Subtypes of Nicotinic Acetylcholine Receptors

The nicotinic ACh receptors (nAChRs) are members of a superfamily of ligand-gated ion channels. The receptors exist at the skeletal neuromuscular junction, autonomic ganglia, adrenal medulla and in the CNS. They are the natural targets for ACh as well as pharmacologically administered drugs, including nicotine. The receptor forms a pentameric structure consisting of homomeric a and b subunits. In humans, 8 a subunits (a2 through a7, a9, and a10) and three b subunits (b2 through b4) have been...

Opioid Analgesics

The term opioid refers broadly to all compounds related to opium, a natural product derived from the poppy. Opiates are drugs derived from opium and include the natural products morphine, codeine, and thebaine, and many semisynthetic derivatives. Endogenous opioid peptides, or endorphins, are the naturally occurring ligands for opioid receptors. Opiates exert their effects by mimicking these peptides. The term narcotic is derived from the Greek word for stupor it originally referred to any drug...

Gefitinib

The EGFR belongs to the ERB family of receptor tyrosine kinases. The EGFR type 1 (ErbBl or HER1) is overexpressed in many common malignancies, and may be activated by autocrine loops in many others. A truncated version of the EGFR (EGFRvIII) that has lost a portion of the extracellular ligand-binding domain and is constitutively activated is found in a subset of patients with glioblastoma. Gefitinib (iressa quinazoline) was discovered by screening a library for compounds that inhibited EGFR...

Info

METROGEL (metronidazole), 1083 Metronidazole 687-688 for acne vulgaris, 1083 adverse effects, 688 for amebiasis, 681, 688 antimicrobial effects, 687 antiparasitic effects, 687 for bacterial infections, 688 chemistry, 687 contraindications, 689 for Crohn's disease, 659 for H. pylori infection, 631 interactions, 688 mechanisms of action, 687 resistance to, 631, 687 therapeutic uses, 688 for trichomoniasis, 681, 688 METVIX (5-Aminolevulinic acid), 1082 Metyrosine, 172, 553 mevacor (lovastatin),...

Chemotherapy Of Leprosy

Leprosy is a continuum between two extremes. At one end of the spectrum is tuberculoid leprosy, characterized by skin macules with clear centers and well-defined margins. M. leprae is rarely found in smears made from quiescent lesions but may appear during activity. Noncaseating foci are present. The patient's cell-mediated immunity is normal, and a skin test for infection by leprosy is invariably positive. The disease is characterized by prolonged remissions with periodic reactivation. The...

Classification Of Sympathomimetic Drugs

Catecholamines and sympathomimetic drugs are classified as direct, indirect, or mixed acting. Direct-acting agents act directly on one or more of the adrenergic receptors. Indirect-acting drugs increase the availability of norepinephrine (NE) or epinephrine (Epi) to stimulate adrenergic receptors (by releasing or displacing NE from sympathetic nerve varicosities e.g., amphetamine by blocking the transport of NE into sympathetic neurons e.g., cocaine or by blocking the metabolizing enzymes, MAO...

Cardiac Glycosides

Pharmacological Effects Cardiac glycosides exert positive inotropic effects and thus are also used in heart failure (see Chapter 33). Their inotropic action results from increased intracellular Ca2+, which also forms the basis for arrhythmias related to cardiac glycoside intoxication. Cardiac glycosides increase phase 4 slope (i.e., increase the rate of automaticity), especially if K o is low. They also exert prominent vagotonic actions, resulting in inhibition of Ca2+ currents in the AV node...

Receptor Properties

Biochemical techniques and molecular cloning studies have revealed two major motifs and one minor motif of transmitter receptors. The first, oligomeric ion channel receptors, are composed of multiple subunits, usually with four transmembrane domains (Figure 12-3). The ion channel receptors (ionotropic receptors or IRs) for neurotransmitters contain sites for reversible phosphorylation by protein kinases and phosphoprotein phosphatases and for voltage gating. Receptors with this structure...

Eicosanoid Catabolism

Most eicosanoids are efficiently and rapidly inactivated. About 95 of infused PGE2 (but not PGI)) is inactivated during one passage through the pulmonary circulation. Broadly speaking, the enzymatic catabolic reactions are of two types a relatively rapid initial step, catalyzed by widely distributed prostaglandin-specific enzymes, wherein prostaglandins lose most of their biological activity and a second step in which these metabolites are oxidized, probably by enzymes identical to those...

Terconazole

Its mechanism of action is similar to that of the imidazoles. The 80-mg vaginal suppository is inserted at bedtime for 3 days, while the 0.4 vaginal cream is used for 7 days and the 0.8 cream for 3 days. Clinical efficacy and patient acceptance of both preparations are at least as good as for clotrimazole in patients with vaginal candidiasis. Butoconazole, an imidazole, is pharmacologically quite comparable to clotrimazole. Butoconazole nitrate (mycelex 3, others) is available as a 2 vaginal...

Thrombopoietic Growth Factors

Interleukin-11 Interleukin-11 is a 23 kDa cytokine that stimulates hematopoiesis, intestinal epithelial cell growth, and osteoclastogenesis and inhibits adipogenesis. IL-11 enhances megakaryocyte maturation. Recombinant human interleukin-11 oprelvekin (neumega) is a bacterially derived, 19 kDa polypeptide that lacks the amino terminal Pro residue and is not glycosylated. The recombinant protein has a 7-hour t1 2 after subcutaneous injection. In normal subjects, daily administration of...

Inhibitors Of The Biosynthesis And Action Of Adrenocortical Steroids

Four pharmacologic agents are useful inhibitors of adrenocortical secretion. Mitotane (o,p'-DDD), an adrenocorticolytic agent, is discussed in Chapter 51. The other inhibitors of steroid hormone biosynthesis are aminoglutethimide, ketoconazole, and trilostane. Aminoglutethimide and ketoconazole are discussed below. Trilostane is a competitive inhibitor of the conversion of pregnenolone to progesterone, a reaction catalyzed by 3(3-hydroxysteroid dehydrogenase. All of these agents pose the common...

Neurotransmission The Autonomic And Somatic Motor Nervous Systems

The autonomic nervous system (ANS) is the primary moment-to-moment regulator of the internal environment of the organism, regulating specific functions that occur without conscious control, for example, respiration, circulation, digestion, body temperature, metabolism, sweating, and the secretions of certain endocrine glands. The endocrine system, in contrast, provides slower, more generalized regulation by secreting hormones into the systemic circulation to act at distant, widespread sites...

Clotrimazole

Absorption of clotrimazole is < 0.5 after application to intact skin from the vagina, it is 3-10 . Fungicidal concentrations remain in the vagina for up to 3 days after drug application. The small amount absorbed is metabolized in the liver and excreted in bile. Cutaneous clotrimazole occasionally may cause stinging, erythema, edema, vesication, desquamation, pruritus, and urticaria. When it is applied to the vagina, 1.6 of recipients complain of a mild burning sensation, and rarely of lower...

Chloramphenicol

FIGURE 46-2 Inhibition of bacterial protein synthesis by chloramphenicol. Chloramphenicol binds to the 50S ribo-somal subunit at the peptidyltransferase site and inhibits the transpeptidation reaction. Chloramphenicol binds to the 50S ribosomal subunit near the site of action of clindamycin and the macrolide antibiotics. These agents interfere with the binding of chloramphenicol and thus may interfere with each other's actions if given concurrently. See Figure 46-1 and its legend for additional...

Agents Affecting Mineral Ion Homeostasis And Bone Turnover

PHYSIOLOGY OF MINERAL HOMEOSTASIS AND BONE METABOLISM Calcium Adult men and women possess about 1300 g and 1000 g of calcium respectively, more than 99 of which is in bone and teeth. Although the absolute amount of calcium in the extracellular fluid is small, this fraction is stringently regulated. Normal serum calcium ranges from 8.5 to 10.4 mg dL (4.25-5.2 mEq L, 2.1-2.6 mM) and includes three components ionized ( 50 ), protein-bound ( 40 , predominantly to albumin a decrease in albumin of...

Transporters Involved In Pharmacodynamics Drug Action In The Brain

Neurotransmitters are packaged in vesicles in presynaptic neurons, released in the synapse by vesicle fusion with the plasma membrane, and except for acetylcholine are then taken back into the presynaptic neurons or postsynaptic cells (see Chapter 6). Transporters involved in the neuronal FIGURE 2-8 Model of organic anion secretory transporters in the proximal tubule. Rectangles depict transporters in the SLC22 family, OAT1 (SLC22A6) and OAT3 (SLC22A8), and hexagons depict transporters in the...

Alkyl Sulfonates

Busulfan Busulfan exerts few pharmacological actions other than myelosuppression at conventional doses and often was used in the chronic phase of chronic myelogenous leukemia (CML) to suppress granulocyte counts. In some patients, a severe and prolonged pancytopenia resulted. In high-dose regimens, pulmonary fibrosis, GI mucosal damage, and VOD of the liver become important. Busulfan is well absorbed after oral administration in doses of 2-6 mg day, and has a plasma t1 2 of 2-3 hours. The drug...

Side Effects

Cardiovascular System Although N2O produces a negative inotropic effect on heart muscle in vitro, depressant effects on cardiac function generally are not observed in patients because of the stimulatory effects of nitrous oxide on the sympathetic nervous system. When N2O is coadministered with halogenated inhalational anesthetics, it generally produces an increase in heart rate, arterial blood pressure, and cardiac output. In contrast, when N2O is coadministered with an opioid, it generally...

Quinolones

The quinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin) inhibit MAC bacteria in vitro. M. fortuitum and M. kansasii also are sensitive to these quinolones but M. chelonae usually are resistant. Single-agent therapy of M. fortuitum infection with ciprofloxacin has led to resistance. Ciprofloxacin, 750 mg twice daily or 500 mg three times daily, has been used in a 4-drug regimen (with clarithromycin, rifabutin, and amikacin) as salvage therapy for MAC infections in...

Avoiding Confusion

Units of measure can lead to confusion and medication errors. Older systems of measure such as minims for volume (15 minims 1 mL) and grains for weight (1 grain 60 mg) are obscure and should not be used. Doses always should be listed by metric weight of active ingredient doses for liquid medications should include the volume. Writing 'Vg for micrograms can very easily be misinterpreted as milligrams (mg). Thus, if abbreviated, micrograms should be written mcg and milligrams as mg a zero should...

Saturable Elimination

All active processes are undoubtedly saturable, but they will appear to be linear if values of drug concentrations encountered in practice are much less than Km. When drug concentrations exceed Km nonlinear kinetics are observed. The major consequences of saturation of metabolism or transport are the opposite of those for saturation of protein binding. Saturation of metabolism or transport may decrease CL. Saturable metabolism causes oral first-pass metabolism to be less than expected (higher...

Antineoplastic Agents

Few categories of medication have a narrower therapeutic index and a greater potential for causing harmful side effects than do the antineoplastic drugs. A thorough understanding of their pharmacology, drug interactions, and clinical pharmacokinetics is essential for safe and effective use. The diversity of agents used to treat neoplastic disease is summarized in Table 51-1. Figure 51-1 shows some of the common targets for chemotherapeutic agents currently used to treat neoplastic disease. In...

Gaba

FIGURE 20-5 Schematic wiring diagram of the basal ganglia. The striatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of cerebral cortex. The striatum contains projection neurons expressing predominantly Dx or D2 dopamine receptors, as well as interneurons that use acetylcholine (ACh) as a neurotransmitter. Outflow from the striatum proceeds along two routes. The direct pathway, from the striatum to the substantia nigra pars...

Principles And Guidelines For Prophylaxis And Chemotherapy Of Malaria

Pharmacological control of malaria poses a difficult challenge because P. falciparum, which causes nearly all the deaths from human malaria, has become progressively more resistant to available antimalarial drugs. Fortunately, chloroquine still is effective against malarias caused by P. ovale, P. malariae, most strains of P. vivax, and chloroquine-sensitive strains of P. falciparum found in some geographic areas. However, chloroquine-resistant strains of P. falciparum now prevail in most...

Enteric Nervous System

The activities of the GI tract are controlled locally through a restricted part of the peripheral nervous system called the enteric nervous system (ENS). The ENS is involved in sensorimotor control and consists of both afferent sensory neurons and a number of motor nerves and interneurons that are organized principally into two nerve plexuses the myenteric (Auerbach's) plexus and the submucosal (Meissner's) plexus. The myenteric plexus, located between the longitudinal and circular muscle...

Atovaquone

Atovaquone (mepron) has potent activity against Plasmodium species and the opportunistic pathogens Pneumocystis jirovici and Toxoplasma gondii it is FDA approved for treatment of P. jirovici pneumonia in patients intolerant of trimethoprim-sulfamethoxazole. In patients with uncomplicated P. falciparum malaria, combination therapy with proguanil and atovaquone evoked high cure rates with few relapses and minimal toxicity. A fixed combination of atovaquone with proguanil (malarone) is available...

Mechanopharmacological Therapy Drugeluting Endovascular Stents

Intracoronary stents can ameliorate angina and reduce adverse events in patients with acute coronary syndromes. However, the long-term efficacy of intracoronary stents is limited by subacute luminal restenosis within the stent, which occurs in a substantial fraction of patients. The pathways that lead to in-stent restenosis are complex, but smooth muscle proliferation within the lumen of the stented artery is a common pathological finding. Local antiproliferative therapies at the time of...

Rifampin

Rifampin inhibits the growth of most gram-positive and many gram-negative bacteria. Rifampin in concentrations of 0.005-0.2 g mL inhibits the growth of M. tuberculosis in vitro. Among nontu-berculous mycobacteria, Mycobacterium kansasii is inhibited by 0.25-1 g mL. The majority of strains of Mycobacterium scrofulaceum, Mycobacterium intracellulare, and M. avium are suppressed but certain strains may be resistant. Mycobacterium fortuitum is highly resistant to the drug. Rifampin increases the in...

Fpf

See Glucose-6-phosphate dehydrogenase (G6PD) Gabapentin microsomal enzymes, 324 mechanisms of action, 330 pharmacokinetics, 330 pharmacological effects, 330 side effects, 330 therapeutic uses, 330 GABITRIL (tiagabine), 331 Galactorrhea, antipsychotics and, 303 for Alzheimer's disease, 132, 134, 345 Gallbladder, autonomic regulation, 91 Gallium arsenide, 1137. See also Arsenic Gamma-aminobutyric acid (GABA) as neurotransmitter, 209 , 214 in seizures, 319, 321 transporters, 41-42...

Physiology Of Gastric Secretion

The regulation of gastric acid secretion is shown in Figure 36-1. GASTRIC DEFENSES AGAINST ACID The high H+ in the gastric lumen requires defense mechanisms to protect the esophagus and the stomach. The primary esophageal defense is the lower esophageal sphincter, which prevents reflux of acidic gastric contents into the esophagus. The stomach protects itself from acid damage by a number of mechanisms that require adequate mucosal blood flow, perhaps because of the high metabolic activity and...

Ci

MCPP has been employed to probe brain 5-HT function in human beings. The drug alters a number of neuroendocrine parameters and elicits profound behavioral effects, with anxiety as a prominent symptom. mCPP elevates corticotropin and prolactin secretion (probably via a combination of 5-HTj and 5-HT2A 2C receptor activation) and increases growth hormone secretion (apparently by a 5-HT-independent mechanism). 5-HT2A 2C receptors appear to mediate at least part of the anxiogenic effects of mCPP,...

Errors In Drug Orders

The Institute of Medicine (IOM) estimates that between 44,000 and 98,000 deaths annually in the U.S. result from medical errors. While there is some debate about this estimate, it is clear that medication errors are common and result in significant adverse effects, including death. Databases of anonymously reported errors are maintained jointly by the Institute for Safe Medication Practices (ISMP), the U.S. Pharmacopeia Medication Errors Reporting Program (USP MERP), and the FDA's MedWatch...

Melarsoprol

Proteinuria occurs frequently, and evidence of renal or hepatic dysfunction may necessitate treatment modification. Vomiting and abdominal colic are reduced by injecting melarsoprol slowly into the supine, fasting patient. PRECAUTIONS AND CONTRAINDICATIONS Melarsoprol should be given to patients only under hospital supervision. The initial dose must be based on clinical assessment rather than body weight. Initiation of therapy during a febrile episode is...

Tricyclic Antipsychotic Agents

Several dozen phenothiazine antipsychotic drugs and chemically related agents are used worldwide. Other phenothiazines are marketed primarily for their antiemetic, antihistaminic, or anti-cholinergic effects. Antipsychotic drugs share many pharmacological effects and therapeutic applications. Chlorpro-mazine and haloperidol are prototypic of the older, standard neuroleptic-type agents. Many antipsychotic drugs, especially chlorpromazine and other agents of low potency, have a prominent sedative...

Therapeutic Uses Of Sympathomimetic Drugs Shock

Shock is a life-threatening condition characterized by inadequate perfusion of tissues, hypotension, and, ultimately, failure of organ systems. Treatment of shock consists of specific efforts to reverse the underlying pathogenesis as well as nonspecific measures aimed at correcting hemodynamic abnormalities. Regardless of etiology, the accompanying fall in blood pressure generally leads to marked activation of the sympathetic nervous system. This, in turn, causes peripheral vasoconstriction and...

Hematopoietic Growth Factors

Growth factor physiology Steady-state hematopoiesis encompasses the production of more than 400 billion blood cells each day. This production is tightly regulated and can be increased severalfold with increased demand. The hematopoietic organ also is unique in adult physiology in that several mature cell types are derived from a much smaller number of multipotent progenitors, which develop from a more limited number of pluripotent hematopoietic stem cells. Such cells are capable of maintaining...

Genomic Basis Of Pharmacogenetics Types of Genetic Variants

A polymorphism is a variation in the DNA sequence that is present at an allele frequency of 1 or greater in a population. Two major types of sequence variation have been associated with variation in human phenotype single nucleotide polymorphisms (SNPs) and insertions deletions (indels) (Figure 4-2). SNPs are present in the human genome at approximately one SNP every few hundred to a thousand base pairs, depending on the gene region. Indels are much less frequent, particularly in coding regions...

Selection Of Antihypertensive Drugs In Individual Patients

Choice of an antihypertensive drug should be driven by likely benefit in an individual patient, taking into account concomitant diseases such as diabetes mellitus, problematic adverse effects of specific drugs, and cost. Consensus guidelines recommend diuretics as preferred initial therapy for most patients with uncomplicated stage 1 hypertension who are unresponsive to nonpharmacological measures. Patients are also commonly treated with other drugs p receptor antagonists, ACE inhibitors A...

Effects Of Cyclical Gonadal Steroids On The Reproductive Tract

The cyclical changes in estrogen and progesterone production by the ovaries regulate corresponding events in the fallopian tubes, uterus, cervix, and vagina. Physiologically, these changes prepare the uterus for implantation and pregnancy. If pregnancy does not occur, the uterine endometrium is shed as the menstrual discharge (Figure 57-3).

Treatment Of Claudication And Peripheral Vascular Disease

Most patients with peripheral vascular disease also have coronary artery disease, and the therapeutic approaches for peripheral and coronary arterial diseases overlap. Mortality in patients with peripheral vascular disease is most commonly due to cardiovascular disease, and treatment of coronary disease remains the central focus of therapy. Many patients with advanced peripheral arterial disease are more limited by the consequences of peripheral ischemia than by myocardial ischemia. In the...

Osmotic Diuretics

Osmotic diuretics are freely filtered at the glomerulus, undergo limited reabsorption by the renal tubule, and are relatively inert pharmacologically. Osmotic diuretics are administered in sufficient doses to increase significantly the osmolality of plasma and tubular fluid. Table 28-3 gives pharmacokinetic properties of four osmotic diuretics-glycerin (osmoglyn), isosorbide (ismotic), man-nitol (osmitrol), and urea (ureaphil). The major site of action of osmotic diuretics is the loop of Henle....

Ipsp Due To Selective Increase In Permeability To Anion Usualy Cl-

Voltage-sensitive Ca2+ channel postsynaptic receptor-gated ion channel SYNAPTIC VESICLES excitatory transmitter (O) inhibitory FIGURE 6-2 Steps involved in excitatory and inhibitory neurotransmission. 1. The nerve action potential (AP) consists of a transient self-propagated reversal of charge on the axonal membrane. (The internal potential E. goes from a negative value, through zero potential, to a slightly positive value primarily through increases in Na+ permeability and then returns to...

Artemisinin And Derivatives

The artemisinins are potent antimalarials with no clinical evidence of resistance. They are particularly well suited for the treatment of severe P. falciparum malaria and play a key role in combination therapy of drug-resistant infections. They are not FDA approved, and inactive counterfeits are common. ANTIPARASITIC ACTIVITY Extensive structure-activity studies have confirmed the requirement for an endoperoxide moiety for antimalarial activity. These drugs act rapidly against the asexual...

Copyright 2008 by The McGraw Hill Companies Inc Click here for terms of use

FIGURE 8-1 Steps in the hydrolysis of acetylcholine by acetylcholinesterase and in the inhibition and reactivation of AChE. Only the three residues of the catalytic triad are depicted. The associations and reactions shown are A. Acetylcholine (ACh) catalysis binding of ACh, formation of a tetrahedral transition state, formation of the acetyl enzyme with liberation of choline, rapid hydrolysis of the acetyl enzyme with return to the original state. B. Reversible binding and inhibition by...

Fourthgeneration Cephalosporins

Cefepime and cefpirome (not available in U.S.) are fourth-generation cephalosporins. Cefepime resists hydrolysis by many of the plasmid-encoded f-lactamases. It is a poor inducer of, and is relatively resistant to, chromosomally encoded and some extended-spectrum f-lactamases. Thus, it is active against many Enterobacteriaceae that are resistant to other cephalosporins via induction of f-lactamases but remains susceptible to many bacteria expressing extended-spectrum f-lactamases. Against H....

Barbiturates

FIGURE 19-2 Enhanced GABA synaptic transmission. In the presence of GABA, the GABAa receptor (structure on left) is opened, allowing an influx of Cl-, which in turn increases membrane polarization (see Chapter 16). Some antiseizure drugs (shown in larger blue text) act by reducing the metabolism of GABA. Others act at the GABAa receptor, enhancing Cl- influx in response to GABA. As outlined in the text, gabapentin acts presynaptically to promote GABA release its molecular target is currently...

Antiproliferative and Antimetabolic Drugs

Sirolimus Sirolimus (rapamycin rapamune) is a macrocyclic lactone produced by Streptomyces hygroscopicus. Sirolimus inhibits T-lymphocyte activation and proliferation downstream of the IL-2 and other T-cell growth factor receptors (Figure 52-1). Like cyclosporine and tacrolimus, therapeutic action of sirolimus requires formation of a complex with an immunophilin, in this case FKBP-12. The sirolimus FKBP-12 complex does not affect calcineurin activity but rather inhibits a protein kinase that is...

Quinazoline a Antagonists Prazosin

Prazosin, the prototypic quinazoline a blocker, is a potent and selective aj receptor antagonist. The quinazoline class of a receptor antagonists has largely replaced the nonselective haloalkylamine (e.g., PBZ) and imidazoline (e.g., phentolamine) a receptor antagonists. The affinity of prazosin for aj adrenergic receptors is -1000X that for a2 adrenergic receptors prazosin has similar potencies at aJA, aJB, and a1D subtypes. Interestingly, the drug also is a relatively potent inhibitor of...

Vincristine

Vincristine sulfate (ONCOVIN, vincasar PFS, others) used together with glucocorticoids is the treatment of choice to induce remissions in childhood leukemia common dosages for these drugs are vincristine, intravenously, 2 mg m2 of body surface area weekly, and prednisone, orally, 40 mg m2 daily. Adult patients with Hodgkin's disease or non-Hodgkin's lymphomas usually receive vincristine as part of a complex protocol. When used in the MOPP regimen (see below), the recommended dose of vincristine...

Pharmacological Phenomena

Tolerance While abuse and addiction are complex conditions combining the many variables outlined earlier, there are a number of relevant pharmacological phenomena that occur independently of social and psychological dimensions. First are the changes in the way the body responds to a drug with repeated use. Tolerance, the most common response to repetitive use of the same drug, can be defined as the reduction in response to the drug after repeated administrations. Figure 23-1 shows an idealized...

Pharmacologic Properties The Quaternary Derivatives Ipratropium and Tiotropium

Ipratropium bromide (atrovent, others) is a quaternary ammonium derivative of atropine. Oxitropium bromide is a quaternary derivative of scopolamine. Ipratropium blocks all subtypes of muscarinic receptors and thus blocks presynaptic muscarinic inhibition of ACh release. The most recently developed and bronchoselective member of this family, tiotropium bromide (spiriva), has a longer duration of action and shows some selectivity for Mj and M3 receptors, with lower affinity for M2 receptors, and...

O

*For a discussion of phenothiazines, see Chapter 18. Preparations are designated as follows O, oral solids L, oral liquids I, Injection S, suppository T, topical. Many -receptor antagonists also are available in preparations 4 that contain multiple drugs. 'Trade name drug also contains other medications. Also has antiserotonin properties. Dibenzoxepin Tricyclics (Doxepin) Doxepin, the only drug in this class, is marketed as a tricyclic antidepressant (see Chapter 17). It also is a remarkably...

Giardiasis

Giardiasis, caused by Giardia intestinalis, is the most commonly reported intestinal protozoal infection in the U.S. Infection results from ingestion of cysts in fecally contaminated water or food. Human-to-human transmission via the fecal-oral route is especially common among children in day-care centers and nurseries, institutionalized individuals, and male homosexuals. Infection with Giardia results in an asymptomatic carrier state, acute self-limited diarrhea, or chronic diarrhea....

Calcineurin Inhibitors

Perhaps the most effective immunosuppressive drugs in routine use are the calcineurin inhibitors, cyclosporine and tacrolimus, which target intracellular signaling pathways induced as a consequence of T-cell-receptor activation. Although they are structurally unrelated and bind to distinct molecular targets, they inhibit normal T-cell signal transduction essentially by the same mechanism (see Figure 52-1). FIGURE 52-1 Mechanisms of action of cyclosporine, tacrolimus, and sirolimus on T cells....

Dimercaprol

Dimercaprol (2,3-dimercaptopropanol) was developed during World War II as an antidote to lewisite, a vesicant arsenical war gas, hence its alternative name, British antilewisite (BAL). Arsenicals and other heavy metals form a very stable and relatively nontoxic chelate ring with the dimercaprol. It is an oily fluid with a pungent, disagreeable odor typical of mercaptans. Because of its instability in aqueous solutions, peanut oil is the solvent employed in pharmaceutical preparations....

Parenteral Inotropic Agents

GENERAL CONSIDERATIONS Patients with heart failure are most commonly hospitalized because of fluid retention that results in dyspnea and peripheral edema. Accordingly, relief of congestion through the use of diuretics and venodilators remains a therapeutic priority. A subset of these patients may present with clinical evidence of reduced forward cardiac output, including fatigue, azotemia, and alterations in mental status. Patients who present with more severe decompensation typically require...

Antiprotozoal Effects

Antimalarial Actions Pyrimethamine is a slow-acting blood schizontocide with antimalarial effects in vivo similar to those of proguanil (see below). However, pyrimethamine has greater antimalarial potency, and its t1 2 is much longer than that of cycloguanil, the active metabolite of proguanil. Pyrimethamine's efficacy against hepatic forms of P. falciparum is less than that of proguanil, and at therapeutic doses, pyrimethamine fails to eradicate the latent tissue forms of P. vivax or...

Maintenance Dose

In most clinical situations, drugs are administered in a series of repetitive doses or as a continuous infusion to maintain a steady-state concentration of drug associated with the therapeutic window. Calculation of the appropriate maintenance dosage is a primary goal. To maintain the chosen steady-state or target concentration, the rate of drug administration is adjusted such that the rate of input equals the rate of loss. This relationship is expressed here in terms of the desired target...

Ascaris Lumbricoides And Toxocara Canis

A. lumbricoides, known as the roundworm, affects up to 90 of persons in some tropical regions but also is seen in temperate climates. Mebendazole, albendazole, and pyrantel pamoate (antiminth, others) are preferred drugs all infected persons should be treated. Mebendazole and albendazole are preferred for therapy of asymptomatic-to-moderate ascariasis. Both compounds should be used with caution to treat heavy Ascaris infections, alone or with hookworms. Rarely, hyperactive ascarids may migrate...

Ethambutol

Antibacterialactivity, mechanism of action, resistance Nearly all strains of M. tuberculosis and M. kansasii and many strains of MAC are sensitive to ethambutol. Sensitivities of other mycobacteria are variable. Ethambutol has no effect on other bacteria. Growth inhibition by ethambutol requires 24 hours and is mediated by inhibition of ara-binosyl transferases involved in cell wall biosynthesis. Resistance to ethambutol develops very slowly in vitro, but can result from single amino acid...

Tetracaine

Tetracaine (pontocaine), a long-acting amino ester, is significantly more potent and has a longer duration of action than procaine. Tetracaine may exhibit increased systemic toxicity because it is more slowly metabolized than the other commonly used ester local anesthetics. it is widely used in spinal anesthesia when a drug of long duration is needed. Tetracaine also is incorporated into several topical anesthetic preparations. Tetracaine is rarely used in peripheral nerve blocks because of the...

Antiandrogen Therapy In Prostate Cancer

Although the antiandrogenic treatment of metastatic prostate carcinoma is palliative, life expectancy is increased and thousands of patients have benefited. When distant metastases already are present, hormonal therapy becomes the primary treatment for prostate cancer. Pharmacological approaches to reduce the concentrations of endogenous androgens or inhibit their action include antiandrogens, or more commonly, the administration of gonadotropin-releasing hormone (GnRH) agonists or antagonists...

Visceral Afferent Fibers

Afferent fibers from visceral structures are the first link in the reflex arcs of the autonomic system. With certain exceptions, such as local axon reflexes, most visceral reflexes are mediated through the central nervous system (CNS). Information on the status of the visceral organs is transmitted to the CNS through the cranial nerve (parasympathetic) visceral sensory system and the spinal (sympathetic) visceral afferent system. The cranial visceral sensory system carries mainly...

Principles In The Clinical Use Of Antiarrhythmic Drugs

Drugs that modify cardiac electrophysiology often have a narrow therapeutic index. Moreover, antiar-rhythmic drugs can induce new arrhythmias with possibly fatal consequences. Nonpharmacological treatments, such as cardiac pacing, electrical defibrillation, or ablation of targeted regions, are indicated for some arrhythmias in other cases, no therapy is required, even though an arrhythmia is detected. Therefore, the fundamental principles of therapeutics described here must be applied to...

Aminoglycosides

The aminoglycosides are first-line therapy for a limited number of very specific, often historically prominent infections, such as plague, tularemia, and tuberculosis they also are frequently used to treat infections caused by aerobic gram-negative bacteria. Their clinical roles have diminished as less toxic alternatives have become available. Unlike most inhibitors of microbial protein synthesis, which are bacteriostatic, the aminoglycosides are bactericidal. Resistance most commonly arises...

Naked Monoclonal Antibodies

Rituximab Rituximab (rituxan) is a chimeric monoclonal antibody that targets the CD20 B-cell antigen (Tables 51-3 and 51-4), which is found on cells from the pre-B-cell stage through terminal differentiation to plasma cells and is expressed on 90 of B-cell neoplasms. Monoclonal antibody binding to CD20 generates transmembrane signals in B-cells, but it is not known how ligation of the CD20 receptor produces cell death independent of ADCC or complement-mediated pathways. Rituximab initially was...

Prejunctional Sites

Both cholinergic and adrenergic nerve terminal varicosities contain autoreceptors and hetero-receptors. ACh release therefore is subject to complex regulation by mediators, including ACh itself acting on M2 and M4 autoreceptors, and other transmitters (e.g., NE acting on a2A and a2C adrenergic receptors) or locally-produced substances (e.g., NO). ACh-mediated inhibition of ACh release following activation of M2 and M4 autoreceptors is thought to represent a physiological negative-feedback...

Regulation of Receptors

Receptors not only initiate regulation of biochemical events and physiological function but also are themselves subject to many regulatory and homeostatic controls. These controls include regulation of the synthesis and degradation of the receptor by multiple mechanisms, covalent modification, association with other regulatory proteins, and or relocalization within the cell. Transducer and effector proteins are regulated similarly. Modulating inputs may come from other receptors, directly or...

Ldlc

CHD or equivalent 2+ risk factors 0-1 risk factor > 100 or > 3.5 > 130 or > 4.5 > 160 or > 5.5 > 100 or > 3.5 > 130 or > 6.0 > 160 or > 7.0 ABBREVIATIONS CHD, coronary heart disease HDL-C, high-density lipoprotein cholesterol LDL-C, low-density-lipoprotein cholesterol TC, total cholesterol. ABBREVIATIONS CHD, coronary heart disease HDL-C, high-density lipoprotein cholesterol LDL-C, low-density-lipoprotein cholesterol TC, total cholesterol. should be managed with...

Antacids

Antacids continue to be used by patients for a variety of indications. Many factors, including palata-bility, determine the effectiveness and choice of antacid (Table 36-1). Although sodium bicarbonate effectively neutralizes acid, it is very water-soluble and rapidly absorbed from the stomach, and the alkali and sodium loads may pose a risk for patients with cardiac or renal failure. Depending on particle size and crystal structure, CaCO3 rapidly and effectively neutralizes gastric H+, but the...

M

Phosphorylase X Protected from enzyme FIGURE 45-1 Sites of activity of various plasmid-mediated enzymes capable of inactivating aminoglycosides. The symbol X indicates regions of the molecules that are protected from the designated enzyme. In gentamicin Cp R1 R2 CH3 in gentamicin C2, R1 CH3, R2 H in gentamicin C1a, R1 R2 H. The primary site of action of the aminoglycosides is the 30S ribosomal subunit some aminoglycosides also bind to several sites on the 50S ribosomal subunit. Aminoglycosides...

Distribution Blood Pressure

Topically administered drugs may undergo systemic distribution primarily by nasal mucosal absorption and possibly by local ocular distribution by transcorneal transconjunctival absorption. figure 63-3 Possible absorption pathways of an ophthalmic drug following topical application to the eye. Solid black arrows represent the corneal route dashed blue arrows represent the conjunctival scleral route the black dashed line represents the nasolacrimal absorption pathway. figure 63-3 Possible...

Clearance

Clearance is the most important concept to consider when designing a rational regimen for long-term drug administration. The clinician usually wants to maintain steady-state concentrations of a drug within a therapeutic window associated with therapeutic efficacy and a minimum of toxicity for a given agent. Assuming complete bioavailability, the steady-state concentration of drug in the body will be achieved when the rate of drug elimination equals the rate of drug administration. Thus where CL...

Nystatin

Nystatin is a tetraene macrolide that is structurally similar to amphotericin B and has the same mechanism of action. Nystatin is not absorbed from the GI tract, skin, or vagina. Nystatin (mycostatin, nilstat, others) is used only for candidiasis and is supplied in preparations intended for cutaneous, vaginal, or oral administration for this purpose. infections of the nails and hyperkeratinized or crusted skin lesions do not respond. Topical preparations include ointments, creams, and powders,...

Pharmacogenetics and Drug Development

Pharmacogenetics will likely impact drug development in several ways. Genome-wide approaches hold promise for identification of new drug targets and new drugs. In addition, accounting for genetic genomic interindividual variability may lead to genotype-specific development of new drugs and to genotype-specific dosing regimens. Pharmacogenetics may identify subsets of patients who will have a very high or a very low likelihood of responding to an agent. This will permit testing of the drug in a...

Edetate Calcium Disodium

Ethylenediaminetetraacetic acid (EDTA) is a polycarboxylic acid chelator its sodium salt (edetate disodium, Na2EDTA), and a number of closely related compounds chelate many divalent and triva-lent metals. The cation used to make a water-soluble salt of EDTA has an important role in the toxicity of the chelator. Na2EDTA causes hypocalcemic tetany. However, edetate calcium disodium (CaNa2EDTA) can be used for treatment of poisoning by metals that have higher affinity for the chelating agent than...

Agents Used to Assist in Ocular Diagnosis

A number of agents are used in an ocular examination (e.g., mydriatic agents and topical anesthetics, and dyes to evaluate corneal surface integrity) to facilitate intraocular surgery (e.g., mydriatic and miotic agents, topical and local anesthetics) and to help in making a diagnosis in cases of aniso-coria and retinal abnormalities (e.g., intravenous contrast agents). The autonomic agents have been discussed earlier. The diagnostic and therapeutic uses of topical and intravenous dyes and of...

Treatment Of Lead Poisoning

Initial treatment of the acute phase of lead intoxication involves supportive measures. Prevention of further exposure is important. Seizures are treated with diazepam or phenytoin (see Chapter 19), fluid and electrolyte balances must be maintained, and cerebral edema is treated with mannitol and dexamethasone or controlled hyperventilation. The concentration of lead in blood should be determined or at least a blood sample obtained for analysis prior to initiation of chelation therapy....

Selective Estrogen Receptor Downregulators

SERDs, also termed pure antiestrogens, include compounds such as fulvestrant, RU 58668, SR 16234, ZD 164384, and ZK 191703. SERDs, unlike SERMs, are devoid of any estrogen agonist activity and function as pure antagonists. FULVESTRANT Fulvestrant (faslodex) is the first FDA-approved agent in the new class of ER downregulators. Fulvestrant is approved for postmenopausal women with ER-positive metasta-tic breast cancer that has progressed despite antiestrogen therapy. Fulvestrant binds to the ER...

Osmotic Agents And Drugs Affecting Carbonic Anhydrase

The main osmotic drugs for ocular use include glycerin, mannitol (see Chapter 28), and hypertonic saline. Ophthalmologists occasionally use glycerin and mannitol for short-term management of acute rises in IOP. Sporadically, these agents are used intraoperatively to dehydrate the vitreous prior to anterior segment surgical procedures. Many patients with acute glaucoma do not tolerate oral medications because of nausea therefore, intravenous administration of mannitol and or acetazolamide may be...

Overview Of Antianginal Therapeutic Strategies

In evaluating trials in which different forms of antianginal therapy are compared, careful attention must be paid to the patient population studied and to the pathophysiology and stage of the disease. The efficacy of antianginal treatment will depend on the severity of angina, the presence of coronary vasospasm, and myocardial O2 demand. Optimally, the dose of each agent should be titrated to maximum benefit. Task forces from the ACC and the AHA have published guidelines that are useful in the...

Ganglionic Neurotransmission

Neurotransmission in autonomic ganglia is a more complex process than that described by a single neurotransmitter-receptor system, with at least 4 distinct changes in membrane potential elicited by stimulation of the preganglionic nerve. The primary event involves a rapid depolarization of postsynaptic sites by ACh. An action potential is generated in the postganglionic neuron when the initial EPSP attains sufficient amplitude in mammalian sympathetic ganglia in vivo, effective transmission...

Principles Of Diuretic Action

Diuretics are drugs that increase the rate of urine flow clinically useful diuretics also increase the rate of excretion of Na+ (natriuresis) and an accompanying anion, usually Cl-. Most clinical applications of diuretics aim to reduce extracellular fluid volume by decreasing total-body NaCl content. Although continued administration of a diuretic causes a sustained net deficit in total-body Na+, the time course of natriuresis is finite because renal compensatory mechanisms bring Na+ excretion...

Proximal Tubule

FIGURE 28-2 NaHCO3 reabsorption in proximal tubule and mechanism of diuretic action of carbonic anhydrase (CA) inhibitors. A, antiporter S, symporter CH, ion channel. (The actual reaction catalyzed by carbonic anhydrase is OH- + CO2 HCO3- however, H2O OH- + H+ and HCO3- + H+ H2CO3, so the net reaction is H2O + CO2 H2CO3.) Numbers in parentheses indicate stoichiometry. BL and LM indicate basolateral and luminal membranes, respectively. The sizes of type for Na+, K+, and H+ reflect relative...

Dipyridamole

Dipyridamole (persantine) is a vasodilator that, in combination with warfarin, inhibits emboliza-tion from prosthetic heart valves. A single study suggests that dipyridamole plus aspirin reduces strokes in patients with prior strokes or transient ischemic attack. A formulation containing 200 mg of dipyridamole, in an extended-release form, and 25 mg of aspirin (aggrenox) is available. Dipyridamole interferes with platelet function by increasing the cellular concentration of cyclic AMP. This...

Gastric Acid Secretion

Acting at H2 receptors, histamine is a powerful gastric secretagogue and evokes a copious secretion of acid from parietal cells (see Figure 36-1) it also increases the output of pepsin and intrinsic factor. Although the secretion of gastric acid also is evoked by stimulation of the vagus nerve and by the enteric hormone gastrin, presumably by activation of M3 and CCK2 receptors on the parietal cell, acetylcholine and gastrin also stimulate histamine release from the ente-rochromaffin-like cell....

Ch3

5'-Deoxyadenosylcobalamin -5'-Deoxyadenosyl FIGURE 53-7 The structures and nomenclature of vitamin Bn congeners. FIGURE 53-7 The structures and nomenclature of vitamin Bn congeners. metabolic functions The active coenzymes methylcobalamin and 5-deoxyadeno-sylcobalamin are essential for cell growth and replication. Methylcobalamin is required for the conversion of homocysteine to methionine and its derivative, SAM. In addition, when concentrations of vitamin B12 are inadequate, folate becomes...

Nucleophilic attack of unstable aziridine ring by electron donor

(-SH of protein, -N- of protein or DNA base, 5 of DNA base or phosphate) FIGURE 51-3 Mechanism of action of alkylating agents. FIGURE 51-3 Mechanism of action of alkylating agents. ing agents (procarbazine, temozolomide), which have greater capacity for mutagenesis and carcinogenesis. This suggests that cross-Linking of DNA strands is a much greater threat to cellular survival than effects such as single-base alkylation and the resulting depurination and chain scission. On the other hand, the...

Chronic Arsenic Poisoning

The most common early signs of chronic arsenic poisoning are muscle weakness and aching, skin pigmentation (especially of the neck, eyelids, nipples, and axillae), hyperkeratosis, and edema. GI involvement is less prominent in long-term exposures. Other signs and symptoms that should arouse suspicion of arsenic poisoning include garlic odor of the breath and perspiration, excessive salivation and sweating, stomatitis, generalized itching, sore throat, coryza, lacrimation, numbness, burning or...

J

Make ascites and purify monoclonal antibody Make ascites and purify monoclonal antibody FIGURE 52-2 Generation of monoclonal antibodies. Mice are immunized with the selected antigen, and spleen or lymph node is harvested and B cells separated. These B cells are fused to a suitable B-cell myeloma that has been selected for its inability to grow in medium supplemented with hypoxanthine, aminopterin, and thymidine (HAT). only myelomas that fuse with B cells can survive in HAT-supplemented medium....

Actions of Drugs Not Mediated by Receptors

Some drug effects do not occur via macromolecular receptors, such as therapeutic neutralization of gastric acid by a base (antacid). Drugs such as mannitol act according to colligative properties, increasing the osmolality of various body fluids and causing changes in the distribution of water to promote diuresis, catharsis, expansion of circulating volume in the vascular compartment, or reduction of cerebral edema (see Chapter 28). The introduction of cholesterol-binding agents orally (e.g.,...

T

I 2 (half-life), 10 Tachykinins, 211 Tachyphylaxis, 20 Tacrine for Alzheimer's disease, 132, 134, 345 chemistry, 126, 128 interaction with proton pump inhibitors, 623 mechanisms of action, 126 Tacrolimus, 913-914, 1088 adverse effects, 914, 1088 contraindications, 1088 dermatologic uses, 1088 disposition, 913 interactions, 914 with itraconazole, 803 with mycophenolate mofetil, 916 with voriconazole, 806 mechanisms of action, 910 , 911 , 913 pharmacokinetics, 913 therapeutic uses, 914, 1088...

Antiestrogen Therapy

Antiestrogen approaches for the therapy of hormone-receptor positive breast cancer include the use of selective estrogen-receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (Ais). selective estrogen receptor modulators SERMs bind to the ER and exert either estrogenic or antiestrogenic effects depending on the specific organ. The recent decline in breast cancer mortality is believed to be in part due to the widespread utilization of...

H2n

Metoclopramide is absorbed rapidly after oral ingestion, undergoes sulfation and glucuronide conjugation by the liver, and is excreted principally in the urine, with a t 2 of 4 6 hours. Peak concentrations occur within 1 hour after a single oral dose the duration of action is 1 2 hours. Metoclopramide is available for oral and parenteral use. The usual initial oral dose range is 10 mg, 30 minutes before each meal and at bedtime. The onset of action is within 30-60 minutes after an oral dose. In...

Clinical Uses Of Localanesthetics

Local anesthesia is the loss of sensation in a body part without the loss of consciousness or the impairment of central control of vital functions. It offers two major advantages. First, physiological perturbations associated with general anesthesia are avoided second, neurophysiological responses to pain and stress can be modified beneficially. However, local anesthetics can produce deleterious side effects. Proper choice of a local anesthetic and care in its use are the primary determinants...

Neomycin

Neomycin is a broad-spectrum antibiotic. Gram-negative species that are highly sensitive are E. coli, Enterobacter aerogenes, Klebsiella pneumoniae, and Proteus vulgaris. Gram-positive microorganisms that are inhibited include S. aureus and E. faecalis. M. tuberculosis also is sensitive to neomycin. Strains of P. aeruginosa are resistant to neomycin. Neomycin sulfate is available for topical and oral administration. Neomycin and polymyxin B have been used for irrigation of the bladder. For this...

Neuroendocrine Effects

Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH), thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and ACTH. As a result of the decreased concentrations of pituitary trophic hormones, plasma concentrations of sex steroids and cortisol decline. Thyrotropin secretion is relatively unaffected. The administration of m agonists increases the...

Mean Arterial Blood Pressure

FIGURE 30-5 Interactions among salt intake, the renal pressure-natriuresis mechanism, and the rennin-angiotensin system to stablilize long-term levels of arterial blood pressure despite large variations in dietary sodium intake. The orally active renin inhibitor aliskiren (tekturna) is now available for the treatment of hypertension. In studies to date, it has produced a dose-dependent decrease in blood pressure with few adverse effects. Renin inhibitors will likely provide an attractive...

Pharmacological Actions

The complex and often unpredictable changes that occur in the body after administration of nicotine are due not only to its actions on a variety of neuroeffector and chemosensitive sites but also to the fact that the alkaloid can stimulate and desensitize receptors. The ultimate response of any one system represents the summation of stimulatory and inhibitory effects of nicotine. For example, the drug can increase heart rate by excitation of sympathetic or paralysis of parasympathetic cardiac...