ANTIVIRAL ANTIFUNGAL ANTIPROTOSOAL ANTISPIROCHETES AGENTS
(Remantadinum, Interferonum, Acyclovirum, Idoxoridinum, Laferonum, Azidotimidinum, Biiochinolum, Metronidaasolum, Emetini hydrochloridum, Chingaminum, Chiniofonum, Tinidasolum, Furasolidonum, aminochinolum).
(Levamisolum (Decaris), Pirantelum, Piperasini adipinas, Naphtamonum, Pirivinii paomas, Mebendasolum (Vermox), Fenasalum, Dytrasinum, Chloxilum, Antimonili natrium tartras, Praziqantelum.
(Dopanum, Sarcolisinum, Chlorbutinum, Cyclophosphanum, Myelosanum, Cyclophosphamidum, Metotrexatum, Phtoruracilum, Mercaptopurinum, Vincristinum, Vinblastinum, Colhaminum, Doxorubicini hydrochloridum, Dactinomicinum, Fosfestrolum, Prednisolonum, Tamoxifenum, Propes, Asparginase).
PHARMACOTHERAPY IN THE DENTAL PRACTISE
(trypsinum crystallisatum, chymotrypsinum crystallisatum, DNA-aza, lidaza, folia Salviae, infusa flores Chamommilae, romasulan, decoctum corticis Quercus, mucilaginis semeni Lini, retinoli acetas, tocopheroli acetas, ergocalciferol, Natrium phthoridum, Ftorlac,alcohol is ethyl for treatment of channels of roots, ether for treatment of channels of roots.
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.
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
Acyclovir (Figure 49–2) 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
(Figure 49–3). 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.
Oral acyclovir has multiple uses (Table 49–1). 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.
Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis. The compound has in vitro activity against HSV-1, HSV-2, vaccinia, and some adenoviruses. It is phosphorylated intracellularly to its active form by cellular enzymes, then competes with thymidine triphosphate for incorporation by the viral DNA polymerase.
Incorporation of trifluridine triphosphate into both viral and cellular DNA prevents its systemic use. Application of a 1% solution is effective in treating primary keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 and HSV-2. Topical application of trifluridine solution, alone or in combination with interferon alfa, has been used successfully in the treatment of acyclovir-resistant HSV infections.
Ganciclovir is an acyclic guanosine analog åðat requires triphosphorylation for activation prior to inhibiting the viral DNA polymerase. Initial phosphorylation is catalyzed by the virus-specified protein kinase phosphotransferase UL97 in CMV-infected cells. The activated compound competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation. Ganciclovir has in vitro activity against CMV, HSV, VZV, EBV, and HHV-8. Its activity against CMV is up to 100 times greater than that of acyclovir.
Intravenous ganciclovir has been shown to delay progression of CMV retinitis in patients with AIDS when compared with no treatment (Table 49–2). Dual therapy with foscarnet and ganciclovir has been shown to be more effective in delaying progression of retinitis than either drug administered alone (see Foscarnet, below), although side effects are compounded. Intravenous ganciclovir is also used to treat CMV colitis and esophagitis. Intravenous ganciclovir, followed by either oral ganciclovir or high-dose oral acyclovir, reduces the risk of CMV infection in transplant recipients. Use of intravenous ganciclovir to treat CMV pneumonitis in immunocompromised patients may be beneficial, particularly in combination with intravenous cytomegalovirus immunoglobulin. Oral ganciclovir is indicated for prevention of end-organ CMV disease in AIDS patients and as maintenance therapy of CMV retinitis following induction. Although less effective than intravenous ganciclovir, the risk of myelosuppression and of catheter-related complications is diminished.
A large and increasing number of antiretroviral agents are currently available for treatment of HIV- 1-infected patients (Table 49–3). 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 (azidothymidine; AZT) is a deoxythymidine analog (Figure 49–4) that is well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum. Plasma protein binding is approximately 35%. The serum half-life averages 1 hour, and the intracellular half-life of the phosphorylated compound is 3.3 hours. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver. Clearance of zidovudine is reduced by approximately 50% in uremic patients, and toxicity may increase in patients with advanced hepatic insufficiency.
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.
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. Activity against HBV is described below (see Anti-Hepatitis Agents).
Zalcitabine (ddC) is a cytosine analog (Figure 49–4) that has synergistic anti-HIV-1 activity with a variety of antiretroviral agents against both zidovudine-sensitive and zidovudine-resistant strains of HIV-1.
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 (Table 49–3).
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.
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.
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.
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 fraction not 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.
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. By preventing cleavage of the Gag-Pol polyprotein, protease inhibitors result in the production of immature, noninfectious viral particles. Unfortunately, specific genotypic alterations that confer phenotypic resistance is fairly common with these agents, thus contraindicating monotherapy. The issue of cross-resistance among agents in this class of drugs is complex and requires further investigation; it appears to require a minimum of four substitutions in the gene. A syndrome of redistribution and accumulation of body fat that includes central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and a cushingoid appearance has been observed in patients receiving antiretroviral therapy.
Ritonavir is an inhibitor of HIV-1 and HIV-2 proteases with high bioavailability (about 75%) that increases when the drug is given with food. Metabolism to an active metabolite occurs via the CYP3A and CYP2D6 isoforms; excretion is primarily in the feces. Caution is advised when administering the drug to persons with impaired hepatic function. Capsules (but not the oral solution) should be refrigerated for storage. Resistance is associated with mutations at positions 84, 82, 71, 63, and 46, of which the I84V mutation appears to be the most critical.
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.
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. Trough levels of lopinavir are greater than the median HIV-1 wild type 50% inhibitory concentration, thus maintaining potent viral suppression as well as providing a pharmacologic barrier to the emergence of resistance. In addition to improved patient compliance because of the reduced pill burden with twice-daily dosing, lopinavir/ritonavir is generally well tolerated.
Other Antiviral Agents
Interferons have been studied for numerous clinical indications. In addition to HBV and HCV infections (see Anti-Hepatitis Agents, above), intralesional injection of interferon alfa-2b or alfa-n3 may be used for treatment of condylomata acuminata.
In addition to oral administration for hepatitis C infection in combination with interferon alfa (see above), aerosolized ribavirin is administered by nebulizer (20 mg/mL for 12–18 hours per day for 3–7 days) to children and infants with severe respiratory syncytial virus (RSV) bronchiolitis or pneumonia, reducing the severity and duration of illness. Aerosolized ribavirin has also been used to treat influenza A and B infection but has not gained widespread use. Aerosolized ribavirin is generally well tolerated but may cause conjunctival or bronchial irritation. Health care workers should be protected against extended inhalation exposure.
Intravenous ribavirin decreases mortality in Lassa fever and other viral hemorrhagic fevers if started early. Clinical benefit has been reported in cases of severe measles pneumonitis, and continuous infusion of ribavirin decreased virus shedding in several patients with severe lower respiratory tract influenza or parainfluenza infections. Peak plasma concentrations are approximately tenfold higher than with oral administration and occur earlier (ie, at 0.5 hours after dosing). At steady state, cerebrospinal fluid levels are about 70% of those in plasma.
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 A and B are antifungal antibiotics produced by Streptomyces nodosus. Amphotericin A is not in clinical use.
Systemic Antifungal Drugs for Mucocutaneous Infections
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 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 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.
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.
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.
Several classes of antimalarial drugs are available (Table 53–1; Figure 53–1). 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 in number 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. The choice of drugs for amebiasis depends on the clinical presentation (Figure 53–2; Table 53–4).
Treatment of Specific Forms of Amebiasis
Asymptomatic Intestinal Infection
Asymptomatic carriers generally are not treated in endemic areas but in nonendemic 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.
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.
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
should be considered. Dehydroemetine and emetine are toxic alternative drugs.
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.
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
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.
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.
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-EDTA is 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.
Blood Lead (µg/dL)
No action needed
Identify and minimize lead exposure
from exposure if symptomatic
Remove from work with lead. Immediate medical evaluation indicated. Chelation not indicated unless significant symptoms due to lead poisoning
Same as above. Chelation may be indicated if symptomatic. Important to consult on individual case basis
Management guidelines adopted from the California Department of Health Services, Childhood Lead Poisoning Prevention Branch & Occupational Lead Poisoning Prevention Program
(A). Cyanide ions (CN-) enter the organism in the form of hydrocyanic acid (HCN); the latter can be inhaled, released from cyanide salts in the acidic stomach juice, or enzymatically liberated from bitter almonds in the gastrointestinal tract. The lethal dose of HCN can be as low as 50 mg. CN- binds with high affinity to trivalent iron and thereby arrests utilization of oxygen via mitochondrial cytochrome oxidases of the respiratory chain. An internal asphyxiation (histotoxic hypoxia) ensues while erythrocytes remain charged with O2 (venous blood colored bright red). In small amounts, cyanide can be converted to the relatively nontoxic thiocyanate (SCN-) by hepatic “rhodanese” or sulfur transferase. As a therapeutic measure, thiosulfate can be given i.v. to promote formation of thiocyanate, which is eliminated in urine. However, this reaction is slow in onset. A more effective emergency treatment is the i.v. administration of the methemoglobin- forming agent 4-dimethylaminophenol, which rapidly generates trivalent from divalent iron in hemoglobin.
Competition between methemoglobin and cytochrome oxidase for CN- ions favors the formation of cyanmethemoglobin. Hydroxocobalamin is an alternative, very effective antidote central cobalt atom binds CN- with high affinity to generate cyanocobalamin.Tolonium chloride (Toluidin Blue). Brown-colored methemoglobin, containing tri- instead of divalent iron, is incapable of carrying O2. Under normal conditions, methemoglobin is produced continuously, but reduced again with the help of glucose-6-phosphate dehydrogenase. Substances that promote formation of methemoglobin (B) may cause a lethal deficiency of O2. Tolonium chloride is a redox dye that can be given i.v. to reduce methemoglobin. Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type. Phosphorylation of acetylcholinesterase causes an irreversible inhibition of acetylcholine because its breakdown and hence flooding of the organism with the transmitter. Possible sequelae are exaggerated parasympathomimetic activity, blockade of ganglionic and neuromuscular transmission, and respiratory paralysis. Therapeutic measures include: 1.
administration of atropine in high dosage to shield muscarinic acetylcholine receptors; and 2. reactivation of acetylcholinesterase by obidoxime, which successively binds to the enzyme, captures the phosphate residue by a nucleophilic attack, and then dissociates
from the active
center to release the enzyme from inhibition. Ferric Ferrocyanide (“
is a product of incomplete
combustion of natural or petroleum gas. Common sources in the home include
faulty central heating systems, gas appliances and fires. Blocked flues and
chimneys mean the gas can't escape and is inhaled by the unsuspecting
individual. In the
Car exhausts are also a common source of carbon monoxide. A lethal level of carbon monoxide in the blood can develop within ten minutes inside a closed garage.
Inhaling carbon monoxide reduces the blood's ability to carry oxygen
Inhaling carbon monoxide reduces the blood's ability to carry oxygen, leaving the body's organs and cells starved of oxygen.
The symptoms of mild carbon monoxide poisoning may be non-specific and similar to those of viral cold infections: headache, nausea, dizziness, sore throat and dry cough. In children, the symptoms are similar to those of a stomach upset, with nausea and vomiting.
More severe poisoning can result in a fast and irregular heart rate, over-breathing (hyperventilation), confusion, drowsiness and difficulty breathing. Seizures and loss of consciousness may also occur.
Symptoms can occur a few days or even months after exposure to carbon monoxide. Such symptoms include confusion, loss of memory and problems with coordination.
It's important to consider that carbon monoxide poisoning may be a possibility if:
other people in the home or place of work suffer similar symptoms symptoms tends to disappear when someone goes away (for example, on holiday) and they're no longer exposed to the carbon monoxide gas symptoms tend to be seasonal (for example, headaches during the winter when indoor heating is used more often)
Diagnosis and treatment
Carbon monoxide poisoning can be confirmed by finding high levels in the blood. Treatment includes making sure the patient is away from any source of the gas, providing basic life support as appropriate and giving oxygen before transferring the patient to hospital.
Those people who suffer mild poisoning invariably make a full recovery. Between 10 and 50 per cent of those with severe poisoning may suffer long-term problems.
Carbon monoxide poisoning is preventable, so it's important to be aware of what may cause it and how to minimise the risk of exposure by putting these safety tips into practice:
have chimneys and flues checked regularly
make sure gas appliances and heating systems are inspected every year
for extra protection, fit carbon monoxide alarms - available from DIY stores
never run cars, motorbikes or lawnmowers in a closed garage
Heavy Metal Intoxication
Some metals such as iron are essential for life, while others such as lead are present in all organisms but serve no useful biologic purpose. Some of the oldest diseases of humans can be traced to heavy metal poisoning associated with metal mining, refining, and use. Even with the present recognition of the hazards of heavy metals, the incidence of intoxication remains significant and the need for preventive strategies and effective therapy remains high. When intoxication occurs, chelator molecules (from chela "claw") may be used to bind the metal and facilitate its excretion from the body. Chelator drugs are discussed in the second part of this chapter.
Unithiol (Dimercaptopropanesulfonic Acid, DMPS)
Unithiol, a dimercapto chelating 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
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.
Indications & Toxicity
Unithiol has no FDA-approved indications, but experimental studies and its pharmacologic and pharmacodynamic profile suggest that intravenous unithiol offers advantages over intramuscular dimercaprol or oral succimer in the initial treatment of severe acute poisoning by inorganic mercury or arsenic. Aqueous preparations of unithiol (usually 50 mg/mL in sterile water) can be administered at a dose of 3–5 mg/kg every 4 hours by slow intravenous infusion over 20 minutes.
If a few days of treatment are accompanied by stabilization of the patient's cardiovascular and gastrointestinal status, it may be possible to change to oral administration at a dose of 4–8 mg/kg every 6–8 hours. Oral unithiol may also be considered as an alternative to oral succimer in the treatment of lead intoxication.
Unithiol has been reported to have a low overall incidence of adverse effects (< 4%). Self-limited dermatologic reactions (drug exanthems or urticaria) are the most commonly reported adverse effects, though isolated cases of major allergic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported. Because rapid intravenous infusion may cause vasodilation and hypotension, unithiol should be infused slowly over an interval of 15–20 minutes.
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.
Parenteral: Powder to reconstitute, 500 mg/vial
Dimercaprol (BAL in Oil)
Parenteral: 100 mg/mL for IM injection
Edetate calcium [calcium EDTA] (Calcium Dis odium Versenate)
Parenteral: 200 mg/mL for injection
Penicillamine (Cuprimine, Depen)
Oral: 125, 250 mg capsules; 250 mg tablets
Oral: 100 mg capsules
Bulk powder available for compounding as oral capsules, or for infusion (50 mg/mL).
PHARMACOTHERAPY IN THE STOMATHOLOGY PRACTICE
In the last years in our country the market of services of stomatologies develops stormily. Domestic specialists got access to modern technologies of treatment of diseases of stomatologies, which are used in the world. Appearance at the pharmaceutical market of new medications is predefined these.
The structure of lecture is formed after units of nosologies of basic diseases of stomatologies and exposition of principles of treatment, and basic medications which are used here.The science concerned with the diagnosis, prevention, and treatment of diseases of the teeth, gums, and related structures of the mouth and including the repair or replacement of defective teeth.
There are a number of different medications your dentist may prescribe, depending on your condition. Some medications are prescribed to fight certain oral diseases, to prevent or treat infections, or to control pain and relieve anxiety.
Here you will find a description of the most commonly used medications in dental care. The dose of the drugs and instructions on how to take them will differ from patient to patient, depending on what the drug is being used for, patient's age, weight and other considerations.
Even though your dentist will provide information to you about any medication he or she may give to you, make sure you fully understand the reasons for taking a medication and inform your dentist of any health conditions you may have.
Medications to Control Pain and Anxiety
Local anesthesia, general anesthesia, nitrous oxide or intravenous sedation is commonly used in dental procedures to help control pain and anxiety. Other pain-relievers include prescription or nonprescription anti-inflammatory medications, acetaminophen (Tylenol) and anesthetics.
Corticosteroids are anti-inflammatory medications that are used to relieve the discomfort and redness of mouth and gum problems. Corticosteroids are available by prescription only and are available as pastes under such brand names as Kenalog in Orabase, Orabase-HCA, Oracort, and Oralone.
Your dentist may recommend a nonprescription anti-inflammatory drug - such as Motrin -- to relieve mild pain and/or swelling caused by dental appliances, toothaches and fevers. Tylenol may also be given.
Note: Unless directed by your dentist, never give infants and children aspirin.
Dental anesthetics are used in the mouth to relieve pain or irritation caused by many conditions, including toothache, teething, and sores in or around the mouth (such as cold sores, canker sores, and fever blisters). Also, some of these medicines are used to relieve pain or irritation caused by dentures or other dental appliances, including braces.
Dental anesthetics (non-injectable)
Dental anesthetics should not be used if certain kinds of infections are present. Check package directions or check with a dentist or medical doctor if uncertain. Dental anesthetics should be used only for temporary pain relief. If problems such as toothache, mouth sores, or pain from dentures or braces continue, check with a dentist. Check with a doctor if sore throat pain is severe, lasts more than two days, or is accompanied by other symptoms such as fever, headache, skin rash, swelling, nausea, or vomiting. Patients should not eat or chew gum while the mouth is numb from a dental anesthetic. There is a risk of accidently biting the tongue or the inside of the mouth. Also nothing should be eaten or drunk for one hour after applying a dental anesthetic to the back of the mouth or throat, since the medicine may interfere with swallowing and may cause choking. If normal feeling does not return to the mouth within a few hours after receiving a dental anesthetic or if it is difficult to open the mouth, check with a dentist.
Oraqix is a new needle-free dental local anesthetic approved by the FDA for the use in adults who require localized anesthesia in periodontal pockets during scaling and/or root planning (SRP) procedures. Oraqix is an excellent choice for adult patients who require localized anesthesia during SRP procedures and may be fearful of needle-injected anesthesia.Oraqix, a mixture of lidocaine and prilocaine, is applied at room temperature using a blunt tip applicator to periodontal pockets as a liquid and transforms almost instantly into a stay-in-place gel at body temperature. Spillover numbness of the gums or tongue was not reported in Oraqix clinical trials. Oraqix has a quick 30-second onset action time. The two-step application, first on the gingival margin (exterior gum tissue) and then into the periodontal pocket itself, takes only a minute to fully anesthetize the area around either one tooth or an entire quadrant of the mouth. Oraqix is not for injection, and should only be used with the Oraqix Dispenser. The site-specific anesthetic property of Oraqix allows the general dentist, periodontist or dental hygienist to work on an individual tooth, a quadrant, or the whole mouth. Typically one cartridge (1.7g) or less of Oraqix will be sufficient for one quadrant of the dentition. The duration of effectiveness for each application is approximately twenty minutes and the maximum recommended dose at one treatment session is five cartridges. Clinical studies have demonstrated both the safety and efficacy of Oraqix. In clinical trials, the most common side effects of Oraqix were application site reaction, headache and taste perversion. Oraqix is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to any other component of the product.
Now a leading Topical Anesthetic used by Dental Professionals is available to the consumer. Our 20% Benzocaine Topical Anesthetic is a fast acting formula developed for the relief of pain associated with Toothaches, Canker Sores, Denture Pain and Sore Gums. Available in 3 pleasant flavors and in economical tubes or convenient sachets
Anesthetics are available either by prescription or over-the-counter and come in many dosage forms including aerosol spray, dental paste, gel, lozenges, ointments, and solutions. Dental anesthetics are contained in such brand name products as Anbesol, Chloraseptic, Orajel, and Xylocaine.
Medications to Control Plaque and Gingivitis
Chlorhexidine is an antibiotic used to control plaque and gingivitis in the mouth or in periodontal pockets (the space between your gum and tooth). The medication is available as a mouth rinse and as a gelatin-filled chip that is placed in the deep gum pockets next to your teeth after root planing. The medication in the gelatin-filled chip is released slowly over about 7 days. Dental products containing this antibacterial are marketed under various prescription-only brand names, such as Peridex, PerioChip, and PerioGard, as well as other over-the-counter trade names.
Bacteria & plaque cause the gums to become inflamed and bleed easily.
Plaque gets into the space between the gum the tooth, but there's still time to prevent the gum from detaching and forming "pockets". Professional cleaning good home care are usually enough to restore healthy gums, with no permanent damage.
Your dentist may recommend the use of an over-the-counter antiseptic mouth rinse product to reduce plaque and gingivitis and kill the germs that cause bad breath.
Most commonly used are ethanol (60-90%), 1-propanol (60-70%) and 2-propanol/isopropanol (70-80%) or mixtures of these alcohols. They are commonly referred to as "surgical alcohol". Used to disinfect the skin before injections are given, often along with iodine (tincture of iodine) or some cationic surfactants (benzalkonium
Also known as Quats or QAC's, include the chemicals benzalkonium chloride (BAC), cetyl trimethylammonium bromide (CTMB), cetylpyridinium chloride (Cetrim), cetylpyridinium chloride (CPC) and benzethonium chloride (BZT). Benzalkonium chloride is used in some pre-operative skin disinfectants (conc. 0.05 - 0.5%) and antiseptic towels. The antimicrobial activity of Quats is inactivated by anionic surfactants, such as soaps. Related disinfectants include chlorhexidine and octenidine.
A biguanidine derivative, used in concentrations of 0.5 - 4.0% alone or in lower concentrations in combination with other compounds, such as alcohols. Used as a skin antiseptic and to treat inflammation of the gums (gingivitis). The microbicidal action is somewhat slow, but remanent. It is a cationic surfactant, similar to Quats.
Used as a 6% (20Vols) solution to clean and deodorize wounds and ulcers. More common 1% or 2% solutions of hydrogen peroxide have been used in household first aid for scrapes, etc. However, even this less potent form is no longer recommended for typical wound care as the strong oxidization causes scar formation and increases healing time. Gentle washing with mild soap and water or rinsing a scrape with sterile saline is a better practice.
Usually used in an alcoholic solution (called tincture of iodine) or as Lugol's iodine solution as a pre and post-operative antiseptic. No longer recommended to disinfect minor wounds because it induces scar tissue formation and increases healing time. Gentle washing with mild soap and water or rinsing a scrape with sterile saline is a better practice. Novel iodine antiseptics containing povidone-iodine (an iodophor, complex of povidone, a water-soluble polymer, with triiodide anions I3-, containing about 10% of active iodine) are far better tolerated, don't affect wound healing negativelly and leave a depot of active iodine, creating the so-called "remanent," or persistent, effect. The great advantage of iodine antiseptics is the widest scope of antimicrobial activity, killing all principial pathogenes and given enough time even spores, which are considered to be the most difficult form of microorganisms to be inactivated by disinfectants and antiseptics.
A cationic surfactant and bis-(dihydropyridinyl)-decane derivative, used in concentrations of 0.1 - 2.0%. It is similar in its action to the Quats, but is of somewhat broader spectrum of activity. Octenidine is currently increasingly used in continental Europe as a QAC's and chlorhexidine (with respect to its slow action and concerns about the carcinogenic impurity 4-chloroaniline) substitute in water- or alcohol-based skin, mucosa and wound antiseptic. In aqueous formulations, it is often potentiated with addition of 2-phenoxyethanol.
Phenol is germicidal in strong solution, inhibitory in weaker ones. Used as a "scrub" for pre-operative hand cleansing. Used in the form of a powder as an antiseptic baby powder, where it is dusted onto the navel as it heals. Also used in mouthwashes and throat lozenges, where it has a painkilling effect as well as an antiseptic one. Example: TCP. Other phenolic antiseptics include historically important, but today rarely used (sometimes in dental surgery) thymol, today obsolete hexachlorophene, still used triclosan and sodium 3,5-dibromo-4-hydroxybenzenesulfonate (Dibromol).
It's a gum disease that includes gingivitis as well as periodontitis. Periodontal disease is an advanced bacterial infection affecting both the gums and the bone which support your teeth. Left untreated, it often leads to tooth loss.
-- times of hormonal changes such as pregnancy, puberty, menstruation
-- stress, which limits the body's ability to fight off infections
-- certain drugs and medications which can affect your overall health
-- smoking is another factor negatively affecting the health of your gums
-- pressure on supporting tissues from grinding or clenching your teeth
-- diabetes, a condition which carries more risk for developing infections
-- poor nutrition makes it harder for the immune system to fight off infection
Since periodontal disease attacks below the gum line, you probably won't experience any noticeable symptoms at first. With gingivitis, a mild form of periodontal disease, the gums redden, become swollen & sensitive, plus they bleed easily when brushed. Without treatment, gingivitis can advance to periodontitis where more serious symptoms manifest with:
toxic bacteria producing bad breath
-- progressive and destructive infection
-- degeneration of supportive tissues and bone
-- gums receding from teeth forming deep pockets around them
-- loosening and/or shifting of the teeth
-- eventual extraction and tooth loss
If you're a smoker, quit immediately. There are numerous studies concluding that smoking substantially increases your risks of gum disease and subsequent tooth loss. The next best preventative measure to avoid gum disease would be daily brushing and flossing to remove the build-up of plague or tartar, a sticky, colorless film which forms on your teeth.
Personal daily cleaning will help minimize the danger, however, keep in mind that only regular visits to your dentist for a thorough cleaning and examination two times a year will prevent gum disease before it begins.
Tetracyclines (the class of drugs including demeclocycline, doxycycline, minocycline, oxytetracycline and tetracycline) and the drug triclosan (marketed as Irgasan DP300) are also used in dentistry. These medications may be used either in combination with surgery and other therapies, or alone, to reduce or temporarily eliminate bacteria associated with periodontal disease, to suppress the destruction of the tooth's attachment to the bone or to reduce the pain and irritation of canker sores.
Doxycycline (dox-i-SYE-kleen) periodontal system contains the antibiotic doxycycline and is used to help treat periodontal disease (a disease of your gums), which is caused by bacteria growing beneath the gum line. Doxycycline works by preventing the growth of the bacteria. Doxycycline periodontal system is placed in deep gum pockets next to your teeth in order to reduce the depth of the pockets.
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.
It is still true that the chemical structures and even the existence of receptors for most clinically useful drugs can only be inferred from the chemical structures of the drugs themselves. By noting which chemical groups are required for specific pharmacologic effects of chemical congeners of a drug, pharmacologists imagine the complementary shape and distribution of electrical charge of the receptor site. In recent years, however, investigators have begun to characterize drug receptors in biochemical terms. Most of these receptors turn out to be proteins, presumably because the polypeptide structure provides the necessary diversity and specificity of shape and charge.
The best-characterized drug receptors are regulatory proteins, which mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids, and hormones. This class of receptors mediates effects of many of the most useful therapeutic agents, which either mimic actions of endogenous agonists or, acting as antagonists, prevent responses to endogenous chemical signals. Although the physiologist or endocrinologist may think of these regulatory proteins as the only class of receptors, virtually any kind of protein molecule may serve as a receptor for a drug. Other classes of proteins that have been clearly
identified as drug receptors include enzymes, which may be inhibited (or, less commonly, activated) by binding a drug (eg, dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate); transport proteins (eg, Na+K+-ATPase, the membrane receptor for cardioactive digitalis glycosides); and structural proteins (eg, tubulin, the receptor for colchicine, an anti-inflammatory agent).
Of the membrane-bound proteins that serve as receptors for neurohormones and drugs, the nicotinic cholinergic receptor is the best-characterized. This receptor is a pentamer composed of 5 peptide subunits. All 5 peptides span the membrane's lipid bilayer, but only one or 2 peptides bind acetylcholine, the neurotransmitter. The binding of acetylcholine triggers opening of a transmembrane channel or pore through which sodium ions penetrate from the extracellular fluid into the cell, an event that initiates an excitatory postsynaptic potential in the nerve or muscle cells that are targets for nicotinic stimulation. The function of the remaining subunits of the nicotinic receptor is the subject of intensive investigation. These subunits somehow transduce the binding of a cholinergic ligand into opening the ion channel and probably constitute the channel itself. Thus, the nicotinic receptor, a single oligomeric protein molecule, performs 2 distinct functions as a receptor: 1) specific recognition of a drug or regulatory ligand (binding of acetylcholine), and 2) initiation of a biochemical event (opening of the sodium channel) that leads to the characteristic response of the cell (an excitatory postsynaptic potential).
The relation between dose of a drug and the clinically observed response may be quite complex. In carefully controlled in vitro systems, however, the relation between concentration of a drug and its effect is often simple and can be described with mathematical precision. We will analyze this simple, idealized relation first because it underlies virtually all of the more complex relations between dose and effect that occur when drugs are given to patients.
Even in intact animals or patients, responses to low doses of a drug usually increase in direct proportion to dose. As doses increase, however, the incremental response diminishes; finally, doses may be reached at which no further increase in response can be achieved. In idealized or in vitro systems, the relation between drug concentration and effect is described by a hyperbolic curve.
Based on the maximal pharmacologic response that occurs when all receptors are occupied, agonists can be divided into 2 classes: Partial agonists produce a lower maximal response, at full receptor occupancy, than do full agonists. As compared to full agonists, partial agonists produce concentration-effect curves that resemble curves observed with full agonists in the presence of a noncompetitive antagonist that irreversibly blocks receptor sites. Nonetheless, radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites at concentrations that will fail to produce a maximal response comparable to that seen with full agonists. In addition, the failure of partial agonists to produce a "full" maximal response is not due to decreased affinity for binding to receptors. Such drugs compete, frequently with high affinity, for the full complement of receptors. Indeed, the partial agonists' ability to occupy the total receptor population is indicated by the fact that partial agonists competitively inhibit the responses produced by full agonists.
The precise molecular mechanism that accounts for blunted maximal responses to partial agonists is not known. It is simplest to imagine that the partial agonist produces an effect on receptors that is intermediate between the effect produced by a full agonist and that produced by a competitive antagonist. The full agonist changes receptor conformation in a way that initiates subsequent* pharmacologic effects of receptor occupancy, while the "pure" competitive antagonist produces no such change in receptor conformation; in this view, the partial agonist changes receptor conformation, but not to the extent necessary to result in full efficacy of the occupied receptor.
To express this idea, pharmacologists refer to the efficacy (or ''maximal efficacy") of a drug as a way of indicating the relation between pharmacologic response and occupancy of receptor sites. Efficacy for a full agonist is considered to be 1.0, while the efficacy of a pure antagonist is zero. Partial agonists have efficacious between zero and 1.0. Many drugs used as competitive antagonists are in fact weak partial agonists.
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.
In general, use of a drug as a physiologic antagonist produces effects that are less specific and less easy to control than are the effects of a receptor-specific antagonist. Thus, for example, to treat bradycardia caused by increased vagal tone associated with the acute pain of a myocardial infarction, the physician could use isoproterenol, a beta-adrenergic agonist that increases heart rate by mimicking sympathetic stimulation of the heart. However, use of this physiologic antagonist would be less rational—and potentially more dangerous—than would use of a receptor-specific antagonist such as atropine (a competitive antagonist at the muscarinic receptors through which vagal stimuli slow heart rate).
The existence of a specific drug receptor is usually inferred from studying the structure-activity relationship of a group of structurally similar congeners of the drug that mimic or antagonize its effects.
Evidence that a particular drug acts via 2 or more distinct receptors usually presents an important therapeutic opportunity, because it suggests the possibility of developing new drugs that will exhibit enhanced selectivity for one receptor over the other. Such opportunities have been extensively exploited with the receptors for histamine, acetylcholine, and norepineph-rine. Thus, for example, beta-adrenergic antagonists can block cardioacceleration produced by norepinephrine without preventing catecholamine regulation of arteriolar constriction, which is mediated by alpha-adrenergic receptors. Similarly, alpha-adrenergic agonists can induce vasoconstriction without stimulating beta receptors in the heart.
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.
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:
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.Variation in concentration of an endogenous receptor ligand.
This mechanism contributes greatly to variability in responses to pharmacologic antagonists. Thus, propranolol, a beta-adrenergic antagonist, will markedly slow the heart rate of a patient whose endogenous catecholamines are elevated (as in heart failure or pheochromocytoma) but will not affect the resting heart rate of a well-trained marathon runner. A partial agonist may exhibit even more dramatically different responses: Saralasin, a weak partial agonist at angiotensin II receptors, lowers blood pressure in patients with hypertension caused by increased angiotensin II production and raises blood pressure in patients who produce low amounts of angiotensin.
In assessing clinical response to antagonist drugs, the physician must always make a judgment about the probable stimulation of receptors by endogenous agonists. Thus, unsatisfactory response to a dose of a competitive antagonist might be due to greatly elevated endogenous agonist, and a larger dose of antagonist would be appropriate. Alternatively, the unsatisfactory response might be due to low rates of stimulation by agonist; this would suggest that the diagnosis is wrong and that a different mode of therapy, rather than more drug, is indicated.
Experimental studies have documented changes in drug responsiveness caused by increases or decreases in the number of receptor sites or by alterations in the efficiency of coupling of receptors to distal effector mechanisms. Although such changes have not been rigorously documented in human beings, it is likely that they account for much of the individual variability in response to some drugs, particularly those that act at receptors for hormones, biogenic amines, and neurotransmitters. In some cases, the change in receptor number is caused by other hormones; for example, thyroid hormones increase both the number of beta-adrenergic receptors in rat heart muscle and the cardiac sensitivity to catecholamines. Similar changes probably contribute to the tachycardia of thyrotoxicosis in patients and may account for the usefulness of propranolol, a beta-adrenergic antagonist, in ameliorating symptoms of this disease.
In other cases, the agonist ligand itself induces a decrease in the number ("down regulation") or coupling efficiency of its receptors. Receptor-specific de-sensitization mechanisms presumably act physiologically to allow cells to adapt to changes in rates of stimulation by hormones and neurotransmitters in their environment. These mechanisms may contribute to tachyphylaxis or tolerance to the effects of some drugs, particularly the biogenic amines and their congeners. Recent investigations suggest, in addition, that similar adaptive mechanisms may be responsible for so-called "overshoot" phenomena that follow withdrawal of certain drugs (propranolol, opiates, some antihypertensive agents, etc). Thus, for example, an antagonist may actually raise the number of receptors in a cell by preventing down regulation caused by endogenous agonist; when the antagonist is withdrawn, the elevated receptor number allows an exaggerated response to physiologic concentrations of agonist.
Therapeutic strategies required to deal with receptor-specific changes in drug responsiveness vary according to the clinical situation. In some cases, the dose of an agonist must be increased to achieve a continuing satisfactory response, while in other cases different or additional drugs should be administered. Cessation of treatment with certain drugs should be gradual and carefully monitored.
Although a drug initiates its actions by binding to receptors, the response observed in a patient depends on the functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ systems. Clinically, changes in these postreceptor processes represent the largest and most important class of mechanisms that cause variation in responsiveness to drug therapy.
Before initiating therapy with a drug, the physician should be aware of patient characteristics that may limit the clinical response. These characteristics include the age, sex, and general health of the patient and—most importantly—the severity and pathophysiologic mechanism of the disease. Once treatment is begun, the most important potential cause of failure to achieve a satisfactory response is that the diagnosis is wrong or physiologically incomplete. Thus, congestive heart failure will not respond satisfactorily to agents that increase myocardial contractility if the underlying pathologic mechanism is unrecognized stenosis of the mitral valve rather than myocardial insufficiency. Conversely, drug therapy will always be most successful when it is accurately directed at the pathophysiologic mechanism responsible for the disease.
When the diagnosis is correct and the drug is appropriate, treatment may still not produce an optimal result. An unsatisfactory therapeutic response can often be traced to compensatory mechanisms in the patient that respond to and oppose the beneficial effects of the drug. Compensatory increases in sympathetic nervous tone and fluid retention by the kidney, for example, can contribute to tolerance to antihy-pertensive effects of a vasodilator drug. In such cases, additional drugs may be required to achieve a useful therapeutic response.
Although we classify drugs according to their principal actions, it is clear that no drug causes only a single, specific effect. Why is this so? It is exceedingly unlikely that any kind of drug molecule will bind to only a single molecular species of receptor, if only because the number of potential receptors in a patient is astronomically large. (Consider that the human genome codes for approximately 104 different peptide gene products and that the chemical complexity of each of these peptides is sufficient to provide many different potential binding sites.) Even if the chemical structure of a drug allowed it to bind to only one kind of receptor, the biochemical processes controlled by such receptors would take place in multiple cell types and would be coupled to many other biochemical functions; as a result, the patient and the physician would probably perceive more than one drug effect.
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.
Beneficial and toxic effects mediated by the same receptor-effector mechanism. Much of the serious drug toxicity in clinical practice represents a direct pharmacologic extension of the therapeutic actions of the drug. In some of these cases (bleeding caused by anticoagulant therapy; hypoglycemic coma due to insulin), toxicity may be avoided by judicious management of the dose of drug administered, guided by careful monitoring of effect (measurements of blood coagulation or serum glucose) and aided by ancillary measures (avoiding tissue trauma that may lead to hemorrhage; regulation of carbohydrate intake). In still other cases, the toxicity may be avoided by not administering the drug at all, if the therapeutic indication is weak or if other therapy is available (eg, sedative-hypnotics ordinarily should not be used to treat patients whose complaints of insomnia are due to underlying mental depression).
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.
Examples of drugs in this category include digitalis glycosides, which may be used to augment cardiac contractility but also produce cardiac arrhythmias, gastrointestinal effects, and changes in vision (all probably mediated by inhibition of Na+K+-ATPase in cell membranes); methotrexate, used to treat leukemia and other neoplastic diseases, which also kills normal cells in bone marrow and gastrointestinal mucosa (all mediated by inhibition of the enzyme dihydrofolate reductase); and congeners of glucocorticoid hormones, used to treat asthma or inflammatory disorders, which also can produce protein catabolism, psychosis, and other toxicities (all thought to be mediated by similar or identical glucocorticoid receptors). In addition to these and other well-documented examples, it is likely that "side effects" of many drugs are mediated by receptors identical to those that produce the recognized beneficial effect.
Three therapeutic strategies are used to avoid or mitigate this sort of toxicity. First, the drug should always be administered at the lowest dose that produces acceptable benefit, recognizing that complete abolition of signs or symptoms of the disease may not be achieved. Second (as described above for guanethidine), adjunctive drugs that act through different receptor mechanisms and produce different toxicity’s may allow lowering the dose of the first drug, thus limiting its toxicity (eg, use of other immunosuppressive agents added to glucocorticoids in treating inflammatory disorders). Third, selectivity of the drug's actions may be increased by manipulating the concentrations of drug available to receptors in different parts of the body. Such "anatomic" selectivity may be achieved, for example, by aerosol administration of a glucocorticoid to bronchi or by selective arterial infusion of an antimetabolite into an organ containing tumor cells.
Beneficial and toxic effects mediated by different types of receptors: Therapeutic advantages resulting from new chemical entities with improved receptor selectivity were mentioned earlier in this chapter and are described in detail in later chapters. Such drugs include the alpha- and beta-adrenergic agonists and antagonists, the H1 and H2 antihistamines, nicotinic and muscarinic blocking agents, and receptor-selective steroid hormones. All of these receptors are grouped in functional families, each responsive to a small class of endogenous agonists. The receptors—and their associated therapeutic uses— were discovered by analyzing effects of the physiologic chemical signals—catehecholamines, histamine, acetylcholine, and corticosteroids.
A number of other drugs were discovered in a similar way, although they may not act at receptors for known hormones or neurotransmitters. These drugs were discovered by exploiting toxic or side effects of other agents, observed in a different clinical context. Examples include quinidine, the sulfonylureas, thiazide diuretics, tricyclic antidepressants, monoamine oxidase inhibitors, and phenothiazine antipsychotics among many others.
It is likely that some of these drugs will eventually be shown to act via receptors for endogenous agonists, as was recently established for morphine, a potent analgesic agent. Morphine has been shown to act on receptors physiologically stimulated by the opioid peptides. Pharmacologists now subclassify the opioid receptors, in a fashion reminiscent of earlier studies of adrenergic and cholinergic reactions.
Thus, the propensity of drugs to bind to different classes of receptor sites is not only a potentially vexing problem in treating patients – it also presents a continuing challenge to pharmacology and an opportunity for developing new and more useful drugs.
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 3 L, blood volume about 5.5 L, extracellular fluid outside plasma 12 L, and total body water about 42 L. However, many drugs exhibit volumes of distribution, according to equation, far in excess of these known body fluid volumes. For example, digoxin, which is relatively hydrophobic, is distributed into muscle and adipose tissue, leaving a very small amount of drug in the plasma. Volume of distribution can change as a function of several variables, including the patient's age, sex, and disease. For example, the same 500 /zg of digoxin in a middle-aged patient with congestive heart failure might yield a concentration of 1 ng/mL, corresponding to a 500-L volume of distribution.
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.
Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route. For an intravenous dose of the drug, bioavailability is equal to unity. For a drug administered orally, bioavailability may be less than unity for several reasons. The drug may be incompletely absorbed. It may be metabolized in the gut, the gut wall, the portal blood, or the liver prior to entry into the systemic circulation. It may undergo enterohepatic cycling with incomplete reabsorption following elimination into the bile. Biotransformation of some drugs in the liver following oral administration is an important factor in the pharmacokinetic profile, as discussed below.
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 in nonlinear 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.
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 "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.
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.
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.
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.
Humans are daily exposed to a wide variety of foreign compounds called xenobiotics—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 in nature. 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.
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.
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.
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.
Parent drugs or their phase I metabolites that contain suitable chemical groups often undergo coupling or conjugation reactions with an endogenous substance to yield drug conjugates (table 1). In general, conjugates are polar molecules that are readily excreted and often inactive. Conjugate formation involves high-energy intermediates and specific transfer enzymes. Such enzymes (transferases) may be located in microsomes or in the cytosol. They catalyze the coupling of an activated endogenous substance (such as the uridine 5'-diphosphate [UDP] derivative of glucuronic acid) with a drug (or endogenous compound), or of an activated drug (such as the S-CoA derivative of benzoic acid) with an endogenous substrate. Because the endogenous substrates originate in the diet, nutrition plays a critical role in the regulation of drug conjugations.
Drug conjugations were once believed to represent terminal inactivation events and as such have been viewed as "true detoxification" reactions. However, this concept must be modified, since it is now known that certain conjugation reactions (0-sulfation of N-hydroxyacetylaminofluorene and N-acetylation of isoniazid) may lead to the formation of reactive species responsible for the hepatotoxicity of the drug.
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 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 than nonexposed individuals. Such differences make it difficult to determine effective and safe doses of drugs that have narrow therapeutic indices.
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.
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.
Many substrates, by virtue of their relatively high lipophilicity, are retained not only at the active site of the enzyme but remain nonspecifically 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 (see table 2). 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 (table 3). 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.
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.
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 in normal 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.
Metabolism of drugs and other foreign chemicals may not always be an innocuous biochemical event leading to detoxification and elimination of the compound. Indeed, several compounds have been shown to be metabolically transformed to reactive intermediates that are toxic to various organs. Such toxic reactions may not be apparent at low levels of exposure to parent compounds when alternative detoxification mechanisms are not yet overwhelmed or compromised and the availability of endogenous detoxifying cosubstrates (glutathione, glucuronic acid, sulfate) is not limited. However, when these possibilities are exhausted, the toxic pathway may prevail resulting in overt organ toxicity or carcinogenesis. The number of specific examples of such drug-induced toxicity is expanding rapidly. An example is acetaminophen (paracetamol-induced hepatotoxicity. This analgesic antipyretic drug is quite safe in therapeutic doses (1.2 g/daily). It normally undergoes glucuronidation and sulfation to the corresponding conjugates, which together comprise 95% of the total excreted metabo-lites. The alternative cytochrome P-450-dependent glutathione (GSH) conjugation pathway accounts for the remaining 5%. When acetaminophen intake far exceeds therapeutic doses, the glueuronidation and sulfation pathways are saturated, and the cytochrome P-450-dependent pathway becomes increasingly important. Little or no hepatotoxicity results as long as glutathione is available for conjugation. However, with time, hepatic glutathione is depleted faster than it can be regenerated, and accumulation of a reactive and toxic metabolite occurs. In the absence of intracellular nucleophiles such as glutathione, this reactive metabolite (thought to be an N-hydroxylated product or an N-acetylbenzoiminoquinone) reacts with nucleophilic groups present on cellular macro-molecules such as protein, resulting in hepatotoxicity.
The chemical and toxicologic characterization of the electrophilic nature of the reactive acetaminophen metabolite has led to the development of effective antidotes—cysteamine and acetylcysteine (Mucomyst). Administration of acetylcysteine (the safer of the 2) within 24 hours following acetaminophen over-dosage has been shown to protect victims from fulminant hepatotoxicity and death.
Similar mechanistic interpretations can be invoked to explain the nephrotoxicity of phenacetin and the hepatotoxicity of aflatoxin and of benzo(a)pyrene, a pyrolytic product of organic matter present in cigarette tar and smoke and in smoked foods.