Antimuscarinic Poisoning

Antimuscarinic poisoning can result from the intake of excessive doses of belladonna alkaloids, synthetic an-timuscarinic drugs, and drugs from other pharmacological groups that have significant antimuscarinic activity (Table 13.2). Signs of peripheral muscarinic blockade (e.g., speech disturbances, swallowing difficulties, cardioac-celeration, and pupillary dilation) are most common at lower doses, whereas CNS effects (e.g., headache, restlessness, ataxia, and hallucinations) are more apparent...

Factors Affecting Rate Of Gastrointestinal Absorption

In addition to the lipid-water partition coefficient of drugs, local blood flow, and intestinal surface area, other factors may affect absorption from the gastrointestinal tract. The rate of gastric emptying markedly influences the rate at which drugs are absorbed, whether they are acids, bases, or neutral substances. In general, factors that accelerate gastric emptying time, thus permitting drugs to reach the large absorptive surface of the small intestine sooner, will increase drug absorption...

Griseofulvin

Griseofulvin (Gris-PEG, Grifulvin, Grisactin, Fulvicin) is an oral fungistatic agent used in the long-term treatment of dermatophyte infections caused by Epidermophyton, Microsporum, and Trichophyton spp. Produced by the mold Penicillium griseofulvin, this agent inhibits fungal growth by binding to the microtubules responsible for mitotic spindle formation, leading to defective cell wall development. Ineffective topically, griseofulvin is administered orally but has poor gastrointestinal...

Substance P

The first neuropeptide to be isolated and characterized is known as substance P. Although this 11-amino acid peptide (undecapeptide) has been known for more than 60 years, its exact physiological role is still not clear. Substance P occurs in high concentrations in neurons projecting into the substantia gelatinosa layer of the spinal cord from dorsal root ganglia, among many other areas of the brain. Substance P can directly depolarize motor neurons in a manner analogous to that of other...

Suramin

Suramin (Germanin) is a derivative of a nonmetallic dye whose antiparasitic mechanism of action is not clear. It appears to act on parasite specific a-glyc-erophosphate oxidase, thymidylate synthetase, dihydro-folate reductase, and protein kinase but not on host enzymes. Suramin is not absorbed from the intestinal tract and is administered intravenously. Although the initial high plasma levels drop rapidly, suramin binds tightly to and is slowly released from plasma proteins, and so it persists...

Study Questions

A patient comes to your office with effort-induced angina and resting tachycardia. You choose the following drug to treat the patient because it slows heart rate by blocking L-type calcium channels in the SA node 2. Which of the following hemodynamic effects of ni-troglycerin are primarily responsible for the beneficial results observed in patients with secondary angina (A) Reduction in the force of myocardial contraction (B) Reduction in systemic vascular resistance (af-terload) (D) Reduction...

Synthesis Storage Release and Removal of Norepinephrine

Transmission in noradrenergic neurons is somewhat more complex, particularly in regard to the mechanisms by which the transmitter is removed from the biophase subsequent to its release. Noradrenergic transmission is represented diagrammatically in Figure 9.3. Synthesis of norepinephrine begins with the amino acid tyrosine, which enters the neuron by active transport, perhaps facilitated by a permease. In the neuronal cytosol, tyrosine is converted by the enzyme tyrosine hydroxylase to...

Glandular Tissue

Histamine stimulates the secretion of gastric acid and pepsin through an effect on the H2-receptors of the parietal cells of the gastric mucosa. Secretion of acid is a complex process that is stimulated by histamine, acetyl-choline, and gastrin and inhibited by somatostatin. The ability of H2-receptor antagonists to inhibit the enhanced gastric acid secretion caused by acetylcholine and gastrin suggests that histamine release is of primary importance in this process. Histamine also stimulates...

Supplemental Reading

Novel platelet inhibitors. Annu Rev Med 2001 52 161-184. Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost 1999 82 259-270. Diener HC. Stroke prevention Antiplatelet and antithrombotic therapy. Haemostasis 2000 30 14-26. Ferguson JJ and Zaqqa M. Platelet glycoprotein Ilb IIIa receptor antagonists Current concepts and future directions. Drugs 1999 58 965-982. Goldhaber SZ. A contemporary approach to thrombolytic therapy for pulmonary embolism. Vasc Med 2000 5 115-123....

Angiotensin Converting Enzyme A Peptidyl Dipeptide Hydrolase

Metabolism of angiotensinogen by renin produces the decapeptide angiotensin I. This relatively inactive pep-tide is acted on by a dipeptidase-converting enzyme to produce the very active octapeptide angiotensin II. In addition to converting enzyme, angiotensin I can be acted on by prolyl endopeptidase, an enzyme that removes the first amino acid to form angiotensin 1-7, a peptide primarily active in the brain. ACE has been identified in vascular endothelial cells, epithelial cells of the...

Concept of Anesthetic Dose Based on Partial Pressure Minimum Alveolar Concentration

Since the anesthesiologist has control over the partial pressure of anesthetic delivered to the lung, it can be manipulated to control the anesthetic gas concentration in the brain, hence the level of unconsciousness. For this reason, anesthetic dose is usually expressed in terms of the alveolar tension required at equilibrium to produce a defined depth of anesthesia. The dose is determined experimentally as the partial pressure needed to eliminate movement in 50 of patients challenged with a...

Drugs Useful for Treating Diarrhea Adsorbents and Bulking Agents

Kaolin powder and other hydrated aluminum silicate clays, often combined with pectin (a complex carbohydrate), are the most widely used adsorbent powders (e.g., Kaopectate). Kaolin is a naturally occurring hydrated aluminum silicate that is prepared for medicinal use as a very finely divided powder. The rationale behind its use in acute nonspecific diarrhea stems from its ability to adsorb some of the bacterial toxins that often cause the condition. It is almost harmless and is effective in...

Carbamates

Carbamate anticholinesterase agents are carbamic acid esters that are hydrolyzed by AChE in a manner similar to that of ACh. Carbamates have this general structure The clinically useful carbamates generally contain a tertiary or quaternary amine group that can bind non-covalently to the anionic site of the enzyme. The inhibition of AChE by neostigmine (Prostigmin) illustrates the general mechanism. The quaternary ammonium group of neostigmine binds electrostatically to the an-ionic site of the...

Answers

Rapacuronium is a skeletal muscle relaxant that works by competing with ACh for receptors at the postjunctional membrane. Nicotine and succinyl-choline also act at the end plate receptors but cause depolarization. Hexamethonium is a ganglion blocker that has essentially no activity at the end plate receptors, and scopolamine blocks cholinergic muscarinic receptors and thus does not act at the end plate receptors. 2. C. The patient has a rare genetic defect that results in susceptibility to...

Absorption Distribution and Excretion

Vancomycin is poorly absorbed from the gastrointestinal tract, resulting in high concentrations in the feces. In neutropenic patients and others with altered gastrointestinal mucosa with denudation, significant oral absorption of vancomycin may occur and may be accompanied by additive toxicity if rapid infusion or large parenteral doses of the drug are given concomitantly. Except for the treatment of staphylococcal enterocolitis and pseudomembranous colitis, it is administered intra venously....

Mechanism of Ganglionic Blockade

Large doses of nicotine produce a prolonged blockade of ganglionic nicotinic receptors. Unlike the blockade of ganglionic transmission produced by most ganglionic blocking agents, that is, a nondepolarizing competitive antagonism, the blockade produced by nicotine consists of two phases. Phase 1 can be described as persistent depolarization of the ganglion cell. The initial application of nicotine to the ganglion cells depolarizes the cell, which initiates an action potential. After a few...

Hypogonadism

Testicular failure may occur before puberty and present as delayed puberty and the eunuchoid phenotype, or after puberty, with the development of infertility, impotence, or decreased libido in otherwise fully virilized males. The source of hypogonadism can be testicular, as occurs in primary hypogonadism, or it may result from abnormalities of the hypothalamic-pituitary axis, as in secondary hypogonadism. Prepuberal hypogonadism is often unsuspected until a delay in male sexual development is...

Direct Thrombin Inhibitor Anticoagulants

Two drugs that are direct inhibitors of thrombin but that do not involve antithrombin III or vitamin K in their mechanism of action have been approved to provide intravenous anticoagulation in patients with he-parin-induced thrombocytopenia. Lepirudin (Refludan) and bivalirudin (Angiomax), which are analogues of the leech peptide anticoagulant hirudin, bind in a 1 1 complex with thrombin to inhibit its protease activity. Argatroban (Acova, Novastan), a synthetic analogue of arginine, interacts...

Adverse Effects Contraindications and Drug Interactions

The adverse effects of valacyclovir and acyclovir are similar. Toxicity is generally minimal, consisting largely of headache, nausea, and diarrhea. Less frequently observed are skin rash, fatigue, fever, hair loss, and depression. Reversible renal dysfunction (azotemia) and neurotoxicity (tremor, seizure, delirium) are dose-limiting toxicities of intravenous acyclovir. Adequate hydration and slow drug infusion can minimize the risk of renal toxicity. Aside from drug hypersensitivity, there are...

Stimulant Cathartics

The stimulant cathartics contain a variety of drugs whose exact mode of action is not known, although it is thought that they act on the mucosa of the intestine to stimulate peristalsis either by irritation or by exciting reflexes in the myenteric plexuses. All act in the lumen of the GI tract and are inactive if given parenterally. They produce irritation of the mucosa if given in large doses, and this irritation affects water and ion transport. However, a direct local irritation may not be...

The Dopamine Hypothesis of Schizophrenia

The dopamine hypothesis of schizophrenia is the most fully developed theory of causation for this disorder, and until recently, it has been the foundation for the rationale underlying drug therapy for this disease. The hypothesis is based on multiple lines of evidence suggesting that excessive dopaminergic activity underlies schizophrenia (1) drugs that increase dopaminergic activity, such as levodopa and amphetamines, either aggravate existing schizophrenia or induce a psychosis...

L

Case Study Diabetes and Erectile Dysfunction A 48-year-old white man went to the local urology clinic with the chief complaint of sexual incompatibility associated with failure to attain an erection. He states that he has a family history of diabetes mellitus but is not receiving any insulin or oral hypo-glycemic drugs. He is married and has fathered two children, aged 12 and 15. Blood chemistries and hormone levels are as follows total insulin (free and bound), 15 microunits mL T4 (thyroxine),...

Absorption Of Drugs From The Lung

The lungs serve as a major site of administration for a number of agents given for both local and systemic effects. Such drugs can be inhaled as gases (e.g., volatile anesthetics) or as aerosols (suspended liquid droplets or solid particles). Absorption of agents from the lung is facilitated by the large surface area of the pulmonary alveolar membranes (50-100 m2), the limited thickness of these membranes (approximately 0.2 and the high blood flow to the alveolar region. Pulmonary absorption of...

Doxorubicin and Daunorubicin

The anthracycline antibiotics are fermentation products of Streptomyces peucetius. Daunorubicin (Cerubidine) is used to treat acute leukemias, while its structural analogue, doxorubicin (Adriamycin) is extensively employed against a broad spectrum of cancers. Although the two drugs have similar pharmacological and toxico-logical properties, doxorubicin is more potent against most animal and human tumors and will be discussed in greater detail. Doxorubicin binds tightly to DNA by its ability to...

Contraindications And Cautions

Muscarinic blocking agents are contraindicated in angle-closure glaucoma. Caution also should be used in 1. Which of the responses to atropine listed below is most likely to be different in an elderly versus a young patient 2. You have successfully prescribed neostigmine to a young patient with myasthenia gravis, and her muscle strength has improved markedly. However, she also exhibits cardiovascular and gastrointestinal signs of excessive vagal tone, which you would like to block with...

Diabetes Mellitus

Diabetes mellitus affects approximately 5 to 8 of the population. A large number of individuals are asymptomatic and do not know they have the disease. The recent rise in obesity in the United States accounts for much of the observed and anticipated rise in cases of diabetes mellitus in this country. Although insulin treatment has greatly increased the life expectancy of the diabetic patient, diabetes remains the third leading cause of death by disease, the second leading cause of blindness,...

Chemotherapy

Introduction to Chemotherapy 509 Steven M. Belknap 44. Synthetic Organic Antimicrobials Sulfonamides, Trimethoprim, Nitrofurans, Quinolones, Methenamine 515 Marcia A. Miller-Hjelle, Vijaya Somaraju, and J. Thomas Hjelle 45. -Lactam Antibiotics 526 James F. Graumlich 46. Aminoglycoside Antibiotics 538 Steven Belknap 47. Tetracyclines, Chloramphenicol, Macrolides, and Lincosamides 544 48. Bacitracin, Glycopeptide Antibiotics, and the Polymyxins 552 49. Drugs Used in Tuberculosis and Leprosy...

Oral Cholecystography Agents

The iodine-containing oral cholecystographic contrast agents (OCAs) include sodium ipodate (Oragrafin), iopanoic acid (Telepaque), tyropanoic acid (Bilopaque), and iocetamic acid (Cholebrine).They all inhibit D1 and D2. These actions make OCAs useful as adjunctive therapy with other antithyroid drugs by promoting a rapid fall in the plasma T3 concentration of the seriously thyrotoxic patient. In addition, the metabolism of OCAs results in the release of large amounts of I into the circulation....

Lambert Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that is often associated with small-cell lung carcinoma. It is characterized by fatigability, hyporeflexia, and autonomic dysfunction. The neuromuscular junction appears normal in morphology, and postjunctional receptor function is unchanged. However, particles at the active zones of nerve terminals that correspond to Ca++ channels are reduced in number and disorganized, and patients with LEMS have high titers of antibodies...

Phentolamine

Human erectile tissue has a population of membrane receptors that are predominantly of the a-adrenoceptor subtype. Phentolamine (Vasomax) is a nonselective a-adrenoceptor blocking agent (see Chapter 11), and like other such agents, it has been used to treat ED. Nonselective adrenoceptor antagonists may provoke a reflex that increases both sympathetic outflow and the release of norepinephrine. Phentolamine has been used orally and intracaver-nosally in the treatment of ED. Following oral...

Clinical Uses Of Catecholamines

The clinical uses of catecholamines are based on their actions on bronchial smooth muscle, blood vessels, and the heart. Epinephrine is also useful for the treatment of allergic reactions that are due to liberation of hista-mine in the body, because it produces certain physiological effects opposite to those produced by histamine. It is the primary treatment for anaphylactic shock and is useful in the therapy of urticaria, angioneurotic edema, and serum sickness. Epinephrine also has been used...

Mary E Davis and Mark J Reasor

The discipline of toxicology considers the adverse effects of chemicals, including drugs, and other agents, such as biological toxins and radiation, on biological systems. Toxicity associated with drug action can generally be characterized as either an extension of the therapeutic effect, such as the fatal central nervous system (CNS) depression that may follow a barbiturate overdose, or as an effect that is unrelated to the therapeutic effect, such as the liver damage that may result from an...

Codeine and Other Phenanthrene Derivatives

Like morphine, codeine is a naturally occurring opioid found in the poppy plant. Codeine is indicated for the treatment of mild to moderate pain and for its antitus-sive effects. It is widely used as an opioid antitussive because at antitussive doses it has few side effects and has excellent oral bioavailability. Codeine is metabolized in part to morphine, which is believed to account for its analgesic effect. It is one of the most commonly used opioids in combination with nonopioids for the...

Nucleoside Reverse Transcriptase Inhibitors

The NRTIs are nucleoside analogues that act as competitive inhibitors of reverse transcriptase. After conversion to the triphosphate form by host cell kinases, these drugs compete with nucleoside triphosphates for access to reverse transcriptase. All NRTIs lack a 3'-hydroxyl group thus, their incorporation into a growing DNA chain results in its termination. These drugs block HIV replication and therefore the infection of new cells, but they have little effect on cells already infected with...

Classification of Viruses

Viruses are composed of one or more strands of a nucleic acid (core) enclosed by a protein coat (capsid). Many viruses possess an outer envelope of protein or lipoprotein. Viral cores can contain either DNA or RNA thus, viruses may be classified as DNA viruses or RNA viruses. Further classification is usually based on morphology, cellular site of viral multiplication, or other characteristics. Examples of DNA viruses and the diseases that they produce include adenoviruses (colds,...

Differential Blockade

Peripheral nerve functions are not affected equally by local anesthetics. Loss of sympathetic function usually is followed by loss of temperature sensation sensation to pinprick, touch, and deep pressure and last, motor function. This phenomenon is called differential blockade. Differential blockade is the result of a number of factors, including the size of the nerve, the presence and amount of myelin, and the location of particular fibers within a nerve bundle. For conduction to be...

The Chemistry Of Drugreceptor Binding

Biological receptors are capable of combining with drugs in a number of ways, and the forces that attract the drug to its receptor must be sufficiently strong and long-lasting to permit the initiation of the sequence of events that ends with the biological response. Those forces are chemical bonds, and a number of types of bonds participate in the formation of the initial drug-receptor complex. The bond formed when two atoms share a pair of electrons is called a covalent bond. It possesses a...

Adverse Effects

Colistin and polymyxin B can cause extreme nephro-toxicity when used parenterally, and any preexisting renal insufficiency will potentiate the nephrotoxicity caused by these antibiotics. Neurotoxicity is a rare adverse reaction that can be recognized by perioral paresthesia, numbness, weakness, ataxia, and blurred vision. These drugs may precipitate respiratory arrest both in patients given muscle relaxants during anesthesia and in persons with myas-thenia gravis. 1. A pediatric nurse is found...

Absorption Distribution and Excretion of Nicotine

Nicotine is well absorbed from the mucous membranes in the oral cavity, gastrointestinal tract, and respiratory system. If tobacco smoke is held in the mouth for 2 seconds, 66 to 77 of the nicotine in the smoke will be absorbed across the oral mucosa. If tobacco smoke is inhaled, approximately 90 to 98 of the nicotine will be absorbed. Nicotine is distributed throughout the body, readily crossing the blood-brain and placental barriers. The liver, kidney, and lung metabolize approximately 80 to...

General Principles Of Immunosuppressive Therapy

Before describing individual drugs, it is important to consider three principles of immunosuppressive therapy. (1) Primary immune responses are more readily inhibited than are secondary responses. Therefore, components of the primary phase of the immune response, such as processing, proliferation, and differentiation, will be the most sensitive to drug action. Drugs that are effective in suppressing an immune response in an unsensitized person generally will show much less effect, if any, in a...

Absorption Of Drugs Through The Skin

Most drugs that have been incorporated into creams or ointments are applied to the skin for their local effect. The diffusion rate of a drug through the skin is largely determined by the compound's lipid-water partition coefficient. However, the stratum corneum, or outer layer of the epidermis, forms a barrier against the rapid penetration of most drugs. This is due in large part to the relatively close-packed cellular arrangement and decreased amount of lipid in these cells. Thus, even highly...

PTH in Target Tissues

PTH has two levels of action in bone. First, in response to acute decreases in serum calcium, PTH stimulates surface osteocytes to increase the outward flux of calcium ion from bone to rapidly restore serum calcium. Thus, during brief periods of hypocalcemia, PTH release results in mobilization of calcium from labile areas of bone that lie adjacent to osteoclasts. This effect is not associated with any significant increase in plasma phosphate or bone resorption. Second, PTH induces...

Dopamine

Quantitatively, dopamine is the most important of the biogenic amine neurotransmitters in the CNS. The three major distinct dopaminergic systems in the mammalian brain are categorized according to the lengths of the neurons. There is a system comprising ultrashort neurons within amacrine cells of the retina and peri-glomerular cells in the olfactory bulb. Of the several intermediate-length dopaminergic neuronal systems, the best studied are neurons in the tuberobasal ventral hypothalamus that...

Biomedical Ethics In Pharmacology An Introduction And Framework

The relationship between physicians, scientists, and the pharmaceutical industry is a mutually advantageous one that is fraught with ethical complexity. Seemingly straightforward questions, such as whether a physician ought to enroll patients in a drug trial, which drug to prescribe when any one of several may be effective, and how to stay abreast of new drugs while remaining objective, become difficult when examined closely. This chapter provides a conceptual framework for bioethical analysis,...

Trimethoprim Sulfamethoxazole

TMP-SMX (Septra, Bactrim) is used in the treatment of genitourinary, GI, and respiratory tract infections caused by susceptible bacteria. E. coli, enterococci, P. mirabilis, some indole-positive strains of Proteus spp., and Klebsiella pneumoniae are usually sensitive to this combination therapy for both chronic and recurrent UTIs. Trimethoprim is present in vaginal secretions in high enough levels to be active against many of the organisms found in the introital area that are often responsible...

Absorption Metabolism and Excretion

Hydralazine is well absorbed (65-90 ) after oral administration. Its peak antihypertensive effect occurs in about 1 hour, and its duration of action is about 6 hours. The major pathways for its metabolism include ring hydroxylation, with subsequent glucuronide conjugation and N-acetylation. Hydralazine exhibits a first-pass effect in that a large part of an orally administered dose is metabolized before the drug reaches the systemic circulation. The first-pass metabolism occurs in the...

Alcoholism

Alcoholism is among the major health problems in most countries. Dependence on ethanol, as with other addictive drugs, is expressed as drug-seeking behavior and is associated with a withdrawal syndrome that occurs after abrupt cessation of drinking. The ethanol withdrawal syndrome is characterized by tremors, seizures, hyper-thermia, hallucinations, and autonomic hyperactivity. A number of organs are affected adversely by chronic ethanol use, the result of a direct cytotoxic action. Hepatic...

Info

Some insulins have been modified through genetic engineering to produce insulin analogues, derivatives that possess novel pharmacokinetic properties (lispro, insulin aspart, and insulin glargine).The duration of action can vary with factors such as injection volume, injection site, and blood flow at the site of administration. Rapid-acting insulin analogues (lispro, insulin aspart Humalog, Novolog ) have been engineered to contain amino acid modifications that...

The Inflammatory Process

Inflammation begins when a stimulus, such as infection, physical stress, or chemical stress, produces cellular damage (Fig. 36.1). This damage initiates the activation of transcription factors that control the expression of many inflammatory mediators. Among the more important inflammatory mediators are the eicosanoids, biological oxidants, cytokines, adhesion factors, and digestive enzymes (proteases, hyaluronidase, collagenase, and elastase). Only the first three of these are therapeutic...

Ratio of Preganglionic to Postganglionic Neurons

A single sympathetic preganglionic fiber branches a number of times after entering a ganglion and makes synaptic connection with a number of postganglionic neurons. Furthermore, some branches of this pregan-glionic fiber may ascend or descend to adjacent vertebral ganglia and terminate on an additional number of postganglionic neurons in these ganglia as well. Therefore, activity in a single sympathetic preganglionic neuron may result in the activation of a number of effector cells in widely...

Adverse Effects and Contraindications

The side effects of corticosteroids range from minor to severe and life threatening. The nature and severity of side effects depend on the route, dose, and frequency of administration, as well as the specific agent used. Side effects are much more prevalent with systemic administration than with inhalant administration. The potential consequences of systemic administration of the corti-costeroids include adrenal suppression, cushingoid changes, growth retardation, cataracts, osteoporosis, CNS...

Antihistamines

Several H histamine antagonists (e.g., diphenhydramine, promethazine, and hydroxyzine) have been used as sedative-hypnotics, since they produce some degree of sedation. While this sedation is usually considered a side effect of their antihistaminic activity, in some cases the sedation is sufficient to allow the drugs to be used in the treatment of anxiety and sleep disturbances. For these drugs, the anxiolytic properties are thought to be a direct consequence of their ability to produce...

Older Sedativehypnotic And Anxiolytic Agents

Before the introduction of the benzodiazepines, a number of drugs from different chemical and pharmacological classes were used in the treatment of anxiety and insomnia. However, these drugs are more toxic and produce more serious side effects than do the benzodi-azepines. Many also have significant abuse potential. Consequently, most of these compounds are no longer widely used. These drugs include the barbiturates (e.g., pentobarbital, amobarbital), carbamates (e.g., meproba-mate),...

Adverse Reaction Surveillance

Almost all drugs have adverse effects associated with their use these range in severity from mild inconveniences to severe morbidity and death. Some adverse ef fects are extensions of the drug's pharmacological effect and are predictable, for example, orthostatic hypotension with some antihypertensive agents, arrhythmias with certain cardioactive drugs, and electrolyte imbalance with diuretics. Other adverse effects are not predictable and may occur rarely or be delayed for months or years...

Individual Drugs Used To Stimulate The Immune System

A number of disorders can be treated with immuno-stimulating agents (also known as biological response modifiers or immunomodulating agents) these drugs enhance the body's immune response. These conditions include immunodeficiency diseases, cancer, some types of viral and fungal infections, and certain autoimmune disorders. The drugs may work on cellular or humoral immune systems or both. Immunostimulating agents are nonspecific they cause general stimulation of the immune system. Among the...

A2Adrenoceptor Agonists

-Adrenoceptor agonists have received attention for their ability to produce sedation and analgesia. Their sedative properties may be related to action on a2-re-ceptors in the locus ceruleus, and analgesia likely occurs via a2-receptors in the spinal cord and locus ceruleus. Agents used when sedation is desirable include oral clonidine (Catapres) and IV dexmedetomidine (Prece-dex), which has recently been approved in the United States for sedation in intensive care units. A solution of...

Muscarinic Receptors and Signal Transduction

Classical studies by Sir Henry Dale demonstrated that the receptors activated by muscarine, an alkaloid isolated from the mushroom Amanita muscaria, are the same receptors activated by ACh released from parasympathetic nerve endings, from which the general notion that muscarinic agonists have parasympatho-mimetic properties was born. This conclusion is true but incomplete, and we now know that muscarinic receptors have a broader distribution and many functional roles. To understand the actions...

Dapsone and Sulfones

The sulfones are structural analogues of PABA and are competitive inhibitors of folic acid synthesis. Sulfones are bacteriostatic and are used only in the treatment of leprosy. Dapsone (Avlosulfon) is the most widely used sulfone for the long-term therapy of leprosy. Although the sulfones are highly effective against most strains of M. leprae, a small number of organisms, especially those found in lepromatous leprosy patients, are less susceptible and can persist for many years, resulting in...

The Patientdrugpathogen Interaction

In the laboratory the strain of pathogen, the number of infecting organisms, the culture medium, the antibiotic concentration, and the duration of antibiotic exposure can be precisely specified. This precision cannot be obtained in patients. In addition, chemotherapy of human disease is complex, as it depends on a complex patient-drug-pathogen interaction. This interaction has six components Pharmacokinetics What the patient does to the drug. For example, a patient with renal failure will have...

Managing Chemotherapy

Initial therapy is usually empirical and the regimen is adjusted according to the results of culture and sensitivity testing. Physicians must select a drug, administration route, dosage, and dosing interval. These may be changed several times during therapy. For example, severe nausea and high severity of illness may necessitate initial par-enteral antibiotic administration. Several days later, when the nausea has abated and the patient is clinically stable, the patient may be switched to oral...

Steroid Transport in Blood

Glucocorticoids secreted into the systemic circulation are reversibly bound to a specific a-globulin known as transcortin or corticosteroid-binding globulin. This binding system has a high affinity and low capacity for corti-costeroids, which contrasts with the low-affinity binding of these compounds to plasma albumin. Approximately 80 of the normal cortisol content in human plasma (12 g dL) is bound to corticosteroid-binding globulin, while 10 is bound to serum albumin the remaining 10 is the...

Oxytocin

Oxytocin (Pitocin, Syntocinon) causes milk release (letdown) by stimulating contraction of the myoepithelial cells of the milk ducts in lactating mammary glands this forces milk from the alveoli of the breast. Oxytocin release is stimulated by suckling and by auditory and visual stimuli, such as a baby's cry. Oxytocin is available as a nasal spray, which is used as an aid to lactation when milk ejection is impaired. Oxytocin also stimulates contraction of uterine smooth muscle in late phases of...

Allylamines

The allylamines (naftifine hydrochloride and terbinafine hydrochloride) are reversible noncompetitive inhibitors of the fungal enzyme squalene monooxygenase (squa-lene 2,3-epoxidase), which coverts squalene to lanos-terol. With a decrease in lanosterol production, ergos-terol production is also diminished, affecting fungal cell membrane synthesis and function. These agents generally exhibit fungicidal activity against dermatophytes and fungistatic activity against yeasts. Naftifine...

Mechanism of Ganglionic Stimulation

Nicotine, lobeline, trimethylammonium, and DMPP stimulate all autonomic ganglia by simple combination with ganglionic nicotinic receptors on the postsynaptic membrane. This leads to membrane depolarization, an influx of sodium and calcium ions, and the generation of a fast EPSP. These agents produce general stimulation of autonomic ganglia and a complex pattern of mixed sympathetic and parasympathetic responses. In addition to autonomic ganglia, nicotinic receptors are found in a variety of...

Clinical Manifestations of Hypothyroidism

During the perinatal period, there is an absolute requirement for thyroid hormone for the development and maturation of the nervous and musculoskeletal systems. In the perinatal nervous system, thyroid hormone plays a critical role in normal growth of the cerebral and cerebellar cortices, the proliferation of axons, the branching of dendrites, synaptogenesis, myelination, cell migration, and so on. Thyroid hormone also plays a major role in the maturation of bone. A deficiency of thyroid...

Tumor Growth And Growth Fraction

The rate of growth of human and experimental cancers is initially quite rapid (exponential) and then slows until a plateau is reached. The decrease in growth rate with increasing tumor size is related both to a decrease in the proportion of cancer cells actively proliferating (termed the growth fraction) and to an increase in the rate of cell loss due to hypoxic necrosis, poor nutrient supply, im-munological defense mechanisms, and other processes. The rate of spontaneous cell death for some...

Antigen Mediated Histamine Release

Specific antigen-antibody interactions initiate the degranulation of tissue mast cells and blood basophils as part of the immediate hypersensitivity reaction. Immunoglobulin E (IgE) antibodies (reaginic antibodies) directed against an allergenic substance attach to the outer surface of the cell membrane and initiate a series of biochemical events that culminate in the release of the secretory granule contents (Fig. 38.1). Although allergens are the most frequent initiators of immediate...

Absorption Distribution Metabolism and Excretion

After oral administration, ethanol is almost completely absorbed throughout the gastrointestinal tract. The rate of absorption is largely determined by the quantity consumed, the concentration in the beverage, the rate of consumption, and the composition of the gastric contents. Eating food before or during drinking retards absorption, especially if the food has a high lipid content. After absorption, ethanol is distributed throughout body water. In organs with high blood flow, such as the...

Drugs Affecting The Endocrine System

Hypothalamic and Pituitary Gland Hormones 677 60. Adrenocortical Hormones and Drugs Affecting the Adrenal Cortex 686 Ronald P Rubin 61. Estrogens, Progestins, and SERMs 704 Jeannine S. Strobl 62. Uterine Stimulants and Relaxants 716 Leo R. Brancazio and Robert E. Stitzel 63. Androgens, Antiandrogens, and Anabolic Steroids 724 Frank L. Schwartz and Roman J. Miller 64. Drugs Used in the Treatment of Erectile Dysfunction 735 John A. Thomas and Michael J. Thomas 65. Thyroid and Antithyroid...

Clinical Education and Product Marketing

The second area for ethical concern is clinical education and product marketing. The line between education and marketing is frequently a blurry one, and it is often difficult to separate a company's desire to educate physicians about products that may genuinely enhance patient care from the company's desire to increase profits. As the gatekeepers for all prescription drugs, physicians have the power to determine which drugs will compete successfully in the marketplace, making doctors the...

Lethal Versus Inhibitory Effects

Antibiotics can be classified according to their effects on the biochemistry or molecular biology of pathogens. There are ribosomal inhibitors (macrolides), cell wall disrupters (p-lactams), DNA disturbers (fluoroquinolones), and metabolic poisons (trimethoprim-sulfamethoxazole). Antibiotics also can be classified according to whether they are static (inhibitory) or cidal (lethal). The classification of drugs as either static or cidal is based on laboratory assessment of the interaction of...

Physiological Effects Of Thyroid Hormones

There is no discrete target tissue for thyroid hormones virtually every cell in the body is affected by thyroid hormones in some way. These hormones are intimately involved in the maintenance of normal function in virtually every cell type, including cellular responsiveness to other hormones, to the availability of metabolic substrates, to growth factors, and so on. Thyroid dysfunction can produce dramatic changes in the metabolism of proteins, carbohydrates, and lipids at the cellular level...

Contraindications Cautions and Drug Interactions

Oral anticoagulants are ordinarily contraindicated in the presence of active or past gastrointestinal ulceration thrombocytopenia hepatic or renal disease malignant hypertension recent brain, eye, or spinal cord surgery bacterial endocarditis chronic alcoholism and pregnancy. These agents also should not be prescribed for individuals with physically hazardous occupations. Minor hemorrhage caused by oral anticoagulant overdosage can be treated by discontinuing drug administration. Oral or...

Pharmacological Aspects

CNS depressants, including barbiturate, benzodiazepine, and ethanol, produce a similar intoxication. These drugs are abused for their euphoric effects and as a means to reduce anxiety and limit insomnia. As the dose of depressant increases, along with the degree of intoxication, the effects progress from anxiety reduction and muscle relaxation to motor impairment and unconsciousness. The difference between the classes of drugs is primarily dose responsiveness. Intoxication progresses from mild...

Isotretinoin

Isotretinoin (Accutane) alters keratinization in the acroinfundibulum of sebaceous glands and shrinks them, thereby reducing sebum excretion and comedo-genesis. These features underlie its usefulness in acne vulgaris, since sebum secretion is a hallmark of acne-prone skin. Furthermore, the drug has antiinflammatory activity. Isotretinoin is rapidly absorbed orally, with peak blood concentrations 3 hours after ingestion. It is not stored in tissue, and the elimination half-life is 10 to 20...

Sex Hormonebinding Proteins

Circulating testosterone is reversibly bound to two major plasma proteins, albumin and gamma globulin. Binding to albumin is a relatively nonspecific low-affinity and high-capacity association. In contrast, binding to the specific -globulin fraction, called sex hormone-binding globulin (SHBG), is a high-affinity steroid-specific interaction. Under physiological conditions, 98 of testosterone is protein bound, 40 to albumin and 58 to SHBG. Thus, 2 or less of circulating testosterone is unbound...

Ganglionic Stimulants

A variety of agents, including nicotine, lobeline, and di-methylphenyl piperazinium (DMPP), can stimulate gan-glionic nicotinic receptors. Although these drugs have little or no therapeutic use, they offer considerable interest for several reasons. First, drugs such as nicotine that both stimulate and block ganglionic receptors have proved valuable as an aid in identifying and localizing postgan-glionic fibers. Second, nicotine's use as a potent insecticide and rodenticide and its presence in...

Stool Softeners

Fecal softeners are substances that are not absorbed from the alimentary canal and act by increasing the bulk of the feces and softening the stool so that it is easier to pass. Mineral oil has been in use for many years, either as the oil or as a white emulsion it is a mixture of liquid hydrocarbons. Its use has been criticized for many reasons. It dissolves the fat-soluble vitamins and prevents their absorption. It is itself absorbed slightly and appears in the mesenteric lymph nodes, and if...

Prolactin

Human prolactin is similar in structure to human growth hormone, and both are good lactogens. In women, pro-lactin acts with other hormones on the mammary gland during pregnancy to develop lactation and after birth to maintain it. Hyperprolactinemia causes impotence in men and amenorrhea and infertility in women. Chronically elevated levels of circulating prolactin are associated with suppression of 17-p-estradiol and testosterone production in the ovaries and testes. Prolactin serum levels...

The Log Cell Kill Hypothesis

Cytotoxic drugs act by first-order kinetics that is, at a given dose, they kill a constant fraction of the tumor cells rather than a fixed number of cells. For example, a drug dose that would result in a three-log cell kill (i.e., 99.9 cytotoxicity) would reduce the tumor burden of an animal that has 108 leukemic cells to 105 cells. This killing of a fraction of cells rather than an absolute number per dose is called the log cell kill hypothesis. The earliest detectable human cancers usually...

Drug Induced Osteopenia

Chronic administration of many drugs, especially anti-convulsant medications, glucocorticoids, and GnRH agonists, are known to produce osteopenia and osteoporosis. The anticonvulsants inhibit formation of active D3 chronic glucocorticoid therapy increases bone turnover by altering osteoblast differentiation and inhibiting collagen synthesis and the GnRH agonists induce chemical hypogonadism. Clinical trials have demonstrated that the use of the bisphosphonates, nasal calcitonin, or human rPTH...

Combination Chemotherapy

The value of combination chemotherapy has been proved in humans. The combined use of two or more drugs often is superior to single-agent treatment in many cancers, and certain principles have been used in designing such treatments 1. Each drug used in the combination regimen should have some individual therapeutic activity against the particular tumor being treated. A drug that is not active against a tumor when used as a single agent is likely to increase tox-icity without increasing the...

Figure 422

Pharmacokinetic factors that affect substantivity of rinsing agents. Although chlorhexidine affects virtually all bacteria, gram-positive bacteria are more susceptible than are gram-negative organisms. Furthermore, Streptococcus mutans and Antinomies viscosus seem to be particularly sensitive. S. mutans has been associated with the formation of carious lesions in fissures and on interproximal tooth surfaces and has been identified in large numbers in plaque and saliva samples of subjects with...

Glaucoma

Long-lasting AChE inhibitors, such as demecarium (Humorsol), echothiophate, and physostigmine are also effective in treating open-angle glaucoma, although they have now been largely replaced by less toxic drugs. Topical application of long-acting cholinesterase inhibitors to the eye not only presents the risk of systemic effects, but they can cause cataracts this is a primary reason for reluctance to use these drugs even in resistant cases of glaucoma. Pilocarpine should be used rather than...

Adverse Reactions to Insulin Therapy

The most common side effect associated with insulin therapy is hypoglycemia, which may result in such CNS symptoms as tremors, lethargy, hunger, confusion, motor and sensory deficits, seizures, and unconsciousness. Adrenergic manifestations include anxiety, palpitations, tachycardia, and diaphoresis. In many cases, diabetics are aware that hypoglycemia is developing, and prompt administration of oral carbohydrates (e.g., fruit juice or glucose tablets) can restore normoglycemia. In more severe...

Antiplatelet Drugs

The formation of platelet aggregates and thrombi in arterial blood may precipitate coronary vasospasm and occlusion, myocardial infarction, and stroke and contribute to atherosclerotic plaque development. Drugs that inhibit platelet function are administered for the relatively specific prophylaxis of arterial thrombosis and for the prophylaxis and therapeutic management of myocardial infarction and stroke. After an infarction or stroke, antiplatelet therapy must be initiated within 2 hours to...

Vincristine Vinblastine and Vinorelbine

Vincristine (Oncovin) and vinblastine (Velban) are both produced by the leaves of the periwinkle plant. Despite their structural similarity, there are significant differences between them in regard to clinical usefulness and toxicity. The vinca alkaloids bind avidly to tubulin, a class of proteins that form the mitotic spindle during cell division. The drugs cause cellular arrest in metaphase during mitosis, and cell division cannot be completed. Although the vinca alkaloids usually have been...

Use of Vasoconstrictors

The most commonly used vasoconstrictors, the sympa-thomimetic drugs, are often added to local anesthetics to delay absorption of the anesthetic from its injection site. By slowing absorption, these drugs reduce the anesthetic's systemic toxicity and keep it in contact with nerve fibers longer, thereby increasing the drug's duration of action. Administration of lidocaine 1 with ep-inephrine results in the same degree of blockade as that produced by lidocaine 2 without the vasoconstrictor. Many...

Cisapride and Tegaserod

Cisapride (Propulsid) and tegaserod (Zelnorm) are both serotonin-4 (5-HT4) receptor agonists that stimulate GI motility. Cisapride appears to act by facilitating the release of acetylcholine from the myenteric plexus. It has no antiadrenergic, antidopaminergic, or choliner-gic side effects. Following oral administration, peak plasma levels occur in 1.5 to 2 hours the drug's half-life is 10 hours. Cisapride has been successfully used to treat gastroparesis and mild gastroesophageal reflux...

Status Asthmaticus

Status asthmaticus is a life-threatening exacerbation of asthma symptoms that is unresponsive to standard therapy. It must be treated very aggressively, and hospital-ization may be necessary. A provocative factor such as prolonged allergen exposure or a respiratory infection often precedes status asthmaticus. A rapid increase in the daily use of bronchodilators to control acute symptoms is a danger sign of an impending crisis. Treatment includes oxygen, inhaled short-acting p2-agonists, and...

Thioguanine

6-Thioguanine is a purine analogue structurally related to 6-mercaptopurine and azathioprine. Thioguanine interferes with several enzymes required for de novo purine synthesis, and its metabolites are incorporated into DNA and RNA, further impeding nucleic acid synthesis. The mechanism of action of thioguanine in psoriasis is not clearly understood it has been hypothesized to affect the proliferation and trafficking of lymphocytes as well as the proliferation of keratinocytes. Absorption of...

Acyclovir and Valacyclovir

Acyclovir (Zovirax) is a guanine nucleoside analogue most effective against HSV-1 and HSV-2, but it has some activity against VCV, CMV, and EBV. Valacyclovir (Valtrex) is the l-valine ester prodrug of acyclovir. Acyclovir is converted to its active metabolite via three phosphorylation steps. First, viral thymidine kinase converts acyclovir to acyclovir monophosphate. Next, host cell enzymes convert the monophosphate to the diphos-phate and then to the active compound, acyclovir triphosphate....

Gonadotropin Releasing Hormone

GnRH (gonadorelin, luteinizing hormone-releasing hormone) is a decapeptide that stimulates production of LH and FSH. It is released in bursts from the hypothalamus at regular intervals, about every 2 hours, although in women the interval may lengthen in the luteal end of the menstrual cycle. The pituitary gland responds to these regular pulses by producing LH and FSH. The pattern of LH and FSH in cycling women, including the large burst of LH release before ovulation, can be stimulated by...

Mycophenolate Mofetil

Mycophenolate mofetil (MMF, CellCept) is an ester prodrug of mycophenolic acid (MPA), a Penicillium-de-rived immunosuppressive agent (see Chapter 57) that blocks de novo purine synthesis by noncompetitively inhibiting the enzyme inosine monophosphate dehydro-genase. MPA preferentially suppresses the proliferation of cells, such as T and B lymphocytes, that lack the purine salvage pathway and must synthesize de novo the guanosine nucleotides required for DNA and RNA synthesis. MPA has been used...

Chemistry Of Uric Acid

Humans excrete approximately 0.7 g uric acid daily. Most of this is derived from the metabolic breakdown of the purine bases adenine and guanine. Uric acid is less ionized and less water soluble at most acidic pH's. It exists mostly as the monovalent salt sodium urate. However, uric acid itself may be the predominant form found in an acid urine. Because the urine becomes more acidic as it moves through the renal tubular system, filtered urate is increasingly converted to uric acid. The...

Antistaphylococcal penicillinaseresistant Penicillins

Nafcillin, oxacillin, cloxacillin, and dicloxacillin are more resistant to bacterial p-lactamases than is penicillin G. Consequently, these antibiotics are effective against streptococci and most community-acquired penicilli-nase-producing staphylococci. Methicillin, which is no longer marketed in the United States, is another peni-cillinase-resistant antibiotic similar to nafcillin and oxacillin. For historical reasons, staphylococci resistant to oxacillin or nafcillin are labeled methicillin...

Probucol

Probucol (Lorelco) is a hypocholesterolemic drug with few side effects that modestly (15-30 ) decreases elevated plasma LDL cholesterol levels. The marginal TABLE 23.4 Summary of Major Drug Interactions Drug Interactions and Special Precautions Statins Inhibition of cytochromal P450 3A4 can greatly increase serum statin levels. Grapefruit juice inhibits intestinal P450 3A4 and raises serum statins. Fluvastatin may increase warfarin toxicity because both compete with P450 2C9 for metabolism....

Ginkgo Biloba Leaf Extract

Ginkgo, or maidenhair tree (Ginkgo biloba), is thought to be the most ancient of living tree species, and it is now also one of the top selling herbs in Europe and the United States because of its reputed ability to improve cognitive function. Ginkgo leaf extract is prepared from ginkgo leaf by a complex process that removes toxic ginkgolic acid. This reduces the risk of allergic reactions to the leaves if they are consumed directly. Ginkgo leaf extract contains 24 flavone glycosides (including...

Valproic Acid Sodium Valproate

Although it is marketed as both valproic acid (Depakene) and as sodium valproate (Depakote), it is the valproate ion that is absorbed from the gastrointestinal tract and is the active form. As with several other AEDs, it is difficult to ascribe a single mechanism of action to valproic acid. This compound has broad anticonvulsant activity, both in experimental studies and in the therapeutic management of human epilepsy. Valproic acid has been shown to block voltage-dependent sodium channels at...

P2Adrenoceptor Agonists

Although -adrenoceptor agonists (see Chapter 10) are the most commonly used tocolytic agents in the United States, they are not completely successful in treating preterm labor. Prophylactic administration of these agents to patients at high risk for preterm labor is not always effective. There is, however, clear evidence that (2-agonists can arrest preterm labor for at least 48 to 72 hours. The efficacy of these drugs beyond this time frame is in dispute. Even a short delay in delivery can be...