Antiplatelet Agents

Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug. Abnormal, or inappropriate, platelet aggregation is a key step in the pathophysiology of arterial ischemic events. The primary categories of antiplatelet agents include aspirin, ADP inhibitors, phosphodiesterase/adenosine uptake inhibitors, and glycoprotein IIb/IIIa inhibitors. Common indications for antiplatelet agents include the treatment and prevention of ischemic heart disease Ischemic heart disease Coronary heart disease (CHD), or ischemic heart disease, describes a situation in which an inadequate supply of blood to the myocardium exists due to a stenosis of the coronary arteries, typically from atherosclerosis. Coronary Heart Disease and stroke, peripheral artery disease Peripheral artery disease Peripheral artery disease (PAD) is obstruction of the arterial lumen resulting in decreased blood flow to the distal limbs. The disease can be a result of atherosclerosis or thrombosis. Patients may be asymptomatic or have progressive claudication, skin discoloration, ischemic ulcers, or gangrene. Peripheral Artery Disease, and other conditions associated with a high risk for arterial thrombosis.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug.

General indications

Antiplatelets are used in the treatment and/or prevention of arterial thrombosis. Common indications include:

  • Acute coronary syndrome (ACS)
  • Angina
  • Percutaneous coronary intervention (PCI) with stenting
  • Mechanical heart valves
  • Atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation
  • Acute ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke
  • Peripheral artery disease
  • Essential thrombocythemia Essential thrombocythemia Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the clonal thrombocytosis linked to somatic mutations involving Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL). Patients can be asymptomatic or present with vasomotor symptoms. Essential Thrombocythemia
  • Primary prevention of coronary artery disease

Classification

There are several primary classes of antiplatelet agents:

  • Aspirin
  • ADP inhibitors/P2Y12 receptor antagonists
  • Phosphodiesterase inhibitors Phosphodiesterase inhibitors Phosphodiesterase (PDE) inhibitors are a group of drugs that act by inhibiting PDE enzymes. Phosphodiesterase inhibitors have various mechanisms of action depending on the subtype of PDE targeted, but their main action is increasing the amount of intracellular cAMP or cGMP, which in turn results in physiologic effects such as reducing inflammation, promoting smooth muscle relaxation, and vasodilation. Phosphodiesterase Inhibitors/adenosine uptake inhibitors
  • Glycoprotein (GP) IIb/IIIa inhibitors
Mechanisms of action of antiplatelet agents

Mechanisms of action of antiplatelet agents
5-HT: 5-hydroxytryptamine
TxA2: thromboxane A2
VWF: von Willebrand factor

Image by Lecturio.

Platelets and Formation of the Platelet Plug

After endothelial injury occurs, exposure of the blood to the subendothelial components triggers formation of the platelet plug. This process is known as primary hemostasis Hemostasis Hemostasis refers to the innate, stepwise body processes that occur following vessel injury, resulting in clot formation and cessation of bleeding. Hemostasis occurs in 2 phases, namely, primary and secondary. Primary hemostasis involves forming a plug that stops the bleeding temporarily. Secondary hemostasis involves the activation of the coagulation cascade. Hemostasis. (Formation of the fibrin clot via the coagulation cascade is secondary hemostasis Hemostasis Hemostasis refers to the innate, stepwise body processes that occur following vessel injury, resulting in clot formation and cessation of bleeding. Hemostasis occurs in 2 phases, namely, primary and secondary. Primary hemostasis involves forming a plug that stops the bleeding temporarily. Secondary hemostasis involves the activation of the coagulation cascade. Hemostasis.) 

Steps in formation of the platelet plug

  • Adhesion
  • Activation
  • Aggregation
  • Secretion
Formation of the temporary hemostatic plug

Formation of the temporary hemostatic plug:
The disrupted endothelial surface exposes VWF to the passing blood. Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets bind to the VWF via their GpIb receptors and are activated. Platelet activation triggers them to secrete ADP, which stimulates the expression of the GpIIb/IIIa receptors on the platelets. The GpIIb/IIIa receptors bind to fibrinogen, which is able to bind a platelet on each end, causing platelets to aggregate. As more platelets are bound to one another, the platelet plug is generated. As the coagulation cascade is activated, thrombin converts the weaker fibrinogen into the stronger fibrin, creating a much more stable clot.

Image by Lecturio.

Platelet adhesion

Exposure of the blood to subendothelial components at the site of injury causes platelets to adhere to that site.

  • GPIb receptors on platelets bind to exposed von Willebrand factor (VWF) within the subendothelial matrix: The bond is strong enough to withstand the shearing force of flowing blood.
  • Other adhesion interactions occur:
    • Involve collagen, other glycoprotein receptors, and tyrosine kinase receptors
    • Contribute to both adhesion and activation of platelets
  • Adherent platelets are activated.

Platelet activation

Activated platelets enhance further platelet adhesion and aggregation and stimulate secretion of the platelet granules. 

  • Platelet activators:
    • Potent platelet activators:
      • Thrombin: produced in the coagulation cascade
      • Collagen: interact with platelets at the site of injury
    • Weaker platelet activators:
      • ADP: acts in an autocrine fashion → released by platelets to help activate other platelets
      • Thromboxane A2 (sometimes classified as a potent activator)
      • Epinephrine
  • Activated platelets:
    • Undergo a shape change to become an elongated pseudopod → new shape is extremely adherent
    • Activate the GPIIb/IIIa receptor so that the platelets are capable of binding to fibrinogen
    • Release the platelet granules (see Platelet Secretion below) → assist in activation of the coagulation cascade

Platelet aggregation

  • GPIIb/IIIa receptors on activated platelets begin binding to fibrinogen.
  • Fibrinogen is a symmetrical molecule that can bind 2 platelets at the same time (1 on each end of the fibrinogen).
  • Fibrinogen bridges form between platelets
  • Results in platelet aggregation and formation of the primary hemostatic plug

Platelet secretion

Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets contain granules, each of which releases a number of different substances when platelets are activated. Functions of secreted substances include:

  • Recruit and activate additional platelets
  • Stimulate expression of GPIIb/IIIa on platelets → enhanced aggregation
  • Promotes vasoconstriction
  • Stimulates the vascular repair process via fibroblast/smooth muscle cell recruitment
  • Contributes to initiation of the coagulation cascade

Aspirin

Medication overview

Table: Aspirin
Mechanism of Action
  • Irreversible inhibitor of cyclooxygenases 1 and 2 (COX-1 and COX-2) 
    • COX enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes produce the precursors to thromboxane A2 (TXA2)
    • TXA2 assists in platelet activation (stimulates expression of the GPIIb/IIIa receptor) and is a vasoconstrictor. 
Physiologic effects
  • COX inhibition → ↓ production of TXA2 → ↓ platelet activation and vasoconstriction
  • Permanently inhibits platelet aggregation for the duration of the platelet’s life → new platelets restore platelet function after 3–7 days 
Absorption
  • Orally administered
  • Immediate release: rapid absorption
  • Enteric-coated: variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables (depends on food and pH in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach)
  • Bioavailability: 50%–75% 
  • Time to peak activity: 
    • Immediate release: 1–2 hours (20 minutes when chewed)
    • Enteric-coated: 3–4 hours 
Distribution
  • VD = 10 L
  • Distributes readily into most body fluids and tissues
  • Protein binding: 
    • High protein binding at typical doses: approximately 90%–94%
    • Protein binding ↓ as salicylate concentration ↑ (e.g., may be only 30% bound in cases of overdose)
Metabolism
  • Hydrolyzed to salicylate (active form) by esterases in the GI mucosa, blood, and synovial fluid
  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver to salicyluric acid (less active, more rapidly excreted)
Elimination
  • Renal
  • Half-life: dose-dependent
    • 3 hours at lower doses (300–600 mg)
    • 5–6 hours at medium doses (approximately 1 g)
    • Up to 10 hours with higher doses
Specific indications
  • ACS
  • Prophylaxis against a subsequent MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • Acute ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke
  • Peripheral arterial ischemia
  • Other typical uses:
    • Pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain/ inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
Specific contraindications Children < 16 years of age (risk of Reye’s syndrome if child develops a viral infection)
Complications/adverse effects
  • Severe bleeding (0.3%)
  • Gastric ulceration
  • Reye’s syndrome 
  • Tinnitus
  • Hyperventilation/ respiratory alkalosis Respiratory alkalosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. When hypoventilation occurs, excess carbon dioxide is blown off and respiratory alkalosis develops. The kidneys respond by decreasing serum bicarbonate (HCO3-) through increased HCO3- excretion or decreased excretion of H+. Respiratory Alkalosis
VD: volume of distribution
Overview of prostaglandin and thromboxane synthesis

Overview of prostaglandin and thromboxane synthesis
PG: prostaglandin

Image by Lecturio.

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Overdose of Aspirin

Clinical presentation

  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Tinnitus
  • Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo
  • Nausea, vomiting, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Altered mental status (occurs via direct toxicity, neuroglycopenia, and/or cerebral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema)
  • Hyperventilation (occurs via direct action on the respiratory center to ↑ RR and tidal volume)
  • Acid–base abnormalities: 
    • Respiratory alkalosis
    • Anion-gap metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis (lactic acids and ketoacids)
    • These abnormalities represent mixed primary acid–base abnormalities, rather than compensation mechanisms.
  • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema (typically in older adults with chronic salicylate intoxication)
  • Cardiac arrhythmias
  • Hypovolemia
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia

Diagnosis

  • Salicylate levels:
    • Therapeutic levels are typically 10–30 mg/dL
    • Toxicity is associated with values > 40 mg/dL 
    • Levels should be measured every 2 hours until:
      • Levels are decreasing on 2 consecutive draws.
      • Levels are < 40 mg/dL.
      • Patient is asymptomatic and has a normal respiratory effort.
  • Other lab values to check:
    • Basic metabolic panel:
      • ↑ Creatinine (renal failure) → patient requires hemodialysis
      • ↓ Potassium → may interfere with urinary alkalinization; should be treated aggressively
      • Assess acid–base status (e.g., HCO3, Cl).
    • Lactate: may be ↑ 
    • Arterial blood gas (ABG): to assess acid–base status

Management

  • Stabilize patients whose condition is unstable by addressing the airway, breathing, and circulation.
  • GI decontamination with activated charcoal
  • Give supplemental glucose to avoid neuroglycopenia.
  • Give potassium to treat hypokalemia.
  • Alkalinization of the plasma and urine with sodium bicarbonate
  • Consider hemodialysis, especially in patients with:
    • Altered mental status
    • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema or respiratory distress
    • Cerebral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Acute or chronic kidney injury (sufficient to impair salicylate elimination)
    • Fluid overload
    • Severe acidemia (pH < 7.2)
    • Markedly elevated salicylate concentrations (e.g., > 90 mg/dL)

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ADP Inhibitors/P2Y12 Receptor Inhibitors

Table: ADP inhibitors/P2Y12 receptor inhibitors
Agents
  • Clopidogrel (Plavix®)
  • Prasugrel (Effient®) 
  • Ticagrelor
  • Cangrelor
  • Ticlopidine (no longer used)
Mechanism of Action
  • Inhibit binding of ADP to P2Y12 receptors on platelets
    • Clopidogrel and prasugrel: irreversible inhibition
    • Ticagrelor: reversible inhibition 
Physiologic effects
  • Activated P2Y12 receptors stimulate the expression of GPIIb/IIIa receptors (which are critical in platelet aggregation)
  • ↓ ADP → ↓ activation of the P2Y12 receptors → ↓ GPIIb/IIIa receptors → ↓ platelet aggregation
Specific indications
  • Prevention of thrombotic strokes and TIAs
  • Acute coronary syndrome
  • Reduce restenosis of stents
  • Clopidogrel: can be used in place of aspirin in cases of aspirin allergy
  • Ticagrelor and cangrelor: often used in the catheterization lab
Specific contraindications Prasugrel: history of an ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke or TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA)
Complications
  • TTP, rare
  • Ticlopidine (high toxicity rate is the reason it is no longer used):
    • Severe bleeding (5%)
    • Severe neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia (1%)
TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA): transient ischemic attack Transient ischemic attack Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA)
TTP: thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition due to either a congenital or an acquired deficiency of ADAMTS-13, a metalloproteinase that cleaves multimers of von Willebrand factor (VWF). The large multimers then aggregate excessive platelets resulting in microvascular thrombosis and an increase in consumption of platelets. Thrombotic Thrombocytopenic Purpura
Table: Pharmacokinetics of select ADP inhibitors
Medication Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor
Absorption
  • Rapidly absorbed
  • Dose-dependent onset of action
  • Time to peak: approximately 45 minutes
  • Rapidly absorbed
  • Time to peak: approximately 30 minutes
  • Rapidly absorbed
  • Time to peak: approximately 2 hours
Distribution Highly protein-bound (98%)
  • VD: 44–68 L
  • Highly protein-bound (approximately 98%)
  • VD: 88 L
  • Highly protein-bound (> 99%)
Metabolism Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver via:
  • CYP2C19 oxidation to an active thiol metabolite
  • Hydrolysis to an inactive carboxylic acid derivative
Hydrolyzed in the intestines and serum to an inactive thiolactone intermediate, which is then converted to an active metabolite via CYP3A4 and CYP2B6 oxidation Metabolized by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver to an active metabolite via CYP3A4
Elimination
  • Renal (50%) and fecal (46%)
  • Half-life:
    • Parent drug: approximately 6 hours
    • Thiol metabolite: approximately 30 minutes
    • Approximately 2% may have a half-life of up to 11 days
  • Renal (approximately 68%) and fecal (approximately 27%)
  • Half-life: approximately 7 hours
  • Fecal (approximately 58%) and renal (approximately 26%)
  • Half-life: approximately 7‒9 hours

Phosphodiesterase (PDE)/Adenosine Uptake Inhibitors

Table: PDE/adenosine uptake inhibitors
Agents Dipyridamole (Persantine®) Cilostazol
Mechanism of Action Dual mechanisms of action:
  • Inhibit PDE
      • PDE degrades cAMP
      • cAMP inhibits platelet aggregation
      • By inhibiting PDE → cAMP ↑ which → ↓ platelet aggregation
  • Inhibit uptake of adenosine
    • Inhibiting adenosine uptake → ↑ plasma adenosine
    • Adenosine:
      • Activates the A2 receptor on the platelet surface
      • Causes selective vasodilation of the coronary arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries
    • A2 receptor activation stimulates ↑ cAMP levels within the platelet
    • Inhibiting adenosine uptake → ↑ A2 stimulation → ↑ cAMP → ↓ platelet aggregation
Physiologic effects
  • ↑ cAMP → ↓ platelet aggregation
  • Vasodilation
Absorption
  • Rapid
  • Time to peak concentration: 2–2.5 hours 
  • Orally absorbed
  • Time to peak concentration: 2–3 hours 
Distribution
  • VD: 2–3 L/kg
  • Protein binding: approximately 95% 
Protein binding: 95%
Metabolism
  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver to a glucuronide conjugate
  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, primarily via CYP2C19 and CYP3A4
Elimination
  • Fecal
  • Half-life: 10–12 hours 
  • Renal (74%)
  • Fecal (20%)
  • Half-life: 11–13 hours 
Specific indications
  • Adjunct to warfarin in patients with heart valve replacements
  • Adjunct to aspirin in patients for secondary prevention of stroke (i.e., after a first stroke, patients get aspirin; if they have a stroke on aspirin, they continue aspirin and add dipyridamole)
Intermittent claudication
Specific contraindications
  • Unstable angina
  • ACS
  • Recent MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • Heart block
Heart failure
Complications
  • Severe bleeding (1–2%)
  • Worsening angina
May induce tachycardia, tachyarrhythmias, and/or hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
Adverse effects
  • Dizziness
  • Vomiting and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Headache
  • Diarrhea
  • Palpitations
  • Dizziness
PDE: phosphodiesterase

Glycoprotein IIb/IIIa Inhibitors

The 2 primary GPIIb/IIIa inhibitors are eptifibatide (Integrilin®) and tirofiban (Aggrastat®). Abciximab is a monoclonal antibody that is also in this category; however, it is no longer available in the United States.

Table: Glycoprotein IIb/IIIa Inhibitors
Agents Eptifibatide (Integrilin®) Tirofiban (Aggrastat®)
Mechanism of Action Binds to and reversibly inhibits the GPIIb/IIIa receptor 
Physiologic effects Prevents GPIIb/IIIa receptors from binding fibrinogen and thus prevents platelet aggregation
Absorption
  • Rapid
  • Time to peak: approximately 1 hour
  • Rapid
  • Onset of action seen within 10 minutes
Distribution
  • Protein binding: approximately 25%
  • VD: 22–42 L
  • Protein binding: 65% (concentration-dependent) 
Metabolism Negligible
Elimination
  • Renal 
  • Half-life: approximately 2.5 hours
  • Renal (approximately 65%) and fecal (approximately 25%) primarily as unchanged drug
  • Half-life: approximately 2 hours 
Specific indications
  • Used in ACS
  • Prevents restenosis after angioplasty
Specific contraindications Severe thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
Complications
  • Bleeding
  • Thrombocytopenia with long-term use (typically only short-term use)

Clinical Relevance

Some of the most common therapeutic uses of antiplatelet agents include:

  • Myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction: ischemia of the myocardial tissue due to complete obstruction or drastic constriction of coronary artery. This ischemia is usually accompanied by an increase in cardiac enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, typical ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes, and chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain. Treatment depends on the timing of presentation and available resources, but most patients initially receive antiplatelet agents, anticoagulation therapy, and medications that decrease oxygen demand of the heart.
  • Thromboembolic ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke: ischemia of the brain due to thrombotic or embolic obstruction of blood flow. Thrombotic strokes are caused by clots in the large or small vessels of the brain. Embolic strokes are due to clots that break off from somewhere else and ultimately become lodged in the brain; they are often due to cardiac sources. Patients will present with neurologic deficits, and diagnosis is made with CT. Management is complex, but initial treatment often involves the use of antiplatelet agents and anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants.
  • Peripheral artery disease (PAD): obstruction of the arterial lumen resulting in decreased blood flow to the distal limbs. This obstruction can be a result of atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis or thrombosis. Patients may be asymptomatic, or they may have progressive claudication, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin discoloration, ischemic ulcers, or gangrene. Imaging studies can determine the location and extent of the arterial disease. Treatment varies depending on the severity but can include lifestyle modifications, antiplatelet therapy, phosphodiesterase inhibitors, and revascularization.
  • Atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation (AF, or Afib Afib Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation): supraventricular tachyarrhythmia Tachyarrhythmia A tachyarrhythmia is a rapid heart rhythm, regular or irregular, with a rate > 100 beats/min. Tachyarrhythmia may or may not be accompanied by symptoms of hemodynamic change. Tachyarrhythmias and most common kind of arrhythmia. Atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Diagnosis is confirmed by an ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) that will show an “irregularly irregular” heartbeat with no distinct P waves and narrow QRS complexes. Atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation increases the risk of thromboembolic events, and antiplatelet and/or anticoagulation therapy is often indicated. Treatment is based primarily on ventricular rate and rhythm control.
  • Essential thrombocythemia Essential thrombocythemia Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the clonal thrombocytosis linked to somatic mutations involving Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL). Patients can be asymptomatic or present with vasomotor symptoms. Essential Thrombocythemia: type of myeloproliferative neoplasm characterized by excessive production of platelets, resulting in increased thrombotic and hemorrhagic risks. The clinical course of essential thrombocythemia can also be complicated by progression to myelofibrosis and acute myeloid leukemia Acute Myeloid Leukemia Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia. The diagnosis is based on laboratory finding of thrombocytosis, bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy, and genetic studies. Treatment aims to reduce platelet count by cytoreductive agents (hydroxyurea) and to decrease thrombosis risk with aspirin and systemic anticoagulation.

References

  1. Thachil J. (2016). Antiplatelet therapy—a summary for the general physicians. Clinical Medicine Journal 16:152–160. https://doi.org/10.7861/clinmedicine.16-2-152
  2. Longo, D., et al. (2012). In Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine, 18th ed., vol, 2, pp. 2207–2215.
  3. Boyer, E.W., Weibrecht, K.W. (2020). Salicylate (aspirin) poisoning in adults. UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/salicylate-aspirin-poisoning-in-adults
  4. Aspirin: Drug information (2021). UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/aspirin-drug-information
  5. Clopidogrel: Drug information (2021). UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/clopidogrel-drug-information
  6. Prasugrel: Drug information (2021). UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/prasugrel-drug-information
  7. Ticagrelor: Drug information (2021). UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/ticagrelor-drug-information 
  8. Dipyridamole: Drug information (2021). UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/dipyridamole-drug-information 
  9. Cilostazol: Drug information (2021). UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/cilostazol-drug-information 
  10. Eptifibatide: Drug information (2021). UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/eptifibatide-drug-information 
  11. Tirofiban: Drug information (2021). UpToDate. Retrieved May 12, 2021, from https://www.uptodate.com/contents/tirofiban-drug-information

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