Properties Of Biological Membranes That Influence Drug Passage

Although some substances are translocated by specialized transport mechanisms and small polar compounds may filter through membrane pores, most foreign compounds penetrate cells by diffusing through lipid membranes. A model of membrane structure, shown in Figure 3.2, envisions the membrane as a mosaic structure composed of a discontinuous bimolecular lipid layer with fluidlike properties. A smaller component consists of glycoproteins or lipoproteins that are embedded in the lipid matrix and...

Reproductive Toxicity

Most drugs and chemicals pose a threat to the developing fetus. An estimated 4 to 5 of developmental defects in humans result from prenatal exposure to drugs or environmental chemicals. This is particularly important, since women with irregular menstrual cycles may be exposed to teratogens and enter the sensitive period of organogenesis before pregnancy is suspected. Gestation is generally considered to consist of three periods of development, each with differing sensitivities to chemicals....

Uses in Ophthalmology

Antimuscarinic drugs are widely used in ophthalmology to produce mydriasis and cycloplegia. These actions permit an accurate determination of the refractive state of the eye, and the antimuscarinics are also useful in treating specific ocular diseases and for the treatment of patients following iridectomy. Atropine, scopolamine, cyclopentolate (Cyclogyl, AK-Pentolate, and others) and tropicamide (Mydriacyl, Tropicacyl, and others) are among the antimuscarinic drugs used in ophthalmology. All of...

Hydroquinone

Hydroquinone interferes with the production of the pigment melanin by epidermal melanocytes through at least two mechanisms it competitively inhibits tyrosi-nase, one of the principal enzymes responsible for converting tyrosine to melanin, and it selectively damages melanocytes and melanosomes (the organelles within which melanin is stored). Hydroquinone is applied topically to treat disorders characterized by excessive melanin in the epidermis, such as melasma. In the United States,...

Filgrastim

Filgrastim (Neupogen) is a human recombinant granulocyte colony-stimulating factor (rG-CSF) produced using recombinant DNA technology. It acts on precursor hematopoietic cells in the bone marrow by binding to specific receptors that stimulate cellular proliferation and differentiation into neutrophils. It also enhances some neutrophil functions, including phagocytosis and antibody-dependent killing. Filgrastim is used to accelerate recovery of neutrophils after chemotherapy, both to prevent...

Other Cytotoxic Drugs

Although azathioprine is the most popular cytotoxic drug used for immunosuppression, others have been employed. Among these is cyclophosphamide, a cycle-specific agent that acts by cross-linking and alkylating DNA, thereby preventing correct duplication during cell divisions. Methotrexate is a phase-specific agent that acts by inhibiting folate metabolism. It is highly toxic and appears to offer no advantages over azathio-prine. Chlorambucil, an alkylating agent, has actions similar to those of...

Answers

The principal neurotransmitter released from preganglionic nerve terminals in all autonomic ganglia is acetylcholine. It acts on the postganglionic cell body to activate a nicotinic-cholinergic receptor resulting in a fast EPSP. Dopamine or norepinephrine or both are the mediators released from SIF cells or interneurons. Neuropeptide Y is a peptide neurotransmitter. Angiotensin and serotonin are modulatory mediators. These last three contribute to the late very slow EPSP. 2. C. The slow EPSP...

Mechanism of Action

In epilepsy certain neurons and or groups of neurons become hyperexcitable and begin firing bursts of action potentials that propagate in a synchronous manner to other brain structures (and in the case of generalized seizures, to practically all areas of the brain). These may be the result of abnormalities in neuronal membrane stability or in the connections among neurons. It is known that the epileptic bursts consist of sodium-dependent action potentials and a calcium-dependent depolarizing...

Individual Agents

The pharmacological agents useful in this disorder may be grouped under five broad categories of treatment (Table 64.2). Such a classification system takes into account the mode of drug action, the route of administration, and the means by which target organ selectivity is achieved. Oral medication for treatment of ED is relatively new. Earlier measures often employed the intracaver- TABLE 64.2 Classification by Mode of Action for Treatments of Erectile Dysfunction I Central initiator Compounds...

H2co3

Is recycled across the apical cell membrane back into the urine. The recirculation of K+ is important to the generation of the electropositive voltage within the lumen, which serves as a driving force for passive transport of Na+, Ca++, and Mg++ through the tight junctions joining adjacent cells. Hence, although K+ is transported by the Na+-K+-2Cl cotransporter, the primary solute absorbed into the blood is NaCl. Sodium reabsorption in thick ascending limbs depends on the amount, or load, of...

Pyrazolone Derivatives

Phenylbutazone (Butazolidin) is metabolized to oxy-phenbutazone (Phlogistol), and both compounds have all of the activities associated with the NSAIDs. Their use is accompanied by serious adverse reactions, such as anemia, nephritis, renal failure or necrosis, and liver damage. Because of their toxicity, they are prescribed only for the treatment of pain associated with gout or phlebitis or as a last resort for other painful inflammatory diseases resistant to newer and less toxic treatments....

Antimalarial Drugs

Like dapsone, the antimalarial drugs chloroquine, hy-droxychloroquine, and quinacrine are useful in some noninfectious skin diseases, although the mechanism of their therapeutic effect is unknown. Their pharmacology is discussed in Chapter 53. Antimalarial drugs have many effects, including impairment of lysosomal phagosomal activity, inhibition of neutrophilic iodination and locomotion, and diminution of macrophage and T-cell responsiveness in vitro. Chloroquine (Aralen) and hydroxychloroquine...

Absorption Of Drugs After Parenteral Administration

Intramuscular and Subcutaneous Administration Intramuscular and subcutaneous injections are by far the most common means of parenteral drug administration. Because of the high tissue blood flow and the ability of the injected solution to diffuse laterally, drug absorption generally is more rapid after intramuscular than after subcutaneous injection. Drug absorption from intramuscular and subcutaneous sites depends on the quantity and composition of the connective tissue, the capillary density,...

Drug Therapy Of Hiv Infection

The replicative cycle of HIV presents many opportunities for the targeting of antiviral agents. The drugs in clinical use are classified as nucleoside reverse tran-scriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NTRTIs), and protease inhibitors (PI). Single agents are seldom used to treat HIV infection. Instead, multidrug therapy is used to counteract the rapid mutation rate of HIV and to minimize drug...

Drug Metabolism and Disposition in Pediatric and Gerontological Stages of Life

The clinical responses to drug administration can be greatly influenced both by the chronological age of the patient and by the relative maturity of the particular organ system that is being targeted. Human development follows a continuum of time-related events. There are unique therapeutic differences and concerns associated with the treatment of the very young and the elderly patient. Age-dependent changes in body function are known to alter the pharmacokinetic parameters that determine each...

Clinical Manifestations of Thyrotoxicosis

The signs and symptoms of thyrotoxicosis, regardless of the cause, may include the following increased basal metabolic rate, heat intolerance, tachycardia, widened pulse pressure, cardiac arrhythmias, skeletal muscle weakness, muscle wasting, tremor, hyperreflexia, emotional instability, nervousness, insomnia, change in menstrual pattern, frequent bowel movements (occasionally diarrhea), and weight loss despite an increased appetite. In addition, very frequent manifestations of all forms of...

Anticholinergic Drugs

Before the introduction of levodopa, the belladonna alkaloids (e.g., atropine and scopolamine) were the primary agents used in the treatment of parkinsonism. The belladonna alkaloids have been replaced by anticholinergic agents with more selective central nervous system (CNS) effects. Trihexyphenidyl (Artane), ben-ztropine mesylate (Cogentin), biperiden (Akineton), and procyclidine (Kemadrin) are useful in most types of parkinsonism. The efficacy of anticholinergic drugs in parkinsonism is...

Cholinoceptors

The action of administered acetylcholine on effector systems innervated by parasympathetic postganglionic neurons (smooth muscle cells, cardiac muscle cells, and exocrine gland cells) resembled the actions produced by the naturally occurring plant alkaloid muscarine. The actions of both acetylcholine and muscarine on the visceral effectors are similar to those produced by parasympathetic nerve stimulation. Furthermore, the effects of acetylcholine, muscarine, and parasympa-thetic nerve...

Adrenoceptors

Adrenoceptors interact not only with norepinephrine but also with the adrenal medullary hormone epineph-rine and a number of chemically related drugs. However, the responses produced by the drugs in different autonomic structures differ quantitatively or qualitatively from one another. On the basis of the observed selectivity of action among agonists and antagonists, it was proposed that two types of adrenoceptors exist. These were designated as a- and (3-adrenoceptors. Subsequently, it has...

Receptors On The Autonomic Effector Cells

The receptors for acetylcholine and related drugs (cholinoreceptors) and for norepinephrine and related drugs (adrenoceptors) are different. Acetylcholine will not interact with receptors for norepinephrine, and nor-epinephrine will not interact with cholinoreceptors. These receptors are selective not only for their respective agonists but also for their respective antagonist drugs that is, drugs that antagonize or block acetylcholine at cholinoreceptors will not antagonize norepi-nephrine at...

Figure

Primary route of metabolism of norepinephrine and epinephrine. COMT, catechol-O-methyltransferase MAO, monoamine oxidase. Although either COMT or MAO may act first on circulating norepinephrine or epinephrine, COMT is the more rapidly acting enzyme, and therefore more molecules are O-methylated and then deaminated than the reverse. Some norepinephrine and epinephrine appear unchanged in the urine. The larger portion, however, is metabolized and the products of metabolism excreted in the urine,...

Thyrotoxic Crisis or Thyroid Storm

Thyrotoxic crisis, thyroid storm, or accelerated hyper-thyroidism is an extreme accentuation of thyrotoxicosis. Although uncommon, this serious complication of hy-perthyroidism usually occurs in association with Grave's disease and occasionally with toxic multinodular goiter. If unrecognized, it is invariably fatal. Thyroid storm is usually abrupt in onset and occurs in patients whose preexisting thyrotoxicosis has been treated incompletely or not at all. Thyrotoxic crisis may be related to...

Leishmaniasis and Trypanosomiasis

The flagellate leishmania is transmitted to humans by the bite of the female sandfly of the genus Phlebotomus. Three principal diseases result from infection with Leishmania spp. L. donovani causes visceral leishmania-sis (kala-azar) L. tropica and L. major produce cutaneous leishmaniasis, and L. braziliensis causes South American mucocutaneous leishmaniasis. In visceral leishmaniasis, the protozoan parasitizes the reticuloen-dothelial cells, and this results in an enlargement of the lymph...

Doseresponse Relationship

To understand drug-receptor interactions, it is necessary to quantify the relationship between the drug and the biological effect it produces. Since the degree of effect produced by a drug is generally a function of the amount administered, we can express this relationship in terms of a dose-response curve. Because we cannot always quantify the concentration of drug in the biophase in the intact individual, it is customary to correlate effect with dose administered. In general, biological...

Thyroid USP and Thyroglobulin

Thyroid USP (Thyrar, Thyroid Strong, S-P-T) is derived from dried and defatted thyroid glands of domestic an imals (bovine, ovine, or porcine), while Tg (Proloid) is a partially purified extract of frozen porcine thyroid glands. Although used extensively in the past, these preparations are rarely used today. The total thyroid hormone content of thyroid glands and the ratio of T3 to T4 vary somewhat from one species to another. Thyroid USP preparations are therefore standardized on the basis of...

Clinical Uses

Bacitracin is highly active against staphylococci, Streptococcus pyogenes, and C. difficile. Its high degree of activity against the group A streptococci is used in the laboratory as a means of differentiating between the Lancefield group A streptococci and other streptococci. Bacitracin is well tolerated topically and orally and is frequently used in combination with other agents (no tably polymyxin B and neomycin) in the form of creams, ointments, and aerosol preparations. Hydrocortisone has...

Absorption Distribution Metabolism and Excretion

Unlike other imidazoles, ketoconazole (Nizoral) can be absorbed orally, but it requires an acidic gastric environment patients concurrently treated with H2 blockers or who have achlorhydria have minimal drug absorption. Serum protein binding exceeds 90 . The drug is metabolized in the liver and excreted in the bile. The initial half-life of ketoconazole is 2 hours 8 to 12 hours after ingestion, the half-life increases to 9 hours. Reductions in renal and hepatic function do not alter plasma drug...

Schedules of Administration

Although the effects of various schedules are not always predictable, drugs that are rapidly metabolized, excreted, or both, especially if they are phase specific and thus act on only one portion of the cell cycle (e.g., cytarabine), appear to be more effective when administered by continuous infusion or frequent dose fraction-ation than by high-dose intermittent therapy. On the other hand, intermittent high-dose treatment of Burkitt's lymphoma with cyclophosphamide is more effective than...

Antacids

The rationale for the use of antacids in peptic ulcer disease lies in the assumption that buffering of H+ in the stomach permits healing. The use of both low and high doses of antacids is effective in healing peptic ulcers as compared with placebo. Healing rates are comparable with those observed after the use of histamine (H2) blocking agents. The buffering agents in the various antacid preparations consist of combinations of ingredients that include sodium bicarbonate, calcium carbonate,...

Somatostatin Analogue

Octreotide acetate (Sandostatin) is a synthetic peptide analogue of the hormone somatostatin. Its actions include inhibition of the pituitary secretion of growth hormone and an inhibition of pancreatic islet cell secretion of insulin and glucagon. Unlike somatostatin, which has a plasma half-life of a few minutes, octreotide has a plasma elimination half-life of 1 to 2 hours. Excretion of the drug is primarily renal. Octreotide is useful in inhibiting the secretion of various autacoids and...

Cyclophosphamide

Cyclophosphamide (Cytoxan) is the most versatile and useful of the nitrogen mustards. Preclinical testing showed it to have a favorable therapeutic index and to possess the broadest spectrum of antitumor activity of all alkylating agents. As with the other nitrogen mustards, cyclophosphamide administration results in the formation of cross-links within DNA due to a reaction of the two chloroethyl moieties of cyclophosphamide with adjacent nucleotide bases. Cyclophosphamide must be activated...

Treatment Of Major Depression

It is often surprising for the student to learn that mood-elevating agents do not act as stimulants of the central nervous system (CNS). With the exception of varying degrees of sedation, the antidepressants have little effect on behavior early in treatment. During this period patients will, however, have side effects specific to the class and agent being used. Only after 2 to 3 weeks of dosing will a therapeutic benefit on depression emerge. At this point the patient begins to demonstrate...

Derivatives of ACh Methacholine Carbachol and Bethanechol

The therapeutic usefulness of ACh is limited by (1) its lack of selectivity as an agonist for different types of choli-noreceptors and (2) its rapid degradation by cholin-esterases. These limitations have been circumvented in part by the development of three choline ester derivatives of ACh methacholine (Provocholine), carbachol (Isopto Carbachol, Miostat) and bethanechol (Urecholine). Methacholine differs from ACh only in the addition of a methyl group at the p-carbon of ACh. This modification...

Uses in Respiratory Disorders

For a long time, muscarinic receptor-blocking drugs occupied a major place in the therapy of asthma, but they have been largely displaced by the adrenergic drugs (see Chapter 41). The problems associated with the use of antimuscarinic alkaloids in respiratory disorders are low therapeutic index and impaired expectoration. The latter is a consequence of their inhibition of mucous secretion, ciliary activity, and mucous transport. Ipratropium bromide (Atrovent), in contrast, is a synthetic...

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...

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...

Case Study Pharmacology Gastric Emptying Time

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,...

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...

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...

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,...

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...

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...

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...