Portal bypass

The ammonia produced by enteric bacteria and absorbed into portal venous blood and the ammonia produced by tissues are rapidly removed from circulation by the liver and converted to urea. Only traces (10—20 Ig/dL) thus normally are present in peripheral blood. This is essential, since ammonia is toxic to the central nervous system. Should portal blood bypass the liver, systemic blood ammonia levels may rise to toxic levels. This occurs in severely impaired hepatic function or the development of collateral links between the portal and systemic veins in cirrhosis. Symptoms of ammonia intoxication include tremor, slurred speech, blurred vision, coma, and ultimately death. Ammonia may be toxic to the brain in part because it reacts with a-ketoglutarate to form glutamate. The resulting depleted levels of a-ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons. 

Type A HE is induced by acute liver failure, Type B results from portal-systemic bypass without intrinsic liver disease, and Type C occurs with cirrhosis. HE may be classified as episodic, persistent, or minimal. 

Liver disease may decrease hepatic metabolism resulting in enhanced responses to parent chemicals however, for many compounds, metabolism is only slightly impaired in moderate to severe liver disease. Disease-induced alterations in clearance and volume of distribution often act in opposite directions with respect to their effect on half-life. Bioavailability may be markedly increased in liver disease with portal/systemic anastomosis (the connection of normally separate parts so they intercommunicate) so that orally administered chemicals bypass hepatic first-pass metabolism. Altered receptor sensitivity has been observed for some chemical substances in liver cirrhosis. When liver tissue repair is inhibited by chemical co-exposure, even an inconsequential level of liver injury may lead to fulminating liver failure from a nonlethal exposure of hepatotoxic-ants. (Several articles, as reviewed by Dybing and Spderlund 1999.)... 

The hepatic first-pass effect can be avoided to a great extent by use of sublingual tablets and transdermal preparations and to a lesser extent by use of rectal suppositories. Sublingual absorption provides direct access to systemic—not portal—veins. The transdermal route offers the same advantage. Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena cava, thus bypassing the liver. However, suppositories tend to move upward in the rectum into a region where veins that lead to the liver predominate. Thus, only about 50% of a rectal dose can be assumed to bypass the liver. 

Gastric and oesophageal varices are abnormally dilated collateral vessels in the stomach or oesophagus which arise as a result of increased portal vein pressure (portal hypertension) in cirrhosis or portal vein obstruction. The collateral vessels, or varices, enable blood to bypass... 

Portosystemic collaterals can divert up to 80% of the portal vein blood away from the liver. This initially results in haemodynamic disorders with subsequent (multifactorial) hyperdynamic splanchnic circulation. More and more varices develop around the bypasses in various venous areas, primarily in the form of oesophageal varices. Damage to the mucous membrane in the stomach and in the colon takes the form of hypertensive... 

The occurrence of hepatic encephalopathy (HE) is only possible under the following conditions (1.) a serious (acute or chronic) liver disease, in which the detoxification function is significantly restricted, has to be present, and/or (2.) a functional or anatomic portosystemic collateral circulation must exist — this can be placed surgically or in the form of a TIPS (72, 90) -through which the nondetoxified portal blood bypasses the liver, so that toxic substances can reach the brain. 

Occlusion of the hepatic artery is responsible for a 50% reduction in oxygen supply. Even if an unimpaired oxygen supply via the portal vein is guaranteed, arterial occlusion usually causes ischaemic infarction. The clinical and morphological pictures are characterized (1.) by the speed with which an occlusion develops and (2.) by the presence of variants that can be used as a bypass or of collaterals that have already been established in gradual vascular occlusion. This results in a broad clinical spectrum, which may range from a symptom-free condition to liver hypoxia, including infarction up to hepatic coma. 

Venous bypass Insertion of a combined venovenous and portoven-ous bypass reduces the negative effects of the anhepatic operative phase (lasting 30-120 minutes) by interrupting the blood flow in the portal vein and inferior vena cava. This measure allows greater haemodynamic stability during the anhepatic phase. 

Some drugs may be absorbed into the lymphatic circulation through the lacteal or lymphatic vessels under the microvilli. Absorption of drugs through the lymphatic system bypasses the first-pass effect due to liver metabolism, because drug absorption through the hepatic portal vein is avoided. The lymphatics are important in the absorption of dietary lipids and may be partially responsible for the absorption for some lipophilic drugs such as bleomycin or aclarubicin which may dissolve in chylomicrons and be systemi-cally absorbed via the lymphatic system. 

The portal blood represents the major pathway for the majority of orally administered drugs as it has higher capacity to transport both water soluble and poorly water soluble compounds. During this process, hydrophilic molecules are carried to the liver via the hepatic portal vein, and then by the hepatic artery gain across to the systemic circulation for subsequent delivery to their sites of action. On the other hand, highly lipophilic drugs (log P > 5) that cross the same epithelial barrier are transported to the intestinal lymphatics, which directly delivers them to the vena cava, thereby bypassing the hepatic first-pass metabolism. ... 

Hepatic avoidance using lymphatic output oral DDS. A liver-bypass drug delivery system that promotes absorption redistribution of lipophilic drug from the hepatic portal blood supply to the lymphatic system, thereby avoiding first-pass liver metabolism. 

The first pass effect occurs when medication is administered orally, is absorbed into the GI tract, and enters the bloodstream. Medication particles are transported through the portal vein into the liver, where the medication is metabolized. Medication can bypass the first pass effect by being administered sublingual (under the tongue) or buccal (between the gums and the cheek). These sites absorb medication directly into the bloodstream and avoid the stomach, where medication particles might be destroyed by hydrochloric acid. 

This unusual form of lactic acidosis is due to increased production and accumulation of D-lactate in circulation. The normal isomer synthesized in the human body is L-lactate but the D-lactate isomer can occur in patients with jejunoileal bypass, small bowel resection, or other types of short bowel syndrome. In these patients, ingested starch and glucose bypass the normal metabolism in the small intestine and lead to increased delivery of nutrients to the colon where gram-positive, anaerobic bacteria (e.g., Lactobacilli) ferment glucose to D-lactate. The D-lactate is absorbed via the portal circulation. 

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