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Bicalutamide, 907, 1021, 1021 BICILLIN L-A (penicillin G benzathine), 734 BICNU (carmustine), 865 Bicuculline, 213 BIDIL (isosorbide-hydralazine), 568 Bier's block, 250 BILARCIL (metrifonate), 704 Bile acids, 651-652, 652 Bile-acid sequestrants adverse effects, 616 for diarrhea, 642-643 interactions, 616 with ezetimibe, 620 with thiazide diuretics, 489 for lipid lowering, 616 mechanisms of action, 615-616 with statins, 615 therapeutic uses, 616 Biliary tract and, 121 obstruction, vitamin K for,...

Doxorubicin

Doxorubicin (adriamycin, others) is available for intravenous use. The recommended dose is 50-75 mg2m2, administered as a single rapid intravenous infusion that is repeated after 21 days. A doxorubicin liposomal product (doxil) is available for treatment of AIDS-related Kaposi's sarcoma and is given intravenously in a dose of 20 mg2m2 over 30 minutes and repeated every 3 weeks. As for daunorubicin, patients should be advised that the drug may impart a red color to the urine. Doxorubicin is...

Pharmacological Effects of Muscarinic Stimulation

CARDIOVASCULAR SYSTEM ACh has four primary effects on the cardiovascular system vasodilation, a decrease in cardiac rate (the negative chronotropic effect), a decrease in the rate of conduction in the specialized tissues of the SA and atrioventricular (AV) nodes (the negative dromotropic effect), and a decrease in the force of cardiac contraction (the negative inotropic effect). The last effect is of lesser significance in ventricular than in atrial muscle. Certain of the above responses can be...

Genitourinary Tract

Overactive urinary bladder disease can be successfully treated with muscarinic antagonists, primarily tolterodine and trospium chloride, which lower intravesicular pressure, increase capacity, and reduce the frequency of contractions by antagonizing parasympathetic control of the bladder. Oxybu-tynin is used as a transdermal system (oxytrol) that delivers 3.9 mg day and is associated with a lower incidence of side effects than the oral immediate- or extended-release formulations. Tolterodine is...

Adverse Effects And Drug Interactions

Proton pump inhibitors generally cause remarkably few adverse effects. The most common are nausea, abdominal pain, constipation, flatulence, and diarrhea. Subacute myopathy, arthralgias, headaches, and rashes also have been reported. Proton pump inhibitors can interact with warfarin (esomeprazole, lansoprazole, omeprazole, and rabeprazole), diazepam (esomeprazole and omeprazole), and cyclosporine (omeprazole and rabeprazole). Omeprazole inhibits CYP2C19 (thereby decreasing the clearance of...

Therapeutic Uses

Ganciclovir is effective for treatment and chronic suppression of CMV retinitis in immunocompromised patients and for prevention of CMV disease in transplant recipients. In CMV retinitis, induction treatment (5 mg kg intravenously every 12 hours for 10 21 days) is associated with improvement or stabilization in 85 of patients. Reduced viral excretion is usually evident by 1 week, and funduscopic improvement by 2 weeks. Because of the high risk of relapse, AIDS patients with retinitis require...

Central Nervous System

A selective action of Li+ is inhibition of inositol monophosphatase, thereby interfering with the phosphatidylinositol pathway (Figure 18 1). This effect can decrease cerebral inositol concentrations, possibly interfering with neurotransmission mechanisms by affecting the phosphatidyli-nositol pathway and decreasing the activation of PKC, particularly the a and b isoforms. This effect also is shared by valproic acid (particularly for PKC) but not carbamazepine. A major substrate for cerebral...

Fcf

Perfluoropentane Silicone oils Nonfluorinated (ch3)3sio (ch3)2sio nsi(ch3)3 (ch3)3sio (c3h4f3)(ch3)sio n (ch3)3s5io (c6h5)(ch3)sio n si(ch3)3 Duration of 30-35 days Duration of 55-65 days Viscosity range from 1000 to 30,000 cs* Viscosity range from 1000 to 10,000 cs* May terminate as trimethylsiloxy (shown) or polyphenylmethylsiloxane, viscosity not reported *cs, centistoke (unit of viscosity).

Clofazimine

Clofazimine (lamprene) binds preferentially to GC-rich mycobacterial DNA, increases mycobacterial phospholipase A2 activity, and inhibits microbial K+ transport. It is weakly bactericidal against M. intracellulare. The drug also exerts an anti-inflammatory effect and prevents the development of erythema nodosum leprosum. Clofazimine is recommended as a component of multiple-drug therapy for leprosy. It also is useful for treatment of chronic skin ulcers produced by Mycobacterium ulcerans....

Poorly Absorbed Sulfonamides

Sulfasalazine (azulfidine) is very poorly absorbed from the GI tract and is used in the therapy of ulcerative colitis and Crohn's disease (see Chapter 38). SULFONAMIDES FOR TOPICAL USE Sulfacetamide Sulfacetamide is the N1-acetyl-substituted derivative of sulfanilamide. Its aqueous solubility is 90 times that of sulfadiazine. This drug (isopto-cetamide, others) is employed extensively for ophthalmic infections. Very high aqueous concentrations are not irritating to the eye and are effective...

Anthelmintic Action

Microfilarial forms of susceptible species are most affected by diethylcarbamazine, which elicits rapid disappearance from blood for W. bancrofti, B. malayi, and L. loa. The drug kills microfilariae of O. volvulus in skin but not in nodules that contain the adult (female) worms. It does not affect the microfilariae of W. bancrofti in a hydrocele. Diethylcarbamazine appears to exert a direct toxic effect on W. bancrofti microfilariae it also kills worms of adult L. loa and probably adult W....

Adrenergic Transmission

Norepinephrine (NE), dopamine (DA), and epinephrine (Epi) are catecholamines. NE is the principal transmitter of most sympathetic postganglionic fibers and of certain tracts in the CNS. DA is the predominant transmitter of the mammalian extrapyramidal system and of several mesocortical and mesolimbic neuronal pathways. Epi is the major hormone of the adrenal medulla. There are important interactions between the endogenous catecholamines and many of the drugs used in the treatment of...

Iron Poisoning

Large amounts of ferrous salts are toxic, but fatalities in adults are rare. Most deaths occur in children, particularly between the ages of 12 and 24 months. As little as 1-2 g of iron may cause death, but 2-10 g usually is ingested in fatal cases. The frequency of iron poisoning relates to its availability in the household, particularly the supply that remains after a pregnancy. The colored sugar coating of many of the commercially available tablets gives them the appearance of candy. All...

Drug Therapy Of Dyslipidemia

The statins are the most effective and best-tolerated agents for treating dyslipidemia. These drugs are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes an early, rate-limiting step in cholesterol biosynthesis. Higher doses of the more potent statins (e.g., atorvastatin, simvastatin, and rosuvastatin) also can reduce triglyceride levels caused by elevated VLDL levels. Some statins also are indicated for raising HDL-C levels, although the...

1

L-Methylmalonyl Succinyl Glutamic CoA CoA acid FIGURE 53-6 Interrelationships and metabolic roles of vitamin B12 and folic acid. See text for explanation and Figure 53-9 for structures of the various folate coenzymes. FIGLU, formiminoglutamic acid, which arises from the catabolism of histidine TcII, transcobalamin II CH3H4PteGlu1, methyltetrahydrofolate. reaction in carbohydrate and lipid metabolism. This reaction has no direct relationship to the metabolic pathways that involve folate. In...

Nafcillin

Nafcillin (see Table 44-1) is highly resistant to penicillinase and has proven effective against infections caused by penicillinase-producing strains of S. aureus. Nafcillin is slightly more active than oxacillin against penicillin G-resistant S. aureus. While it is the most active of the penicillinase-resistant penicillins for most microorganisms, it is not as potent as penicillin G. Oral absorption of nafcillin is irregular, and injectable preparations should be used. Nafcillin is 90 bound to...

Ganglionic Stimulating Drugs

Nicotine and several other compounds stimulate ganglionic nicotinic receptors (Figure 9-4). Nicotine Nicotine is medically and socially significant because of its presence in tobacco, its toxicity, and its propensity to cause dependence in its users. The chronic effects of nicotine and the untoward effects of the chronic use of tobacco are considered in Chapter 23. Nicotine is one of the few natural liquid alkaloids. It is a colorless, volatile base (pKa 8.5) that turns brown and acquires the...

Bile Acids

Bile acids and their conjugates are essential components of bile that are synthesized from cholesterol in the liver. The major bile acids in human adults are depicted in Figure 37-4. Bile acids induce bile flow, feedback-inhibit cholesterol synthesis, promote intestinal excretion of cholesterol, and facilitate the dispersion and absorption of lipids and fat-soluble vitamins. After secretion into the biliary tract, bile acids are largely (95 ) reabsorbed in the intestine (mainly in the terminal...

Pentostatin 2Deoxycoformycin

Pentostatin, a transition-state analog of the intermediate in the ADA reaction, is a potent inhibitor of ADA. Its effects mimic the phenotype of genetic ADA deficiency, which is associated with severe immunodeficiency affecting both T- and B-cell functions. Inhibition of ADA by pentostatin leads to accumulation of intracellular adenosine and deoxyadenosine nucleotides, which can block DNA synthesis by inhibiting ribonucleotide reductase. Deoxyadenosine also inactivates S-adenosyl homocysteine...

The Dynamic Information Base

The information available to guide drug therapy is continually evolving. Among the available sources are textbooks of pharmacology and therapeutics, medical journals, published treatment guidelines, analytical evaluations of drugs, drug compendia, professional seminars and meetings, and advertising. A strategy to extract objective and unbiased data is required for the practice of rational, evidence-based therapeutics. Patient-centered acquisition of relevant information is a centerpiece of such...

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FIGURE 33-1 Pathophysiological mechanisms of heart failure and major sites of drug action. Heart failure is accompanied by compensatory neurohormonal responses including activation of the sympathetic nervous and renin-angiotensin systems. Although these responses initially help to maintain cardiovascular function by increasing ventricular preload and systemic vascular tone, with time they contribute to the progression of myocardial failure. Increased ventricular afterload, due to systemic...

Raloxifene Oh

Hepatic metabolism of tamoxifen produces N-desmethyltamoxifen, which has affinity for ER comparable to that of tamoxifen, and lesser amounts of the highly active metabolites 4-hydroxytamoxifen and endoxifen, which have 25-50 times higher affinity for both ERa and ERfi. Raloxifene is a nonsteroidal, polyhydroxylated compound. Clomiphene has two isomers zuclomiphene (cis-clomiphene), a weak estrogen agonist, and enclomiphene (trans-clomiphene), a potent antagonist. Fulvestrant is a 7a-alkylamide...

Firstgeneration Cephalosporins

The antibacterial spectrum of cefazolin is typical of first-generation cephalosporins except that it has activity against some Enterobacter spp. Cefazolin is relatively well tolerated it is excreted by glomerular filtration and is 85 bound to plasma proteins. Cefazolin usually is preferred among the first-generation cephalosporins because it can be administered less frequently owing to its longer t1 2. Cephalexin has the same antibacterial spectrum as the other first-generation cephalosporins....

Basic Pharmacology Of Vasopressin

VASOPRESSIN RECEPTORS The cellular effects of vasopressin are mediated mainly by its interactions with the 3 types of receptors, Vla Vlb, and V2. The Vla receptor is the most widespread subtype of vasopressin receptor it is found in vascular smooth muscle, the adrenal gland, myometrium, the bladder, adipocytes, hepatocytes, platelets, renal medullary interstitial cells, vasa recta in the renal microcirculation, epithelial cells in the renal cortical collecting-duct, spleen, testis, and many CNS...

Enhanced Elimination of the Poison biotransformation

Many chemicals are biotransformed into toxic forms. Thus, inhibition of biotransformation should decrease the toxicity. For example, ethanol is used to inhibit the conversion of methanol to its highly toxic metabolite, formic acid, by alcohol dehydrogenase (see Chapter 22). Acetaminophen is converted by the CYP system to an electrophilic metabolite that is detoxified by glutathione, a cellular nucleophile (Figure 64-1). Acetaminophen does not cause hepatotoxicity until glutathione is depleted,...

Chnh

FIGURE 53-9 The structures and nomenclature of pteroylglutamic acid (folic acid) and its congeners. X represents additional residues of glutamate polyglutamates are the storage and active forms of the vitamin. The subscript that designates the number of residues of glutamate is frequently omitted because this number is variable. Synthesis of purines. Two steps in the synthesis of purine nucleotides require the participation of derivatives of folic acid. Glycinamide ribonucleotide is formylated...

Drugs For Tuberculosis Isoniazid

Isoniazid (nydrazid, others) remains the primary drug for tuberculosis. All patients with disease caused by sensitive strains should receive the drug if they can tolerate it. antibacterialactivityand mechanism of action Isoniazid is bacteriostatic for resting bacilli but bactericidal for dividing microorganisms. Isoniazid is a prodrug that is converted by mycobacterial catalase-peroxidase into an active metabolite. It inhibits biosynthesis of mycolic acids long, branched lipids that are...

Cladribine

An ADA-resistant purine analog, cladribine (2-chlorodeoxyadenosine 2-CdA) has demonstrated potent activity in hairy cell leukemia, CLL, and low-grade lymphomas. After intracellular phosphorylation by deoxycytidine kinase and conversion to cladribine triphosphate, it is incorporated into DNA. It produces DNA strand breaks and depletion of NAD and adenosine triphosphate (ATP), as well as apoptosis, and is a potent inhibitor of ribonucleotide reductase. The drug does not require cell division to...

Idiosyncratic reactions

Idiosyncrasy is an abnormal reactivity to a chemical that is peculiar to a given individual. The idiosyncratic response may take the form of extreme sensitivity to low doses or extreme insensi-tivity to high doses of chemicals. Certain idiosyncratic reactions can result from genetic polymorphisms that cause individual differences in drug pharmacokinetics for example, an increased incidence of peripheral neuropathy is seen in patients with inherited deficiencies in acetylation when isoniazid is...

CCCT or TT

FIGURE 4-7 Effect of genotype on response to estrogen hormone replacement therapy. Depicted are pretreatment (base line) and posttreatment (follow-up) high-density lipoprotein (HDL) cholesterol levels in women of the C C vs. C T or T T HMG-CoAreductase genotype. POLYMORPHISM-MODIFYING DISEASES AND DRUG RESPONSES Some genes may affect the underlying disease being treated without directly interacting with the drug. Modifier polymorphisms are important for the de novo risk of some events and for...

Introduction To Human Protozoal Infections Amebiasis

Amebiasis affects 10 of the world's population. In the U.S., amebiasis is usually seen in those living in crowded, unsanitary conditions. Entamoeba dispar accounts for 90 of human infections and E. histolytica for only 10 , but only E. histolytica causes human disease. Humans are the only known hosts for these protozoa, which are transmitted almost exclusively by the fecal-oral route. E. histolytica cysts ingested from contaminated food or water transform into trophozoites that reside in the...

Other Protozoal Infections

Babesiosis is a tick-borne zoonosis caused by parasites that invade erythrocytes, producing a febrile illness, hemolysis, and hemoglobinuria. Infection usually is self-limiting but can be severe or even fatal in asplenic or severely immunocompromised individuals. Standard therapy is a combination of clindamycin and quinine, but azithromycin plus atovaquone was as effective with fewer adverse effects. Microsporidia are unicellular eukaryotic fungal parasites that cause a number of disease...

Udp

3 '-phosphoadenosine-5' phosphosulfate CoAS CO CH, + RNH, RNH CO CH, + CoA-SH RO-. RS-. RN- + AdoMet RO-CH, + AdoHomCys GSH + R GS-R Procaine, aspirin, Clofibrate, meperidine, enalapril, cocaine Lidocaine, procainamide, indomethacin Acetaminophen, morphine, oxazepam, lorazepam Sulfonamides, isoniazid, dapsone, clonazepam (see Table 3-3) L-Dopa, methyldopa, mercaptopurine, Captopril Adriamycin, fosfomycin, busulfan drugs (see below and Figure 3-5). Steroid hormones and herbal products such as...

Ethionamide

Mechanism ofaction and antibacterialactivity, resistance Ethionamide is a prodrug that is activated by an NADPH-specific monooxygenase to a sulfoxide, and thence to 2-ethyl-4-aminopyridine. Although these products are not toxic, a transient intermediate presumably is the active antibiotic. Like isoniazid, ethionamide inhibits mycobacterial growth by inhibiting the activity of the enoyl-ACP reductase of fatty acid synthase II. Both drugs thus inhibit mycolic acid biosynthesis with consequent...

Dactinomycin Actinomycin D

Actinomycin D, first isolated from a species of Streptomyces, has beneficial effects in the treatment of solid tumors in children and choriocarcinoma. The actinomycins bind double-helical DNA the planar phenoxazone ring intercalates between adjacent guanine-cytosine base pairs of DNA and the polypeptide chains extend along the minor groove of the helix, resulting in a dactinomycin-DNA complex with great stability. Binding of dactinomycin blocks transcription of DNA by RNA polymerase. The...

Antimitotic Drugs Vinca Alkaloids

Vinblastine and vincristine alkaloids purified from the periwinkle plant are used for treatment of leukemias, lymphomas, and testicular cancer. A closely related derivative, vinorelbine, has important activity against lung cancer and breast cancer. The vinca alkaloids are cell cycle-specific agents, and in common with other drugs such as colchicine, podophyllotoxin, and taxanes, block cells in mitosis. The vinca alkaloids bind specifically to -tubulin and block its ability to polymerize with...

Anatomically Defined Reentry

Reentry can occur when impulses propagate by more than one pathway between two points in the heart, and those pathways have heterogeneous electrophysiological properties. Patients with Wolff-Parkinson-White (WPW) syndrome have accessory connections between the atrium and ventricle. With each sinus node depolarization, impulses can excite the ventricle via the normal structures (AV node) or the accessory pathway. However, the electrophysiological properties of the AV node and accessory pathways...

Polymyxin B And Colistin

The polymyxins are a group of closely related antibiotics elaborated by various strains of Bacillus polymyxa. Colistin is produced by Bacillus colistinus. These drugs, which are cationic detergents, are basic peptides of 1000 Da. Colistin (polymyxin E) is available as colistin sulfate for oral use and as colistimethate sodium for parenteral administration (not recommended). The antimicrobial activities of polymyxin B and colistin are restricted to gram-negative bacteria. Polymyxins are...

General Principles Of Surgical Anesthesia

The practice of anesthesia is usually neither therapeutic nor diagnostic, and the exceptions to this (e.g., treatment of status asthmaticus with halothane and intractable angina with epidural local anesthetics) should not obscure this critical point. Hence, administration of general anesthesia and developments of new anesthetic agents and physiologic monitoring technology have been driven by three general objectives 1. Minimizing the potentially deleterious effects of anesthetic agents and...

Guanadrel

Guanadrel (hylorel) specifically inhibits the function of peripheral postganglionic adrenergic neurons. It is an exogenous false neurotransmitter that is accumulated, stored, and released Like NE but is inactive at adrenergic receptors. The drug is actively transported into neurons by the same transporter (NET) that mediates NE reuptake (see Chapter 6). When given intravenously, guanadrel initially releases NE in an amount sufficient to increase arterial blood pressure. This is not noticeable...

Cytarabine Cytosine Arabinoside AraC

Cytarabine (1- -d-arabinofuranosylcytosine Ara-C) is the single most effective agent for induction of remission in AML. Ara-C is an analog of 2'-deoxycytidine the 2'-hydroxyl hinders rotation of the pyrimidine base around the nucleosidic bond and interferes with base stacking. Ara-C penetrates cells by a carrier-mediated process shared by physiological nucleosides. In infants and adults with ALL and the t(4 11) MLL translocation, high-dose Ara-C is particularly effective in these patients, the...

Daunorubicin Doxorubicin Epirubicin Idarubicin and Mitoxantrone

These anthracycline antibiotics are among the most important antitumor agents. They are derived from the fungus Streptococcus peucetius var. caesius. Idarubicin and epirubicin are analogs of the naturally produced anthracyclines, differing only slightly in chemical structure, but having somewhat distinct patterns of clinical activity. Daunorubicin and idarubicin have been used primarily in the acute leukemias, whereas doxorubicin and epirubicin display broader activity against human solid...

Pharmacodynamic Variability

Individuals vary in the magnitude of their response to the same concentration of a single drug or to similar drugs, and a given individual may not always respond in the same way to the same drug FIGURE 5-3 The Log concentration effect relationship. Representative log concentration-effect curve illustrating its four characterizing variables. Here, the effect is measured as a function of increasing drug concentration in the plasma. Similar relationships also can be plotted as a function of the...

Release Of Other Autacoids

The release of histamine only partially explains the biological effects that ensue from immediate hypersensitivity reactions. This is so because a broad spectrum of other inflammatory mediators is released on mast cell activation. Stimulation of IgE receptors also activates phospholipase A2(PLA2), leading to the production of a host of mediators, including platelet-activating factor (PAF) and metabolites of arachidonic acid. Leukotriene D4, which is generated in this way, is a potent contractor...

Mechanism Of Action And Resistance

Metronidazole is a prodrug that is activated by reduction of the nitro group by susceptible organisms. Unlike their aerobic counterparts, anaerobic and microaerophilic pathogens such as T. vaginalis, E. histolytica, and G. lamblia and anaerobic bacteria contain electron transport components that have a sufficiently negative redox potential to donate electrons to metronidazole. Electron transfer forms a highly reactive nitro radical anion that kills susceptible organisms by radical-mediated...

Mechanism Of The Positive Inotropic Effect

All cardiac glycosides are potent and highly selective inhibitors of the active transport of Na+ and K+ across cell membranes by their reversible binding to the a subunit of the Na+, K+-ATPase. Both Na+ and Ca2+ ions enter cardiac muscle cells during each depolarization (Figure 33-2). Ca2+ entry triggers contraction it then is resequestered by the sarcoplasmic reticular Ca2+-ATPase (SERCA2) and also is removed from the cell by the Na+-Ca2+ exchanger (NCX) and by a sarcolemmal Ca2+-ATPase....

Pharmacological Properties

The pharmacological properties of anti-ChE agents can be predicted by knowing where ACh is released physiologically by nerve impulses, the degree of nerve impulse activity, and the responses of the corresponding effector organs to ACh (see Chapter 6). The anti-ChE agents potentially can produce all the following effects (1) stimulation of muscarinic receptor responses at autonomic effector organs (2) stimulation, followed by depression or paralysis, of all autonomic ganglia and skeletal muscle...

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...

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...

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....