Diphtheria Tetanus Pertussis (Whole Cell) Hepatitis B (rDNA) and Haemophilus type b conjugate vaccin

Indications

• Dyspepsia
• Peptic ulcer disease
• Gastroesophageal reflux disease (GERD)
• Heartburn
• Diarrhea
• Mucosal irritations

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines.

Adults: Refer to the BNF for specific dosing recommendations based on the condition being treated.

Mechanism of action

Aluminum acts as an astringent, causing local shrinkage or constriction of body tissues through osmotic flow of fluids away from the area of application. This mechanism assists in reducing mucous secretions and managing conditions such as peptic ulcers and diarrhea. Additionally, it can help in drying and hardening of tissues when applied topically.

Pharmacodynamics

Aluminum-based antacids work by neutralizing gastric acid, leading to an increase in gastric pH. This action helps to alleviate symptoms associated with excess gastric acid, such as heartburn and discomfort. The astringent properties of aluminum also contribute to its therapeutic effects in managing mucosal irritations and secretions.

Pharmacokinetics

Aluminum is absorbed minimally when taken orally, with a bioavailability of about 0.1 to 0.5%. The majority of aluminum is excreted renally, and its half-life can be prolonged in individuals with renal impairment. Long-term use may lead to accumulation and potential toxicity, particularly impacting bone and neurological health.

Interactions

• aluminiumhydroxide+deferasirox: Severe (decreases exposure)
• aluminiumhydroxide+enteralfeeds: Unknown (increases risk of blocked enteral or nasogastric tubes)
• aluminiumhydroxide+roxadustat: Unknown (decreases exposure)

Pregnancy

Aluminum compounds are generally considered safe in pregnancy when used as directed. However, excessive exposure should be avoided.

Breast-feeding

Aluminum is excreted in breast milk; caution is advised when administered to nursing mothers.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• aluminium hydroxide suspension
• aluminium hydroxide tablets

Indications

• Vaccination against infectious diseases
• Allergy testing and immunotherapy
• Monoclonal antibody production
• Transplantation to prevent organ rejection

Dosage

Children: Dosing of antigens in children also depends on the specific antigen and the clinical indication. For pediatric vaccinations, refer to the BNF for Children.

Adults: Dosing of antigens is highly variable and depends on the specific antigen and the clinical indication. For vaccine administration, refer to national immunization guidelines.

Mechanism of action

Antigens work by binding to specific receptors on the surface of immune cells, such as B cells and T cells. This binding triggers a cascade of immune responses, including the proliferation of specific immune cell populations and the production of antibodies that target the antigen. This process is crucial for the development of adaptive immunity, allowing the body to remember and respond more effectively to future encounters with the same antigen.

Pharmacodynamics

The pharmacodynamics of antigens involve the interaction with the immune system to elicit a response. The magnitude and quality of this response can vary based on several factors, including the nature of the antigen, the route of exposure, and the host's immune status. Antigens can be classified as T-cell dependent or T-cell independent, influencing the type of immune response generated.

Pharmacokinetics

Antigens are processed by antigen-presenting cells (APCs) that present peptide fragments to T cells. The pharmacokinetics of antigens can vary widely depending on their form (e.g., live attenuated, inactivated, or subunit vaccines). Generally, once introduced into the body, antigens are taken up by APCs, which then migrate to lymph nodes to activate T and B cells. The duration of immune response can be influenced by the type of antigen and the presence of adjuvants.

Pregnancy

Safety during pregnancy depends on the specific type of antigen. Consult relevant guidelines for specific antigens.

Breast-feeding

Safety during breastfeeding varies by antigen type. Consult relevant guidelines for specific antigens.

Storage

Store at controlled room temperature, away from light and moisture. Specific storage conditions may vary based on the type of antigen.

Dosage

Children: Refer to the specific drug contained within the capsule for appropriate dosing guidelines.

Adults: Refer to the specific drug contained within the capsule for appropriate dosing guidelines.

Mechanism of action

Capsules themselves do not have a specific mechanism of action, as they are a form of drug delivery. The active pharmaceutical ingredient contained within the capsule will exert its pharmacological effects upon dissolution and absorption in the gastrointestinal tract, engaging specific receptors or pathways depending on the nature of the drug.

Pharmacodynamics

The pharmacodynamics of a drug encapsulated in a capsule will depend on the specific drug contained within. Generally, once the capsule dissolves, the active ingredient is released and absorbed into the bloodstream, where it can exert its effects, such as altering physiological functions, inhibiting or stimulating biological processes, or affecting cell signaling pathways. The onset of action, therapeutic effects, and side effects will vary widely based on the pharmacological class of the drug.

Pharmacokinetics

The pharmacokinetics of a drug in capsule form will vary depending on the active ingredient. In general, the pharmacokinetics include absorption, distribution, metabolism, and excretion (ADME). After oral administration, capsules dissolve in the stomach or intestines, releasing the active ingredient for absorption into the systemic circulation. The drug may then be distributed throughout the body, metabolized primarily by the liver, and excreted via urine or feces. The rate of absorption and bioavailability will depend on factors such as the solubility of the drug, the presence of food, and the formulation of the capsule.

Pregnancy

The safety of capsular during pregnancy has not been established. It should be used only if clearly needed and the potential benefits outweigh the risks.

Breast-feeding

It is not known whether capsular is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from direct sunlight and moisture. Keep out of reach of children.

Indications

• Diphtheria prevention through vaccination
• Management of diphtheria infections
• Treatment of complications arising from diphtheria toxin

Dosage

Children: Refer to established guidelines for the management of diphtheria in children. Treatment typically includes administration of diphtheria antitoxin and antibiotics.

Adults: Refer to established guidelines for the management of diphtheria. Treatment typically includes administration of diphtheria antitoxin and antibiotics.

Mechanism of action

Corynebacterium diphtheriae produces diphtheria toxin, which is a potent exotoxin that inhibits protein synthesis in host cells. The toxin binds to the heparin-binding epidermal growth factor (HB-EGF) receptor on cell membranes, facilitating its entry into cells. Once inside, it catalyzes the ADP-ribosylation of elongation factor-2 (EF-2), halting protein synthesis and leading to cell death.

Pharmacodynamics

The toxicity of diphtheria is primarily due to the action of its exotoxin. The severity of the disease is correlated with the amount of toxin produced, which can lead to local tissue necrosis in the throat, systemic effects such as myocarditis and neuropathy, and can be fatal if untreated. The immune response to the toxin plays a crucial role in recovery, as patients who have been previously vaccinated may exhibit milder disease due to pre-existing immunity.

Pharmacokinetics

The pharmacokinetics of diphtheria toxin involve its release into the bloodstream after local infections in the throat. The toxin can disseminate to various tissues, including the heart and nervous system, leading to systemic manifestations. The half-life of the toxin is not well established, but it is rapidly cleared from circulation following the development of antibodies in the host, which neutralize the toxin's effects.

Adverse effects

• Local reactions at the injection site
• Fever
• Fatigue
• Allergic reactions
• Anaphylaxis (rare)

Precautions

• History of severe allergic reactions to diphtheria toxoid or any component of the vaccine
• Use with caution in individuals with immunocompromised conditions

Pregnancy

Diphtheria vaccination is generally considered safe during pregnancy and is recommended to protect both the mother and fetus from potential exposure.

Breast-feeding

Diphtheria vaccination is safe during breastfeeding and is recommended as it helps to protect the infant.

Storage

Store in a refrigerator at 2-8 degrees Celsius. Do not freeze.

Formulations

• Diphtheria toxoid vaccine (inactivated)
• Diphtheria-tetanus-pertussis (DTP) combination vaccine

Indications

• Prevention of postoperative nausea and vomiting
• Treatment of nausea and vomiting
• Premedication for surgical procedures

Dosage

Children: Refer to the BNF for Children for age-appropriate dosing guidelines.

Adults: Refer to the BNF for specific dosing recommendations based on the clinical context and patient condition.

Mechanism of action

Droperidol primarily acts as an antagonist at dopamine D2 receptors in the central nervous system. This blockade of dopamine receptors leads to a decrease in nausea and vomiting, as dopamine is a key neurotransmitter involved in these processes. Furthermore, droperidol may also have some affinity for other receptor types, including adrenergic and serotonin receptors, contributing to its sedative and antiemetic effects.

Pharmacodynamics

The pharmacodynamic profile of droperidol includes its ability to reduce the incidence of nausea and vomiting through central action. It can also produce sedation and anxiolytic effects, making it useful in preoperative settings. The onset of action is typically rapid, with effects observed shortly after administration. Droperidol has a dose-dependent relationship, where higher doses may lead to increased sedation and potential extrapyramidal side effects due to its dopamine antagonism.

Pharmacokinetics

Droperidol is well-absorbed after parenteral administration, with peak plasma concentrations occurring within 30 minutes to 1 hour. It is metabolized in the liver, primarily via cytochrome P450 enzymes, and has a relatively short half-life, generally ranging from 1 to 3 hours. Droperidol is excreted mainly in urine as metabolites, with less than 1% of the dose excreted unchanged. The drug's pharmacokinetic profile can be influenced by factors such as age, liver function, and concurrent medications.

Interactions

• droperidol + dopaminereceptor agonists: Severe (decreases effects)
• droperidol + levodopa: Unknown (decreases effects)

Indications

• Acute viral hepatitis
• Chronic hepatitis B
• Chronic hepatitis C
• Autoimmune hepatitis
• Alcoholic hepatitis
• Non-alcoholic fatty liver disease

Dosage

Children: Paediatric dosing also varies significantly based on the specific condition and medication. As with adult dosing, it is important to refer to the BNF for Children for specific recommendations.

Adults: Dosing for adult patients varies widely depending on the specific antiviral agent used and the type of hepatitis. It is essential to refer to specific guidelines or the BNF for precise dosing.

Mechanism of action

In viral hepatitis, the viruses typically enter liver cells and replicate, leading to cellular injury and inflammation. The immune response to the infection contributes to liver damage. Antiviral therapies aim to inhibit viral replication, either by directly targeting viral enzymes or by modulating the host immune response.

Pharmacodynamics

The pharmacodynamics of antiviral agents used in hepatitis treatment involve the inhibition of viral replication, reduction of viral load, and improvement of liver function. This can lead to a decrease in serum liver enzymes (ALT and AST) and an improvement in clinical symptoms. In chronic hepatitis B and C, sustained virologic response is the goal, indicating effective viral suppression.

Pharmacokinetics

The pharmacokinetics of antiviral medications used for hepatitis can vary significantly depending on the specific drug. Generally, these agents are absorbed from the gastrointestinal tract, metabolized in the liver, and excreted through urine or feces. The half-lives of these drugs can vary, influencing dosing schedules.

Pregnancy

Consult medical guidelines as hepatitis can pose risks during pregnancy; specific management depends on the type of hepatitis.

Breast-feeding

Consult healthcare providers, as the safety of certain hepatitis medications during breastfeeding varies.

Storage

Store in a cool, dry place away from direct sunlight; specific storage conditions may vary based on the medication used.

Mechanism of action

Polysaccharides exert their effects through various mechanisms, often involving the modulation of immune responses. For example, certain polysaccharides can act as pathogen-associated molecular patterns (PAMPs) that are recognized by pattern recognition receptors on immune cells, leading to the activation of innate immunity. Additionally, some polysaccharides can enhance the proliferation and activation of lymphocytes, such as T-cells and B-cells, thereby influencing adaptive immune responses. Some polysaccharides also play a role in anticoagulation by inhibiting thrombin and other factors in the coagulation cascade.

Pharmacodynamics

The pharmacodynamics of polysaccharides vary widely depending on their structure and the specific biological pathways they influence. For instance, polysaccharides that act as immunomodulators can increase cytokine production, enhance phagocytosis by macrophages, and promote the differentiation of immune cells, leading to a more robust immune response. Furthermore, polysaccharides can exhibit anti-inflammatory properties by modulating the release of pro-inflammatory cytokines and chemokines. In the case of anticoagulant polysaccharides, their action may involve the binding and inhibition of specific clotting factors, thus preventing thrombus formation.

Pharmacokinetics

The pharmacokinetics of polysaccharides depend on their molecular weight, structure, and route of administration. Generally, polysaccharides are poorly absorbed in the gastrointestinal tract when taken orally due to their large size and complexity. However, certain polysaccharides are designed for parenteral administration, where they can be directly introduced into the bloodstream. Following administration, they may be metabolized by specific enzymes or by gut microbiota. The elimination half-life can vary significantly, influenced by factors such as the degree of sulfation or acetylation, which can affect their

Pregnancy

Polysaccharides are generally considered safe during pregnancy, but specific formulations should be evaluated on a case-by-case basis. Always consult a healthcare provider.

Breast-feeding

Polysaccharides are typically considered safe during breastfeeding, although individual formulations may vary. Consultation with a healthcare provider is recommended.

Storage

Polysaccharides should be stored in a cool, dry place, away from direct sunlight and moisture. Specific storage conditions may vary depending on the formulation.

Dosage

Children: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Adults: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Mechanism of action

The mechanism of action for purified compounds varies widely depending on the specific substance. Generally, purified drugs exert their effects by interacting with specific biological targets, such as receptors, enzymes, or ion channels, leading to a desired therapeutic effect. This interaction can involve binding to receptors to activate or inhibit signaling pathways, modulating enzymatic activity, or altering physiological processes.

Pharmacodynamics

Pharmacodynamics describes the effects of a drug on the body and the relationship between drug concentration and effect. For purified drugs, this can involve dose-response relationships and the time course of their action. The purified form often enhances potency and reduces variability in response among patients, which can lead to more predictable therapeutic outcomes. The overall effect is determined by the drug's affinity for its target, the efficacy of the drug-receptor interaction, and the downstream signaling pathways activated as a result of this interaction.

Pharmacokinetics

Pharmacokinetics involves the absorption, distribution, metabolism, and excretion (ADME) of a drug. For purified substances, absorption can be more efficient due to the absence of impurities that may affect solubility or stability. Distribution may also be enhanced, leading to higher bioavailability. Metabolism can be influenced by the structure of the purified compound, as it may be metabolized more readily by liver enzymes. Excretion typically occurs through the kidneys or liver, depending on the molecular characteristics of the purified drug.

Pregnancy

Consult with a healthcare professional, as the safety of purified forms of medications during pregnancy may vary depending on the specific substance.

Breast-feeding

Consult with a healthcare professional, as the safety of purified forms of medications during breastfeeding may vary depending on the specific substance.

Storage

Store in a cool, dry place, away from light and moisture, and keep out of reach of children.

Indications

• Topical treatment of skin conditions
• Emulsifying agents in pharmaceutical formulations
• Wound healing applications
• Delivery of poorly soluble drugs

Dosage

Children: Refer to specific product guidelines and BNF for appropriate dosing regimens.

Adults: Refer to specific product guidelines and BNF for appropriate dosing regimens.

Mechanism of action

Surface-active agents, or surfactants, lower the surface tension between two substances, such as between a liquid and a solid or between two liquids. This property enables them to spread easily and improve the solubility of drugs in various formulations. In the context of drug delivery, surfactants can facilitate the absorption of medications across biological membranes by disrupting lipid bilayers, thus enhancing bioavailability.

Pharmacodynamics

Pharmacodynamics refers to the effects of drugs on the body and their mechanisms of action. For surface-active agents, the pharmacodynamic properties include their ability to alter surface tension and enhance wetting, spreading, and emulsification. These properties allow for improved penetration of active ingredients into tissues and can enhance the therapeutic effects of topically applied drugs.

Pharmacokinetics

Pharmacokinetics involves the absorption, distribution, metabolism, and excretion (ADME) of drugs. Surface-active agents typically exhibit limited systemic absorption when applied topically, leading to localized effects. The rate of absorption can be influenced by the formulation, the presence of other excipients, and the condition of the skin or mucosal surface. Metabolism may occur to a minimal extent, and excretion primarily happens through the skin or via the lymphatic system.

Pregnancy

Consult healthcare professional before use.

Breast-feeding

Consult healthcare professional before use.

Storage

Store in a cool, dry place away from direct sunlight.

Indications

• Tetanus prophylaxis
• Treatment of tetanus infection
• Management of tetanus symptoms

Dosage

Children: Refer to the specific guidelines for tetanus immunoglobulin and other supportive treatments as per clinical protocols.

Adults: Refer to the specific guidelines for tetanus immunoglobulin and other supportive treatments as per clinical protocols.

Mechanism of action

The tetanus toxin binds to the presynaptic membrane of motor neurons and is transported retrogradely to the spinal cord, where it interferes with neurotransmitter release, particularly inhibiting the release of glycine and gamma-aminobutyric acid (GABA), leading to unopposed motor neuron activity and resultant muscle rigidity and spasms.

Pharmacodynamics

Tetanus toxin is one of the most potent toxins known, with effects that can manifest within hours of exposure. The toxin's ability to block inhibitory neurotransmitter release results in a state of continuous muscle contraction, known as tetany. The clinical presentation of tetanus includes trismus (lockjaw), muscle rigidity, and autonomic instability, among others.

Pharmacokinetics

The pharmacokinetics of tetanus toxin are complex due to its high potency and the nature of its action. Following entry into the body, the toxin binds to nerve endings and is internalized, leading to its effects on neurotransmitter release. The half-life of the toxin is not well defined as it does not circulate freely in the bloodstream but acts locally at the neuromuscular junction. Recovery from the effects of the toxin may take weeks to months, depending on the severity of the infection and the treatment provided.

Adverse effects

• Pain at the injection site
• Fever
• Fatigue
• Headache
• Nausea

Precautions

• Ensure patient is up to date with vaccinations
• Monitor for allergic reactions post-vaccination
• Consider history of neurological disorders

Pregnancy

Tetanus vaccination is considered safe during pregnancy and is recommended to protect both the mother and the newborn.

Breast-feeding

Tetanus vaccination is safe during breastfeeding and does not affect the nursing infant.

Storage

Store in a refrigerator at 2–8 degrees Celsius. Do not freeze.

Formulations

• Tetanus toxoid vaccine

Indications

• Preservative in vaccines
• Antibacterial agent
• Antifungal agent

Dosage

Children: Refer to the BNF for Children for specific dosage guidelines, especially in

Adults: Refer to specific product guidelines or the BNF for detailed dosage information, as thimerosal is primarily used as a preservative in vaccines rather than in therapeutic doses.

Mechanism of action

Thimerosal inhibits sulfhydryl-containing active sites of various enzymes and binds to sulfhydryl compounds, including glutathione and cysteine. It activates the InsP3 calcium channel on the endoplasmic reticulum, leading to the release of intracellular calcium and subsequent cellular functions dependent on calcium signaling. Ethylmercury, the metabolite of thimerosal, is lipophilic and can cross the blood-brain barrier, contributing to its biological effects.

Pharmacodynamics

Thimerosal exhibits antibacterial and antifungal properties, functioning as a preservative in vaccines. Its pharmacological effects are mediated through interactions with cellular thiols and modulation of calcium signaling pathways. The toxic effects of high doses of thimerosal, such as oxidative stress and apoptosis, have been observed in vitro, although the effects of low-dose exposure remain less understood.

Pharmacokinetics

Thimerosal is rapidly metabolized to ethylmercury, which is eliminated from the body more quickly than methylmercury. Ethylmercury has a shorter half-life, leading to limited accumulation and toxic potential when used in vaccine formulations. The octanol/water partition coefficients indicate that both organomercury compounds, including ethylmercury, can primarily exist within cells, allowing them to cross cellular membranes effectively.

Adverse effects

• Hypersensitivity reactions
• Local reactions at injection site
• Neurotoxic effects at high doses
• Possible kidney pathology with toxic quantities

Precautions

• Use with caution in individuals with known hypersensitivity to thimerosal or other mercury compounds
• Monitoring for adverse effects in patients receiving multiple vaccines containing thimerosal

Pregnancy

Thimerosal should be used in pregnant women only if clearly needed, as the effects on fetal development are not fully established.

Breast-feeding

Thimerosal is considered compatible with breastfeeding, but caution is advised due to potential mercury exposure.

Storage

Store in a cool, dry place away from light. Protect from freezing. Ensure proper disposal of any unused or expired vaccine containing thimerosal.

Formulations

• Thimerosal-containing vaccines (various formulations)

Indications

• Diphtheria prophylaxis
• Tetanus prophylaxis
• Pertussis prophylaxis (when combined with other vaccines)

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations for pediatric immunization with toxoids.

Adults: Refer to specific guidelines for each toxoid vaccine, as dosing may vary based on the type of vaccine and individual patient factors.

Mechanism of action

Toxoids work by stimulating the immune system to produce antibodies against the toxin without causing disease. When administered, the immune system recognizes the toxoid as a foreign substance and generates a specific immune response. This includes the production of immunoglobulin G (IgG) antibodies that can neutralize the active toxin if the individual is exposed to the bacteria in the future.

Pharmacodynamics

The pharmacodynamics of toxoids involve the activation of the adaptive immune response. After vaccination, dendritic cells present the antigen to T cells, which then help B cells differentiate into plasma cells that produce specific antibodies. The presence of these antibodies provides immunity against the toxin by neutralizing its effects, thereby preventing the disease associated with the original bacterial toxin.

Pharmacokinetics

Toxoids are typically administered via intramuscular or subcutaneous injection. Following administration, they are gradually taken up by antigen-presenting cells, which then process and present the toxoid to T cells. The immunogenic response can develop over several weeks. The duration of immunity can vary, necessitating booster doses to maintain adequate antibody levels over time.

Adverse effects

• Local reactions at the injection site, such as pain, swelling, or redness.
• Fever.
• Fatigue.
• Headache.
• Allergic reactions in rare cases.

Precautions

• Use with caution in individuals with a history of severe allergic reactions to a vaccine component.
• Monitor patients for allergic reactions post-vaccination.

Pregnancy

Toxoids are generally considered safe during pregnancy; however, consultation with a healthcare provider is recommended.

Breast-feeding

Toxoids are considered safe for use during breastfeeding.

Storage

Store in a refrigerator at 2-8°C. Do not freeze. Protect from light.

Formulations

• Diphtheria toxoid
• Tetanus toxoid
• Pertussis toxoid

Mechanism of action

Aluminum Acetate is an astringent. An astrignent is a chemical that tends to shrink or constrict body tissues, usually locally after topical medicinal application. The shrinkage or constriction is through osmotic flow of water (or other fluids) away from the area where the astringent was applied. Astringent medicines cause shrinkage of mucous membranes or exposed tissues and are often used internally to check discharge of blood serum or mucous secretions. This can happen with a sore throat, hemorrhages, diarrhea, or with peptic ulcers. Externally applied astringents, which cause mild coagulation of skin proteins, dry, harden, and protect the skin. Acne sufferers are often advised to use astringents if they have oily skin. Astringents also help heal stretch marks and other scars. Mild astringent solutions are used in the relief of such minor skin irritations as those resulting from superficial cuts, allergies, insect bites, or fungal infections such as athlete's foot. Excessive dietary aluminum has been proposed to be a factor contributing to several neurological disorders in humans. Six 8-week-old female Swiss Webster mice were fed for 10 wk purified diets containing 100 (control), 500 or 1000 ug aluminum/g diet. Brain and liver lipid peroxidation was determined by evaluating the production of 2-thiobarbituric acid reactive substances in brain and liver homogenates in the presence or absence of 50 uM ferrous iron. 2-Thiobarbituric acid reactive substances production in the absence of iron in brain homogenates from mice fed the 1000 ug/g diet was higher (30%) than that in the 100 ug/g control group (3.1 vs 2.4 nmol 2-thiobarbituric acid reactive substances/mg protein). The addition of ferrous iron increased 2-thiobarbituric acid reactive substances production in brain homogenates from all 3 dietary groups. The iron induced 2-thiobarbituric acid reactive substances production was 26% higher in the 1000 ug/g brain homogenates than in the 100 ug/g group (4.9 vs 3.9 nmol 2-thiobarbituric acid reactive substances/mg protein). Brain 2-thiobarbituric acid reactive substances production in the presence and absence of iron was similar between the 100 and 500 ug/g aluminum groups. 2-Thiobarbituric acid reactive substances production in liver homogenates measured either with or without iron was similar for the 3 groups. These results show that, in mice, dietary aluminum intoxication leads to increased brain 2-thiobarbituric acid reactive substance production, suggesting that enhanced lipid peroxidation may be one possible mechanism underlying the neurological damage associated with increased tissue aluminum. Evidence is presented indicating that dementias are associated with a relative insufficiency of magnesium in the brain. Such insufficiency may be attributable to low intake or retention of magnesium; high intake of a neurotoxic metal, such as aluminum, which inhibits activity of magnesium requiring enzymes; or impaired transport of magnesium and/or enhanced transport of the neurotoxic metal into brain tissue. It is proposed that Alzheimer's disease involves a defective transport process, characterized by both an abnormally high incorporation of aluminum and an abnormally low incorporation that an altered serum protein contributes to the progression of Alzheimer's disease by having a greater affinity for aluminum than for magnesium, in contrast to the normal protein, which binds magnesium better than aluminum. The altered protein crosses the blood-brain barrier more efficiently than the normal protein and competes with the normal protein in binding to brain neurons. Binding of the altered protein to the target neurons would both facilitate aluminum uptake and impede magnesium uptake. Evidence suggests that albumin is the serum protein that is altered. Aluminum is established as a neurotoxin, although the basis for its toxicity is unknown. It recently has been shown to alter the function of the blood-brain barrier, which regulates ex

Mechanism of action

Although its mechanism of action is not fully understood, thimerosal inhibits sulfhydryl-containing active site of various enzymes and binds to sulfhydryl compounds, including glutathione, cysteine, and sulfhydryl groups of proteins. In addition, thimerosal activates the InsP3 calcium channel on the endoplasmic reticular membrane, thereby triggering the release of intracellular calcium resulting in a calcium-induced calcium-influx of extracellular calcium. Therefore, thimerosal may induce or inhibit various cellular functions that are dependent on the signaling of calcium. Ethylmercury is metabolized to inorganic mercury more rapidly than methylmercury. This difference in metabolism may account for kidney pathology that can result from toxic quantities. Also, whereas the increase in oxidative stress and induction of apoptosis observed in vitro with large doses (405 μg/L to 101 mg/L) of thimerosal may explain its damaging neurological effects. The effects of low-dose ethylmercury are not completely understood to date. It is known, however, that the shorter half-life of ethylmercury (the metabolite of thimerosal) allows for very limited opportunities of ethylmercury derived from thimerosal in vaccines. Ethylmercury is a lipophilic cation that is capable of crossing the blood-brain barrier. The octanol/water partition coefficients of methyl and ethylmercury are 1.4 to 1.8, at intracellular pH and [Cl−], therefore, both organomercury compounds will primarily exist as intracellular lipophilic cations. It has been demonstrated that lipophilic cations accumulate inside mitochondria, in a Nernstian fashion, driven by the steady state membrane potential. As the typical mitochondrial membrane potential of astrocytes and neurons is between 140–170 mV, one would expect the concentration of these organomercury compounds within mitochondria to be approximately 1000 times greater than the cytosolic concentration.

Pharmacodynamics

Thimerosal is an organomercurial compound and derivative of thiosalicyclic acid with antibacterial and antifungal properties. Thimerosal, which consists of approximately 50% mercury by weight, has been one of the most widely used preservatives in vaccines. It is metabolized/degraded to ethylmercury and thiosalicylate. Ethylmercury is an organomercurial that must be carefully distinguished from methylmercury, a closely related substance that has been the focus of many studies. Methylmercury is the type of mercury found in various species of fish. Experimental data demonstrates that the toxicokinetics of thimerosal (ethylmercury) is vastly different from that of methyl-mercury. Thus, methyl-mercury is not a suitable reference for assessing the risk from exposure to thimerosal-derived mercury. Prior to the recent initiative to reduce or eliminate thimerosal from childhood vaccines, the maximum cumulative exposure to mercury via routine childhood vaccinations during the first 6 months of life was 187.5 micrograms. In the most recently formulated vaccines, the maximum cumulative exposure during the first 6 months of life should now be less than 3 micrograms of mercury. Currently, thimerosal may still be used in the early stages of manufacturing of certain childhood vaccines, however, only a trace remains after a chemical purification process. Note that the dose above is indicated for children 1-6 months of age is applicable only in the United States, and other countries may have varying indications.