Benzoic Acid

BRAND NAMES

Common brand names that include benzoic acid as an ingredient are Whitfield's Ointment and Whitolyn Ointment, which are used for treating fungal skin infections. Other brand examples are COBESAL and DERMICURE PLUS. 

MECHANISM OF ACTION

Benzoic acid works as an antimicrobial by penetrating microbial cell membranes in its un-dissociated form, then dissociating inside the cell to lower the intracellular pH, which inhibits critical metabolic enzymes and processes, disrupts membrane permeability, and leads to the depletion of energy (ATP), ultimately inhibiting growth and survival. Its effectiveness is dependent on the external pH, with better performance in acidic conditions where more undissociated acid is present. 

PHARMACOKINETICS

Absorption

Benzoic acid is rapidly and extensively absorbed orally, with a high bioavailability of about 95% and an absorption half-life of 0.8 hours. Absorption is nearly complete within two hours. Absorption primarily occurs in the small intestine via the monocarboxylic acid transporter, with higher rates in the jejunum compared to other segments.

Distribution

The volume of distribution for benzoic acid has not been consistently reported across different species, with one study in channel catfish showing a steady-state volume of distribution of 369 ml/kg after intravenous dosing. For humans, there is no directly cited volume of distribution.

Metabolism

Benzoic acid is primarily metabolized in the liver to its benzoyl-CoA form, which then conjugates with glycine to form hippuric acid. This hippuric acid is then excreted in the urine, making it the main metabolic pathway for benzoic acid in humans. While this process is largely efficient, it can be affected by liver health, with conditions like fatty liver or chronic liver disease potentially decreasing the rate of metabolism. 

Excretion

Benzoic acid is primarily excreted from the body as its glycine conjugate, hippuric acid. After being processed in the liver, this conjugate is then eliminated from the body via the kidneys through the urine.

PHARMACODYNAMICS

Benzoic acid's pharmacodynamics center on its antimicrobial action, achieved by penetrating microbial cell membranes in its un-dissociated form, dissociating inside, and causing a drop in intracellular pH. This intracellular acidification disrupts essential enzyme activities and metabolic processes, ultimately inhibiting and killing microorganisms. It also functions as a preservative in medications by inhibiting microbial growth. 

ADMINISTRATION

• Topical Administration:

Benzoic acid is used in antifungal creams and ointments, like Whitfield's ointment, for ringworm or athlete's foot.

It is applied directly to the skin, avoiding open wounds and mucous membranes.

Minor skin irritation is a possible side effect. 

• Oral/Intravenous (IV) Administration:

Sodium benzoate, the salt form, is used for urea cycle disorders causing high ammonia.

It is given IV for acute cases or orally for long-term management.

The drug works by conjugating with glycine to remove excess nitrogen.

Close monitoring is required due to the sodium content and potential side effects like nausea. 

DOSAGE AND STRENGTHS

• Topical Use:

Often used in combination with salicylic acid for treating fungal skin infections.

Whitfield's ointment:

• 6% benzoic acid
• 3% salicylic acid
• Used for topical antifungal treatment

Other topical formulations may vary in concentration from 2% to 10%, depending on the product and its purpose (e.g., antiseptic or keratolytic action).

• Oral Use (Very Rare):

Benzoic acid is not commonly used orally due to potential toxicity at high doses. However, as a preservative, it appears in oral and ingestible products in very small quantities, often in the form of sodium benzoate.

Acceptable Daily Intake (ADI):

• WHO/FAO: 0–5 mg/kg body weight/day (as benzoic acid or sodium benzoate)

DRUG INTERACTIONS

Benzoic acid can interact with other drugs by either decreasing their effectiveness or increasing the risk of toxicity. For example, it can decrease the excretion of certain drugs like dinoprostone and doripenem, while increasing the efficacy of others such as ethyl biscoumacetate. Interactions are also possible with medications affecting liver function, like valproic acid, as well as topical treatments and alcohol, which can increase benzoic acid absorption and side effects. 

FOOD INTERACTIONS

Benzoic acid's primary food interaction is with vitamin C, where their combination can form benzene, a known carcinogen, under certain conditions like high temperatures or prolonged storage. It is also a food preservative that functions best in acidic foods like soft drinks and fermented vegetables, though its effectiveness can be reduced in higher pH environments. Overconsumption of benzoic acid can cause nausea and diarrhea, and its interaction with proteins can lead to the formation of amyloid-like fibrils.

CONTRAINDICATIONS

Topical benzoic acid is contraindicated in individuals with a known allergy to benzoic acid or salicylates (aspirin). It should also not be applied to mucous membranes, eyes, or open wounds. 

SIDE EFFECTS

• Redness, or burning sensation
• Stinging feeling.
• Dryness or peeling of the skin.
• Allergic skin reactions, which can cause itching and rash.
• Coughing.
• Wheezing.
• Shortness of breath.
• Inflammation.
• Irritation to the digestive tract.
• Upset stomach or vomiting.

OVERDOSE

A benzoic acid overdose can cause symptoms including nausea, vomiting, diarrhea, skin and respiratory irritation, allergic reactions, and in more severe cases, convulsions. While benzoic acid has low toxicity in humans and is quickly metabolized and excreted, high doses can be detrimental. Symptoms are usually related to ingestion or high-concentration exposure. Treatment is supportive in nature and aims to alleviate and manage the symptoms.

TOXICITY

Benzoic acid is primarily an irritant, with high concentrations or prolonged exposure causing skin, eye, and respiratory tract irritation, including redness, rash, coughing, and shortness of breath. While considered generally safe at approved levels, ingestion of high doses may cause adverse effects like metabolic acidosis or convulsions in animals. Benzoic acid is not considered a carcinogen but can be converted into mutagens in the presence of certain chemicals.