MIFUPEN 350MG/30MG TABLET

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

• 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

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

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.