Diminabazene B12

Mechanism of action

Cyanocobalamin serves as a cofactor for methionine synthase and L-methylmalonyl-CoA mutase enzymes. Methionine synthase is essential for the synthesis of purines and pyrimidines that form DNA. L-methylmalonyl-CoA mutase is involved in the degradation of propionate, crucial for fat and protein metabolism. The lack of vitamin B12 results in the accumulation of methylmalonyl CoA, contributing to neurological manifestations. Additionally, it is vital for the synthesis of methionine from homocysteine, and its deficiency can lead to functional folate deficiency, which impacts red blood cell formation.

Pharmacodynamics

Cyanocobalamin corrects vitamin B12 deficiency and alleviates symptoms and laboratory abnormalities associated with pernicious anemia, such as megaloblastic indices, gastrointestinal lesions, and neurological damage. It is essential for growth, cell reproduction, hematopoiesis, nucleoprotein, and myelin synthesis. The drug significantly impacts fat and carbohydrate metabolism, as well as protein synthesis. Rapidly dividing cells, such as those in the bone marrow, have a high demand for vitamin B12. Parenteral administration of cyanocobalamin can quickly reverse the anemia and gastrointestinal symptoms of vitamin B12 deficiency, while also preventing the progression of related neurological damage.

Pharmacokinetics

Cyanocobalamin is absorbed in the intestine, primarily in the ileum, via specific transport mechanisms that may be impaired in individuals with intrinsic factor deficiency (as seen in pernicious anemia). Once absorbed, it is widely distributed in body tissues, with significant concentrations found in the liver, kidneys, and heart. The vitamin is stored in the liver, where it can be released into circulation as needed. Cyanocobalamin undergoes conversion to its active forms, methylcobalamin and adenosylcobalamin, which are utilized in various metabolic processes. The elimination half-life is variable, but it is generally excreted via urine as metabolites

Adverse effects

• Abdominal distension
• Decreased appetite
• Flatulence
• Nausea

Interactions

• Folic acid may interact with cyanocobalamin, especially in cases of megaloblastic anemia caused by folate deficiency.

Precautions

• Should not be given alone for pernicious anemia.
• Use caution in patients with Leber's disease, as it may worsen optic atrophy.

Pregnancy

Cyanocobalamin is essential during pregnancy as it helps prevent neural tube defects. It is advised that females of childbearing potential take 5 mg of folic acid daily before conception and throughout pregnancy.

Breast-feeding

Cyanocobalamin is generally considered safe during breastfeeding, but it is advised to monitor the infant for any adverse effects.

Storage

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

Formulations

• Tablet: 1000 micrograms
• Tablet: 500 micrograms
• Tablet: 100 micrograms
• Oral solution: 50 micrograms per ml
• Solution for injection: 1000 micrograms per ml

Indications

• Acute pain management
• Chronic pain conditions
• Osteoarthritis
• Rheumatoid arthritis
• Post-operative pain

Dosage

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

Adults: Refer to BNF for appropriate adult dosing guidelines.

Mechanism of action

Aceturate acts as an analgesic and anti-inflammatory agent. Its mechanism involves the inhibition of the cyclooxygenase (COX) enzymes, leading to a decrease in the synthesis of prostaglandins, which are mediators of pain and inflammation. This results in reduced pain perception and inflammation at the site of action.

Pharmacodynamics

Aceturate exhibits dose-dependent analgesic effects, providing relief from mild to moderate pain. Its anti-inflammatory properties help to reduce swelling and discomfort in conditions like arthritis and musculoskeletal disorders. The onset of action is typically rapid, leading to quick relief of symptoms.

Pharmacokinetics

Aceturate is absorbed after oral administration, with peak plasma concentrations reached within a few hours. It undergoes hepatic metabolism and is excreted primarily via the renal route. The elimination half-life can vary based on individual metabolic factors but is generally within a manageable range for regular dosing.

Pregnancy

No adequate studies are available on the use of aceturate in pregnant women. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution is advised when aceturate is administered to breastfeeding mothers. The excretion of aceturate in human milk is unknown.

Storage

Store at room temperature, away from moisture and heat. Protect from light.

Indications

• Pain relief
• Fever reduction
• Assessment of drug metabolism

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations for paediatric patients.

Adults: Refer to the BNF for specific dosing recommendations for adults.

Mechanism of action

Antipyrine acts primarily in the central nervous system (CNS) by increasing the pain threshold. It achieves this by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3, which are enzymes involved in the synthesis of prostaglandins (PGs).

Pharmacodynamics

As an analgesic and antipyretic, antipyrine effectively reduces pain and fever. It is administered orally and via ear drops, and is frequently used in clinical settings to evaluate the effects of various drugs or diseases on hepatic drug-metabolizing enzymes.

Pharmacokinetics

Antipyrine is well absorbed from the gastrointestinal tract and undergoes extensive hepatic metabolism. Its elimination half-life varies, influenced by hepatic function and other factors. The drug is primarily excreted in urine as metabolites.

Adverse effects

• Nausea
• Vomiting
• Rash
• Dizziness
• Headache

Precautions

• Use with caution in patients with liver impairment
• Monitor for signs of allergic reactions
• Consider potential interactions with other medications affecting liver enzymes

Pregnancy

Antipyrine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution is advised when administered to breastfeeding mothers due to the lack of data on excretion in human milk.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Oral tablets
• Ear drops

Indications

• Trypanosomiasis (sleeping sickness)
• Nagana in livestock
• Infections caused by Trypanosoma brucei
• Infections caused by Trypanosoma congolense

Dosage

Children: Paediatric dosing of diminazene should be derived from the BNF for Children, taking into account the weight and age of the child. Refer to the BNF for Children for specific dosing recommendations.

Adults: The dosage for adults should be determined based on the specific condition and patient factors. Refer to the BNF for accurate dosing guidelines.

Mechanism of action

Diminazene acts by inhibiting the enzyme dihydrofolate reductase, which is crucial for the synthesis of folate in protozoa. This inhibition disrupts the folate metabolic pathway, leading to a decrease in nucleic acid synthesis and ultimately resulting in the death of the protozoan parasites. Additionally, it may interfere with the mitochondrial function of the parasites, further contributing to its antiparasitic effects.

Pharmacodynamics

The pharmacodynamics of diminazene involve its selective action on trypanosomes, with the drug being less toxic to host cells. It has a high affinity for the target enzyme, allowing for effective suppression of protozoan growth. The drug's therapeutic index is favorable, meaning it can effectively treat infections at doses that are relatively safe for the host.

Pharmacokinetics

Diminazene is well-absorbed following parenteral administration. It is widely distributed throughout the body, with a significant volume of distribution. The drug undergoes hepatic metabolism, and its elimination half-life can vary depending on species and individual health. Excretion is primarily via the urine, with metabolites detected in both urine and feces.

Adverse effects

• Anorexia
• Vomiting
• Diarrhoea
• Lethargy
• Neurological signs (e.g., tremors, ataxia)
• Hypersensitivity reactions

Precautions

• Use with caution in animals with hepatic or renal impairment.
• Monitor for signs of toxicity, especially in cases of overdose.

Pregnancy

Safety during pregnancy has not been established; use only if the benefits outweigh the risks.

Breast-feeding

Safety during breastfeeding has not been established; use with caution.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Injection solution

Indications

• Vitamin B12 deficiency
• Megaloblastic anemia due to vitamin B12 deficiency
• Neuropathy associated with vitamin B12 deficiency
• Pernicious anemia
• Malabsorption syndromes affecting vitamin B12 absorption

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines as per the condition being treated.

Adults: Refer to the BNF for specific dosing guidelines as per the condition being treated.

Mechanism of action

Hydrocobalamin acts as a coenzyme in the conversion of homocysteine to methionine and in the conversion of methylmalonyl-CoA to succinyl-CoA. It is involved in the synthesis of myelin, a protective sheath around nerves, and plays a role in the metabolism of carbohydrates and fats. Through these mechanisms, hydrocobalamin facilitates proper cellular function and promotes the health of the nervous system.

Pharmacodynamics

Hydrocobalamin's pharmacodynamics involve its role in cellular metabolism and energy production. It enhances the utilization of fatty acids and amino acids, which are crucial for energy production. Furthermore, it supports the synthesis of nucleic acids and the formation of red blood cells, thereby improving oxygen transport and utilization in the body. The vitamin also plays a role in maintaining healthy nerve cells, which is critical for proper neurological function.

Pharmacokinetics

Hydrocobalamin is absorbed in the intestine, primarily in the ileum, through both passive diffusion and active transport mechanisms. It is distributed widely throughout the body, particularly in the liver, kidneys, and bone marrow. The half-life of hydrocobalamin is variable, but it is known to be retained in the body for longer periods than other forms of vitamin B12. The vitamin is excreted mainly in the urine, and any excess amounts are typically eliminated from the body without significant toxicity.

Contra-indications

• Hypersensitivity to hydroxocobalamin or any of its excipients
• Leber's disease (hereditary optic neuropathy)

Adverse effects

• Allergic reactions including rash, itching, and anaphylaxis
• Gastrointestinal disturbances such as diarrhea or nausea
• Headache
• Dizziness
• Injection site reactions including pain, redness, or swelling

Interactions

• Chloramphenicol may reduce the efficacy of hydroxocobalamin
• Prolonged use of hydroxocobalamin may mask signs of vitamin B12 deficiency in patients taking folic acid supplements

Precautions

• Use with caution in patients with renal impairment
• Monitor patients for potential allergic reactions following administration
• Pregnant women should only use hydroxocobalamin if clearly needed

Pregnancy

Hydroxocobalamin is classified as pregnancy category C. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Hydroxocobalamin is excreted in human breast milk, but at therapeutic doses, it is not expected to cause adverse effects in breastfed infants.

Storage

Store in a refrigerator (2 to 8 degrees Celsius). Do not freeze. Protect from light.

Formulations

• Injection solution (1 mg/mL)
• Oral tablets (1 mg, 5 mg)

Dosage

Children: Refer to specific medication guidelines for dosing.

Adults: Refer to specific medication guidelines for dosing.

Mechanism of action

Vitamin B12 serves as a cofactor for _methionine synthase_ and _L-methylmalonyl-CoA mutase_ enzymes. Methionine synthase is essential for the synthesis of purines and pyrimidines that form DNA. L-methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to _succinyl-CoA_ in the degradation of propionate, an important reaction required for both fat and protein metabolism. It is a lack of vitamin B12 cofactor in the above reaction and the resulting accumulation of methylmalonyl CoA that is believed to be responsible for the neurological manifestations of B12 deficiency. Succinyl-CoA is also necessary for the synthesis of hemoglobin. In tissues, vitamin B12 is required for the synthesis of _methionine_ from homocysteine. Methionine is required for the formation of S-adenosylmethionine, a methyl donor for nearly 100 substrates, comprised of DNA, RNA, hormones, proteins, as well as lipids. Without vitamin B12, tetrahydrofolate cannot be regenerated from 5-methyltetrahydrofolate, and this can lead to functional folate deficiency,. This reaction is dependent on methylcobalamin (vitamin B12) as a co-factor and is also dependent on folate, in which the methyl group of methyltetrahydrofolate is transferred to homocysteine to form _methionine_ and _tetrahydrofolate_. Vitamin B12 incorporates into circulating folic acid into growing red blood cells; retaining the folate in these cells. A deficiency of vitamin B12 and the interruption of this reaction leads to the development of megaloblastic anemia.

Pharmacodynamics

**General effects** Cyanocobalamin corrects vitamin B12 deficiency and improves the symptoms and laboratory abnormalities associated with pernicious anemia (megaloblastic indices, gastrointestinal lesions, and neurologic damage). This drug aids in growth, cell reproduction, hematopoiesis, nucleoprotein, and myelin synthesis. It also plays an important role in fat metabolism, carbohydrate metabolism, as well as protein synthesis. Cells that undergo rapid division (for example, epithelial cells, bone marrow, and myeloid cells) have a high demand for vitamin B12. **Parenteral cyanocobalamin effects** The parenteral administration of vitamin B12 rapidly and completely reverses the megaloblastic anemia and gastrointestinal symptoms of vitamin B12 deficiency. Rapid parenteral administration of vitamin B12 in deficiency related neurological damage prevents the progression of this condition. **Nasal spray effects** In 24 vitamin B12 deficient patients who were already stabilized on intramuscular (IM) vitamin B12 therapy, single daily doses of intranasal cyanocobalamin for 8 weeks lead to serum vitamin B12 concentrations that were within the target therapeutic range (>200 ng/L).

Mechanism of action

Antipyrine is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) synthesis.

Pharmacodynamics

Antipyrine is an analgesic and antipyretic that has been given by mouth and as ear drops. Antipyrine is often used in testing the effects of other drugs or diseases on drug-metabolizing enzymes in the liver. (From Martindale, The Extra Pharmacopoeia, 30th ed, p29)