Metabolism of Ammonia

and its Intoxication

• Ammonia is produced by all tissues during metabolism.

• Ammonia is disposed of primarily by formation of urea in the liver

• Level of ammonia in the blood must be kept very low because even slightly elevated concentrations (Hyperammonemia) are toxic to the central nervous system

• Normal concentration: 25-40 mol/l (0.4-0.7 mg/l)

• Ammonia is toxic to the CNS therefore there must be a metabolic mechanism by which nitrogen is moved from peripheral tissues to the liver

Ammonia

Synthesis of Glutamine in Peripheral Tissue and Transport to the Liver

Summary of sources of ammonia for urea cycle

Transport of Ammonia in the circulation

• Although ammonia is constantly produced in the tissues. It

is present at very low levels in blood. This is due to both:

• The rapid removal of blood ammonia by the liver

• Several tissues particularly release amino acid nitrogen in

the form of glutamine or alanine rather than as free

ammonia

Transport of Ammonia

• Two ways of nitrogen transport from peripheral tissues (muscle) to the liver:

• Alanine cycle: Glutamate is formed by transamination reactions

Glutamate is not

deaminated in

peripheral tissues

The glucose–alanine cycle. P

age

98

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2. Nitrogen can be transported as glutamine.

2. Transportation of ammonia by Gln

CONH2

(CH2)2

CHNH2

COOH

Gln synthetaseCOOH

(CH2)2

CHNH2

COOH

+ NH3

ATP ADP + Pi

Glu GlnGlutaminase

H2O

• After transport in the bloodstream, the glutamine enters the liver and NH4 is liberated in mitochondria by the enzyme glutaminase.

Urea

• Formation of urea in the liver is the most important disposal route for ammonia. Urea travels in the blood from the liver to the kidney

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Major fate of waste nitrogen

O

H2N C NH2urea

Causes of Increased Plasma Level of Ammonia

l ) Decreased urea synthesis and inadequate removal of ammonia

2) Excessive generation of ammonia

Ammonia Intoxication

• This is essential since NH3 is toxic to central nervous system.

• In severely impaired hepatic function, cirrhois, ammonia intoxication develops.

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Krebs citric acid cycle

glutamine

g-aminobutyric acid

acetyl COA

NH3

Glutamic acid

Glycose Glucose-6-phosphate

Pyruvic acid

Lactic acid

Oxaloacetic acid

Citric acid

Succinic acid

a-Ketoglu- taric acid

ATP

Choline Acetylcholine

①Excessive consumption of a- ketoglutaric acid

→ hindering tricarboxylic acid cycle

③Inhibiting activity of pyruvic acid decarboxylase → generation of acetyl coenzyme A↓ →impairing TA cycle

Krebs citric acid cycle ④ Excessive consumption of ATP by synthesis of glutamine

② Excessive consumption reduced coenzyme I → hindering delivery of H+ in respiratory chain →ATP generation↓

l ) Interfering cerebral energy metabolism

ATP

ATP

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2) Changing neurotransmitter in the brain

① Excitative neurotransmitter↓

Glutamic acid consumed by combination with NH3

Inhibition of pyruvic acid decarboxylase by NH3

glutamine

g-aminobutyric acid

acetyl COA

NH3

Glutamic acid

Glycose Glucose-6-phosphate

Pyruvic acid

Lactic acid

Oxaloacetic acid

Citric acid

Succinic acid

a-Ketoglu- taric acid

ATP

Choline Acetylcholine

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.

3) Direct inhibitory effect on neural cell

membrane

Interfere membrane potential and excitation of neuron

by inhibiting Na+-K+-ATPase and competitively inhibit K+

enter cells.

Intoxication of ammonia on the brain Impairment of energy metabolism in brain

• ammonia reacts with α-ketoglutatrate to produce glutamate and glutamine

• consumption of α-ketoglutatrate, NADH and ATP, inhibition of pyruvate decarboxylase leading to the reduction of acetyl CoA and acetylcholine

Alteration of neurotransmitters

• Decreased excitatory neurotransmitters glutamate and acetylcholine

• Increased inhibitory neurotransmitters glutamine and gamma-aminobutyric acid

Inhibiting action on nerve cell membrane

Severe hepatic dysfunction

Urea synthesis

hyperammonemia

Elevated level of brain ammonia

Brain dysfunction

Summary of ammonia intoxication

• Symptoms:

• Tremor, slurred speech, blurred vision, coma

• When ammonia concentration increases in blood and other biological fluİds, it diffuses across blood-brain barrier. It can cause comma and death

Hyperammonemia

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