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...

O

ABSORPTION, FATE, AND EXCRETION The sulfonylureas have similar spectra of activities thus, their pharmacokinetics are their most distinctive characteristics. All are effectively absorbed from the gastrointestinal tract, although food and hyperglycemia can reduce the absorption. In view of the time required for absorption, sulfonylureas with short half-lives may be more effective when given 30 minutes before eating. Sulfonylureas in plasma are largely (90-99 ) bound to protein, especially...

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...

Info

Copyright 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. FIGURE 25-1 Metabolism of arachidonic acid. The cyclooxygenase (COX) pathway is highlighted in gray. The lipoxygenase (LOX) pathways are expanded in Figure 25-2. Cyclic endoperoxides (PGG2 and PGH2) arise from the sequential cyclooxygenase and hydroperoxidase actions of COX-1 or COX-2 on arachidonic acid released from membrane phospholipids. Subsequent products are generated by tissue-specific synthases and transduce...

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

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...

Physicochemical Factors In Transfer Of Drugs Across Membranes

The absorption, distribution, metabolism, and excretion of a drug all involve its passage across cell membranes (Figure 1 1). The plasma membrane consists of a bilayer of amphipathic lipids with their hydrocarbon chains oriented inward to the center of the bilayer to form a continuous hydrophobic phase and their hydrophilic heads oriented outward. Individual lipid molecules in the bilayer vary according to the particular membrane and can move laterally and organize themselves with cholesterol...

Noncompetitive antagonism

FIGURE 1-10 Mechanisms of receptor antagonism. A. Competitive antagonism occurs when the agonist A and antagonist I compete for the same binding site on the receptor. Response curves for the agonist are shifted to the right in a concentration-related manner by the antagonist such that the EC50 for the agonist increases (e.g., L versus L', L, and L') with the concentration of the antagonist. B. If the antagonist binds to the same site as the agonist but does so irreversibly or...

Opioid Antagonists

These agents have obvious therapeutic utility in the treatment of opioid overdose. As the understanding of the role of endogenous opioid systems in pathophysiological states (e.g., shock, stroke, spinal cord and brain trauma) increases, additional therapeutic indications for these antagonists may develop. If endogenous opioid systems have not been activated, the pharmacological actions of opioid antagonists depend on whether or not an opioid agonist has been administered previously, on the...

Therapeutic Uses Of Ace Inhibitors And Clinical Summary

ACE Inhibitors in Hypertension ACE inhibition lowers systemic vascular resistance and mean, diastolic, and systolic blood pressures in various hypertensive states (see Chapter 32). ACE inhibitors commonly lower blood pressure in hypertensive subjects, except in those with primary aldosteronism. The initial change in blood pressure is most marked in subjects with high PRA and AngII plasma levels prior to treatment. Several weeks into treatment, additional patients show sizable reductions in...

Spx

FIGURE 55-1 Secretion and actions of growth hormone. Two hypothalamic factors, growth hormone-releasing hormone (GHRH) and somatostatin (SST), act on the somatotropes in the anterior pituitary to regulate growth hormone secretion. SST also inhibits GHRH release. Growth hormone exerts direct effects on target tissues and indirect effects mediated by stimulating the release of insulin-like growth factor-1 (IGF-1). The gastric peptide ghrelin enhances growth hormone release, directly by actions at...

Miscellaneous Immunosuppressant And Antiinflammatory Agents

Mycophenolate mofetil (cellcept) is an immunosuppressant approved for prophylaxis of organ rejection in patients with renal, cardiac, and hepatic transplants (see Chapter 52). Mycophenolic acid depletes guanosine nucleotides essential for DNA and RNA synthesis, and functions as a specific inhibitor of T- and B-lymphocyte activation and proliferation. The drug also may enhance apoptosis. Mycophenolate mofetil is used increasingly to treat inflammatory and autoimmune diseases in dermatology in...

Pharmacological Properties The Prototypical Alkaloids Atropine and Scopolamine

Atropine and scopolamine differ quantitatively in antimuscarinic actions, particularly in their ability to affect the CNS. Atropine has almost no detectable effect on the CNS at doses that are used clinically. In contrast, scopolamine has prominent central effects at low therapeutic doses. The basis for this difference is probably the greater permeation of scopolamine across the blood-brain barrier. Because atropine has limited CNS effects, it is preferred to scopolamine for most purposes....

Side Effects

Cardiovascular System The most predictable side effect of halothane is a dose-dependent reduction in arterial blood pressure. Mean arterial pressure typically decreases -20-25 at MAC concentrations of halothane, primarily as a result of direct myocardial depression, and perhaps an inability of the heart to respond to the effector arm of the baroreceptor reflex. Halothane-induced reductions in blood pressure and heart rate generally disappear after several hours of constant halothane...

Mushroom Poisoning Mycetism

Mushrooms are a rich source of toxins mushroom poisoning has increased as the result of the popularity of hunting wild mushrooms. High concentrations of muscarine are present in various species of Inocybe and Clitocybe. The symptoms of muscarine intoxication (salivation, lacrima-tion, nausea, vomiting, headache, visual disturbances, abdominal colic, diarrhea, bronchospasm, bradycardia, hypotension, shock) develop within 30-60 minutes of ingestion. Treatment with atropine ( -2 mg intramuscularly...

Clonidine Guanabenz and Guanfacine

The detailed pharmacology of the a2 adrenergic agonists clonidine (catapres), guanabenz, (wytensin), and guanfacine (tenex) is discussed in Chapter 10. These drugs stimulate the a2A subtype of a2 adrenergic receptors in the brainstem, reducing sympathetic outflow from the CNS. Patients who have had a spinal cord transection above the level of the sympathetic outflow tracts do not display a hypotensive response to clonidine. At doses higher than those required to stimulate central a2A receptors,...

Antiseizure Barbiturates

Most barbiturates have antiseizure properties. The discussion below is limited to the two barbiturates that exert maximal antiseizure action at doses below those required for hypnosis, a property that determines their clinical utility as antiseizure agents. The pharmacology of barbiturates is considered in Chapter 16. Phenobarbital (luminal, others) was the first effective organic antiseizure agent. It has relatively low toxicity, is inexpensive, and is still an effective and widely used drug...

Cholinomimetic Choline Esters And Natural Alkaloids

Muscarinic cholinergic receptor agonists can be divided into two groups (1) ACh and several synthetic choline esters, and (2) the naturally occurring cholinomimetic alkaloids (particularly pilocarpine, muscarine, and arecoline) and their synthetic congeners. The structures and pharmacologic properties of a congeneric series are summarized by Table 7-1 and Figure 7-1. Methacholine (acetyl-8-methylcholine) differs from ACh chiefly in its greater duration and selectivity of action. Its action is...

Absorption Fate And Excretion Of Muscarinic Antagonists

Belladonna alkaloids and the tertiary synthetic and semisynthetic derivatives are absorbed rapidly from the GI tract and mucosal surfaces absorption from intact skin is limited, although efficient absorption does occur in the postauricular region for some agents, allowing delivery via transdermal patch. Systemic absorption of inhaled or orally ingested quaternary muscarinic antagonists is minimal, even from the conjunctiva of the eye the quaternary agents do not cross the blood-brain barrier....

Antidiarrheal Agents

DIARRHEA GENERAL PRINCIPLES AND APPROACH TO TREATMENT Diarrhea is defined as excessive fluid weight, with 200 g day representing the upper limit of normal stool water weight for healthy adults. Since stool weight is largely determined by stool water, most cases of diarrhea result from disorders of intestinal water and electrolyte transport. Diarrhea can be caused by an increased osmotic load within the intestine (resulting in retention of water within the lumen) excessive secretion of...

Helium

Helium (He) is an inert gas whose low density, low solubility, and high thermal conductivity provide the basis for its medical and diagnostic uses the gas is supplied in brown cylinders. Helium can be mixed with oxygen and administered by mask or tracheal tube. Under hyperbaric conditions, it can be substituted for the bulk of other gases, resulting in a mixture of much lower density that is easier to breathe. The primary uses of helium are in pulmonary function testing, the treatment of...

Causes of Diuretic Resistance in Heart Failure

Noncompliance with medical regimen excess dietary Na+ intake Decreased renal perfusion and glomerular filtration rate due to Excessive intravascular volume depletion and hypotension due to aggressive diuretic or vasodilator therapy Decline in cardiac output due to worsening heart failure, arrhythmias, or other primary cardiac causes Selective reduction in glomerular perfusion pressure following initiation (or dose increase) of ACE inhibitor therapy Nonsteroidal anti-inflammatory drugs Primary...

Inhibitors Of Carbonic Anhydrase

The three carbonic anhydrase inhibitors available in the U.S. are acetazolamide (diamox), dichlor-phenamide (daranide), and methazolamide (GlaucTabs). Proximal tubular epithelial cells are richly endowed with the zinc metalloenzyme carbonic anhydrase, which is found in the luminal and basolateral membranes (type IV carbonic anhydrase), as well as in the cytoplasm (type II carbonic anhydrase). Carbonic anhydrase plays a key role in NaHCO3 reabsorption and acid secretion. In the proximal tubule,...

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a condition that affects up to 15 of the U.S. population. Patients may complain of a variety of symptoms, the most characteristic of which is recurrent abdominal pain associated with altered bowel movements. IBS appears to result from a varying combination of disturbances in visceral motor and sensory function, often associated with significant affective disorders. The disturbances in bowel function can be either constipation or diarrhea or both at different...

Ketanserin

Atypical Antipsychotic Drugs Clozapine (Clozaril), a 5-HT2A 2C receptor antagonist, represents a class of atypical antipsychotic drugs with reduced incidence of extrapyramidal side effects compared to the classical neuroleptics, and possibly a greater efficacy for reducing negative symptoms of schizophrenia (see Chapter 18). Clozapine also has a high affinity for subtypes of DA receptors. one of the newest strategies for the design of additional atypical antipsychotic drugs is to combine 5-HT2A...

Effects Of Ethanol On Physiological Systems

William Shakespeare described the acute pharmacological effects of imbibing ethanol in the Porter scene (Act 2, Scene 3) of Macbeth. The Porter, awakened from an alcohol-induced sleep by Macduff, explains three effects of alcohol and then wrestles with a fourth effect that combines the contradictory aspects of soaring overconfidence with physical impairment Porter . . . and drink, sir, is a great provoker of three things. Macduff What three things does drink especially provoke Porter Marry,...

Clinical Pharmacology Nitrogen Mustards

The unique pharmacological characteristics of the individual agents are considered here. mechlorethamine Mechlorethamine was the first clinically used nitrogen mustard and is the most reactive drug in this class. Severe local reactions of exposed tissues necessitate rapid intravenous injection of mechlorethamine for most uses. In either water or body fluids, at rates affected markedly by pH, mechlorethamine rapidly undergoes chemical degradation as it combines with either water or cellular...

Use of Immunomodulatory Drugs for Ophthalmic Therapy

GLUCOCORTICOIDS Glucocorticoids have an important role in managing ocular inflammatory diseases their chemistry and pharmacology are described in Chapter 59. Currently the glucocorticoids formulated for topical administration to the eye are dexamethasone (decadron, others), prednisolone (pred forte, others), fluorometholone (fml, others), loteprednol (alrex, lotemax), medrysone (hms), and rimexolone (vexol). Because of their anti-inflammatory effects, topical glucocorticoids are used in...

Use of Autonomic Agents in the

Autonomic drugs are used extensively for diagnostic and surgical purposes and for the treatment of glaucoma, uveitis, and strabismus. The autonomic agents used in ophthalmology as well as the responses (i.e., mydriasis and cycloplegia) to muscarinic cholinergic antagonists are summarized in Table 63-5 (also see Chapters 6 through 10). Glaucoma Characterized by progressive optic nerve cupping and visual field loss, glaucoma is responsible for the bilateral blindness of 90,000 Americans (half of...

Parenteral Vasodilators

The failing left ventricle is characterized by depression of myocardial contractility and increased sensitivity to alterations of left ventricular afterload. This latter attribute of the failing ventricle is manifest by a greater proportional reduction of stroke volume as the impedance to ejection is increased. Conversely, afterload reduction in this setting can be associated with substantial increases in stroke volume. This increased afterload dependence underlies the beneficial effects of...

Symptoms Of Deficiency

The chief manifestation of vitamin K deficiency is an increased bleeding tendency (see discussion of hypoprothrombinemia in section on oral anticoagulants, above). Ecchymoses, epistaxis, hematuria, GI bleeding, and postoperative hemorrhage are common intracranial hemorrhage may occur. Hemoptysis is uncommon. The discovery of a vitamin K-dependent protein in bone suggests that the fetal bone abnormalities associated with the administration of oral anticoagulants during the first trimester of...

Antiviral Agents for Ophthalmic

Generic Name (TRADE NAME) Route of Administration Ocular Toxicity Indication for Use Trifluridine (viroptic) Vidarabine (vira-a) Acyclovir (Zovirax) (vitrasert) Formivirsen (vitravene) Cidofovir (vistide) Oral, intravenous (200-mg capsules, 400- and 800-mg tablets) 500-mg tablets) Intravenous, Intravitreal Intravenous, oral, Intravitreal implant Intravitreal injection Intravenous conjunctivitis Herpes simplex keratitis and conjunctivitis Herpes zoster ophthalmicus Herpes simplex iridocyclitis...

Therapeutic Uses

Vitamin K is used therapeutically to correct the bleeding tendency or hemorrhage associated with its deficiency. Vitamin K deficiency can result from inadequate intake, absorption, or utilization of the vitamin, or as a consequence of the action of a vitamin K antagonist. Phylloquinone (aquamephyton, konakion, mephyton) is available as tablets and in a dispersion with buffered polysorbate and propylene glycol (konakion) or polyoxyethylated fatty acid derivatives and dextrose (aquamephyton)....

Paralytic Ileus And Atony Of The Urinary Bladder

In the treatment of both these conditions, neostigmine generally is preferred among the anti-ChE agents. The direct parasympathomimetic agents (Chapter 7) are employed for the same purposes. The usual subcutaneous dose of neostigmine methylsulfate for postoperative paralytic ileus is 0.5 mg, given as needed. Peristaltic activity commences 10 30 minutes after parenteral administration, whereas 2 4 hours are required after oral administration of neostigmine bromide (15 30 mg). It may be necessary...

Pharmacokinetic Interactions Caused by Diminished Drug Delivery to the Site of Action

For drugs administered orally, impaired gastrointestinal (GI) absorption is an important consideration. For example, aluminum ions in certain antacids or ferrous ions in oral iron supplements form insoluble chelates of tetracycline antibiotics, thereby preventing their absorption. The antifungal ketoconazole is a weak base that is only soluble at acid pH. Drugs that inhibit gastric acidity, such as the proton pump inhibitors and histamine H2 receptor antagonists, impair the dissolution and...

Prokinetic Agents And Other Stimulants Of Gi Contractility

Prokinetic agents enhance coordinated GI motility and transit of material in the GI tract. Although ACh, when released from primary motor neurons in the myenteric plexus, is the principal immediate mediator of muscle contractility, most clinically useful prokinetic agents act upstream of ACh, at receptor sites on the motor neuron itself, or even more indirectly, on neurons one or two orders removed. These agents appear to enhance the release of excitatory neurotransmitter at the nerve-muscle...

Gonadotropinreleasing Hormone And Gonadotropins

LH and FSH were named initially based on their actions on the ovary. These pituitary hormones, together with the related placental hormone hCG, are collectively referred to as the gonadotropins because of their actions on the gonads. The regulation of gonadotropin secretion is described in detail in Chapters 57 and 58. LH and FSH are synthesized and secreted by gonadotropes hCG is synthesized the syncytiotrophoblast of the placenta. Pituitary gonadotropin production is stimulated by GnRH and is...

B2Selective Adrenergic Receptor Agonists

In treating asthma, preferential activation of b2 receptors without stimulation of b1 receptors in the heart is desirable. Drugs with preferential affinity for b2 receptors over b1 receptors have been developed, but selectivity is not absolute and is lost at high concentrations. Administration by inhalation of small doses of a b2 agonist in aerosol form leads to effective activation of b2 receptors in the bronchi but very low systemic drug concentrations. Consequently, there is less potential...

Drugs and Biological Agents Used in Ophthalmic Surgery

Adjuncts in anterior segment surgery Viscoelastic substances assist in ocular surgery by maintaining spaces, moving tissue, and protecting surfaces. These substances are prepared from hyaluronate, chondroitin sulfate, or hydroxypropylmethylcellulose, share the following important physical characteristics viscosity, shear flow, elasticity, cohesiveness, and coata-bility, and are broadly characterized as dispersive or cohesive. They are used almost exclusively in anterior segment surgery....

Miscellaneous Agents Hydroxyurea

This drug has unique and diverse biological effects that have led to exploration of its clinical utility as an antileukemic drug, radiation sensitizer, and an inducer of HbF in patients with sickle cell disease. Its use has been encouraged because the drug is orally administered and its toxicity in most patients is modest and limited to myelosuppression. Hydroxyurea (HU) inhibits the enzyme ribonu-cleoside diphosphate reductase, which catalyzes the reductive conversion of ribonucleotides to...

Inhalational Anesthetics

Structures of the currently used inhalational anesthetics are shown in Figure 13-3. One of the troublesome properties of the inhalational anesthetics is their low safety margin. The inhalational anesthetics have therapeutic indices (LD50 ED50) that range from 2-4, making these among the most dangerous drugs in clinical use. The toxicity of these drugs is largely a function of their side effects, and each of the inhalational anesthetics has a unique side-effect profile. Hence, the selection of...

Oh Dihydroartemisinin

Heme iron within the parasite catalyzes cleavage of the endoperoxide bridge, followed by rearrangement to produce a carbon-centered radical that alkylates and damages macromolecules in the parasite. Artemisinin and its derivatives exhibit antiparasitic activity against other protozoa, including Leishmania major and Toxoplasma gondii, and have been used alone or in combination in patients with schistosomiasis. The semisynthetic artemisinins are available for oral...

Melarsoprol

Melarsoprol (Mel B arsobal) is supplied as a 3.6 (w v) solution in propylene glycol for intravenous administration. It is available in the U.S. only from the CDC. ANTIPROTOZOAL EFFECTS Melarsoprol is a prodrug that is metabolized rapidly (t1 2 of 30 minutes) to melarsen oxide, the active form. Arsenoxides react avidly and reversibly with sulfhydryl groups and thereby inactivate many enzymes. Melarsoprol reacts with trypanothione to form melarsen oxide-trypanothione adduct, which potently...

Antimetabolites Folic Acid Analogs

Antifolate chemotherapy produced the first cure of a solid tumor, choriocarcinoma. Introduction of high-dose regimens with rescue of host toxicity by the reduced folate, leucovorin (folinic acid, citrovorum factor, 5-formyl tetrahydrofolate, N5-formyl FH4), further extended the effectiveness of these drugs to both systemic and CNS lymphomas, osteogenic sarcoma, and leukemias. Most recently, analogs that differ from methotrexate in their transport properties and sites of action have proven...

Clinical Use Of Vasopressin Peptides

THERAPEUTIC USES Only two antidiuretic peptides are available for clinical use in the U.S. Vasopressin (synthetic 8-l-arginine vasopressin pitressin) is available as a sterile aqueous solution it may be administered subcutaneously, intramuscularly, or intranasally. Desmopressin acetate (synthetic 1-deamino-8-d-arginine vasopressin ddavp, others) is available as a sterile aqueous solution packaged for intravenous or subcutaneous injection, in a nasal solution for intranasal administration with...

Drug Receptors

Quantitatively proteins form the most important class of drug receptors. Examples include the receptors for hormones, growth factors, transcription factors, and neurotransmitters the enzymes of crucial metabolic or regulatory pathways (e.g., dihydrofolate reductase, acetylcholinesterase, and cyclic nucleotide phosphodiesterases) proteins involved in transport processes (e.g., Na+,K+-ATPase) secreted glycoproteins (e.g., Wnts) and structural proteins (e.g., tubulin). Specific binding properties...

Long Loop Negative Feedback

Pharmacological Interventions Physiological interrelationships Major pathways modulating renin rc B Macula Densa Cell Juxtaglomerular Cell FIGURE 30-2 A. Schematic portrayal of the three major physiological pathways regulating renin release. See text for details. MD, macula densa PGI2 PGE2 prostaglandins and E2 NSAIDs, nonsteroidal anti-inflammatory drugs Angll, angiotensin II ACE, angiotensin-converting enzyme, ATj R, angiotensin subtype 1 receptor NE Epi, norepinephrine epinephrine JGCs,...

Importance Of Enzyme Turnover Rate In The Relief Of Aspirin Action

Copyright 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. Mechanism of Action and Therapeutic Effects of NSAIDs Prostaglandins are released whenever cells are damaged, and aspirin and tNSAIDs inhibit their biosynthesis in all cell types. However, aspirin and tNSAIDs generally do not inhibit the formation of other inflammatory mediators, including other eicosanoids such as the LTs (see Chapter 25). While the clinical effects of these drugs are explicable in terms of...

Paraaminobenzoic Acid

FIGURE 43-1 Structural formulas of selected sulfonamides and para-aminobenzoic acid. The N of the para-NH group is designated as N4 that of the amide NH2, as N1. After systemic administration, sulfadiazine and sulfisoxazole attain concentrations in cerebrospinal fluid (CSF) that may be effective in meningitis. Sulfonamides readily cross the placenta to reach the fetal circulation, potentially exerting both antibacterial and toxic effects. The sulfonamides are metabolized in the liver. The major...

Other Agents That Suppress Motility

Smooth muscle relaxants such as organic nitrates and Ca2+ channel antagonists (see Chapter 31) often produce temporary, if partial, relief of symptoms in motility disorders such as achalasia, in which the lower esophageal sphincter fails to relax, resulting in a functional obstruction to the passage of food and severe difficulty in swallowing. Another approach relies on the use of botulinum toxin, injected in doses of 80 200 units directly into the lower esophageal sphincter via an endoscope....

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

44 SECTION I General Principles Table 3-1 Cytochrome P450s (P450 or CYP) Flavin-containing monooxygenases (FMO) Epoxide hydrolases (mEH, sEH) Phase 2 transferases Sulfotransferases (SULT) UDP-glucuronosyltransferases (UGT) Glutathione-S-transferases (GST) N-acetyltransferases (NAT) Methyltransferases (MT) Alcohol dehydrogenases Aldehyde dehydrogenases NADPH-quinone oxidoreductase (NQO) C and O oxidation, dealkylation, others N, S, and P oxidation Hydrolysis of epoxides Addition of sulfate...

Clinical Uses Of Ethanol

Dehydrated alcohol may be injected in close proximity to nerves or sympathetic ganglia to relieve the long-lasting pain related to trigeminal neuralgia, inoperable carcinoma, and other conditions. Epidural, subarachnoid, and lumbar paravertebral injections of ethanol also have been employed for inoperable pain. For example, lumbar paravertebral injections of ethanol may destroy sympathetic ganglia and thereby produce vasodilation, relieve pain, and promote healing of lesions in patients with...

Testosterone And Other Androgens

Synthesis, secretion, and transport of testosterone Leydig cells in the testes synthesize testosterone by the pathways shown in Figure 58-1. In women, testosterone primarily serves as a precursor to estrogens but also is the predominant circulating androgen. Testosterone secretion is greater in men than in women at almost all stages of life, a difference that explains almost all other differences between men and women. In the first trimester in utero, placental human chorionic gonadotropin...

Tolerance And Rebound With Acidsuppressing Medications

Tolerance to the acid-suppressing effects of H2 receptor antagonists may account for a diminished therapeutic effect with continued drug administration. Tolerance can develop within 3 days of starting treatment and may be resistant to increased doses. Diminished sensitivity may result from the effect of the secondary hypergastrinemia to stimulate histamine release from ECL cells. Proton pump inhibitors, despite even greater elevations of endogenous gastrin, do not cause this phenomenon,...

Nats

FIGURE 3-2 The fraction of clinically used drugs metabolized by the major phase 1 and phase 2 enzymes. The relative size of each pie section represents the estimated percentage of drugs metabolized by the major phase 1 (panel A) and phase 2 (panel B) enzymes. In some cases, more than a single enzyme is responsible for metabolism of a single drug. CYP, cytochrome P450 DPYD, dihydropyrimidine dehydrogenase GST, glutathione-S-transferase NAT, N-acetyltransferase SULT, sulfotransferase, TPMT,...

A1 Adrenergic Antagonists

Drugs that selectively block a1 adrenergic receptors without affecting a2 adrenergic receptors also are used in hypertension (Table 32-2). Prazosin (minipress), terazosin (Hytrin), and doxazosin (Cardura) are the agents approved in the U.S. for this indication. PHARMACOLOGICAL EFFECTS Initially, a1 adrenergic receptor antagonists reduce arteriolar resistance and increase venous capacitance this causes a sympathetically mediated reflex increase in heart rate and plasma renin activity. During...

Anthelmintic Action

The BZAs inhibit microtubule polymerization by binding to -tubulin. The selective toxicity of these agents likely results because the BZAs bind parasite -tubulin with much higher affinity than they do the mammalian protein. Drug resistance in nematodes may involve expression of a mutated -tubulin. There is no evidence of emerging resistance among human nematodes. The BZAs are versatile anthelmintic agents, particularly against GI nematodes, where their action is not dictated by systemic drug...

Interactions between chemicals

Concurrent exposures may alter the pharmacokinetics of drugs by changing rates of absorption, the degree of protein binding, or the rates of biotransformation or excretion of one or both interacting compounds. The pharmacodynamics of chemicals can be altered by competition at the receptor for example, atropine is used to treat organophosphate insecticide toxicity because it blocks muscarinic cholinergic receptors and prevents their stimulation by the excess acetylcholine accruing from...

R

Leukotrienes Prostaglandins Purines Histamine Proteases PAF Protons etc. Bronchoconstriction (P, 1, m, t), bronchial hyperreactivity FIGURE 27-1 Simplified view of allergic inflammation in the airways. Asthma is an episodic narrowing of the bronchi thought to be caused by an underlying chronic inflammatory disorder. In allergic asthma, inhaled allergen initiates the inflammatory response by interacting with IgE bound to mast cells and basophils. This leads to a cascade of events involving other...

Oxytocin

Oxytocin is a cyclic nonapeptide that differs from vasopressin by only 2 amino acids (see Chapter 29). It is synthesized as a larger precursor molecule in cell bodies of the paraventricular nucleus, and to a lesser extent, the supraoptic nucleus in the hypothalamus. The precursor is rapidly converted by proteolysis to the active hormone and its neurophysin, packaged into secretory granules as an oxytocin-neurophysin complex, and secreted from nerve endings that terminate primarily in the...