FLUSTAT COMBINATION PRODUCT SYRUP

Indications

• Mild to moderate pain
• Fever
• Headaches
• Muscle aches
• Arthritis
• Backaches
• Toothaches
• Colds

Dosage

Adults: For adults, the typical dosage is 500 mg to 1 g every 4 to 6 hours, with a maximum daily limit of 4 g. In cases of intravenous administration, the dosage is 15 mg/kg every

Mechanism of action

Paracetamol is thought to exert its analgesic effects by inhibiting cyclo-oxygenase (COX) enzymes, specifically COX-1 and COX-2, which are involved in the synthesis of prostaglandins responsible for pain sensation. Unlike most NSAIDs, paracetamol does not exhibit peripheral anti-inflammatory effects. Its antipyretic action is believed to result from direct action on heat-regulating centers in the brain, leading to peripheral vasodilation and sweating.

Pharmacodynamics

Paracetamol has been shown to have both antipyretic and analgesic effects, lacking any significant anti-inflammatory activity. It does not interfere with platelet aggregation or disrupt hemostasis, making it a safer option for individuals at risk of bleeding. Allergic reactions to paracetamol are rare. The drug does not affect uric acid secretion or acid-base balance when used at recommended doses.

Pharmacokinetics

Paracetamol is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 30 to 60 minutes after oral administration. It is primarily metabolized in the liver via conjugation with glucuronide and sulfate, with a minor pathway involving cytochrome P450 enzymes. The elimination half-life ranges from 1 to 4 hours, with renal excretion of metabolites as the primary route of elimination.

Adverse effects

• Nausea and vomiting
• Liver injury
• Renal damage
• Hypersensitivity reactions
• Flushing
• Hypotension
• Anorectal erythema
• Angioedema
• Agranulocytosis
• Thrombocytopenia
• Leukopenia
• Severe cutaneous adverse reactions (SCARs)

Interactions

• Increased risk of methaemoglobinaemia with topical prilocaine
• Increased risk of methaemoglobinaemia with topical anaesthetics
• Increased anticoagulant effect with coumarins
• Increased risk of hepatotoxicity with imatinib
• Decreased exposure with rifampicin
• Decreased exposure with pitolisant

Precautions

• Monitor patients with liver disease or heavy alcohol use for increased risk of hepatotoxicity
• Adjust doses in patients taking enzyme-inducing antiepileptic medications
• Use caution in patients with renal impairment
• Clinical judgement is required for dose adjustment in weight-based dosing

Pregnancy

Paracetamol is generally considered safe to use during pregnancy for pain and fever relief, but should be used at the lowest effective dose for the shortest duration necessary.

Breast-feeding

Paracetamol is excreted in breast milk in small amounts and is considered safe for use while breastfeeding.

Storage

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

Formulations

• Oral tablets (500 mg)
• Oral suspension (120 mg/5 mL, 500 mg/5 mL)
• Rectal suppositories (various strengths)
• Intravenous infusion (various strengths)

Indications

• Cough
• Pseudobulbar affect

Dosage

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

Adults: Refer to the BNF for specific dosing guidelines based on the formulation and clinical context.

Mechanism of action

Dextromethorphan acts as a low-affinity uncompetitive antagonist of NMDA receptors and as an agonist at sigma-1 receptors. It also antagonizes α3/β4 nicotinic receptors. The clinical effects are thought to arise from NMDA receptor blockade and serotonin (5-HT) uptake inhibition, which may lead to increased serotonin receptor stimulation. However, the precise mechanisms by which these actions translate into therapeutic effects remain incompletely understood.

Pharmacodynamics

Dextromethorphan is considered an opioid-like molecule with a moderate therapeutic window, indicating that while it is effective at standard doses, higher doses can lead to intoxication. It has a moderate duration of action, making it suitable for use in cough management. Due to its potential for abuse and risk of intoxication, patients are advised to use it cautiously.

Pharmacokinetics

Dextromethorphan is metabolized primarily in the liver through the cytochrome P450 enzyme system, leading to the formation of its active metabolite, dextrorphan. The pharmacokinetics may be influenced by individual variations in metabolic pathways, which can affect the drug's efficacy and safety profile.

Contra-indications

• Hypersensitivity to dextromethorphan or any of its components
• Concurrent use with monoamine oxidase inhibitors (MAOIs)
• Severe respiratory insufficiency or asthma
• Persistent cough due to smoking, emphysema, or chronic bronchitis

Adverse effects

• Dizziness
• Nausea
• Vomiting
• Drowsiness
• Confusion
• Constipation
• Abdominal discomfort
• Euphoria or dysphoria
• Serotonin syndrome (when used with serotonergic drugs)

Interactions

• May interact with MAOIs, leading to serious side effects
• Potential interactions with other CNS depressants, leading to increased sedation
• May enhance the effects of alcohol
• Can interact with medications that affect serotonin levels, increasing the risk of serotonin syndrome

Precautions

• Use with caution in patients with a history of substance abuse
• Monitor use in patients with hepatic impairment
• Caution advised in patients with a history of seizures
• Should not be used in children under 2 years unless directed by a physician

Pregnancy

Dextromethorphan should be used during pregnancy only if clearly needed. Consult a healthcare provider for advice.

Breast-feeding

Dextromethorphan is excreted in breast milk. Caution is advised when administered to nursing mothers.

Storage

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

Formulations

• Oral syrup
• Tablets
• Capsules
• Lozenges

Indications

• Nasal congestion
• Cough-cold formulations
• Appetite suppression

Dosage

Adults: Refer to the BNF for

Mechanism of action

Phenylpropanolamine acts directly on alpha- and, to a lesser extent, beta-adrenergic receptors in the respiratory tract mucosa. Activation of alpha-adrenergic receptors induces vasoconstriction, which decreases tissue hyperemia, edema, and nasal congestion, thereby improving nasal airway patency. PPA may also stimulate beta-receptors, resulting in tachycardia and a positive inotropic effect. The drug likely functions by releasing norepinephrine from its storage sites, with alpha-adrenergic effects emerging from inhibition of adenyl cyclase activity and beta-adrenergic effects from cyclic adenosine 3',5'-monophosphate (AMP) production via adenyl cyclase activation. Repeated use can lead to norepinephrine depletion, resulting in tachyphylaxis.

Pharmacodynamics

Phenylpropanolamine, classified as a sympathomimetic, primarily serves as a decongestant. Its usage has declined due to safety concerns, particularly the risk of hemorrhagic stroke in female patients. Despite its decongestant properties, the FDA has advised against its use in over-the-counter products since 2000, reflecting its potential adverse effects.

Pharmacokinetics

The pharmacokinetics of phenylpropanolamine include its absorption, distribution, metabolism, and excretion characteristics, though specific data on half-life and bioavailability are not detailed in the provided information. Its sympathomimetic effects are mediated through adrenergic receptor stimulation, and prolonged use may lead to decreased efficacy due to tachyphylaxis.

Contra-indications

• Hypersensitivity to phenylpropanolamine or any component of the formulation
• Severe hypertension
• Severe coronary artery disease
• Hyperthyroidism
• Glaucoma
• Concurrent use of monoamine oxidase inhibitors (MAOIs)

Adverse effects

• Hypertension
• Tachycardia
• Nervousness
• Dizziness
• Insomnia
• Headache
• Dry mouth
• Nausea
• Vomiting
• Constipation

Interactions

• MAO inhibitors - may cause hypertensive crisis
• Tricyclic antidepressants - may enhance hypertensive effect
• Beta-blockers - may diminish the effectiveness of phenylpropanolamine
• Other sympathomimetics - increased risk of cardiovascular side effects

Precautions

• Use with caution in patients with cardiovascular disease
• Monitor blood pressure regularly during treatment
• Caution in patients with diabetes, prostate enlargement, or urinary retention
• Not recommended for use in children under 12 years of age

Pregnancy

Phenylpropanolamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Safety in pregnancy has not been established.

Breast-feeding

It is not known whether phenylpropanolamine is excreted in human milk. Caution is advised when administering to breastfeeding women.

Storage

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

Formulations

• Phenylpropanolamine hydrochloride tablet
• Phenylpropanolamine syrup

Indications

• Nasal congestion due to allergies
• Common cold
• Sinusitis
• Appetite suppression

Dosage

Children: Refer to specific product guidelines for dosing information, as it can vary by formulation and indication.

Adults: Refer to specific product guidelines for dosing information, as it can vary by formulation and indication.

Mechanism of action

Phenylpropanolamine acts primarily as an adrenergic agonist, stimulating alpha-1 adrenergic receptors. This stimulation results in vasoconstriction of blood vessels in the nasal mucosa, leading to decreased edema and congestion. Additionally, it may have effects on the central nervous system, contributing to appetite suppression.

Pharmacodynamics

The pharmacodynamics of phenylpropanolamine involves its action on adrenergic receptors, particularly alpha-1 receptors, which mediate smooth muscle contraction and vasoconstriction. This leads to increased blood pressure and decreased blood flow to the nasal mucosa, ameliorating symptoms of nasal congestion. Its central effects may also include increased alertness and decreased appetite, although these effects vary among individuals.

Pharmacokinetics

Phenylpropanolamine is absorbed from the gastrointestinal tract and reaches peak plasma concentrations within 1 to 3 hours after oral administration. It is metabolized by monoamine oxidase and other pathways in the liver, with a half-life ranging from 2 to 4 hours. The drug is primarily excreted in the urine, both as unchanged drug and metabolites. Factors such as age, liver function, and other medications can influence its pharmacokinetics.

Contra-indications

• Hypersensitivity to phenylpropanolamine or any component of the formulation
• Severe hypertension
• Severe cardiovascular disorders
• Hyperthyroidism
• Glaucoma
• Use in patients taking monoamine oxidase inhibitors (MAOIs)

Adverse effects

• Insomnia
• Nervousness
• Dizziness
• Headache
• Tachycardia
• Palpitations
• Hypertension
• Dry mouth
• Nausea

Interactions

• Increased risk of hypertension when used with other sympathomimetics
• Potentially increased effects with MAOIs leading to hypertensive crises
• May decrease effectiveness of antihypertensive medications

Precautions

• Use with caution in patients with a history of hypertension
• Monitor blood pressure regularly during treatment
• Caution in patients with diabetes mellitus or prostate enlargement
• Avoid use in pregnant or breastfeeding women unless clearly necessary

Pregnancy

Phenylpropanolamine is not recommended during pregnancy due to potential risks. Consult a healthcare provider for alternative treatments.

Breast-feeding

It is advisable to avoid phenylpropanolamine while breastfeeding due to potential effects on the infant. Consult a healthcare provider for safer alternatives.

Storage

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

Formulations

• Tablets
• Capsules
• Syrup

Mechanism of action

According to its FDA labeling, acetaminophen's exact mechanism of action has not been fully established - despite this, it is often categorized alongside NSAIDs (non-steroidal anti-inflammatory drugs) due to its ability to inhibit the cyclo-oxygenase (COX) pathways. It is thought to exert central actions which ultimately lead to the alleviation of pain symptoms. One theory is that acetaminophen increases the pain threshold by inhibiting two isoforms of cyclo-oxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis. Prostaglandins are responsible for eliciting pain sensations. Acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, therefore, has no peripheral anti-inflammatory effects. Though acetylsalicylic acid (aspirin) is an irreversible inhibitor of COX and directly blocks the active site of this enzyme, studies have shown that acetaminophen (paracetamol) blocks COX indirectly. Studies also suggest that acetaminophen selectively blocks a variant type of the COX enzyme that is unique from the known variants COX-1 and COX-2. This enzyme has been referred to as _COX-3_. The antipyretic actions of acetaminophen are likely attributed to direct action on heat-regulating centers in the brain, resulting in peripheral vasodilation, sweating, and loss of body heat. The exact mechanism of action of this drug is not fully understood at this time, but future research may contribute to deeper knowledge. Although further investigation is warranted, the active metabolite of acetaminophen (AM404) was shown to interact with several molecular targets, including the Ca_v3.2 calcium channel, the cannabinoid CB1 receptors, TRPV1 receptors, and Na_v1.8 and Na_v1.7 channels. Acetaminophen produces analgesia and antipyresis by a mechanism similar to that of salicylates. Unlike salicylates, however, acetaminophen does not have uricosuric activity. There is some evidence that acetaminophen has weak anti-inflammatory activity in some nonrheumatoid conditions (e.g., in patients who have had oral surgery). ... Acetaminophen lowers body temperature in patients with fever but rarely lowers normal body temperature. The drug acts on the hypothalamus to produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow. The effects of acetaminophen on cyclooxygenase activity have not been fully determined. Acetaminophen is a weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily. The inhibitory effect of acetaminophen on cyclooxygenase-1 is limited, and the drug does not inhibit platelet function. Therapeutic doses of acetaminophen appear to have little effect on cardiovascular and respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing. Acetaminophen (N-acetyl-p-aminophenol (APAP)) is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, /the researchers/ hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase

Pharmacodynamics

Animal and clinical studies have determined that acetaminophen has both antipyretic and analgesic effects. This drug has been shown to lack anti-inflammatory effects. As opposed to the _salicylate_ drug class, acetaminophen does not disrupt tubular secretion of uric acid and does not affect acid-base balance if taken at the recommended doses. Acetaminophen does not disrupt hemostasis and does not have inhibitory activities against platelet aggregation. Allergic reactions are rare occurrences following acetaminophen use.

Mechanism of action

Dextromethorphan is a low-affinity uncompetitive NMDA antagonist and sigma-1 receptor agonist. It is also an antagonist of α3/β4 nicotinic receptors. However, the mechanism by which dextromethorphan's receptor agonism and antagonism translate to a clinical effect is not well understood. Dextromethorphan (DXM) is the dextro isomer of levomethorphan, a semisynthetic morphine derivative. Although structurally similar to other /CNS depressants/, DXM does not act as a mu receptor opioid (eg, morphine, heroin). DXM and its metabolite, dextrorphan, act as potent blockers of the N-methyl-d-aspartate (NMDA) receptor. Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients. Dextromethorphan (DM) is a dextrorotatory morphinan and an over-the-counter non-opioid cough suppressant. We have previously shown that DM protects against LPS-induced dopaminergic neurodegeneration through inhibition of microglia activation. Here, we investigated protective effects of DM against endotoxin shock induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice and the mechanism underlying its protective effect. Mice were given multiple injections of DM (12.5 mg/kg, s.c.) 30 min before and 2, 4 hr after an injection of LPS/GalN (20 ug/700 mg/kg). DM administration decreased LPS/GalN-induced mortality and hepatotoxicity, as evidenced by increased survival rate, decreased serum alanine aminotransferase activity and improved pathology. Furthermore, DM was also effective when it was given 30 min after LPS/GalN injection. The protection was likely associated with reduced serum and liver tumor necrosis factor alpha (TNF-alpha) levels. DM also attenuated production of superoxide and intracellular reactive oxygen species in Kupffer cells and neutrophils. Real-time RT-PCR analysis revealed that DM administration suppressed the expression of a variety of inflammation-related genes such as macrophage inflammatory protein-2, CXC chemokine, thrombospondin-1, intercellular adhesion molecular-1 and interleukin-6. DM also decreased the expression of genes related to cell-death pathways, such as the DNA damage protein genes GADD45 and GADD153. In summary, DM is effective in protecting mice against LPS/GalN-induced hepatotoxicity, and the mechanism is likely through a faster TNF-alpha clearance, and decrease of superoxide production and inflammation and cell-death related components. This study not only extends neuroprotective effect of DM, but also suggests that DM may be a novel compound for the therapeutic intervention for sepsis. /The

Pharmacodynamics

Dextromethorphan is an opioid-like molecule indicated in combination with other medication in the treatment of coughs and pseudobulbar affect. It has a moderate therapeutic window, as intoxication can occur at higher doses. Dextromethorphan has a moderate duration of action. Patients should be counselled regarding the risk of intoxication.

Mechanism of action

Phenylpropanolamine acts directly on alpha- and, to a lesser degree, beta-adrenergic receptors in the mucosa of the respiratory tract. Stimulation of alpha-adrenergic receptors produces vasoconstriction, reduces tissue hyperemia, edema, and nasal congestion, and increases nasal airway patency. PPA indirectly stimulates beta-receptors, producing tachycardia and a positive inotropic effect. The mechanism of action of phenylpropanolamine has not been conclusively determined. The drug may directly stimulate adrenergic receptors but probably indirectly stimulates both A- and B-adrenergic receptors by releasing norepinephrine from its storage sites. It is believed that B-adrenergic effects result from stimulation of cyclic adenosine 3',5'-monophosphate (AMP) production by activation of the enzyme adenyl cyclase, whereas A-adrenergic effects result from inhibition of adenyl cyclase activity. With prolonged use or too frequent administration, indirectly acting sympathomimetics may deplete norepinephrine in sympathetic nerve endings and tachyphylaxis may develop. Tachyphylaxis induced by one indirectly acting sympathomimetic may result in refractoriness to other drugs of the same class. /Phenylpropanolamine hydrochloride/ Whether the alpha1- and alpha2-adrenoceptor mediated increases in diastolic blood pressure effected by phenylpropanolamine and its enantiomers are altered by, or independent of beta2-mediated vasodilation, or beta2-adrenoceptor blockade were studied in pithed rats. The pressor responses were enhanced in the presence of the antagonist ICI-118551 and diminished in the presence of albuterol. It was concluded that each form of phenylpropanolamine possesses the intrinsic ability to interact with all of the adrenoceptors in the system used and that the interaction with those adrenoceptors determines the net increase in diastolic blood pressure that follows the intravenous administration of the compounds. These findings have a bearing on the recent controversy regarding the use of beta-blocking agents in the treatment of overdosage of phenylpropanolamine.

Pharmacodynamics

Phenylpropanolamine (PPA), a sympathomimetic agent structurally similar to pseudoephedrine, is used to treat nasal congestion. Phenylpropanolamine is found in appetite suppressant formulations and with guaifenesinin in cough-cold formulations. In 2000, the FDA requested that all drug companies discontinue marketing products containing phenylpropanolamine, due to an increased risk of hemorrhagic stroke in women who used phenylpropanolamine.