Therapeutic Drug Monitoring

Given the multiple factors that alter drug disposition, measurement of the concentration in body fluids can assist in individualizing therapy with selected drugs. Determination of the concentration of a drug is particularly useful when well-defined criteria are met 1. A demonstrated relationship exists between the concentration of drug in plasma and the desired therapeutic effect or the toxic effect to be avoided. The range of plasma levels between that required for efficacy and that at which...

Sympatholytic Agents

A and adrenergic antagonists are mainstays of antihypertensive therapy (Table 32-2). Adrenergic Receptor Antagonists receptor antagonists have antihypertensive effects. The pharmacology of these drugs is discussed in Chapter 10. Antagonism of adrenergic receptors affects blood pressure through a number of mechanisms, including reducing cardiac output. Adrenergic receptor antagonists also act on the juxtaglomerular complex to reduce renin secretion and thereby diminish production of circulating...

Info

Figure 60-1 Human proinsulin and its conversion to insulin. The amino acid sequence of human proinsulin is shown. By proteolytic cleavage, four basic amino acids (residues 31, 32, 64, and 65) and the connecting peptide are removed, converting proinsulin to insulin. The sites of action of the endopeptidases PC2 and PC3 are shown. figure 60-1 Human proinsulin and its conversion to insulin. The amino acid sequence of human proinsulin is shown. By proteolytic cleavage, four basic amino acids...

Therapeutic Uses

For the treatment of hypertension and angina, the initial oral dose generally is 40 80 mg day, titrated upward until the desired response is obtained, typically at < 320 mg day. In hypertension, the full antihypertensive effect may not develop for several weeks. If propranolol is taken twice daily for hypertension, blood pressure should be measured just prior to a dose to ensure that the duration of effect is sufficiently prolonged. Adequacy of b adrenergic blockade can be assessed by...

Mt

Presynaptic terminal T vesicular transporter Postsynaptic terminal-expressing D receptors (GPCRs) FIGURE 20-2 Dopaminergic terminal. Dopamine (DA) is synthesized in neuronal terminals from tyrosine by the sequential actions of tyrosine hydroxylase (TH), producing the intermediary l-dihydroxyphenylalanine (l-DOPA), and aromatic l-amino acid decarboxylase (AAD). In the terminal, DA is transported into storage vesicles by a vesicular membrane transporter (T). Release, triggered by depolarization...

Exocrine Glands

Choline esters and muscarinic alkaloids stimulate secretion of glands that receive parasympa-thetic or sympathetic cholinergic innervation, including the lacrimal, salivary, digestive, tracheo-bronchial, and sweat glands. Pilocarpine in particular causes marked diaphoresis (2-3 L of sweat may be secreted) and markedly increases salivation. Muscarine and arecoline also are potent diaphoretic agents. Accompanying side effects may include hiccough, salivation, nausea, vomiting, weakness, and...

Drug Addiction And Drug Abuse Drug Dependence

Although many physicians are concerned about creating addicts, relatively few individuals begin their drug addiction problems by misuse of prescription drugs. Confusion exists because the correct use of prescribed medications for pain, anxiety, and even hypertension commonly produces tolerance and physical dependence. These are normal physiological adaptations to repeated use of drugs from many different categories. Tolerance and physical dependence are explained in more detail later, but it...

Dermatological Pharmacology The Structure And Function Of Skin

A unique aspect of dermatological pharmacology is the direct accessibility of the skin as a target organ for diagnosis and treatment (Figure 62-1). The skin acts as a two-way barrier to prevent absorption or loss of water and electrolytes. The barrier resides in the outermost layer of the epidermis, the stratum corneum, as evidenced by approximately equal rates of penetration of chemicals through isolated stratum corneum or whole skin. Having lost their nuclei and cytoplasmic organelles, the...

Benign Prostatic Hyperplasia BPH

The symptoms of BPH (e.g., urethral obstruction leading to weak stream, urinary frequency, and nocturia) result from mechanical pressure on the urethra (due to an increase in smooth muscle mass) and an a-mediated increase in smooth muscle tone in the prostate and neck of the bladder. a1 receptors in the trigone muscle of the bladder and urethra contribute to the resistance to outflow of urine prazosin reduces this. The efficacy and importance of a receptor antagonists in the medical treatment...

Midodrine

Midodrine (proamatine) is an orally effective a1 receptor agonist. It is a prodrug its activity is due to its conversion to an active metabolite, desglymidodrine, which achieves peak concentrations 1 hour after a dose of midodrine. The t 2 of desglymidodrine is 3 hours its duration of action is 4-6 hours. Midodrine stimulates contraction of both arterial and venous smooth muscle, and has useful effects in treating autonomic insufficiency and postural hypotension. A frequent complication in...

F

BLIND AND PAINFUL EYE Retrobulbar injection of either absolute or 95 ethanol may provide relief from chronic pain associated with a blind and painful eye. Retrobulbar chlorpro-mazine also has been used. This treatment is preceded by administration of local anesthesia. Local infiltration of the ciliary nerves provides symptomatic relief from pain, but other nerve fibers may be damaged, causing paralysis of the extraocular muscles, including those in the eyelids, or neu-roparalytic keratitis. The...

Choline Acetyltransferase

Choline acetyltransferase catalyzes the synthesis of ACh the acetylation of choline with acetyl coenzyme A (CoA). Choline acetyltransferase, like other protein constituents of the neuron, is synthesized within the perikaryon and then is transported along the length of the axon to its terminal. Axonal terminals contain a large number of mitochondria, where acetyl CoA is synthesized. Choline is taken up from the extracellular fluid into the axoplasm by active transport. The synthetic step occurs...

Other Sympathomimetics

Several sympathomimetic drugs are used primarily as vasoconstrictors for local application to the nasal mucous membrane or the eye propylhexedrine (benzedrex, others), naphazoline (privine, naphcon, others), oxymetazoline (afrin, ocuclear, others), and xylometazoline (otrivin, others) see Table 10-1 . Ethylnorepinephrine (bronkephrine) is a b agonist that is used as a bron-chodilator the drug also has a agonist activity, which may cause local vasoconstriction and thereby reduce bronchial...

Hypersensitivity Reactions

The sulfonamides are associated with a number of skin and mucous membrane manifestations attributed to sensitization to sulfonamide, including various rashes, erythema nodosum, erythema multiforme of the Stevens-Johnson type, Behcet's syndrome, exfoliative dermatitis, and photosen-sitivity. These hypersensitivity reactions usually occur after the first week of therapy but may appear earlier in previously sensitized individuals. Fever, malaise, and pruritus frequently are present simultaneously....

Entry Inhibitors

Enfuvirtide is a 36-amino-acid synthetic peptide whose sequence is derived from a part of the transmembrane pg41 region of HIV-1. Enfuvirtide is not active against HIV-2 but has a broad range of potencies against HIV-1 isolates. MECHANISMS OF ACTION AND RESISTANCE The peptide blocks the interaction between the N36 and C34 sequences of the gp41 glycoprotein by binding to a hydrophobic groove in the N36 coil. This prevents formation of a six-helix bundle critical for membrane fusion and viral...

Sunscreens

Photoprotection from the acute and chronic effects of sun exposure is readily available with sunscreens that include chemical agents to absorb incident solar radiation in the UVB and or UVA ranges and physical agents that contain particulate materials that can block or reflect incident energy and reduce its transmission to the skin. Many of the sunscreens available are mixtures of organic chemical absorbers and particulate physical substances. Ideal sunscreens provide a broad spectrum of...

Pharmacotherapy Of Alcoholism

Currently, three drugs are approved in the U.S. for treatment of alcoholism disulfiram (ANTABUSE), naltrexone (revia), and acamprosate. Disulfiram has a long history of use but has fallen into disfavor because of its side effects and problems with patient adherence to therapy. Naltrexone and acamprosate were introduced more recently. The goal of these medications is to assist the patient in maintaining abstinence. Naltrexone is chemically related to the highly selective opioid-receptor...

Miscellaneous Medical Uses For Antipsychotic Drugs

Many antipsychotic agents can prevent vomiting due to specific etiologies when given in relatively low, nonsedative doses (see Chapter 37). Antipsychotic drugs are useful in the management of several syndromes with psychiatric features that also are characterized by movement disorders (e.g., Tourette's syndrome and Huntington's disease). Haloperidol currently is regarded as a drug of choice for these conditions, although it probably is not unique in its antidyskinetic actions. Pimozide also is...

Acute Ethanol Intoxication

An increased reaction time, diminished fine motor control, impulsivity, and impaired judgment become evident when the concentration of ethanol in the blood is 20-30 mg dL. More than 50 of persons are grossly intoxicated by a concentration of 150 mg dL. In fatal cases, the average concentration is -400 mg dL, although alcohol-tolerant individuals often can withstand comparable BALs. The definition of intoxication varies by state and country. In the U.S., most states set the ethanol level defined...

Therapy Of Hypertension

Hypertension is the most common cardiovascular disease its prevalence increases with advancing age. Elevated arterial pressure causes pathological changes in the vasculature and hypertrophy of the left ventricle. Hypertension is the principal cause of stroke, is a major risk factor for coronary artery disease and its complications, and is a major contributor to cardiac failure, renal insufficiency, and dissecting aortic aneurysm. Hypertension is defined as a sustained increase in blood pressure...

Antimalarial Agents

The major antimalarials used commonly in dermatology include chloroquine (aralen), hydroxychloroquine (plaquenil), and to a lesser extent, quinacrine (no longer available in the U.S.) all three drugs are useful because of their anti-inflammatory effects, especially in connective tissue disorders and photosensitivity diseases (see Chapter 39). The mechanism of action of the immunological and anti-inflammatory effects of antimalarials include inhibition of phospholipase A2, inhibition of platelet...

Zanamivir

Mechanisms ofaction and resistance Zanamivir inhibits viral neuraminidase and thus causes viral aggregation at the cell surface and reduced spread of virus within the respiratory tract. In vitro resistance to zanamivir results from mutations in the viral hemagglutinin and or neu-raminidase. Hemagglutinin variants generally have mutations in or near the receptor binding site that make them less dependent on neuraminidase for release from cells, although they typically retain some drug...

Estramustine

Estramustine (emcyt), a combination of estradiol coupled to normustine (nornitrogen mustard) by a carbamate link, has weaker estrogenic and antineoplastic activity than estradiol and other alky-lating agents, respectively. While the combination was intended to enhance the uptake of the alky-lating agent into estradiol-sensitive prostate cancer cells, estramustine does not appear to function as an alkylating agent. Rather, estramustine binds to -tubulin and microtubule-associated proteins,...

Sympathetic Branch Of The

The cells that give rise to the preganglionic fibers of this division lie mainly in the intermediolat-eral columns of the spinal cord and extend from the first thoracic to the second or third lumbar segment. The axons from these cells are carried in the anterior (ventral) nerve roots and synapse with neurons lying in sympathetic ganglia outside the cerebrospinal axis. Sympathetic ganglia are found in three locations paravertebral, prevertebral, and terminal. The 22 pairs of paravertebral...

Luteal Phase

FIGURE 57-3 Hormonal relationships of the human menstrual cycle. A. Average daily values of LH, FSH, estradiol (E2), and progesterone in plasma samples from women exhibiting normal 28-day menstrual cycles. Changes in the ovarian follicle (top) and endometrium (bottom) also are illustrated schematically. Frequent plasma sampling reveals pulsatile patterns of gonadotropin release. Characteristic profiles are illustrated schematically for the follicular phase (day 9, inset on left) and luteal...

Overview Of Diuretic

Diuretics are used clinically to treat hypertension (see Chapter 32) and to reduce edema associated with cardiac, renal, and hepatic disorders. Three fundamental strategies exist for mobilizing edema fluid correct the underlying disease, restrict Na+ intake, or administer diuretics. The most desirable course of action would be to correct the primary disease however, this often is impossible. Restriction of Na+ intake is the favored nonpharmacologic approach to the treatment of edema and...

Monoclonal Antibodies

Cancer cells express a variety of antigens that are attractive targets for monoclonal antibody-based therapy (Table 51-3). Several monoclonal antibodies are FDA-approved for treating lymphoid and solid tumor malignancies, including rituximab and alemtuz,umab for lymphoid malignancies, and trastuzumab for breast cancer. Because murine monoclonal antibodies have a short t1 2 and induce a human anti-mouse antibody immune response, they usually are chimerized or humanized when used as therapeutic...

Acetylcholinesterase Inhibitors

Acetylcholinesterase (AChE) terminates the action of acetylcholine (ACh) at the junctions of the various cholinergic nerve endings with their effector organs or postsynaptic sites. Inhibitors of AChE, or anticholinesterase (anti-ChE) agents, cause ACh to accumulate in the vicinity of cholinergic nerve terminals and thus can produce effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems such is the basis of their clinical use...

Mopgal

FIGURE 6-6 Metabolism of catecholamines. Norepinephrine and epinephrine are first oxidatively deaminated by monoamine oxidase (MAO) to 3,4-dihydroxyphenylglycoaldehyde (DOPGAL) and then either reduced to 3,4-dihy-droxyphenylethylene glycol (DOPEG) or oxidized to 3,4-dihydroxymandelic acid (DOMA). Alternatively, they can be methylated initially by catechol-O- methyltransferase (COMT) to normetanephrine and metanephrine, respectively. Most of the products of either enzyme then are metabolized by...

Photochemotherapy

Electromagnetic radiation is defined by its wavelength and frequency for convenience, it can be classified into different regions based on its photon energy. For therapeutic purposes, dermatologists are most concerned with the ultraviolet (UV) B (290 320 nm), A-I (320 340 nm), and A-II (340-400 nm) and visible (400-800 nm) spectrum. UVB is the most erythrogenic and melanogenic. It is the major action spectrum for sunburn, tanning, skin cancer, and photoaging. The longer wavelengths of UVA are a...

Bisphosphonates

Bisphosphonates are pyrophosphate analogs (Figure 61-8) they contain 2 phosphonate groups attached to a germinal (central) carbon that replaces the oxygen in pyrophosphate. They have a strong affinity for bone, especially areas undergoing remodeling. They are used extensively in conditions characterized by osteoclast-mediated bone resorption, including osteoporosis, steroid-induced osteoporosis, Paget's disease, tumor-associated osteolysis, breast and prostate cancer, and hypercalcemia. 0-P-o p...

Cardiac Glycosides

Beneficial effects of cardiac glycosides in the treatment of heart failure have been attributed to a positive inotropic effect on failing myocardium and efficacy in controlling the ventricular rate response to atrial fibrillation. The cardiac glycosides also modulate autonomic nervous system activity, and it is likely that this mechanism contributes substantially to their efficacy in the management of heart failure. However, the advent of alternative therapies that both palliate symptoms and...

Imipenem

Penicillinase-producing strains), and Listeria are all susceptible. Although some strains of methicillin-resistant staphylococci are susceptible, many are not. Activity is excellent against the Enterobacteriaceae, including organisms that are cephalosporin-resistant by virtue of expression of extended-spectrum b-lactamases. Most strains of Pseudomonas and Acinetobac-ter are inhibited. Anaerobes, including B. fragilis, are highly susceptible. Pharmacokinetics and Adverse Reactions Imipenem is...

Tyrosine Phosphorylation And The Insulin Action Cascade

Receptors for insulin and IGF-1 belong to the family of receptor tyrosine kinases, and tyrosine kinase activity is essential for insulin signaling (Figure 60 2). The activated receptors undergo autophosphorylation, which activates their tyrosine kinase activity toward other substrates, principally the four insulin receptor substrates IRS-1, 2, 3, and 4 and Shc Tyrosine phosphorylated IRS proteins recruit signaling cascades via the interaction of SH2 domains with phosphotyrosines, recruiting...

The Therapeutic Index

The dose of a drug required to produce a specified effect in 50 of the population is the median effective dose (ED50, Figure 5-4B). In preclinical studies of drugs, the median lethal dose (LD50) is determined in experimental animals. The LD50 ED50 ratio is an indication of the therapeutic index, which is a statement of how selective the drug is in producing its desired versus its adverse effects. In clinical studies, the dose, or preferably the concentration, of a drug required to produce toxic...

Virus maturation inhibition

Inhibits glycosyltransferase, thereby reducing glycoprotein maturation causes membrane changes > blocks budding FIGURE 49-3 Interferon-mediated antiviral activity occurs via multiple mechanisms. The binding of IFN to specific cell surface receptor molecules signals the cell to produce a series of antiviral proteins. The stages of viral replication that are inhibited by various IFN-induced antiviral proteins are shown. Most of these act to inhibit the translation of viral proteins (mechanism...

N

Interfering with normal locomotion and can decrease rigidity in patients with cerebral palsy. In contrast to effects in animals, there is only a limited selectivity in human beings. Clonazepam in nonsedative doses does cause muscle relaxation, but diazepam and most other benzodiazepines do not. Tolerance occurs to the muscle relaxant and ataxic effects of these drugs. Experimentally, benzodiazepines inhibit some types of seizure activity. Clonazepam, nitrazepam, and nordazepam have more...

O

FIGURE 22-1 Metabolism of ethanol and methanol. drugs, however, after acute consumption of ethanol because ethanol competes with them for oxidation by the enzyme system (e.g., phenytoin and warfarin). The large increase in the hepatic NADH NAD+ ratio during ethanol oxidation has profound consequences in addition to limiting the rate of ethanol metabolism. Enzymes requiring NAD+ are inhibited thus, lactate accumulates, activity of the tricarboxylic acid cycle is reduced, and acetyl coenzyme A...

Basic Mechanisms Of Membrane Transport Transporters Versus Channels

Both channels and transporters facilitate the membrane permeation of inorganic ions and organic compounds. Channels have two primary states, open and closed, that are stochastic phenomena. Only in the open state do channels act as pores for their selected ions, allowing permeation across the plasma membrane. After opening, channels return to the closed state as a function of time. FIGURE 2-2 Hepatic drug transporters. Membrane transporters, shown as hexagons with arrows, work in concert with...

Voriconazole

Tacrolimus, phenytoin, rifabutin, warfarin, and sirolimus. Because the sirolimus AUC increases 11-fold when voriconazole is given, coadministration is contraindicated. Omeprazole dose should be reduced by half if 40 mg or more per day is given. Until more experience with voriconazole is gained, it is prudent to be observant for drug interactions that occur with other azoles (Table 48 1). Voriconazole is superior to C-AMB as primary therapy of invasive aspergillosis. Although not approved,...

Oct

All sympathetically innervated tissue Adrenal medulla Liver Stomach Pancreas DA Epi > > NE Liver endothelial cells Syncytiotrophoblast DA > > NE > Epi Kidney Brain and distal tubules Glial cells of DArich regions, some nonadrenergic neurons Hepatocytes Glial cells, others Myocytes Endothelial cells Cortex, proximal and distal tubules Syncytiotrophoblast (basal membrane) Photoreceptors, ganglion amacrine cells Isocyanines, corticosterone, O-methyl-isoproterenol ABBREVIATIONS NET,...

Diseases Affecting The Vasopressin System

DIABETES INSIPIDUS (DI) DI is a disease of impaired renal conservation of water owing either to an inadequate secretion of vasopressin from the neurohypophysis (central DI) or to an insufficient renal response to vasopressin (nephrogenic DI). Very rarely, DI can be caused by an abnormally high rate of degradation of vasopressin by circulating vasopressinases. Pregnancy may accentuate or reveal central and or nephrogenic DI by increasing plasma levels of vasopressinase and by reducing the renal...

Cytotoxic And Immunosuppressant Drugs

Cytotoxic and immunosuppressive drugs are used in dermatology for immunologically mediated diseases such as psoriasis, the autoimmune blistering diseases, and leukocytoclastic vasculitis. These agents are discussed in detail in Chapters 51 and 52. methotrexate The antimetabolite methotrexate suppresses immunocompetent cells in the skin, and it also decreases the expression of cutaneous lymphocyte-associated antigen (CLA)-positive T cells and endothelial cell E-selectin, which may account for...

Common Adverse Effects

Allopurinol is tolerated well by most patients. The most common adverse effects are hypersensitiv-ity reactions that may occur after months or years of medication. The effects usually subside within a few days after medication is discontinued. Serious reactions preclude further use of the drug. The cutaneous reaction caused by allopurinol is predominantly a pruritic, erythematous, or maculopapular eruption, but occasionally the lesion is urticarial or purpuric. Rarely, toxic epidermal...

Econazole

Miconazole readily penetrates the stratum corneum and persists there for > 4 days after application. Less than 1 is absorbed into the blood. systemic absorption from the vagina is < 1.3 . Adverse effects from vaginal application include burning, itching, or irritation in 7 of recipients, and infrequently, pelvic cramps (0.2 ), headache, hives, or skin rash. Irritation, burning, and maceration are rare after cutaneous application. Miconazole is considered safe for use during pregnancy.

Bone Physiology

The skeleton is the primary structural support for the body and also provides a protected environment for hematopoiesis. It contains both a large mineralized matrix and a highly active cellular component. A process called modeling drives the growth and development of endochondral bone. Once new bone is laid down, it is subject to a continuous process of breakdown and renewal, called remodeling, by which bone mass is adjusted throughout adult life. This remodeling is carried out by multiple...

Clinical Responses and Monitoring of Phase I and Phase II Neuromuscular Blockade by Succinylcholine Infusion

Train of four and tetanic stimulation Acetylcholinesterase inhibition Muscle response Repolarization toward -80 mV Slow transition Usually higher or follows prolonged infusion More prolonged Fade* Fasciculations flaccid paralysis Flaccid paralysis *Post-tetanic potentiation follows fade. blocking agents (e.g., bronchospasm, hypotension, excessive bronchial and salivary secretion) appear to be caused by the release of histamine. Succinylcholine, mivacurium, doxacurium, and atracurium also cause...

Cyp2b6

Tolbutamide, warfarin, phenytoin, nonsteroidal anti-inflammatories Mephenytoin, omeprazole, hexobarbital, mephobarbital, propranolol, proguanil, phenytoin blockers, antidepressants, antipsychotics, codeine, debrisoquine, dextromethorphan, encainide, flecainide, fluoxetine, guanoxan, N-propylajmaline, perhexiline, phenacetin, phenformin, propafenone, sparteine Macrolides, cyclosporine, tacrolimus, Ca2+ channel blockers, midazolam, terfenadine, lidocaine, dapsone, quinidine, triazolam, etoposide,...

Mupirocin

Mupirocin (bactroban) is active against many gram-positive and selected gram-negative bacteria. It has good activity against S. pyogenes and methicillin-susceptible and methicillin-resistant strains of S. aureus. It is bactericidal at concentrations achieved with topical application. Mupirocin inhibits bacterial protein synthesis by reversible inhibition of Ile tRNA synthase. There is no cross-resistance with other antibiotic classes. clinically insignificant, low-level resistance results from...

Fludarabine Phosphate

A fluorinated deamination-resistant nucleotide analog of the antiviral agent vidarabine (9-b-d-arabinofuranosyl-adenine), this compound is active in CLL and low-grade lymphomas. After rapid extracellular dephosphorylation to the nucleoside fludarabine, it is rephosphorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. This antimetabolite inhibits DNA poly-merase, DNA primase, DNA ligase, and ribonucleotide reductase, and is incorporated into DNA and RNA. The...

Antiflatulence Agents

Gas is a common but relatively vague GI complaint, used in reference not only to flatulence and eructation, but also bloating or fullness. Although few if any symptoms can be directly attributable to excessive intestinal gas, over-the-counter and herbal preparations that are touted as antiflatulent are very popular. One of these is simethicone, a mixture of siloxane polymers stabilized with silicon dioxide. For a complete Bibliographical listing see Goodman & Gilman's The Pharmacological...

Drug Treatment Of Psychoses

SHORT-TERM TREATMENT The antipsychotic drugs are effective in acute psychoses of unknown etiology, including mania, acute idiopathic psychoses, and acute exacerbations of schizophrenia. The best studied indications are for the acute and chronic phases of schizophrenia and in acute mania. Antipsychotic drugs also are used empirically in many other neuromedical and idio-pathic disorders with prominent psychotic symptoms or severe agitation. Neuroleptic agents are effective antipsychotics and are...

Wty

131I (radioactive iodine), 991-992 Ibandronate, 1070 , 1073 Ibuprofen adverse effects, 452 versus aspirin, 433 chemistry, 452 in children, 433 dosage, 433 , 452 interactions, 451-452 with lithium, 315 pharmacokinetics, 433 , 452 pharmacological properties, 451 Ibutilide, for cardiac arrhythmias, 587 , 589, 593 , 598 IDAMYCIN (idarubicin), 888 Idarubicin, 888 Idoxuridine, 815 , 824-825 IDV. See Indinavir IFEX (ifosfamide), 862 IFNs. See Interferon(s) Ifosfamide dosage, 862 pharmacokinetics,...

Pharmacology And Toxicology Of Ethanol

The two-carbon alcohol ethanol, CH3CH2OH, is a CNS depressant that is widely available to adults its use is legal and accepted in many societies, and its abuse is a societal problem. The relevant pharmacological properties of ethanol include effects on the gastrointestinal (GI), cardiovascular, and central nervous systems (CNS), effects on disease processes, and effects on prenatal development. Ethanol disturbs the fine balance between excitatory and inhibitory influences in the brain,...

Absorption Fate And Excretion

Absorption of quaternary ammonium and sulfonium compounds from the GI tract is incomplete and unpredictable, due to the limited ability of these ionized substances to penetrate cell membranes and depression of propulsive movements of the small intestine and gastric emptying. Absorption of mecamylamine is less erratic, but reduced bowel activity and paralytic ileus are a danger. After absorption, the quaternary ammonium- and sulfonium-blocking agents are confined primarily to the extracellular...

At1 Angiotensin Ii Receptor Antagonists

Nonpeptide antagonists of the ATj angiotensin II receptor approved for the treatment of hypertension include losartan (cozaar), candesartan (atacand), irbesartan (avapro), valsartan (diovan), telmisartan (micardis), and eprosartan (teveten). By antagonizing the effects of AnglI, these agents relax smooth muscle and thereby promote vasodilation, increase renal salt and water excretion, reduce plasma volume, and decrease cellular hypertrophy (see Chapter 30). Distinct subtypes of AnglI receptors...

Bntx

BNTX, 7-benzylidenenaltroxone EKC, ethylketocyclazosine NTB, benzofuran analog of naltrindole nor-BNI, nor-binaltorphimine. DAMGO, CTOR, DPDPE, DSLET, see Table 21-1. BNTX, 7-benzylidenenaltroxone EKC, ethylketocyclazosine NTB, benzofuran analog of naltrindole nor-BNI, nor-binaltorphimine. DAMGO, CTOR, DPDPE, DSLET, see Table 21-1. sites. Respiratory depression and miosis may be less severe with k agonists. Instead of euphoria, k receptor agonists produce dysphoric and psychotomimetic effects....

Rectal Administration

The rectal route, though less predictable, can be used when oral ingestion is precluded because the patient is unconscious or when vomiting is present. Approximately 50 of the drug that is absorbed from the rectum will bypass the liver, thus reducing the hepatic first-pass effect. Factors relevant to absorption are circumvented by intravenous injection of drugs because bioavailability is rapid and complete. Also, drug delivery is controlled, can be adjusted to the response of the patient and is...

Thalidomide And Lenalidomide

Thalidomide has been reintroduced to clinical practice as an oral agent for the management of erythema nodosum leprosum (ENL) and in other disease settings, most notably MM. Lenalidomide is a thalidomide derivative with improved potency and safety profile compared to thalidomide. Thalidomide is a nonpolar racemic mixture of cell permeable and rapidly interconverting S(-) and R(+) isomers. The precise mechanisms responsible for thalidomide's clinical activity remain to be elucidated. Multiple...

Selective Neuronal Vulnerability

A striking feature of these disease processes is their specificity for particular types of neurons. In PD there is extensive destruction of the dopaminergic neurons of the substantia nigra neurons in the cortex and many other areas of the brain are unaffected. In contrast, neural injury in AD is most severe in the hippocampus and neocortex, and even varies dramatically in different functional cortical regions. In HD, the mutant gene responsible for the disorder is expressed throughout the brain...

Importance of Pharmacogenetics to Variability in Drug Response

An individual's response to a given drug depends on a complex interplay among many environmental and genetic factors (Figure 4-1). Genetic factors account for most of the variation in metabolic rates for many drugs. Heritability can account for 75-85 of the variability in pharmacokinetic half-lives for drugs that are eliminated by metabolism. Cytotoxicity of drugs also appears to be heritable. Several genetic polymorphisms of drug-metabolizing enzymes result in monogenic traits in which...

Toxicities Of Alkylating Agents Bone Marrow Toxicity

The alkylating agents differ in their patterns of antitumor activity and in the sites and severity of their side effects. Most cause dose-limiting toxicity to bone marrow and intestinal mucosa. Most alkylating agents, including nitrogen mustard, melphalan, chlorambucil, cyclophosphamide, and ifosfamide, cause acute myelosuppression, with a nadir of the peripheral blood granulocyte count at 6-10 days and recovery in 14-21 days. Cyclophosphamide has lesser effects on peripheral blood platelet...

Classifying Antiarrhythmic Drugs

To the extent that the clinical actions of drugs can be predicted, classifying drugs by common elec-trophysiological properties is useful. However, differences in pharmacological effects occur even among drugs that share the same classification, some of which may be responsible for the observed clinical differences in responses to drugs of the same broad class (Table 34-3). Another way of approaching therapy is to attempt to classify arrhythmia mechanisms and then to target drug therapy to the...

Pharmacotherapy Of Gout

Gout results from the precipitation of urate crystals in the tissues and the subsequent inflammatory response. Acute gout usually causes an exquisitely painful distal monoarthritis, but it also can cause joint destruction, subcutaneous deposits (tophi), and renal calculi and damage. Gout affects -0.5-1 of the population of Western countries. The pathophysiology of gout is understood poorly. While a prerequisite, hyperuricemia does not inevitably lead to gout. Uric acid, the end product of...

Nitrofurantoin

Nitrofurantoin (furadantin, macrobid, others) is a synthetic nitrofuran that is used to prevent and treat urinary tract infections. Bacteria reduce nitrofurantoin to toxic products that apparently mediate cell damage. The antibacterial activity is higher in acidic urine. Nitrofurantoin is absorbed rapidly and completely from the GI tract. Antibacterial concentrations are not achieved in plasma at recommended doses because the drug is eliminated rapidly. The plasma t 2 is < 1 hour 40 is...

Ptu

Figure 56-2 Major pathways of thyroid hormone biosynthesis and release. abbreviations Tg, thyroglobulin DIT, diiodotyrosine MIT, monoiodotyrosine TPO, thyroid peroxidase HOI, hypoiodous acid EOI, enzyme-linked species PTU, propylthiouracil MMI, methimazole ECF, extracellular fluid. figure 56-3 Pathways of iodothyronine deiodination. Two distinct 5'-deiodinase enzymes convert T4 to T3 they are selenoproteins that are encoded by distinct genes and are differentially expressed and regulated. The...

Contraindications And Interactions

At very high doses, mefloquine causes teratogenesis and developmental abnormalities in rodents. Mefloquine is approved for use during pregnancy by the CDC and after the first trimester by the World Health Organization (WHO). However, there have been studies suggesting an increased rate of fetal loss with mefloquine use, especially during the first trimester. The evidence for mefloquine 's safety in pregnancy is not fully convincing, and alternatives should be sought. Pregnancy also should be...

Ht

Somatodendritic Autoreceptors (5-HT1A) FIGURE 11-2 Two classes of 5-HT autoreceptors with differential localizations. Somatodendritic 5-HT1A autoreceptors decrease raphe cell firing when activated by 5-HT released from axon collaterals of the same or adjacent neurons. The receptor subtype of the presynaptic autoreceptor on axon terminals in the human forebrain has different pharmacological properties and has been classified as 5-HT1D this receptor modulates the release of 5-HT. Postsynaptic...

Potential Roles of Aldosterone in the Pathophysiology of Heart Failure

Increased Na+ and water retention K+ and Mg2+ loss Reduced myocardial norepinephrine uptake Myocardial fibrosis, fibroblast proliferation Alterations in Na+ channel expression Edema, elevated cardiac filling pressures Arrhythmogenesis and risk of sudden cardiac death Potentiation of norepinephrine effects myocardial remodeling and arrhythmogenesis Reduced parasympathetic activity and risk of sudden cardiac death Remodeling and ventricular dysfunction Increased excitability and contractility of...

Fluconazole

Histoplasmosis, blastomycosis, sporotrichosis, and ringworm and neither prevents nor treats aspergillosis or mucormycosis. Nausea and vomiting may occur at doses > 200 mg day patients receiving 800 mg daily may require parenteral antiemetics. Regardless of dose, side effects in patients receiving > 7 days of drug include nausea, headache, skin rash, vomiting, abdominal pain, and diarrhea (all at 1-4 ). Reversible alopecia may occur with prolonged therapy at 400 mg daily. Rare deaths due to...

Deferoxamine

Deferoxamine is isolated as the iron chelate from Streptomyces pilosus and is treated chemically to obtain the metal-free ligand. Deferoxamine has the desirable properties of a remarkably high affinity for ferric iron (K 1031 M-1) coupled with a very low affinity for calcium (Ka 102 M-1). Studies in vitro have shown that it removes iron from hemosiderin and ferritin and, to a lesser extent, from transferrin. Iron in hemoglobin or cytochromes is not removed by deferoxamine. Deferoxamine...

Tegaserod Maleate

Chemistry, Mechanism of Action, and Pharmacological Properties Tegaserod (zelnorm), an aminoguanidine indole, is structurally related to serotonin and is a partial 5-HT4 agonist with negligible affinity for other receptor subtypes. Tegaserod has multiple effects on the GI tract. It stimulates motility and accelerates transit in the esophagus, stomach, small bowel, and ascending colon. It also stimulates chloride secretion. The clinical efficacy of tegaserod has been shown for male and female...

Triazenes

Dacarbazine (dtic) Dacarbazine functions as a methylating agent after metabolic activation in the liver. The active form is a monomethyl triazeno metabolite, MTIC, which kills cells in all phases of the cell cycle. Resistance has been ascribed to removal of methyl groups from the O6-guanine bases in DNA by AGT. Dacarbazine is administered intravenously. After an initial rapid phase of disappearance (t1 2 20 minutes), dacarbazine is removed from plasma with a terminal t1 2 of 5 hours. The t1 2...

Glucocorticoids

Glucocorticoids are prescribed frequently for their immunosuppressive and anti-inflammatory properties. They are administered locally, through topical and intralesional routes, and systemically, through intramuscular, intravenous, and oral routes. Mechanisms of glucocorticoid action are numerous, as discussed in Chapter 59. These include apoptosis of lymphocytes, inhibitory effects on the arachidonic acid cascade, depression of production of many cytokines, and myriad effects on inflammatory...

Preventing Diversion

Prescription blanks often are stolen and used to sustain abuse of controlled substances and to divert legitimate drug products to the illicit market. To prevent such diversion, prescription pads should be protected in the same manner as one would protect a personal checkbook. A prescription blank should never be pre-signed for a staff member to fill in at a later time. Also, a minimum number of pads should be stocked, and they should be kept in a locked, secure location except when in use. If a...

Acute Lead Poisoning

Acute lead poisoning is relatively infrequent and follows ingestion of acid-soluble lead compounds or inhalation of lead vapors. Local actions in the mouth produce marked astringency, thirst, and a metallic taste. Nausea, abdominal pain, and vomiting ensue. The vomitus may be milky from the presence of lead chloride. Although the abdominal pain is severe, it is unlike that of chronic poisoning. Stools may be black from lead sulfide, and there may be diarrhea or constipation. If large amounts of...

Alkylating Agents

In 1942, Goodman, Gilman, and colleagues launched the modern era of cancer chemotherapy with clinical studies of several nitrogen mustards in patients with lymphoma. At present five major types of alkylating agents are used in the chemotherapy of neoplastic diseases (1) the nitrogen mustards, (2) the ethyleneimines, (3) the alkyl sulfonates, (4) the nitrosoureas, and (5) the triazenes. The methylhydrazine and platinum complexes also are included here, even though they do not formally alkylate...

Methylhydrazines

Procarbazine Several methylhydrazine derivatives have anticancer activity, but only procarbazine is used clinically. The antineoplastic activity of procarbazine results from its conversion by hepatic CYPs to highly reactive alkylating species that methylate DNA. The first step in activation involves oxidation of the hydrazine function, yielding an azo metabolite that exists in equilibrium with its hydrazone tautomer. N-oxidation of azoprocarbazine generates the isomeric benzylazoxy and...

Interactions With Other Drugs

Severe reactions may follow the administration of meperidine to patients being treated with MAO inhibitors. An excitatory reaction (serotonin syndrome) with delirium, hyperthermia, headache, hyper- or hypotension, rigidity, convulsions, coma, and death may be due to the ability of meperidine to block neuronal reuptake of 5-HT and the resulting serotonergic overactivity. Therefore, meperidine and its congeners should not be used in patients taking MAO inhibitors. Potentiation owing to inhibition...

Adrenergic Agonists And Antagonists I Catecholamines And Sympathomimetic Drugs

Actions of catecholamines and sympathomimetic agents can be classified into seven broad types (1) peripheral excitatory actions on smooth muscles (e.g., in blood vessels supplying skin, kidney, and mucous membranes) and on gland cells (e.g., in salivary and sweat glands) (2) peripheral inhibitory action on certain other types of smooth muscle (e.g., in the wall of the gut, bronchial tree, and blood vessels supplying skeletal muscle) (3) cardiac excitatory action (increased rate and force of...

Levulan Kerastick

(5-Aminolevulinic acid), 1082 LEXAPRO (escitalopram), 281 LH. See Luteinizing hormone LHADI (recombinant luteinizing hormone), 977 LIBRAX (chlordiazepoxide), 123 LIBRIUM (chlordiazepoxide), 268 Lichen planus cyclosporine for, 1087 PUVA for, 1081 tacrolimus for, 1088 Liddle's syndrome, 493, 494 Lidocaine adverse effects, 246, 599 for cardiac arrhythmias dosage, 593 electrophysiological actions, 587 mechanisms of action, 598-599 pharmacokinetics, 593 , 599 chemistry, 242 clinical uses, 246 CNS...

Inflammatory And Allergic Responses

The proinflammatory actions of PAF and its elaboration by endothelial cells, leukocytes, and mast cells under inflammatory conditions are well characterized. PAF and PAF-like molecules are thought to contribute to the pathophysiology of inflammatory disorders, including anaphylaxis, bronchial asthma, endotoxic shock, and skin diseases. The plasma concentration of PAF is increased in experimental anaphylactic shock, and the administration of PAF reproduces many of its signs and symptoms,...

Doxorubicin

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

Pharmacological Effects of Muscarinic Stimulation

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

Genitourinary Tract

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

Adverse Effects And Drug Interactions

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

Central Nervous System

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

Fcf

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

Clofazimine

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

Poorly Absorbed Sulfonamides

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

Anthelmintic Action

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

Adrenergic Transmission

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

Iron Poisoning

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

Drug Therapy Of Dyslipidemia

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

1

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

Nafcillin

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

Ganglionic Stimulating Drugs

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

Bile Acids

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

Pentostatin 2Deoxycoformycin

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

The Dynamic Information Base

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