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Anabolism is defined as the formation of substances himalaya herbals acne-n-pimple cream discount 30gm v-gel amex, which can store the energy C. The metabolic rate is increased after consumption of a meal that is rich in protein 19. Oxidation is the combination of a substance with oxygen, or loss of hydrogen or an electron B. Co-enzyme A is a high-energy compound which is formed from adenine, ribose, pantothenic acid and thioethanolamine C. Vitamin B2 (riboflavin) concentration is higher in the foetus than in the mother D. A 40-year-old man presented with a painful swelling in the big toe and is suspected to be suffering from gout. Which of the following nutrients and the deficiency disorder related to it is correctly matched Cardinal signs of inflammation are: redness, swelling, heat, pain and loss of function. Chemical mediators involved in production of an inflammatory response include globulin permeability factor, bradykinin, 5-hydroxytryptamine, plasma kinins, histamine, etc. Inflammation is known as acute when it occurs due to an early response by the body and is of short duration. The inflammatory response is termed as chronic when it lasts for a longer duration of time and occurs after delay. Response by chronic inflammatory cells is the characteristic feature of chronic inflammation. These alterations include: haemodynamic changes and changes in vascular permeability. The earliest vascular response is characterised by constriction of small vessels, rapidly followed by dilatation and a brief increase in the velocity of blood flow. Progressive vasodilatation causes raised local hydrostatic pressure and transudation into the extracellular space. The crucial factor in formation of an inflammatory exudate is increased permeability of the vessel wall to plasma proteins. A transudate, on the other hand, has a low protein concentration (less than 25 g/L) and can result from a low serum protein concentration, high central venous pressure or portal hypertension. The change in permeability of the vessel wall could be related to the widening of gaps between the endothelial cells. The exudate contains immunoglobulins and other antibacterial factors as well as fibrinogen, which may form the fibrin clot, thereby causing the exudate to clot upon standing. Vasodilatation results in increased blood volume in microvascular bed of the inflammed area, which is responsible for redness and warmth at the site of acute inflammation. Increased transudation of fluid into the extracellular space is responsible for swelling at the local site of acute inflammation. Slowing or stasis of microcirculation follows which causes increased concentration of red cells, and thus, raised blood viscosity. Stasis or slowing of blood flow is followed by leucocytic margination or peripheral orientation of neutrophils along the vascular endothelium. The leucocytes briefly adhere to the vascular endothelium, moving and migrating through the gaps between the endothelial cells into the extravascular space. In case of cutaneous wound healing, macrophages replace neutrophils within 48 to 96 hours. The process of engulfment of foreign particulate material, whether by polymorphs or the monocytes involves its initial recognition and opsonisation. While the mechanisms for phagocytosis are largely intracellular (oxidative and non-oxidative bactericidal), a few extracellular mechanisms can also occur. The energy requirements for phagocytosis are derived from aerobic glycolysis in the cells. Another early feature of acute inflammation is the release of histamine and heparin due to the degranulation of mast cells in the adjacent tissues. Additionally, many chemical substances may be involved in the process of acute inflammation. The cells participating in the acute inflammatory process include circulating leucocytes, plasma cells and tissue macrophages. A phase of demolition may occur which is characterised by the engulfment of fibrin, red cells, pus cells, bacteria, etc. However in case of substantial tissue necrosis, the process of autolysis may result in pus (dead cells, debris, etc. One of the essential features of an abscess is a lining pyogenic membrane consisting of necrotic tissue. In cases of acute inflammation where the destruction is extensive or the bacteria persist in small numbers at the site of inflammation, the acute inflammatory process may develop into a chronic inflammatory process. Other features of chronic infection may include evidence of the repair process, characterised by migration of capillaries and fibroblasts and formation of collagen. There may be endoarteritis obliterans, a condition in which there is occlusion of small-sized arteries by intimal proliferation; accumulation of lymphocytes and plasma cells in the perivascular space; and excessive growth of the regenerating normal tissues. A chronic inflammatory process may produce systemic features such as fever, anaemia, leucocytosis, raised erythrocyte sedimentation rate and development of secondary amyloidosis in the long-standing cases. Amyloidosis is characterised by deposition of "amyloid material" (complex mucopolysaccharide containing globulins) in the connective tissue stroma and the walls of blood vessels of certain tissues and organs. Chronic inflammation is associated with increased levels of immunoglobulin G in the blood. In chronic inflammation the inflammatory and healing processes proceed side by side. In cases of non-specific chronic suppurative inflammation, abscesses may be formed. Example, in cases of chronic pyelonephritis, there is formation of multiple renal abscesses. Chronic inflammatory process in these cases may result in the formation of a solid tumour like mass or granulomas showing predominance of macrophages. A granuloma is composed of modified macrophages known as epithelioid cells in the centre, with some interspersed multinucleate giant cells, surrounded peripherally by lymphocytes (mainly T cells), and fibroblasts or collagen depending upon the age of granuloma. Examples include tuberculosis, syphilis, (the gumma), yaws, leprosy, actinomycosis, reaction to foreign bodies (talc granulomas), certain collagen diseases. When macrophages encounter insoluble material, they may coalesce to form giant cells. Regeneration can be described as restoration to original tissue by proliferation of parenchymal cells. On the other hand, repair is healing which occurs due to the proliferation of connective tissue resulting in fibrosis and scarring. The process of repair involves initial inflammatory reaction by the body, clearance by proteolytic enzymes, followed by contraction, fibroplasia, angiogenesis and epidermal ingrowth. Contraction occurs due to the shortening of the newly formed collagen fibres and due to the contraction of myofibroblasts. Fibroplasia is associated with budding of the adjacent capillaries, involving the canalisation of solid endothelial buds. This is followed by the migration of fibroblasts and macrophages into the wound cavity resulting in the formation of a vascular granulation tissue. This increasingly strengthens the scar tissues causing the scar to become relatively acellular and avascular. This is followed by the migration of healthy epidermal cells down the sides of the wound and across the granulation and fibrous tissues. Healing by First intention (Primary Union) Healing by first intention can occur in a wound, which is clean and uninfected; created after surgical incision; and/or is associated with minimal loss of cells and tissue. It includes the cases where the edges of wound are approximated by surgical sutures. In cases where the wound edges are opposed, healing proceeds rapidly to closure and this is known as primary healing. The basic events occurring in healing by secondary union are similar to primary union but differ in the extent of tissue defect which needs to be bridged.

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In the female the rectum is related anteriorly to the vagina and the lower part of the uterus herbal viagra purchase 30 gm v-gel. In both sexes the upper part of the rectum may be related anteriorly to the sigmoid colon and/or coils of ileum. Laterally: In the upper part, the rectum may be related to the sigmoid colon and/or coils of ileum. In the lower part, the rectum is related to the right and left coccygei and the right and left levator ani muscles. Blood Supply Blood supply to the rectum is from the inferior mesenteric artery through its rectal branches. Nerve Supply Its parasympathetic supply is derived from the hypogastric plexus of S234 origin. Lymphatic Drainage the rectum and the upper two-thirds of the anal canal drain into the internal and common iliac nodes, the sacral nodes and along the superior arteries in to the pre-aortic nodes. T It serves as a colour contrast between the bluish pink area above and black skin below. Blood supply: Superior rectal artery (branch of inferior mesenteric artery); middle rectal artery (branch of internal iliac artery); and inferior rectal artery (branch of internal pudendal artery). External anal sphincter: the external sphincter is a voluntary sphincter, which surrounds the entire length of the anal canal. This is made up of striated muscle, which comprises of the following three parts: 1. Superficial part: It is elliptical in shape and lies external to the lower part of the internal sphincter between the levels of the pectinate line and the white line. The fibres of this part are attached posteriorly to the coccyx and anococcygeal raphe, and anteriorly to the perineal body. Deep part: this lies external to the upper half of the internal sphincter (above the level of the pectinate line). Nerve supply to the external anal sphincter is by the inferior rectal branch of the pudendal nerve and perineal branch of the fourth sacral nerve. The Anal Musculature the anal canal is surrounded by a number of sphincters, which help in keeping it closed except during defaecation. These sphincters keep the lateral walls of the anal canal approximated when the anal canal is empty, resulting in the formation of an anterior-posterior slit. These sphincters are as follows: Internal anal sphincter: this is formed by thickening of the circular smooth muscle coat of the lower part of rectum. It surrounds the upper three-fourths of the anal canal and extends from the upper end of the anal canal up to the white line. It is externally separated from the external sphincter muscle by a conjoint sheath derived from levator ani and the longitudinal muscles of the rectum. Relations of the Anal Canal Posteriorly: the anal canal is separated from the coccyx by a mass of fibromuscular tissue that is called the anococcygeal ligament (or body). Anteriorly: In front of the anal canal there is another similar fibromuscular mass called the perineal body. The perineal body separates the anal canal from the membranous urethra and the bulb of the penis in the male; and from the vagina in the female. The boundaries of ischiorectal fossae are as follows: Roof: the levator ani muscle forms the inner wall and roof of the ischiorectal fossae Medially: the sphincter ani externus and the anal fascia Laterally: the tuberosity of the ischium, the obturator fascia and the obturator internus muscle Anteriorly: the fascia of Colles covering the transversus perinei superficialis, and the inferior fascia of the urogenital diaphragm Posteriorly: the gluteus maximus and the sacrotuberous ligament. Blood Supply to the Pelvis Abdominal aorta divides at the level of the fourth lumbar vertebra into two common iliac vessels. These pass downwards and laterally and divide opposite the sacroiliac joint into two vessels: the internal iliac and the external iliac vessel. While the external iliac vessels mainly supply the lower extremity, the internal iliac vessels supply the pelvis. The blood supply to the pelvis is mainly by the internal iliac artery, also known as the hypogastric artery. The place of division of hypogastric artery varies between the upper margin of sacrum and the upper border of the greater sciatic foramen. Relations of the internal iliac vessels are as follows: T Anterior: Ureter T Posterior: Internal iliac vein, lumbosacral trunk and piriformis muscle T Lateral: External iliac vein (near its origin); obturator nerve (lower down). Other significant blood vessels supplying the pelvis are as follows: as the sacrum and coccyx to supply the sacrum. Superior Rectal Artery and Vein this artery is a branch of the inferior mesenteric artery and supplies the superior two-thirds of the rectum. The ovarian artery is a branch of the abdominal aorta that supplies the ovary and the uterine tube. Median Sacral Artery the median sacral artery arises directly from the abdominal aorta at the point where it bifurcates into the two common iliac arteries. It descends over the L4 and L5 vertebrae as well External Pudendal Artery the external pudendal artery arises from the femoral artery. It supplies the skin over the pubic symphysis (the mons pubis in the female) and gives off anterior scrotal and labial arteries and the dorsal artery of the penis and clitoris. Sometimes, the superior vesical artery may branch out directly from the anterior trunk - - - Rectum Supplies the posterior bladder, seminal vesicle, and prostate Gives rise to anterior and posterior branches, which encircle the margin of the obturator foramen. The deep circumflex iliac artery and the corresponding vein runs along the internal surface of the ala of the ilium to supply the muscles located there. At its origin it is crossed by the ovarian vessels in the female, and occasionally by the ureter. The external iliac artery passes obliquely downward and laterally along the medial border of the psoas major, from the bifurcation of the common iliac to a point beneath the inguinal ligament. The external iliac artery continues as the femoral artery below the inguinal ligament. At the upper part of its course, the external iliac vein lies partly behind it, but lower down lies entirely to its medial side. It contains motor, sensory (pain and reflex), and postganglionic sympathetic fibres. The pudendal nerve traverses the greater sciatic foramen below the piriformis, crosses the back of the ischial spine, and enters the perineum through the lesser sciatic foramen. It traverses the pudendal canal in the lateral wall of the ischiorectal fossa, gives off the inferior rectal nerve, and divides into the perineal nerve and the dorsal nerve of the penis (or clitoris). The perineal nerve divides into a deep branch to perineal muscles and a superficial branch to the scrotum (or labium majus). Pelvic Part of Autonomic Nervous System: Hypogastric Plexus Sympathetic fibres reach the pelvis by downward continuations of the sympathetic trunk and of the aortic plexus. In front of the sacrum, the sympathetic trunks consist largely of preganglionic fibres and present three or four ganglia each. This forms the hypogastric plexus of nerves, which supplies the viscera of pelvic cavity. This plexus is situated in front of the last lumbar vertebra and sacral promontory. It is formed by the presacral nerve, which lies in front of sacral promontory and divides into two hypogastric nerves which pass downwards and laterally along the pelvic wall. They help to form the inferior hypogastric plexus, which is a diffuse plexus that lies in the region of uterosacral ligaments. The inferior hypogastric plexus is formed from the fibres of the sacral splanchnic nerves, pelvic splanchnic nerves and hypogastric nerves. The lumbosacral trunk comprises of the anterior divisions of the lumbar, sacral nerves and the coccygeal nerve. Pudendal canal which begins at the posterior border of the ischiorectal fossa and ends at the posterior edge of the urogenital diaphragm 4. The deep perineal space which is the fascial space between the superior and inferior fasciae of the urogenital diaphragm 5. The dorsal nerve of the clitoris: the dorsal nerve of the clitoris supplies the skin surrounding this structure. Dorsal nerve of the clitoris and the inferior hypogastric plexus also provide sensory innervation for the peritoneum in the pouch of Douglas.

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Also herbs mac and cheese buy discount v-gel 30gm,simeprevircontainsacomponent of sulfonamide, so caution is advised for patients who have had previous reactionstosulfonamides. Significant adverse effects may occur when given with amiodarone (serious symptomatic bradycardia). It may also raise levels of sedative anxiolytics such as midazolam and triazolam, which both have a narrow therapeutic index. Becausesimeprevircan cause liver injury, liver enzymes, bilirubin, and uric acid should be checked before initiating therapy and repeated as indicated. Elbasvir, ledipasvir, and ombitasvir are combined in fixed dosages withotherantiviraldrugs. The most common adverse reactions are headache and fatigue (in combination withsofosbuvir). Cardiac monitoring should be undertaken if it becomes necessary to administer amiodarone while the patient is taking daclatasvir. If digoxin is administered, because it has a narrow therapeutic index, it is important to monitor patient statusandserumdigoxinlevels. Sofosbuvir is a prodrug that is metabolized to its active form through intracellular processes. If sofosbuvir is administered with amiodarone, dangerous symptomatic bradycardia may occur. Of these, about 11,000 require hospitalization for deep fatigue, muscle pain, and jaundice. However, when chronic infection does develop, it can lead to cirrhosis, hepatic failure, hepatocellular carcinoma, and death. The alfa interferons are administered subcutaneously; the nucleoside analogs are administered orally. The interferons are more effective than the nucleoside analogs but are also more expensive and less well tolerated. Development of resistance is common with lamivudine and telbivudine and relatively rare with theotherfivedrugs. With all seven drugs-and especially the nucleoside analogs-the rate of relapse after cessation of treatment is high. InterferonAlfa Only two forms of interferon alfa-interferon alfa-2b [Intron A] and peginterferon alfa-2a [Pegasys]-are approved for chronic hepatitis B. In clinical trials, the incidence of most side effects was no greater than with placebo. Lactic acidosis, pancreatitis, and severe hepatomegaly are rare but dangerouscomplications. Increased serum creatinine, a sign of kidney damage, was seen in 4% of patients who received 48 weeks of therapy andin9%ofpatientswhoreceived96weeksoftherapy. Toreducerisk,kidney function should be assessed at baseline and periodically thereafter, paying special attention to patients at high risk. Forpatientswithgoodkidney function, the dosage is 10mg once a day, taken with or without food. Recent evidence indicates that, with long-term use (3 years), entecavir can reverse fibrosis and cirrhosis. Entecavir is a nucleoside analog that undergoes conversion to entecavir triphosphate (its active form) within the body. Entecavir is neither a substrate for, inhibitorof,norinducerofcytochromeP450enzymes. If the patient develops clinical or laboratory findings that suggest lactic acidosis or pronounced hepatotoxicity, entecavir should be withdrawn. Acute severe exacerbations of hepatitis B have developed after discontinuation of entecavir and other drugs for hepatitis B. As with lamivudine, resistance can be significant: after 2 years of treatment with telbivudine, resistance develops in 9% to 22% of patients. Telbivudine is a thymidine nucleoside analog that undergoes intracellular conversion to its active form: telbivudine triphosphate. However,becausetelbivudineis eliminated primarily by renal excretion, drugs that impair renal function may raise its level. Also, other drugs that cause muscle injury may increase risk in patientstakingtelbivudine. Theusualdosage for adults and children is 600mg once a day, taken with or without food. However, as with other nucleoside analogs, discontinuation of treatment is followed by exacerbation of hepatitis. Tenofovirissuppliedin150-,200-,250-,and300-mgtabletsand in a 40-mg/g powder for oral dosing. Thecostof influenza is huge: direct and indirect expenses total between $3 billion and $5 billionannually. Influenza is a highly contagious infection spread by aerosolized droplets produced by coughing or sneezing. Influenza is characterized by fever, cough, chills, sore throat, headache, and myalgia (muscle pain). For typical patients, infection results in 5 to 6 days of restrictedactivity,3to4daysofbeddisability,and3daysofabsencefromwork orschool. Because influenza viruses are constantly evolving, influenza vaccines must continuously change too. However, among older vaccine recipients, protection may be lost in 4 months or even less. Because the influenza virus evolves rapidly, influenza vaccines are reformulated annually. People who have not been vaccinated previously may experiencefever,myalgia,andmalaiselasting1or2days. In any case, emergency equipment should be available whenevervaccinationsaregiven. As noted earlier, people at high risk for flu complications, including pregnant women, should not receive the live influenza vaccine. InactivatedInfluenzaVaccine:Intradermal Fluzone Intradermal is the first influenza vaccine formulated for intradermal injection. This live virus drug should not be administered to people who are immunocompromised, pregnant, or otherwise at high risk for influenza complications. However, children aged 2 through 8 years who have not been vaccinated before require two doses, administered at least 1 month apart. At this time, three neuraminidase inhibitors are available: oseltamivir, peramivir, and zanamivir. Both oseltamivir and zanamivir are approved for influenza prophylaxis and treatment. Whenusedfortreatment,dosingmustbeginearly-nolaterthan2daysafter symptom onset, and preferably much sooner. Antiviral effects derive from inhibiting neuraminidase, a viral enzyme required for replication. As a result of neuraminidase inhibition, newly formed viral particles are unable to bud off from the cytoplasmic membrane of infected host cells. In addition, the drug is active against the socalledswineflu,thevariantofinfluenzaAtypeH1N1thatcausedtheinfluenza pandemicin2009. Rarely, oseltamivir has caused severe hypersensitivity reactions, including anaphylaxis and serious skin reactions. Preparations,Dosage,andAdministration Oseltamivir [Tamiflu] is available in capsules (30, 45, and 75mg) and as a powder(360mg)tobereconstitutedtoa6-mg/mLoralsuspension. Fortreatment,thedosageforpatients13yearsandolderis75mgtwicedailyfor 5 days, beginning no later than 2 days after the onset of symptoms. Dosage should be reduced to 75mg once daily in patients with significant renal impairment. The dosage for children 1 year old through 12 years old is based on body weight as follows: 15kg or less, 30mg once daily; 15 to 23kg, 45mg once daily; 23. Zanamivir ActionsandUses Zanamivir[Relenza],administeredbyoralinhalation,isapprovedfortreatment of acute uncomplicated influenza in patients at least 7 years old, and for prophylaxis of influenza in people at least 5 years old. AdverseEffectsandInteractions In patients with healthy lung function, serious adverse effects are uncommon. Administration is by oral inhalation using the Diskhaler provided by the manufacturer.

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The pouch of Douglas extends down up to the upper one-third of the posterior vaginal wall herbals for cholesterol purchase v-gel 30gm on-line. Blood Supply the vagina is supplied by the uterine and vaginal branches of the internal iliac artery. Other sources include inferior vesical and middle rectal arteries, which anastomose freely on the vaginal wall. The venous drainage of vagina is to the vaginal venous plexus with the vaginal vein draining into the internal iliac vein or the uterine vein. Nerve Supply the uterovaginal nerve plexus lying in the base of the broad ligament on the either side of the supravaginal part of the cervix gives rise to the parasympathetic and sympathetic nerves supplying the vagina. The sympathetic fibres are derived from lumbar splanchnic nerves, whereas the parasympathetic fibres are derived from the pelvic splanchnic nerves. The inferior fibres from the uterovaginal plexus supply the superior part of the vagina. These are derived from the inferior hypogastric plexus and the pelvic splanchnic nerves. The nerve supply to the lower part of the vagina is from the branch of pudendal nerve called the deep perineal nerve. Lymphatic Drainage the lower one-third of the vagina drains to the superficial inguinal lymph nodes (similar to the vulval drainage), while the upper two-thirds drain into the external and internal iliac and sacral nodes (similar to that of cervix). Relations Anteriorly: the vagina is related anteriorly to the cervix, ureters, and bladder and is fused with the urethra. When an oocyte is released from an ovary, the fimbriae guide it towards the infundibulum of the fallopian tube. Fallopian tube has a lining of ciliated cells interspersed with non-ciliated secretory cells ("peg" cells). The fallopian tube must be sufficiently mobile to assist the ovum onwards by peristalsis. Presence of cilia along with the muscles of the tubal wall helps in propelling an oocyte downwards through the fallopian tube into the uterine cavity where it ultimately implants in form of a blastocyst. The fallopian tube runs in the upper margin of the broad ligament part of which is known as the mesosalpinx. This encloses the tube in such a way that it is completely covered with peritoneum except for a narrow strip along its inferior aspect. Starting from the lateral to medial side, the fallopian tube can be divided into four parts, which are as follows: 1. Infundibulum: this is the funnel-shaped distal end of the tube, which opens into the peritoneal cavity through the abdominal ostium. The finger-like projections of the fimbriated end of the infundibulum (fimbriae) spread over the medial surface of the ovary. Ampulla: this is the widest and the largest part of the tube, which lies medial to the infundibulum. Isthmus: this is the thick-walled part of the tube, which enters the uterine cornu. Uterine part: this includes the short intramural segment of the tube, which passes through the wall of the uterus and opens via the uterine ostium into the uterine cavity at the uterine cornu. It is commonly situated on the lateral wall of the pelvis in the angle between the external iliac vein and the ureter, where it can be palpated upon bimanual examination. In postmenopausal women, the ovaries become smaller and shrunken and are covered with scar tissue. In the woman of reproductive age group, the developing egg cells (oocytes) are contained by the fluid-filled cavities called follicles, present in the ovarian walls. Each ovary is suspended by a short fold of peritoneum known as the mesovarium, which arises from the broad ligament and convey the ovarian vessels. The ovaries lie above the pelvic brim at the time of birth and do not descend down until the cavity of the pelvis deepens during childhood. The enlarging uterus at the time of pregnancy is more likely to pull the ovaries into the abdominal cavity. In the prepubertal woman, the connective tissue capsule over the surface of the ovary is covered by a smooth layer of ovarian mesothelium or surface germinal epithelium. This usually comprises of a single layer of cuboidal cells and is usually continuous at the hilum with the peritoneum and the mesovarium. These cubical cells lie on a dense layer of connective tissue, the tunica albuginea and give the ovarian surface a dull, greyish appearance. After puberty, the surface epithelium becomes progressively scarred and distorted because of the repeated rupture of the ovarian follicles and discharge of oocytes during ovulation. The Graafian follicles are interspersed throughout the stroma, and some of them may be seen bulging at the surface of the ovary; they vary in size according to their stage of development. The ovaries lie close to the lateral pelvic walls suspended from the posterior surfaces of the broad ligaments. Therefore, ovarian disease, which involves the parietal peritoneum at this site, may produce pain referred via the nerve to the medial side of the thigh. The suspensory ligament of the ovary (or infundibulopelvic ligament) extends from the ovary to the lateral pelvic wall. It is not considered a true ligament because it does not physically support any anatomical structure. The ovarian artery descends in the suspensory ligament and, by way of the broad ligament and mesovarium, enters the hilum of the ovary. The ovarian ligament, on the other hand, connects the ovary to the body of the uterus, immediately posterior and inferior to the entrance of the uterine tube. It is a short ligament present medially within the mesovarium and lies beneath the posterior layer of the broad ligament. Blood Supply the ovary derives its blood supply directly from the abdominal aorta. The ovary is supplied by the ovarian artery, a direct branch of the abdominal aorta. After crossing the pelvic brim this vessel enters the broad ligament and divides into terminal branches within the mesovarium. The left ovarian vein drains into the left renal vein and the right ovarian vein drains directly into the inferior vena cava. The ovarian artery arises from the aorta just below the renal artery and runs downwards on the anterior surface of the psoas muscle to the pelvic brim, where it crosses in front of the ureter and then passes into the infundibulopelvic fold of the broad ligament. As the ureter crosses the brim of the pelvis it lies in front of the bifurcation of the common iliac artery. It runs downwards and forwards on the lateral wall of the pelvis to reach the pelvic floor, and then passes inwards and forwards to pass beneath the uterine artery. Since the ovary is suspended inside the peritoneal cavity and its surface is not covered with peritoneum, the oocyte expelled at the time of ovulation passes into the peritoneal cavity. However, its intraperitoneal life is short because it is soon trapped by the fimbriae of the infundibulum of the uterine tube. Each ovary has tubal and uterine ends, medial and lateral surfaces, and mesovarian (anterior) and free (posterior) borders. Relations of the Ovarian Artery Right ovarian artery: Right ovarian artery crosses the inferior vena cava and is crossed by the following: T Middle colic vessels T Caecal veins T Terminal ileal vein T Ileocolic vein. Left ovarian artery: the left ovarian artery is crossed by the following: T the left colic and the sigmoid branches of the inferior mesenteric vessels T Descending colon. Relations the superior or tubal end: this is closely related to the uterine tube and is attached to the suspensory ligament of the ovary. Lateral surface: Lateral surface of the ovary is in contact with the parietal peritoneum that lines the sidewall of the pelvis. Nerve Supply the nerve supply to the ovaries (the ovarian plexus) includes parasympathetic, postganglionic sympathetic and autonomic afferent fibres. Lymphatic Supply the lymphatics from the ovary drain into the para-aortic nodes on both sides of the midline.

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Cocaine Cocaine herbals and liver damage v-gel 30gm, a naturally occurring alkaloid, acts as a local anesthetic and also stimulates the sympathetic nervous system by blocking the neuronal reuptake of norepinephrine at both peripheral and central synapses. Cocaine produces both vasoconstriction and cardiac stimulation and elevates blood pressure. The vasoconstrictive effect can cause ischemia and necrosis of the nasal mucosa in people who abuse cocaine. After being stung by a bee, a woman experiences urticaria, laryngeal edema, difficult breathing, and hypotension. Midodrine is a selective 1-adrenoceptor agonist that is used to treat postural (orthostatic) hypotension. None of the other options increases systemic vascular resistance or counteracts postural hypotension. These drugs also activate -adrenoceptors in the heart and increase heart rate, but do not typically cause low blood pressure, blurred vision, sedation, or muscle weakness. The preferred treatment for severe hypersensitivity reactions (anaphylaxis) is epinephrine. Sequestration of calcium (E) causes muscle relaxation, but this action is not invoked by 2-receptor stimulation. A man with diabetic autonomic neuropathy complains of dizziness and fainting when arising from bed in the morning. A child with asthma is being treated with an adrenoceptor agonist to prevent bronchospasm. Phenoxybenzamine is a noncompetitive antagonist, and phentolamine is a competitive antagonist. Phenoxybenzamine is administered orally and undergoes nonenzymatic chemical transformation to an active metabolite that forms a long-lasting covalent bond with -adrenoceptors, resulting in noncompetitive receptor blockade. The drug exhibits a slow onset of action owing to the time required to form its active metabolite, but it has a long duration of action of 3 to 4 days because of its stable drugreceptor binding. Phenoxybenzamine decreases vascular resistance and lowers both supine and standing blood pressure. As shown in Table 9-1, phenoxybenzamine is used to treat hypertensive episodes in patients with pheochromocytoma, which is a tumor of the adrenal medulla that secretes huge amounts of catecholamines, causing extremely high blood pressure. In this setting, phenoxybenzamine is used to control hypertension until surgery can be performed to remove the tumor (Box 9-1). Phentolamine is an imidazoline compound that is structurally related to oxymetazoline and other agents in the imidazoline class of adrenoceptor agonists (see Chapter 8). After intravenous administration, the onset of action is almost immediate, and the duration of action is 10 to 15 minutes. After intramuscular or subcutaneous administration, the onset of action is 15 to 20 minutes, and the duration is 3 to 4 hours. It is used in the treatment of acute hypertensive episodes caused by adrenoceptor agonists. It is also used to counteract localized ischemia caused by accidental injection or extravasation (leakage from an intravenous infusion) of epinephrine or other vasopressor amines. Accidental injection of a finger with an epinephrine autoinjector may result in localized vasoconstriction, ischemia, and necrosis. Excessive sympathetic nervous system activity contributes to a number of diseases, including common cardiovascular disorders such as hypertension, angina pectoris, and cardiac arrhythmias. Drugs that reduce sympathetic stimulation, sympatholytic drugs, are used in the management of cardiovascular diseases and other diseases such as glaucoma, migraine headache, and urinary obstruction. The adrenoceptor antagonists are the most important group of sympatholytic drugs used today. The sympathetic neuronal blocking agents discussed in Chapter 5 also have a sympatholytic effect but are largely obsolescent. The adrenoceptor antagonists include drugs that block -adrenoceptors, -adrenoceptors, or both. Their therapeutic effects are almost entirely caused by blockade of 1- and 1-adrenoceptors. Blockade of 1-adrenoceptors relaxes vascular and other smooth muscles in tissues innervated by the sympathetic nervous system, whereas blockade of 1adrenoceptors reduces sympathetic stimulation of the heart. Blockade of 2- or 2-adrenoceptors is responsible for many of the adverse effects of these drugs, and drugs that selectively block either 1- or 1-adrenoceptors have been developed in an effort to avoid these adverse effects. Competitive and noncompetitive blockade of epinephrineinduced aortic smooth muscle contraction by phentolamine and phenoxybenzamine. Because phentolamine is a competitive -adrenoceptor antagonist, epinephrine can surmount its effect. Because phenoxybenzamine is a noncompetitive antagonist, it reduces the maximal effect of epinephrine. Onphysical examinationhispulseis86beats/min,hisrespirationrateis 24/min, and his blood pressure is 210/110mmHg. He is given oxygen and intravenous labetalol to gradually reduce heart rate and blood pressure. His blood pressure is gradually reduced to 118/65mmHg, and he is started on a high-salt diet to maintain plasma volume. A week later he undergoes laparoscopic left adrenalectomy and his medications are gradually withdrawn. Thediagnosisis established by abdominal imaging and measurement of urinary catecholamines and vanillylmandelic acid. Alternatively,metyrosine(seeChapters5 and 10) can be used with phenoxybenzamine to control blood pressure preoperatively, and the drug is useful in managing patients when surgery is contraindicated or when the tumor has metastasized. If the tumor is unilateral, replacement of corticosteroids is not necessaryafteradrenalectomy. Phentolamine and other nonselective -blockers are not useful in treating chronic hypertension, because they evoke reflex tachycardia and may cause dizziness, headache, and nasal congestion. Agents that selectively antagonize 1-adrenoceptors include alfuzosin, doxazosin, prazosin, silodosin, tamsulosin, and terazosin. These drugs are primarily used to treat urinary symptoms in men with benign prostatic hyperplasia. The selective 1-adrenoceptor antagonists are administered orally and undergo varying amounts of first-pass and systemic metabolism. The drugs are highly bound to plasma proteins, and they are excreted in the bile, urine, and feces. The selective lblockers relax vascular and other smooth muscles, including those of the urinary bladder, urethra, and prostate. Because they produce vasodilation and decrease blood pressure, they are used to treat essential (primary) hypertension. The selective 1-blockers do not cause as much reflex tachycardia as do phentolamine and other agents that nonselectively block both 1- and 2-adrenoceptors. This is because blockade of 2-adrenoceptors on sympathetic neurons prevents feedback inhibition of norepinephrine release and thereby leads to increased activation of cardiac 1-adrenoceptors and tachycardia. The use of Selective 1-Antagonists selective 1-blockers to treat hypertension is discussed in greater detail in Chapter 10. The selective 1-blockers are quite helpful in treating lower urinary tract symptoms associated with benign prostatic hyperplasia and other conditions. Men with these conditions complain of urinary frequency, urgency, and nocturia (need to urinate more frequently at night). Prostatic enlargement may obstruct urinary outflow, and there is good evidence that activation of 1-adrenoceptors in the bladder, the urethra, and the nervous system contributes to urinary tract obstruction in these men. These drugs can be used in combination with finasteride or dutasteride (see Chapter 34) for relief of urinary symptoms. Tadalafil has also been approved for treating symptoms of benign prostatic hyperplasia (see Chapter 6). The most common adverse effects of 1-blockers include hypotension, dizziness, and sedation, which are attributed to excessive vasodilation and to the central nervous system effects of these drugs. Doxazosin and terazosin appear to be associated with a higher incidence of these adverse effects than tamsulosin and alfuzosin. Specific Drugs Prazosin, whose half-life is shorter than the half-lives of other 1-antagonists, has a duration of action of about 6 hours. It undergoes considerable first-pass and systemic metabolism before renal and biliary excretion. Doxazosin and terazosin are longer-acting 1-blockers that are usually administered once a day to treat hypertension or to relieve lower urinary tract symptoms.

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Diastolic dysfunction can result from decreased compliance (increased stiffness) of ventricular tissue secondary to left ventricular hypertrophy or fibrosis herbs chicken soup generic v-gel 30 gm with amex. Hence, both systolic and diastolic heart failure can be caused or exacerbated by the process of cardiac remodeling. In cases of left ventricular failure (left-sided heart failure), the left ventricle does not adequately pump blood forward, so the pressure in the pulmonary circulation increases. When the increased pressure forces fluid into the lung interstitium, this causes congestion and edema. Pulmonary edema reduces the diffusion of oxygen and carbon dioxide between alveoli and the pulmonary cap illaries. This causes hypoxemia (deficient oxygenation of the blood) and can lead to dyspnea (difficulty in breathing), including exertional dyspnea (dyspnea provoked by exer cise), orthopnea (intensified dyspnea when lying flat), and paroxysmal nocturnal dyspnea (edemainduced broncho constriction when sleeping). The overall mortality rate in patients with heart failure is about eight times as high as that in the normal population, and the 5year mortality rate for patients with heart failure approaches 50%. Pathophysiology of Heart Failure Heart failure is the end stage of a number of cardiovascular disorders that ultimately impair the ability of the ventricle to fill with blood or to eject blood into the circulation. Other important causes of heart failure include hypertension, valvular disorders, arrhythmias, viral and con genital cardiomyopathy, and constrictive pericarditis. For this reason, patients with heart failure often experience symptoms of weakness and fatigue and have reduced exercise capacity. In cases of right ventricular failure (right-sided heart failure), congestion in the peripheral veins leads to ankle edema in the ambulatory patient and to sacral edema in the bedridden patient. It also leads to hepatojugular reflux, characterized by an increase in jugular vein distention when pressure is applied over the liver. Ultimately, rightsided failure can lead to leftsided failure as the left ventricle is forced to work harder in an attempt to maintain cardiac output. The reduction in cardiac output that occurs in heart failure triggers a cascade of compensatory neuroendocrine responses. Although these responses attempt to restore cardiac output via the FrankStarling mechanism. The reduction in tissue perfusion activates both the sympa thetic nervous system and the reninangiotensinaldosterone system, both of which in turn stimulate vasoconstriction. Arterial vasoconstriction increases aortic impedance to left ventricular ejection and thereby decreases cardiac output, especially in patients with a weak, dilated heart. Hence, the net result of the neuroendocrine responses is often a further reduction in cardiac output and an increase in circulatory congestion. Mechanisms and Effects of Drugs for Heart Failure the primary goals of drug therapy for heart failure are to improve symptoms, slow or reverse deterioration in myo cardial function, and prolong survival. Drugs can also be used to treat underlying conditions, control arrhythmias, prevent thrombosis, and treat anemia. The pharmacologic agents used to treat heart failure include drugs that (1) increase cardiac output, (2) reduce pulmonary and systemic congestion, and (3) slow or reverse cardiac remodeling. Cardiac output can be increased by posi tively inotropic drugs that increase cardiac contractility and by vasodilators that reduce cardiac afterload and the imped ance to left ventricular ejection. Diuret ics are used to mobilize edematous fluid and reduce plasma volume, thereby decreasing circulatory congestion. Angio tensin and sympathetic inhibitors have been shown to favor ably influence cardiac remodeling and increase survival in persons with heart failure. Each of these drugs partly coun teracts the loss of myocardial function and the maladaptive responses that occur during heart failure; however, none of the current therapies, either alone or in combination, has been completely satisfactory. Because heart failure has such a high incidence and poor prognosis, a much greater effort has been expended in the search for better means to treat it. The most significant development in recent decades has been the use of angiotensin inhibitors, adrenoceptor blockers, and other agents that attenuate cardiac remodeling and reduce the mortality rate in patients with heart failure. Ultimately, however, the successful treatment of patients with heart failure may require the development of drugs that activate genes capable of repairing or replacing myocardial tissue. These drugs increase cardiac contractility by increasing calcium levels in cardiac myocytes. Digoxin Despite the fact that the digitalis glycosides such as digoxin have been used to treat heart failure for more than 200 years, their effectiveness and place in therapy have been difficult to establish. Recent clinical trials indicate that digoxin pro vides a definite, yet limited, benefit to patients with heart failure caused by systolic dysfunction. Drug Properties Many digitalis glycosides have been isolated from plant and animal sources, including the leaves of Digitalis (foxglove) plants and the skin secretions of certain toads. Digoxin is the only digitalis glycoside that is extensively used today, having replaced digitoxin and crude digitalis leaf prepara tions in the treatment of heart failure and other cardiac disorders. The digitalis glyco sides are composed of a steroid nucleus, a lactone ring, and three sugar residues linked by glycosidic bonds. The stereo chemical configuration of the steroid nucleus of digitalis glycosides is different from that of human steroids, and the digitalis glycosides lack most of the effects produced by gonadal or adrenal steroids. As shown in Table 122, digoxin is adequately absorbed from the gut and has a long half-life of about 36 hours. Drugs that increase cardiac contractility are said to have a positive inotropic effect and are commonly referred to as inotropic drugs or agents. The direct and indirect actions of digoxin produce a unique constellation of effects on the cardiovascular system. It has a positive inotropic effect (an increase in the force of contraction), a negative chronotropic effect (a decrease in the heart rate), and a negative dromotropic effect (a decrease in conduction velocity). Among the various inotropic drugs, digoxin is unique in its ability to strengthen cardiac contraction while decreasing heart rate. Moreover, digoxin increases parasym pathetic tone while reducing sympathetic tone, and this may partly account for its beneficial effects. When the sodium pump is inhibited, the concentration of intracellular sodium is increased, thereby increasing the activity of the sodium calcium exchanger and causing more calcium to enter the cardiac myocyte. The increase in cytoplasmic calcium stimulates the release of additional calcium from the sarcoplasmic reticulum and increases the rate of myofibril shortening (muscle contraction), and the peak systolic muscle tension. The stroke volume is the amount of blood pumped by the ventricle during each systole, and the cardiac output is the amount of blood ejected from either ventricle of the heart per minute. In patients with heart failure, the reduction in sympathetic tone is caused partly by the withdrawal of reflex sympathetic stimulation secondary to the improved cardiac output produced by digoxin. The high sodium concentration increases the activity of the sodiumcalcium exchanger (Ex), thereby causing more calcium to enter or remain inside the cardiac myocyte. Calcium activates muscle fiber shortening and increases cardiac contractility, which in turn increases stroke volume at any given fiber length (preload). The positively inotropic drugs increase stroke volume at any given fiber length and thereby decrease venous pressure and preload. These abnormal depo larizations occur during or immediately after normal cardiac repolarization and lead to extrasystoles (premature or coupled beats) and tachycardia (rapid beating of the heart). The afterdepolarizations appear to be caused by excessive calcium influx into cardiac cells, and they are more likely to occur after higher doses of digoxin have been given. The most common adverse effects of digoxin are gastrointestinal, cardiac, and neurologic reac tions. These reactions are often associated with elevated serum concentrations and may forewarn of more serious toxicity. Hypokalemia can precipitate arrhythmias in patients receiv ing digoxin, and the serum potassium level should be deter mined immediately if arrhythmias occur in these patients. The neurologic effects of digoxin toxicity are usually caused by excessive plasma levels of the drug, and include blurred vision and yellow, green, or blue chromatopsia (a condition in which objects appear unnaturally colored). Because digoxin has some estrogenic activity, it occasion ally causes gynecomastia (excessive growth of male mammary glands). Because antacids and cholestyramine can reduce the absorption of digoxin and decrease its therapeutic effects, their administration should be separated from the administration of digoxin by at least 2 hours. Diltiazem, quinidine, and verapamil reduce digoxin clearance and increase serum digoxin levels, contributing to digitalis toxic ity. When digoxin is used concurrently with these drugs, only 50% of the usual dose of digoxin should be given, and serum digoxin levels should be monitored.

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The most characteristic adverse effect of the potassiumsparing diuretics is hyperkalemia vaadi herbals products review purchase v-gel discount, but this is unlikely to occur unless the patient also ingests potassium supplements or other drugs that increase serum potassium levels. Spironolactone Spironolactone is a structural analog of aldosterone that competitively blocks aldosterone binding to the mineralocorticoid receptor in epithelial cells of the late distal tubule and collecting duct. By blocking these actions, spironolactone reduces sodium reabsorption and the accompanying secretion of potassium. Spironolactone is adequately absorbed from the gut and has a long duration of action despite its short elimination half-life, indicating that its cellular actions persist longer than do circulating drug levels (see Table 13-2). Spironolactone is used to prevent hypokalemia in the same manner as amiloride and triamterene, and it has a special role in the treatment of primary hyperaldosteronism. Clinical trials have shown that spironolactone reduces mortality in persons with heart failure, as described in Chapter 12. Its use in this condition, however, has been associated with an increased incidence of hyperkalemia. Because of its antiandrogenic effect, spironolactone is also used in the treatment of polycystic ovary disease and hirsutism in women. Eplerenone is a newer aldosterone antagonist that produces fewer endocrine side effects than does spironolactone. Eplerenone is used to counteract the effects of excessive aldosterone in persons with heart failure (see Chapter 12). Dorzolamide is partly absorbed from the eye into the circulation and undergoes some metabolic transformation before it is excreted in the urine. The drug is eliminated in a biphasic manner, with a rapid decline in serum levels followed by a much slower release from erythrocytes, and it has a half-life of 4 months. The pharmacokinetic properties of acetazolamide and dorzolamide are outlined in Table 13-2. This enzyme catalyzes the conversion of carbon dioxide and water to carbonic acid, which spontaneously decomposes to bicarbonate and hydrogen ions. Now some of these drugs, including dorzolamide, are available for topical ocular administration. Dorzolamide is administered every 8 hours in the treatment of chronic ocular hypertension and open-angle glaucoma. This leads to alkalinization of the urine and produces a mild form of hyperchloremic metabolic acidosis. The hyperchloremia results from the increased reabsorption of chloride as a compensation for reduced bicarbonate reabsorption. They are effective in the prevention and treatment of high-altitude Osmotic Diuretics Glycerol and mannitol are examples of osmotic diuretics. These diuretics increase the osmotic pressure of the plasma and thereby attract water from interstitial and transcellular fluids. Because of this action, mannitol is used to treat cerebral edema and reduce intracranial pressure. By attracting water from ocular fluids into the circulation, the drugs reduce intraocular volume and pressure. Glycerol is administered orally for this purpose, whereas mannitol is administered intravenously. After intravenous administration, it is filtered at the glomerulus but is not reabsorbed from the renal tubules. It osmotically attracts and retains water as it moves through the nephron and into the urine. This action reduces the tubular sodium concentration and the concentration gradient between the tubular fluid and cells and thereby retards the reabsorption of sodium. The diuretic effect of mannitol has been used to improve renal function in the oliguric phase of acute renal failure. Evidence for a renoprotective effect of mannitol has been obtained in studies of persons having renal transplantation. Mannitol has also been administered along with intravenous fluids to maintain renal function and reduce the renal toxicity of antineoplastic platinum compounds. The primary adverse effect of mannitol is excessive plasma volume expansion, which is most likely to occur if the drug is administered too rapidly or with too large a volume of intravenous fluid. Excessive plasma volume can lead to heart failure and pulmonary congestion and edema in susceptible patients. Conditions that cause edema as a result of increased hydrostatic pressure include heart failure and certain renal diseases, all of which cause sodium and water retention. Conditions that cause edema as a result of inadequate colloid osmotic pressure include severe dietary protein deficiency and hepatic diseases. In conditions such as cirrhosis, the liver is unable to synthesize adequate albumin and other plasma proteins to maintain plasma osmotic pressure. Hepatic cirrhosis can lead to ascites (accumulation of fluid within the peritoneal cavity) and portal hypertension. This disorder can be managed with dietary salt restriction and the use of diuretics. Nephrotic syndrome, a renal disease that leads to excessive protein excretion in the urine (proteinuria), can cause edema by this mechanism. Infection, neoplasms, and thromboembolism can also cause edema by various mechanisms that include inflammation, increased capillary fluid permeability, and increased hydrostatic pressure caused by obstruction of blood vessels. The primary treatment of edema is to correct the underlying disorder and restore plasma osmotic pressure and hydrostatic pressure to normal values. In milder forms of edema, diuretics can be used as short-term adjunct treatments that serve to mobilize edematous fluid while an attempt is made to correct the underlying cause. Most cases of mild peripheral edema, however, can be managed without pharmacologic therapy by correcting the underlying disorder or discontinuing a causative drug. By counteracting respiratory alkalosis, the drugs enhance ventilation acclimatization and maintain oxygenation during sleep at a high altitude. Less commonly, they are associated with various hypersensitivity reactions and blood cell deficiencies. Conivaptan and tolvaptan are nonpeptide antagonists of antidiuretic hormone (arginine vasopressin). The V2 receptors are coupled with insertion of aquaporin channels in the apical membranes of the renal collecting ducts, leading to reabsorption of water (antidiuretic effect). By activating these receptors, antidiuretic hormone helps maintain plasma osmolality in the normal range. Antagonism of V2 receptors by conivaptan and tolvaptan causes free water excretion or aquaresis, and the drugs are called aquaretics. Conivaptan and tolvaptan are approved for treating euvolemic and hypervolemic hyponatremia (low serum sodium concentration) in hospitalized patients, but they are contraindicated in hypovolemic hyponatremia. Conivaptan is given as an intravenous infusion, usually for 4 days, and typically increases free water clearance by 3800 mL and serum sodium concentration by 6. Almost 70% of patients achieve a normal serum sodium concentration of 135 mEq/L after 4 days of conivaptan therapy. Conivaptan and tolvaptan may increase serum levels of midazolam, simvastatin, and other drugs metabolized by 3A4. The most common adverse reactions reported with conivaptan are infusion site reactions. Loop-acting diuretics such as furosemide can cause ototoxicity more frequently than other diuretics. Potassium-sparing diuretics such as spironolactone can cause hyperkalemia, especially in persons with renal insufficiency. Thiazide diuretics such as hydrochlorothiazide (C) and loop-acting diuretics such as furosemide (B) are more likely to cause hypokalemia. Mannitol (E) and acetazolamide (D) have less effect on potassium excretion and serum potassium levels. Carbonic anhydrase inhibitors such as acetazolamide increase renal sodium bicarbonate excretion and alkalinize the urine. Urine alkalinization increases the ionization of weakly acidic drugs such as amphetamine and thereby increases their renal excretion. Other diuretics do not significantly affect the renal excretion of weakly acidic drugs. Loop-acting diuretics such as furosemide increase renal calcium excretion and are used in the treatment of hypercalcemia. Thiazide diuretics such as hydrochlorothiazide (C) decrease calcium excretion and would worsen hypercalcemia.

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Therapeutic doses of bethanechol given orally or subcutaneously have little effect on blood pressure wise woman herbals 1 generic 30 gm v-gel, but the drug should never be administered intravenously, because this can cause hypotension and bradycardia. Carbachol is available as a solution that is instilled intraocularly to produce miosis during ophthalmic surgery, such as cataract surgery and iridectomy. It is no longer used in treating open-angle glaucoma, having been replaced by agents with fewer side effects. Pilocarpine is a tertiary amine alkaloid that is obtained from Pilocarpus, a small shrub. Pilocarpine, which has greater affinity for muscarinic receptors than for nicotinic receptors, can produce all the effects of muscarinic receptor stimulation. Pilocarpine is a second-line drug for the treatment of chronic open-angle glaucoma, in which it lowers intraocular pressure by increasing the outflow of aqueous humor (Box 6-1). It is also used in the treatment of acute angleclosure glaucoma, a medical emergency in which blindness can result if the intraocular pressure is not lowered immediately. The main side effects of ocular pilocarpine administration are decreased night vision, which is caused by miosis, and difficulty in focusing on distant objects, which occurs because the lens is accommodated for close vision. In patients with xerostomia (dry mouth), pilocarpine is administered orally to stimulate salivary gland secretion. Low doses can be used to produce this effect with minimal side effects in many patients because of the high sensitivity of the salivary glands to muscarinic stimulation. Adverse effects include increased sweating, nausea, and visual disturbances caused by druginduced miosis. As with other acetylcholine receptor agonists, cevimeline should be used cautiously in persons with asthma or cardiac arrhythmias. Varenicline is a partial agonist at the nicotinic receptor subtype found in the brain that mediates the reinforcing effects of nicotine in smokers. The drug is used as an aid to smoking cessation and has been found to reduce both the craving and withdrawal effects caused by the absence of nicotine (see Chapter 25). Muscarine is found in mushrooms of the genera Inocybe and Clitocybe, and the consumption of these poisonous mushrooms can cause diarrhea, sweating, salivation, and lacrimation. Muscarine is also found in trace amounts in Amanita muscaria, the original source of muscarine, but the toxicity of this mushroom is largely a result of the ibotenic acid it contains. Nicotine is derived from Nicotiana plants and is contained in cigarettes and other tobacco products. Drugs That Inhibit Cholinesterase the cholinesterase inhibitors prevent the breakdown of acetylcholine at all cholinergic synapses. The shorter-acting drugs are referred to as reversible cholinesterase inhibitors, whereas longer-acting compounds are called quasireversible cholinesterase inhibitors. The properties and clinical uses of inhibitors from each group are outlined in Table 6-3. Varioustypesofdrugscan be used to reduce intraocular pressure before irreversible opticnervedamageoccurs. In this pathway, aqueous humor flows through the ciliary muscles into the suprachoroidalspace. Other types of drugs act by reducing the amount of aqueous humor produced by the ciliary processes. Chapter6 y AcetylcholineReceptorAgonists 59 Reversible Cholinesterase Inhibitors Edrophonium ChemistryandPharmacokinetics. Edrophonium is a positively charged alcohol that reversibly binds to a negatively charged (anionic) site on cholinesterase, but it is not a substrate for the enzyme. The reversible binding and rapid renal excretion of the drug are responsible for its short duration of action (about 10 minutes). Edrophonium prevents the hydrolysis of acetylcholine by cholinesterase, and it rapidly increases acetylcholine concentrations at cholinergic synapses such as the somatic neuromuscular junction. Edrophonium is useful in the initial diagnosis myasthenia gravis and in distinguishing between a myasthenic crisis and a cholinergic crisis in myasthenia patients being treated with a cholinesterase inhibitor such as pyridostigmine (see later). Myasthenia gravis is an autoimmune disease in which antibodies are directed against nicotinic receptors in skeletal muscle. These antibodies inactivate and destroy the receptors and thereby impair neuromuscular transmission, causing severe fatigue. Patients with myasthenia gravis may experience muscle weakness from either undertreatment or overtreatment with a cholinesterase inhibitor drug. In the untreated condition and in patients not receiving adequate doses of the drug, muscle weakness is caused by an acetylcholine deficiency and is called a myasthenic crisis. In this situation, a test dose of edrophonium will increase acetylcholine levels and muscle strength. In patients who are overtreated with a cholinesterase inhibitor, muscle weakness is caused by an excessive amount of acetylcholine at the neuromuscular junction, causing a depolarization blockade similar to that produced by succinylcholine (see Chapter 7). This condition is called a cholinergic crisis, and a test dose of edrophonium will cause the muscle weakness to increase. Physostigmine is a plant alkaloid that is well absorbed from the gut and penetrates the blood-brain barrier. Neostigmine and pyridostigmine are synthetic drugs that exist as positively charged compounds at physiologic pH. Neostigmine and related drugs are substrates for cholinesterase in a manner similar to that of acetylcholine, except that the drug-enzyme intermediate is slowly hydrolyzed (degraded) by the enzyme. While the enzyme is occupied by neostigmine or a related drug, it is unable to hydrolyze acetylcholine, the synaptic concentration of which is thereby increased. When used in the long-term treatment of myasthenia gravis, neostigmine or pyridostigmine improves muscle tone and reduces eyelid and facial ptosis. Although either drug can also reduce diplopia (double vision) and blurred vision, diplopia is relatively resistant to treatment with tolerated doses of these drugs. If excessive doses are used, muscle weakness can increase as a result of a depolarizing neuromuscular blockade resulting from excessive levels of acetylcholine (see earlier). Corticosteroids and other immunosuppressant drugs are used in treating myasthenia and reduce the formation of antibodies to the nicotinic receptor. Thymectomy is sometimes performed to counteract autoimmune mechanisms in persons with myasthenia gravis. Neostigmine, pyridostigmine, and edrophonium are routinely used during surgery to reverse the effects of curariform drugs when muscle relaxation is no longer required (see Chapter 7). Neostigmine has been used in the treatment of postoperative urinary retention and abdominal distention, but other treatments are usually preferred. Physostigmine has been used to treat glaucoma, but other drugs are employed today. The drug is available for parenteral administration as an antidote to counteract seizures and other central nervous system effects caused by an atropine overdose or an overdose of another antimuscarinic drug. Donepezil, galantamine, and rivastigmine are centrally acting, reversible cholinesterase inhibitors that readily cross the blood-brain barrier and act to increase the concentration of acetylcholine at central cholinergic synapses. These drugs are used in the treatment of Alzheimer disease and are discussed in Chapter 24. Quasi-reversible Cholinesterase Inhibitors the quasi-reversible cholinesterase inhibitors are all organophosphate compounds. A few of them, including echothiophate, isoflurophate, and malathion, have been used as therapeutic agents. Most of them are used as pesticides, however, and some of them (such as soman and sarin) were developed as chemical warfare agents. Because of the widespread use of organophosphates as pesticides, they are responsible for cases of accidental and intentional poisoning every year (Box 6-2). Most of these organophosphates are highly lipid soluble and are effectively absorbed from all sites in the body, including the skin, mucous membranes, and gut. Organophosphate toxicity can occur after dermal or ocular exposure or after the oral ingestion of these compounds. The organophosphates form a tight covalently bound intermediate with the catalytic site of cholinesterase. The phosphorylated intermediate is then hydrolyzed very slowly by the enzyme, accounting for the long duration of action of these compounds. The covalently bound intermediate is further stabilized by a spontaneous process called aging, in which a portion of the drug molecule (the "leaving group") is removed.