15B16: Exam Report

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

37.5% of candidates passed this question.

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.

O2i / 15B16: Describe ammonia metabolism & excretion (70 marks). Outline the pharmacology of lactulose (30 marks)

Definition

Ammonia = major metabolic by-product of protein and nucleic acid catabolism

Present in equilibrium body fluid as NH3 and NH4+:

NH3 + H+ ⇔ NH4

  • pKa 9.25 therefore at physiological pH, there is excess of ionised form
  • NH3 diffuses freely
  • NH4 is carried to the liver by active transport
  • Blood Ammonia < 35mmol/L

Ammonia Source

  • Most ammonia is formed in extrahepatic tissues (kidney, intestine)
  • Most ammonia is transported to liver as a-acids
  • XS a-acids are degraded by transamination, deamination and decarboxylation

Ammonia Transport to Liver

2 mechanisms

a) N H 3  + Glutamate  Glutamine synthetase →  Glutamine  →  Liver 

b) Pyruvate → Alanine → Liver

Ammonia Detoxification by Liver

90% of nitrogen enters urea cycle

2NH4+ + CO2⇔Urea + 2H+ + H2O

  1. Formation of CARBAMOYL PHOSPHATE from Ammonia & HCO3
  2. Condensation of carbamoyl phosphate with ORNITHINE → CITRULLINE
  3. Citrulline condenses with ASPARTATE → ARGININOSUCCINATE
  4. Arginosuccinate is hydrolysed to FUMARATE + ARGININE
  5. ARGININE is cleaved → UREA + ORNITHINE
  6. ORNITHINE re-enters mitochondria and combines with CARBAMOYL PHOSPHATE to form CITRULLINE
  7. UREA ⇔25% Enterohepatic Circulation, 75% excreted by kidneys
Mitochondria

The Urea Cycle removes ammonia and irreversibly removes HCO3–

But the whole process is acid-base neutral as the HCO3– made is removed almost as soon as it’s made:

2 a-acids → 2NH4+ + 2HCO3– → Urea/Glutamine

Enterohepatic Circulation

  • Urea diffuses → blood → intestine
  • Bacterial Urase cleaves Urea to liberate NH3 + CO2
  • Some NH3 → feces
  • Some NH3 → reabsorbed into blood → via Enterohepatic Circulation
  • Neomycin ↓bacterial degredation of Urea in intestine

Ammonia/Urea Handling by Kidney

  • Urea constitutes half of solute load in urine
  • Urea freely filtered by glomerulus
  • Half is reabsorbed in PCT
  • An amount equal to reabsorbed portion is secreted back into LoH
  • Half is reabsorbed again in Collecting Duct
  • Overall half filtered load is excreted

Ammoniagenesis From Glutamine

  • Glutamine from liver
  • Taken up by PCT cells
  • In PCT: Glutamine → NH4+ + HCO3–
  • This new HCO3– diffuses into interstitium
  • NH4+ is secreted into tubule lumen via transport exchanger for Na+
  • Eventually it is excreted in urine

Lactulose

Chemical

Non-absorbable synthetic, non digestible dissacharide

OSMOTIC LAXITIVE

Presentation

Tablets, syrup

Dose

30ml bd → qid for Hepatic Encephalopathy

Route

Oral

MoA

A synthetic sugar of Fructose & Galactose

In colon broken down by colonic bacteria to monosaccharides

This ↑osmotic pressure = ↑water retention in stool

Also draws NH3 out of body (same way it draws out H20)

PD

GI: ↑ water retention of stool

PK

A

Not absorbed/no human enzyme can hydrolyse

D

N/A

M

Metabolised by gut bacteria

Metabolites have osmotic & peristaltic effect

Metabolised completely (no lactulose in faeces)

E

Fecal

T1/2 = 2hrs

Adverse Effects

Diarrhoea

Bloating

Gas