The Chloride Ion (DB14547): A Comprehensive Monograph on its Physicochemical Properties, Physiological Functions, and Clinical Significance

Section 1: Introduction: Beyond a Simple Molecule

The chloride ion (Cl−), cataloged in the DrugBank database as DB14547, represents a unique entry in the pharmacological compendium.[1] Unlike conventional therapeutic agents, which are typically xenobiotic compounds designed to elicit a specific biological response, chloride is the most abundant extracellular anion in the human body, a fundamental electrolyte indispensable for life.[3] Its classification as an investigational "Small Molecule" within such a database stems not from a primary pharmacological activity in the traditional sense, but from its ubiquitous presence in a vast array of therapeutic formulations, where it serves as a counter-ion, an essential component of intravenous hydration solutions, or as part of an active pharmaceutical ingredient.[1]

The presence of chloride ion in listings for clinical trials for conditions ranging from urinary tract infections to various cancers can be misleading.[7] A detailed examination reveals that in these contexts, chloride is not the substance under investigation. Instead, it is a constituent of the therapeutic regimen—for example, as the counter-ion in chlorhexidine, a ligand in the cisplatin molecule, or the principal anion in the 0.9% sodium chloride (saline) solution used as a vehicle for drug delivery or for patient hydration.[7] This distinction is critical: chloride's

pharmacological presence in a formulation is distinct from its pharmacological activity. Therefore, a comprehensive understanding of chloride requires a multi-faceted approach that views it simultaneously as a chemical entity, a key physiological regulator, a diagnostic marker, a therapeutic component, and a central figure in numerous pathologies. The central theme unifying these perspectives is the critical importance of maintaining chloride homeostasis—the delicate balance of chloride concentration across body compartments—for human health.[11]

This report provides an exhaustive analysis of the chloride ion. It begins by defining its fundamental chemical and physical properties before delving into its indispensable and diverse physiological roles. The subsequent sections will detail the body's complex systems for handling chloride (absorption, distribution, and excretion), the molecular machinery of its transport across cell membranes, its significance in clinical diagnostics and therapeutics, the pathophysiology of its imbalance, and its toxicological profile. The report will conclude by synthesizing these elements to provide a holistic understanding of this vital ion.

Section 2: Identification and Physicochemical Profile

2.1. Nomenclature and Identifiers

To establish a comprehensive identity, the chloride ion is recognized across numerous scientific and regulatory databases by a standardized set of names and identifiers.

• Systematic IUPAC Name: chloride [2]
• Synonyms: The ion is referred to by a variety of synonyms, including Chloride ion, Chloride(1-), Chlorine anion, Perchloride, and Hydrochloric acid, ion(1-).[1]
• Key Database Identifiers:
• CAS Registry Number: 16887-00-6 [1]
• DrugBank Accession Number: DB14547 [1]
• PubChem Compound ID (CID): 312 [2]
• ChEBI ID: CHEBI:17996 [2]
• FDA UNII: Q32ZN48698 [2]
• Human Metabolome Database (HMDB) ID: HMDB0000492 [2]
• KEGG ID: C00698 [2]
• MeSH Entry Terms: Chloride, Chlorides, Chloride Ion Level [2]

2.2. Chemical Structure and Properties

The chloride ion is formed when an atom of the element chlorine (atomic number 17), a member of the halogen group, gains a single electron to achieve a stable electron configuration, a process known as reduction.[2] This results in a monoatomic anion with a formal charge of -1.[2] The resulting ion (

Cl−) is significantly larger (diameter 167 pm) than a neutral chlorine atom (diameter 99 pm) due to the additional electron in its valence shell.[3] The ion is colorless and diamagnetic.[3]

While physical properties such as melting point (247-248 °C, with decomposition) and boiling point (62.7 °C) are cited in chemical catalogs, it is important to note that these values pertain to specific "CHLORIDE STANDARD" solutions (e.g., aqueous solutions for analytical chemistry) and not to the ion in an isolated or solid state.[15] In biological systems and therapeutic formulations, the chloride ion exists in solution, typically in water, where it is highly soluble when paired with common cations to form salts such as sodium chloride (NaCl), potassium chloride (KCl), and calcium chloride (

CaCl2​).[3]

Table 1: Key Identifiers and Physicochemical Properties of the Chloride Ion

Property/Identifier	Value	Reference(s)
Generic Name	Chloride ion	1
Systematic IUPAC Name	chloride	2
CAS Number	16887-00-6	1
DrugBank ID	DB14547	1
PubChem CID	312	2
ChEBI ID	CHEBI:17996	2
UNII	Q32ZN48698	2
Molecular Formula	Cl−	3
Average Mass	35.45 g/mol	2
Monoisotopic Mass	34.969401 Da	16
Formal Charge	-1	16
SMILES	[Cl-]	2
InChIKey	VEXZGXHMUGYMC-UHFFFAOYSA-M	2

Section 3: The Indispensable Physiological Roles of Chloride

Chloride is classified as an essential dietary mineral and a key macromineral, constituting approximately 0.15% of total body weight in an average adult.[3] It is the most abundant anion in the extracellular fluid (ECF), where its presence is fundamental to a wide spectrum of physiological processes. Its roles extend far beyond simple charge balancing, making it an active and critical participant in maintaining systemic homeostasis.[3]

3.1. Fluid Balance and Osmotic Homeostasis

The most prominent role of chloride is in the regulation of fluid balance and osmotic pressure.[3] As the principal anion in the ECF, it accounts for approximately 70% of the total negative charge and contributes to about one-third of the ECF's tonicity.[3] The concentration of chloride in blood plasma is maintained within a narrow range, typically around 100 mM.[3]

In concert with sodium, the primary extracellular cation, chloride is a major determinant of osmotic pressure. This osmotic force governs the movement of water across cell membranes between the intracellular and extracellular compartments.[4] This regulation is vital for maintaining proper cell volume, which prevents cells from shrinking or swelling excessively, and for controlling the overall volume of the ECF, which directly impacts blood volume and blood pressure.[28] Much of this effect is achieved because chloride passively follows the active transport of sodium to maintain electroneutrality, a foundational principle of electrolyte physiology.[26]

3.2. Acid-Base Regulation

Chloride is integral to maintaining the body's acid-base balance, ensuring that blood pH remains within the narrow physiological range of 7.35 to 7.45.[3] Its most critical function in this regard is the

chloride-bicarbonate shift, also known as the "Hamburger shift".[24] This process occurs in red blood cells and is the linchpin connecting the respiratory and metabolic systems for acid-base control. As carbon dioxide (

CO2​) produced by tissues diffuses into red blood cells, the enzyme carbonic anhydrase rapidly converts it to carbonic acid (H2​CO3​), which then dissociates into a hydrogen ion (H+) and a bicarbonate ion (HCO3−​). To prevent the buildup of bicarbonate within the cell and to facilitate its transport in the plasma, a specific anion exchanger protein transports bicarbonate out of the red blood cell in exchange for a chloride ion moving in.[24] This exchange maintains electrical neutrality and allows the blood to carry large amounts of

CO2​ in the form of bicarbonate to the lungs, where the process reverses for exhalation. This single, chloride-dependent mechanism is a physiological nexus, directly linking respiratory gas exchange (CO2​ transport), metabolic acid-base status (plasma HCO3−​ levels), and renal regulation of electrolytes.[24]

This exchange establishes an inverse relationship between plasma chloride and bicarbonate concentrations; to maintain electroneutrality, a rise in one is typically compensated by a fall in the other.[24] This relationship is clinically vital for diagnosing acid-base disorders using the

anion gap, calculated as [Na+]−([Cl−]+[HCO3−​]). A normal anion gap in the presence of metabolic acidosis often points to a primary loss of bicarbonate, which is compensated by a rise in chloride (hyperchloremic metabolic acidosis).[24]

3.3. Neurotransmission and Electrical Excitability

Chloride homeostasis is of paramount importance for the proper functioning of the central nervous system (CNS).[12] While often described as passively following sodium in bulk fluid dynamics, in the nervous system, the regulated movement of chloride is an independent and primary driver of function. The concentration gradient of chloride across the neuronal membrane dictates the nature of the response to key neurotransmitters like

γ-aminobutyric acid (GABA) and glycine.[35]

In most mature neurons, intracellular chloride concentration is kept low by transporters such as KCC2, resulting in a chloride equilibrium potential (ECl​) that is more negative than the resting membrane potential.[3] Consequently, when ligand-gated anion channels like the GABA-A receptor or glycine receptor are activated, they open a pore permeable to chloride. The resulting influx of negatively charged chloride ions causes the neuronal membrane to hyperpolarize (become more negative), generating an

Inhibitory Postsynaptic Potential (IPSP).[12] This IPSP makes it more difficult for the neuron to reach the threshold for firing an action potential, thus mediating fast synaptic inhibition, a process fundamental to neural coding, information processing, and preventing over-excitation that can lead to seizures.[12]

Chloride is also crucial for the function of glial cells, which support neurons. In astrocytes and microglia, chloride channels are involved in cell volume regulation, neurotransmitter uptake, and mediating inflammatory responses.[12] Furthermore, neurons can modulate their own excitability by regulating chloride flux through channels like ClC-2, demonstrating chloride's dynamic role in shaping neural circuits.[37]

3.4. Gastrointestinal and Exocrine Function

In the gastrointestinal system, chloride performs several vital functions. It is an indispensable component of gastric acid. Parietal cells in the stomach lining actively secrete hydrogen ions and chloride ions into the stomach lumen, forming hydrochloric acid (HCl).[3] This highly acidic environment (maintaining a chloride concentration of ~150 mM) is essential for the digestion of proteins by activating pepsin and for killing ingested pathogens.[4]

Chloride channels are also abundant in the pancreas and the epithelial lining of the intestines, where they are critical for regulating the secretion of fluids.[30] The movement of chloride ions out of epithelial cells creates an electrical gradient that drives the paracellular movement of sodium and, consequently, the osmotic movement of water into the lumen. This process is essential for producing pancreatic juice and for hydrating the mucus layer that protects and lubricates the intestinal surface.[30] The profound consequences of dysfunctional chloride transport are starkly illustrated by the genetic disease

cystic fibrosis, which is caused by mutations in the CFTR chloride channel. The resulting defect in chloride and fluid secretion leads to thick, sticky mucus that obstructs airways and pancreatic ducts, causing severe respiratory and digestive complications.[30]

Section 4: Pharmacokinetics: The Physiological Handling of a Core Electrolyte

The principles of pharmacokinetics—Absorption, Distribution, Metabolism, and Excretion (ADME)—are typically applied to xenobiotics. For an endogenous and essential ion like chloride, this framework is adapted to describe the body's sophisticated homeostatic mechanisms that regulate its concentration and movement.[40]

4.1. Absorption (Gastrointestinal Handling)

Dietary chloride is absorbed with high efficiency along the length of the intestine, primarily in the small intestine and colon.[4] Three principal mechanisms facilitate this absorption [42]:

1. Paracellular Pathway: This is a passive process, predominant in the leaky epithelium of the small intestine. The active absorption of sodium and other solutes creates a favorable electrochemical gradient that drives chloride movement between the epithelial cells, from the lumen into the bloodstream.[42]
2. Electroneutral NaCl Absorption: This is the primary mechanism for chloride absorption in the ileum and colon. It involves the coordinated action of two types of exchangers on the apical (luminal) membrane of enterocytes: a sodium-hydrogen (Na+/H+) exchanger (e.g., NHE3) and a chloride-bicarbonate (Cl−/HCO3−​) exchanger (e.g., SLC26A3/DRA). The net result is the absorption of both sodium and chloride from the intestinal lumen.[42]
3. HCO3−​-dependent Cl− Absorption: A third, less characterized pathway exists that is dependent on bicarbonate but is not directly coupled to the Na+/H+ exchanger.[42]

The overall process of chloride absorption is regulated by various neuroendocrine signals, including the hormone aldosterone and inputs from the enteric nervous system.[45]

4.2. Distribution

Once absorbed, chloride is distributed throughout the body, but its concentration varies dramatically between compartments. It is predominantly an extracellular ion. The ECF, including blood plasma and interstitial fluid, maintains a high chloride concentration of approximately 94-110 mM.[4] In contrast, the

intracellular chloride concentration is kept much lower in most cells, typically ranging from 5 to 100 mM depending on the specific cell type and its function.[3] This steep concentration gradient is actively maintained by various ion transporters and is the potential energy source for many of chloride's physiological roles, most notably in neuronal inhibition. An average 70 kg adult human body contains a total of about 115 grams of chloride.[4]

4.3. Metabolism

As a fundamental, monoatomic ion, chloride does not undergo metabolism in the conventional pharmacological sense. It is not enzymatically converted into other molecules or metabolites.[41] Its biological activity is entirely dependent on its concentration, its electrochemical potential, and its regulated transport across cellular membranes.

4.4. Excretion and Homeostatic Regulation (Renal Handling)

The kidneys are the ultimate regulators of chloride homeostasis, meticulously adjusting excretion to match dietary intake and maintain stable plasma concentrations.[3] The renal handling of chloride is a complex, segment-specific process that is tightly linked to sodium handling.[47]

The kidney's strategy for chloride reabsorption showcases a sophisticated physiological design. It employs an energy-efficient, passive mechanism for bulk reabsorption in the proximal tubule, followed by a powerful, energy-intensive active transport system in the thick ascending limb for the specialized function of urine concentration and dilution. This dual approach is not only physiologically elegant but also provides distinct targets for pharmacological intervention, such as loop diuretics.

• Glomerular Filtration: Chloride is freely filtered from the blood into the tubular fluid at the glomerulus.[48]
• Tubular Reabsorption: Under normal conditions, over 99% of the filtered chloride is reabsorbed back into the blood.[4]
• Proximal Tubule: This segment reabsorbs the majority (over 60%) of the filtered chloride. This process is largely passive. In the early proximal tubule, the avid reabsorption of bicarbonate, glucose, and amino acids, along with osmotically obliged water, leads to a significant increase in the concentration of chloride in the remaining tubular fluid. This creates a strong concentration gradient that drives the passive diffusion of chloride through the paracellular pathway (between cells) into the peritubular fluid in the later parts of the proximal tubule.[4]
• Thick Ascending Limb of the Loop of Henle (TALH): This segment is a major site of active chloride reabsorption and is impermeable to water. The key transporter here is the apical Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2), which moves one sodium ion, one potassium ion, and two chloride ions from the tubular lumen into the cell. Chloride then exits the cell across the basolateral membrane through chloride channels (e.g., ClC-NKB).[48] This powerful mechanism is a primary target of loop diuretics like furosemide.
• Distal Convoluted Tubule (DCT): Chloride is reabsorbed along with sodium via the apical Na⁺-Cl⁻ cotransporter (NCC), which is the target of thiazide diuretics.[48]
• Collecting Duct: This final segment fine-tunes chloride excretion. Reabsorption can occur passively through the paracellular route, driven by the electrical gradient created by sodium reabsorption through the ENaC channel. Additionally, specialized intercalated cells utilize the pendrin transporter, a Cl−/HCO3−​ exchanger, to mediate chloride reabsorption.[48]
• Hormonal Control: The hormone aldosterone, acting on the distal tubule and collecting duct, enhances the reabsorption of sodium and, consequently, chloride, playing a crucial role in the long-term regulation of chloride balance and blood pressure.[4]

Section 5: Pharmacodynamics: Molecular Mechanisms of Chloride Transport

The physiological effects of chloride are mediated by a diverse array of membrane proteins—channels and transporters—that facilitate its movement across biological membranes. These proteins represent the "pharmacodynamic" targets for both endogenous regulation and pharmacological modulation, and defects in their function are the basis of numerous genetic diseases known as channelopathies.[52]

5.1. Overview of Chloride Transport Proteins

Chloride movement is governed by two main classes of proteins: channels, which form pores that allow the passive diffusion of chloride down its electrochemical gradient at high rates, and transporters (or carriers), which bind chloride and undergo conformational changes to move it across the membrane, often coupling its transport to that of another ion (cotransport or exchange) or an energy source.[55] These proteins are expressed not only on the cell surface but also on the membranes of intracellular organelles, where they are crucial for processes like acidification.[58]

5.2. The ClC Family of Channels and Exchangers

The ClC family is a structurally and functionally diverse group of chloride-transporting proteins found in virtually all organisms.[55] They function as dimers, with each subunit forming its own independent ion translocation pathway.[55] A remarkable feature of this family is that while all members share a common architectural fold, some function as bona fide chloride channels, while others operate as chloride/proton (

2Cl−/H+) exchangers.[55]

• ClC-1: This is a voltage-gated chloride channel predominantly expressed in the sarcolemma of skeletal muscle. Its primary function is to stabilize the resting membrane potential and facilitate rapid repolarization after an action potential. This high chloride conductance is necessary to counteract the accumulation of potassium in the T-tubules during repeated muscle contractions. Loss-of-function mutations in the gene encoding ClC-1 cause myotonia congenita, a disorder characterized by muscle stiffness and delayed relaxation.[57]
• ClC-Ka and ClC-Kb: These are closely related chloride channels found almost exclusively in the kidney and the inner ear. They require an accessory β-subunit, barttin, for proper function and trafficking to the cell membrane. In the thick ascending limb of Henle's loop and the distal convoluted tubule, ClC-Kb is crucial for basolateral chloride exit, a key step in renal salt reabsorption. In the inner ear, both channels are essential for the secretion of potassium into the endolymph, a process required for hearing. Mutations in the gene for ClC-Kb cause Bartter syndrome type III (a salt-wasting renal disorder), while mutations in the gene for barttin cause Bartter syndrome type IV, which presents with both salt wasting and congenital deafness.[57]
• ClC-5: This protein is a 2Cl−/H+ exchanger located in the membranes of early endosomes, particularly in the proximal tubule cells of the kidney. It is vital for the process of endocytosis, likely by facilitating endosomal acidification. Mutations in the gene for ClC-5 cause Dent's disease, an X-linked disorder characterized by low-molecular-weight proteinuria and kidney stones.[60]
• ClC-7: This is another 2Cl−/H+ exchanger, primarily located in the membranes of lysosomes and at the ruffled border of bone-resorbing osteoclasts. It requires the Ostm1 β-subunit for function. In osteoclasts, ClC-7 is essential for the acidification of the resorption lacuna, a process necessary for dissolving bone mineral. Loss-of-function mutations in either ClC-7 or Ostm1 cause osteopetrosis, a severe genetic disease characterized by dense, brittle bones, along with neurodegeneration and retinal degeneration.[60]

5.3. Other Major Chloride Channels and Transporters

Beyond the ClC family, several other protein families are critical for chloride transport and physiology.

• CFTR (Cystic Fibrosis Transmembrane Conductance Regulator): A member of the ABC transporter superfamily, CFTR functions as an ATP-gated chloride channel. It is expressed in the apical membrane of epithelial cells in many organs, including the lungs, pancreas, intestines, and sweat glands. Its primary role is to secrete chloride, which drives fluid secretion. Mutations in the CFTR gene cause cystic fibrosis.[59]
• Ligand-Gated Anion Channels: This class includes the GABA-A and glycine receptors, which are pentameric channels central to fast inhibitory neurotransmission in the CNS. Binding of their respective neurotransmitters opens an intrinsic chloride channel, leading to an IPSP in mature neurons.[12]
• Solute Carrier (SLC) Family Transporters: This large family includes several anion exchangers vital for chloride homeostasis. The SLC26 family (e.g., SLC26A3/DRA) and SLC4 family mediate chloride-bicarbonate exchange in the intestines and kidneys, which is essential for chloride absorption and acid-base balance. Mutations in SLC26A3 cause congenital chloride diarrhea.[42]

Table 2: Summary of Major Chloride Channels and Transporters, Their Location, and Physiological Function

Protein/Family	Primary Location(s)	Primary Function	Associated Channelopathy/Disease	Reference(s)
ClC-1	Skeletal muscle	Membrane repolarization, stabilizes potential	Myotonia congenita	57
ClC-2	Ubiquitous; CNS, epithelia	Cell volume regulation, neuronal [Cl−]i​	Leukodystrophy, azoospermia	57
ClC-Ka/Kb (+ barttin)	Kidney (nephron), Inner ear	Renal salt reabsorption, endolymph secretion	Bartter syndrome (types III & IV)	57
ClC-5	Kidney (proximal tubule endosomes)	Endosomal acidification, endocytosis	Dent's disease	60
ClC-7 (+ Ostm1)	Lysosomes, Osteoclasts	Bone resorption, lysosomal function	Osteopetrosis, neurodegeneration	60
CFTR	Epithelial cells (airway, gut, etc.)	Chloride and fluid secretion	Cystic fibrosis	59
GABA-A/Glycine Receptors	CNS (postsynaptic membranes)	Fast inhibitory neurotransmission	Epilepsy, hyperekplexia	12
CaCCs (e.g., TMEM16A)	Smooth muscle, Epithelia	Smooth muscle contraction, fluid secretion	(Associated with various pathologies)	61
VRACs	Ubiquitous	Regulatory volume decrease (cell swelling)	(Associated with various pathologies)	62
SLC26A3 (DRA)	Colon, Ileum	Intestinal Cl−/HCO3−​ exchange	Congenital chloride diarrhea	43

Section 6: Clinical Significance and Therapeutic Applications

The central role of chloride in physiology translates directly into its importance in clinical medicine, where it serves as a key diagnostic marker and is a fundamental component of many therapeutic interventions.

6.1. Chloride as a Diagnostic Marker

The measurement of chloride concentration in blood and urine is a routine and vital part of clinical assessment.

• Serum and Urine Chloride Tests: A chloride blood test measures the concentration in the serum and is almost always included in a basic or comprehensive metabolic panel, alongside other key electrolytes like sodium, potassium, and bicarbonate.[46] A urine chloride test can also be performed, often to help determine the cause of an acid-base or fluid balance disorder.[64]
• Normal Ranges: The typical reference range for serum chloride in adults is 96 to 107 milliequivalents per liter (mEq/L or mmol/L).[46] Ranges may be slightly different for children (95-112 mmol/L) and newborns (96-113 mmol/L), and minor variations can exist between laboratories.[64]
• Interpretation of Abnormal Levels: Abnormal chloride levels are rarely an isolated finding and must be interpreted in the context of the patient's clinical condition and other electrolyte values.
• Hyperchloremia (high levels) can be indicative of dehydration, kidney disease (especially renal tubular acidosis), or metabolic acidosis.[46]
• Hypochloremia (low levels) may suggest conditions such as congestive heart failure, chronic lung diseases, Addison's disease, or metabolic alkalosis, often resulting from fluid loss via prolonged vomiting or diuretic use.[46]

6.2. Therapeutic Formulations: Chloride as a Constituent

Chloride is a primary component of many of the most commonly used medical solutions.

• Sodium Chloride (Saline) Solutions: Intravenous solutions of sodium chloride are cornerstones of fluid and electrolyte therapy.
• Isotonic Saline (0.9% NaCl): Often called "normal saline," this solution is isotonic with respect to body fluids and is widely used for fluid resuscitation in cases of dehydration, hemorrhage, or shock. It is also the most common vehicle for the parenteral administration of compatible drugs.[72]
• Hypotonic Saline (e.g., 0.45% NaCl): Used to treat cellular dehydration and hypernatremia, as it provides more water than salt, causing fluid to shift into cells.[74]
• Hypertonic Saline (e.g., 3% or 5% NaCl): Used cautiously in critical care settings to treat severe, symptomatic hyponatremia and to reduce cerebral edema by drawing water out of brain cells.[74]
• Potassium Chloride Solutions: The primary therapeutic use of potassium chloride, available in both oral and intravenous forms, is the prevention and treatment of hypokalemia (low potassium levels).[79]
• Balanced Crystalloid Solutions: Solutions like Lactated Ringer's and Plasma-Lyte contain chloride, but at concentrations closer to that of human plasma, along with a buffer (lactate or acetate) that is metabolized to bicarbonate. They are increasingly preferred for large-volume resuscitation to avoid the hyperchloremic acidosis associated with large volumes of 0.9% saline.[74]

Table 3: Composition and Clinical Uses of Common Intravenous Crystalloid Solutions

Solution Name	Type	Composition (mmol/L)	Osmolarity (mOsm/L)	Primary Clinical Uses	Key Clinical Considerations	Reference(s)
0.9% NaCl (Normal Saline)	Isotonic	Na⁺ 154, Cl⁻ 154	~308	Fluid resuscitation (hemorrhage, shock), treatment of mild hyponatremia, vehicle for drug delivery	Risk of hyperchloremic metabolic acidosis with large volumes. Caution in heart or renal failure.	74
Lactated Ringer's (LR)	Isotonic	Na⁺ 130, Cl⁻ 109, K⁺ 4, Ca²⁺ 3, Lactate 28	~273	Fluid resuscitation (burns, trauma, GI losses), surgery, treatment of metabolic acidosis	Contains potassium; use with caution in renal failure. Lactate is metabolized by the liver.	74
0.45% NaCl (Half-Normal Saline)	Hypotonic	Na⁺ 77, Cl⁻ 77	~154	Treatment of cellular dehydration and hypernatremia, maintenance fluid	Can cause fluid to shift into cells, risking cerebral edema. Can worsen hypovolemia and hypotension.	74
5% Dextrose in Water (D5W)	Isotonic (in bag) → Hypotonic (in body)	Dextrose 50 g/L	~253	Provides free water to treat hypernatremia and for renal solute excretion, provides minimal calories	Does not provide electrolytes. Rapidly becomes hypotonic as dextrose is metabolized, risking cellular edema.	74
3% NaCl	Hypertonic	Na⁺ 513, Cl⁻ 513	~1027	Emergency treatment of severe, symptomatic hyponatremia and cerebral edema	High risk of hypernatremia, fluid overload, and osmotic demyelination syndrome. Administer slowly in an ICU setting.	74

6.3. Investigational Context: Deconstructing DrugBank Listings

A critical analysis of the clinical trials associated with DrugBank ID DB14547 confirms that chloride ion itself is not being investigated as a primary therapeutic agent for the listed conditions.[7] For example:

• In a Phase 4 trial for preventing bacteriuria, chloride ion is listed alongside chlorhexidine, an antiseptic agent.[7]
• In a Phase 2 trial for bacterial vaginosis, it is listed with sodium chloride.[8]
• In Phase 2 trials for anal and oral cavity cancers, it is listed alongside chemotherapeutic agents like cisplatin and fluorouracil.[9]

In every case, the presence of chloride is incidental to the primary drug's mechanism of action. It is either the counter-ion of the active molecule, a component of the formulation's excipients (e.g., saline), or part of the standard supportive care (e.g., intravenous hydration) provided to patients in the trial. This underscores the initial point that its inclusion in a drug database is a matter of chemical classification rather than a reflection of its use as a targeted therapy.

Section 7: Pathophysiology of Chloride Imbalance (Dyschloremia)

Disturbances in serum chloride concentration, collectively known as dyschloremia, are common in clinical practice and are intrinsically linked to disorders of fluid balance and acid-base status.

7.1. Hypochloremia (Low Serum Chloride)

• Definition: Hypochloremia is defined as a serum chloride level below the normal range, typically less than 96 mEq/L.[88]
• Causes: The most common causes involve the loss of chloride-rich fluids.
• Gastrointestinal Losses: Prolonged vomiting or nasogastric suction leads to the direct loss of hydrochloric acid (HCl) from the stomach and is a classic cause.[89]
• Renal Losses: The use of loop and thiazide diuretics, which block chloride reabsorption in the TALH and DCT, respectively, is a frequent iatrogenic cause.[88] Genetic disorders affecting these transporters, such as Bartter and Gitelman syndromes, also cause renal chloride wasting.[88]
• Other Causes: Conditions like congestive heart failure, chronic respiratory acidosis (where the kidney excretes chloride to retain bicarbonate as compensation), Addison's disease, and excessive sweating in cystic fibrosis can also lead to hypochloremia.[71]
• Pathophysiology: Hypochloremia is the characteristic electrolyte abnormality of metabolic alkalosis.[5] The loss of chloride, a strong anion, from the ECF results in a relative increase in the concentration of bicarbonate, a weak base, to maintain electroneutrality. Furthermore, the volume depletion that often accompanies chloride loss (e.g., from vomiting) activates the renin-angiotensin-aldosterone system, which promotes renal reabsorption of sodium and bicarbonate, thereby generating and maintaining the alkalotic state.[5]
• Clinical Manifestations and Treatment: Mild hypochloremia is often asymptomatic. When present, symptoms are typically due to the underlying cause or the associated metabolic alkalosis and may include weakness, dehydration, muscle twitching, and irritability.[89] Diagnosis is made via a serum metabolic panel. A low urine chloride level (<25 mEq/L) strongly suggests an extrarenal cause like vomiting, whereas a high urine chloride level points to a renal cause like diuretic use.[91] Treatment is aimed at correcting the underlying disorder and replenishing chloride, typically with intravenous 0.9% sodium chloride solution.[92]

7.2. Hyperchloremia (High Serum Chloride)

• Definition: Hyperchloremia is an elevated serum chloride level, typically above 107-110 mEq/L.[93]
• Causes:
• Iatrogenic Administration: A leading cause in hospitalized patients is the administration of large volumes of chloride-rich fluids, especially 0.9% saline.[32]
• Dehydration: Loss of free water or hypotonic fluid (e.g., from fever, diabetes insipidus) concentrates the chloride in the ECF.[93]
• Renal Causes: Renal tubular acidosis (RTA) is a key cause, where the kidney's inability to excrete acid or reabsorb bicarbonate leads to compensatory retention of chloride.[93] Kidney failure can also impair chloride regulation.[93]
• Gastrointestinal Losses: Severe diarrhea results in the loss of bicarbonate-rich intestinal fluid, leading to a relative excess of chloride in the plasma.[93]
• Pathophysiology: Hyperchloremia is the hallmark of normal anion gap metabolic acidosis (NAGMA), also known as hyperchloremic metabolic acidosis.[24] The primary defect is a loss of bicarbonate (e.g., from diarrhea) or impaired renal acid excretion (e.g., in RTA). To maintain electroneutrality in the ECF, the kidneys increase the reabsorption of chloride to replace the lost bicarbonate, resulting in an elevated serum chloride level.[95]
• Clinical Manifestations and Treatment: Symptoms are often nonspecific and related to the underlying acidosis, including fatigue, weakness, and deep, rapid breathing (Kussmaul respirations) as a respiratory compensation.[93] Diagnosis requires serum electrolytes and an arterial blood gas analysis. Treatment focuses on the underlying cause, such as rehydration with a balanced, low-chloride crystalloid (e.g., Lactated Ringer's) instead of saline, and, in severe cases, administration of sodium bicarbonate to correct the acidosis.[93]

7.3. Chloride Channelopathies

These are a group of genetic disorders caused by mutations in genes encoding chloride channels or transporters, leading to a wide range of tissue-specific pathologies. Key examples include:

• Cystic Fibrosis: Caused by mutations in the CFTR chloride channel.[53]
• Myotonia Congenita: Caused by mutations in the ClC-1 skeletal muscle chloride channel.[57]
• Bartter Syndrome and Gitelman Syndrome: Caused by mutations in various renal transporters, including ClC-Kb and NCC, leading to salt wasting.[88]
• Dent's Disease: Caused by mutations in the ClC-5 endosomal exchanger.[60]

Table 4: Clinical Comparison of Hypochloremia and Hyperchloremia

Feature	Hypochloremia	Hyperchloremia	Reference(s)
Definition	Serum Cl− < 96 mEq/L	Serum Cl− > 107 mEq/L	88
Primary Associated Acid-Base Disorder	Metabolic Alkalosis	Normal Anion Gap Metabolic Acidosis (NAGMA)	88
Key GI Causes	Vomiting, Nasogastric suction	Severe diarrhea, Pancreatic fistula	88
Key Renal Causes	Diuretic use (loop, thiazide), Bartter/Gitelman syndromes	Renal Tubular Acidosis (RTA), Kidney failure	88
Key Iatrogenic Causes	Bicarbonate administration	Excessive 0.9% NaCl infusion	88
Common Symptoms	Weakness, muscle cramps/twitching, dehydration	Weakness, fatigue, thirst, Kussmaul breathing	89
Primary Treatment Approach	Correct underlying cause; IV 0.9% NaCl	Correct underlying cause; IV balanced fluids (e.g., LR); Bicarbonate if severe	92

Section 8: Toxicology and Safety Profile

While chloride is essential for life, exposure to elemental chlorine or excessive administration of chloride-containing solutions can be harmful.

8.1. Toxicity of Chlorine and Related Compounds

The primary toxicological concern is with chlorine gas (Cl2​), not the chloride ion. Chlorine gas is a potent pulmonary irritant. When inhaled, it reacts with water on the mucosal surfaces of the respiratory tract to form hydrochloric acid (HCl) and hypochlorous acid (HOCl), both of which cause severe chemical burns and tissue damage.[102]

• Symptoms: Exposure is dose-dependent. Low concentrations (1-3 ppm) cause eye, nose, and throat irritation. Higher concentrations lead to coughing, bronchospasm, chest pain, and the development of life-threatening non-cardiogenic pulmonary edema.[102]
• Treatment: There is no specific antidote. Management is supportive and includes immediate removal from the source of exposure, administration of humidified oxygen, bronchodilators for bronchospasm, and advanced respiratory support for pulmonary edema.[102]
• Other Exposures: Ingestion of household cleaning products containing chlorine (e.g., bleach) can cause severe corrosive injury to the gastrointestinal tract.[106] Chronic exposure to compounds like vinyl chloride is associated with specific pathologies, including a rare form of liver cancer.[107]

8.2. Adverse Effects of Therapeutic Chloride Administration

A central theme in modern critical care is the recognition that iatrogenic chloride imbalance, particularly hyperchloremia, is a common and potentially harmful consequence of medical therapy. This is primarily driven by the widespread use of 0.9% sodium chloride, which has a chloride concentration (154 mmol/L) significantly higher than that of normal plasma (~100 mmol/L).[32] The administration of large volumes of this fluid, common during resuscitation, can directly cause hyperchloremia and the associated normal anion gap metabolic acidosis.[32] This iatrogenic acidosis has been associated with adverse clinical outcomes, including an increased incidence of acute kidney injury.[32] This understanding has fueled a significant shift towards using "balanced" or "chloride-sparing" crystalloid solutions (e.g., Lactated Ringer's) for large-volume fluid resuscitation.[82]

• Sodium Chloride Solutions: The primary risks of excessive administration are hypernatremia, hyperchloremia, and fluid overload, which can manifest as peripheral or pulmonary edema and can precipitate or exacerbate congestive heart failure.[86] Hypertonic solutions also carry a risk of infusion site reactions, such as phlebitis and tissue damage if extravasation occurs.[86]
• Potassium Chloride Solutions: The most dangerous adverse effect is hyperkalemia, which can lead to muscle weakness, paralysis, and life-threatening cardiac arrhythmias, including cardiac arrest.[113] Oral formulations can cause significant gastrointestinal irritation, including nausea, vomiting, abdominal pain, and, in the case of solid dosage forms, ulceration or perforation.[114]

8.3. Contraindications and Precautions

• Sodium Chloride: Administration is contraindicated in patients with pre-existing hypernatremia, hyperchloremia, or states of fluid retention.[112] It must be used with extreme caution in patients with congestive heart failure, severe renal insufficiency, cirrhosis, or other conditions associated with sodium retention.[112]
• Potassium Chloride: It is absolutely contraindicated in patients with hyperkalemia. Extreme caution is required in patients with renal impairment, as their inability to excrete potassium puts them at high risk for developing life-threatening hyperkalemia.[118] Concomitant use with drugs that raise potassium levels (e.g., ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics, NSAIDs) significantly increases this risk and requires careful monitoring.[81]

Section 9: Dietary Considerations and Public Health

9.1. Dietary Sources of Chloride

The vast majority of dietary chloride comes from sodium chloride, or table salt, which is added to foods during processing and cooking.[28] Processed foods such as cured meats, cheeses, canned goods, and sauces are particularly high in sodium chloride.[119]

Chloride is also naturally present in many unprocessed foods, although typically at much lower levels. Good natural sources include seaweed, rye, tomatoes, lettuce, celery, and olives.[120]

Potassium chloride is another source, often used in "salt substitutes" for individuals on sodium-restricted diets.[120]

9.2. Recommended Daily Intake

Health authorities have established guidelines for adequate chloride intake. However, public health messaging focuses primarily on limiting sodium intake due to its well-established link with hypertension.

• Adequate Intake (AI): The Institute of Medicine (IOM) in the United States has set an AI for chloride, which varies by age. For adults aged 19-50, the AI is 2.3 grams (2,300 mg) per day.[39]
• Upper Intake Level (UL): A tolerable upper intake level for chloride alone has not been established. This is because chloride intake is almost exclusively linked to cation intake (primarily sodium), and the adverse effects of high salt consumption, such as elevated blood pressure, are attributed to sodium.[124] Therefore, public health recommendations focus on limiting total sodium chloride (salt) intake to less than 5 grams per day.[124]

Table 5: Recommended Daily Intake of Chloride by Age Group (Adequate Intake)

Age Group	Adequate Intake (g/day)	Reference(s)
Infants (0–6 months)	0.18	123
Infants (7–12 months)	0.57	123
Children (1–3 years)	1.5	39
Children (4–8 years)	1.9	39
Children (9–13 years)	2.3	39
Adolescents (14–18 years)	2.3	39
Adults (19–50 years)	2.3	39
Adults (51–70 years)	2.0	39
Adults (> 70 years)	1.8	39
Pregnancy/Lactation	2.3	123

Note: The European Food Safety Authority (EFSA) has set a Dietary Reference Value (DRV) of 3.1 g/day for adults, which is considered both adequate and safe.[119] The EU Scientific Committee on Food has cited an RDA of 800 mg/day.[124] These differences reflect varying methodologies and data interpretations.

Section 10: Conclusion: A Synthesis of the Chloride Ion's Multifaceted Role

The chloride ion, though cataloged as a simple molecule in pharmacological databases, is a cornerstone of human physiology. This report has demonstrated that its significance extends far beyond its chemical identity as the anion of chlorine. It is a dynamic and indispensable electrolyte whose precise regulation is fundamental to the function of nearly every organ system.

The analysis has underscored chloride's multifaceted roles: it is the primary architect of extracellular fluid volume and osmotic pressure; a critical partner in the intricate dance of acid-base balance through the chloride-bicarbonate shift; and a key modulator of the nervous system's electrical symphony, mediating synaptic inhibition. Its presence is essential for digestion and the proper function of exocrine glands. The body's sophisticated mechanisms for its absorption in the gut and its meticulous handling by the kidneys highlight the evolutionary importance of maintaining chloride homeostasis.

Furthermore, this report has clarified that chloride's classification as an investigational "drug" is a functional artifact of database categorization. In clinical practice, its importance lies not as a primary therapeutic agent but as a vital diagnostic marker of underlying disease and as a fundamental component of life-sustaining therapeutic solutions. The growing understanding of the iatrogenic consequences of using high-chloride fluids like 0.9% saline has already begun to reshape clinical practice, favoring more physiologically balanced solutions.

Future research will continue to unravel the complexities of chloride's role, particularly in the context of the diverse family of chloride channels and transporters. As the molecular basis of chloride channelopathies becomes clearer, these proteins are emerging as promising targets for novel drug development. Ultimately, a comprehensive appreciation of the chloride ion—from its atomic structure to its systemic impact—is not merely an academic exercise; it is essential for effective diagnosis, rational therapeutics, and the fundamental care of human health.

Works cited

1. Chloride ion: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed July 26, 2025, https://go.drugbank.com/drugs/DB14547
2. Chloride | Cl- | CID 312 - PubChem, accessed July 26, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Chloride-Ion
3. Chloride - Wikipedia, accessed July 26, 2025, https://en.wikipedia.org/wiki/Chloride
4. Chloride ions in health and disease - PMC, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11065649/
5. Chloride - eClinpath, accessed July 26, 2025, https://eclinpath.com/chemistry/electrolytes/chloride/
6. Sodium chloride: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 26, 2025, https://go.drugbank.com/drugs/DB09153
7. UTI Unknown Status Phase 4 Trials for Chloride ion (DB14547) | DrugBank Online, accessed July 26, 2025, https://go.drugbank.com/indications/DBCOND0021578/clinical_trials/DB14547?phase=4&status=unknown_status
8. Bacterial Vaginosis (BV) Unknown Status Phase 2 Trials for Chloride ion (DB14547), accessed July 26, 2025, https://go.drugbank.com/indications/DBCOND0071525/clinical_trials/DB14547?phase=2&status=unknown_status
9. Oral Cavity Squamous Cell Carcinoma Recruiting Phase 2 Trials for Chloride ion (DB14547), accessed July 26, 2025, https://go.drugbank.com/indications/DBCOND0070694/clinical_trials/DB14547?phase=2&status=recruiting
10. Chloride ion Completed Phase 2 Trials for Stage IIB Anal Cancer AJCC v8 / Stage II Anal Cancer AJCC v8 / Stage IIA Anal Cancer AJCC v8 / Stage III Anal Cancer AJCC v8 / Stage IIIB Anal Cancer AJCC v8 / Stage IIIA Anal Cancer AJCC v8 / Stage IIIC Anal Cancer AJCC v8 / Anal Squamous Cell Carcinoma / Stage I Anal Cancer AJCC v8 Treatment - DrugBank, accessed July 26, 2025, https://go.drugbank.com/drugs/DB14547/clinical_trials?conditions=DBCOND0074911%2CDBCOND0116426%2CDBCOND0116427%2CDBCOND0116428%2CDBCOND0109340%2CDBCOND0116429%2CDBCOND0116430%2CDBCOND0116431%2CDBCOND0116432&phase=2&purpose=treatment&status=completed
11. pmc.ncbi.nlm.nih.gov, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11065649/#:~:text=Cl%E2%88%92%20are%20vital%20for%20maintaining,2%2C4%E2%80%939%5D.
12. Pharmacological modulation of chloride channels as a therapeutic ..., accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10017882/
13. Pharmacological modulation of chloride channels as a therapeutic strategy for neurological disorders - Frontiers, accessed July 26, 2025, https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1122444/full
14. CAS 16887-00-6: Chloride - CymitQuimica, accessed July 26, 2025, https://cymitquimica.com/cas/16887-00-6/
15. CHLORIDE STANDARD | 16887-00-6 - ChemicalBook, accessed July 26, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB6403296.htm
16. CHEBI:17996 - chloride - EMBL-EBI, accessed July 26, 2025, https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:17996
17. What is the chloride ion? - Proprep, accessed July 26, 2025, https://www.proprep.com/questions/what-is-the-chloride-ion
18. What is the formula for chloride ion? - YouTube, accessed July 26, 2025, https://www.youtube.com/watch?v=sq4uQ3mNzeQ
19. CHLORIDE STANDARD CAS#: 16887-00-6 - ChemicalBook, accessed July 26, 2025, https://m.chemicalbook.com/ProductChemicalPropertiesCB6403296_EN.htm
20. Understanding Chloride: Properties, Uses, and Health Implications - Gas-Sensing.com, accessed July 26, 2025, https://www.gas-sensing.com/news/understanding-chloride-properties-uses-and-health-implications/
21. Showing metabocard for Chloride ion (HMDB0000492) - Human Metabolome Database, accessed July 26, 2025, https://www.hmdb.ca/metabolites/HMDB0000492
22. Chloride anion | Cl - ChemSpider, accessed July 26, 2025, https://www.chemspider.com/Chemical-Structure.306.html
23. PDBj Mine: Chemie - CL - CHLORIDE ION - Protein Data Bank Japan, accessed July 26, 2025, https://pdbj.org/chemie/summary/CL
24. Chloride cl- - Radiometer - Radiometer America, accessed July 26, 2025, https://www.radiometeramerica.com/en-us/products/blood-gas-testing/parameters/chloride
25. www.biocare.com.tw, accessed July 26, 2025, https://www.biocare.com.tw/press/chloride-the-master-of-body-function-balance/#:~:text=Maintain%20cell%20osmotic%20pressure%3A%20Chloride,osmotic%20pressure%20with%20sodium%20ions.
26. 10.5: Electrolytes Important for Fluid Balance - Medicine LibreTexts, accessed July 26, 2025, https://med.libretexts.org/Courses/American_Public_University/APUS%3A_An_Introduction_to_Nutrition_(Byerley)/APUS%3A_An_Introduction_to_Nutrition_1st_Edition/10%3A_Water_Electrolytes_Acid-Base_Balance/10.05%3A_Electrolytes_Important_for_Fluid_Balance
27. 22.1. Osmoregulation and Osmotic Balance – Concepts of Biology - BC Open Textbooks, accessed July 26, 2025, https://opentextbc.ca/biology/chapter/22-1-osmoregulation-and-osmotic-balance/
28. Chloride - The Nutrition Source, accessed July 26, 2025, https://nutritionsource.hsph.harvard.edu/chloride/
29. Chloride - (Anatomy and Physiology II) - Vocab, Definition, Explanations | Fiveable, accessed July 26, 2025, https://library.fiveable.me/key-terms/anatomy-physiology-ii/chloride
30. Chloride – Human Nutrition 2e, accessed July 26, 2025, https://pressbooks.oer.hawaii.edu/humannutrition2e22/chapter/3-chloride/
31. Physiology, Acid Base Balance - StatPearls - NCBI Bookshelf, accessed July 26, 2025, https://www.ncbi.nlm.nih.gov/books/NBK507807/
32. Serum chloride levels in critical illness—the hidden story - PMC, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5899079/
33. Acid-Base Regulation - Endocrine and Metabolic Disorders - MSD Manuals, accessed July 26, 2025, https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/acid-base-regulation-and-disorders/acid-base-regulation
34. pmc.ncbi.nlm.nih.gov, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10995984/#:~:text=Acid%2Dbase%20balance%3A%20Chloride's%20integral,valuable%20in%20diagnosing%20metabolic%20acidosis.
35. Chloride Homeostasis in Neurons With Special Emphasis on the Olivocerebellar System: Differential Roles for Transporters and Channels - Frontiers, accessed July 26, 2025, https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2018.00101/full
36. Graded potential - Wikipedia, accessed July 26, 2025, https://en.wikipedia.org/wiki/Graded_potential
37. Chloride channels render nerve cells more excitable - Max-Planck-Gesellschaft, accessed July 26, 2025, https://www.mpg.de/623143/pressRelease201004203
38. Chloride ions in health and disease | Bioscience Reports - Portland Press, accessed July 26, 2025, https://portlandpress.com/bioscirep/article/44/5/BSR20240029/234283/Chloride-ions-in-health-and-disease
39. Chloride – Human Nutrition [DEPRECATED] - UH Pressbooks, accessed July 26, 2025, https://pressbooks-dev.oer.hawaii.edu/humannutrition/chapter/chloride/
40. Pharmacokinetics - Pharmacology - Merck Veterinary Manual, accessed July 26, 2025, https://www.merckvetmanual.com/pharmacology/pharmacology-introduction/pharmacokinetics
41. Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination | Clinical Gate, accessed July 26, 2025, https://clinicalgate.com/pharmacokinetics-absorption-distribution-metabolism-and-elimination/
42. Chloride Absorption Mechanisms in the Intestine - J-Stage, accessed July 26, 2025, https://www.jstage.jst.go.jp/article/membrane/36/6/36_293/_article
43. Physiology of Intestinal Absorption and Secretion - PMC, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4956471/
44. Chloride Absorption Mechanisms in the Intestine - J-Stage, accessed July 26, 2025, https://www.jstage.jst.go.jp/article/membrane/36/6/36_293/_article/-char/en
45. Absorption in the Large Intestine - Regulation - TeachMePhysiology, accessed July 26, 2025, https://teachmephysiology.com/gastrointestinal-system/large-intestine/absorption-large-intestine/
46. Chloride Blood Test: What It Is, Purpose, Procedure & Results - Cleveland Clinic, accessed July 26, 2025, https://my.clevelandclinic.org/health/diagnostics/22023-chloride-blood-test
47. Basic Renal Processes for Sodium, Chloride, and Water - AccessMedicine, accessed July 26, 2025, https://accessmedicine.mhmedical.com/content.aspx?bookid=2348§ionid=185664120
48. Hyperchloremia – Why and how | Nefrología, accessed July 26, 2025, https://www.revistanefrologia.com/en-hyperchloremia-why-how-articulo-S021169951630025X
49. CHLORIDE TRANSPORT IN THE PROXIMAL RENAL TUBULE - Annual Reviews, accessed July 26, 2025, https://www.annualreviews.org/doi/pdf/10.1146/annurev.ph.50.030188.000525
50. Renal handling of substances, accessed July 26, 2025, https://www.zmchdahod.org/pdf/college/renal_system_lecture_4_Physiology_29_01_2019.pdf
51. Renal chloride transport and diuretics. - American Heart Association Journals, accessed July 26, 2025, https://www.ahajournals.org/doi/pdf/10.1161/01.CIR.53.4.587
52. Chloride transport modulators as drug candidates - American Journal of Physiology, accessed July 26, 2025, https://journals.physiology.org/doi/abs/10.1152/ajpcell.00334.2021
53. Ion channels | Pharmacology Education Project, accessed July 26, 2025, https://www.pharmacologyeducation.org/pharmacology/ion-channels
54. Membrane Transporters and Channels as Targets for Drugs | Frontiers Research Topic, accessed July 26, 2025, https://www.frontiersin.org/research-topics/6684/membrane-transporters-and-channels-as-targets-for-drugs/magazine
55. ClC Channels and Transporters: Structure, Physiological ... - Frontiers, accessed July 26, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00151/full
56. (PDF) Transporters as Channels - ResearchGate, accessed July 26, 2025, https://www.researchgate.net/publication/6737456_Transporters_as_Channels
57. ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies - PMC - PubMed Central, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5362633/
58. Intracellular Chloride Channels: Novel Biomarkers in Diseases - Frontiers, accessed July 26, 2025, https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00096/full
59. Biochemistry, Chloride Channels - StatPearls - NCBI Bookshelf, accessed July 26, 2025, https://www.ncbi.nlm.nih.gov/books/NBK545138/
60. CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease, accessed July 26, 2025, https://journals.physiology.org/doi/abs/10.1152/physrev.00047.2017
61. Chloride ion channels and transporters - European Pharmaceutical Review, accessed July 26, 2025, https://www.europeanpharmaceuticalreview.com/article/20848/chloride-ion-channels-and-transporters/
62. The function of chloride channels in digestive system disease (Review), accessed July 26, 2025, https://www.spandidos-publications.com/10.3892/ijmm.2025.5540
63. Chloride channels as drug targets - PMC - PubMed Central, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3601949/
64. Chloride - Content - Health Encyclopedia - University of Rochester Medical Center, accessed July 26, 2025, https://www.urmc.rochester.edu/encyclopedia/content?ContentTypeID=167&ContentID=chloride
65. Chloride Blood Test: Procedure, Reasons, and Results - WebMD, accessed July 26, 2025, https://www.webmd.com/a-to-z-guides/what-is-a-chloride-test
66. Test ID CLU Chloride, 24 Hour, Urine - Mayo Clinic Laboratories Rochester, accessed July 26, 2025, https://mml.testcatalog.org/show/CLU
67. RCHLU - Overview: Chloride, Random, Urine - Mayo Clinic Laboratories, accessed July 26, 2025, https://www.mayocliniclabs.com/test-catalog/overview/610607
68. Chloride test - blood Information | Mount Sinai - New York, accessed July 26, 2025, https://www.mountsinai.org/health-library/tests/chloride-test-blood
69. CL - Overview: Chloride, Serum - Mayo Clinic Laboratories, accessed July 26, 2025, https://www.mayocliniclabs.com/test-catalog/overview/8460
70. Chloride, Serum - Mayo Clinic Laboratories | Pediatric Catalog, accessed July 26, 2025, https://pediatric.testcatalog.org/show/CL
71. Chloride Blood Test: MedlinePlus Medical Test, accessed July 26, 2025, https://medlineplus.gov/lab-tests/chloride-blood-test/
72. www.mayoclinic.org, accessed July 26, 2025, https://www.mayoclinic.org/drugs-supplements/sodium-chloride-oral-route/description/drg-20122545#:~:text=Back%20to%20top-,Description,medicine%20is%20available%20without%20prescription.
73. What Is Sodium Chloride and How Is It Used? - Healthline, accessed July 26, 2025, https://www.healthline.com/health/sodium-chloride
74. 15.3 Intravenous Solutions – Nursing Fundamentals 2e - WisTech Open, accessed July 26, 2025, https://wtcs.pressbooks.pub/nursingfundamentals/chapter/15-3-intravenous-solutions/
75. SODIUM CHLORIDE 0.9% = NaCl 0.9% | MSF Medical Guidelines, accessed July 26, 2025, https://medicalguidelines.msf.org/en/viewport/EssDr/english/sodium-chloride-0-9-nacl-16687700.html
76. Sodium Chloride 0.9% Intravenous Infusion BP - Summary of Product Characteristics (SmPC) - (emc) | 1871, accessed July 26, 2025, https://www.medicines.org.uk/emc/product/1871/smpc
77. Types, Usage and Examples of IV Fluids - AZ IV Medics, accessed July 26, 2025, https://www.azivmedics.com/iv-fluids
78. Crystalloid Fluids - StatPearls - NCBI Bookshelf, accessed July 26, 2025, https://www.ncbi.nlm.nih.gov/books/NBK537326/
79. go.drugbank.com, accessed July 26, 2025, https://go.drugbank.com/drugs/DB00761#:~:text=Potassium%20chloride%20is%20a%20potassium%20salt%20used%20to%20treat%20hypokalemia.&text=A%20white%20crystal%20or%20crystalline,and%20in%20fertilizers%20and%20explosives.
80. Potassium Chloride Solution or Powder for Solution - Cleveland Clinic, accessed July 26, 2025, https://my.clevelandclinic.org/health/drugs/21385-potassium-chloride-solution-or-powder-for-solution
81. Potassium Chloride (Klor-Con, K-Dur, and others) - Uses, Side Effects, and More - WebMD, accessed July 26, 2025, https://www.webmd.com/drugs/2/drug-676-7058/potassium-chloride-oral/potassium-extended-release-dispersible-tablet-oral/details
82. Balanced Crystalloid Solutions | American Journal of Respiratory and Critical Care Medicine, accessed July 26, 2025, https://www.atsjournals.org/doi/10.1164/rccm.201809-1677CI
83. Intravenous (IV) Fluids - Nursing Center, accessed July 26, 2025, https://www.nursingcenter.com/getattachment/clinical-resources/nursing-pocket-cards/iv-fluids/Pocket-Card_IV-Fluids_November-2024.pdf.aspx
84. Composition of commonly used crystalloids | NICE, accessed July 26, 2025, https://www.nice.org.uk/guidance/cg174/resources/composition-of-commonly-used-crystalloids-table-191662813
85. Intravenous Crystalloid Solutions – The Essentials - Florida Veterinary Medical Association, accessed July 26, 2025, https://fvma.org/intravenous-crystalloid-solutions-the-essentials/
86. INDICATIONS AND USAGE 3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes. CONTRAINDICAT - accessdata.fda.gov, accessed July 26, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019022s031lbl.pdf
87. Chloride ion Completed Phase 4 Trials for Pain Treatment | DrugBank Online, accessed July 26, 2025, https://go.drugbank.com/drugs/DB14547/clinical_trials?conditions=DBCOND0012160&phase=4&purpose=treatment&status=completed
88. Hypochloremia - Wikipedia, accessed July 26, 2025, https://en.wikipedia.org/wiki/Hypochloremia
89. Hypochloremia (Low Chloride) - Chemocare, accessed July 26, 2025, https://chemocare.com/sideeffect/hypochloremia
90. Serum Chloride - Clinical Methods - NCBI Bookshelf, accessed July 26, 2025, https://www.ncbi.nlm.nih.gov/books/NBK309/
91. Final Diagnosis -- Hypochloremic metabolic alkalosis, accessed July 26, 2025, https://path.upmc.edu/cases/case587/dx.html
92. Hypochloremia: Levels, Symptoms, Treatment, and More - Healthline, accessed July 26, 2025, https://www.healthline.com/health/hypochloremia
93. Hyperchloremia - Wikipedia, accessed July 26, 2025, https://en.wikipedia.org/wiki/Hyperchloremia
94. What are the causes of hyperchloremia (elevated chloride levels)? - Dr.Oracle AI, accessed July 26, 2025, https://www.droracle.ai/articles/29267/what-are-the-causes-of-hyperchloremia-elevated-chloride-levels
95. What are the causes of hyperchloremia (elevated chloride levels)? - Dr.Oracle, accessed July 26, 2025, https://www.droracle.ai/articles/37513/causes-of-hyperchloremia
96. Hyperchloremia: Causes, Symptoms, and Treatments - Healthgrades Health Library, accessed July 26, 2025, https://resources.healthgrades.com/right-care/symptoms-and-conditions/hyperchloremia
97. Renal Tubular Acidosis - Genitourinary Disorders - MSD Manual Professional Edition, accessed July 26, 2025, https://www.msdmanuals.com/professional/genitourinary-disorders/renal-transport-abnormalities/renal-tubular-acidosis
98. Hyperchloremic Acidosis - StatPearls - NCBI Bookshelf, accessed July 26, 2025, https://www.ncbi.nlm.nih.gov/books/NBK482340/
99. Metabolic Acidosis - Endocrine and Metabolic Disorders - Merck Manual Professional Edition, accessed July 26, 2025, https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/acid-base-regulation-and-disorders/metabolic-acidosis
100. High Chloride Levels in Blood: Causes and Treatment - Healthline, accessed July 26, 2025, https://www.healthline.com/health/hyperchloremia
101. Hypochloremia: Causes, Symptoms and Treatment - Medicover Hospitals, accessed July 26, 2025, https://www.medicoverhospitals.in/diseases/hypochloremia/
102. Chlorine Gas Toxicity - StatPearls - NCBI Bookshelf, accessed July 26, 2025, https://www.ncbi.nlm.nih.gov/books/NBK537213/
103. www.ncbi.nlm.nih.gov, accessed July 26, 2025, https://www.ncbi.nlm.nih.gov/books/NBK537213/#:~:text=Acute%20exposure%20at%20high%20levels,%2C%20sore%20throat%2C%20and%20hemoptysis.
104. Chlorine Gas Inhalation: Human Clinical Evidence of Toxicity and Experience in Animal Models - PMC, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3136961/
105. Hydrogen Chloride | Medical Management Guidelines | Toxic Substance Portal - CDC, accessed July 26, 2025, https://wwwn.cdc.gov/TSP/MMG/MMGDetails.aspx?mmgid=758&toxid=147
106. Chlorine Poisoning: Symptoms, Diagnosis, and Treatments - Healthline, accessed July 26, 2025, https://www.healthline.com/health/chlorine-poisoning
107. Vinyl Chloride Toxicity - StatPearls - NCBI Bookshelf, accessed July 26, 2025, https://www.ncbi.nlm.nih.gov/books/NBK544334/
108. Clinical physiology aspects of chloremia in fluid therapy: a systematic review - PMC, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7727154/
109. Hyperchloraemia in sepsis - PMC, accessed July 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5869346/
110. Hyperchloremia in Critically Ill Patients in ICU: Review Article, accessed July 26, 2025, https://www.ajol.info/index.php/ejhm/article/view/223663/211009
111. Sodium Chloride Injection BP 0.9% - Medsafe, accessed July 26, 2025, https://www.medsafe.govt.nz/profs/datasheet/s/SodiumChlorideBPinj.pdf
112. 23.4% Sodium Chloride Injection, USP 400 mEq (4 mEq/mL) Additive Solution, accessed July 26, 2025, https://labeling.pfizer.com/ShowLabeling.aspx?id=4613
113. potassium chloride for injection concentrate, USP Adverse Reactions, accessed July 26, 2025, https://www.pfizermedicalinformation.com/potassium-chloride/adverse-reactions
114. Potassium Chloride Side Effects: Common, Severe, Long Term - Drugs.com, accessed July 26, 2025, https://www.drugs.com/sfx/potassium-chloride-side-effects.html
115. Potassium: MedlinePlus Drug Information, accessed July 26, 2025, https://medlineplus.gov/druginfo/meds/a601099.html
116. Sodium Chloride Injection 3% 5%: Package Insert / Prescribing Info - Drugs.com, accessed July 26, 2025, https://www.drugs.com/pro/sodium-chloride-injection-3-5.html
117. 0.9% Sodium Chloride Injection USP - DailyMed, accessed July 26, 2025, https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=47a0313f-36df-4fa6-a828-c9e1946ba9b0
118. Potassium chloride dosing, indications, interactions, adverse effects, and more, accessed July 26, 2025, https://reference.medscape.com/drug/kdur-slow-k-potassium-chloride-344450
119. Chloride: foods, functions, how much do you need & more | Eufic, accessed July 26, 2025, https://www.eufic.org/en/vitamins-and-minerals/article/chloride-foods-functions-how-much-do-you-need-more
120. Chloride in diet Information | Mount Sinai - New York, accessed July 26, 2025, https://www.mountsinai.org/health-library/nutrition/chloride-in-diet
121. Nutrition 101: Chloride | Food List - HealthCastle.com, accessed July 26, 2025, https://www.healthcastle.com/chloride/
122. www.mountsinai.org, accessed July 26, 2025, https://www.mountsinai.org/health-library/nutrition/chloride-in-diet#:~:text=Food%20Sources,also%20found%20in%20many%20foods.
123. Chloride in Diet - UF Health, accessed July 26, 2025, https://ufhealth.org/conditions-and-treatments/chloride-in-diet
124. Unbelievable facts about chloride - Blog - Jakefood, accessed July 26, 2025, https://jakefood.com/2018/chloride/