Maradol Injection

Indications

• Fluid and electrolyte imbalances
• Hyponatremia
• Diabetic ketoacidosis
• Prophylaxis of sodium chloride deficiency
• Chronic renal salt wasting
• Dry eye conditions (as eye drops)

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines based on the child's age and clinical condition.

Adults: Fluid and electrolyte replacement should be individualized based on clinical circumstances. For oral supplementation, adult patients may take 4-8 tablets daily, with a maximum of 20 tablets in severe depletion. For intravenous infusion, the volume of sodium chloride solution required to replace deficits may vary; consult product literature for precise guidance.

Mechanism of action

Sodium and chloride ions function together to control extracellular volume and blood pressure. Disturbances in sodium concentrations in the extracellular fluid can lead to water balance disorders. Sodium chloride can induce uterine contractions when used in hypertonic solutions, contributing to its abortifacient properties. The precise mechanism may involve prostaglandins released from damaged decidual cells.

Pharmacodynamics

Sodium, as the primary cation in extracellular fluid, is essential for maintaining fluid distribution, osmotic pressure, and overall fluid balance. It works in conjunction with chloride and bicarbonate to regulate the acid-base equilibrium of body fluids. Changes in sodium levels significantly impact water distribution and electrolyte balance within the body.

Pharmacokinetics

Sodium chloride is readily absorbed and distributed in body fluids, influencing extracellular fluid volume and osmotic pressure. It is excreted primarily through the kidneys, with renal function significantly affecting sodium retention and excretion. The pharmacokinetics may vary based on the route of administration (oral or intravenous) and the formulation used.

Adverse effects

• Abdominal cramps
• Acidosis
• Hyperchloraemic diarrhoea
• Generalised oedema
• Hypertension
• Hypotension
• Irritability
• Muscle complaints
• Nausea
• Vomiting
• Chills
• Fever
• Hypervolemia
• Local reaction
• Localized pain
• Paraesthesia
• Skin reactions
• Tremor
• Vascular irritation
• Venous thrombosis

Precautions

• Avoid excessive administration in elderly patients or those with cardiac failure.
• Monitor for signs of fluid overload, especially in patients with impaired renal function.
• Consider potential for dilutional hyponatraemia.

Pregnancy

Intra-amniotic instillation of hypertonic sodium chloride can induce abortion and fetal death; caution is advised.

Storage

Store in a cool, dry place, away from direct sunlight. Ensure containers are tightly closed.

Formulations

• Sodium chloride 0.9% infusion
• Sodium chloride 5% eye drops
• Sodium chloride effervescent tablets

Indications

• Moderate to severe pain
• Postoperative pain
• Chronic pain management

Dosage

Children: For children aged 12-17 years, initially 50 mg, then adjusted according to response; usual maximum is 400 mg/24 hours.

Adults: Initially, 50-100 mg every 4-6 hours as needed. Maximum dose is 400 mg/24 hours.

Mechanism of action

Tramadol exerts its analgesic effects primarily through the modulation of pain pathways in the brain. It is a weak agonist of the mu-opioid receptor and also inhibits the reuptake of norepinephrine and serotonin, which contributes to its analgesic activity. This dual mechanism helps in managing pain by both blocking pain signals at the receptor level and enhancing descending inhibitory pathways.

Pharmacodynamics

Tramadol's pharmacodynamic properties are characterized by its ability to produce analgesia with a lower risk of respiratory depression compared to stronger opioids. It has a ceiling effect on respiratory depression, making it safer for use in non-opioid-tolerant patients. Common side effects include fatigue, dizziness, and gastrointestinal disturbances, while serious risks include seizures and serotonin syndrome, especially when combined with other serotonergic drugs.

Pharmacokinetics

Tramadol is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 1-2 hours post-administration. It has a bioavailability of about 68% due to first-pass metabolism. The drug is extensively metabolized in the liver, primarily via cytochrome P450 enzymes, with a half-life of approximately 6-7 hours. It is excreted mainly in the urine, both as metabolites and unchanged drug.

Contra-indications

• Acute intoxication with alcohol
• Acute intoxication with analgesics
• Acute intoxication with hypnotics
• Acute intoxication with opioids
• Compromised respiratory function
• Uncontrolled epilepsy

Adverse effects

• Fatigue
• Postural hypotension
• Dyspnoea
• Epileptiform seizures
• Respiratory disorders
• Sleep disorders
• Blurred vision
• Asthma exacerbation
• Hypoglycaemia

Interactions

• Increased risk of respiratory depression with other CNS depressants
• May enhance the effects of alcohol
• Potential interaction with serotonergic drugs leading to serotonin syndrome

Precautions

• History of excessive bronchial secretions
• History of epilepsy-use only if compelling reasons exist
• Impaired consciousness
• Use with caution in patients susceptible to seizures
• Variation in metabolism may affect therapeutic effects

Pregnancy

Tramadol should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Use with caution.

Breast-feeding

Tramadol is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

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

Formulations

• Tablets
• Oral solution
• Injectable forms (intravenous, intramuscular, subcutaneous)

Indications

• Relief of discomfort in mild urinary tract infections
• Alkalinization of urine
• Management of metabolic acidosis

Dosage

Children: Refer to BNF for Children for specific dosing in paediatric patients.

Adults: 10 mL three times a day, diluted well with water.

Mechanism of action

Sodium citrate acts as a systemic alkalinizing agent. In the body, it is metabolized to bicarbonate, which helps to neutralize excess acid in the blood and urine, thus raising the pH and promoting the solubility of uric acid and cystine. This process can aid in the prevention of certain types of kidney stones and alleviate symptoms associated with acidotic states.

Pharmacodynamics

The pharmacodynamic effects of sodium citrate include the alkalinization of urine, which can help dissolve uric acid and cystine stones. By increasing urine pH, it enhances the solubility of these substances and reduces crystallization. Additionally, sodium citrate can help in managing metabolic acidosis by increasing bicarbonate concentrations in the bloodstream.

Pharmacokinetics

Sodium citrate is readily absorbed from the gastrointestinal tract. Following absorption, it is metabolized in the liver to bicarbonate, which is then distributed throughout the body. The elimination half-life is variable and depends on the individual's renal function and metabolic state. In patients with renal impairment, caution is advised due to the risk of hyperkalemia and electrolyte imbalances.

Contra-indications

• Addison’s disease
• dehydration
• hyperkalaemia
• ventricular arrhythmia
• inflammatory bowel disease
• intestinal obstruction

Adverse effects

• hyperkalaemia
• nausea
• vomiting
• gastrointestinal discomfort
• electrolyte imbalance
• metabolic acidosis
• chills

Interactions

• methenamine: Severe (decreases efficacy)
• sucralfate: Severe (increases risk of adverse effects)

Precautions

• Use with caution in cardiac disease
• Use with caution in the elderly
• Use with caution in renal impairment
• Use with caution in hepatic impairment

Pregnancy

Use only if clearly needed, as safety has not been established.

Breast-feeding

Use with caution, as it is not known whether sodium citrate is excreted in human milk.

Storage

Store at room temperature, protected from light. Keep out of reach of children.

Formulations

• Oral solution containing citric acid and potassium citrate
• Effervescent tablets containing citric acid and potassium citrate
• Sodium citrate for bladder washouts

Indications

• Hyponatremia
• Electrolyte imbalance
• Fluid replacement therapy

Dosage

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

Adults: Refer to the BNF for specific dosing guidelines.

Mechanism of action

Sodium acetate works as a source of sodium ions, especially in patients with hyponatremia. Sodium is essential for regulating extracellular fluid volume, controlling water distribution, fluid and electrolyte balance, and the osmotic pressure of body fluids. It also plays a vital role in nerve conduction, muscle contraction, acid-base balance, and cell nutrient uptake.

Pharmacodynamics

Sodium is the principal cation of extracellular fluid, making up more than 90% of total cations at its normal plasma concentration of approximately 140 mEq/liter. It plays a primary role in controlling total body water and its distribution. Additionally, acetate ions act as hydrogen ion acceptors, serving as an alternative to bicarbonate in physiological processes.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Sodium acetate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Sodium acetate is excreted in breast milk, but the effects on a nursing infant are unknown. Caution should be exercised when administering to a breastfeeding mother.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Sodium acetate injection
• Sodium acetate oral solution

Indications

• Moderate to moderately severe pain
• Post-operative pain
• Chronic pain management

Dosage

Children: Refer to BNF for Children for specific pediatric dosing recommendations.

Adults: Refer to BNF for specific dosing information based on individual patient needs and clinical circumstances.

Mechanism of action

Tramadol acts primarily as a μ-opioid receptor agonist, binding with low affinity compared to morphine. It exists as a racemic mixture, with both enantiomers contributing to its analgesic effects: (+)-tramadol and its active metabolite (+)-O-desmethyl-tramadol (M1) act on the μ-opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These actions work together to enhance pain modulation across multiple pathways.

Pharmacodynamics

Tramadol modulates the descending pain pathways in the central nervous system, resulting in analgesia. It can produce side effects similar to other opioids, such as dizziness, nausea, and constipation, but does not cause histamine release. It may also cause respiratory depression through its action on brain stem respiratory centers. Notably, tramadol can cause miosis, or constricted pupils, even in the absence of light.

Pharmacokinetics

Tramadol is absorbed rapidly after oral administration, reaching peak plasma concentrations within 1 to 2 hours. It is extensively metabolized in the liver, primarily via CYP2D6 and CYP3A4 enzymes, resulting in its active metabolite, M1. The elimination half-life ranges from 5 to 6 hours, and it is primarily excreted in the urine. The pharmacokinetics may vary due to genetic polymorphisms affecting metabolic enzymes.

Adverse effects

• dizziness
• somnolence
• nausea
• constipation
• sweating
• pruritus
• respiratory depression
• orthostatic hypotension
• miosis

Interactions

• carbamazepine+tramadol: Moderate (decreases concentration)
• bupropion+tramadol: Unknown (decreases efficacy)
• cinacalcet+tramadol: Unknown (decreases efficacy)
• terbinafine+tramadol: Unknown (decreases efficacy)

Pregnancy

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

Breast-feeding

Tramadol is excreted in breast milk, and caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• tablets
• capsules
• injection
• oral solution

Mechanism of action

Sodium and chloride - major electrolytes of the fluid compartment outside of cells (i.e., extracellular) - work together to control extracellular volume and blood pressure. Disturbances in sodium concentrations in the extracellular fluid are associated with disorders of water balance. Intra-amniotic instillation of 20% sodium chloride injection induces abortion and fetal death. Although the mechanism has not been conclusively determined, some studies indicate that the drug's abortifacient activity may be mediated by prostaglandins released from decidual cells damaged by hypertonic solutions of sodium chloride. Hypertonic sodium chloride-induced uterine contractions are usually sufficient to cause evacuation of both the fetus and placenta; however, abortion may be incomplete in 25-40% of patients. /20% injection/

Pharmacodynamics

Sodium, the major cation of the extracellular fluid, functions primarily in the control of water distribution, fluid balance, and osmotic pressure of body fluids. Sodium is also associated with chloride and bicarbonate in the regulation of the acid-base equilibrium of body fluid. Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the acid-base balance of the body are reflected by changes in the chloride concentration.

Mechanism of action

It works as a source of sodium ions especially in cases of hyponatremic patients. Sodium has a primary role in regulating extracellular fluid volume. It controls water distribution, fluid and electrolyte balance and the osmotic pressure of body fluids. Sodium is also involved in nerve conduction, muscle contraction, acid-base balance and cell nutrient uptake.

Pharmacodynamics

Sodium is the principal cation of extracellular fluid. It comprises more than 90% of total cations at its normal plasma concentration of approximately 140 mEq/liter. The sodium ion exerts a primary role in controlling total body water and its distribution. Acetate ions acts as hydrogen ion acceptor which is alternative to bicarbonate.

Mechanism of action

Tramadol is a centrally acting μ-opioid receptor agonist and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to [codeine] and [morphine]. Tramadol binds weakly to κ- and δ-opioid receptors and to the μ-opioid receptor with 6000-fold less affinity than morphine. Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol has also been shown to affect a number of pain modulators including alpha2-adrenoreceptors, neurokinin 1 receptors, the voltage-gated sodium channel type II alpha subunit, transient receptor potential cation channel subfamily V member 1 (TRPV1 - also known as the capsaicin receptor), muscarinic receptors (M1 and M3), N-methyl-D-aspartate receptor (also known as the NMDA receptor or glutamate receptor), Adenosine A1 receptors, and nicotinic acetylcholine receptor. In addition to the above neuronal targets, tramadol has a number of effects on inflammatory and immune mediators involved in the pain response. This includes inhibitory effects on cytokines, prostaglandin E2 (PGE2), nuclear factor-κB, and glial cells as well as a change in the polarization state of M1 macrophages. Tramadol is a racemic mixture (R & S) that has a complicated mechanism of action. It has some mu-opioid receptor action, but this effect is 10 times lower than codeine and 6000 timex lower than morphine. Tramadol also inhibits the reuptake of norepinephrine (NE) and serotonin (5 HT) and produces secondary effects on alpha-2 adrenergic receptors in pain pathways. One isomer has greater effect on 5 HT reuptake and greater affinity for mu-opiate receptors. The other isomer is more potent for NE reuptake and less active for inhibiting 5 HT reuptake. Taken together, the effects of of tramadol may be explained through inhibition of 5 HT reuptake, action on alpha2 receptors, and mild activity on opiate mu-receptors. The transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to mu-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively. We examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording. Tramadol and M1 (0.01-10 uM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1-10 uM) and M1 (1-10 uM) significant

Pharmacodynamics

Tramadol modulates the descending pain pathways within the central nervous system through the binding of parent and M1 metabolite to μ-opioid receptors and the weak inhibition of the reuptake of norepinephrine and serotonin. Apart from analgesia, tramadol may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. **Central Nervous System** In contrast to [morphine], tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Tramadol produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO2 tension and to electrical stimulation. Tramadol depresses the cough reflex by a direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose. Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections), or with concomitant use of other drugs known to reduce the seizure threshold. Tramadol can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g., anti-depressants, migraine medications). Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Tramadol should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, St. John’s Wort) due to the risk of serotonin syndrome. **Gastrointestinal Tract and Other Smooth Muscle** Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase. **Endocrine System** Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes. Hyponatremia has been reported very rarely with the use of tramadol, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diureti