Question 16

Describe ammonia metabolism and excretion (70% of marks). Outline the 
pharmacology of lactulose (30% of marks).

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College Answer

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.

Discussion

  • Properties of ammonia:
    • a toxic metabolite of protein and purine synthesis which mainly causes neurological dysfunction and cerebral oedema
    • Ammonia, NH3 is non-polar and can diffuse through lipid bilayers
    • 98% exists in ionised form (ammonium, NH4+) at physiological pH, which is less lipid-soluble and is trapped in water compartments
    • It has a very short half-life (1-4 min) and is metabolised in the liver and resting skeletal muscle
  • The main sources of ammonia in the body are:
    • Amino acid metabolism in the liver and skeletal muscle
    • Purine nucleotide cycle in skeletal muscle
    • Renal tubular synthesis (from glutamine)
    • Urea hydrolysis in the intestine
  • Elimination of ammonia is mainly via hepatic urea cycle metabolism:
    • Ammonia and CO2 are combined to form urea, (NH2)2CO, in an enzyme cycle which recycles ornithine 
    • Only hepatocytes possess the full set of enzymes to complete these reactions
    • Approximately 420 mmol of urea is produced every day
    • Most of this is eliminated in the kidneys
    • Some (~13-30%) undergoes enterohepatic recirculation where urea is excreted into the gut, hydrolysed back into ammonia by gut organisms, is reabsorbed into the portal blood and returns to the liver.

As for "outline the pharmacology of lactulose"...is this what they wanted?

Class Osmotic laxative
Chemistry Disaccharide of glucose and fructose
Routes of administration Oral, rectal (as enema)
Absorption Non-absorbable
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)

References

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).