCNS) drugs. Agents falling into these two major classes are summarized.
In general, CCS drugs are most effective in hematologic malignancies and in solid tumors in which a relatively large proportion of the cells are proliferating or are in the growth fraction. CCNS drugs (many of which bind to cellular DNA and damage these macromolecules) are particularly useful in low growth fraction solid tumors as well as in high growth fraction tumors. In all instances, effective agents sterilize or inactivate tumor stem cells, which are often only a small fraction of the cells within a tumor. Non-stem cells (eg, those that have irreversibly differentiated) are considered sterile by definition and are not a significant component of the cancer problem.
Polyfunctional Alkylating Agents
The major clinically useful alkylating agents (Figure 55–3) have a structure containing a bis- (chloroethyl)amine, ethyleneimine, or nitrosourea moiety. Among the bis(chloroethyl)amines, cyclophosphamide, mechlorethamine, melphalan, and chlorambucil are the most useful. Ifosfamide is closely related to cyclophosphamide but has a somewhat different spectrum of activity and toxicity. Thiotepa and busulfan are used for specialized purposes for ovarian cancer and chronic myeloid leukemia, respectively. The major nitrosoureas are carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU). A variety of investigational alkylating agents have been synthesized that link various carrier molecules such as amino acids, nucleic acid bases, hormones, or sugar moieties to a group capable of alkylation; however, successful site-directed alkylation has not been achieved to date.
Active alkylating agents have direct vesicant effects and can damage tissues at the site of injection as well as produce systemic toxicity. Toxicities are generally dose-related and occur particularly in rapidly growing tissues such as bone marrow, the gastrointestinal tract, and the reproductive system.
After intravenous injection, nausea and vomiting usually occur within 30–60 minutes with mechlorethamine, cyclophosphamide, or carmustine. The emetogenic effects are mediated by the central nervous system and can be reduced by pretreatment with 5-HT3 (serotonin) receptor antagonists such as ondansetron or granisetron. Subcutaneous injection of mechlorethamine or carmustine leads to tissue necrosis and sloughing.
Cyclophosphamide in its parent form does not have direct cytotoxic effects, and it must be activated to cytotoxic forms by microsomal enzymes (Figure 55–5). The liver microsomal cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are believed to be delivered by the bloodstream to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4- ketocyclophosphamide and carboxyphosphamide.
Antimetabolites (Structural Analogs)
The development of drugs with actions on intermediary metabolism of proliferating cells has been important both clinically and conceptually. While biochemical properties unique to all cancer cells have yet to be discovered, neoplastic cells do have a number of quantitative differences in metabolism from normal cells that render them more susceptible to a number of antimetabolites or structural analogs. Many of these agents have been rationally designed and synthesized based on knowledge of cellular processes, and a few have been discovered as antibiotics.
Mechanisms of Action
The biochemical pathways that have thus far proved to be most vulnerable to antimetabolites have been those relating to nucleotide and nucleic acid synthesis. In a number of instances, when an enzyme is known to have a major effect on pathways leading to cell replication, inhibitors of the reaction it catalyzes have proved to be useful anticancer drugs.
Methotrexate
Methotrexate (MTX) is a folic acid antagonist that binds to the active catalytic site of dihydrofolate reductase (DHFR), interfering with the synthesis of the reduced form that accepts one-carbon units.
Lack of this cofactor interrupts the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine, thereby interfering with the formation of DNA, RNA, and proteins.
The enzyme binds methotrexate with high affinity, and at pH 6.0, virtually no dissociation of the enzyme-inhibitor complex occurs (inhibition constant about 1 nmol/L). At physiologic pH, reversible competitive kinetics occur (inhibition constant about 1 mol/L). Intracellular formation of polyglutamate derivatives appears to be important in the therapeutic action of methotrexate. The polyglutamates of methotrexate are selectively retained within cancer cells and have increased inhibitory effects on enzymes involved in folate metabolism, making them important determinants of the duration of action of methotrexate.
Purine Antagonists
6-Thiopurines
Mercaptopurine (6-MP) was the first of the thiopurine series found useful as an anticancer drug. Like other thiopurines, it must be metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to the nucleotide form (6-thioinosinic acid), which in turn inhibits a number of the enzymes of purine nucleotide interconversion. Significant amounts of thioguanylic acid and 6- methylmercaptopurine ribotide (MMPR) are also formed from 6-MP. These metabolites may also contribute to the action of the mercaptopurine. Mercaptopurine is used primarily in the treatment of childhood acute leukemia, and a closely related analog, azathioprine, is used as an immunosuppressive agent.
Thioguanine (6-TG) inhibits several enzymes in the purine nucleotide pathway. A variety of metabolic lesions are associated with the cytotoxic action of the purinethiols. These include inhibition of purine nucleotide interconversion; decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis; interference with the formation of DNA and RNA; and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia.
Pyrimidine Antagonists
Fluorouracil
5-Fluorouracil (5-FU) is a prodrug and undergoes a complex series of biotransformation reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2′- deoxyuridine-5′-monophosphate (FdUMP), forms a covalently bound ternary complex with the enzyme thymidylate synthase and the reduced folate N5,10- methylenetetrahydrofolate, a reaction critical for the synthesis of thymidylate. This results in inhibition of DNA synthesis through
“thymineless death.” 5-FU is converted to 5-fluorouridine-5′-triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. In addition, 5-FU is converted to 5-fluorodeoxyuridine-5′-triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function. Thus, the cytotoxicity of fluorouracil is felt to be the result of effects on both DNA- and RNA-mediated events.
Fluorouracil is normally given intravenously and has a short metabolic half-life on the order of 15 minutes. It is not administered by the oral route because its bioavailability is erratic due to the high levels of the breakdown enzyme dihydropyrimidine dehydrogenase present in the gut mucosa. Floxuridine (5-fluoro-2′-deoxyuridine, FUDR) has an action similar to that of fluorouracil, and it is only used for hepatic artery infusions. A cream incorporating fluorouracil is used topically for treating basal cell cancers of the skin.
Fluorouracil is the most widely used agent for the treatment of colorectal cancer, both as adjuvant therapy as well as for advanced disease. In addition, it has activity against a wide variety of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus.
Plant Alkaloids
VInblastine
Vinblastine is an alkaloid derived from Vinca rosea, the periwinkle plant. Its mechanism of action involves depolymerization of microtubules, which are an important part of the cytoskeleton and the mitotic spindle. The drug binds specifically to the microtubule protein tubulin in dimeric form; the drug-tubulin complex adds to the forming end of the microtubules to terminate assembly, and depolymerization of the microtubules then occurs. This results in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation. Toxicity includes nausea and vomiting, bone marrow suppression, and alopecia. It has clinical activity in the treatment of Hodgkin’s disease, non-Hodgkin’s lymphomas, breast cancer, and germ cell cancer.
VIncristine
Vincristine is also an alkaloid derivative of Vinca rosea and is closely related in structure to vinblastine. Its mechanism of action is considered to be identical to that of vinblastine in that it functions as a mitotic spindle poison leading to arrest of cells in the M phase of the cell cycle. Despite these similarities to vinblastine, vincristine has a strikingly different spectrum of clinical activity and qualitatively different toxicities.
Vincristine has been effectively combined with prednisone for remission induction in acute lymphoblastic leukemia in children. It is also active in various hematologic malignancies such as Hodgkin’s and non-Hodgkin’s lymphoma and
multiple myeloma and in several pediatric tumors including rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, and Wilms’ tumor. The main doselimiting toxicity is neurotoxicity, usually expressed as a peripheral sensory neuropathy, although autonomic nervous system dysfunction—with orthostatic hypotension, sphincter problems, and paralytic ileus—cranial nerve palsies, ataxia, seizures, and coma have been observed. While myelosuppression can occur, it is generally milder and much less significant than with vinblastine.
The other potential side effect that can develop is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
Anthracyclines
The anthracycline antibiotics, isolated from Streptomyces peucetius var caesius, are among the most widely used cytotoxic anticancer drugs. Two congeners, doxorubicin and daunorubicin, are FDAapproved, and their structures are shown below. Several other anthracycline analogs have entered clinical practice, including idarubicin, epirubicin, and mitoxantrone. Daunorubicin was the first agent in this class to be isolated, and it is still used in the treatment of acute myeloid leukemia.
Doxorubicin has a broad spectrum of clinical activity against hematologic malignancies as well as a wide range of solid tumors. The entire class of anthracyclines exert their cytotoxic action through four major mechanisms. These are (1) inhibition of topoisomerase II; (2) high-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand scission; (3) binding to cellular membranes to alter fluidity and ion transport; and (4) generation of semiquinone free radicals and oxygen free radicals through an enzyme-mediated reductive process. This latter mechanism has now been established as being the cause of the drug’s cardiac toxicity.
Doxorubicin is one of the most important anticancer drugs, with major clinical activity in carcinomas of the breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung; in soft tissue sarcomas; and in several childhood cancers, including neuroblastoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma. It is also widely used in hematologic malignancies, including acute lymphoblastic leukemia, multiple myeloma, and Hodgkin’s and non-Hodgkin’s lymphomas. It is generally used in combination with other anticancer agents (eg, cyclophosphamide, cisplatin, and fluorouracil), and responses and remission duration tend to be improved with combination regimens as opposed to single-agent therapy. Daunorubicin has a far narrower spectrum of activity than doxorubicin. Daunorubicin has been mainly used for the treatment of acute myeloid leukemia, although there has been a shift in clinical practice toward using idarubicin, an analog of daunorubicin. Its efficacy in solid tumors appears to be limited.
Dactinomycin
Dactinomycin is an antitumor antibiotic isolated from a Streptomyces organism. It binds tightly to double-stranded DNA through intercalation between adjacent guanine-cytosine base pairs and inhibits all forms of DNA-dependent RNA synthesis, with ribosomal RNA formation being most sensitive to drug action.
Dactinomycin is mainly used to treat pediatric tumors such as Wilms’ tumor, rhabdomyosarcoma, and Ewing’s sarcoma, but it has activity also against germ cell tumors and gestational trophoblastic disease. Dactinomycin can also induce a “radiation recall reaction.”
Asparaginase (L-asparagineamidohydrolase) is an enzyme that is isolated from various bacteria for clinical use. The drug is used to treat childhood acute lymphocytic leukemia. It hydrolyzes circulating L-asparagine to aspartic acid and ammonia. Because tumor cells lack asparagines synthetase, they require an exogenous source of L-asparagine. Thus, depletion of L-asparagine results in effective inhibition of protein synthesis. In contrast, normal cells can synthesize Lasparagine and thus are less susceptible to the cytotoxic action of asparaginase. The main side effect of this agent is a hypersensitivity reaction manifested by fever, chills, nausea and vomiting, skin rash, and urticaria. Severe cases can present with bronchospasm, respiratory failure, and hypotension. Other toxicities include an increased risk of both clotting and bleeding as a result of alterations in various clotting factors, pancreatitis, and neurologic toxicity with lethargy, confusion, hallucinations, and coma.
The alkylating agents, procarbazine, etoposide, and ionizing radiation are all considered to be leukemogenic. AML has been observed in up to 15% of patients with Hodgkin’s disease who have received radiotherapy plus MOPP chemotherapy and in patients with multiple myeloma, ovarian carcinoma, or breast carcinoma treated with melphalan. The risk of AML is observed as early as 2–4 years after the initiation of chemotherapy and peaks at 5 and 9 years. With improvements in the clinical efficacy of various combination chemotherapy regimens resulting in prolonged survival and in some cases actual cure of cancer, the issue of how second cancers may affect long-term survival
assumes greater importance. There is already evidence that certain alkylating agents (eg, cyclophosphamide) may be less carcinogenic than others (eg, melphalan). Systematic testing of the carcinogenicity of anticancer drugs in several animal models should allow less toxic agents to be identified and substituted for other more carcinogenic ones in chemotherapy regimens.
Pharmacotherapy of drug poisoning and extremam state. Radioprotectors. Common pharmacology
Pharmacotherapy of drug poisoning and extremam state
treatment of poisonings
Drugs used to counteract drug overdosage are considered under the appropriate headings, e.g., physostigmine with atropine; naloxone with opioids; flumazenil with benzodiazepines; antibody (Fab fragments) with digitalis; and N-acetyl-cysteine with acetaminophen intoxication.
Chelating agents (A) serve as antidotes in poisoning with heavy metals. They act to complex and, thus, “inactivate” heavy metal ions. Chelates (from Greek: chele = claw [of crayfish]) represent complexes between a metal ion and molecules that carry several binding sites for the metal ion. Because of their high affinity, chelating agents “attract” metal ions present in the organism. The chelates are non-toxic, are excreted predominantly via the kidney, maintain a tight organometallic bond also in the concentrated, usually acidic, milieu of tubular urine and thus promote the elimination of metal ions.
Na2Ca-EDTAis used to treat lead poisoning. This antidote cannot penetrate cell membranes and must be given parenterally. Because of its high binding affinity, the lead ion displaces Ca2+ from its bond. The lead-containing chelate is eliminated renally. Nephrotoxicity predominates among the unwanted effects.
Na3Ca-Pentetate is a complex of diethylenetriaminopentaacetic acid (DPTA) and serves as antidote in lead and other metal intoxications.Dimercaprol (BAL, British Anti-Lewisite) was developed in World War II as an antidote against vesicant organic arsenicals (B). It is able to chelate various metal ions. Dimercaprol forms a liquid, rapidly decomposing substance that is given intramuscularly in an oily vehicle. A related compound, both in terms of structure and activity, is dimercaptopropanesulfonic acid, whose sodium salt is suitable for oral administration. Shivering, fever, and skin reactions are potential adverse effects.
Deferoxamine derives from the bacterium Streptomyces pilosus. The substance possesses a very high ironbinding capacity, but does not withdraw iron from hemoglobin or cytochromes. It is poorly absorbed enterally and must be given parenterally to cause increased excretion of iron. Oral administration is indicated only if enteral absorption of iron is to be curtailed.
Unwanted effects include allergic reactions. It should be noted that blood letting is the most effective means of removing iron from the body; however, this method is unsuitable for treating conditions of iron overload associated with anemia. D-penicillamine can promote the elimination of copper (e.g., in Wilson’s disease) and of lead ions. It can be given orally. Two additional uses are cystinuria and rheumatoid arthritis. In the former, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In the latter, penicillamine can be used as a basal egimen. The therapeutic effect may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibited. Unwanted effects are: cutaneous damage (diminished resistance to mechanical stress with a tendency to form blisters), nephrotoxicity, bone marrow depression, and taste disturbances.
Management guidelines for blood lead levels in adults differ significantly from management guidelines for blood lead levels in children. In adults, a blood lead level greater than or equal to 25 µg/dL (micrograms per deciliter) is considered elevated. However, the majority of adults have blood lead levels less than 3 µg/dL. In children, any blood lead level at or above 10 µg/dL is considered elevated. The difference in elevated levels between children and adults is largely attributed to the fact that children are still growing and developing and a small amount of lead that may have little effect on an adult can be detrimental to a child’s health.
Methods of Enhancing Elimination of Toxins
After appropriate diagnostic and decontamination procedures and administration of antidotes, it is important to consider whether measures for enhancing elimination, such as hemodialysis or urinary alkalinization, can improve clinical outcome.
Peritoneal Dialysis This is a relatively simple and available technique but is inefficient in removing most drugs.
Hemodialysis is more efficient than peritoneal dialysis and has been well studied. It assists in correction of fluid and electrolyte imbalance and may also enhance removal of toxic metabolites (eg, formate in methanol poisoning, oxalate and glycolate in ethylene glycol poisoning). The efficiency of both peritoneal dialysis and hemodialysis is a function of the molecular weight, water solubility, protein binding, endogenous clearance, and distribution in the body of the specific toxin.
Hemodialysis is especially useful in overdose cases in which fluid and electrolyte imbalances are present (eg, salicylate intoxication).
Hemoperfusion Blood is pumped from the patient via a venous catheter through a column of adsorbent material and then recirculated to the patient. Hemoperfusion does not improve fluid and electrolyte balance. However, it does remove many high-molecular-weight toxins that have poor water solubility because the perfusion cartridge has a large surface area for adsorption that is directly perfused with the blood and is not impeded by a membrane. The rate-limiting factors in removal of toxins by hemoperfusion are the affinity of the charcoal or adsorbent resin for the drug, the rate of blood flow through the cartridge, and the rate of equilibration of the drug from the peripheral tissues to the blood. Hemoperfusion may enhance whole body clearance of salicylate, phenytoin, ethchlorvynol, phenobarbital, theophylline, and carbamazepine.
Forced Diuresis and Urinary pH Manipulation Previously popular but of unproved value, forced diuresis may cause volume overload and electrolyte abnormalities and is not recommended. Renal elimination of a few toxins can be enhanced by alteration of urinary pH. For example, urinary alkalinization is useful in cases of salicylate overdose. Acidification may increase the urine concentration of drugs such as phencyclidine and amphetamines but is not advised because it may worsen renal complications from rhabdomyolysis, which often accompanies the intoxication.
Opiates (heroin, morphine, meperidine, codeine, others)
Addictive drugs, usually taken by needle (except codeine; intravenous or skin-popping; there are ways of inhaling “the dragon” heroin). Your lecturer is not impressed with the adverse personality or health consequences of opiate use itself (well, it’s constipating and bad for the libido). However, the stuff is addictive, expensive, and illegal (which causes some of the problems) and overdose (even in an addict with marvelous tolerance) is very lethal.
Unlike cocaine, heroin is not known to have any direct tissue toxicities. There are maybe 4000 deaths from heroin overdose in the US each year. Those dying of heroin overdose either (1) stopped breathing from medullary depression, or (2) got pulmonary edema (nobody knows why opiates can do this, but it’s likely that it’s neurally-mediated, because of tolerance and because brain injury itself can produce similar edema). Of course, there are plenty of heroin-related deaths due to lifestyle and/or unsanitary injection practices.
It’s commonplace for an “accidental” overdose to have been preceded by a critical life-event, and many of these “unfortunate tragic accidents” are probably suicides (Forens. Sci. Int. 62: 129, 1993).
* Confusingly, there is an illness seen only in people who snort cooked heroin, and that much be due to a poison generated in this way. It looks clinically and anatomically like prion disease, but some patients recover; it’s called “heroin spongiform encephalopathy” and is recognizable now on MRI scans:
Unithiol (Dimercaptopropanesulfonic Acid, DMPS)
Unithiol, a dimercaptochelating agent that is a water-soluble analog of dimercaprol, has been available in the official formularies of Russia and other former Soviet countries since 1958 and in Germany since 1976. It has been legally available from compounding pharmacists in the United States since 1999. Unithiol can be administered orally and intravenously. Bioavailability by the oral route is approximately 50%, with peak blood levels occurring in approximately 3.7 hours.
Over 80% of an intravenous dose is excreted in the urine, mainly as cyclic DMPS sulfides. The elimination half-time for total unithiol (parent drug and its transformation products) is approximately 20 hours. Unithiol exhibits protective effects against the toxic action of mercury and arsenic in animal models, and it increases the excretion of mercury, arsenic, and lead in humans.
Penicillamine (D-Dimethylcysteine)
Penicillamine is a white crystalline, water-soluble derivative of penicillin. DPenicillamine is less toxic than the L isomer and consequently is the preferred therapeutic form.
Penicillamine is readily absorbed from the gut and is resistant to metabolic degradation.
Indications & Toxicity
Penicillamine is used chiefly for treatment of poisoning with copper or to prevent copper accumulation, as in Wilson’s disease (hepatolenticular degeneration). It is also used occasionally in the treatment of severe rheumatoid arthritis (Chapter 36: Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout). Its ability to increase urinary excretion of lead and mercury had occasioned its use as outpatient treatment for intoxication with these metals, but succimer, with its stronger metal-mobilizing capacity and lower side effect profile, has generally replaced penicillamine for these purposes.
Adverse effects have been seen in up to one third of patients receiving penicillamine.
Hypersensitivity reactions include rash, pruritus, and drug fever, and the drug should be used with extreme caution, if at all, in patients with a history of penicillin allergy. Nephrotoxicity with proteinuria has also been reported, and protracted use of the drug may result in renal insufficiency.
Pancytopenia has been associated with prolonged drug intake. Pyridoxine deficiency is a frequent toxic effect of other forms of the drug but is rarely seen with the D form. An acetylated derivative, N-acetylpenicillamine, has been used experimentally in mercury poisoning and may have superior metal-mobilizing capacity, but it is not commercially available.
COMMON PHARMACOLOGY
Drug receptors and pharmacodynamics
The therapeutic and toxic effects of drugs result from their interactions with molecules in the patient. In most instances, drugs act by associating with specific macromolecules in ways that alter their biochemical or biophysical activity. This idea, now almost a century old, is embodied in the terms receptive substances and receptor: the component of a cell or organism that ‘ interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects.
Initially, the existence of receptors was inferred from observations of the chemical and physiologic specificity of drug effects. Thus, Ehrlich noted that certain synthetic organic agents had characteristic antiparasitic effects while other agents did not, although their chemical structures differed only slightly. Langley noted that curare did not prevent electrical stimulation of muscle contraction but did block contraction triggered by nicotine. From these simple beginnings, receptors have now become the central focus of investigation of drug effects and their mechanisms of action (pharmacodynamics). The receptor concept, extended to endocrinology, immunology, and molecular biology, has proved essential for explaining many complexities of biologic regulation. Drug receptors are now being isolated and characterized as macromolecules, thus opening the way to precise understanding of the molecular basis of drug action.
In addition to its usefulness for explaining biology, the receptor concept has immensely important practical consequences for the development of drugs and for making therapeutic decisions in clinical practice. These consequences—explained more fully in later sections of this chapter—form the basis for understanding the actions and clinical uses of drugs described in every chapter of this book. They may be briefly summarized as follows:
1).Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. The receptor’s affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors often limits the maximal effect a drug may produce.
2). Receptors are responsible for selectivity of drug action. The molecular size, shape, and electrical charge of a drug determine whether—and with what avidity —it will bind to a particular receptor among the vast array of chemically different binding sites available in a cell, animal, or patient. Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease the new drug’s affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects.
3). Receptors mediate the actions of pharmacologic antagonists. Many drugs and endogenous chemical signals, such as hormones, regulate the function of receptor macromolecules as agonists; they change the function of a macromolecule as a more or less direct result of binding to it.
Pure pharmacologic antagonists, however, bind to receptors without directly altering the receptors’ function. Thus, the effect of a pure antagonist on a cell or in a patient depends entirely upon its preventing the binding and blocking the biologic actions of agonists molecules. Some of the most useful drugs in clinical medicine are pharmacologic antagonists.
Drug receptors and pharmacodynamics
Agonist-receptor interactions presumably result in full or ”tight” coupling of full agonists to response, in less tight coupling of partial agonists, and in ‘ ‘uncoupling” of pure antagonists. However, it is possible for even full agonists to become ‘ ‘uncoupled” from responses as the result of changes in coupling processes that take place distal to the receptor.
High efficiency of receptor-effector coupling may also be interpreted as the result of spare receptors. Receptors are said to be “spare” for a given pharmacologic response when the maximal response can be elicited by an agonist at a concentration that does not result in occupancy of the full complement of available receptors. Experimentally, spare receptors may be demonstrated by using noncompetitive (irreversible) antagonists to prevent binding of agonist to a proportion of available receptors and showing that high concentrations of agonist can still produce an undiminished maximal response.
The spare receptors are not qualitatively different from nonspare ones. They are not “hidden” or unavailable, and they can be coupled to response. This will happen if the concentration or amount of a cellular component other than the receptor limits the coupling of receptor occupancy to response.
Not all of the mechanisms of pharmacologic antagonism involve interactions of drugs or endogenous ligands at a single type of receptor. Indeed, chemical antagonists need not involve a receptor at all. Thus, one drug may antagonize the actions of a second drug by binding to and inactivating the second drug. For example, protamine, a protein that is positively charged at physiologic pH, is used clinically to counteract the effects of heparin, an anticoagulant that is negatively charged; in this case, one drug antagonizes the other simply by binding it and making it unavailable for interactions with proteins involved in formation of a blood clot.
The clinician often uses drugs that take advantage of physiologic antagonism between endogenous regulatory pathways. Many physiologic functions are controlled by opposing regulatory pathways. For example, several catabolic actions of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin. Although glucocorticoids and insulin act on quite distinct receptor-effector systems, the clinician must sometimes administer insulin to oppose the hyperglycemic effects of glucocorticoid hormones, whether the latter are elevated by endogenous synthesis (eg, an inoperable tumor of the adrenal cortex) or as a result of glucocorticoid therapy.
The quantal dose-effect curve is often characterized by stating the median effective dose (ED50), the dose at which 50% of individuals exhibit the specified quantal effect. Similarly, the dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50). If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined. Such values provide a convenient way of comparing the potencies of drugs in experimental and clinical settings. Thus, if the ED50s of 2 drugs for producing a specified quantal effect are 5 and 500 mg, respectively, then the first drug can be said to be 100 times more potent than the second for that particular effect. Similarly, one can obtain a valuable index of the selectivity of a drug’s action by comparing its ED50s for 2 different quantal effects in a population (eg, cough suppression versus sedation for opiate drugs; increase in heart rate versus increased vasoconstriction for adrenergic amines; anti-inflammatory effects versus sodium retention for corticosteroids; etc).
Quantal dose-effect curves may also be used to generate information regarding the margin of safety to be expected from a particular drug used to produce a specified effect. One measure, which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect, is the therapeutic index. In animal studies, the therapeutic index is usually defined as the ratio of the TD50 to the ED50 for some therapeutically relevant effect. The clinical usefulness of a drug usually relates to a much more conservative definition of therapeutic index and critically depends upon the severity of the disease under treatment. Thus, for the treatment of headache the physician might require a very large therapeutic index, defined as the ratio of the dose required to cause serious toxicity in a very small percentage of subjects (TD 0.001) to the dose required to ameliorate headache in a very large proportion of subjects (ED 99). For treatment of a lethal disease, such as Hodgkin’s lymphoma, an acceptable therapeutic index might be defined less stringently.
Variation in drug responsiveness
Individuals may vary considerably in their responsiveness to a drug; indeed, a single individual may respond differently to the same drug at different times during the course of treatment. Occasionally, individuals exhibit an unusual or idiosyncratic drug response, one that is infrequently observed in most patients. These idiosyncratic responses are usually caused by genetic differences in metabolism of the drug or by immunologic mechanisms, including allergic reactions.
Quantitative variations in drug response are in general more common and more clinically important. An individual patient is hyporeactive or hyperreactive to a drug in that the intensity of effect of a given dose of drug is diminished or increased in comparison to the effect seen in most individuals. The term hypersensitivity usually refers to allergic or other immunologic responses to drugs. With some drugs, the intensity of response to a given dose may change during the course of therapy; in these cases, responsiveness usually decreases as a consequence of continued drug administration, producing a state of relative tolerance to the drug’s effects. When responsiveness diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis.
The general clinical implications of individual variability in drug responsiveness are clear: The physician must be prepared to change either the dose of drug or the choice of drug, depending upon the response observed in the patient. Even before administering the first dose of a drug, the physician should consider factors that may help in predicting the direction and extent of possible variation in responsiveness. These include the propensity of a particular drug to produce tolerance or tachyphylaxis as well as the effects of age, sex, body size, disease state, and simultaneous administration of other drugs.
Four general mechanisms may contribute to variation in drug responsiveness among patients or within an individual patient at different times. The classification described below is necessarily artificial in that most variation in clinical responsiveness is caused by more than one mechanism. Nonetheless, the classification may be useful because certain mechanisms of variation are best dealt with according to different therapeutic strategies:
Alteration in concentration of drug that reaches the receptor.
Patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood. Any of these pharmacokinetic differences may alter the concentration of drug that reaches relevant receptors and thus alter clinical response. These pharmacokinetic differences can often be predicted on the basis of age, weight, sex, disease state, or liver and kidney function of the patient, and such predictions may be used to guide quantitative decisions regarding an initial dosing regimen. Repeated measurements of drug concentrations in blood during the course of treatment are often helpful in dealing with the variability of clinical response caused by pharmacokinetic differences among individuals.
Accordingly, drugs are only selective—rather than specific—in their actions, because they bind to one or a few types of receptor more tightly than to others, and because these receptors control discrete processes that result in distinct effects. As we have seen, selectivity can be measured by comparing binding affinities of a drug to different receptors or by comparing ED50s for different effects of a drug in vivo. In drug development and in clinical medicine, selectivity is usually considered by separating effects into 2 categories: beneficial or therapeutic effects versus toxic effects. Pharmaceutical advertisements and physicians occasionally use the term side effect, implying that the effect in question is insignificant or occurs via a pathway that is to one side of the principal action of the drug; such implications are frequently erroneous.
It is important to recognize that the designation of a particular drug effect as either therapeutic or toxic is a value judgment and not a statement about the phar-macologic mechanism underlying the effect. As a value judgment, such a designation depends on the clinical context in which the drug is used.
is only because of their selectivity that drugs are useful in clinical medicine. Thus, it is important, both in the management of patients and in the development and evaluation of new drugs, to analyze ways in which beneficial and toxic effects of drugs may be related, in order to increase selectivity and usefulness of drug therapy. Fig 2-10 depicts 3 possible relations between the therapeutic and toxic effects of a drug based on analysis of the receptor-effector mechanisms involved.
In certain situations, a drug is clearly necessary and beneficial but produces unacceptable toxicity when given in doses that produce optimal benefit. In such situations, it may be necessary to add another drug to the treatment regimen. For example, sympatholytic agent octadinum (guanethidine) lowers blood pressure in essential hypertension by inhibiting cardiovascular stimulation by sympathetic nerves; as an inevitable consequence, patients will suffer from symptoms of postural hypotension if the dose of drug is large enough. (Note that postural hypotension has been called a ”side effect” of guanethidine, although in fact it is a direct effect, closely related to the drug’s principal therapeutic action.) Appropriate management of such a problem takes advantage of the fact that blood pressure is regulated by changes in blood volume and tone of arterial smooth muscle in addition to the sympathetic nerves. Thus, concomitant administration of diuretics and vasodilators may allow the dose of guanethidine to be lowered, with relief of postural hypotension and continued control of blood pressure.
Pharmacokinetics: absorption, distribution and excretion
When a clinician prescribes a drug and the patient takes it, their main concern is with the effect on the patient’s disease. Several processes are going forward from the time a dose is administered until the appearance of any therapeutic effect. These pharmacokinetic processes, defined above, determine how rapidly and in what concentration and for how long the drug will appear at the target organ. Input, distribution, and loss—are the major pharmacokinetic variables. In most cases, input will consist of absorption from the most convenient site that meets the requirements for speed and completeness of absorption. For most drugs, oral administration is appropriate, and measurable concentrations of the drug in the blood result. The pattern of the concentration-time curve in the blood is a function of the input, distribution, and loss factors. In this chapter, we will examine the quantitative aspects of these relationships.
A fundamental hypothesis of pharmacokinetics is that a relationship exists between a pharmacologic or toxic effect of a drug and the concentration of the drug in a readily accessible site of the body (eg, blood).
This hypothesis has been documented for many drugs, although for some drugs no clear relationship has been found between pharmacologic effect and plasma or blood concentrations. In most cases, the concentration of drug in the general circulation will be related to its concentration at the site of action. The drug will then elicit a number of pharmacologic effects at the site of action. These pharmacologic effects may include toxic effects in addition to the desired clinical effect. The clinician then must balance the toxic potential of a particular dose of a drug with its efficacy to determine the utility of that agent in that clinical situation. Pharmacokinetics plays its role in the dose efficacy scheme by providing the quantitative relationship between drug efficacy and drug dose, with the aid of measurements of drug concentrations in various biologic fluids.
The importance of pharmacokinetics in patient care rests upon the improvement in drug efficacy that can be attained when the measurement of drug levels in the general circulation is added to traditional methods of predicting the dose of the drug. Knowledge of the relationship between efficacy and drug concentration measurements allows the clinician to take into account the various pathologic and physiologic features of a particular patient that make him or her different from the normal individual in responding to a dose of the drug.
Several pathologic and physiologic processes dictate dosage adjustment in individual patients (eg, heart failure, renal failure). They do so by modifying specific pharmacokinetic parameters. The 2 basic variables are clearance, the measure of the ability of the body to eliminate the drug, and volume of distribution, the measure of the apparent space in the body available to contain the drug.
Volume of distribution relates the amount of drug in the body to the concentration of drug (C) in blood or plasma.Volume of distribution is defined in terms of blood or plasma concentrations, depending upon the fluid measured, and reflects the apparent space available in both the general circulation and the tissues of distribution. The plasma volume of a normal 70-kg man is
Depending on the pKa of the drug, the degree of plasma protein binding, the partition coefficient of the drug in the fatty tissues, and the degree of binding to other tissues within the body, volume of distribution may vary widely. For a drug extensively bound to plasma proteins but not to tissue proteins, most of the drug in the body will be retained in the blood, and the volume of distribution will have a lower limit of approximately
A further definition of clearance is useful in understanding the effects of physiologic and pathologic variables on drug elimination, particularly with respect to a specific organ. The rate of elimination of a drug by a single organ can be defined in terms of the blood flow entering and exiting from the organ and the concentration of drug in the blood. The rate of presentation of drug to the organ is the product of blood flow and entering drug concentration, while the rate of exit of drug from the organ is the product of blood flow and exiting drug concentration. The difference between these rates at steady state is the rate of drug elimination.
Half-life is a useful kinetic parameter in that it indicates the time required to attain steady state or to decay from steady-state conditions after a change (ie, starting or stopping) in a particular rate of drug administration (the dosing regimen). However, as an indicator of either drug elimination or distribution, it has little value. Early studies of drug pharmacokinetics in diseased subjects were compromised by reliance on drug half-life as the sole measure of alterations in drug disposition. Disease states can affect both of the physiologically related parameters, volume of distribution and clearance; thus, the derived parameter, h/3, will not necessarily reflect the expected change in drug elimination.
Absorption, bioavailability and routes of administration
In addition to the definition given above, bioavailability is often used to indicate the rate at which an administered dose reaches the general circulation. In general, the relative order of peak times following the administration of different dosage forms of the drug thus corresponds to the rates of availability of the drug from the various dosage forms. The extent of availability may be measured by using either drug concentration in the blood or drug amounts in the urine. The area under the blood concentration-time curve (area under the curve, AUC) for a drug is a common measure of the extent of availability. For most drugs, drug clearance is linear (a constant function of concentration), and the relative areas under the curve or the total amounts of unchanged drug excreted in the urine quantitatively describe the relative availability of the drug from the different dosage forms. However, even ionlinear cases, where clearance is dose-dependent, the relative areas under the curve will yield a measurement of the rank order of availability from different dosage forms or from different sites of administration.
In many cases, the duration of pharmacologic effect is a function of the length of time the blood concentration curve is above the minimum effective concentration, and the intensity of the effect is usually a function of the height of the blood level curve above the minimum effective concentration.
Extraction ratio and the first-pass effect
For most drugs, disposition or loss from the biologic system is independent of input, where disposition is defined as what happens to the active drug after it reaches a site in the circulation where drug concentration measurements can be made. Although disposition processes may be independent of input, the inverse is not necessarily true, since disposition can markedly affect the extent of availability. Drug absorbed from the stomach and the intestine must pass through the liver before reaching a site in the circulation that can be sampled for measurement. Thus, if a drug is metabolized in the liver or excreted in bile, some of the active drug absorbed from the gastrointestinal tract will be inactivated by hepatic processes before the drug can reach the general circulation and be distributed to its sites of action. If the metabolizing or biliary excreting capacity of the liver is great, the effect on the extent of availability will be substantial (first-pass effect). Thus, if the hepatic clearance for a drug is large the extent of availability for this drug will be low when it is given by a route that yields first-pass metabolic effects. This decrease in availability is a function of the physiologic site from which absorption takes place, and no amount of dosage form modification can improve the fractional availability. Of course, therapeutic blood levels may still be reached by this route of administration if larger doses are given. However, in this case, the levels of the drug metabolites will be increased significantly over those that would occur following intravenous administration, especially if the drug has a large volume of distribution. Therefore, the toxicity potential and elimination kinetics of the metabolites must be thoroughly understood before a decision to administer a large oral dose is made.
The first-passeffectcan be avoided to a great extent by use of sublingual tablets and to some extent by use of rectal suppositories. The capillaries in the lower and mid sections of the rectum drain into the inferior and middle hemorrhoidal veins, which in turn drain into the inferior vena cava, thus bypassing the liver. However, suppositories tend to move upward in the rectum into a region where veins that lead to the liver, such as the superior hemorrhoidal, predominate. In addition, there are extensive anastomoses between the superior and middle hemorrhoidal veins; thus, only about 50% of a rectal dose can be assumed to bypass the liver. The lungs represent a good temporary clearing site for a number of drugs, especially basic compounds, as a result of partition into lipid tissues. The lungs also provide a filtering function for particulate matter that may be given by intravenous injection. The lung may serve as a site of first-pass loss by excretion and possible metabolism for drugs administered by nongastrointestinal (“parenteral”) routes.
THE USE OF PHARMACOKINETICS IN DESIGNING A DOSAGE REGIMEN
The “dosage” of a drug represents a decision about 4 variables: 1) the amount of drug to be administered at one time; 2) the route of administration; 3) the interval between doses; and 4) the period of time over which drug administration is to be continued. The choice of the route of administration and the implications of this choice upon the extent and rate of drug availability were discussed in the previous section. Most patterns of administration fall into 2 classes, both of which may be described using pharmacokinetic principles: 1) continuous input by intravenous infusion (or any route that delivers drug at a constant rate), and 2) a series of intermittent drug doses, usually of equal size and given at approximately equally spaced intervals.
Maintenance dose
In most clinical situations, drugs are administered in such a way as to maintain a steady state of drug in the body. Thus, calculation of the appropriate maintenance dose is a primary goal. Dosing rate is also defined as the product of the extent of availability (F) and the dose divided by the dosing interval. Thus, if the clinician can specify the desired plasma drug concentration and knows the clearance and availability for that drug in a particular patient, the appropriate dosing rate can be calculated.
Loading dose
When the time to reach steady state is appreciable, as it is for drugs with long half-lives, it may be desirable to administer a loading dose that promptly raises the concentration of drug in plasma to the projected steady-state value. In theory, only the amount of the loading dose need be computed, not the rate of its administration; to a first approximation, this is so. The amount of drug required to achieve a given steady-state concentration in the plasma is the amount that must be in the body when the desired steady state is reached. (For intermittent dosage schemes, the amount is that at the average concentration). The volume of distribution (Vd) is the proportionality factor that relates the total amount of drug in the body to the concentration in the plasma. However, in some cases the distribution phase may not be ignored, particularly in connection with the calculation of loading doses. If the rate of absorption is rapid relative to distribution (this is always true for intravenous bolus administration), the concentration of drug in plasma that results from an appropriate loading dose can initially be considerably higher than desired. Severe toxicity may occur, albeit transiently. This may be particularly important, for example, in the administration of antiarrhythmic drugs, where an almost immediate toxic response is obtained when plasma concentrations exceed a particular level. Thus, while the estimation of the amount of a loading dose may be quite correct, the rate of administration can sometimes be crucial in preventing excessive drug concentrations, and slow administration of an intravenous drug (over minutes rather than seconds) is almost always wise. For intravenous doses of theophylline, initial injections should be given over a 20-minute period to avoid the possibility of high plasma levels during the distribution phase.
THE EFFECT OF DISEASE ON PHARMACOKINETIC PROCESSES
Disease states may modify all of the variables listed in Table 3-1. The ability to predict or understand how pathologic conditions may modify drug kinetics requires an understanding of the interrelationship between the variables. Clearance is the most important parameter in the design of drug dosage regimens. As shown in equation (5), clearance of an eliminating organ may be defined in terms of blood flow to the organ and the extraction ratio.
When the capability for elimination is of the same order of magnitude as the blood flow, clearance is dependent upon the blood flow as well as on the intrinsic clearance and plasma protein binding. Enzyme induction or hepatic disease may change the rate of imipramine metabolism in an isolated hepatic microsomal enzyme system, but no change in clearance is found in the whole animal with similar hepatic changes. This is explained by the fact that imipramine is a high-extraction-ratio drug and clearance is limited by blood flow rate, so that changes in dim due to enzyme induction or liver disease have no effect on clearance. Also, although imipramine is highly protein-bound, changes in protein binding due to disease or competitive binding should have no effect on clearance even though volume of distribution is changed. In the latter case, a change in volume of distribution with no change in clearance will result in a change in half-life, although the elimination mechanisms have not been altered.
The differences between clearance and half-life are important in defining the underlying mechanisms for the effect of a disease state on drug disposition. For example, the half-life of diazepam increases with age. One explanation for this change is that the ability of the liver to metabolize this drug decreases as a function of age.
In many reports hepatic disease has been shown to reduce drug clearance and prolong half-life. However, for many other drugs known to be eliminated by hepatic processes, no changes in clearance or half-life have been noted with hepatic disease. This reflects the fact that hepatic disease does not always affect the hepatic intrinsic clearance. This may be due to the multiplicity of liver metabolizing enzymes available to degrade drugs and other exogenous compounds. There is no reliable marker of hepatic drug-metabolizing function that can be used to predict changes in liver clearance in a manner analogous to the changes in drug renal clearance that can be predicted as a function of creatinine clearance.
Generally, hepatic impairment would be expected to reduce clearance and prolong half-life or to cause no change in drug elimination. However, there is some evidence that hepatic disease can also increase clearance and shorten half-life. For example, the clearance of tolbutamide may increase and its half-life decrease with no change in volume of distribution in individuals with acute viral hepatitis during the acute phase of illness in comparison to the recovery period. Tolbutamide is a low-extraction-ratio drug, and its hepatic clearance may be described by equation. The explanation for the observations appears to be an increase in the unbound fraction of drug in plasma (fu) in the absence of a change in dim. The half-life is changed, since total clearance is changed without a change in volume of distribution. For many drugs, volume of distribution would be expected to increase as the free fraction of drug in plasma increases. However, the volume of distribution for tolbutamide is quite small (11 L/70 kg), and the majority of the distribution space is related to blood volume, which is independent of fu.
Pharmacokinetic changes in renal disease may also be explained in terms of clearance concepts. However, since the net renal excretion of a drug is determined by filtration, active secretion, and reabsorption, the treatment of renal clearance is more complicated than that described above.
The secretion of drug in the kidney will depend on the relative binding of drug to the active transport carriers in relation to the binding to plasma proteins, the degree of saturation of these carriers, transfer of the drug across the tubular membrane, and the rate of delivery of the drug to the secretory site. With a model that combines these factors, the influence of changes in protein binding, blood flow, and number of functioning nephrons may be predicted and explained in a manner analogous to the examples given above for hepatic elimination.
Pharmacokinetics: drug biotransformation
Humans are daily exposed to a wide variety of foreign compounds calledxenobiotics—substances absorbed across the lungs or skin or, more commonly, ingested either unintentionally as compounds present in food and drink or deliberately as drugs for therapeutic or “recreational” purposes. Exposure to environmental xenobiotics may be inadvertent and accidental and may even be inescapable. Some xenobiotics are innocuous, but many can provoke biologic responses both pharmacologic and toxic iature. These biologic responses often depend on conversion of the absorbed or ingested substance into an active metabolite. The discussion that follows is applicable to xenobiotics in general as well as to drugs and to some extent to endogenous compounds.
parent drug and may even be inactive. However, some biotransformation products have enhanced activity or toxic properties, including mutagenicity, teratogenicity, and carcinogenicity. This observation undermines the once popular theory that drug-biotransforming enzymes evolved as a biochemical defense mechanism for the detoxification of environmental xenobiotics. It is noteworthy that the synthesis of endogenous substrates such as steroid hormones, cholesterol, and bile acids involves many enzyme-catalyzed pathways associated with the metabolism of xenobiotics. The same is true of the formation and excretion of endogenous metabolic products such as bilirubin, the end catabolite of heme. Finally, drug-metabolizing enzymes have been exploited through the design of pharmacologically inactive pro-drugs that are converted in vivo to the pharmacologically active species.
WHY IS DRUG BIOTRANSFORMATION NECESSARY? Renal excretion plays a pivotal role in terminating the biologic activity of a few drugs, particularly those that have small molecular volumes or possess polar characteristics such as functional groups fully ionized at physiologic pH. Most drugs do not possess such physicochemical properties. Pharmacologically active organic molecules tend to be highly lipophilic and remain un-ionized or only partially ionized at physiologic pH. They are often strongly bound to plasma proteins. Such substances are not readily filtered at the glomerulus. The lipophilic nature of renal tubular membranes also facilitates the reabsorption of hydrophobic compounds following their glomerular filtration. Consequently, most drugs would have a prolonged duration of action if termination of their action depended solely on renal excretion. An alternative process that may lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excretable products. The role metabolism may play in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and phenobarbital would have half-lives greater than 100 years if it were not for their metabolic conversion to more water-soluble compounds.
THE ROLE OF BIOTRANSFORMATION IN DRUG DISPOSITION. Most metabolic biotransformations occur at some point between absorption of the drug into the general circulation and its renal elimination. A few transformations occur in the intestinal lumen or intestinal wall. In general, all of these reactions can be assigned to one of 2 major categories, called phase I and phase II reactions.
Phase I reactions usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH). Often these metabolites are inactive, although in some instances activity is only modified.
If phase I metabolites are sufficiently polar, they may be readily excreted. However, many phase 1 products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with the newly established functional group to form a highly polar conjugate. Such conjugation or synthetic reactions are the hallmarks of phase II metabolism. A great variety of drugs undergo these sequential biotransformation reactions, although in some instances the parent drug may already possess a functional group that may form a conjugate directly. For example, the hydrazide moiety of isoniazid is known to form an N-acetyl conjugates – in a phase II reaction – that is a substrate for a phase I type reaction, namely, hydrolysis to isonicotinic acid. Thus, phase II reactions may actually precede phase I reactions.
WHERE DO DRUG BIOTRANSFORMATIONS OCCUR? Although every tissue has some ability t( metabolize drugs, the liver is the principal organ o drug metabolism. Other tissues that display consider able activity include the gastrointestinal tract, the lungs, the skin, and the kidneys. Following oral ad ministration, many drugs (eg, isoproterenol, meperi dine. pentazocine, morphine) are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism. This process has been called a first-pass effect. Some orally administered drugs (eg, clonazepam, chlorpromazine) are more extensively metabolized in the intestine than in the liver. Thus, intestinal metabolism may contribute to the overall first-pass effect. First-pass effects may so greatly limit the bioavailability of orally administered drugs that alternative routes of administration must be employed to achieve therapeutically effective blood levels. The lower gut harbors intestinal microorganisms that are capable of many biotransformation reactions. In addition, drugs may be metabolized by gastric acid (eg, penicillin), digestive enzymes (eg, polypeptides such as insulin), or by enzymes in the wall of the intestine (eg, sympathomimetic catecholamines).
Although drug biotransformation in vivo can occur by spontaneous, noncatalyzed chemical reactions, the vast majority are catalyzed by specific cellular enzymes. At the subcellular level, these enzymes may be located in the endoplasmic reticulum, mitochondria, cytosol, lysosomes, or even the nuclear envelope or plasma membrane.
MICROSOMAL MIXED FUNCTION OXIDASE SYSTEM
Many drug-metabolizing enzymes are located in the lipophilic membranes of the endoplasmic reticulum of the liver and other tissues. When these lamellar membranes are isolated by homogenization and fractionation of the cell, they re-form into vesicles called microsomes. Microsomes retain most of the morphologic and functional characteristics of the intact membranes, including the rough and smooth surface features of the rough (ribosome-studded) and smooth (no ribosomes) endoplasmic reticulum. Whereas the rough microsomes tend to be dedicated to protein synthesis, the smooth microsomes are relatively rich in enzymes responsible for oxidative drug metabolism. In particular, they contain the important class of enzymes known as the mixed function oxidases (MFO), or monooxygenases. The activity of this enzyme system requires both a reducing agent (NADPH) and molecular oxygen; in a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water.
In this oxidation-reduction process, 2 microsomal enzymes play a key role. The first of these is a flavo-protein, NADPH-cytochrome P-450 reductase. One mol of this enzyme (molecular weight ~ 80,000) contains 1 mol each of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Because cytochrome c can serve as an electron acceptor, the enzyme is often referred to as NADPH-cytochrome c reductase. The second microsomal enzyme is a hemoprotein called cytochrome P-450 and serves as the terminal oxidase. The name cytochrome P-450 is derived from the spectral properties of this hemoprotein. In its reduced (ferrous) form, it binds carbon monoxide to give a ferrocarbonyl adduct that absorbs maximally in the visible region of the electromagnetic spectrum at 450 nm. As with other naturally occurring heme-containing proteins, the iron present in this molecule is complexed with protoporphyrin IX. Over half of the heme synthesized in the liver is committed to hepatic cytochrome P-450 formation. The relative abundance of cytochrome P-450, as compared to that of the reductase in the liver, contributes to making cytochrome P-450 heme reduction the rate-limiting step in hepatic drug oxidations.
Microsomal drug oxidations require cytochrome P-450, cytochrome P-450 reductase, NADPH, and molecular oxygen. Briefly, oxidized (Fe+) cytochrome P-450 combines with a drug substrate to form a binary complex (step 1). NADPH donates an electron to the flavoprotein reductase, which in turn reduces the oxidized cytochrome P-450-drug complex (step 2). A second electron is introduced from NADPH via the same flavoprotein reductase, which serves to reduce molecular oxygen and to form an “activated oxygen “-cytochrome P-450-substrate complex (step 3). This complex in turn transfers ‘ ‘activated” oxygen to the drug substrate to form the oxidized product (step 4).
The potent oxidizing properties of this activated oxygen permit oxidation of a large number of substrates. Substrate specificity is very low for this enzyme complex. High solubility in lipids is the only common structural feature of the wide variety of structurally unrelated drugs and chemicals that serve as substrates in this system.
Enzyme induction
An interesting feature of some of these chemically dissimilar drug substrates is their ability, on repeated administration, to ‘ ‘induce” cytochrome P-450 by enhancing the rate of its synthesis or reducing its rate of degradation. Induction results in an acceleration of metabolism and usually in a decrease in the phar-macologic action of the inducer and also ofcoadminis-tered drugs. However, in the case of drugs meta-bolically transformed to reactive intermediates, enzyme induction may exacerbate drug-mediated tissue toxicity.
Various substrates appear to induce forms of cytochrome P-450 having different molecular weights and exhibiting different substrate specificities and im-munochemical and spectral characteristics. The 2 isozymes that have been most extensively studied are: 1). cytochrome P-450b, or LMz (for liver microsomal form 2), which is induced by treatment with phenobar-bital; and 2). cytochrome P-448 (cytochrome Pi-450, or P-450c, or LIVLi), which is induced by polycyclic aromatic hydrocarbons, of which 3-methylcholanthrene is a prototype. Environmental pollutants are capable of inducing cytochrome P-450. For example, exposure to benzo(a)pyrene, present in tobacco smoke, charcoal-broiled meat, and other organic pyrolysis products is known to induce cytochrome P-448 and to alter the rates of drug metabolism in both experimental animals and in humans. Other environmental chemicals known to induce specific cytochrome P-450 isozymes include the polychlorinated biphenyls (PCBs), which are used widely in industry as insulating materials and plasticizers, and 2,3,7,8-tetrachlorodibenzo-beta-dioxon (dioxin, TCDD), a trace by-product of the chemical synthesis of the defoliant 2,4,5-trichlorophenol.
Enzyme inhibition
Other drug substrates may inhibit cytochrome P-450 enzyme activity. A well-known inhibitor is proadifen. This compound binds avidly to the cytochrome molecule and thereby competitively inhibits the metabolism of potential substrates. Cimetidine is a popular therapeutic agent that has been found to impair the in vivo metabolism of other drugs by the same mechanism. Some substrates irreversibly inhibit cytochrome P-450 via covalent interaction of a metabolically generated reactive intermediate that may react with either the apoprotein or the heme moiety of the cytochrome. A growing list of such inhibitors includes the steroids ethinylestradiol, norethindrone, and spironolactone; the anesthetic agent fluroxene; the barbiturates secobarbital and allobarbital; the analgesic sedatives allylisopropylacetylurea, diethylpentenamide, and ethchlorvynol; the solvent carbon disulfide; and propylthiouracil.
The dose and the frequency of administration required to achieve effective therapeutic blood and tissue levels vary in different patients because of individual differences in drug distribution and rates of drug metabolism and elimination. These differences are determined by genetic factors and nongenetic variables such as age, sex, liver size, liver function, circadian rhythm, body temperature, and nutritional and environmental factors such as concomitant exposure to inducers or inhibitors of drug metabolism. The discussion that follows will summarize the most important variables relating to drug metabolism that are of clinical relevance.
Individual Differences
Individual differences in metabolic rate depend on the nature of the drug itself. Thus, within the same population, steady-state plasma levels may reflect a 30-fold variation in the metabolism of one drug only a 2-fold variation in the metabolism of another.
Genetic factors that influence enzyme levels account for some of these differences. Succinylcholine, for example, is metabolized only half as rapidly in persons with genetically determined defects in pseudocholines-terase as in normals. Analogous pharmacogenetic differences are seen in the acetylation ofisoniazid and the hydroxylation of warfarin. Similarly, genetically determined defects in the oxidative metabolism of de-brisoquine, phenacetin, guanoxan, sparteine, and phenformin have been recently reported. The defects are apparently transmitted as autosomal recessive traits and may be expressed at any one of the multiple metabolic transformations that a chemical might undergo in vivo. Environmental factors also contribute to individual variations in drug metabolism. Cigarette smokers metabolize some drugs more rapidly than nonsmokers because of enzyme induction (see p 37). Industrial workers exposed to some pesticides metabolize certain drugs more rapidly thaonexposed individuals. Such differences make it difficult to determine effective and safe doses of drugs that have narrow therapeutic indices.
Age andsex
Increased susceptibility to the pharmacologic or toxic activity of drugs has been reported in very young and old patients as compared to young adults. Although this may reflect differences in absorption, distribution, and elimination, differences in drug metabolism cannot be ruled out—a possibility supported by studies in other mammalian species indicating that drugs are metabolized at reduced rates during the pre-pubertal period and senescence. Slower metabolism could be due to reduced activity of metabolic enzymes or reduced availability of essential endogenous cofac-tors. Similar trends have been observed in humans, but incontrovertible evidence is yet to be obtained.
The activities are divided by age…
Sex-dependent variations in drug metabolism have been well documented in rats but not in other rodents. Young adult male rats metabolize drugs much faster than mature female rats or prepubertal male rats. These differences in drug metabolism have been clearly associated with androgenic hormones. A few clinical reports suggest that similar sex-dependent differences in drug metabolism also exist in humans for benzodiazepines, estrogens, salicylates.
Drug-drug interactions during metabolism
Many substrates, by virtue of their relatively high lipophilicity, are retained not only at the active site of the enzyme but remaionspecifically bound to the lipid membrane of the endoplasmic reticulum. In this state, they may induce microsomal enzymes; depending on the residual drug levels at the active site, they also may competitively inhibit metabolism of a simultaneously administered drug. Such drugs include various sedative-hypnotics, tranquilizers, anticonvulsants, and insecticides. Patients who routinely ingest barbiturates, other sedative-hypnotics, or tranquilizers may require considerably higher doses of warfarin or dicumarol, when being treated with these oral anticoagulants, to maintain a prolonged prothrombin time. On the other hand, discontinuation of the sedative may result in reduced metabolism of the anticoagulant and bleeding – a toxic effect of the enhanced plasma levels of the anticoagulant. Similar interactions have been observed in individuals receiving various combination drug regimens such as tranquilizers or sedatives with contraceptive agents, sedatives with anticonvulsant drugs, and even alcohol with hypoglycemic drugs (tolbutamide).
It must also be noted that an inducer may enhance not only the metabolism of other drugs but also its own metabolism. Thus, continued use of a drug may result in one form of tolerance – progressively reduced effectiveness due to enhancement of its own metabolism.
Conversely, simultaneous administration of 2 or more drugs may result in impaired elimination of the more slowly metabolized drug and prolongation or potentiation of its pharmacologic effects. Both competitive substrate inhibition and irreversible substrate-mediated enzyme inactivation may augment plasma drug levels and lead to toxic effects from drugs with narrow therapeutic indices. For example, it has been shown that dicumarol inhibits the metabolism of the anticonvulsant phenytoin and leads to the expression of side effects such as ataxia and drowsiness. Similarly, allopurinol both prolongs the duration and enhances the chemotherapeutic action of mercaptopurine by competitive inhibition of xanthine oxidase.
Consequently, to avoid bone marrow toxicity, the dose of mercaptopurine is usually reduced in patients receiving allopurinol. Cimetidine, a drug used in the treatment of peptic ulcer, has been shown to potentiate the pharmacologic actions of anticoagulants and sedatives. The metabolism of Chlordiazepoxide has been shown to be inhibited by 63% after a single dose of cimetidine; such effects are reversed within 48 hours after withdrawal of cimetidine. For such interactions to occur, drug metabolism must follow zero-order kinetics. Elimination of most drugs proceeds, however, by exponential (first-order) kinetics, thus greatly reducing the probability of such metabolically dependent interactions.
Impairment of metabolism may also result if a simultaneously administered drug irreversibly inactivates a common metabolizing enzyme, as is the case with secobarbital or novonal (diethylpentenamide) overdoses. These compounds, in the course of their metabolism by cytochrome P-450, inactivate the enzyme and result in impairment of their own metabolism and that of other cosubstrates.
Interactions between drugs and endogenous compounds
Various drugs require conjugation with endogenous substrates such as glutathione, glucuronic acid, and sulfuric acid for their inactivation. Consequently, different drugs may compete for the same endogenous substrates, and the faster-reacting drug may effectively deplete endogenous substrate levels and impair the metabolism of the slower-reacting drug. If the latter has a steep dose-response curve or a narrow margin of safety, potentiation of its pharmacologic and toxic effects may result.
Diseases affecting drug metabolism
Acute or chronic diseases that affect liver architecture or function markedly affect hepatic metabolism of some drugs. Such conditions include fat accumulation, alcoholic hepatitis, active or inactive alcoholic cirrhosis, hemochromatosis, chronic active hepatitis, biliary cirrhosis, and acute viral or drug hepatitis. Depending on their severity, these conditions impair hepatic drug-metabolizing enzymes, particularly microsomal oxidases, and thereby markedly affect drug elimination. For example, the half-lives of Chlordiazepoxide and diazepam in patients with liver cirrhosis or acute viral hepatitis are greatly increased, with a corresponding prolongation of their effects. Consequently, these drugs may cause coma in patients with liver disease when given in ordinary doses.
Liver cancer has been reported to impair hepatic drug metabolism in humans. For example, aminopyrine metabolism is slower in patients with malignant hepatic tumors than iormal controls. These patients also exhibit markedly diminished aminopyrine clearance rates. Studies with biopsy specimens of livers from patients with hepatocellular carcinoma also indicate impaired ability to oxidatively metabolize drugs in vitro. This is associated with a correspondingly reduced cytochrome P-450 content.
Cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited. These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow. Pulmonary disease may affect drug metabolism as indicated by the impaired hydrolysis of procainamide and procaine in patients with chronic respiratory insufficiency and the increased half-life of antipyrine in patients with lung cancer. Impairment of enzyme activity or defective formation of enzymes associated with heavy metal poisoning or porphyria also results in reduction of hepatic drug metabolism. For example, lead poisoning has been shown to increase the half-life of antipyrine in humans.
Although the effects of endocrine dysfunction on drug metabolism have been well explored in experimental animal models, corresponding data for humans with endocrine disorders are scanty. Thyroid dysfunction has been associated with altered metabolism of some drugs and of some endogenous compounds as well. Hypothyroidism increases the half-life of antipyrine, digoxin, methamizole, andpractolol, as hyperthyroidism has the opposite effect. A few clinical studies in diabetic patients indicate no apparent impairment of drug metabolism, as reflected by the half-lives of antipyrine, tolbutamide, and phenylbutazone. In contrast, the metabolism of several drugs is impaired in male rats treated with diabetogenic agents such as alloxan or streptozocin. These alterations are abolished by administration of insulin, which has no direct influence on hepatic drug-metabolizing enzymes. Malfunctions of the pituitary, adrenal cortex, and gonads markedly impair hepatic drug metabolism in rats. On the basis of these findings, it may be supposed that such disorders could significantly affect drug metabolism in humans. However, until sufficient evidence is obtained from clinical studies in patients, such extrapolations must be considered tentative.
Rapidly metabolized drugs whose hepatic clearance is blood flow-limited: Alprenolol, Lidocaine, Meperidine, Morphine, Pentazocine, Propoxyphene, Propranolol, Verapamil, Amitriptyline, Chlormethiazole, Desipramine, Imipramine, Isoniazid, Labetalol.
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