SINUTAB-WITH-CODEINE COMBINATION PRODUCT TABLET

Indications

• Mild to moderate pain
• Short-term treatment of acute moderate pain
• Dry or painful cough

Dosage

Children: Children aged 12-17 years: 30-60 mg every 6 hours if required for a maximum of 3 days; maximum 240 mg per day. Use is contraindicated in children under 12 years.

Adults: 30 mg 3-4 times daily; usual dose 15-60 mg 3-4 times daily; maximum dose 240 mg per day.

Mechanism of action

Codeine is metabolized in the liver to morphine, which binds to mu-opioid receptors in the central nervous system, resulting in analgesia. This action alters the perception of and response to painful stimuli, providing relief from pain. Additionally, it may reduce the cough reflex through action on the cough center in the medulla.

Pharmacodynamics

As an opioid, codeine has a dose-dependent effect on pain relief and is associated with side effects typical of opioids, such as sedation, constipation, and potential respiratory depression. Its efficacy varies significantly among individuals due to genetic differences in metabolism, particularly involving the CYP2D6 enzyme, which converts codeine to morphine.

Pharmacokinetics

Codeine phosphate is well absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism in the liver, where it is converted to its active metabolite, morphine, and other metabolites. The peak plasma concentration occurs approximately 1-2 hours after oral administration. Codeine has a half-life of 3-4 hours, and both codeine and its metabolites are eliminated primarily via the kidneys.

Contra-indications

• Children under 12 years old
• Patients of any age known to be CYP2D6 ultra-rapid metabolisers
• Acute ulcerative colitis
• Antibiotic-associated colitis
• Children under 18 years who undergo the removal of tonsils or adenoids

Adverse effects

• Drowsiness
• Constipation
• Nausea
• Vomiting
• Dizziness
• Dry mouth
• Fatigue
• Malaise
• Mood alterations
• Hypotension
• Hypothermia
• Increased intracranial pressure
• Nightmares
• Muscle rigidity
• Lymphadenopathy
• Pancreatitis

Interactions

• CNS depressants (e.g. benzodiazepines, alcohol)
• MAO inhibitors
• Other opioids
• Antidepressants
• Antipsychotics
• Antihistamines

Precautions

• Use with caution in patients with respiratory depression
• History of substance abuse
• Cardiac arrhythmias
• Gallstones
• Mild to moderate pain in adolescents aged 12–18 years with breathing problems

Pregnancy

Codeine phosphate should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. There is a risk of neonatal opioid withdrawal syndrome if used in late pregnancy.

Breast-feeding

Codeine phosphate is not recommended for breastfeeding mothers due to the risk of opioid toxicity in infants. It is present in breast milk and the metabolism of codeine can vary significantly between individuals.

Storage

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

Formulations

• Codeine phosphate 30 mg capsules
• Codeine phosphate 30 mg tablets
• Combination products with paracetamol (e.g. Kapake, Solpadol, Tylex, Zapain)

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

• Mild to moderate pain relief
• Cough suppression
• Cough associated with tuberculosis
• Insomnia due to cough

Dosage

Children: Refer to

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

Mechanism of action

Codeine exerts its analgesic and antitussive effects mainly through the agonism of mu-opioid receptors in the central nervous system. Although only a small portion of codeine is metabolized to morphine, the analgesic effect is believed to be mediated by codeine-6-glucuronide, which has an affinity for mu receptors and can be converted to morphine-6-glucuronide, a more potent metabolite. The activation of G-proteins reduces intracellular cAMP and calcium levels, leading to hyperpolarization of nociceptive neurons and impaired pain signal transmission. Additionally, codeine suppresses the cough reflex by acting on the cough center in the medulla.

Pharmacodynamics

Codeine is classified as a weak narcotic pain reliever and cough suppressant. It increases pain tolerance and reduces discomfort while also inducing sedation, drowsiness, and respiratory depression. Codeine's antitussive action is effective particularly in cases of cough associated with tuberculosis and insomnia due to coughing. Furthermore, it may decrease intestinal motility, leading to constipation, and chronic use can result in obstructive bowel disease in susceptible individuals.

Pharmacokinetics

Codeine is absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 1 to 2 hours after administration. It is metabolized primarily in the liver by the cytochrome P450 system, particularly CYP2D6, which converts a small percentage to morphine. Codeine has a variable half-life, typically ranging from 3 to 4 hours. It is excreted mainly in the urine, primarily as metabolites.

Contra-indications

• Hypersensitivity to codeine or any of its components
• Severe respiratory depression
• Acute or severe bronchial asthma or hypercapnia
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping MAOIs
• Paralytic ileus

Adverse effects

• Sedation
• Drowsiness
• Respiratory depression
• Constipation
• Nausea
• Vomiting
• Dry mouth
• Dizziness
• Headache
• Itching or rash

Interactions

• bupropion+codeine: Unknown (decreases efficacy)
• cinacalcet+codeine: Unknown (decreases efficacy)
• terbinafine+codeine: Unknown (decreases efficacy)
• rifampicin+codeine: Unknown (decreases exposure)

Precautions

• Use with caution in patients with a history of substance use disorder
• Monitor for signs of respiratory depression, especially in opioid-naïve patients
• Caution in elderly patients or those with impaired hepatic or renal function
• Risk of addiction, abuse, and misuse
• Avoid abrupt discontinuation in patients on prolonged therapy

Pregnancy

Use only if clearly needed, as codeine may affect the fetus. Prolonged use during pregnancy may lead to neonatal withdrawal syndrome.

Breast-feeding

Caution is advised as codeine is excreted in breast milk and may cause respiratory depression in nursing infants.

Storage

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

Formulations

• Oral tablets
• Oral solution
• Syrup
• Combination products with other analgesics or cough suppressants

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

Indications

• Allergic rhinitis
• Allergic conjunctivitis
• Urticaria

Dosage

Children: Refer to the BNF for Children for specific dosage guidance.

Adults: Refer to the BNF for specific dosage guidance.

Mechanism of action

Phenyltoloxamine interferes with the agonist activity of histamine at the H1 receptor, which helps in the attenuation of inflammatory processes. It operates through the phospholipase C and phosphatidylinositol (PIP2) signaling pathways, leading to a reduction in the activity of the NF-kB immune response transcription factor. This mechanism decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Additionally, it enhances mast cell stability by lowering calcium ion concentration, which reduces further histamine release. Furthermore, phenyltoloxamine's ability to cross the blood-brain barrier results in sedation and various CNS effects.

Pharmacodynamics

As a first-generation H1 antihistamine, phenyltoloxamine has significant central nervous system effects due to its ability to cross the blood-brain barrier. This results in common adverse effects such as drowsiness, sedation, and fatigue. These sedative effects may contribute to its potential adjunctive analgesic and antitussive actions in specific clinical scenarios, particularly when distress from pain or cough is prevalent.

Pharmacokinetics

The pharmacokinetics of phenyltoloxamine, like many first-generation antihistamines, are characterized by rapid absorption and significant distribution throughout the body, including the central nervous system. The metabolism and elimination pathways are not well-defined in the provided sources, but first-generation antihistamines are generally metabolized in the liver and excreted primarily via the kidneys.

Adverse effects

• Drowsiness
• Sedation
• Somnolence
• Fatigue
• Nervousness
• Insomnia

Pregnancy

Safety in pregnancy has not been established. Use only if clearly needed and after assessing potential benefits and risks.

Breast-feeding

It is not known if phenyltoloxamine is excreted in human milk. Caution is advised when administered to breastfeeding women.

Storage

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

Formulations

• Tablets
• 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

Although the exact mechanism of action of codeine is still unknown, it is generally thought to be mediated through the agonism of opioid receptors, particularly the mu-opioid receptors. Morphine was previously postulated to contribute to the analgesic effect of codeine due to the O-demethylation of codeine to morphine by CYP2D6. Particularly, CYP2D6 poor metabolizer did not experience the analgesic effect of codeine. However, this is unlikely to be the main mechanism of action of codeine as only 5% of codeine is metabolized to morphine. Other hypotheses also postulate that codeine-6-glucuronide, the main metabolite of codeine, mediates the analgesic effect of codeine as it not only has an affinity to the mu receptors as codeine but also can be metabolized to morphine-6-glucuronide, which was observed to be more potent than morphine. Binding to the mu receptors by codeine activates the G-proteins Gα_i, causing a decrease in intracellular cAMP and Ca²⁺ level. This causes hyperpolarization of nociceptive neurons, thus imparing the transmission of pain signals. Codeine causes suppression of the cough reflex by a direct effect on the cough center in the medulla of the brain and appears to exert a drying effect on respiratory tract mucosa and to increase viscosity of bronchial secretions.

Pharmacodynamics

**General effects** Codeine is a weak narcotic pain reliever and cough suppressant that is similar to morphine and hydrocodone. A small amount of ingested codeine is converted to morphine in the body. Codeine increases tolerance to pain, reducing existing discomfort. In addition to decreasing pain, codeine also causes sedation, drowsiness, and respiratory depression. **Antitussive activity** This drug has shown antitussive activity in clinical trials and has been effective in cough secondary to tuberculosis and insomnia due to coughing. Codeine suppresses the cough reflex through a direct effect on the cough center in the medulla. **Effects on intestinal motility** Codeine may reduce intestinal motility through both a local and possibly central mechanism of action. This may possibly lead to constipation. The chronic use of opioids, including codeine sulfate, may lead to obstructive bowel disease, particularly in patients with underlying disorders of intestinal motility. **Effects on the central nervous system** Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is much less potent as an analgesic. Its primary site of action is at the _mu_ opioid receptors distributed throughout the central nervous system. The sedative activities of codeine are less potent than those of morphine. Codeine may cause respiratory system depression by the activation of μ-opioid receptors at specific sites in the central nervous system. **Effects on blood pressure** This drug poses an increased risk of compromised ability to maintain blood pressure due to peripheral vasodilation and other mechanisms. **Effects on chronic cancer pain and other types of pain** Codeine is an opioid analgesic with similar indications to those of morphine, however, is much less potent in its pain alleviating properties. Its primary action takes place at the mu opioid receptors, which are distributed throughout the central nervous system. The average duration of action is about 4 hours. Regular dosing of opioid analgesics such as codeine in patients with severe cancer pain has been well documented to improve symptoms,.

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.

Mechanism of action

As a first-generation H1 antihistamine, phenyltoloxamine interferes with the agonist activity of histamine at the H1 receptor and are ostensibly used to attenuate inflammatory processes as a means to treat conditions like allergic rhinitis, allergic conjunctivitis, and urticaria. Reduction of the activity of the NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) immune response transcription factor via the phospholipase C and phosphatidylinositol (PIP2) signaling pathways also serves to decrease antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Moreover, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. Additionally, first-generation antihistamines like phenyltoloxamine readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects, like nervousness and insomnia. By comparison, second-generation antihistamines are more selective for H1 receptors in the peripheral nervous system and do not cross the blood-brain barrier, resulting in fewer adverse drug effects overall. Furthermore, although some studies propose that phenyltoloxamine may possess some intrinsic antispasmodic and distinct local anesthetic properties, the specific mechanisms of action for these effects have not been formalized. Also, even though the combination of phenyltoloxamine's ability to cross the blood-brain barrier and cause various tranquilizing effects may explain to some extent how it may be able to potentiate analgesic effects, there are also studies that observed no potentiating effects associated with phenyltoloxamine use either.

Pharmacodynamics

As a member of the first generation H1 antihistamines, it is known that phenyltoloxamine - like virtually all first generation H1 antihistamines - has a propensity for crossing the blood-brain barrier and acting on H1 histamine receptors there to interfere with neurotransmission. The most common results of this kind of first generation H1 antihistamine CNS neurotransmission interference are adverse effects like drowsiness, sedation, somnolence, and fatigue. Given these effects, under specific circumstances like a patient experiencing a pain or a cough that may be preoccupying all of their waking energy and attention, it is perhaps possible that the sedative and tranquilizing characteristics of phenyltoloxamine may be the factors that contribute to its apparent adjunctive analgesic and antitussive actions.