Instaclop Plus Capsules

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

• Prevention of atherothrombotic events in patients with acute coronary syndrome
• Secondary prevention of ischaemic stroke
• Prevention of atherothrombotic events in peripheral arterial disease

Mechanism of action

Clopidogrel is activated through a two-step metabolic process to form an active thiol-containing metabolite. This metabolite irreversibly binds to the P2Y12 ADP receptors on platelets, preventing ADP from activating the GPIIb/IIIa complex, which is crucial for platelet aggregation. As a result, clopidogrel inhibits platelet aggregation for the lifespan of the platelets (approximately 7 to 10 days). The inhibition of the P2Y12 receptor reduces platelet activation and aggregation not just from ADP, but also from other agonists.

Pharmacodynamics

Clopidogrel is a prodrug that serves as a potent antiplatelet agent, effectively reducing the risk of myocardial infarction and stroke. Its pharmacological effects are long-lasting, allowing for once-daily dosing. Clopidogrel exhibits a broad therapeutic window, and its dosage ranges from 75 mg to 300 mg per day, depending on the clinical scenario. Its action helps maintain blood flow and prevent occlusive vascular events.

Pharmacokinetics

Clopidogrel is well absorbed in the gastrointestinal tract, with peak plasma concentrations occurring within 1 to 2 hours after oral administration. It undergoes extensive hepatic metabolism, primarily through CYP450 enzymes, which convert it into its active form. The elimination half-life of clopidogrel is approximately 6 hours, but the antiplatelet effect lasts much longer due to the irreversible nature of its action on platelets. It is primarily excreted through urine, with a majority of the dose eliminated as inactive metabolites.

Contra-indications

• Active bleeding

Adverse effects

• Confusion
• Fever
• Gynaecomastia
• Hallucination
• Hepatic disorders
• Hypotension
• Myalgia
• Neutropenia
• Severe cutaneous adverse reactions (SCARs)
• Stomatitis
• Taste altered
• Ulcerative colitis
• Vasculitis
• Vertigo
• Wound haemorrhage

Interactions

• Voriconazole + clopidogrel: Severe (decreases efficacy)
• HIV protease inhibitors + clopidogrel: Severe (decreases efficacy)
• Moclobemide + clopidogrel: Severe (decreases efficacy)
• Ritonavir + clopidogrel: Severe (decreases efficacy)
• Clopidogrel + pioglitazone: Moderate (increases exposure)
• Clopidogrel + treprostinil: Moderate (increases exposure)
• Clopidogrel + apalutamide: Unknown (increases exposure)
• Clopidogrel + enzalutamide: Unknown (increases exposure)
• Fluconazole + clopidogrel: Unknown (decreases efficacy)
• Clopidogrel + anti-androgens: Unknown (increases exposure)

Precautions

• Caution with history of hypersensitivity reactions to thienopyridines
• Caution in moderate hepatic impairment
• Caution in renal impairment
• Discontinue 7 days before elective surgery if antiplatelet effect not desirable
• Patients at risk of increased bleeding from trauma, surgery, or other pathological conditions

Pregnancy

Manufacturer advises avoid-no information available.

Breast-feeding

Manufacturer advises avoid.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Clopidogrel 75 mg tablet
• Clopidogrel 300 mg tablet
• Clopidogrel oral suspension

Indications

• Acid-base imbalance
• Buffering agent in biochemical reactions
• Industrial applications

Mechanism of action

Bisulfate acts as a buffering agent, helping to maintain the pH of biological fluids. It can donate protons (H+) in solution, contributing to acid-base homeostasis. This property is essential in various metabolic pathways, particularly in the regulation of cellular functions and enzyme activities.

Pharmacodynamics

The pharmacodynamics of bisulfate involve its ability to interact with other ions and compounds in the body, influencing acid-base balance. By acting as a proton donor, bisulfate contributes to the overall acidity or alkalinity of the environment, which can affect cellular metabolism and function. It plays a significant role in respiratory and metabolic acidosis and alkalosis.

Pharmacokinetics

The pharmacokinetics of bisulfate are not extensively detailed in traditional pharmacological literature. However, it is known that bisulfate can be rapidly absorbed and utilized in metabolic processes. Its effects are largely dependent on the physiological conditions of the body, including the presence of other electrolytes and the overall acid-base status.

Pregnancy

There are no specific studies on the use of bisulfate in pregnancy. Caution is advised when administering to pregnant women.

Breast-feeding

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

Storage

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

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

Clopidogrel is activated via a 2 steps reaction to an active thiol-containing metabolite. This active form is a platelet inhibitor that irreversibly binds to P2Y₁₂ ADP receptors on platelets. This binding prevents ADP binding to P2Y₁₂ receptors, activation of the glycoprotein GPIIb/IIIa complex, and platelet aggregation. Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. The P2Y12 receptor plays a crucial role in the regulation of platelet activation by several agonists, which is irreversibly antagonized by the active metabolite of clopidogrel, a widely used anti-thrombotic drug. In this study, we investigated whether reduction of platelet reactivity leads to reduced inflammatory responses using a rat model of erosive arthritis. We evaluated the effect of clopidogrel on inflammation in Lewis rats in a peptidoglycan polysaccharide (PG-PS)-induced arthritis model with four groups of rats: 1) untreated, 2) clopidogrel-treated, 3) PG-PS-induced, and 4) PG-PS-induced and clopidogrel-treated. There were significant differences between the PG-PS+clopidogrel group when compared to the PG-PS group including: increased joint diameter and clinical manifestations of inflammation, elevated plasma levels of pro-inflammatory cytokines (IL-1 beta, interferon (IFN) gamma, and IL-6), an elevated neutrophil blood count and an increased circulating platelet count. Plasma levels of IL-10 were significantly lower in the PG-PS+clopidogrel group compared to the PG-PS group. Plasma levels of platelet factor 4 (PF4) were elevated in both the PG-PS and the PG-PS+clopidogrel groups, however PF4 levels showed no difference upon clopidogrel treatment, suggesting that the pro- inflammatory effect of clopidogrel may be due to its action on cells other than platelets. Histology indicated an increase in leukocyte infiltration at the inflammatory area of the joint, increased pannus formation, blood vessel proliferation, subsynovial fibrosis and cartilage erosion upon treatment with clopidogrel in PG-PS-induced arthritis animals. In summary, animals treated with clopidogrel showed a pro-inflammatory effect in the PG-PS-induced arthritis animal model, which might not be mediated by platelets.

Pharmacodynamics

Clopidogrel is a prodrug of a platelet inhibitor used to reduce the risk of myocardial infarction and stroke. It has a long duration of action as it is taken once daily and a large therapeutic window as it is given in doses of 75-300mg daily.