ASPLADIN

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

• Mild to moderate pain relief
• Fever reduction
• Management of inflammatory conditions such as rheumatoid arthritis and osteoarthritis
• Prevention of cardiovascular events in patients with a history of myocardial infarction or stroke
• Management of acute coronary syndrome

Dosage

Children: Refer to the BNF for Children for appropriate dosing in paediatric patients, as this may differ significantly from adult dosing.

Adults: Refer to the BNF for specific dosing guidelines, as doses may vary based on the indication and patient factors.

Mechanism of action

Aspirin works primarily by irreversibly inhibiting cyclooxygenase (COX-1 and COX-2) enzymes, leading to a decrease in the synthesis of prostaglandins and thromboxanes. This results in reduced inflammation, pain, and fever. The inhibition of COX-1 also reduces platelet aggregation by decreasing thromboxane A2 production, which is crucial for platelet activation and aggregation.

Pharmacodynamics

The analgesic effects of aspirin are attributed to its ability to inhibit the generation of prostaglandins, which mediate pain and inflammation. In addition to its pain-relieving and anti-inflammatory effects, aspirin's antiplatelet action is significant in the context of cardiovascular health, as it reduces the risk of thrombus formation in blood vessels.

Pharmacokinetics

Aspirin is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1 to 2 hours after oral administration. It is extensively metabolized in the liver, primarily via hydrolysis to salicylic acid, which has its own therapeutic effects. The elimination half-life varies depending on the dose, ranging from 15 to 20 minutes for aspirin and several hours for salicylic acid. Aspirin and its metabolites are excreted primarily in the urine.

Contra-indications

• Active gastrointestinal bleeding
• History of peptic ulcer disease
• Severe renal impairment
• Severe hepatic impairment
• Hypersensitivity to acetylsalicylic acid or other NSAIDs
• Children and teenagers with viral infections (risk of Reye's syndrome)

Adverse effects

• Gastrointestinal irritation and bleeding
• Nausea and vomiting
• Dyspepsia
• Allergic reactions such as rash or asthma exacerbation
• Tinnitus (ringing in the ears)
• Renal impairment
• Hepatic dysfunction

Interactions

• Increased risk of gastrointestinal bleeding with other NSAIDs or anticoagulants
• Enhanced effects of anticoagulants (e.g., warfarin, heparin)
• Reduced effectiveness of antihypertensive drugs (e.g., ACE inhibitors)
• Increased risk of renal impairment with diuretics
• Potential interaction with methotrexate, leading to increased toxicity

Precautions

• Use with caution in patients with a history of gastrointestinal disorders
• Monitor renal function in long-term use or in patients with renal impairment
• Assess the risk of bleeding before surgery or dental procedures
• Caution in patients with asthma or nasal polyps due to potential hypersensitivity reactions
• Consider the potential for Reye's syndrome in children and adolescents

Pregnancy

Use during pregnancy is generally not recommended, particularly in the third trimester, due to the risk of adverse effects on the fetus and complications during delivery.

Breast-feeding

Acetylsalicylic acid is excreted in breast milk; caution is advised if used while breastfeeding.

Storage

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

Formulations

• Tablets
• Enteric-coated tablets
• Effervescent tablets
• Suppositories
• Oral suspension

Indications

• Food preservation
• Antioxidant applications
• Reduction of oxidative stress

Dosage

Children: Refer to specific guidelines or consult a healthcare professional for dosing recommendations, as doses can vary based on the indication.

Adults: Refer to specific guidelines or consult a healthcare professional for dosing recommendations, as doses can vary based on the indication.

Mechanism of action

Bisulphate acts as a reducing agent, donating electrons to other molecules, which can help in neutralizing free radicals and preventing oxidative stress. It interacts with sulfite oxidase in the body, facilitating the conversion of sulfite to sulfate, a less toxic form. This mechanism is particularly relevant in the context of sulfite metabolism and detoxification.

Pharmacodynamics

Bisulphate's pharmacodynamics are primarily related to its antioxidant properties. It helps to protect cells from oxidative damage by scavenging free radicals. The compound also plays a role in maintaining the acid-base balance in the body, as it can act as a buffer in certain physiological conditions.

Pharmacokinetics

Bisulphate is rapidly absorbed and metabolized in the body. It is primarily metabolized in the liver, where it is converted to sulfate. The elimination route is mainly through urine, where it is excreted as sulfate. The half-life of bisulphate is short, necessitating frequent dosing in certain applications.

Adverse effects

• Headache
• Nausea
• Diarrhea
• Skin rash
• Hypersensitivity reactions

Precautions

• Use with caution in patients with asthma or respiratory issues
• Monitor for allergic reactions in sensitive individuals

Pregnancy

The safety of bisulphate during pregnancy has not been established. Use only if clearly needed and after assessing risks versus benefits.

Breast-feeding

It is not known whether bisulphate is excreted in human milk. Caution is advised when administering to nursing mothers.

Storage

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

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.