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On examination order viagra super active with american express erectile dysfunction treated by, the cervix is erythematous and the discharge reveals numerous leukocytes discount viagra super active 100mg mastercard erectile dysfunction treatment injection. O t her vaginal organisms order viagra super active 100mg erectile dysfunction medication options, such as anaerobic bact eria buy viagra super active toronto erectile dysfunction doctor delhi, are also usually involved in t he mix. In the fir st st age of syph ilis, ch an cr es m ay ap p ear on the ext er n al gen it alia or alon g the vagin al wall, bu t n ot in the en d ocer vix as wit h Chla- mydia and gonorrhea. The surgeon has direct visualization of the tubes with this method, and looks for pur u lent disch ar ge exuding from the fimbria of the t ubes. The clinical criteria that may support this diagnosis include: abdominal tenderness, cervical motion tenderness, adnexal tenderness, vaginal discharge, fever, and pelvic mass on physical examination or ultrasound. A pelvic mass, such as a tubo-ovarian abscess, may be visualized using sonography; h owever, it would st ill not spec- ify the origin of the mass. Actinomycesisraelii is a G r am-posit ive an aer obe, wh ich is gen er ally sen sit ive t o p en icillin. Chlamydia and gonorrhea are the only other answer choices t ypically involved in t he development of acute salpingit is; however, neither one of them are associated with sulfur granules. Cent ral locat ion of the pain and exacerbation with menses are more suggestive of a gynecologic et iology. Chlamydial cervicitis is the most common cause of mucopurulent cervical discharge. Although gonorrhea is also associated with a mucopurulent dis- ch ar ge, it is less com m on t h an Chlamydia. T h e mucus in the mu copur u lent discharge is due to involvement of the columnar (mucin-containing) glandu- lar cells of the endocer vix. Patients who engage in oral sex are at increased risk of acquiring gonococ- cal ph ar yn git is. Typically, n o sympt om s are n ot ed by the pat ient u n less the disease disseminates. Chlamydia is not a common cause of pharyngitis most likely because, un like Neisseria gonorrhoeae, it lacks the pili that allow the gon ococcal bact er ia t o ad h er e t o the su r face of the colu m n ar epit h eliu m at the back of the throat. Patients may present with subtle findings and sonography is usually required for diagnosis. Next step: Careful history and physical examination to try to discern what gen er al cat egor y the p ain seem s t o belon g, an d if n on gyn ecologic, r efer t o the appropriate consult ant. Co n s i d e r a t i o n s This is a 42-year-old G2P2 woman with worsening lower abdominal/ pelvic pain of 3 years’duration. We are not given further information about the nature of the pain, but this is critically important to t ry to reach a presumptive diagnosis. For in st an ce, pain that is associat ed wit h bloat ing, diarrh ea/ con st ipat ion may be gast r oin t est in al ( G I ) in n at u r e; u r in ar y u r gen cy or fr equ en cy su ggest s u r in ar y et iol- ogy; a patient with a history of depression or sexual abuse may suggest a psycho- logical disorder ; pain that is burn ing or radiat ing may be neurologic. If the pregnancy test is negative, then typically the baseline work-up would include ch lamydia an d gon or r h ea assays, u r in alysis an d u r in e cu lt u r e an d sen sit ivit y, com - plete blood count, and then pelvic ultrasound. If there is no response, an additional careful his- tory and physical examination should be repeated. If there is no nongynecologic eti- ology noted, then a diagnostic laparoscopy is reasonable to assess for endometriosis. The remaining 10% to 15% will have a variety of other causes such as genitourinary, gastrointestinal, neuromuscular, musculoskel- et al, and psychological. Gynecologic causes are in Table 37– 1, and non-gynecologic cau ses in Table 37– 2. His t o r y a n d Ph ys ica l Exa m The approach to chronic pelvic pain begins with a careful history and physical examinat ion. Women often have been dismissed as histrionic or exaggerating, or “hormonal”; thus, the physician should be encouraging and validate the patient’s perception of the pain. The evolution of the pain over time and response to various treatments is likewise very important. Pain that varies markedly over the menstrual cycle is likely due to a hormonal process such as endometriosis or adenomyosis. Cyclic pain in a patient who had under- gon e a bilat er al ooph or ect omy m ay be du e t o r esidu al ovar ian syn d r om e, in wh ich small amount s of ovarian t issue are t rapped in t he ret roperit oneum. Suppression of ovulation can be confirmatory, and treatment with surgical excision is curative. Gastrointestinal etiologies can include inflammatory bowel disease or irritable bowel syndrome. Psych o so cia l In q u irie s In approaching possible psychological or psychosocial reasons, the physician must be very judicious in when and how these questions are asked. Affected patients may misperceive the line of query as “You think I’m crazy like the rest of the doctors”. Sometimes, these topics are reserved for the second visit, or put in the review of syst em. Ex a m i n a t i o n The patient’s mood and posture are important to observe—flat affect or anxiety or in pain. The extremities and joint s are impor t ant t o assess for ar t h rit is or ar t h algias. The abdomen should be observed carefully for distension, surgical scars, and discoloration. The abdomen should be mapped carefully for locat ion, radiat ion, and severit y; the abdominal wall sh ould be palpat ed wit h and without abdominal wall flexion to try to discern musculoskelet al condit ion. T here should be an evaluat ion of t rigger point s, which are t ender point s t hat cause t he patient to “jump. The vulva and vaginal area should be carefully palpated for tenderness, such as wit h a cotton-t ipped applicator to assess for vulvodynia or vest ibulit is, condit ions of severe tenderness. The pelvic musculature such as the levator muscles, obturators, and peri- formis muscles sh ou ld be carefully palpat ed. T h e examin at ion sh ou ld begin wit h the nontender regions initially and then moving toward the more painful areas. Tender nodules of the uterosacral ligaments or a fixed retroverted uterus may suggest endometriosis. A pelvic t ransvaginal ult rasound examinat ion is import ant t o assess for ut erine masses, adnexal masses, and perit oneal fluid. Co n s u l t a t i o n The patient should be referred to the appropriate consultant if the history, physi- cal, labor at or y, or imagin g su ggest s a n on gyn ecologic et iology. For in st an ce, if the patient has abdominal bloating, nausea, or diarrhea, then a gastrointestinal con- sult at ion is indicat ed. If t he pat ient has a hist ory of depression, sexual abuse, or trauma, then a psychiatric consultation is important. If a gyne- cologic etiology is suspected, then laparoscopy can be useful to est ablish a diagno- sis: principally endometriosis or pelvic adhesions. If after a 3- to 6- month trial of medications there is no relief, and careful search does not reveal nongynecologic con dit ion s, t h en a d iagn ost ic lapar oscopy is r eason able. In t h ese in st an ces, it is oft en h elpfu l t o h ave a mu lt idisciplin ar y team, such as a gynecologist, physical therapist, psychologist, sex therapist, pain specialist, and anest hesiologist. Excisional surgical procedures such as hysterectomy, oophorectomy, or salpingectomy should be used judiciously, since pelvic pain may persist or even worsen if there is no clear indication for these operat ions. Acupunct ure, ner ve blocks and t rig- ger p oin t in ject ion s can alleviat e p ain. O piate medications should be used with extreme caution since addiction is com- mon. Psychiatric evaluat ion should be obt ained when there is a reason, such as depression or a history of abuse. In cases of neuropat hic pain, t ricyclic ant idepressant t herapy can be help- ful. T his 16-year-old nulliparous female has primary dysmenorrhea, which is a condit ion wit h pain usually st art ing wit hin 6 mont hs of menarche. The mechanism is elevated prostaglandin F2 alpha levels, leading to intense uterine contractions, causing the pain with menses. Sh e d e n ie s b e in g t re a t e d fo r va g in it is o r se xu a lly t ra n sm it t e d d ise a se s. Sh e is in g o o d h e a lt h a n d t a ke s n o medications other than an oral contraceptive agent. Th e e x t e r n a l g e n i t a l i a a r e n o r m a l ; the s p e c u l u m e x a m i n a t i o n r e v e a l s a h o m o g e - neous, white vaginal discharge and a fishy odor. T h e sp ecu lu m exam in at ion r eveals a homogeneous, white vaginal discharge and a fishy odor. Best treatment for this condition: Metronidazole orally or vaginally; clindamy- cin is an alt er n at ive. Co n s i d e r a t i o n s This 18-year-old woman complains of a vaginal discharge that has a fishy odor, wh ich is the most common sympt om of bact erial vaginosis. The vaginal epit helium is not eryt hemat ous or inflamed, which also fit s wit h bact erial vaginosis. There- fore, ant ibiot ic t h erapy t arget ing anaerobes, su ch as met ron idazole or clin damycin, is appropriat e. Bact er ial vagin osis is n ot a t r u e in fect ion, b u t r at h er an over gr owt h of an aer obic bacteria, which replaces the normal lactobacilli of the vagina. The most common symptom is a fish y or “mu st y” od or, oft en exacer bat ed by m en ses or in t er cou r se. Sin ce bot h of these situations introduce an alkaline substance, the vaginal pH is elevated above normal. The addition of 10% potassium hydroxide solution leads to the release of amines, causing a fishy odor (whiff test ).

At this point the steady-state equi- state the rate of drug administration equals the rate of drug librium is achieved viagra super active 25mg otc erectile dysfunction doctor malaysia. The time required to reach the steady state depends on the half-life (t1/2); it does not depend on the dose or dosage interval discount 25mg viagra super active overnight delivery erectile dysfunction doctors in nj. The steady-state drug concentration depends on the drug dose administered per unit of time and on the drug’s clearance or half-life order viagra super active 25 mg free shipping erectile dysfunction doctor in philadelphia. The maintenance dose is then parent compound or as drug metabolites discount viagra super active 25 mg without prescription statistics for erectile dysfunction, and undergo calculated as the rate of drug elimination multiplied by the the processes of glomerular fltration, active tubular dosage intervals. If the drug is administered orally, its bio- secretion, and passive tubular reabsorption. If drug elimina- • Most drugs are absorbed by passive diffusion across tion mechanisms (biotransformation and excretion) cell membranes or between cells. The rate of passive become saturated, a drug can exhibit zero-order diffusion of a drug across cell membranes is propor- kinetics, in which the rate of drug elimination is tional to the drug’s lipid solubility and the surface area constant. Only the nonionized form of • In frst-order kinetics, a drug’s half-life and clearance weak acids and bases is lipid soluble. The half-life is the time required of a weak acid or base can be determined from the for the plasma drug concentration to decrease by pKa of the drug and the pH of the body fuid in which 50%. Factors that reduce bioavailability • The volume of distribution is the volume of fuid in include incomplete tablet disintegration and frst-pass which a drug would need to be dissolved to have the and gastric inactivation of a drug. Phase I reactions include oxidative, reductive, achieve the steady-state condition. A, The steady-state plasma drug concentration is pro- portional to the dose administered per unit of time. B, The steady-state plasma drug concentration is directly proportional to the half-life (and is inversely related to clearance). C, The average steady-state concentration is the same for intermittent infusion as it is for continuous infusion. With intermittent drug administration, however, the plasma concentrations fuctuate between doses, and the size of fuctuations increases as the dosage interval increases. D, Plasma drug concentrations after intermittent oral administration are affected by the rates of drug absorption, distribution, and elimination. If only one dose is given, the peak in plasma drug concentration is followed by a continuous decline in the curve. Chapter 2 y Pharmacokinetics 25 • A loading dose is a single or divided dose given to 5. The volume of distribution of a drug will be greater if the rapidly establish a therapeutic plasma drug concentra- drug tion. The dose can be calculated by multiplying the (A) is more ionized inside cells than in plasma volume of distribution by the desired plasma drug (B) is administered very rapidly concentration. If food decreases the rate but not the extent of the absorp- tion of a particular drug from the gastrointestinal tract, Answers And explAnAtions then taking the drug with food will result in a smaller (A) area under the plasma drug concentration time curve 1. If (B) maximal plasma drug concentration the rate of drug absorption is reduced, then the maximal (C) time at which the maximal plasma drug concentra- plasma drug concentration will be less because more time tion occurs will be available for drug distribution and elimination (D) fractional bioavailability while the drug is being absorbed. Moreover, the time (E) total clearance at which the maximal plasma drug concentration occurs 2. If the extent of drug absorption (fraction (A) the elimination half-life is proportional to the plasma absorbed) does not change, then the area under the curve drug concentration and fractional bioavailability will not change. The answer is E: the rate of drug elimination (mg/min) (C) hepatic drug metabolizing enzymes are saturated is proportional to the plasma drug concentration. In frst- (D) drug clearance will increase if the plasma drug con- order elimination, drug half-life and clearance do not centration increases vary with the plasma drug concentration, but the rate of (E) the rate of drug elimination (mg/min) is proportional drug elimination (quantity per time) is proportional to to the plasma drug concentration plasma drug concentration at any time. How long will it take to reach a safe plasma concentration In this case, it will take four drug half-lives, or 24 hours, of 2 mg/L if the drug’s half-life is 6 hours? The dose required to establish (B) 24 hours a target plasma drug concentration is calculated by mul- (C) 48 hours tiplying the clearance by the target concentration and (D) 72 hours dosage interval. The answer is A: is more ionized inside cells than in every 8 hours to obtain an average steady-state plasma plasma. When a drug is more ionized inside cells, the drug concentration of 5 mg/L if the drug’s volume of drug becomes sequestered in the cells and the volume of distribution is 30 L and its clearance is 8 L/hr? This study starts at the binding of a drug to its target translocate to the nucleus on ligand (steroid) binding. In receptor or enzyme, continues through a signal transduction the nucleus, the steroid-receptor complex alters the tran- pathway by which the receptor activates second messenger scription rate of specifc genes (Fig. Other macromole- also a quantitative aspect to pharmacodynamics in charac- cules that serve as receptors include the various lipids and terizing the dose-response curve, which is the relationship phospholipids that make up the membrane. Some of the between drug dose and the magnitude of the pharmacologic effects of general anesthetics and alcohol are caused by inter- effect. There are also numerous other receptor-like regions determine ligand binding and selectivity. Intracel- proteins predicted from the human genome for which an lular loops, especially the third one, mediate the receptor endogenous ligand is not identifed, called orphan recep- interaction with its effector molecule, a guanine nucleotide tors. Families of receptor types are enzymes by competitive or noncompetitive inhibition. A grouped by their sequence similarity using bioinformatics, ligand that binds to the same active, catalytic site as the and this classifcation supports results from earlier in vivo endogenous substrate is called a competitive inhibitor. In many cases, each type of that bind at a different site on the enzyme and alter the receptor corresponds to a single, unique gene with subtypes shape of the molecule, thereby reducing its catalytic activity, of receptors arising from different transcripts of the same are called noncompetitive inhibitors. At ligand-gated ion channels, drugs can Receptor Binding and Affnity bind at the same site (called an orthosteric site) as the To initiate a cellular response, a drug must frst bind to a endogenous ligand and directly compete for the receptor receptor. Drugs can also bind at a different site, called an allo- forming hydrogen, ionic, or hydrophobic (van der Waals) steric site, that alters the response of the endogenous ligand bonds with a receptor site (Fig. These weak bonds are binding to the ligand-gated ion channel and increase or reversible and enable the drug to dissociate from the receptor decrease the fow of ions. The binding inactivate voltage-gated ion channels; these are ion channel of drugs to receptors often exhibits stereospecifcity, so that proteins that do not have an endogenous ligand (as ligand- only one of the stereoisomers (enantiomers) will form a gated ion channels do) but open or close as a function of the three-point attachment with the receptor. Neurotransmitter transporter drugs form relatively permanent covalent bonds with a spe- proteins are large, 12-transmembrane domain proteins that cifc receptor. The N-terminal of the receptor protein is outside the cell and the C-terminal is C-term on the inside. Steroid Ligand-gated ion channels Diazepam and ondansetron hormones diffuse through the cell membrane and bind to steroid receptors in the cytoplasm. Binding of the steroid ligand displaces accessory heat- Voltage-gated ion channels Lidocaine and verapamil shock proteins (hsp) and allows steroid receptor dimerization. These receptors constitute a superfamily of receptors for many endogenous ligands and drugs, including receptors – for acetylcholine, epinephrine, histamine, opioids, and sero- tonin. Figure 3-4 illustrates signal transduction for a recep- O tor that is coupled with G proteins. The heterotrimeric G proteins have three subunits, Hydrogen bond β-Adrenoceptor known as Gα, Gβ, and Gγ. Several types of Gα subunits H exist, each of which determines a specifc cellular response. The Gβ and Gγ subunits O are so tightly bound together that they do not dissociate and are therefore written as Gβγ. The Gβγ subunit also has β-Adrenoceptor signaling function when separated from Gα on ligand- No hydrogen bond + +2 B receptor activation, for example, by altering K or Ca channel conductance. Protein Weak hydrophobic kinase A phosphorylates the enzyme glycogen phosphory- bond; no – lase, which then increases the breakdown of glycogen to free hydrogen glucose, providing the fuel needed by the muscles to respond bonds to the event that initiated the release of epinephrine. A, l-Isoproterenol, a β- Ca+2 ions also activate calcium-dependent kinases and a adrenoceptor agonist, forms hydrogen, ionic, and hydrophobic (van der number of other enzyme cascades. B, d-Isoproterenol binds to two sites on the β-adrenoceptor but is unable to bind with the third site. C, l-Propranolol, a β-adrenoceptor antagonist, binds to two sites Ligand-Gated Ion Channels on the receptor in the same way that l-isoproterenol does. The naphthyloxy Ligand-gated ion channels are a large class of membrane group (N) forms weak bonds with the third receptor site, but these are not proteins that share similar subunit structure and are assem- suffciently strong for the drug to have intrinsic (agonist) activity. A, A typical G protein–coupled receptor contains a ligand-binding site on the external surface of the plasma membrane and a G protein–binding site on the internal surface. A large number kinases, tyrosine kinase–associated receptors, receptor tyro- of ligands activate these receptors, including epidermal sine phosphatases, and receptor serine/threonine kinases. These 30 Section I y Principles of Pharmacology receptors are composed of a single transmembrane protein, signal transduction proceeds at a basal rate in the absence with an extracellular binding domain, and in this case, an of any ligand binding to the receptor. When a increases the rate of signal transduction when it binds to growth factor or insulin binds to its receptor, kinase activity the receptor, whereas an inverse agonist decreases the rate phosphorylates tyrosine residues of the receptor protein of signal transduction. Non- competitive antagonists block the agonist site irreversibly, Nuclear Receptors usually by forming a covalent bond. The nuclear receptor family consists of two types of recep- tors that have similar protein structure. These steroid receptors are located inside protein–coupling effciency and alters the binding affnity. Phosphorylation also signals On activation, the heat shock protein dissociates and two the cell to internalize the membrane receptor. Through steroid-receptor proteins dimerize and translocate to the internalization and regulation of the receptor gene, the nucleus. This nonsteroid ligands including thyroid hormone, vitamin A longer-term adaptation is called down-regulation.

The reduced plasma volume serves effects of thiazide diuretics on serum lipid levels are dis- to increase sodium and water reabsorption from the pro- cussed in greater detail in Chapter 10 discount viagra super active uk erectile dysfunction treatment bangladesh. As a result buy generic viagra super active 50mg on line impotence 17 year old male, the urine output management of cardiovascular and renal diseases (see Table falls best viagra super active 25mg erectile dysfunction drugs and glaucoma. Chapter 13 y Diuretics 125 Nephron Blood Hyperuricemia Uric acid Thiazides inhibit Blood Na+ K+ Thiazides H+ increase K+ Kaliuresis Metabolic alkalosis Hypokalemia Body cells H+ K+ H+ Increased K+ H+ excretion A Pancreas Blood Pancreas Insulin Thiazides decrease Hyperglycemia B Figure 13-1 order viagra super active master card impotence stress. A, Inhibition of uric acid secretion in the proximal tubule can lead to hyperuricemia and gout. Hypokalemia can lead to metabolic alkalosis by promoting the exchange of intracellular potassium for hydrogen ions and by increasing the excretion of hydrogen ions. The increased excretion is caused by lack of availability of potassium for exchange with sodium in the collecting duct. B, In the presence of hypokalemia, the amount of insulin secreted by the pancreas can be reduced, thereby leading to hyperglycemia. These drugs include chlorthalidone, indapamide, The several thiazide compounds that are available have and metolazone. Indapamide has both diuretic and vasodi- almost identical actions but differ in their potency and phar- lator actions and is indicated for the treatment of hyperten- macokinetic properties. Loop Diuretics Thiazide-like Diuretics Drug Properties Thiazide-like diuretics have a different chemical structure, Chemistry and Pharmacokinetics. They are the preferred diuretics in the treatment of persons with renal 100 impairment, because (unlike thiazide and other diuretics) Loop diuretics they are effective in patients whose creatinine clearance drops below 30 mL/min. Loop diuretics are often the drugs of choice for patients with edema caused by heart failure, cirrhosis, and other disorders. Although they are prescribed 50 for patients with hypertension, the thiazide diuretics are usually preferred for this condition. Loop diuretics can be Thiazide diuretics used to treat hypercalcemia, whereas the thiazide diuretics can increase serum calcium levels slightly. Loop comparison with other loop diuretics, torsemide has a diuretics produce dose-dependent diuresis throughout their therapeutic dosage range, whereas thiazide diuretics have a relatively fat dose-response somewhat longer half-life and a signifcantly longer duration curve and a limited maximal response. All three of the drugs are partly metabolized before they are excreted in the urine. Loop diuretics Ethacrynic acid is the only loop diuretic that is not a sul- inhibit the Na+,K+,2Cl− symporter in the ascending limb of fonamide derivative, and it is occasionally used when patients the loop of Henle and thereby exert a powerful natriuretic are allergic or intolerant to the sulfonamide drugs in this effect. Otherwise, it is seldom used because it tends to inhibit the reabsorption of a greater percentage of fltered produce more ototoxicity than do other loop diuretics. Loop diuretics are sometimes called high-ceiling diuretics because they produce a dose-dependent diuresis Potassium-Sparing Diuretics throughout their clinical dosage range. This property can be Two types of potassium-sparing diuretics exist: the epithelial contrasted with the rather fat dose-response curve and sodium channel blockers and the aldosterone receptor limited diuretic capability of thiazides and other diuretic antagonists. In addition to their natriuretic effect, the loop diuretics Amiloride and Triamterene produce kaliuresis by increasing the exchange of sodium and Amiloride and triamterene are epithelial sodium channel potassium in the late distal tubule and collecting duct via the blockers. By blocking the entry of sodium into the principal same mechanisms as those described for the thiazide diuret- tubular cells of the late distal tubule and collecting duct (see ics. Loop diuretics also increase magnesium and calcium Box 13-1), these drugs prevent sodium reabsorption at this excretion by reducing the reabsorption of these ions in the site and indirectly reduce the secretion of potassium into ascending limb (see Box 13-1). Through these actions, the inhibition of the Na+,K+,2Cl− symporter, which reduces the potassium-sparing diuretics produce a modest amount of back-diffusion of potassium into the nephron lumen. Amiloride and triamterene reduction of potassium back-diffusion decreases the tran- are primarily used to prevent and treat hypokalemia induced sepithelial electrical potential that normally drives the para- by thiazide and loop diuretics. Inhibition uses of amiloride, triamterene, and other potassium-sparing of this process thereby increases magnesium and calcium diuretics are outlined in Tables 13-1 to 13-4. The most characteristic adverse effect of the potassium- Adverse Effects and Interactions. Loop diuretics can sparing diuretics is hyperkalemia, but this is unlikely to produce a variety of electrolyte abnormalities, including occur unless the patient also ingests potassium supplements hypokalemia, hypocalcemia, hypomagnesemia, and meta- or other drugs that increase serum potassium levels (e. These diuretics can also increase blood angiotensin antagonists) or unless the patient has a renal glucose and uric acid levels in the same manner as the thia- disorder that predisposes to hyperkalemia. In some patients, use of loop diuretics causes ototoxicity with manifestations such as tinnitus, ear pain, Spironolactone vertigo, and hearing defcits. In most cases the hearing loss Spironolactone is a structural analog of aldosterone that is reversible. Other adverse effects and drug interactions are competitively blocks aldosterone binding to the miner- listed in Table 13-4. Loop diuretics are highly effective in the treatment expression of genes for sodium channels and the sodium of pulmonary edema, partly because of the vasodilation that pump that enable sodium reabsorption and potassium Chapter 13 y Diuretics 127 secretion. By blocking these actions, spironolactone Carbonic Anhydrase Inhibitors reduces sodium reabsorption and the accompanying secre- Drug Properties tion of potassium. Clinical trials have shown that spironolactone reduces mortality in persons with heart failure, as described in Specifc Drugs Chapter 12. Acetazolamide is one of several associated with an increased incidence of hyperkalemia. Dorzol- used in the treatment of polycystic ovary disease and hir- amide is partly absorbed from the eye into the circulation sutism in women. The drug is eliminated in a biphasic mastia and impotence in men (caused by the drug’s antian- manner, with a rapid decline in serum levels followed by a drogenic effects) and hyperkalemia. Eplerenone is a newer much slower release from erythrocytes, and it has a half-life aldosterone antagonist that produces fewer endocrine side of 4 months. This enzyme catalyzes the conversion of carbon dioxide and water to carbonic acid, which spon- Osmotic Diuretics taneously decomposes to bicarbonate and hydrogen ions. Because of this action, mannitol is used to treat cere- water and other substances that make up the aqueous humor. Glycerol the chronic form of glaucoma, although they must be com- is administered orally for this purpose, whereas mannitol is bined with other drugs to treat the acute form. Now some of these drugs, including dorzol- administration, it is fltered at the glomerulus but is not amide, are available for topical ocular administration. It osmotically attracts and zolamide is administered every 8 hours in the treatment of retains water as it moves through the nephron and into the chronic ocular hypertension and open-angle glaucoma. In the reabsorption of Hence, mannitol has both direct and indirect actions that sodium bicarbonate, bicarbonate must be converted to promote diuresis. The The primary adverse effect of mannitol is excessive hyperchloremia results from the increased reabsorption of plasma volume expansion, which is most likely to occur if chloride as a compensation for reduced bicarbonate the drug is administered too rapidly or with too large a reabsorption. Conditions that cause edema as a result of acidosis produced by the drugs counteracts the respiratory increased hydrostatic pressure include heart failure and alkalosis that can result from hyperventilation in this certain renal diseases, all of which cause sodium and water condition. Conditions that cause edema as a result of inad- enhance ventilation acclimatization and maintain oxygen- equate colloid osmotic pressure include severe dietary ation during sleep at a high altitude. Less commonly, boembolism can also cause edema by various mechanisms they are associated with various hypersensitivity reactions that include infammation, increased capillary fuid perme- and blood cell defciencies. Conivaptan milder forms of edema, diuretics can be used as short-term blocks both V1A and V2 receptors, whereas tolvaptan is V2 adjunct treatments that serve to mobilize edematous fuid selective. The V2 receptors are coupled with insertion of while an attempt is made to correct the underlying cause. By activating these receptors, antidiuretic underlying disorder or discontinuing a causative drug. Antagonism of V2 receptors by conivaptan and tolvaptan causes free water excretion or aquaresis, and the drugs are called aquaretics. They are Almost 70% of patients achieve a normal serum sodium primarily used to treat hypertension, edema, hypercal- concentration of 135 mEq/L after 4 days of conivaptan ciuria, and nephrogenic diabetes insipidus. Tolvaptan is a newer orally administered drug for • Loop diuretics inhibit the Na,K,2Cl symporter in the treating hyponatremia. Conivaptan and tolvaptan may increase serum levels of nary edema, and hypercalcemia. The most common adverse reactions reported with other electrolyte disturbances, as well as hyperglyce- conivaptan are infusion site reactions. Spironolactone is used to treat interstitial space and body cavities, either because of severe heart failure and hyperaldosteronism. The plasma osmotic pressure is primarily infu- to treat cerebral edema, glaucoma, and the oliguria of enced by the osmotic attraction of water by sodium and acute renal failure. Chapter 13 y Diuretics 129 • Carbonic anhydrase inhibitors, which are weak diuret- Answers And explAnAtions ics that inhibit sodium bicarbonate reabsorption from the proximal tubule, can cause a mild form of meta- 1. They reduce aqueous humor secretion as furosemide can cause ototoxicity more frequently than and are primarily used to treat glaucoma. Potassium-sparing receptor antagonists that increase free water excretion diuretics such as spironolactone can cause hyperkalemia, and are used to treat euvolemic or hypervolemic especially in persons with renal insuffciency. Mannitol (E) and acetazolamide (D) have review Questions less effect on potassium excretion and serum potassium levels. Carbonic anhydrase following choices: inhibitors such as acetazolamide increase renal sodium (A) spironolactone bicarbonate excretion and alkalinize the urine. Urine (B) furosemide alkalinization increases the ionization of weakly acidic (C) hydrochlorothiazide drugs such as amphetamine and thereby increases their (D) acetazolamide renal excretion. Other diuretics do not signifcantly affect (E) mannitol the renal excretion of weakly acidic drugs. Administration of this drug to persons with renal insuf- used in the treatment of hypercalcemia. This drug can be used to increase the renal excretion of excretion and would worsen hypercalcemia. This drug can be used to increase calcium excretion in persons with hypercalcemia. The depolarizing pacemaker • Ibutilide (Corvert) current is known the “funny current” or I, and is blocked f • Dofetilide (Tikosyn) by ivabradine (see later). As the impulse is conducted to atrial and ventricular Miscellaneous Drugs muscle cells, these cells are rapidly depolarized by the infux • Adenosine (Adenocard) of sodium through the fast sodium channel. As the cells • Digoxin (Lanoxin) depolarize to about −40 mV, the slow calcium channels • Magnesium Sulfate open.

Operative intervention and percutaneous drainage are two import ant met hods t o achieve source cont rol in a pat ient wit h deep surgical space infect ion purchase viagra super active 25mg erectile dysfunction guilt in an affair, if confirmed cheap 50 mg viagra super active overnight delivery best erectile dysfunction doctor in india. Recognize the sources of fever in postoperative patients and become familiar with diagnostic and treatment strategies for these patients buy viagra super active 25mg otc erectile dysfunction song. Learn the principles of diagnosis and treatment of intra-abdominal infections in t he postoperat ive pat ient best 50 mg viagra super active impotence 27 years old. Co n s i d e r a t i o n s When a patient fails to improve and exhibits persistent fever following definitive surgical t reat ment for an int ra-abdominal infect ious process, we must first ent er- tain the possibility that there are still untreated intra-abdominal infections. We must also consider other potential nosocomial infectious causes, as well as non- infect ious causes for h is fever. Given t he picture of persist ent ileus and fevers, t he possibility of intra-abdominal (deep surgical space) infection should be at the top of our differential diagnosis. W ith his current picture, it is not unreasonable to init iat e broad-spect rum ant imicrobial t herapy t arget ing G I t ract microbial flora. W hen identified, some intra-abdominal abscesses can be accessed and drained by percutaneous approaches (Figure 4– 1). Persistent secondary peritonitis can be the result of inappropriate or inad- equat e ant imicrobial t h erapy, wh ich can be addressed wit h addit ional ant imicrobial therapy or modification of antimicrobial regimen. Dive rt icu la r a b sce ss n o t e d b y a rro w (A) an d the n e vacu at e d b y co m p u t e r t o m o g rap h y– guided percutaneous drainage (B). They are treated primarily by wound explorat ion and drainage; systemic ant ibiot ics may be added when t here is ext en- sive surrounding cellulit is (> 2 cm from the incision margin) or if t he pat ient is immunocompromised. D eep surgical site infect ions may be a clinical manifestation of a deep surgical space infection. This type of infect ion in the sett ing of post abdominal surgery can include seconda r y per it on it is, tertiary peritonitis, an d deep surgical space abscess. Recurrence or persistence of this process can be due to insufficient ant imicrobial t herapy or insufficient cont rol of cont aminat ion process (inadequate source cont rol). Very often in these cases, low virulence or opportunist ic pathogens such as Staphylococ- cus epidermis, Enterococcus faecalis, or Candida sp ecies are id en t ified. T h e t r eat m en t for this con dit ion is somewh at un clear because most cases are relat ed t o poor h ost immune responses. T h e response produces loculat ed, infect ed inflam- matory fluid that cannot be eliminated by the host trans-lymphatic clearance pro- cess. W h en the abscesses are sizeable, su r gical or p er cut an eou s dr ain age are n eed ed to resolve this process. In t h ese sit u at ion s, the t h er apy sh ou ld be in it ially br oad an d t ar get Gram-positive and Gram-negative bacteria. The optimal therapeutic duration and end-point s of t reat ment wit h t his st rat egy remains cont roversial. In general, as t he patients improve clinically and culture results become available, de-escalation of treatment is appropriate. Severe sepsis is defined as sepsis plus sepsis-related organ dysfunction or hypoperfusion. Septic shock is defined as sepsis-induced hypotension that persists despite adequate fluid resuscitation. The Surviving Sepsis Campaign h as in t r o d u ced bundles of care for septic patients. These guidelines, based on basic science and clin ical evid en ce, were in it ially int r odu ced in 2001 an d h ave been r egu lar ly up d at ed, valid at ed, an d im p lem en t ed in t er n at io n ally. These can include infect ions related t o t he original disease and the operat ive processes, such as secondary perit onit is, int ra-abdominal abscess, and surgical sit e infec- tion. In addition, hospital-acquired infections can also occur, including urinary tract infection, pneumonia, catheter-related bacteremia, and antibiotic-associ- ated colit is. The approach to a febrile postoperative patient who has undergone abdominal surgery is to presume that there is an intra-abdominal or surgical site related infectious complication until proven otherwise. The severity of the peritoneal contamination is related to the intestinal location of the perforation, which determines the concentration and diversity 11 14 of the endogenous microbes (ie, colon contents with 10 to 10 aerobic and anaerobic 2 3 microbes per gram of contents versus stomach contents with 10 to 10 aerobic microbes per gram of contents). A number of adaptive host defense responses occur following the inoculat ion of bact eria int o the perit oneal cavit y. Removal of the in fect ion occurs with translymphatic clearance of the sequestered microbes and inflamma- tory cells to help resolve the process. Several factors can influence the effectiveness of the host response, and include the following: (1) the size of the micr obial in ocu- lum; (2) the t iming of diagnosis and t reat ment ; (3) the in h ibit or y, synergist ic, or cumulat ive effect s of microbes on the growt h of ot h er microbes; (4) effect iveness of the host peritoneal defense. Tr e a t m e n t G o a l s The goals in the management of secondary peritonitis are directed toward elimi- nating the source of the microbial spillage (eg, an appendectomy for perforated appendicit is or closure of a perforated duodenal ulcer) and early init iat ion of preemptive antibiotic therapy. With appropriate and timely therapy, second- ary peritonit is resolves in most pat ient s; however, approximately 15% to 30% of the treated individuals may develop complications such as recurrent secondary peritonitis, tertiary peritonitis, or intra-abdominal abscesses. Recurrent second- ary peritonit is can be due to inappropriate ant ibiot ics or insufficient ant ibiot ic treatment duration. The initial systemic antibiotics for patients with infect ions from G I sources should include coverage of t he most likely pat hogens. Table 4– 1 cont ains some of the common ant imicrobial agent s or regimens that are used. A r upt ured appen dix wit h pur u lent drain age is n ot ed in the lower abdomen. Which of the following st at ement s is most accurat e regarding this patient’s condition? The resulting infection is a difficult problem to resolve even with appro- priate surgical treatment and antimicrobial therapy B. T h e m o st co m m o n o r gan ism s in vo lved in this in fect io n are C an d id a an d Pseudomonas C. Treatment can be effectively accomplished with appropriate surgery and a fir st -gen er at ion ceph alosp or in D. The patient should be sufficiently treated with operative removal of the appendix and copious irrigat ion of t he peritoneal cavit y E. T h ey r eq u ir e n o sp ecific t r eat m en t s b ecau se fever is an exp ect ed h o st response to surgical stress C. Presumptive antibiotics can be given if pat ient s exh ibit ph ysiologic sign s of sepsis or if the pat ient s are immunocompromised E. H igh doses of corticosteroids should be prescribed to blunt the physi- ologic responses to infection 4. Following surgery, he has persistent fever and abdo- minal pain despite the administration of ciprofloxacin and metronidazole. Broaden his antibiotic coverage with the addition of vancomycin and flu con azole B. Drain the fluid collection by percutaneous approach and initiate broad- spectrum antibiotics treatment E. Treatment with appropriate antimicrobial regimen will successfully resolve this process B. Su ccessfu l t r eat m en t can n o t b e acco m p lish ed wit h an t im icr o b ial t h er ap y alone C. Antimicrobial therapy is not useful for secondary peritonitis, and treat- ment will only lead to the selection of resistant microbial species E. D espit e t hese t reat ment s, t he pat ient remains febrile an d soon t h ereaft er begin s t o h ave ent eric cont ent s drain in g from h is drainage catheter. In addition, the patient develops drainage of purulent fluid from the in fer ior asp ect of h is m id lin e su r gical in cision. Which of the followin g is t he most appropriate t reat ment for this pat ient? Perform a laparotomy to address the intestinal leakage and drain the fluid collect ion D. H is hospit al cou r se was u n r emar kable, an d h e was d isch ar ged from the h ospit al on p ost - operative day six. The patient was doing well but returned to the emergency department with abdominal pain and vomiting. N on-operative management of small bowel obstruction for 7 days, and surgery if not improved B. At t em p t t o r ed u ce the h er n ia an d o b st r u ct io n b y m an ip u lat io n of the abdomen at t he sit e of herniat ion C. Provide intravenous sedation and muscle relaxants and attempt to manu- ally reduce t he hernia t o relieve t he obst ruct ion manually D. Take the patient to surgery to reduce the herniated intestine, and revise the fascial closure E. The pat ient developed a deep surgical site infec- tion on postoperative day number 4. She remained in the hospital for close observation and wound care with frequent dressing changes. Six days later, the patient is noted to have a significant amount of purulent fluid draining into her wound t h rough a 1-cm fascia defect in the lower aspect of h er surgical incision. The patient described is a 66-year-old man with secondary peritonitis due to perforated appendicitis. Properly selected antimicrobial therapy for sufficient duration of time is impor- tant to reduce the risk for tertiary peritonitis or intra-abdominal abscess forma- tion. The appropriate antibiotics for this patient should be either a single agent or combination regimen covering Gram-negative and anaerobic activities. A first- generation cephalosporin is not the appropriate antibiotic for this patient. N ot every patient wit h postoperat ive fever requires ant imicrobial t herapy; however, if t he fever is also associat ed wit h signs of sepsis or if the pat ient is immunocompromised, preemptive antimicrobial treatment should be initiated while the search for fever source is on goin g.

Instruct them to hold the drug and notify the provider if sustained bradycardia or hypotension develop buy generic viagra super active 100 mg erectile dysfunction essential oil. Beta-Adrenergic Antagonists Therapeutic and Adverse Responses to Beta Blockade In this section we consider the beneficial and adverse responses that can result from blockade of beta-adrenergic receptors purchase viagra super active master card erectile dysfunction jelly. Therapeutic Applications of Beta Blockade Practically all of the therapeutic effects of the beta-adrenergic antagonists result from blockade of beta receptors in the heart purchase viagra super active with visa treatment erectile dysfunction faqs. Because of these effects purchase generic viagra super active on line erectile dysfunction differential diagnosis, beta blockers are useful in a variety of cardiovascular disorders. Angina Pectoris Angina pectoris (cardiac pain due to ischemia) occurs when oxygen supplied to the heart through coronary circulation is insufficient to meet cardiac oxygen demand. Anginal attacks can be precipitated by exertion, intense emotion, and other factors. Hypertension For years, beta blockers were considered drugs of choice for hypertension. However, more recent data indicate they are less beneficial than previously believed. Older proposed mechanisms include reduction of cardiac output through blockade of beta receptors in the heart and suppression of renin release through1 blockade of beta receptors in the kidney (see 1 Chapter 36 for a discussion of the role of renin in blood pressure control). More recently, we have learned that, with long-term use, beta blockers reduce peripheral vascular resistance, which could account for much of their antihypertensive effects. Cardiac Dysrhythmias Beta-adrenergic blocking agents are especially useful for treating dysrhythmias that involve excessive electrical activity in the sinus node and atria. Treatment with a beta blocker can reduce pain, infarct size, mortality, and the risk for reinfarction. Reduction of Perioperative Mortality Beta blockers may decrease the risk for mortality associated with noncardiac surgery in high-risk patients. However, for treatment to be both safe and effective, dosing should begin early (several days to weeks before surgery) and doses should be low initially and then titrated up (to achieve a resting heart rate of 60 to 80 beats/minute). Heart Failure Beta blockers are now considered standard therapy for heart failure. This application is relatively new and may come as a surprise to some readers because, until recently, heart failure was considered an absolute contraindication to beta blockers. At this time, only three beta blockers—carvedilol, bisoprolol, and metoprolol—have been shown effective for heart failure. Hyperthyroidism Hyperthyroidism (excessive production of thyroid hormone) is associated with an increase in the sensitivity of the heart to catecholamines (e. As a result, normal levels of sympathetic activity to the heart can generate tachydysrhythmias and angina pectoris. Migraine Prophylaxis When taken prophylactically, beta-adrenergic blocking agents can reduce the frequency and intensity of migraine attacks. However, although beta blockers are effective as prophylaxis, these drugs are not able to abort a migraine headache after it has begun. Performance Anxiety Public speakers and other performers sometimes experience performance anxiety (“stage fright”). Prominent symptoms are tachycardia, tremors, and sweating brought on by generalized discharge of the sympathetic nervous system. Beta blockers help prevent performance anxiety—including test anxiety—by preventing beta -1 mediated tachycardia. Pheochromocytoma As discussed earlier, a pheochromocytoma secretes large amounts of catecholamines, which can cause excessive stimulation of the heart. Intravenous administration is reserved for acute myocardial infarction (atenolol, metoprolol), cardiac dysrhythmias (esmolol, propranolol), and severe hypertension (labetalol). Adverse Effects of Beta Blockade Although therapeutic responses to beta blockers are due almost entirely to blockade of beta receptors, adverse effects involve both beta and beta1 1 2 blockade. Consequently, the nonselective beta-adrenergic blocking agents (drugs that block beta 1 and beta receptors) produce a broader spectrum of adverse2 effects than do the “cardioselective” beta-adrenergic antagonists (drugs that block only beta receptors at therapeutic doses). Blockade of cardiac beta receptors can produce bradycardia (excessively slow1 heart rate). If necessary, heart rate can be increased using a beta-adrenergic agonist, such as isoproterenol, and atropine (a muscarinic antagonist). Isoproterenol competes with the beta blocker for cardiac beta receptors, thereby1 promoting cardiac stimulation. By blocking muscarinic receptors on the heart, atropine prevents slowing of the heart by the parasympathetic nervous system. Beta blockade can reduce cardiac output by decreasing heart rate and the force1 of myocardial contraction. Because they can decrease cardiac output, beta blockers must be used with great caution in patients with heart failure or reduced cardiac reserve. In both cases, any further decrease in cardiac output could result in insufficient tissue perfusion. In some patients, suppression of cardiac function with a beta blocker can be so great as to cause heart failure. Patients should be informed about the early signs of heart failure (shortness of breath, night coughs, swelling of the extremities) and instructed to notify the prescriber if these occur. It is important to appreciate that, although beta blockers can precipitate heart failure, they are also used to treat heart failure. As a result, if a beta blocker is withdrawn abruptly, anginal pain or ventricular dysrhythmias may develop. This phenomenon of increased cardiac activity in response to abrupt cessation of beta-blocker therapy is referred to as rebound excitation. The risk for rebound excitation can be minimized by withdrawing these drugs gradually (e. Also, they should be advised to carry an adequate supply of their beta blocker when traveling. However, when bronchial beta receptors are blocked in patients with asthma, the resulting2 increase in airway resistance can be life threatening. Accordingly, drugs that block beta receptors2 are contraindicated for people with asthma. If these individuals must use a beta blocker, they should use an agent that is beta1 selective (e. Epinephrine, acting at beta receptors in skeletal muscle and the liver, can2 stimulate glycogenolysis (breakdown of glycogen into glucose). Beta blockade2 will inhibit this process, posing a risk for hypoglycemia in susceptible individuals. Although suppression of beta -mediated 2 glycogenolysis is inconsequential for most people, interference with this process can be detrimental to patients with diabetes. These people are especially dependent on beta -mediated 2 glycogenolysis as a way to overcome insulin-induced hypoglycemia. If the patient with diabetes requires a beta blocker, a beta -1 selective agent should be chosen. Adverse Effects in Neonates From Beta and Beta Blockade1 2 Use of beta blockers during pregnancy can have residual effects on the newborn infant. Specifically, because beta blockers can remain in the circulation for several days after birth, neonates may be at risk for bradycardia (from beta1 blockade), respiratory distress (from beta blockade), and hypoglycemia (from2 beta blockade). Accordingly, for 3 to 5 days after birth, newborns should be2 closely monitored for these effects. Adverse neonatal effects have been observed with at least one beta blocker (betaxolol) and may be a risk with others as well. Properties of Individual Beta Blockers The beta-adrenergic antagonists can be subdivided into three groups: • First-generation (nonselective) beta blockers (e. Propranolol was the first beta blocker2 to receive widespread clinical use and remains one of our most important beta- blocking agents. By blocking beta receptors, propranolol can produce three major effects: (1)2 bronchoconstriction (through beta blockade in the lungs), (2) 2 vasoconstriction (through beta 2 blockade on certain blood vessels), and (3) reduced glycogenolysis (through beta blockade in skeletal muscle and liver). The drug is well absorbed after oral administration, but, because of extensive metabolism on its first pass through the liver, less than 30% of each dose reaches the systemic circulation. Therapeutic Uses Practically all of the applications of propranolol are based on blockade of beta1 receptors in the heart. The most important indications are hypertension, angina pectoris, cardiac dysrhythmias, and myocardial infarction. The role of propranolol and other beta blockers in these disorders is discussed in Chapters 23, 39, 41, 43, and 88. Additional indications include prevention of migraine headache and performance anxiety. Adverse Effects The most serious adverse effects result from blockade of beta receptors in the1 heart and blockade of beta receptors in the lungs. If the heart rate is below normal, the drug should be held and the prescriber should be notified. If necessary, heart rate can be increased by administering atropine and isoproterenol. In patients with heart disease, suppression of myocardial contractility by propranolol can result in heart failure. Patients should be informed about the early signs of heart failure (shortness of breath on mild exertion or when lying supine, night coughs, swelling of the extremities, weight gain from fluid retention) and instructed to notify the prescriber if these occur. Propranolol is generally contraindicated for patients with preexisting heart failure (although other beta blockers are used to treat heart failure). Abrupt withdrawal of propranolol can cause rebound excitation of the heart, resulting in tachycardia and ventricular dysrhythmias. This problem is especially dangerous for patients with preexisting cardiac ischemia. To avoid rebound excitation, propranolol should be withdrawn slowly by giving progressively smaller doses over 1 to 2 weeks.

Stagnation of blood initiates the coagulation cascade buy viagra super active toronto erectile dysfunction electric pump, resulting in the production of fibrin buy viagra super active 25 mg with visa erectile dysfunction medication free trial, which enmeshes red blood cells and platelets to form the thrombus order viagra super active no prescription erectile dysfunction causes mental. The typical venous thrombus has a long tail that can break off to produce an embolus cheap 25mg viagra super active with amex erectile dysfunction natural remedy. Such emboli travel within the vascular system and become lodged at faraway sites, frequently the pulmonary arteries. Hence, unlike an arterial thrombus, whose harmful effects are localized, injury from a venous thrombus occurs secondary to embolization at a site distant from the original thrombus. Overview of Drugs for Thromboembolic Disorders The drugs considered fall into three major groups: (1) anticoagulants, (2) antiplatelet drugs, and (3) thrombolytic drugs, also known as fibrinolytic drugs. Because these drugs are used only in a hospital setting, discussion of thrombolytics occurs in Chapter 89. Although the anticoagulants and the antiplatelet drugs both suppress thrombosis, they do so by different mechanisms. The antiplatelet drugs are most effective at preventing arterial thrombosis, whereas anticoagulants are most effective against venous thrombosis. Anticoagulants By definition, anticoagulants are drugs that reduce formation of fibrin. One anticoagulant—warfarin—inhibits the synthesis of clotting factors, including factor X and thrombin. All other anticoagulants inhibit the activity of clotting factors: either factor Xa, thrombin, or both. Anticoagulants are in three pharmacologic classes—vitamin K antagonists, direct factor Xa inhibitors, and direct thrombin inhibitors (see Table 44. Heparin and Its Derivatives: Drugs That Activate Antithrombin All drugs in this group share the same mechanism of action. Specifically, they greatly enhance the activity of antithrombin, a protein that inactivates two major clotting factors: thrombin and factor Xa. In the absence of thrombin and factor Xa, production of fibrin is reduced, and hence clotting is suppressed. Although all three activate antithrombin, they do not have equal effects on thrombin and factor Xa. Heparin (Unfractionated) Heparin is a rapid-acting anticoagulant administered only by injection. Heparin differs from warfarin (an oral anticoagulant) in several respects, including mechanism, time course, indications, and management of overdose. Chemistry Heparin is not a single molecule, but rather a mixture of long polysaccharide chains, with molecular weights that range from 3000 to 30,000. The active region is a unique pentasaccharide (five-sugar) sequence found randomly along the chain. Because of these negative charges, heparin is highly polar and hence cannot readily cross membranes. Mechanism of Anticoagulant Action Heparin suppresses coagulation by helping antithrombin inactivate clotting factors, primarily thrombin and factor Xa. To inactivate thrombin, heparin must simultaneously bind with both thrombin and antithrombin, thereby forming a ternary complex. In contrast, to inactivate factor Xa, heparin binds only with antithrombin; heparin itself does not bind with factor Xa. All three drugs share a pentasaccharide sequence that allows them to bind with—and activate—antithrombin, a protein that inactivates two major clotting factors: thrombin and factor Xa. All three drugs enable antithrombin to inactivate factor Xa, but only heparin also facilitates inactivation of thrombin. Upper panel: Unfractionated heparin binds with antithrombin, causing a conformational change in antithrombin that greatly increases its ability to interact with factor Xa and thrombin. When the heparin-antithrombin complex binds with thrombin, heparin changes its conformation so that both heparin and antithrombin come in contact with thrombin. Inactivation of factor Xa is different: it only requires contact between activated antithrombin and factor Xa; contact between heparin and factor Xa is unnecessary. By activating antithrombin, and thereby promoting the inactivation of thrombin and factor Xa, heparin ultimately suppresses formation of fibrin. Because fibrin forms the framework of thrombi in veins, heparin is especially useful for prophylaxis of venous thrombosis. Because it cannot cross membranes, heparin does not traverse the placenta and does not enter breast milk. Heparin binds nonspecifically to plasma proteins, mononuclear cells, and endothelial cells. However, in patients with hepatic or renal impairment, the half-life is increased. In addition, heparin is used for patients undergoing open heart surgery and renal dialysis; during these procedures, heparin serves to prevent coagulation in devices of extracorporeal circulation (heart-lung machines, dialyzers). Heparin may also be useful for treating disseminated intravascular coagulation, a complex disorder in which fibrin clots form throughout the vascular system and in which bleeding tendencies may be present; bleeding can occur because massive fibrin production consumes available supplies of clotting factors. Bleeding develops in about 10% of patients and is the principal complication of treatment. These include reduced blood pressure, increased heart rate, bruises, petechiae, hematomas, red or black stools, cloudy or discolored urine, pelvic pain (suggesting ovarian hemorrhage), headache or faintness (suggesting cerebral hemorrhage), and lumbar pain (suggesting adrenal hemorrhage). First, dosage should be carefully controlled so that the activated partial thromboplastin time (see later) does not exceed 2 times the control value. In addition, candidates for heparin therapy should be screened for risk factors (see “Warnings and Contraindications”). B l a c k B o x Wa r n i n g : S p i n a l o r E p i d u r a l H e m a t o m a Heparin and all other anticoagulants pose a risk for spinal or epidural hematoma in patients undergoing spinal puncture or spinal or epidural anesthesia. Pressure on the spinal cord caused by the bleed can result in prolonged or permanent paralysis. Risk for hematoma is increased by the following: • Use of an indwelling epidural catheter • Use of other anticoagulants (e. This is a potentially fatal immune-mediated disorder characterized by reduced platelet counts (thrombocytopenia) and a seemingly paradoxical increase in thrombotic events. The underlying cause is development of antibodies against heparin–platelet protein complexes. These antibodies activate platelets and damage the vascular endothelium, thereby promoting both thrombosis and a rapid loss of circulating platelets. Ischemic injury secondary to thrombosis in the limbs may require amputation of an arm or leg. Platelet counts should be determined frequently (2–3 times a week) during the first 3 weeks of heparin use and monthly thereafter. If 3 severe thrombocytopenia develops (platelet count below 100,000/mm ), heparin should be discontinued. Because commercial heparin is extracted from animal tissues, these preparations may be contaminated with antigens that can promote allergy. Vasospastic reactions that persist for several hours may develop after 1 or more weeks of treatment. Heparin must be used with extreme caution in all patients who have a high likelihood of bleeding. Among these are individuals with hemophilia, increased capillary permeability, dissecting aneurysm, peptic ulcer disease, severe hypertension, or threatened abortion. Heparin must also be used cautiously in patients with severe disease of the liver or kidneys. Heparin is contraindicated for patients with thrombocytopenia and uncontrollable bleeding. In addition, heparin should be avoided both during and immediately after surgery of the eye, brain, or spinal cord. Drug Interactions In heparin-treated patients, platelet aggregation is the major remaining defense against hemorrhage. Aspirin and other drugs that depress platelet function or affect coagulation will weaken this defense and hence must be employed with caution. Laboratory Monitoring The objective of anticoagulant therapy is to reduce blood coagulability to a level that is low enough to prevent thrombosis but not so low as to promote spontaneous bleeding. Because heparin levels can be highly variable, achieving this goal is difficult and requires careful control of dosage based on frequent tests of coagulation. Heparin dosage is titrated on the basis of laboratory monitoring, and hence dosage can be adjusted as needed based on test results. Heparin sodium is supplied in single-dose vials; multidose vials; and unit-dose, preloaded syringes that have their own needles. Two routes are employed: intravenous (either intermittent or continuous) and subcutaneous. Heparin is not administered orally because heparin is too large and too polar to permit intestinal absorption. Postoperative prophylaxis of thrombosis, for example, requires relatively small doses. Because heparin is formulated in widely varying concentrations, you must read the label carefully to ensure that dosing is correct. Children/adolescents Many anticoagulants can be used safely in children, just in smaller doses. Breastfeeding Data are lacking regarding safety of these medications in breastfeeding. In older adults, benefit must outweigh risk for bleeding secondary to falls, decreased renal function, or polypharmacy. In comparison, molecular weights in unfractionated heparin range between 3000 and 30,000, with a mean of 12,000 to 15,000. To inactivate thrombin, a heparin chain must not only contain the pentasaccharide sequence that activates antithrombin but must also be long enough to provide a binding site for thrombin. This binding site is necessary because inactivation of thrombin requires simultaneous binding of thrombin with heparin and antithrombin (see Fig.