Pharmacokinetic Properties Absorption and Distribution

The rate of absorption of a local anesthetic into the bloodstream is affected by the dose administered, the vascularity at the site of injection, and the specific physicochemical properties of the drug itself. Local anesthetics gain entrance into the bloodstream by absorption from the injection site, direct intravenous injection, or absorption across the mucous membranes after topical application. Direct intravascular injection occurs accidentally when the needle used for infiltration of the...

Secondmessenger Systems

Many receptors are capable of initiating a chain of events involving second messengers. Key factors in many of these second-messenger systems are proteins termed G proteins, short for guanine nucleotide-binding proteins. G proteins have the capacity to bind guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). G proteins couple the activation of several different receptors to the next step in a chain of events. In a number of instances, the next step involves the enzyme...

Mecamylamine

Mecamylamine hydrochloride (Inversine) is a secondary amine and can therefore easily penetrate cell membranes. Its absorption from the gastrointestinal tract is more complete than that of the quaternary ammonium compounds. Mecamylamine is well absorbed orally and crosses both the blood-brain and placental barriers its distribution is not confined to the extracellular space. High concentrations of the drug accumulate in the liver and kidney, and it is excreted unchanged by the kidney. In...

Adverse Effects Of Treatment With Thyroid Hormone

The most common adverse effects (i.e., symptoms of hyperthyroidism) are the result of a drug overdose they include cardiac palpitation and arrhythmias, tachycardia, weight loss, tremor, headache, insomnia, and heat intolerance. Symptoms subside if medication is withheld for several days. In patients with longstanding hypothyroidism and those with ischemic heart disease, rapid correction of hypothyroidism may precipitate angina, cardiac arrhythmias, or other adverse effects. For these patients,...

Carbonic Anhydrase Inhibitors

In the late 1930s, it was reported that sulfanilamide and other N-unsubstituted sulfonamides could induce diuresis characterized by excretion of an alkaline urine that is high in sodium bicarbonate. It was soon realized that these compounds inhibited carbonic anhydrase, an enzyme highly concentrated in renal tissue, and that this enzyme was important for the tubular reabsorption of bicarbonate. The common structural motif of carbonic anhydrase inhibitors is an unsubstituted sulfonamide moiety....

Drugs That Decrease Or Neutralize Gastric Acid Secretion

Functionally, the gastric mucosa is divided into three areas of secretion. The cardiac gland area secretes mucus and pepsinogen.The oxyntic (parietal) gland area, which corresponds to the fundus and body of the stomach, secretes hydrogen ions, pepsinogen, and bicarbonate. The pyloric gland area in the antrum secretes gastrin and mucus. The parietal cells secrete H+ in response to gastrin, cholinergic, and histamine stimulation (Fig. 40.1). Both cholinergic- and gastrin-induced types of...

Drug Resistance

Many patients undergoing chemotherapy fail to re spond to treatment from the outset their cancers are re- sistant to the available agents. Other patients respond initially, only to relapse. Cancers can be regarded as populations of cells undergoing spontaneous mutations. The population becomes increasingly heterogeneous as the tumor grows and increasing numbers of mutations occur. Tumors of the same type and size will vary in their responsiveness to therapy because of the chance occurrences of...

Pyrethrins and Pyrethroids

Pyrethrins are naturally occurring pesticides derived from chrysanthemum plants. They are active against many insects and mites. Over-the-counter liquid and gel preparations of pyrethrins with piperonyl butoxide are available for the treatment of pediculosis (piperonyl bu-toxide inhibits the hydrolytic enzymes that metabolize the pyrethrins in the arthropod). A synthetic pyre-throid, permethrin (Elimite), is available by prescription. A lower concentration of permethrin (Nix) is available...

Clinical Uses

As indicated, most of the analeptic stimulants were used as pharmacological treatments for overdosage of CNS depressants. Doxapram (Dopram) is sometimes used to counteract postanesthetic respiratory depression and as an aid in chronic obstructive pulmonary disease. Pentylenetetrazol (Metrazol) was used experimentally on rare occasions to activate the electroencephalogram. Strychnine is used almost exclusively in animal studies as a tool for studying CNS mechanisms because it is a relatively...

Myasthenia Gravis

The acquired form of myasthenia gravis (MG) is an autoimmune disease with an incidence approaching 1 in 10,000. It involves an antibody response against part of the a-subunit of the AChR in muscle. This leads to degradation of AChRs, reduction of synaptic infoldings, and weakness due to diminished postjunctional response. Because anti-AChR antibodies are found in nearly 90 of MG patients, serum testing can serve as a diagnostic tool. MG is often found associated with abnormalities of the...

Location of the Autonomic Ganglia

The sympathetic ganglia consist of two chains of 22 seg-mentally arranged ganglia lateral to the vertebral column. The preganglionic fibers leave the spinal cord in adjacent ventral roots and enter neighboring ganglia, where they make synaptic connections with postgan-glionic neurons. Some preganglionic fibers pass through the vertebral ganglia without making synaptic connections and travel by way of splanchnic nerves to paired prevertebral ganglia in front of the vertebral column, where they...

Thionamides

Thionamides are the primary drugs used to decrease thyroid hormone production. They do not inhibit secretion of stored thyroid hormone, and therefore, when they are used alone, their clinical effects are not appar ent until the preexisting intrathyroidal store of thyroid hormone is depleted. This may take several weeks. Propylthiouracil and methylthiouracil (methimazole Tapazole) are the most commonly used preparations in the United States. Thionamide drugs interfere with peroxidase-catalyzed...

Immune and Defense Mechanisms

The inflammatory response is a highly complex process that involves a number of cell types of the reticuloen-dothelial system and a number of chemical mediators, including prostaglandins, leukotrienes, kinins, and bio-genic amines (See Chapter 36).The inhibitory effects of glucocorticoids on various aspects of the inflammatory and immunological responses constitute the basis for their therapeutic efficacy. All steps of the inflammatory process are blocked there is a diminution in heat,...

Supplemental Reading

Prim Care 2001 28 523-538. Hatlebakk JG. Medical therapy. Management of the refractory patient. Gastroenterol Clin North Am 1999 28 847-860. Huang JQ. Pharmacological and pharmacodynamic essentials of H(2)-receptor antagonists and proton pump inhibitors for the practicing physician. Ballieres Best Pract Res Clin Gastroenterol 2001 15 355-370. Kromer W. Endogenous and exogenous opioids in the control of gastrointestinal motility and secretion. Pharmacol Rev...

Inactivation of Released Histamine

The inactivation of histamine is achieved both by enzymatic metabolism of the amine and by transport processes that reduce the concentration of the compound in the region of its receptors. Histamine metabolism occurs primarily through two pathways (Fig. 38.1). The most important of these involves histamine N-methyltransferase, which catalyzes the transfer of a methyl group from S-adenosyl-1-methionine to one of the imidazole nitrogen substitutions, forming 1-methyl-histamine. This enzyme is...

Systemic Antibiotics

Antibiotics are used in dermatology for both infectious and noninfectious skin eruptions. Noninfectious skin eruptions, such as acne vulgaris and acne rosacea, are often treated with systemic antibiotics. The mechanism of action is not clear, although tetracycline inhibits li-pases derived from resident flora in the sebaceous follicle (Staphylococcus epidermidis, Propionibacterium acnes). These lipases cleave irritating fatty acids from triglycerides in sebum, presumably contributing to...

L

TABLE 3.1 Some Factors Influencing Gastric Emptying Time Factor Increased gastric emptying rate Decreased gastric emptying rate Physiological Liquids, gastric distention Solids, acids, fat Pathological Duodenal ulcers, gastroenterostomy, chronic pancreatitis Acute abdominal trauma and pain, labor of child birth, gastric juices, intestinal obstruction, pneumonia, diabetes mellitus Pharmacological Reserpine, anticholinesterases, guanethidine, cholinergic Anticholinergic drugs, ganglionic blocking...

Absorption Metabolism and Excretion

Valacyclovir is rapidly and completely converted to acy-clovir by intestinal and hepatic first-pass metabolism. The bioavailability of acyclovir following oral valacy-clovir dosing is three to five times that resulting from oral acyclovir administration and is comparable to that of intravenous acyclovir. Acyclovir absorption is variable and incomplete following oral administration. It is about 20 bound to plasma protein and is widely distributed throughout body tissues. Significant amounts may...

Growth and Development

Estrogens cause the growth of the uterus, fallopian tubes, and vagina. Stimulation of proliferation of the vaginal epithelium is checked by the cyclical exposure to progesterone during the luteal phase in the mature female. Estrogens also are responsible for the expression of female secondary sex characteristics during puberty. These include breast enlargement, the distribution of body hair, body contours as determined by subcutaneous fat deposition, and skin texture. During development,...

Figure

Mechanisms involved in the passage of drugs across membranes. (Adapted with permission from Smyth DH. Absorption and Distribution of Drugs. Baltimore Williams & Wilkins, 1964 and Forth W and Rummel W (eds.). Pharmacology of Intestinal Absorption Gastrointestinal Absorption of Drugs. Vols. 1 and 2. Oxford, UK Pergammon, 1975). The rate of filtration depends both on the existence of a pressure gradient as a driving force and on the size of the compound relative to the size of the pore through...

Structure Activity Relationships

Within the basic structure of the steroid molecule (Fig. 60.4), a 4,5 double bond and a 3-ketone group are needed for typical steroid activity. A hydroxyl group on C11 is needed for glucocorticoid activity (cortico-sterone) but is not required for sodium-retaining activity (desoxycorticosterone). The addition of a hydroxyl group on C17, which converts corticosterone to cortisol, also increases glucocorticoid activity. The ultimate aim in altering the steroid molecule is to decrease...

Adverse Effects

Toxic manifestations of gold therapy are most common after a minimal total amount (200-300 mg) of gold has been administered. Serious reactions necessitating discontinuance of therapy or antidotal therapy are encountered in perhaps 5 of the patients. Both oral and parenteral gold therapy frequently produces dermatitis, usually preceded and accompanied by pruritus. Stomatitis may accompany dermatitis, which may be preceded by a metallic taste in the mouth of the patient. Blue or gray skin...

Bulk Forming Laxatives

The bulk-forming laxative group includes the hy-drophilic substances described previously calcium polycarbophil (FiberCon, Equalactin), methylcellulose (Citrucel), and various psyllium seed derivatives (Metamucil). All act by increasing the bulk of the feces, part of this action being due to their capacity to attract water and form a hydrogel. The increased volume of feces stretches the walls of the GI tract and stimulates peristalsis. Their action may not be evident for 2 to 3 days after...

Pentamidine

Pentamidine (Pentam 300) binds to DNA and may inhibit kinetoplast DNA replication and function. It also may act by inhibiting dihydrofolate reductase and interfering with polyamine metabolism. An effect on organism respiration, especially at high doses, also may play a role. Pentamidine is not well absorbed from the intestinal tract after oral administration and generally is given by intramuscular injection. The drug binds to tissues, particularly the kidney, and is slowly excreted, mostly as...

Contraindications

Propafenone is contraindicated in the presence of severe or uncontrolled congestive heart failure cardio-genic shock sinoatrial, A-V, and intraventricular disorders of conduction and sinus node dysfunction, such as sick sinus syndrome. Other contraindications include severe bradycardia, hypotension, obstructive pulmonary disease, and hepatic and renal failure. Because of its weak p-blocking action, propafenone may cause possible dose-related bronchospasm. This problem is greatest in patients...

Clinical Application and Interpretation of MAC

MAC is a valuable index for clinical anesthesia, but it is seldom employed without taking other factors into consideration. For example, inhibiting movement in only 50 of patients is not acceptable. Consequently, if an inhalational agent were being used alone that is, without the administration of other anesthetics or analgesic drugs the anesthesiologist would employ a multiple of its MAC value to ensure immobility. MAC is frequently multiplied by a factor of 1.3 to achieve nearly 100 clinical...

Iodide Transport by Follicular Cells and Iodine Trapping Within Follicles

The thyroid follicular cells transport I across the cell and secrete the precursor protein, Tg, into the fol-licular lumen. In addition, these cells contain an apical membrane-bound enzyme, thyroperoxidase (TPO), and the enzymatic machinery to produce hydrogen peroxide (H2O2). In the presence of H2O2, TPO catalyzes the incorporation of I into tyrosyl residues of Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) and the coupling of these iodotyrosyl residues to form T4 and T3. Thyroid...

Diloxanide Furoate

Diloxanide furoate (Furamide) is an amebicide that is effective against trophozoites in the intestinal tract. In mild or asymptomatic infections, cures of 83 to 95 have been achieved in patients with dysentery, cure rates may be less impressive. The drug is administered only orally and is rapidly absorbed from the gastrointestinal tract following hydrolysis of the ester group. It is remarkably free of side effects, but occasionally flatulence, abdominal distention, anorexia, nausea, vomiting,...

Keratolytics

Drugs that are used to treat hyperkeratosis, a thickening of the stratum corneum, are called keratolytics. Examples of these agents are salicylic acid, urea, lactic acid, and colloidal or precipitated sulfur. The precise mechanisms by which these agents treat hyperkeratosis are not known. Presumably, a common property is the ability to denature keratin, the major structural protein of the epidermis. Other beneficial effects vary among the different drugs. All of them have antimicrobial or...

Budesonide

Recently, budesonide (Entecort EC) has been approved for the treatment of mildly to moderately active Crohn's disease involving the ileum and or ascending colon. Budesonide is a synthetic corticosteroid having a potent glucocorticoid and weak mineralocorticoid activity. In standard in vitro and animal models, budes-onide has an approximately 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical antiinflammatory potency than cortisol. While budesonide is well...

Drugs That Increase Gi Motility

Decreased GI motility can affect one or more parts of the GI tract and can be the result of a systemic disease, intrinsic GI disorder, or medication. Gastroparesis is the term for delayed gastric emptying. Symptoms may range from postprandial bloating and fullness to nausea and vomiting. Half of ingested liquid should be emptied within 30 minutes, and half of a digestible solid should be emptied within 2 hours. Emptying time can be prolonged as a result of autonomic neuropathy seen with...

Renal Urate Homeostasis

The binding of uric acid to plasma proteins is relatively small and probably does not have great physiological significance. However, even this limited binding may be affected by administration of drugs, such as salicylates, phenylbutazone, probenecid, and sulfinpyrazone. These drugs probably affect urate protein binding only secondarily that is, their principal action is to interfere with renal transport of uric acid, which in turn leads to alterations in plasma urate binding. The renal...

Mycophenolate Mofetil

Mycophenolate mofetil (CellCept), in conjunction with cyclosporine and corticosteroids, has clinical applications in the prevention of organ rejection in patients receiving allogeneic renal and cardiac transplants. By effectively inhibiting de novo purine synthesis, it can impair the proliferation of both T and B lymphocytes. Following oral administration, mycophenolate mofetil is almost completely absorbed from the GI tract, metabolized in the liver first to the active compound my-cophenolic...

Growth Hormone

Growth hormone, or somatotropin, is a protein that stimulates linear body growth in children and regulates cellular metabolism in both adults and children. Growth hormone stimulates lipolysis, enhances production of free fatty acids, elevates blood glucose, and promotes positive nitrogen balance. Many of its anabolic actions are mediated by enhanced production of an insulinlike growth factor (IGF-1), a protein produced in many tissues in response to growth hormone. The episodic release of...

Physiological Effects of Histamine

Histamine mediates a diverse group of processes ranging from vasodilation to gastric acid secretion. It produces its effects by binding to and activating receptors on the surface of cardiac, smooth muscle, endothelial, neuronal, and other cells. There are at least four receptor populations, H1, H2, H3, and H4. All four receptor subtypes have been cloned and belong to the G protein-coupled receptor superfamily. The histamine receptors can be distinguished on the basis of their post-receptor...

Nonionic Bisphenols

Triclosan is a broad-spectrum antimicrobial compound. It was originally used in soaps, antiperspirants, and cosmetic toiletries as a germicide. Today, triclosan is incorporated into toothpaste because of its wide spectrum of antimicrobial activities and low toxicity. Triclosan is retained in dental plaque for at least 8 hours, which in addition to its broad antibacterial property could make it suitable for use as an antiplaque agent in oral care preparations. However, the compound is rapidly...

Serious Gram Negative Bacillary Infections

Gentamicin is the aminoglycoside antibiotic most commonly used to treat serious infections due to gramnegative aerobic bacilli, such as Escherichia coli and Klebsiella pneumoniae, and Proteus, Serratia, Acinetobacter, Citrobacter, and Enterobacter spp. Gentamicin also has significant activity against Staphylococcus aureus. The aminoglycosides are often used in combination with p-lactams in the initial empirical therapy of sepsis and of fever in immunocompromised patients. The combination is...

Drugs Affecting The Central Nervous System

Introduction to Central Nervous System Pharmacology 281 25. General Anesthesia Intravenous and Inhalational Agents 291 26. Opioid and Nonopioid Analgesics 310 Sandra P. Welch and Billy R. Martin 27. Local Anesthetics 330 J. David Haddox 28. Agents Affecting Neuromuscular Transmission 338 29. Central Nervous System Stimulants 348 David A. Taylor 30. Sedative-hypnotic and Anxiolytic Drugs 355 31. Drugs Used in Neurodegenerative Disorders 364 32. Antiepileptic Drugs 374 Charles R. Craig 33....

Pharmacological Actions Of Dopamine

Dopamine is a naturally occurring catecholamine it is the immediate biochemical precursor of the norepi-nephrine found in adrenergic neurons and the adrenal medulla. It is also a neurotransmitter in the CNS, where it is released from dopaminergic neurons to act on specific dopamine receptors (see Chapter 31). Dopamine is a unique adrenomimetic drug in that it exerts its cardiovascular actions by (1) releasing norepi-nephrine from adrenergic neurons, (2) interacting with a-and ( 1-adrenoceptors,...

Answers

The primary site of absorption is the small intestine. Because of its large surface area and high blood perfusion rate, the small intestine is optimal for absorbing drugs. Some drug absorption occurs in the stomach and large intestine, but because of their reduced surface area in relative terms and for some drugs less than optimal physicochemical conditions, these tissues play a lesser role in drug absorption. Because of the tissue type, very little drug absorption occurs through the...

Mechanism of Action

Prior to the introduction of the statins in the mid to late 1980s, the bile acid-sequestering drugs cholestyramine (Questran) and colestipol (Colestid) were primary drugs for lowering plasma cholesterol. Today they are second-line drugs that can safely be given with a statin to enhance cholesterol lowering or as an alternative for patients intolerant to a statin or concerned with statin's potential for toxicity. Alone, the resins can achieve 20 to 25 reductions in LDL cholesterol, but when used...

Tretinoin

Topical tretinoin (Retin-A, Renova, Avita), like iso-tretinoin, alters keratinization in the acroinfundibulum. In addition, it reverses certain premalignant and other histological changes associated with the photoaging changes that accompany chronic exposure to ultraviolet radiation. Topically applied tretinoin is indicated in comedogenic and papulopustular acne vulgaris, and its mild exfoliative effects make it sometimes useful in mol-luscum contagiosum, flat warts, and some ichthyotic...

H2Receptor Antagonists

The histamine receptor antagonists (H2 blockers) marketed in the United States are cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid). These agents bind to the H2-receptors on the cell membranes of parietal cells and prevent histamine-induced stimulation of gastric acid secretion. After prolonged use, down-regulation of receptor production occurs, resulting in tolerance to these agents. H2-blockers are approved for the treatment of gastroesophageal reflux...

Fluid and Electrolyte Disturbances

The normal subject may retain sodium and water during steroid therapy, although the synthetic steroid ana logues represent a lesser risk in this regard. Prednisolone produces some edema in doses greater than 30 mg triamcinolone and dexamethasone are much less liable to elicit this effect. Glucocorticoids may also produce an increase in potassium excretion. Muscle weakness and wasting of skeletal muscle mass frequently accompany this potassium-depleting action. The expansion of the extracellular...

Benzodiazepines

Benzodiazepines also possess muscle relaxant activity. Their pharmacology is discussed in Chapter 30. Diazepam (Valium) has been used for control of flexor and extensor spasms, spinal spasticity, and multiple sclerosis. The muscle relaxant effect of the benzodiazepines may be mediated by an action on the primary afferents in the spinal cord, resulting in an increased level of presynaptic inhibition of muscle tone. Polysynaptic reflexes are inhibited. The most troublesome side effect is...

Pharmacology Of Antispasticity Agents

Muscle relaxants have some value for relief of spastic muscle disorders, that is, a state of increased muscle tone that results from an imbalance between central and spinal control of muscle tone. Spasticity is the result of a general release from supraspinal control and is characterized by heightened excitability of a- and 7-motor systems and the appearance of primitive spinal cord reflexes. Treatment is difficult, since relief often can be achieved only at the price of increased muscle...

Other Nondepolarizing Blockers of Importance

Atracurium besylate (Tracrium) is a benzylisoquinolin-ium compound like d-tubocurarine. Its actions are similar to those of d-tubocurarine, but its duration of action is shorter (45 minutes) because of spontaneous degradation of the molecule (Hofmann elimination). Because of this, atracurium is useful in patients with low or atypical plasma cholinesterase and in patients with renal or hepatic impairment. Mivacurium chloride (Mivacron) is a newer agent that is chemically related to atracurium....

Adverse Effects and Precautions

D-Tubocurarine may cause bronchospasms and hypotension by release of histamine from mast cells. This may be counteracted by prior treatment with antihista-mines. d-Tubocurarine produces partial block of sympathetic ganglia and the adrenal medulla, which may also contribute to hypotension. Inhalation anesthetics, such as isoflurane, enflurane, halothane, and nitrous oxide, potentiate the action of nondepolarizing blockers, either through modification of end plate responsiveness or by alteration...

Pharmacological Actions

D-Tubocurarine blocks nicotinic AChRs in muscle end plates and autonomic ganglia but has no effect on mus- carinic AChRs. It does not affect nerve or muscle excitability or conduction of action potentials. Because it is charged, it penetrates cells poorly and does not enter the CNS. However, if applied directly to brain or spinal cord, it will block nicotinic AChR in those tissues. In humans, d-tubocurarine has a moderate onset of action (34 minutes) followed by progressive flaccid paralysis....

Corticosteroids

Serious adverse effects are produced by long-term, high-dose exposure to the corticosteroids therefore, these drugs are not agents of choice for the treatment of rheumatic disease. In general, the use of low-dose corti-costeroids avoids significant side effects (e.g. fluid retention, osteoporosis, GI bleeding, immunosuppression) but does not completely control the disease. However, for patients whose disease is refractory to other agents or who cannot tolerate the side effects of other DMARDs,...

Other Adrenomimetic Agents

A number of adrenomimetic amines are not cate-cholamines. Some of these are directly acting amines that must interact with adrenoceptors to produce a response in effector tissues. Some directly acting compounds, such as phenylephrine and methoxamine, activate a-adrenoceptors almost exclusively, whereas others, like albuterol and terbutaline, are nearly pure p-adrenoceptor agonists. Drugs that exert their pharmacological actions by releasing norepinephrine from its neuronal stores (indirectly...

Pyrimethamine

Pyrimethamine (Daraprim) is the best of a number of 2,4-diaminopyrimidines that were synthesized as potential antimalarial and antibacterial compounds. Trimethoprim (Proloprim) is a closely related compound. Pyrimethamine is well absorbed after oral administration, with peak plasma levels occurring within 3 to 7 hours. An initial loading dose to saturate nonspecific binding sites is not required, as it is with chloroquine. However, the drug binds to tissues, and therefore, its rate of renal...

Info

Three hormones, thyroxine (3,5,3',5'-tetraiodothy-ronine, or T4), triiodothyronine (3,5,3'-triiodothyronine, or T3), and calcitonin (see Chapter 66) are secreted by the thyroid gland. The hormones T4 and T3 are iodine-containing amino acid derivatives and are unique in that they have no discrete target tissue. Every tissue in the body is affected in some way by thyroid hormones, and almost all cells appear to require constant optimal amounts for normal operation. Thyroid hormones exert a wide...

Dapsone

Although dapsone (Avlosulfon) is most often used as an antimicrobial agent, it has important antiinflammatory properties in many noninfectious skin diseases. Its pharmacology and toxicities are discussed in Chapter 49. The mechanism of action of dapsone in skin disease is not clear. Most of the cutaneous diseases for which it is effective manifest inflammation and are characterized by an infiltration of neutrophils the drug's antiinflam-matory effect may arise from its inhibition of...

Adverse Effects Contraindications

The major advantage of the COX-2 inhibitors is their decreased GI effects and formation of gastric ulcerations compared with the COX nonselective agents. However, once an ulcer is present, COX-2 is induced in response, and the COX-2 enzyme is essential for wound healing. Therefore, celecoxib and rofecoxib can delay in wound healing and increase the time for ulcer repair and tissue regeneration. Patients with gastric ulcers should be switched if possible to another antiinflammatory to allow...

Mechlorethamine

Mechlorethamine (nitrogen mustard Mustargen), a derivative of the war gas sulfur mustard, is considered to be the first modern anticancer drug. In the early 1940s it was discovered to be effective in the treatment of human lymphomas. Mechlorethamine in aqueous solution loses a chloride atom and forms a cyclic ethylenimmonium ion. This carbonium ion interacts with nucleophilic groups, such as the N7 and O6 of guanine, and leads to an interstrand cross-linking of DNA. Although there is great...

Pharmacokinetics

To be clinically useful, a chemotherapeutic drug must have both selective toxicity against pathogens and fa vorable pharmacokinetics. The processes of absorption, distribution, metabolism, and elimination compose a drug's pharmacokinetics. The concentration of the drug in a patient's body as a function of time is determined by the dose administered and the drug's pharmacoki-netics in that patient. Absorption from the gastrointestinal tract can be affected by other drugs and by food. Aluminum,...

Clinical Uses and Adverse Effects

Meperidine (Demerol) is a phenylpiperidine derivative of morphine that was developed in the late 1930s as a potential anticholinergic agent. It has some anticholin-ergic side effects that lead to tachycardia, blurred vision, and dry mouth. Meperidine is approximately one-fifth as potent as morphine and is absorbed only half as well when administered orally as parenterally. It has a rapid onset and short duration of action (2 hours), that is, approximately one-fourth that of morphine. Like...

Isoosmotic Electrolyte Colonic Lavage Solutions

Electrolyte colonic lavage solutions (e.g., GoLYTELY, Colyte, Nulytely) contain polyethylene glycol and salts such as sodium sulfate, sodium bicarbonate, sodium chloride, and potassium chloride in an isoosmotic solution. The dose is 4 L ingested over 2 to 4 hours either orally or through a nasogastric tube. There is minimal net absorption or excretion of fluid or electrolytes, and thus these are safe to use in patients with renal insufficiency. The patient has repeated liquid stools until the...

Diethylcarbamazine

Diethylcarbamazine citrate (Hetrazan) is active against several microfilaria and adult filarial worms. It interferes with the metabolism of arachidonic acid and blocks the production of prostaglandins, resulting in capillary vasoconstriction and impairment of the passage of the microfilaria. Diethylcarbamazine also increases the adherence of microfilariae to the vascular wall, platelets, and granulocytes. Diethylcarbamazine is absorbed from the gastrointestinal tract, and peak blood levels are...

Future Directions

Today gingivitis and periodontitis are prevented principally through mechanical plaque control however, dentition free of supragingival and subgingival plaque is extremely difficult to accomplish and maintain. On an annual basis, Americans spend more than 750 million on oral rinsing agents, although few effective plaque-inhibiting oral rinses are available and many are associated with side effects that prohibit long-term use. The goal of future product development is not so much an improvement...

Adverse Effects Contraindications and Drug Interactions

Myelosuppression is the most common serious adverse effect of ganciclovir treatment therefore, patients' blood counts should be closely monitored. Neutropenia and anemia have been reported in 25 to 30 of patients, and thrombocytopenia has been seen in 5 to 10 . Elevated serum creatinine may occur following ganciclovir treatment, and dosage adjustment is required for patients with renal impairment. In animal studies, ganciclovir causes decreased sperm production, teratogenesis, and tumor...

Adverse Effects and Drug Interactions

Serious adverse effects are rare except in AIDS patients. TMP-SMX can cause the same adverse effects as those associated with sulfonamide administration, including skin rashes, central nervous system (CNS) disturbances, and blood dyscrasias. Blood dyscrasias, hepatotoxicity, and skin rashes are particularly common in patients with AIDS. Most of the adverse effects of this combination are due to the sulfamethoxazole component. Tri-methoprim may increase the hematological toxicity of...

Absorption Distribution Metabolism and Excretion

Food in the stomach does not interfere with the absorption of either clindamycin or lincomycin. Peak serum levels can be obtained 1 hour after intravenous administration of clindamycin, and approximately 90 of the antibiotic is protein bound. Lincomycin and clindamycin penetrate most tissues well, including bone. Therefore, bone and joint infections caused by susceptible organisms respond well to treatment with clindamycin. These drugs also concentrate within phagocytic cells, which may offer a...

Low MolecularWeight Heparin

Low-molecular-weight fragments produced by chemical depolymerization and extraction of standard heparin consist of heterogeneous polysaccharide chains of molecular weight 2,000 to 9,000. The LMWH molecules contain the pentasaccharide sequence necessary for binding to antithrombin III but not the 18-saccharide sequence needed for binding to thrombin. Compared to standard heparin, LMWH has a 2- to 4-fold greater antifactor Xa activity than antithrombin activity. LMWH has greater bioavailability...

Premenstrual Edema and Edema of Pregnancy

Many women retain fluid during pregnancy and during the last days of the menstrual cycle. Breast fullness and subcutaneous swelling or puffiness are the most commonly observed symptoms they are largely the result of elevated circulating hormone levels in the blood. Estrogens possess some mineralocorticoid activity, and thus, when present in relatively high concentrations, may produce some expansion of the extracellular fluid compartment. Excessive premenstrual edema frequently responds well to...

Soy and Other Phytoestrogens

Soybeans (Glycine max) are protein-rich legumes widely grown around the world as a food crop. They are the major dietary source of isoflavones, which are broken down in the intestine into the phytoestrogens genis- tein and daidzein. It is believed that the lower risk of breast cancer, cardiovascular disease, and osteoporosis in Asian women is partly due to their high soy diet, since these benefits are lost when they adopt Western dietary habits. Flaxseed, from flax (Linum usitatissimum), is the...

Ganglionic Blocking Agents

The basis for the antihypertensive activity of the ganglionic blockers lies in their ability to block transmission through autonomic ganglia (Fig. 20.2C). This action, which results in a decrease in the number of impulses passing down the postganglionic sympathetic (and parasympathetic) nerves, decreases vascular tone, cardiac output, and blood pressure. These drugs prevent the interaction of acetylcholine (the transmitter of the preganglionic autonomic nerves) with the nicotinic receptors on...

Metabolic Disturbances And Complications Of The Diabetic State

There are only two major sources of blood glucose exogenous, or the ingestion of dietary carbohydrate, and endogenous, which is contributed by hepatic and renal gluconeogenesis and hepatic glycogenolysis. Diabetes mellitus is a metabolic disorder in which carbohydrate metabolism is reduced while that of proteins and lipids is increased. In diabetics, exogenous and endogenous glucose is not used effectively, and it accumulates in the blood (hyperglycemia). As blood glucose levels increase, the...

Carbohydrate Protein and Fat Metabolism

The glucocorticoids increase blood glucose and liver glycogen levels by stimulating gluconeogenesis. The source of this augmented carbohydrate production is protein, and the protein catabolic actions of the gluco-corticoids result in a negative nitrogen balance. The inhibition of protein synthesis by glucocorticoids brings about a transfer of amino acids from muscle and bone to liver, where amino acids are converted to glucose. Supraphysiological concentrations of glucocorticoids will induce...

Pharmacological Aspects

The effects of LSD may be observed for 8 hours. The specific acute effects of a drug like LSD include euphoria, depersonalization, enhanced awareness of sensory input, alterations in the perception of time or space or body image, and to some extent, minor stimulant effects. Sometimes the dreamlike quality of the experience produces relaxation, good humor, and a sense of wonder or euphoria. Often the effect is a function of expectation and environmental conditions. Someone who is anxious about...

Transmission Of The Nerve Impulse

Microscopic studies of the structure of the terminal axons of the autonomic nerves have shown that the axons branch many times on entering the effector tissue, forming a plexus among the innervated cells. Swollen areas found at intervals along the terminal axons are referred to as varicosities (Figs. 9.2 and 9.3). Within each varicosity are mitochondria and numerous vesicles containing neurotransmitters. The vesicles are intimately involved in the release of the transmitter into the synaptic or...

Anabolic Steroids

Historically, drugs used to increase the ability of an athlete to perform in a given sport included the use of stimulants to diminish the onset of fatigue or opiates to diminish the pain of exertion. Recently, abuse of ana-bolic-androgenic steroids (derivatives of testosterone) has increased. They are used to increase muscle size and definition (in the case of body-building competitors) and are sometimes coabused with other growth enhancers, such as human growth hormone. In sports in which...

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...

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...

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...

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...

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...