ASPIRIN AND CODEINE PHOSPHATE

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

• Prevention of thrombus formation after cardiac surgery
• Thromboembolism prophylaxis
• Management of Kawasaki disease
• Pain relief
• Fever reduction
• Anti-inflammatory treatment

Dosage

Children: Refer to BNF for Children for specific dosing; general guidance includes 1-5 mg/kg once daily for children aged 1 month to 11 years (max. dose 75 mg) and 75 mg once daily for children aged 12-17 years.

Adults: For antiplatelet effects, typically 75-150 mg once daily. For inflammatory conditions, doses may range from 300 mg to 3 g daily, divided into several doses.

Mechanism of action

Aspirin irreversibly inhibits cyclooxygenase (COX-1 and COX-2) enzymes, leading to decreased production of thromboxane A2, a potent promoter of platelet aggregation, thereby reducing platelet aggregation and thrombus formation.

Pharmacodynamics

Aspirin's antiplatelet effect is dose-dependent, with lower doses primarily affecting platelet function and higher doses providing anti-inflammatory and analgesic effects. It is effective in reducing the risk of cardiovascular events and managing inflammatory conditions.

Pharmacokinetics

Aspirin is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 1-2 hours post-ingestion. It is extensively metabolized in the liver, and its elimination half-life varies depending on the dose. Aspirin is primarily excreted as salicylic acid and other metabolites in the urine.

Contra-indications

• Active gastrointestinal bleeding
• Severe renal impairment
• Severe hepatic impairment
• Hypersensitivity to aspirin or other NSAIDs
• History of peptic ulcer disease
• Asthma exacerbated by aspirin or other NSAIDs

Adverse effects

• Gastrointestinal irritation
• Dyspepsia
• Gastrointestinal bleeding
• Allergic reactions
• Tinnitus
• Reye's syndrome in children

Interactions

• Severe interaction with bismuth subsalicylate (increases risk of adverse effects)
• Moderate interaction with pemetrexed (increases exposure)
• Unknown interactions with bisphosphonates (increases risk of gastrointestinal irritation and renal impairment)
• Unknown interaction with corticosteroids (decreases concentration)
• Unknown interaction with daptomycin (increases risk of renal impairment)
• Unknown interaction with erlotinib (increases risk of gastrointestinal perforation)

Precautions

• Use with caution in patients with a history of gastrointestinal disorders
• Monitor renal function in long-term use
• Avoid use in children with viral infections due to the risk of Reye's syndrome
• Consider proton pump inhibitors for patients at high risk of gastrointestinal bleeding

Pregnancy

Use with caution; not recommended in the third trimester due to risk of bleeding complications.

Breast-feeding

Generally considered safe; aspirin is excreted in breast milk in small amounts.

Storage

Store below 25°C in a tightly closed container, protect from light.

Formulations

• Tablet
• Liquid formulation
• Effervescent tablet

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

Mechanism of action

Acetylsalicylic acid (ASA) blocks prostaglandin synthesis. It is non-selective for COX-1 and COX-2 enzymes. Inhibition of COX-1 results in the inhibition of platelet aggregation for about 7-10 days (average platelet lifespan). The acetyl group of acetylsalicylic acid binds with a serine residue of the cyclooxygenase-1 (COX-1) enzyme, leading to irreversible inhibition. This prevents the production of pain-causing prostaglandins. This process also stops the conversion of arachidonic acid to thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation. Platelet aggregation can result in clots and harmful venous and arterial thromboembolism, leading to conditions such as pulmonary embolism and stroke. It is important to note that there is 60% homology between the protein structures of COX-1 and COX-2. ASA binds to serine 516 residue on the active site of COX-2 in the same fashion as its binding to the serine 530 residue located on the active site of COX-1. The active site of COX-2 is, however, slightly larger than the active site of COX-1, so that arachidonic acid (which later becomes prostaglandins) manages to bypass the aspirin molecule inactivating COX-2. ASA, therefore, exerts more action on the COX-1 receptor rather than on the COX-2 receptor. A higher dose of acetylsalicylic acid is required for COX-2 inhibition. Produce analgesia through a peripheral action by blocking pain impulse generation and via a central action, possibly in the hypothalamus. The peripheral action may predominate and probably involves inhibition of the synthesis or prostaglandins, and possibly inhibition of the synthesis and/or actions of other substances, which sensitize pain receptors to mechanical or chemical stimulation. /Salicylates/ May produce antipyresis by acting centrally on the hypothalamic heat-regulating center to produce peripheral vasodilation resulting in increased cutaneous blood flow, sweating, and heat loss. The central action may involve inhibition of prostaglandin synthesis in the hypothalamus; however, there is some evidence that fevers caused by endogenous pyrogens that do not act via a prostaglandin mechanism may also respond to salicylate therapy. /Salicylates/ CNS ... ESP NUCLEI LOCATED IN HYPOTHALAMUS PLAYS MAJOR ROLE IN REGULATION OF PERIPHERAL MECHANISMS CONCERNED WITH BODY HEAT PRODN & LOSS. WITH SALICYLATES, HEAT PRODN IS NOT INHIBITED, BUT HEAT LOSS IS INCR BY INCR PERIPHERAL BLOOD FLOW & PERSPIRATION. /SALICYLATES/ Aspirin acetylates prostaglandin endoperoxide synthase (prostaglandin G/H-synthase) and irreversibly inhibits its cyclooxygenase (COX) activity. The enzyme catalyzes the conversion of arachidonic acid to PGH2, the first committed step in prostanoid biosynthesis. Two isoforms of prostaglandin endoperoxide synthase exist, PGHS-1 and PGHS-2 (also referred to as COX-1 and COX-2, respectively). PGHS-1 (COX-1) is expressed constitutively in most cell types, including platelets. PGHS-2 (COX-2) is undetectable in most mammalian cells, but its expression can be induced rapidly in response to mitogenic and inflammatory stimuli. Aspirin is a relatively selective inhibitor of platelet PGHS-1 (cyclooxygenase-1, COX-1). The existence of 2 isoenzymes with different aspirin sensitivities, coupled with extremely different recovery rates of their cyclooxygenase (COX) activity following inactivation by aspirin, at least partially explains the different dosage requirements and durations of aspirin effects on platelet function versus the drug's analgesic and anti-inflammatory effects. Human platelets and vascular endothelial cells process PGH2 to produce thromboxane A2 and prostacyclin (epoprostenol, PGI2), respectively. Thromboxane A2 induces platelet aggregation and vasoconstriction, while prostacyclin inhibits platelet aggregation and induces vasodilation. Aspirin is antithrombotic in a wide range of doses inhibiting thromboxane A2 and prostacyclin. For more Mechanism of Action (Complete) data for ACETYLSALICY

Pharmacodynamics

**Effects on pain and fever** Acetylsalicylic acid disrupts the production of prostaglandins throughout the body by targeting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Prostaglandins are potent, irritating substances that have been shown to cause headaches and pain upon injection into humans. Prostaglandins increase the sensitivity of pain receptors and substances such as histamine and bradykinin. Through the disruption of the production and prevention of release of prostaglandins in inflammation, this drug may stop their action at pain receptors, preventing symptoms of pain. Acetylsalicylic acid is considered an antipyretic agent because of its ability to interfere with the production of brain prostaglandin E1. Prostaglandin E1 is known to be an extremely powerful fever-inducing agent. **Effects on platelet aggregation** The inhibition of platelet aggregation by ASA occurs because of its interference with thromboxane A2 in platelets, caused by COX-1 inhibition. Thromboxane A2 is an important lipid responsible for platelet aggregation, which can lead to clot formation and future risk of heart attack or stroke. **A note on cancer prevention** ASA has been studied in recent years to determine its effect on the prevention of various malignancies. In general, acetylsalicylic acid is involved in the interference of various cancer signaling pathways, sometimes inducing or upregulating tumor suppressor genes. Results of various studies suggest that there are beneficial effects of long-term ASA use in the prevention of several types of cancer, including stomach, colorectal, pancreatic, and liver cancers. Research is ongoing.

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,.