Describe ammonia metabolism and excretion (70% of marks). Outline the
pharmacology of lactulose (30% of marks).
It was expected candidates would identify sources of ammonia (colon from metabolism of proteins, kidney, small amounts from breakdown of red blood cells and metabolism in muscles). The liver converts all circulating ammonia to urea (the urea cycle) (2NH3+CO2 = urea +H2O). Urea then undergoes enterohepatic circulation (25%) or is excreted by kidneys (75%). Ammonia (NH3) is lipid soluble and diffuses into the interstitial cell and tubular fluid by non-ionic diffusion where is buffers H+ to become non diffusible NH4+. No candidate mentioned enterohepatic circulation and most answers had very little detail on the metabolism and excretion and lacked depth.
Lactulose is a non absorbable synthetic, non-digestible disaccharide. It is an osmotic laxative fermented by gut flora producing metabolites (such as acetate) which have osmotic and peristalsis-stimulating effects, and methane causing in flatulence.
Few could describe how lactulose decrease absorption of ammonia and a surprising number of people did not even state that lactulose was an osmotic laxative.
As for "outline the pharmacology of lactulose"...is this what they wanted?
|Chemistry||Disaccharide of glucose and fructose|
|Routes of administration||Oral, rectal (as enema)|
|Solubility||pKa 10.28; highly water-soluble|
|Distribution||Not absorbed; remains in the bowel|
|Target receptor||Does not bind to any receptors|
|Metabolism||Undergoes metabolism by gut bacteria only|
|Elimination||Eliminated in the stool, as metabolic byproducts, gas (methane), and unchanged drug|
|Time course of action||Elimination half-life is about 2 hours; duration of effect may be up to 4-8 hours|
|Mechanism of action||By increasing the osmolality of stool, increases the water content of stool (i.e. prevents the reabsorption of water in the bowel).
Also, by acting as a metabolic substrate, has the effect of diverting bacterial metabolism to the production of non-nitrogenous metabolites, which is beneficial in hepatic encephalopathy
|Clinical effects||Abdominal distension, flatulence, water loss though diarrhoea, electrolyte derangement, volume depletion, malabsorption of nutrients|
|Single best reference for further information||Clausen et al (1997)|
Sharp, Joe C. "Properties of ammonia." Agricultural anhydrous ammonia technology and use (1966): 21-31.
Walker, Valerie. "Ammonia metabolism and hyperammonemic disorders." Advances in clinical chemistry 67 (2014): 73-150.
Adeva, Maria M., et al. "Ammonium metabolism in humans." Metabolism 61.11 (2012): 1495-1511.
Mohiuddin, Shamim S., and Divya Khattar. "Biochemistry, ammonia." (2019).