PARA-COMB

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

• Management of apnea of prematurity
• Enhancement of alertness and cognitive performance
• Relief of headaches, particularly when combined with analgesics
• Enhancement of physical performance in sports

Dosage

Children: For infants, particularly for apnea of prematurity

Adults: The usual adult dose for alertness enhancement is 100 to 200 mg, taken as needed. For the management of apnea of prematurity, doses may vary and should be determined by a healthcare professional.

Mechanism of action

Caffeine acts primarily as an antagonist of adenosine receptors, inhibiting the action of adenosine, which normally promotes sleep and relaxation. This antagonism leads to increased neuronal firing and the release of neurotransmitters such as dopamine and norepinephrine. Caffeine also inhibits phosphodiesterase enzymes, enhancing levels of cyclic AMP and cyclic GMP, which are important for various cellular functions. Additionally, in the context of respiratory function, caffeine stimulates the respiratory centers in the central nervous system, enhancing ventilation.

Pharmacodynamics

Caffeine stimulates the central nervous system, increasing alertness and reducing fatigue. It relaxes smooth muscles, increases cardiac muscle contraction, and can enhance physical performance. Caffeine also promotes gastric acid secretion and gastrointestinal motility, and it exhibits mild diuretic properties. Its effects can lead to restlessness and agitation in some individuals, particularly at higher doses.

Pharmacokinetics

Caffeine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 30 to 120 minutes after ingestion. It is distributed widely throughout body tissues, readily crossing the blood-brain barrier. Caffeine is metabolized primarily in the liver by cytochrome P450 1A2, producing three primary metabolites: paraxanthine, theobromine, and theophylline. The elimination half-life varies significantly among individuals, influenced by factors such as age, liver function, pregnancy, and the use of certain medications. It is primarily excreted in urine.

Adverse effects

• Restlessness
• Agitation
• Insomnia
• Increased heart rate
• Nausea
• Gastrointestinal discomfort
• Headaches

Interactions

• caffeinecitrate+adenosine: Unknown (decreases efficacy)
• caffeinecitrate+antiarrhythmics: Unknown (decreases efficacy)

Precautions

• Use cautiously in patients with a history of anxiety disorders, insomnia, or cardiac arrhythmias.
• Monitor caffeine intake in individuals with certain medical conditions, such as hypertension.

Pregnancy

Caffeine crosses the placenta; excessive intake during pregnancy may be associated with adverse outcomes. It is generally recommended to limit caffeine consumption.

Breast-feeding

Caffeine is excreted in breast milk; moderate consumption is considered safe, but excessive intake may affect the infant's sleep and behavior.

Storage

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

Formulations

• Tablets
• Oral solutions
• Injectable preparations
• Caffeine citrate

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

• Insomnia
• Allergic rhinitis
• Urticaria
• Other allergic reactions

Dosage

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

Adults: Refer to the BNF for specific adult dosing guidelines as it varies based on indication.

Mechanism of action

Doxylamine acts by competitively inhibiting histamine at H1 receptors, which reduces the effects of histamine in the body, leading to decreased allergy symptoms and sedation. Its substantial sedative and anticholinergic effects enhance its utility in treating sleep disturbances.

Pharmacodynamics

Doxylamine is widely recognized for its anti-allergic properties, surpassing many antihistamines in effectiveness, particularly in managing allergy symptoms and inducing sleep. It is more sedating than many prescription hypnotics and has been shown to be superior to phenobarbital in its sedative effects. Its potent anticholinergic properties further contribute to its overall therapeutic profile.

Pharmacokinetics

Doxylamine is well absorbed following oral administration. It undergoes hepatic metabolism and has a relatively long elimination half-life, which contributes to its prolonged sedative effects. The drug's pharmacokinetics may vary based on individual patient factors, including age and liver function.

Contra-indications

• Hypersensitivity to doxylamine or any component of the formulation
• Glaucoma
• Prostatic hypertrophy
• Bladder neck obstruction

Adverse effects

• Drowsiness
• Dizziness
• Dry mouth
• Constipation
• Blurred vision
• Urinary retention

Interactions

• Alcohol may enhance the sedative effects of doxylamine
• CNS depressants can increase sedation and respiratory depression
• MAO inhibitors can prolong and intensify the anticholinergic effects

Precautions

• Use with caution in patients with asthma or other respiratory conditions
• Caution in elderly patients due to increased sensitivity to anticholinergic effects
• Should not be used in patients with severe liver impairment

Pregnancy

Doxylamine is classified as category A in pregnancy; it is generally considered safe when used as directed for short-term management of nausea and vomiting in pregnancy.

Breast-feeding

Doxylamine is excreted in breast milk; caution is advised when administering to nursing mothers as it may cause sedation in the infant.

Storage

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

Formulations

• Tablets
• Liquid formulations

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

The mechanism of action of caffeine is complex, as it impacts several body systems, which are listed below. The effects as they relate to various body systems are described as follows: **General and cellular actions** Caffeine exerts several actions on cells, but the clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participates in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP. This causes lipolysis through activation of hormone-sensitive lipases, releasing fatty acids and glycerol. **Respiratory** The exact mechanism of action of caffeine in treating apnea related to prematurity is unknown, however, there are several proposed mechanisms, including respiratory center stimulation in the central nervous system, a reduced threshold to hypercapnia with increased response, and increased consumption of oxygen, among others. The blocking of the adenosine receptors enhances respiratory drive via an increase in brain medullary response to carbon dioxide, stimulating ventilation and respiratory drive, while increasing contractility of the diaphragm. **Central nervous system** Caffeine demonstrates antagonism of all 4 adenosine receptor subtypes (A1, A2a, A2b, A3) in the central nervous system. Caffeine's effects on alertness and combatting drowsiness are specifically related to the antagonism of the A2a receptor. **Renal system** Caffeine has diuretic effects due to is stimulatory effects on renal blood flow, increase in glomerular filtration, and increase in sodium excretion. **Cardiovascular system** Adenosine receptor antagonism at the A1 receptor by caffeine stimulates inotropic effects in the heart. Blocking of adenosine receptors promotes catecholamine release, leading to stimulatory effects occurring in the heart and the rest of the body. In the blood vessels, caffeine exerts direct antagonism of adenosine receptors, causing vasodilation. It stimulates the endothelial cells in the blood vessel wall to release nitric oxide, potentiating blood vessel relaxation. Catecholamine release, however, antagonizes this and exerts inotropic and chronotropic effects on the heart, ultimately leading to vasoconstriction. Finally, caffeine is shown to raise systolic blood pressure measurements by 5 to 10 mmHg when it is not taken regularly, versus no effect in those who consume it regularly. The vasoconstricting effects of caffeine are beneficial in migraines and other types of headache, which are normally caused by vasodilation in the brain. Caffeine competitively inhibits phosphodiesterase, the enzyme that degrades cyclic 3',5'-adenosine monophosphate (AMP). Increased levels of intracellular cyclic AMP mediate most of caffeine's pharmacologic actions. Caffeine stimulates all levels of the CNS... Caffeine's cortical effects are milder and of shorter duration than those of amphetamines. In slightly larger doses, caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. Caffeine constricts cerebral vasculature. In contrast, the drug directly dilates peripheral blood vessels...

Pharmacodynamics

Caffeine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance. Caffeine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, caffeine acts as a mild diuretic.

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

Like other antihistamines, doxylamine acts by competitively inhibiting histamine at H1 receptors. It also has substantial sedative and anticholinergic effects.

Pharmacodynamics

Doxylamine is an antihistamine commonly used as a sleep aid. This drug is also used to relieve symptoms of hay fever (allergic rhinitis), hives (rash or itching), and other allergic reactions. Doxylamine is a member of the ethanolamine class of antihistamines and has anti-allergy power far superior to virtually every other antihistamine on the market, with the exception of diphenhydramine (Benadryl). It is also the most powerful over-the-counter sedative available in the United States, and more sedating than many prescription hypnotics. In a study, it was found to be superior to even the barbiturate, phenobarbital for use as a sedative. Doxylamine is also a potent anticholinergic.