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Other Loop Diuretics In addition to furosemide purchase cheap famvir hiv infection in zimbabwe, three other loop diuretics are available: ethacrynic acid [Edecrin] cheap 250 mg famvir with mastercard hiv infection rates in nsw, torsemide [Demadex] order generic famvir online hiv infection rate soars in uk, and bumetanide [Burinex, generic only in United States]. They all promote diuresis by inhibiting sodium and chloride reabsorption in the thick ascending limb of the loop of Henle. All are approved for edema caused by heart failure, chronic renal disease, and cirrhosis, but only torsemide, like furosemide, is also approved for hypertension. Thiazides and Related Diuretics The thiazide diuretics have effects similar to those of the loop diuretics. Like the loop diuretics, thiazides increase renal excretion of sodium, chloride, potassium, and water. The principal difference between the thiazides and loop diuretics is that the maximal diuresis produced by the thiazides is considerably lower than the maximal diuresis produced by the loop diuretics. In addition, whereas loop diuretics can be effective even when urine flow is decreased, thiazides cannot. Hydrochlorothiazide Hydrochlorothiazide is the most widely used thiazide diuretic and will serve as our prototype for the group. Because of its use in hypertension, hydrochlorothiazide is one of our most widely used drugs. Mechanism of Action Hydrochlorothiazide promotes urine production by blocking the reabsorption of sodium and chloride in the early segment of the distal convoluted tubule (see Fig. Retention of sodium and chloride in the nephron causes water to be retained as well, thereby producing an increased flow of urine. Because only 10% of filtered sodium and chloride is normally reabsorbed at the site where thiazides act, the maximal urine flow these drugs can produce is lower than with the loop diuretics. The ability of thiazides to promote diuresis is dependent on adequate kidney function. Hence, in contrast to the loop diuretics, thiazides cannot be used to promote fluid loss in patients with severe renal impairment. For many hypertensive patients, blood pressure can be controlled with a thiazide alone, although many other patients require multiple-drug therapy. Edema Thiazides are preferred drugs for mobilizing edema associated with mild to moderate heart failure. Protection Against Postmenopausal Osteoporosis Thiazides promote tubular reabsorption of calcium and may thereby decrease the risk for osteoporosis in postmenopausal women. Before menopause, estrogen from the ovaries acts on renal tubules to promote calcium reabsorption. When menopause occurs, estrogen levels drop, allowing renal excretion of calcium to increase. The resultant decrease in circulating calcium promotes mobilization of calcium from bone and thereby increases the risk for osteoporosis. Because thiazides promote renal calcium retention, they may counteract the calcium loss associated with menopause and may thereby help preserve bone integrity. Adverse Effects The adverse effects of thiazide diuretics are similar to those of the loop diuretics. In fact, with the exception that thiazides are not ototoxic, the adverse effects of the thiazides and loop diuretics are nearly identical. Hyponatremia, Hypochloremia, and Dehydration Loss of sodium, chloride, and water can lead to hyponatremia, hypochloremia, and dehydration. However, because the diuresis produced by thiazides is moderate, these drugs have a smaller effect on sodium, chloride, and water than do the loop diuretics. To evaluate fluid and electrolyte status, electrolyte levels should be determined periodically, and the patient should be weighed on a regular basis. Hypokalemia Like the loop diuretics, the thiazides can cause hypokalemia from excessive potassium excretion. Potassium levels should be measured periodically, and, if serum potassium falls below 3. Hyperglycemia Like the loop diuretics, the thiazides can elevate plasma levels of glucose. Significant hyperglycemia develops only in diabetic patients, who should be especially diligent about monitoring blood glucose. To maintain normal glucose levels, the diabetic patient may require larger doses of insulin or an oral hypoglycemic drug. Hyperuricemia The thiazides, like the loop diuretics, can cause retention of uric acid, thereby elevating plasma uric acid. Although hyperuricemia is usually asymptomatic, it may precipitate gouty arthritis in patients with a history of the disorder. Thiazides increase excretion of magnesium, sometimes causing magnesium deficiency. Drug Interactions The important drug interactions of the thiazides are nearly identical to those of the loop diuretics. By promoting potassium loss, thiazides can increase the risk for toxicity from digoxin. By lowering blood pressure, thiazides can augment the effects of other antihypertensive drugs. By promoting sodium loss, thiazides can reduce renal excretion of lithium, thereby causing the drug to accumulate, possibly to toxic levels. By counterbalancing the potassium-wasting effects of the thiazides, the potassium- sparing diuretics can help prevent excessive potassium loss. In contrast to the loop diuretics, the thiazides can be combined with ototoxic agents without an increased risk for hearing loss. Potassium-Sparing Diuretics The potassium-sparing diuretics can elicit two potentially useful responses. Because their diuretic effects are limited, the potassium-sparing drugs are rarely employed alone to promote diuresis. However, because of their marked ability to decrease potassium excretion, these drugs are often used to counteract potassium loss caused by thiazide and loop diuretics. There are two subcategories of potassium-sparing diuretics: aldosterone antagonists and nonaldosterone antagonists. In the United States only one aldosterone antagonist—spironolactone—is used for diuresis. Spironolactone Mechanism of Action Spironolactone [Aldactone] blocks the actions of aldosterone in the distal nephron. Because aldosterone acts to promote sodium uptake in exchange for potassium secretion (see Fig. The diuresis caused by spironolactone is scanty because most of the filtered sodium load has already been reabsorbed by the time the filtrate reaches the distal nephron. The effects of spironolactone are delayed, taking up to 48 hours to develop (Table 35. Recall that aldosterone acts by stimulating cells of the distal nephron to synthesize the proteins required for sodium and potassium transport. Therefore effects are not visible until the existing proteins complete their normal life cycle—a process that takes 1 or 2 days.

Her father is 5 ft 10 in (178 cm) tall cheap famvir 250 mg visa hiv infection rate nigeria, and her mother is 5 ft 5 in (165 cm) tall purchase cheap famvir on-line hiv process of infection. Over the past 3 years she has dropped from the 25th percentile for height to the 5thpercentile cheap famvir 250 mg otc antiviral year 2012. Additional imaging or laboratory evaluations would not be necessary in this case because this child has no other symptoms aside from short stature. He eventually will enter puberty, but the psychosocial ramifications of remaining shorter and appearing more immature than his peers may warrant treatment. Monthly testosterone injections “jump start” the pubertal process without altering final growth potential; a pediatric endocrinologist might be required to assist. If a child’s growth chart is unavailable, questions about a child’s clothing or shoe size changes may pro- vide valuable information. Obtaining history about parental growth pattern and their onset of puberty also provides important diagnostic clues to the child’s etiology of short stature. Growth hor- mone deficiency is not an emergent condition but the earlier the diagnosis is made the sooner appropriate treatment can be initiated. Obtaining a growth hormone level would not be diagnostically helpful because its secretion is pulsatile. Referral to a pediatric endocrinologist would be warranted if initial screening tests confirm the suspected growth hormone deficiency. Describe laboratory and radiologic tests that are helpful in determining the etiology of precocious puberty. Establish the treatment and follow-up necessary for a child with precocious puberty. Considerations This 5-year-old girl has precocious puberty signs (breast and pubic hair develop- ment and tall stature). She may have true (central) precocious puberty or preco- cious (noncentral) pseudopuberty. Of note, timing of puberty events approximates a normal distribution with a strong genetic component. For example African American children start puberty earlier on average than Caucasian children. A trend toward earlier start of puberty among today’s chil- dren, as compared to previous generations, has been noted. May be caused by gonadal failure, chromosomal abnor- malities (Turner syndrome, Klinefelter syndrome), hypopituitarism, chronic dis- ease, or malnutrition. Hypothalamic-pituitary-gonadal activation leading to secondary sex characteristics. Hormones usually are either exogenous (birth control pills, estrogen, testosterone cream) or from adrenal/ovarian tumors. Girls with precocious pseudopuberty have an independent source of estrogens causing their pubertal changes. An exogenous source of estrogen (birth control pills, hormone replacement) or an estrogen-producing tumor of the ovary or adrenal gland must be considered. Three main patterns of precocious pubertal progression can be identified, particularly in girls. Most girls who are younger than 6 years at onset have rapidly progress- ing sexual precocity, characterized by early physical and osseous maturation with a loss of ultimate height potential. Girls older than 6 years typically have a slowly progressing variant with parallel advancement of osseous maturation and linear growth and preserved height potential. In a small percentage of girls, a spontaneous regression or unsustained central precocious puberty at a young age is seen, with normal pubertal development at an expected age. A neurologic history may identify past hydrocephalus, head trauma, meningo- encephalitis, or the presence of headaches, visual problems, or behavioral changes. The type, sequence, and age at which pubertal changes were first noticed (breast and pubic/axillary hair development, external genitalia maturation, menarche) give valuable information regarding the etiology of the problem. Important questions include the following š Has the child been rapidly outgrowing shoes and clothes (evidence of linear growth acceleration)? Serial height mea- surements are critical for determining the child’s growth velocity. The skin should be examined for café-au-lait spots (neurofibromatosis, tuberous sclerosis), oiliness, and acne. The presence of axillary hair and body odor, the amount of breast tissue, whether the nipples and areolae are enlarging and thinning, and the amount, loca- tion, and character of pubic hair are documented (Tanner staging, Figures 45–1 and 45–2). If the testes are different in size and consistency, a unilateral mass is considered. Testicular transillumination may be helpful in differentiating a mass which is solid versus cystic (hydroceles usually transilluminate). In girls, the clitoris, labia, and vaginal orifice are examined to identify vaginal secretions, maturation of the labia minora, and vaginal mucosa estrogenization (dull, gray-pink, and ruggated rather than shiny, smooth, and red). In precocious puberty, serum sex hormone concentrations usually are appropri- ate for the observed stage of puberty, but inappropriate for the child’s chronologic age. Serum estradiol concentration is elevated in girls, and serum testosterone level is elevated in boys with precocious puberty. Pelvic ultrasonography is indicated if gonadotropin- independent causes of precocious puberty (ovarian tumors/cysts, adrenal tumors) are suspected based on examination. The goal of treating precocious puberty is to prevent premature closure of the epiphyses, allowing the child to reach full adult growth potential. Gonadotropin- releasing hormone agonists are used for the treatment of central precocious puberty. Nearly all boys and most girls with rapidly progressive precocious puberty are candidates for treatment. She takes no medications, and no source of exogenous estrogen is present in the home. Which of the following is the most likely explanation for the child’s breast development? He reports that over the last 2 months he has noticed his penis has gotten longer, frequent erections, and what appears to be a few dark strands of hair. On examination, you confirm that the phal- lus is long for stated age, pubic hair that is curly, and testicles that are less than 2. When you question the father about his onset of puberty, he claims to have noticed changes at 14 years old. Medications in the home include maternal intake of daily multivitamins and paternal gel for decreased libido. Which of the following statements is likely an explanation for this child’s presentation? Noncentral precocious puberty hypothalamic-pituitary-gonadal axis early activation B.

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The most common effects seen when pramipexole is used alone are nausea cheap 250mg famvir with visa stages for hiv infection, dizziness buy discount famvir on-line hiv infection cycle animation, daytime somnolence buy famvir in united states online anti viral ear drops, insomnia, constipation, weakness, and hallucinations. When the drug is combined with levodopa, about half of patients experience orthostatic hypotension and dyskinesias, which are not seen when the drug is used by itself. A few patients have reported sleep attacks (overwhelming and irresistible sleepiness that comes on without warning). Sleep attacks should not be equated with the normal sleepiness that occurs with dopaminergic agents. Pramipexole has been associated with impulse control disorders, including compulsive gambling, shopping, binge eating, and hypersexuality. These behaviors are dose related, begin about 9 months after starting pramipexole, and reverse when the drug is discontinued. Risk factors include younger adulthood, a family or personal history of alcohol abuse, and a personality trait called novelty seeking, characterized by impulsivity, a quick temper, and a low threshold for boredom. Before prescribing pramipexole, clinicians should screen patients for compulsive behaviors. Cimetidine (a drug for peptic ulcer disease) can inhibit renal excretion of pramipexole, thereby increasing its blood level. Ropinirole [Requip], a nonergot dopamine agonist, is similar to pramipexole with respect to receptor specificity, mechanism of action, indications, and adverse effects. In contrast to pramipexole, which is eliminated entirely by renal excretion, ropinirole is eliminated by hepatic metabolism. When ropinirole is used alone, the most common effects are nausea, dizziness, somnolence, and hallucinations. When ropinirole is combined with levodopa, the most important side effects are dyskinesias, hallucinations, and postural hypotension. Note that these occur less frequently than when pramipexole is combined with levodopa. Like pramipexole, ropinirole can promote compulsive gambling, shopping, eating, and hypersexuality. Rotigotine [Neupro] is a nonergot dopamine agonist that is specific for selected dopamine receptors. Although the exact mechanism of action is unknown, it is believed that rotigotine improves dopamine transmission by activating postsynaptic dopamine receptors in the substantia nigra. Because first-pass metabolism of rotigotine is extensive, oral formulations are not manufactured. The time from application to peak is typically 15 to 18 hours but may range from 4 to 27 hours. These include a variety of sleep disorders, dizziness, headache, dose-related hallucinations, and dose-related dyskinesia. Some patients develop skin reactions at the site of application, and hyperhidrosis (excessive perspiration) may occur. Apomorphine is a derivative of morphine but is devoid of typical opioid effects (e. Apomorphine is highly lipophilic but undergoes extensive first-pass metabolism and hence is ineffective when taken orally. After subcutaneous (subQ) injection, the drug undergoes rapid, complete absorption. The most common adverse effects are injection-site reactions, hallucinations, yawning, drowsiness, dyskinesias, rhinorrhea, and nausea and vomiting. During clinical trials, there was a 4% incidence of serious cardiovascular events: angina, myocardial infarction, cardiac arrest, or sudden death. In addition, apomorphine can promote hypersexuality and enhanced erections (the drug is used in Europe to treat erectile dysfunction). Rarely, apomorphine causes priapism (sustained, painful erection), possibly requiring surgical intervention. To prevent nausea and vomiting during clinical trials, nearly all patients were treated with an antiemetic, starting 3 days before the first dose of apomorphine. About half the trial participants discontinued the antiemetic at some point but continued taking apomorphine. The side-effect profile of the ergot derivatives differs from that of the nonergot agents because, in addition to activating dopamine receptors, the ergot drugs cause mild blockade of serotonergic and alpha-adrenergic receptors. Bromocriptine [Cycloset, Parlodel], a derivative of ergot, is a direct-acting dopamine agonist. When combined with levodopa, bromocriptine can prolong therapeutic responses and reduce motor fluctuations. In addition, because bromocriptine allows the dosage of levodopa to be reduced, the incidence of levodopa-induced dyskinesias may be reduced too. The most common dose-limiting effects are psychological reactions (confusion, nightmares, agitation, hallucinations, paranoid delusions). Rarely, bromocriptine causes retroperitoneal fibrosis, pulmonary infiltrates, a Raynaud-like phenomenon, and erythromelalgia (vasodilation in the feet, and sometimes hands, resulting in swelling, redness, warmth, and burning pain). In addition, the ergot derivatives have been associated with valvular heart disease. Consequently, cabergoline is rarely used unless other management attempts have failed. A more concerning adverse effect is the development of cardiac valve regurgitation and subsequent development of heart failure. With both drugs, benefits derive from inhibiting metabolism of levodopa in the periphery; these drugs have no direct therapeutic effects of their own. Like carbidopa, entacapone inhibits metabolism of levodopa in the intestine and peripheral tissues. In clinical trials, entacapone increased the half-life of levodopa by 50% to 75% and thereby caused levodopa blood levels to be more stable and sustained. Pharmacokinetics Entacapone is rapidly absorbed and reaches peak levels in 2 hours. Elimination is by hepatic metabolism followed by excretion in the feces and urine. Adverse Effects Most adverse effects result from increasing levodopa levels, although some are caused by entacapone itself. By increasing levodopa levels, entacapone can cause dyskinesias, orthostatic hypotension, nausea, hallucinations, sleep disturbances, and impulse control disorders (see “Pramipexole”). The most common are vomiting, diarrhea, constipation, and yellow-orange discoloration of the urine. In addition to levodopa, these include methyldopa (an antihypertensive agent), dobutamine (an adrenergic agonist), and isoproterenol (a beta-adrenergic agonist). If entacapone is combined with these drugs, a reduction in their dosages may be needed. As with entacapone, benefits derive from inhibiting levodopa metabolism in the periphery, which prolongs levodopa availability. When given to patients taking levodopa, tolcapone improves motor function and may allow a reduction in levodopa dosage.

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Although the most likely etiology is a fibroadenoma generic 250 mg famvir symptoms of hiv infection in the asymptomatic stage, this diag- nosis needs to be confirmed by biopsy discount famvir www.hiv infection symptoms. Ultrasound of the breast is probably the best imaging modality in a young patient order 250mg famvir with mastercard antiviral in pregnancy, since mammography is hampered by the dense breast tissue. Both core needle and excisional biopsy remove more t issue but are more prone to bruising and pain; an excisional biopsy is a more extensive surgical procedure involving removal of the ent ire mass. She has no family history of breast cancer, is of a young age, and her examinat ion does not cont ain any worrisome feat ures of breast cancer. If t he mass were fixed, or if t h ere were nipple ret ract ion or bloody nipple disch arge, the bet - ter method of biopsy would be a core needle or excisional biopsy to remove more tissue for histologic analysis. Fibr ocyst ic ch an ges are the most comm on breast mass, and is found in up to 90% of females at autopsy. Fibroadenomas are the most common benign tumor, whereas infiltrating ductal carcinoma is the most com mon m align an cy. Alt h ou gh fibr oad en omas are the m ost com mon cau se of a breast mass in a woman less than age 25, the atypical breast cancer must always be con sid er ed. Ev a l u a t i o n One of the key skills of any primary care physician is differentiating normal breast changes from abnormal ones, that is, identification of the dominant breast mass. Fibrocystic changes, the most common of the benign breast conditions, are described as multiple, irregular, “lumpiness of the breast. Fibrocystic changes are ver y co m m o n in p r em en o p au sal wo m en, b u t r are fo llowin g m en o p au se. T h e clin i- cal pr esent at ion is cyclic, pain fu l, en gor ged br east s, mor e pr on ou n ced ju st befor e menstruation, and occasionally associated with serous or green breast discharge. Through careful physical examination, fibrocystic changes can usually be differ- entiated from the 3D -dominant mass suggestive of cancer, but occasionally, a fine- needle or core biopsy must be performed to establish the diagnosis. W it h sever e cases, dan azol (a weak ant ies- trogen and androgenic compound) or even mastectomy are considered. In a woman in the adolescent years or in her 20s, the most common cause of a dominant breast mass is a fibroadenoma. They typically do not respond to ovarian hormones and do not vary during the menstrual cycle. If t he hist ologic examinat ion support s fibroad- enoma (mat ure smoot h muscle cells) and t he mass is small and not growing, careful follow-up is possible. A rare t umor seen in adolescent s an d younger women, cyst o- sarcoma phylloides, is diagnosed by biopsy. Most clinicians will excise any dominant 3D mass occur- ring in a woman over the age of 35 years, or in those with an increased likelihood of mammary cancer (family history). T hese mutations are associated with an increased risk of fallopian tube, peritoneal, and pancreatic cancer. T h e right breast reveals a 5 × 4 cm area of redness, indurat ion, and t enderness. A 25-year-old G0P0 woman states that her mother, who lives in another city, was diagnosed wit h breast cancer at age 45. The most common cause of bloody (serosanguineous) nipple discharge wh en only one duct is involved and in the absence of a breast mass is int ra- ductal papilloma. The highest incidence of this condition is in the 35 to 55 age group; causes and risk factors are unknown. Because malignancy is also a com mon cau se of bloody n ip ple disch ar ge (secon d most com mon cau se! The classic clinical picture includes cyclic, painful, engorged breasts, more pronounced just before menstruation, and occasionally associated with breast discharge. W ith severe cases, danazol (a weak ant iestrogen and androgenic compound) or even mastectomy is considered. A patient who presents with painful, engorged breast s may also have a galact ocele; however, a galact ocele does not have a“lumpy-bumpy”breast examination, nor is it associated with hormonal ch an ges or the m en st r ual cycle. G alact oceles are m am mar y glan d t u mor s that are cyst ic in nature and cont ain milk or milky fluid. T hey t ypically occur wh en t h ere is any sort of obst ruct ion of milk flow in the lact at ing breast. N ipple ret ract ion or skin dimpling over a mass is ver y suggest ive of malig- nancy. In the physical examination, maneuvers to accentuate the skin changes such as “hands on hips” or “arms raised over t he h ead” assist in evaluat ing for these findings. Most clinicians excise any dominant 3D mass occurring in a woman older t h an 35 years or in t h ose wit h an increased likelih ood of mam- mary cancer (family history). H istologic analysis from the excisional biopsy will most likely confirm t he diagnosis of cancer. In females in the adolescent years or in their twenties, the most common cau se of a d om in ant br east mass is a fibr oad en oma. The best way to image the breast of a woman less t han age 30 is usually ult rasound due to t he dense fibrocyst ic ch an ges that int er fer e wit h m am mogr aph ic int er pr et at ion. U lt r asou n d can differentiate a solid versus a cystic mass, and sometimes can suggest a fibro- adenoma; nevert heless, t issue should be obt ained to confirm t he diagnosis. In a woman who has a “red tender indurated breast” who is nonlactating, inflammat ory breast cancer must be ruled out. In flam mat or y br east can cer is aggr essive in n at u r e, an d the skin ch an ges occur due to the cancer cells within the subdermal lymph channels. Immedi- ate diagnosis and t herapy are crucial, whereas delay wit h various ant ibiot ics would be det riment al. Int erest ingly, inflammat ory breast cancer occurs more in younger pat ient s, alt hough women of any age can be affect ed. Sh e h a d used the contraceptive diaphragm or birth control until she went into meno- pause 1 year ago. Her surgical history includes a myomectomy or symptomatic uterine ibroids 10 years ago. Understand that the age of the patient is usually the biggest risk factor for breast cancer. Understand that normal imaging of a palpable breast mass does not rule out can cer. Co n s i d e r a t i o n s This 50-year-old woman came in for a well-woman examination. The physical examinat ion is aimed at screening for common and/ or serious condit ions, such as hypertension, thyroid disease, cervical cancer (Pap smear), colon cancer (stool for occult blood), and breast cancer. D espite t he normal imaging, t here is a possibilit y that the breast mass is malignant. Fine-needle aspi- ration is an acceptable diagnostic modality, but would not be able to discern ductal car cin om a in sit u ver su s invasion.