2. Functions of Chloride
❖Chloride is the major extracellular anion.
❖Functions of Chloride :
1.maintenance osmotic pressure ,acid base balance and electrical
neutrality
2. formation of HCl (provides optimum pH for action of pepsin ,activation of
pepsinogen, kills bacteria )
3. Maintains Homeostasis of Na⁺ ,K ⁺, Cl⁻
4. Activation of Salivary Amylase by Chloride
5. CSF protein content low , high chloride content in CSF is to keep “ Donan
membrane equilibrium )
6.Involved in chloride shift
5. Chloride ion and anion gap
• Sum of bicarbonate ion + chloride ion +10 = sodium ion concentration
• If Sum of bicarbonate ion + chloride ion is far less than sodium ion
concentration ,it may be inferred that possibly there has been addition of
substantial amounts of another anion (anion gap)
• anion gap is seen in lactic acidosis or diabetes ketoacidosis where lactate
or ketone bodies ( acetoacetate and – hydroxy butyrate ) anions fill the
anion gap respectively.
11. Chloride shift in systemic capillaries
In systemic capillaries
• Carbon dioxide is generated by cellular metabolism.
• Carbon dioxide diffuses from tissue to plasma and RBC.
• In RBC ,water and Carbon dioxide combine to form carbonic acid.
• carbonic acid dissociates to give hydrogen (H+ and bicarbonate ions (HCO3-.
• reduced Hb buffers (H+ and (HCO3-.
• Concentration of (HCO3- builds inside RBC.
• (HCO3- diffuses from tissue into plasma and chloride shifts into RBC.
• In pulmonary capillaries the process is reversed.
• Maintenance of electric balance : phenomenon is called Chloride shift
( catalysis by carbonic anhydrase
12. Chloride shift in systemic capillaries
In systemic capillaries
Carbon dioxide is generated by cellular metabolism
Carbon dioxide diffuses from tissue to plasma and RBC
In RBC ,water and Carbon dioxide combine to form carbonic acid
Carbonic acid dissociates to give hydrogen (H+ and bicarbonate ions (HCO3-
Reduced Hb buffers (H+ and (HCO3-
Concentration of (HCO3- builds inside RBC
(HCO3- diffuses from tissue into plasma and chloride shifts into RBC
In pulmonary capillaries the process is reversed. *
Maintenance of electric balance : phenomenon is called Chloride shift
13. Chloride shift in pulmonary capillaries
* In pulmonary capillaries
• (HCO3- diffuses into RBC and chloride shifts into plasma.
• In RBC , bicarbonate ions (HCO3- combine with hydrogen (H+
released from reduced Hb to form carbonic acid.
• carbonic acid dissociates to give hydrogen (H+ and Carbon dioxide.
• Carbon dioxide diffuses from RBC to plasma to be exhaled by alveoli of
lung.
• ( catalysis by carbonic anhydrase
14. Chloride shift in pulmonary capillaries
*In pulmonary capillaries
(HCO3- diffuses into RBC and chloride shifts into plasma
In RBC , bicarbonate ions (HCO3- combine with hydrogen (H+ released from reduced Hb
to form carbonic acid.
Carbonic acid dissociates to give hydrogen (H+ and carbon dioxide
Carbon dioxide diffuses from RBC to plasma to be exhaled by alveoli of lung
16. Absorption and excretion of Chloride
• Dietary Chloride : absorbed completely by the intestinal tract
• It is filtered out by glomerulus and passively absorbed in conjunction
with sodium by proximal tubules.
• Excess Chloride ions are excreted in urine and through sweating .
• Excess sweating stimulates Aldosterone secretion ,which acts on
sweat glands to conserve sodium and Chloride ions.
21. Cystic Fibrosis
❖Cystic Fibrosis (CF is a multisystem disease that presents
• in neonates ,with failure to pass the first feces containing bile,
intestinal debris and mucus ( meconium ileus
• in early childhood with respiratory infections
• in the adults
❖Inheritance of Cystic Fibrosis (CF : autosomal recessive disorder
22. Pathogenesis of Cystic Fibrosis
❖Cystic Fibrosis arises due to mutations in gene located on
chromosome 7 encoding the Cystic Fibrosis transmembrane regulator
(CFTR protein that regulates transmembrane chloride transport .
❖ The most common mutation is F 508 mutation which refers to
deletion of three base pairs , resulting in the absence of Phenylalanine at
position 508 in amino acid sequence of CFTR .
23. Clinical Consequences of Cystic Fibrosis
Absence of Cystic Fibrosis transmembrane regulator (CFTR /chloride
channel leads to following Consequences :
• Exocrine pancreatic insufficiency with impaired secretion of sodium,
bicarbonates and water resulting in increased viscosity (mucoviscoidosis
,obstruction of pancreatic duct , pancreatic fibrosis and obstruction of
pancreatic tissue.
• Chronic airways infection that affects mucus secretion in the bronchi with
recurrent respiratory infections ,bronchiectasis and chronic lung disease
• Malabsorption ,cirrhosis of liver and cholelithiasis due to defective
secretion of chloride and water
• abnormal sweat gland function due to excessive excretion of sodium and
chloride in sweat
• Abnormal urogenital functions
26. Diagnosis of Cystic Fibrosis
❖Diagnosis of Cystic Fibrosis is based on
• Clinical symptoms
• Measurement of pilocarpine induced sweat electrolyte concentration:
Na ⁺ and Cl⁻ in sweat ( 70 mmols /L or mequ /L )
• Neonatal screening test : increased plasma immunoreactive trypsin
• prenatal screening test : for F 508 mutation
30. Management of Cystic Fibrosis
Management of Cystic Fibrosis involves
• Prevention of respiratory infection by antibiotics and physiotherapy
• Maintenance of proper nutrition and pancreatic enzymes in diet
32. Achlorhydria
• Achlorhydria refers to absence of HCL in gastric secretion.
• Physiological Achlorhydria :Aging
• Pathological Achlorhydria
1. Tuberculosis
2. Gastritis
3. Gastric carcinoma
4. Terminal stages of malignancy
33. Hyperchlorhydria
❖ Hyperchlorhydria refers to increase in concentration free acid .
The combined acidity may be normal.
• Hyperchlorhydria is common in
a) Duodenal ulcers
b) Zollinger Ellison syndrome
35. Achylia Gastrica
• Achylia Gastrica refers to the absence of both acids and pepsin and
is associated with pernicious anemia.
36. CTFR and Cholera
❖Cholera is due to trapping of G –protein in the active confirmation by
Cholera toxin - Choleragen, secreted by the intestinal bacteria Vibrio Cholera .
Cholera : acute diarrhea disease that can be life threatening .
It causes the secretion of electrolytes and fluids in large amounts from intestine of the
infected person.
37. Mechanism of action of Cholera toxin - Choleragen
• Cholera toxin – Choleragen has two functional subunits :
B- subunit that bind to GM -1 gangliosides of intestinal epithelial cells
A- subunit that has catalytic activity and enters the cell.
After entering cell it catalyzes the covalent modification of a Gs protein.
G s protein is a subunit of G-protein , s in subscript indicates stimulatory role
of subunit of G-protein.
This modification traps the G-protein in the active conformation, which
activates adenylate cyclase and formation of c-AMP, which in turn activates
protein kinase A (PKA).
Protein kinase A (PKA) opens chloride channel, which are called CTFR Cystic
Fibrosis transmembrane regulator (CFTR .
38. Mechanism of action of Cholera toxin - Choleragen
CTFR and Cholera:
CTFR acts as an ATP regulated chloride channel in the plasma membrane of epithelial
cells.
Opening of chloride channel leads to inhibition Na+ –H + exchanger by phosphorylation.
This ultimately leads to an excessive loss of Na+ in the form of NaCl along with loss of
large amount of water into the intestine.
❖Management of cholera : rehydration with glucose electrolyte solution
39. Mechanism of action of Cholera toxin – Choleragen:1
Cholera toxin – Choleragen has two functional
subunits :
B- subunit that bind to GM -1 gangliosides of
intestinal epithelial cells
A- subunit that has catalytic activity and enters the
cell.
After entering cell it catalyzes the covalent
modification of a Gs protein.
G s protein is a subunit of G-protein , s in subscript
indicates stimulatory role of subunit of G-protein.
40. Mechanism of action of Cholera toxin – Choleragen-2
Covalent modification of a Gs protein traps the G-protein in the
active conformation.
Activation of adenylate cyclase by active G-protein and
formation of c-AMP
Activation protein kinase A (PKA) by c-AMP
Opening of chloride channel (are called CTFR Cystic Fibrosis
transmembrane regulator -CFTR by active Protein kinase A
(PKA)
41. Mechanism of action of Cholera toxin – Choleragen:3
CTFR acts as an ATP regulated chloride channel in the plasma
membrane of epithelial cells.
Opening of chloride channel leads to inhibition Na+ –H+
exchanger by phosphorylation.
This ultimately leads to an excessive loss of Na+ in the form of
NaCl along with loss of large amount of water into the intestine.
Management of cholera : rehydration with glucose electrolyte
solution
