Hematology

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Chapter 16 Hematology

Heparins

Description

Heparin belongs to a family of endogenous substances known as glycosaminoglycans (GAGs). Heparin and its synthetic derivatives are anticoagulants.

Prototype and Common Drugs

image Prototype: heparin (also known as unfractionated heparin [UFH])
image Others: low–molecular-weight heparin (LMWH)

image Dalteparin, enoxaparin, nadroparin, tinzaparin

Pentasaccharides

image Prototype: Fondaparinux

Heparinoids

image Prototype: Danaparoid

MOA (Mechanism of Action)

image The coagulation (clotting) system is composed of many proteins. Most of these proteins are procoagulants, which means they contribute to clotting. Some proteins are anticoagulants that serve to keep the coagulation system in balance.
image When a protein is activated, its name is followed by a small letter a. Each activated protein serves as an enzyme for the next protein downstream in the cascade (Figure 16-1).
image Heparins interfere with the coagulation cascade by amplifying the anticoagulant effect of antithrombin III.
image Antithrombin III, a natural plasma protease inhibitor, is an anticoagulant, and it inhibits thrombin (IIa) and factor Xa.
image To inhibit factor Xa, heparins must bind only antithrombin III.
image To inhibit factor IIa, heparins must bind to both antithrombin III and factor IIa (dual binding not shown Figure 16-1).
image LMWHs are typically too small to bind both antithrombin III and factor IIa. Therefore their anticoagulant effects are exerted largely through factor Xa, with minimal effects on factor IIa.
image

Figure 16-1

Pharmacokinetics

Unfractionated Heparin

image Very complex pharmacokinetics exist because there is a large range in molecular weight of the molecules
image The dose-response curve is difficult to predict, so the dose must be individualized in every patient, with frequent measurements (i.e., activated partial thromboplastin time [aPTT]) made to guide titration.
image UFH binds to a variety of plasma proteins, reducing its bioavailability at low concentrations.

image Levels of these heparin-binding proteins can vary significantly, requiring the use of very high doses in some patients.

image UFH exhibits saturation kinetics, meaning that the elimination half-life (t1/2) increases with increasing dose.
image UFH is administered via the intravenous (IV) or subcutaneous (SC) routes.

image UFH acts immediately after IV administration, and effects last a few hours. Infusion is required to maintain continuous anticoagulation.
image Onset occurs in 60 minutes when UFH is given subcutaneously.

Low–Molecular-Weight Heparin

image LMWH has a more predictable dose-response curve than UFH because there is a smaller range of molecular weights.
image aPTT is not used to measure LMWH activity, but sometimes factor Xa levels can be measured (not commonly performed).
image LMWH is administered via the subcutaneous route. Compared to UFH, LMWH has:

image A longer half-life than heparin
image More predictable pharmacokinetic profile

• Less protein binding
• First-order kinetics

Indications

image Treatment and prevention of inappropriate thrombosis

image Venous thrombosis (and pulmonary embolism [PE]) caused by:

• Stasis (prolonged inactivity: airplane, surgery)
• Endothelial damage (common in orthopedic surgery)
• Hypercoagulable states (the balance of thrombogenesis and thrombolysis inappropriately favors thrombogenesis)

image Arterial thrombosis (less common than venous)

image Initial management of:

image Unstable angina or acute myocardial infarction (MI)
image Coronary angioplasty or stent placement
image Cardiac surgery requiring cardiopulmonary bypass (the bypass tubing activates the clotting cascade because it is a foreign surface)

image Disseminated intravascular coagulation (DIC)

Contraindications

image Previous heparin-induced thrombocytopenia syndrome (HITS) (see Side Effects)
image Coagulopathies: hemophilia, thrombocytopenia (low platelet count)
image Active bleeding: intracranial hemorrhage, gastrointestinal (GI) ulcers, certain cancers

Side Effects

image HITS

image Antibodies against platelet factor 4 are produced and bind to platelets.
image Platelets get activated and sticky, and this causes:

• Thromboses (multiple)
• Platelet consumption resulting in thrombocytopenia
• Bleeding as a result of thrombocytopenia

image Hemorrhage can be reversed with protamine (see later).
image Osteoporosis occurs with long-term therapy; the cause is unknown.
image Hyperkalemia: Although not a common occurrence, heparin can cause increased serum potassium; it is more likely to occur in patients with diabetes or renal disease. In this regard the action of heparin is similar to that of spironolactone, which is an aldosterone blocker classified as a K-sparing diuretic.
image Fever: Rarely, heparin can cause a drug fever.

Important Notes

image To measure the effect of UFH, the aPTT test is used (compare this with prothrombin time [PT] or International Normalized Ratio [INR], which is used with warfarin). It is a measure of time to coagulation (in the laboratory) and is measured in seconds. The higher the number, the more strongly a patient is anticoagulated.
image Unlike UFH, LMWHs do not prolong the aPTT, and they also have a more predictable pharmacokinetic profile. These important differences make LMWH far more convenient for patients to use, with more stable administration and less rigorous monitoring.
image Heparins provide a safe and important alternative to teratogenic warfarin in pregnancy.
image For cases of heparin overdose, protamine sulfate is a strongly basic protein that forms a complex with heparin, acting as a chemical antagonist. LMWH does not have an antidote.
image Danaparoid works by the same mechanism as the heparins, but it is not structurally related to the heparins; it is therefore considered a heparinoid. Therefore it can be used in the management of patients with heparin-induced thrombocytopenia (HIT) too.
image Fondaparinux is synthetic and is based on the structure of the antithrombin binding region of heparin. The binding region of heparin is only 5 saccharide units and is the basis for the pentasaccharide structure of fondaparinux. Fondaparinux could be thought of as really low molecular weight heparin.

Evidence

LMWH versus UFH for Treatment of Venous Thromboembolism

image A 2005 Cochrane review (five studies, N = 1508 participants) found that LMWH may be more efficacious than UFH for the initial treatment of venous thromboembolism (VTE). This Cochrane review also found that LMWH was safer than heparin, with significantly fewer hemorrhagic adverse events.

LMWH versus Warfarin for Treatment of Venous Thromboembolism

image A 2001 Cochrane review (seven studies, N = 1137 participants), updated in 2003, compared warfarin with LMWH for long-term treatment of VTE. There was no difference in the risk of recurrent VTE between warfarin and LMWH. There was a lower risk of bleeding with LMWH (odds ratio [OR] 0.38), and no difference in mortality rates between these two interventions was found.

LMWH and Heparinoids versus UFH for Ischemic Stroke

image A 2008 Cochrane review (nine studies, N = 3137 patients) compared LMWH and heparinoids (danaparoid) with UFH in patients with acute, presumed or confirmed ischemic stroke. The odds of developing a deep vein thrombosis (DVT) were reduced with LMWH compared with UFH (OR 0.55); however, the incidence of key clinical outcomes such as PE, death, and hemorrhage (intracranial or extracranial) was too small to provide a reliable comparison.

FYI

image Heparin was discovered in 1916 by a medical student who was working on a summer research project. He was trying to extract procoagulant substances from various tissues and instead found a potent anticoagulant still used today.
image The name heparin reflects the fact that this substance was extracted from the liver (hepatic).
image Thrombo means blood clot. Cyto means cell. Thrombocytes (also known as platelets) are cells that contribute to blood clots. Penia means decreased. Thrombocytopenia means a low platelet count.

Direct Factor Xa Inhibitors

Description

Direct factor Xa inhibitors are agents that inhibit clotting by inhibiting a specific component of the coagulation cascade.

Prototype

image Prototype: rivaroxaban

MOA (Mechanism of Action)

image The coagulation system is composed of many proteins: most of these proteins are procoagulants, which means they contribute to clotting. Some proteins are anticoagulants, which serve to keep the coagulation system in balance.
image When a protein is activated, its name is given a small letter a at the end. Each activated protein serves as an enzyme for the next protein downstream in the cascade (Figure 16-2).
image Factor Xa converts prothrombin to thrombin (factor IIa). Thrombin is an enzyme that catalyzes the final step in the coagulation cascade, the conversion of fibrinogen to fibrin.
image Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The mesh is created by the cross-linking of fibrin, and this cross-linking step is facilitated by factor XIII.
image In addition to converting fibrinogen to fibrin, thrombin also activates factor XIII; thus thrombin not only catalyzes the creation of the key component of the clot, it also facilitates the provision of structural rigidity to the clot.
image Thrombin also activates factors V, VIII, and XI, therefore amplifying the coagulation cascade. In addition, thrombin activates platelets, leading to their aggregation.
image Direct factor Xa inhibitors directly inhibit the conversion of prothrombin to thrombin without using antithrombin III as an intermediary. The direct inhibition of thrombin formation results in an anticoagulant effect.
image

Figure 16-2

Pharmacokinetics

image Rivaroxaban, the first direct factor Xa inhibitor, is administered orally. It is rapidly absorbed, reaching peak plasma concentrations in 2 to 4 hours, and has an elimination half-life of 9 hours.
image One third of rivaroxaban is eliminated unchanged in the kidneys; therefore dose adjustments should be considered in renal impairment, and an alternative drug should be considered in patients with severe renal impairment.

Indications

image Postsurgical VTE prophylaxis
image As an alternative to heparins in patients with severe HIT

Contraindications

image Active bleeding
image Pregnancy
image Patients at increased risk of bleeding: clotting disorders, history of recent hemorrhagic stroke

Side Effects

image Bleeding: As with all anticoagulants, bleeding is the major side effect.

Important Notes

image There are no monitoring requirements for rivaroxaban. This and the fact that it is an orally administered agent suggest that drugs in its class, and perhaps the direct thrombin inhibitors, will supplant warfarin as the drugs of choice among oral anticoagulants.

Advanced

Drug Interactions

image CYP450 3A4 enzymes are involved in the metabolism of rivaroxaban; thus the potential exists for pharmacokinetic drug interactions with inhibitors or inducers of this isozyme. Rivaroxaban is also a P-glycoprotein (Pgp) substrate, and therefore its levels could also be affected by inhibitors or inducers of Pgp.

Evidence

Postsurgical Venous Thromboembolism Prophylaxis

image The RECORD trials were a series of double-blind randomized controlled trials that compared rivaroxaban with enoxaparin for the prophylactic treatment of VTE after total hip replacement (RECORD-1 and RECORD-2) or total knee replacement (RECORD-3 and RECORD-4). The trials were all relatively large, randomizing 2509 to 4541 patients between the two treatment groups. Rivaroxaban-treated patients had fewer events of VTE and all-cause deaths compared with enoxaparin in each of the four studies. The risk of bleeding was slightly higher with rivaroxaban than with enoxaparin.

FYI

image For a quick summary of the difference between two of the newer oral anticoagulants—direct factor Xa and direct thrombin inhibitors. Direct factor Xa inhibitors inhibit the formation of thrombin, whereas direct thrombin inhibitors allow thrombin to be formed but interfere with the actions of thrombin.

Direct Thrombin Inhibitors

Description

Direct thrombin inhibitors reduce clotting by inhibiting a specific component of the coagulation cascade.

Prototype and Common Drugs

Parenteral

image Prototype: hirudin (lepirudin)
image Others: bivalirudin, desirudin

Oral

image Prototype: argatroban
image Others: dabigatran, ximelagatran

MOA (Mechanism of Action)

image The coagulation (clotting) system is a multistep cascade that eventually leads to the formation of fibrin and development of a clot.
image Thrombin (factor IIa) is an enzyme that catalyzes the final step in the coagulation cascade, the conversion of fibrinogen to fibrin (Figure 16-3).
image Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The mesh is created by the cross-linking of fibrin, and this cross-linking step is facilitated by factor XIII.
image In addition to converting fibrinogen to fibrin, thrombin also activates factor XIII; thus thrombin not only catalyzes the creation of the key component of the clot, it also facilitates the provision of structural rigidity to the clot.
image Thrombin also activates factors V, VIII, and XI, therefore amplifying the coagulation cascade. Thrombin also has antiplatelet effects.
image Thrombin has an active site as well as two other sites, referred to as exosite 1, which binds fibrin, and exosite 2, which binds heparin.
image Direct thrombin inhibitors all bind to thrombin directly at its active site. The bivalent inhibitors (-irudins) also bind at exosite 1 (hence the term “bivalent”, indicating two binding sites), while the univalent inhibitors only bind at the active site.
image The univalent thrombin inhibitors (e.g., argatroban and dabigatran) and bivalirudin all bind reversibly, whereas the other bivalent inhibitors bind thrombin irreversibly.
image The net result of this binding is that the effects of thrombin are inhibited. The inhibition of thrombin results in an anticoagulant effect.
image

Figure 16-3

Pharmacokinetics

image Argatroban has a short half-life and is typically administered by infusion.
image Hirudin is administered by either IV or SC injection, with elimination half-life of 60 minutes and 120 minutes, respectively. It is cleared by the kidneys.
image Bivalirudin is administered intravenously and has rapid onset and offset, with a half-life of about 25 minutes. It is primarily eliminated by proteolysis, although about 20% of elimination is renal.

Indication

image Postsurgical VTE prophylaxis

Bivalirudin

image Severe heparin-induced thrombocytopenia (HIT)

Contraindications

image Patients who are at high risk of bleeding, such as those with the following conditions:

image Uncontrolled active bleeding
image Major bleeding (coagulopathy) disorders
image Acute gastric or duodenal ulcer
image Recent (<6 months) stroke

Side Effects

image Bleeding: As with all anticoagulants, bleeding is the major side effect.

Important Notes

image All of the agents in this class are approved for prophylaxis of DVT and VTE after orthopedic surgery. Patients undergoing knee or hip replacement surgeries, in particular, are at high risk for developing a DVT or VTE. The risk is so high that these patients receive prophylactic anticoagulants for several days postsurgery.
image The theoretical advantage of direct over indirect thrombin inhibitors such as LMWHs is that the direct inhibitors inactivate fibrin-bound thrombin, in addition to the thrombin in the fluid phase. This may lead to a greater inhibition of the thrombus. Direct thrombin inhibitors may also provide more predictable anticoagulation, as they are not bound to plasma proteins (unlike heparin) and are not neutralized by platelet factor 4 (a protein secreted by platelets) and other factors generated at the site of vascular injury.
image The anticoagulation of bivalirudin can be monitored using aPTT.
image Warfarin has been the prototypical oral anticoagulant for decades, but with its narrow margin of safety, significant potential for drug-drug and drug-food interactions, and significant variability in response among patients, there is much anticipation that new oral anticoagulants will soon be able to replace it. The direct thrombin inhibitors, which lack any of these limitations associated with warfarin, are one of the classes that might replace warfarin.

FYI

image The -irudins are based on the anticoagulant activity of leeches. Leeches secrete hirudin, and that facilitates their ability to draw blood from their victim. The recombinant form of hirudin, lepirudin, is used clinically.
image Ximelagatran, the first direct thrombin inhibitor, was withdrawn from the market because of concerns over hepatotoxicity.

Vitamin K Antagonists

Description

Vitamin K antagonists are a family of naturally derived anticoagulants, which are also known as coumarins.

Prototype

image Prototype: warfarin

MOA (Mechanism of Action)

image Vitamin K is key cofactor in the hepatic activation of four coagulation factors. The four vitamin K-dependent clotting factors are II, VII, IX, and X (Figure 16-4).
image To act as a cofactor, vitamin K must be in its reduced form, vitamin K hydroxyquinone. The enzyme vitamin K epoxide reductase (VKOR) converts vitamin K to its reduced form.
image Warfarin inhibits the enzyme VKOR. Blocking formation of the reduced form of vitamin K inhibits the activation of these four clotting factors.
image These clotting factors vary in their half-lives (6 to 50 hours), with factor II having the longest half-life and factor VII having the shortest. This delays the onset of action of warfarin, as one must wait until these clotting factors have been mostly depleted before the full anticoagulant effects have been achieved.
image

Figure 16-4

Pharmacokinetics

image Warfarin is an orally administered anticoagulant.
image Warfarin requires 2 to 3 days of treatment before anticoagulation takes effect. This is because warfarin prevents vitamin K–dependant protein synthesis, and before anticoagulation occurs the plasma proteins must be cleared from the plasma, which takes about 48 hours.
image Drug-drug and drug-food interactions are frequent with this agent.

image Pharmacodynamic: competitive antagonism with vitamin K

• Foods containing vitamin K will oppose warfarin.

image Pharmacokinetic: enzyme induction or inhibition

• Warfarin may also inhibit or induce metabolism of other drugs.

Indications

image Long-term (home) anticoagulation. Note that heparin would be used first for many of these conditions in the hospital and that warfarin would replace heparin on discharge.
image The most common indications include the following:

image PE or DVT treatment
image Atrial fibrillation
image Prevention of thrombus for mechanical heart valves
image Chronic hypercoagulable states

Contraindications

image Pregnancy: Warfarin is teratogenic and can also cause fetal bleeding.
image Recent events that predispose to bleeding include the following:

image Surgery
image Stroke

image Platelet disorders (If you have dysfunctional clotting cells and dysfunctional clotting proteins, there really is not much left to form a clot if you should need it.)

Side Effect

image Hemorrhage

image Minor: Small cuts, nosebleeds, easy bruising, hematuria (blood in urine), and bleeding gums may occur.
image Major: Intracranial bleeding is often catastrophic.

Important Notes

image Warfarin therapy is monitored using the International Normalized Ratio (INR), which is a standardized form of the PT test. Because different laboratories use different reagents to test the PT, every laboratory generates a slightly different result, so the INR corrects for this discrepancy among laboratories.
image Patients must undergo regular blood tests to ensure that their INR levels remain “therapeutic,” which means being in the appropriate range for their problem. For example, DVT treatment requires that the INR be 2.0 to 2.5 but for mechanical valves, the INR should be 2.5 to 3.5.
image The anticoagulant effects of warfarin can be reversed by administration of vitamin K. The time required for vitamin K to work is dependent on the time the liver requires to generate more proteins (many hours).
image Fresh frozen plasma (plasma from another human) can be transfused to immediately replace clotting factors and is the fastest way to correct an overdose of warfarin.
image When warfarin is being administered, all vitamin K–dependent protein synthesis is inhibited. This includes the prothrombotic factors II, VII, IX, and X but also includes the antithrombotic factors protein C and protein S. Protein C and S are inhibited very early with warfarin, and thus there can be a short duration of time when only the natural anticoagulants are inhibited and a paradoxical, temporary hypercoagulable state can be induced with warfarin. Therefore it is important to coadminister heparin with warfarin until the patient’s anticoagulation levels (measured by INR) are in the desired range.

Advanced

image Warfarin is actually a racemic mixture of two enantiomers: R (weak) and S (potent). Each is eliminated by different metabolic pathways:

image S by 2C9
image R by 1A2 (major) as well as 2C19 and 3A4 (both minor)

Pharmacogenetics

image There is significant genetic variability in responses to warfarin owing to variants in 2C9 that metabolize the drug less efficiently and to variants in VKOR. See Chapter 6 for further details.

Evidence

Warfarin versus LMWH for Treatment of Venous Thromboembolism

image A 2001 Cochrane review (seven studies, N = 1137 participants), updated in 2003, compared warfarin with LMWHs for long-term treatment of VTE. There was no difference in the risk of recurrent VTE between warfarin and LMWH. There was a lower risk of bleeding with LMWH (OR 0.38), and no difference in mortality rates between these two interventions.

Warfarin versus Acetylsalicylic Acid for Atrial Fibrillation

image A 2007 Cochrane review (eight studies, N = 9598 participants) compared warfarin with acetylsalicylic acid (ASA) in atrial fibrillation patients who had not had a prior stroke or transient ischemic attack (TIA). Treatment with warfarin led to a lower risk of stroke (OR 0.68), ischemic stroke (OR 0.53), and systemic emboli (OR 0.48). The risk of intracranial hemorrhage was increased with warfarin (OR 1.98). All-cause mortality and vascular deaths were similar between groups, and disabling or fatal strokes and MI were almost reduced with oral anticoagulants, but this did not reach statistical significance.

FYI

image Coumarins were first isolated from spoiled sweet clover and were discovered when cattle consuming this feed began to develop hemorrhagic disease.
image You may hear warfarin referred to as “ rat poison,” as it is commonly used as a rodenticide. However, the dose that a rat receives is very high.

Salicylates

Description

Salicylates comprise a heterogeneous group of agents that are related by chemical structure and by their antiinflammatory effects.

Prototype and Common Drugs

Salicylates

image Prototype: acetylsalicylic acid
image Others: sodium salicylate, salsalate, sodium thiosalicylate, choline salicylate, magnesium salicylate
image Others (derivative): diflunisal

Aminosalicylates

image Prototype: 5-ASA
image Others: sulfasalazine, olsalazine, balsalazide, mesalamine

MOA (Mechanism of Action)

Salicylates

image Like nonsteroidal antiinflammatory drugs (NSAIDs), the salicylates work by inhibiting the actions of the cyclooxygenase (COX) enzyme (Figure 16-5).
image ASA works by irreversibly inhibiting COX-1, an enzyme that catalyzes the formation of cyclic endoperoxide, which in turn is then converted to the following:

image Thromboxane A2 (TXA2) in platelets

• TXA2 is a potent inducer of platelet aggregation and release.
• Inhibition of TXA2 leads to the antiplatelet effects of ASA (Figure 16-6).

image Prostaglandin E2 (PGE2) mediates fever, pain, inflammation, and mucous production.

• Inhibition of PGE2 formation therefore leads to many of the most well known effects of the salicylates, namely their antiinflammatory, analgesic, and antipyretic properties.

image PGI2 (prostacyclin) in endothelial cells

• PGI2 performs essentially the opposite role as TXA2 (see Figure 16-5).

image

Figure 16-5

image

Figure 16-6

Aminosalicylates

image Although the aminosalicylates are related to salicylates in chemical structure, inhibition of prostaglandin (PG) synthesis is believed to play only a minor role, if any, in their efficacy in inflammatory bowel disease.
image Aminosalicylates appear to inhibit inflammatory cytokines. They appear to do this by inhibiting nuclear factor (NF)–κB, a transcription factor for inflammatory cytokines. Aminosalicylates are also peroxisome proliferator–activated receptor–gamma (PPAR-γ) agonists, and PPAR-γ is believed to play an important role in inflammation in ulcerative colitis.

Pharmacokinetics

Salicylates

image Salicylates are also readily absorbed from the skin. They are absorbed to such an extent that systemic poisoning can occur if the agent is applied topically to a large surface area.
image Metabolism of salicylates occurs through glucuronidation and by conjugation to salicyluric acid. A small proportion (approximately 10%) of salicylates is excreted as salicylic acid in the urine, although this proportion can increase with urine that has an alkaline pH and decrease with acidic pH.
image The elimination half-life of ASA is only 20 minutes; however, the salicylate component has a much longer half-life, which is dose dependent (low dose, 2 hours; analgesic dose, 12 hours; high or toxic dose, 15 to 30 hours).

Aminosalicylates

image Aminosalicylates appear to exert their actions directly at the colon and therefore must be delivered directly to the colon.
image These include attaching the drug to a chemical that is then cleaved in the colon, applying an enteric coating that does not dissolve until the drug reaches the distal small intestine, and using microspheres that slowly release drug beginning in the duodenum.
image A newer technology combines a pH-dependent release mechanism initially with a special coating that prolongs release of drug as it passes throughout the colon.

Indications

Salicylates

image Prevention of MI and ischemic stroke
image As an antiinflammatory, including in rheumatoid arthritis
image Analgesia
image As an antipyretic

Aminosalicylates

image Ulcerative colitis
image Crohn’s disease

Contraindications

Acetylsalicylic Acid

image Hypersensitivity (allergy) to ASA. Can be fatal.
image Not for use in children. Causes Reye’s syndrome, an often fatal encephalopathy in children that has been associated with the use of ASA during viral infection.

Side Effects

Salicylates

image GI: GI effects are caused by reduced levels of a PG (produced by COX-1) that protects the lining of the stomach. They can range in severity from upset stomach to GI bleeds and ulcers.
image Bleeding is caused by the antiplatelet effect.
image Tinnitus: Ringing of the ears is typically only seen at higher doses.

Aminosalicylates

image GI: nausea, vomiting, dyspepsia
image Headache
image Hypersensitivity reactions: Many aminosalicylates contain a sulfa moiety, and a number of patients are allergic to sulfur-containing drugs.

Important Notes

image Because the binding of ASA to the platelets is irreversible, the antiplatelet effect of ASA lasts for the lifespan of the platelet, which is about 5 to 7 days. Patients preparing for surgery must stop taking ASA 7 days before surgery.
image As with other NSAIDs, data from long-term epidemiologic studies suggest that ASA might prevent the development of colorectal cancer. The mechanism behind this protective effect has not been clearly established; however, COX is believed to mediate cell growth.
image Salicylates can stimulate respiration. They do this in two ways. Indirectly, they do this by increasing CO2 production, which in turn leads to an increase in the depth of respiration as the body tries to exhale the excess CO2. They also directly stimulate the respiratory center in the brain.
image Salicylate poisoning can therefore lead to severe acid-base disturbances. Stimulation of respiration leads to a respiratory alkalosis, which is compensated for by the kidneys (Figure 16-7).
image Diflunisal is a salicylate derivative that is a competitive COX inhibitor and appears to lack antipyretic effects. It appears to be a more potent analgesic and antiinflammatory than ASA.
image Many of the side effects of sulfasalazine have been attributed to the sulfapyridine component. Therefore later compounds were developed without the sulfapyridine group.
image Sulfasalazine may inhibit intestinal absorption of folate, and thus folate supplementation is typically indicated in patients taking sulfasalazine.
image

Figure 16-7

Advanced

image Salicylates are rapidly absorbed after oral administration. Despite the fact that salicylates are acids, and are therefore ionized in an alkaline environment, raising the pH of the stomach will enhance dissolution, and the net effect will be to enhance absorption. Therefore buffered preparations confer minimal advantage when it comes to rapid absorption.

Evidence

Aspirin Alone or in Combination with Clopidogrel for Prevention of Cardiovascular Events

image A 2007 Cochrane review (two studies, N = 28,165 patients) compared the combination of clopidogrel and aspirin with aspirin alone for preventing cardiovascular events in patients at high risk for cardiovascular disease and those with established cardiovascular disease. The authors included two large trials. CHARISMA patients were at high risk for cardiovascular events, with or without established cardiovascular disease, whereas patients in CURE had had a recent non–ST-segment elevation acute coronary syndrome. In CHARISMA the benefit of combination therapy was minimal: five cardiovascular events avoided and three major bleeds for every 1000 patients over 28 months. In CURE the benefits were more obvious, with 23 events avoided and 10 major bleeds over 9 months.

Single-Dose Aspirin versus Placebo for Acute Pain

image A 1999 Cochrane review (72 trials, N = 3253 participants) compared a single dose of aspirin with placebo for acute pain of moderate to severe intensity. The number needed to treat (NNT) for at least 50% pain relief was 4.4 for 600- to 650-mg doses, 4.0 for a 1000-mg dose, and 2.4 for a 1200-mg dose. A single dose of aspirin produced more drowsiness (number needed to harm [NNH] 28) and gastric irritation (NNH 38) than placebo.

Aspirin for Prevention or Regression of Sporadic Colorectal Adenomas

image A 2004 Cochrane review (nine trials, N = 24,143 participants) examined the use of NSAIDs and aspirin for the prevention or regression of sporadic colorectal adenomas and colorectal cancer. Fewer patients treated with low-dose ASA developed recurrent sporadic colorectal adenomas after 1 to 3 years (NNT 12.5) compared with controls, and these results were driven by one large placebo-controlled study. There was no significant difference in the outcomes for colorectal cancer or for adverse events in any trials.

Aspirin versus Other Antiplatelets for Preventing Serious Vascular Events in High-Risk Patients

image A 2000 Cochrane review (four trials, N = 22,656 patients) compared the thienopyridines ticlopidine and clopidogrel with aspirin for the prevention of serious vascular events in high-risk patients, particularly those who had had previous TIA or ischemic stroke. Thienopyridines reduced the risk of a serious vascular event compared with aspirin, avoiding 11 events per 1000 patients over 2 years (OR 0.91). Thienopyridines also reduced the risk of stroke by seven events per 1000 patients over 2 years. This reduction in risk increased to 16 events per 1000 patients in individuals with a history of TIA or ischemic stroke. The thienopyridines reduced the risk of GI hemorrhage but increased the risk of skin rash and diarrhea versus aspirin. Ticlopidine also significantly increased the risk of neutropenia.

Maintenance of Remission in Ulcerative Colitis

image A 2006 Cochrane review (16 studies, N = 2479) assessed the newer release formulations of 5-ASA versus placebo or sulfasalazine in the maintenance of remission in ulcerative colitis. Compared with placebo, the NNT for failure to maintain clinical or endoscopic remission was six. However, newer formulations of 5-ASA were less effective than sulfasalazine (OR 1.29). Although the incidence of side effects was similar with 5-ASA and with sulfasalazine, the authors noted that sulfasalazine trials enrolled patients who were already tolerating sulfasalazine, perhaps biasing the comparison of side effects in favor of sulfasalazine.

FYI

image ASA originated from salicylic acid, derived from the bark of the willow tree. The use of salicylic acid dates back to ancient times, both in North America and in Europe, and its first official medical use was ascribed to Hippocrates. Chemists began synthesizing salicylic acid in the later nineteenth century. Salicylic acid had some significant GI side effects, and it was these side effects that led Hoffman, a chemist at Bayer, to acetylate the molecule and create what is still perhaps the most successful nonantibiotic in the history of pharmaceutical development.
image ASA therapy is very inexpensive when compared with the other antiplatelets. Given that and its long history of use, it is a first-line agent in MI prevention.
image ASA is more commonly referred to by its original brand name, Aspirin. The word aspirin has been in use for over a century and was derived from the name for another plant, the meadowsweet (Spiraea ulmaria), which has similar properties.
image The aminosalicylates were originally developed as treatments for rheumatoid arthritis. In clinical trials it was noted that rheumatoid arthritis patients who also had ulcerative colitis appeared to experience greater benefit for their ulcerative colitis than for their rheumatoid arthritis.

Adenosine Diphosphate (ADP) Blockers

Description

Adenosine diphosphate (ADP) blockers inhibit platelet aggregation and/or release and are also known as the thienopyridines.

Prototype and Common Drugs

image Prototype: ticlopidine
image Others: clopidogrel, prasugrel, ticagrelor

MOA (Mechanism of Action)

image Platelets are activated by adhering to damaged endothelium by linking of glycoprotein Ia (GPIa) receptors with collagen and GPIb receptors with von Willebrand factor (vWF). The activation of platelets leads to aggregation and clot formation.
image Platelet activation leads to synthesis and release of mediators involved in platelet aggregation:

image TXA2
image Serotonin (5-HT)
image ADP

image Mediators such as ADP promote platelet aggregation by increasing GP receptor expression and promoting binding of fibrinogen to GPIIIa/IIb receptors. These actions are mediated by binding of ADP to the P2Y1 and P2Y12 receptors on platelets. Both P2Y1 and P2Y12 are receptors for ADP, and stimulation of both of these receptors is required for platelet activation.
image Ticlopidine, prasugrel, and clopidogrel are irreversible inhibitors of the P2Y12 receptors and thus inhibit the ADP-dependent pathway of platelet activation and subsequent aggregation (Figure 16-8). Ticagrelor is a reversible inhibitor.
image

Figure 16-8

Pharmacokinetics

image Clopidogrel has a relatively slow onset of action, as it requires approximately 5 days to achieve a plateau in platelet inhibition.
image Because clopidogrel, prasugrel, and ticlopidine are irreversible inhibitors of the ADP receptor, the biologic half-lives of these drugs are longer than their elimination half-lives. The effects of each drug will be notable until the body replenishes its supply of platelets, requiring approximately 5 to 7 days (the life span of a platelet).

Indications

image Prevention of ischemic stroke in patients intolerant to ASA
image Acute myocardial infarction

Contraindications

image Active bleeding: These agents impair clotting and prolong bleeding.
image Significant hepatic impairment: Clopidogrel and ticlopidine agents need a functioning liver in order to be converted to their active metabolites. Hepatic complications have also been reported with both agents but are extremely rare.

Ticlopidine Only

image Hematopoietic disorders: See Side Effects.
image Thrombotic thrombocytopenic purpura (TTP): See Side Effects.

Side Effects

image Bleeding
image Rash, diarrhea: mechanism not known

Serious

image Severe neutropenia is a rare side effect associated with ticlopidine but not with clopidogrel. It necessitates discontinuation of the drug.
image TTP has been associated with ticlopidine and less commonly with clopidogrel.

Important Notes

image There is a significant range of responses to clopidogrel among patients. The extent of platelet inhibition can range from 5% to 90%, with patients at the lower end of the range (<10%) deemed to be “clopidogrel unresponsive.” Genetic polymorphisms are thought to play a role in these variable responses, including alterations in the PGY12 receptor as well as CYP450 mutations.
image Several other ADP-targeting antiplatelet agents are in various stages of clinical development, in an effort to improve on the toxicity issues associated with ticlopidine and the slow onset and prolonged effect of clopidogrel.

Advanced

image TTP is a life-threatening disease caused by abnormal activation and aggregation of platelets because of vWF macromolecules. The platelets aggregate in vessels and form pathologic thrombi, resulting in hemolysis (and anemia), a decreased platelet count (from consumption), central nervous system (CNS) dysfunction or stroke, and renal compromise because of vascular occlusion and fever. These five findings comprise the pentad of TTP.

Evidence

Adenosine Diphosphate Blockers versus Aspirin for Stroke Prevention in High-Risk Patients

image A 2000 Cochrane review (four trials, N = 22,656 patients) compared ADP inhibitors with aspirin for preventing serious vascular events in high-risk patients, including those who had had a prior TIA or ischemic stroke. One large trial (N = 19,185 patients) included clopidogrel, whereas the other three (N = 3471) included ticlopidine. Results suggested that ADP blockers would result in 11 fewer serious vascular events per 1000 patients treated over approximately 2 years. Strokes were also reduced, by seven events per 1000 patients.
image Risk of GI hemorrhage and other GI events was reduced with ADP blockers versus aspirin, but risk of skin rash and diarrhea was increased. The risk of skin rash and diarrhea was greater with ticlopidine than clopidogrel, and ticlopidine was also associated with a higher risk of neutropenia than clopidogrel.

Clopidogrel with or without Aspirin for Preventing Cardiovascular Disease

image A 2007 Cochrane review included two large studies (CHARISMA and CURE, N = 28,165 patients). CHARISMA patients were at high risk for cardiovascular disease but did not necessarily have established cardiovascular disease, whereas patients in CURE had had a recent non–ST-segment elevation acute coronary syndrome. The combination of clopidogrel and aspirin reduced the risk of cardiovascular events by 13 events for every 1000 patients treated; however, six major bleeds would be caused over the same number of patients.
image Results differed between studies, with benefit more evident in CURE (reduction of 23 events and increase of 10 major bleeds over an average of 9 months) than in CHARISMA (reduction of five events and increase of three major bleeds over an average of 28 months).

FYI

image Both ticlopidine and clopidogrel are considerably more expensive than aspirin.

Antiplatelet IIb/IIIa Inhibitors

Description

Antiplatelet IIb/IIIa inhibitors are antiplatelet drugs; they inhibit platelet function.

Prototype and Common Drugs

image Abciximab
image Eptifibatide and tirofiban

MOA (Mechanism of Action)

image IIb/IIIa receptors are located on the outside of platelets, in very high numbers (50,000 to 80,000 per cell); in the resting platelet they are inactive.
image Fibrinogen and vWF bind to IIb/IIIa receptors; once bound, they bind to foreign surfaces and also bridge other platelets to induce platelet aggregation.
image These drugs bind to the IIb/IIIa receptor complex on the platelet and prevent binding of endogenous ligands including fibrinogen and vWF, thus inhibiting aggregation of the platelet (Figure 16-9).
image

Figure 16-9

Pharmacokinetics

image All drugs are administered intravenously.
image Abciximab has a half-life of 10 minutes, but the effect lasts 24 hours because although the drug is cleared from the blood, it is still bound to platelets.
image Eptifibatide has a half-life of 2 hours; its effects last for the duration of drug levels in the body.
image Tirofiban has a half-life of 2.5 hours; its effects last for the duration of drug levels in body.

Indications

image Coronary angioplasty
image High-risk patients with acute MI

Contraindications

image High risk of bleeding, including but not limited to the following:

image Recent surgery
image Recent stroke
image Thrombocytopenia (low platelet count)
image Recent GI bleed

Side Effects

image Bleeding
image Thrombocytopenia is the most serious complication. Thrombocytopenia is immune-mediated and occurs in 5% of patients but is severe in 1%.

Important Notes

image The three drugs in this class are all structurally very different:

image Abciximab is a monoclonal antibody.
image Eptifibatide is a cyclic heptapeptide (seven amino acids).
image Tirofiban is a nonpeptide.

Advanced

image Glanzmann’s thrombasthenia is a condition of deficient IIb/IIIa receptors and is a bleeding disorder.
image Abciximab is less specific for the receptors it binds; it also binds the vitronectin receptor, which regulates plasminogen activity.

Evidence

Coronary Angioplasty

image A meta-analysis in 2007 (38 trials, N = 58,495 patients) demonstrated that with angioplasty compared with placebo, IIb/IIIa blockers decreased mortality at 30 days (OR 0.74) but not at 6 months. Death or MI was decreased both at 30 days (OR 0.67) and at 6 months (OR 0.71), although severe bleeding was increased (OR 1.38; absolute risk increase 8.6 per 1000).

Non–ST-Elevation Myocardial Infarction—No Angioplasty

image A meta-analysis in 2007 (38 trials, N = 58,495 patients) demonstrated that IIb/IIIa blockers did not decrease mortality at 30 days or at 6 months. Death or MI was decreased at 30 days (OR 0.92) and at 6 months (OR 0.88). Severe bleeding was increased (OR 1.27; absolute risk increase 1.2 per 1000).

Stroke

image A meta-analysis in 2006 (two studies, N = 414 patients) did not find statistically significant evidence for safety or efficacy of IIb/IIIa inhibitors for the treatment of ischemic stroke.

FYI

image Eptifibatide is based on a rattlesnake venom peptide, which is a toxin that produces coagulopathy.

Fibrinolytics

Description

Fibrinolytics lyse (break up) blood clots. They are also called clot busters and thrombolytics.

Prototypes and Common Drugs

image There are two major subclasses.

Fibrin Selective

image Prototype: alteplase (also known as recombinant tissue plasminogen activator, or rtPA)
image Others: reteplase, tenecteplase

Nonselective

image Prototype: streptokinase
image Other: urokinase

MOA (Mechanism of Action)

image These agents are plasminogen activators and cleave plasminogen to form plasmin (Figure 16-10).
image Plasmin is a protease that digests fibrin (a fibrinolytic). Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The mesh is created by the cross-linking of fibrin.
image Tissue plasminogen activator is found in the body. It is a serine protease that is released from endothelial cells in response to injury. Its physiologic purpose is to gradually dissolve clots that have formed because of injury. Urokinase is also secreted endogenously and serves the same purpose, although it has some important differences, especially selectivity of action.
image The plasminogen activators can work either in the presence (alteplase, reteplase) or absence (streptokinase, urokinase) of fibrin.
image The physiologic advantage of requiring fibrin for activity is that the fibrinolytic effects will be (mainly) localized to the clot.
image The thrombolytics that do not need fibrin to enhance their activity will activate both bound and circulating plasmin. In addition to fibrin, plasmin also degrades fibrinogen and some clotting factors; thus circulating coagulation factors will be depleted. Therefore these agents are not considered to be “clot specific,” and this in theory may make them less safe to use than agents that need fibrin to work optimally.
image

Figure 16-10

Pharmacokinetics

image The agents in this class are all administered intravenously.
image They all have short elimination half-lives, most around 15 to 20 minutes, although the half-life of alteplase is only 5 minutes. Because of its short half-life, alteplase is typically delivered by infusion after an initial IV bolus, whereas the longer-acting agents can be given with repeat bolus injections.
image Tenecteplase demonstrates biphasic clearance, meaning that it is eliminated in two phases. Therefore its total elimination half-life may be as long as 2 hours.
image These drugs are sometimes trickled in through a long catheter right to the site of a pathologic thrombus so that the concentration of drug is high at the site of the thrombus but low(er) in all other areas of the body.

Indications

image Acute ST elevation myocardial infarction (STEMI)
image Massive pulmonary embolus
image Thrombotic stroke (very specific criteria must be met)

Contraindications

image Any potential source for major bleeding, including the following:

image Prior hemorrhagic stroke
image Active internal bleeding
image Recent surgery

Side Effects

image Hemorrhage is such a major concern that these drugs are used only when very strict criteria are met, because the risk of bleeding can outweigh the benefit of thrombolysis.
image Hypersensitivity: Streptokinase and urokinase are both antigenic.

Important Notes

image There are advantages and disadvantages to using streptokinase versus rt-PA. rt-PA is more clot selective than urokinase or streptokinase, as it does a poor job of activating plasminogen in the absence of fibrin. However streptokinase is much cheaper than rt-PA. Streptokinase also elicits an immune response that can harm the patient.
image The use of streptokinase results in the patient developing antibodies to the drug. If a patient receives streptokinase and subsequently requires repeat fibrinolytic therapy (days to months later), then reteplase should be used.
image Tenecteplase is more fibrin specific than alteplase. It is therefore believed to be less likely to elicit serious bleeding than alteplase, which is the major side effect of concern for drugs in this class.
image Reteplase is believed to work faster than alteplase. Reteplase appears to diffuse more quickly throughout the clot, allowing it to more efficiently lyse the clot.
image Thrombolysis with any of the agents in this class is most successful on newly formed clots. The older the clot is, the more established the fibrin mesh is, and the harder the clot is to dissolve. Therefore time is of the essence when using fibrinolytics. Patients with MI appear to benefit most if they receive therapy within 6 hours of symptoms.

Evidence

Thrombolytics versus Heparin or Placebo for Treatment of Acute Pulmonary Embolism

image A 2009 Cochrane review (eight trials, N = 679 participants) compared thrombolytics with placebo or heparin in patients with acute PE. The rates of mortality, PE recurrence, major hemorrhagic events, and minor hemorrhagic events were similar between thrombolytics and heparin. In one study that examined combination therapy, the use of rt-PA combined with heparin versus heparin alone reduced the need for further treatment for in-hospital events (OR 0.35).

Thrombolytics for Treatment of Ischemic Stroke

image A 2009 Cochrane review (26 trials, N = 7152 participants) compared thrombolytics with controls in patients with definite ischemic stroke. Although thrombolytics reduced the proportion of patients who were dead or dependent at 3 to 6 months after stroke (OR 0.81), they increased the risk of symptomatic intracranial hemorrhage (OR 3.49) and death by 3 to 6 months after stroke (OR 1.31).

Thrombolytics versus Angioplasty in Myocardial Infarction

image A 2003 systematic review (23 trials, N = 7739 participants) compared percutaneous transluminal coronary angioplasty (PTCA) with thrombolytics for acute STEMI. There were fewer overall deaths in the short term with PTCA compared with thrombolytics (incidence of 7% versus 9%, respectively), and also a lower incidence of nonfatal reinfarction (3% versus 7%) and stroke (1% versus 2%) with PTCA versus thrombolytics. The results for PTCA continued to be better than thrombolytics during long-term follow-up.

FYI

image Hemorrhage is a particular problem with agents displaying less specificity for newly formed thrombi (streptokinase and urokinase).
image Thrombolytics are all very expensive but have proven to be an effective method for treating acute MI.
image rt-PA is often simply called tPA.
image Streptokinase is produced by β-hemolytic streptococci.
image Urokinase was originally extracted from urine.

Erythropoietins

Description

Erythropoietins are agents that stimulate the production of red blood cells (RBCs).

Prototype and Common Drugs

image Prototype: epoetin alfa (also known as recombinant human erythropoietin, rHuEPO or simply, EPO)
image Other: darbepoetin alfa

MOA (Mechanism of Action)

image Erythropoietin is an endogenous protein that stimulates the production of RBCs (erythrocytes). Erythropoietin is typically released in response to hypoxia and is largely synthesized in the kidneys, with a small amount coming from the liver (Figure 16-11).
image Patients with a deficiency of erythropoietin will be anemic. This occurs commonly in patients with renal failure.
image Once released, erythropoietin binds to a receptor on the surface of committed erythroid progenitor cells in the bone marrow. Binding to this receptor mediates a variety of intracellular effects through tyrosine kinases, including the inhibition of apoptosis. Inhibiting apoptosis prevents RBCs from dying at an early stage of development. Erythropoietin also promotes proliferation through Janus protein kinase-2 (JAK2) pathways.
image

Figure 16-11

Pharmacokinetics

image Epoetin alpha is administered parenterally by either the SC or the IV route. The elimination half-life of IV Epoetin alpha is approximately 4 to 8 hours.
image Darbepoetin alfa is a modified form of erythropoietin, with amino acid mutations that have led to a prolonged elimination half-life of approximately 24 hours.

Indications

image Anemia:

image In advanced renal failure
image Associated with chemotherapy and acquired immunodeficiency syndrome (AIDS)

Contraindications

image Uncontrolled hypertension: See Side Effects.

Side Effects

image Iron deficiency: If iron stores cannot keep up with erythropoiesis, patients may develop a functional iron deficiency. Patients on chronic erythropoietin therapy will likely need an iron supplement.
image Thrombosis: Serious thromboembolic events have been reported, particularly in patients on dialysis. It is recommended that these patients receive anticoagulant therapy as a prophylactic measure.
image Hypertension: Treatment with erythropoietins can lead to an increase in blood pressure. Although increased hematocrit can lead to increased blood pressure, the mechanism is believed to be more likely a result of the interaction between erythropoietin and vasoactive factors such as angiotensin II.
image Seizures: Seizures have been reported in dialysis patients receiving epoetin alfa.

Important Notes

image Some formulations of erythropoietin contain benzyl alcohol, which has been shown to be toxic to premature infants.
image A link between cancer and erythropoietin use has been proposed. Some studies in certain cancers have reported an increased risk of death and/or worsening of condition with erythropoietin use. Erythropoietin appears to act through receptors similar to those of growth factors associated with neoplasia, although these problems do not appear to be associated with all cancers.
image Hematocrit is frequently monitored during therapy with the erythropoietins. Erythrocytes have a long half-life; therefore the results of any dose adjustments made in response to hematocrit would not be seen for 2 to 6 weeks.

Evidence

Recombinant Human Erythropoietin in Predialysis Patients with Anemia

image A 2005 Cochrane review (15 trials, N = 461 participants) compared the use of rHuEPO with no treatment or placebo in predialysis patients with renal anemia. rHuEPO significantly improved hemoglobin and hematocrit and significantly reduced the number of patients requiring blood transfusions (relative risk [RR] 0.32). Quality of life and exercise capacity were also improved, where reported. rHuEPO did not appear to have an effect on the progression of renal disease, and there was no increase in the incidence of adverse events with rHuEPO therapy.

Recombinant Human Erythropoietin in Preventing Transfusion in Premature Infants

image A 2006 Cochrane review (19 studies, N = 912 infants) compared rHuEPO with placebo or no treatment in reducing the use of RBC transfusions in preterm and/or low–birth-weight infants. The authors found that rHuEPO reduced the risk of having one or more transfusions (typical RR 0.66 [0.59 to 0.74]). rHuEPO also reduced the average volume of blood transfused per infant by 7 mL and the average number of transfusions per infant; however, the clinical significance of these small differences was questioned by the authors. Several hard outcomes such as mortality, hypertension, and numerous other complications were not affected by therapy.

Darbepoetin or Epoetin in Anemia Associated with Cancer Treatment

image A 2006 Cochrane review (57 trials, N = 9353 participants) assessed darbepoetin and epoetin in the prevention or treatment of anemia in cancer patients. Both agents reduced the risk of transfusions (RR 0.64 [0.60 to 0.68]) and resulted in a requirement for an average of one less unit of blood. However, the risk of thromboembolic events was increased (RR 1.67 [1.35 to 2.06]). The authors were not able to conclude whether these agents have an impact on tumor response or overall survival.

FYI

image The chemical structure of epoetin alfa differs slightly from that of human endogenous erythropoietin. Although this difference does not have any clinical relevance, it has proven useful in trying to detect athletes who have been using epoetin alfa for blood doping. This is a practice by which athletes will try to stimulate an artificial increase in hematocrit before a competition to increase the oxygen-carrying capacity of their blood, presumably enhancing performance.

Colony-Stimulating Factors

Description

Colony-stimulating factors (CSFs) are agents that stimulate the production of neutrophils and monocytes.

Prototype and Common Drugs

Granulocyte Colony-Stimulating Factor (G-CSF)

image Prototype: filgrastim
image Other: pegfilgrastim

Granulocyte-Monocyte Colony-Stimulating Factor (GM-CSF)

image Prototype: sargramostim

MOA (Mechanism of Action)

image Neutropenia is a common and serious side effect of cytotoxic cancer chemotherapy. Cytotoxic agents preferentially target rapidly dividing cells, including those of the bone marrow. The major complication of neutropenia is a reduced immune response, greatly increasing the probability of developing infections of both “normal” and opportunistic microbes.
image The CSFs work by binding to receptors on myeloid progenitor cells. These are cells in the bone marrow that make RBCs, platelets, granulocytes, and monocytes. The actions of these receptors are mediated through the Janus protein kinase/signal transducers and activators of transcription (JAK/STAT) pathway.
image G-CSFs stimulate proliferation and differentiation only of progenitors commited to becoming neutrophils.
image GM-CSFs stimulate the production of neutrophils and monocytes, as well as the actions (phagocytosis, superoxide production, and cell-mediated toxicity) of neutrophils, monocytes, and eosinophils (Figure 16-12).
image

Figure 16-12

Pharmacokinetics

image The elimination half-life of filgrastim is 3 to 5 hours and is fairly consistent between the IV and SC routes. It is largely cleared through renal excretion.
image The addition of a polyethylene glycol (PEG) to filgrastim produced pegfilgrastim, which because of its large size is not as readily cleared by the kidneys. Pegfilgrastim therefore has an extended elimination half-life of about 40 hours, compared with filgrastim.

Indications

image Adjunct to myelosuppressive chemotherapy
image Severe chronic neutropenia
image Prevention and treatment of neutropenia in human immunodeficiency virus (HIV) infection

Contraindications

image None of major significance

Side Effects

image Bone loss: G-CSF increases osteoclast activity, leading to bone resorption.
image Joint pain: G-CSF appears to stimulate cytokine release, leading to joint pain.
image Renal dysfunction: G-CSF causes a transient and reversible renal impairment, believed to be caused by leukostasis (clumping of leukocytes) in the kidneys.
image Acute respiratory distress: G-CSF can lead to lung injury because of accumulation and activation of neutrophils in the lungs.
image Splenomegaly or splenic rupture: Cases of splenic rupture have been reported with G-CSF.
image Sickle cell crises: Sometimes fatal, sickle cell crises occur in patients with sickle cell disorders.

Evidence

Colony-Stimulating Factor in Children with Acute Lymphocytic Leukemia

image A 2005 Cochrane review (six studies, N = 332 patients) looked at safety and effectiveness of adjunctive G-CSF or GM-CSF in children with acute lymphocytic leukemia (ALL). There was not enough data to assess survival. CSF significantly reduced the number of episodes of febrile neutropenia, length of hospitalization, and number of infectious disease episodes. CSF did not affect the length of neutropenia episodes or delays in chemotherapy episodes.

FYI

image The CSFs are also referred to as myeloid growth factors. The term myeloid is associated with bone marrow, which is the site of action of these agents.

B Vitamins

Description

B vitamins is the collective name for a series of supplements.

Prototype

image B1: thiamine
image B2: riboflavin
image B3: niacin
image B6: pyridoxine
image B9: folic acid
image B12: cyanocobalamin, hydroxocobalamin

MOA (Mechanism of Action)

Vitamin B1

image Vitamin B1 is converted to thiamine in the body and is a coenzyme in carbohydrate metabolism, including the decarboxylation of pyruvic acid. Increased pyruvic acid levels are therefore indicative of vitamin B1 deficiency. Deficiency can lead to damage in regions of the brain, including the thalamus, midbrain, and brainstem, and this appears to be mediated, at least in part, by oxidative stress. This brain damage manifests as Wernicke-Korsakoff syndrome, a condition associated with alcoholism (Figure 16-13).
image

Figure 16-13 SAM = S-adenosylmethionine; SAH = S-adenosylhomocysteine; THF = tetrahydrofolate; dUMP = deoxyuracilmonophosphate; dTMP = deoxythyminemonophosphate

Vitamin B2

image The two coenzyme forms of vitamin B2 (riboflavin-5-phosphate and flavin adenine dinucleotide) play a role in adenosine triphosphate (ATP) production, through the metabolism of carbohydrates, fats, and proteins. Deficiency typically manifests as fissures in lips or cracks in the mouth, swelling of the tongue, or seborrheic dermatitis. Normochromic-normocytic anemias can also occur, as well as peripheral neuropathy.

Niacin (Vitamin B3)

image Niacin is converted in vivo to nicotinic adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These metabolites serve as coenzymes for a number of reactions involving lipid and protein metabolism, as well as anaerobic reactions in the Krebs cycle.
image Niacin binds to a G protein–coupled receptor in adipocytes and inhibits lipolysis in adipose tissue. This reduces the supply of free fatty acids, and because the liver uses free fatty acids to produce triglycerides, which are then used in very low-density lipoprotein (VLDL) synthesis, VLDL is reduced. Accordingly, niacin decreases low-density lipoprotein (LDL) and also increases high-density lipoprotein (HDL) by reducing its catabolism.

Vitamin B6

image Vitamin B6 is converted to the coenzyme pyridoxal-5-phosphate (PLP), which plays a role in amino acid and fatty metabolism. Of note, B6 facilitates the metabolism of tryptophan to niacin, methionine to cysteine, and glutamic acid to γ-aminobutyric acid (GABA).

Vitamin B12 and Folic Acid

image Vitamin B12 and folic acid play key roles in DNA synthesis. Active forms of folic acid serve as enzyme cofactors that play key roles in the synthesis of purines and pyrimidines, as well as amino acids, in the body.
image A deficiency of folic acid or B12 therefore has the greatest impact on cells that are actively dividing, such as the cells of the bone marrow, which are involved in erythropoiesis. Therefore the primary complication of deficiencies of these vitamins is anemia.
image Specifically, B12 deficiency results in abnormal DNA replication, which prevents cells from maturing properly, leading to production of large, dysfunctional RBC precursors (megaloblasts) that do not leave the marrow, or abnormal cells that do leave the marrow.
image A B12 deficiency can also affect the nervous system, causing inflammation, demyelination, and neuronal cell death.

Pharmacokinetics

image Vitamin B1 combines with ATP to form thiamine in vivo. The maximum amount of B1 that can be absorbed in a single dose is 4 to 8 mg. The absorption of thiamine is markedly reduced in alcoholics and in those with folate deficiency.
image Vitamin B1 is stored in the body, in heart, liver, skeletal muscle, kidneys, and brain. It undergoes hepatic metabolism and is excreted by the kidneys. Large doses of vitamin B1 may simply be renally excreted.
image Vitamin B2 absorption occurs by active transport in the upper ileum, and this transport mechanism is saturable (maximum of 20 to 25 mg vitamin B2 can be absorbed in a single dose). It is widely distributed to tissues, but very little is stored. Riboflavin is excreted in urine unchanged.
image Niacin (B3) is converted to niacinamide in the liver. This conversion is saturable, so when patients take higher doses for an antihyperlipidemic effect, much of the niacin is not converted to niacinamide and instead is excreted unchanged in urine. Niacinamide is widely distributed and undergoes further hepatic metabolism before being excreted in urine.
image Vitamin B6 absorption is not via active transport, and therefore is not saturable. It is stored, and its metabolite is excreted in urine.
image Gastric intrinsic factor facilitates the absorption of vitamin B12, and absorption is also pH sensitive. Intrinsic factor is secreted by parietal cells, so patients who have had gastric surgery or some other disruption of their parietal cells may have a relative deficiency of intrinsic factor and thus a vitamin B12 deficiency. These patients can be treated with intramuscular injections of B12, which bypasses the need for intrinsic factor.
image After ingestion, folic acid is converted to its active form, tetrahydrofolate, by the liver.

Indications

Vitamin B12

image Pernicious anemia
image Megaloblastic and macrocytic anemias caused by poor B12 absorption

Folic Acid

image Megaloblastic and macrocytic anemias
image Prevention of neural tube defects in neonates
image Adjunct to methotrexate to prevent methotrexate toxicity
image Pernicious anemia (combined with B12)

Pyridoxine

image Sideroblastic anemias (particularly those secondary to isoniazid and pyrazinamide)

Thiamine

image Prophylaxis for B1 deficiency: beriberi, Wernicke’s encephalopathy

Riboflavin

image No specific indication other than treatment of deficiency; typically adjunctively with other B vitamins

Niacin

image Hypercholesterolemia

Contraindications

image None of major significance

Side Effects

image The B vitamins are generally well tolerated.
image Adverse effects can be seen at high doses (15 mg daily) of folic acid, although these are well above the recommended daily intake, which is typically 1 mg or less.

Niacin

image At the recommended daily intake, niacin is well tolerated; however, when used as an antihyperlipidemic, it is often used at high doses, which can result in the following:

image Flushing is caused by vasodilation of cutaneous vessels, typically accompanied by pruritus and tingling. This is believed to be caused by cutaneous PG release and can be mitigated by pretreatment with aspirin or by use of a sustained-release formulation of niacin.
image Hepatic dysfunction can increase serum transaminase and cause hepatitis.
image GI effects include nausea and abdominal discomfort.
image Reduced glucose tolerance is an infrequent, typically reversible side effect whose mechanism has not been established.

Important Notes

image B12 preparations are available that contain intrinsic factor from animal sources. Although these might be useful initially in patients with intrinsic factor deficiency, patients typically become less responsive to the intrinsic factor, perhaps because of an antibody response launched against the animal protein.
image Folinic acid, also known as leucovorin, is a reduced form of folic acid. It is used as rescue therapy in patients who are being treated with methotrexate. Methotrexate is an antifolate drug, and patients who are on high doses or chronic therapy are likely to experience severe symptoms of folate deficiency unless they are treated adjunctively with leucovorin.
image Folic acid alone will not be effective in treating pernicious anemia, as it does not address the neurologic complications. If used in pernicious anemia, folic acid should be given as an adjunct to vitamin B12.
image Pyridoxine is used as an antidote for overdoses. See Table 16-1.
image Although vitamin B3 can be sourced from the diet, concentrations of niacin in foods are not high enough to have an antihyperlipidemic effect. That is why patients who are using niacin to reduce cholesterol will take high doses of niacin supplements.

TABLE 16-1 Agents That Use Pyridoxine As an Antidote

Overdose Agent Mechanism of Toxicity Mechanism of Pyridoxine as Antidote
Isoniazid (INH)
Seizures
INH depletes pyridoxal-5-phosphate (P5P), a cofactor in conversion of glutamic acid to γ-aminobutyric acid (GABA). This leads to increased glutamic acid (excitatory) and reduced GABA (inhibitory).

Pyridoxine replenishes P5P. Mushrooms (false morel)
Seizures
Similar mechanism to INH–enhanced glutamic acid, reduced GABA because of depleted P5P.

Pyridoxine replenishes P5P. Ethanol Ethanol is primarily converted to acetaldehyde, a toxic metabolite. Pyridoxine accelerates the metabolism of ethanol, reducing exposure time to acetaldehyde.

Evidence

Folic Acid with or without Vitamin B12 for Cognition

image A 2008 Cochrane review (eight studies, N = 1317 participants) examined the effects of folic acid supplementation, with or without vitamin B12, on healthy elderly or demented participants, in preventing cognitive impairment or slowing its progress. The authors found no evidence that folic acid, with or without B12, has a positive impact on mood and cognitive function in healthy elderly people.
image However, one trial enrolled healthy elderly people with elevated homocysteine levels and found a significant improvement in global functioning, memory storage, and information-processing speed.
image The evidence for the use of folic acid in patients with cognitive disorders is scant, with only one small study showing a benefit when combined with cholinesterase inhibitors in Alzheimer’s disease.

FYI

image Cyanocobalamin and hydroxocobalamin are synthetic forms of vitamin B12.
image The discovery of vitamin B12 as a treatment for pernicious anemia began with an experiment in the 1920s in which patients with this condition were fed large quantities of raw liver. A few years later, it was discovered that patients whose stomachs had been removed did not respond to the liver “cure.” It was hypothesized that an “intrinsic factor” must be secreted by the stomach to facilitate the absorption of the yet-unnamed curative “extrinsic factor.” This extrinsic factor was later isolated from the liver, and named vitamin B12.
image The preferred source of B vitamins for daily supplementation is from the diet. Food sources and recommended intakes are summarized in Table 16-2.

TABLE 16-2 Sources and Recommended Dietary Intakes for Various B Vitamins

Vitamin Recommended Dietary Allowances Sources
B1 (thiamine)
Infants: 0.2-0.3 mg
Children: 0.5-0.9 mg
Adults: 1.0-1.2 mg

Fortified breads, cereals, pasta, whole grains (especially wheat germ), lean meats (especially pork), fish, dried beans, peas, and soybeans B2 (riboflavin)
Infants: 0.3-0.4 mg
Children: 0.5-0.9 mg
Adults: 1.0-1.3 mg
Pregnancy: 1.4 mg
Lactation: 1.6 mg

Dairy, eggs, enriched cereals and grains, meats, liver, and green vegetables (such as asparagus or broccoli) B3 (niacin)   Meats, fish, legumes, whole grains B6 (pyridoxine)
Infants: 0.1-0.3 mg
Children: 0.5-1.0 mg
Adults: 1.3-1.7 mg
Cereal grains, legumes, vegetables (carrots, spinach, peas), potatoes, milk, cheese, eggs, fish, liver, meats, and flour B9 (folate)
Infants: 65-80 mcg
Children: 150-300 mcg
Adults: 400 mcg (men, women over age 50)
800 mcg (women under age 50)
Asparagus, avocados, cantaloupe, strawberries, oranges, legumes, and fortified cereals and grains B12 (cyanocobalamin)
Infants: 0.4-0.5 mcg
Children: 0.9-1.8 mcg
Adults: 2.4 mcg
Pregnancy: 2.6 mcg
Lactation: 2.8 mcg
Dairy, eggs, fish, liver, meats, chicken, and fortified cereals

Iron

Description

Iron formulations are used for treatment of iron deficiency.

Prototypes and Common Drugs

Oral

image Prototype: ferrous sulfate
image Others: ferrous fumarate, ferrous gluconate, polysaccharide-iron complex

IV

image Prototype: iron dextran
image Others: Sodium ferric gluconate, iron sucrose

MOA (Mechanism of Action)

image Most iron is recycled through the body; RBCs contain the majority of iron in hemoglobin. Because the life span of an RBC is about 120 days, in 1 day about 0.8% of the RBCs are broken down, and their iron is recycled:

image Senescent (old) RBCs are taken up by the reticular system (spleen and macrophages) and are relieved of their iron (Figure 16-14).
image The iron is bound to ferritin (the main cellular storage protein), and a smaller amount is stored as protein deposits called hemosiderin.
image Iron that is released is transported by transferrin (the transport protein).
image Transferrin delivers the iron to either the liver for storage or to bone marrow for further hemoglobin and RBC production.

image Iron that is lost from the body must be replaced, which is usually accomplished through diet, but abnormal states overwhelm the dietary iron and supplemental iron is required.
image

Figure 16-14

Pharmacokinetics

image Ferrous iron (Fe2+) is better absorbed than ferric iron (Fe3+) and is absorbed in the duodenum. About 25% of ferrous iron is absorbed.
image Iron from animals (heme iron) is ferrous; iron from vegetarian foods (nonheme iron) is ferric, and so a smaller percentage is available for absorption.
image Iron should be taken on an empty stomach; many foods inhibit iron absorption. Other factors that markedly decrease absorption include antacids, H2 blockers, proton pump antagonists, and calcium supplements.
image Most ingested iron either is not absorbed or is lost with the enterocytes when their turnover results in shedding into the lumen of the GI tract.
image Some oral compounds are combined with ascorbic acid, which is designed to enhance absorption.

Indications

image Iron deficiency anemia:

image Parenteral (IV) iron is indicated for patients who are noncompliant or unable to tolerate oral iron.

treatment and prevention

Contraindication

image Anaphylaxis-like reactions to the IV formulations

Side Effects

Oral Administration

image GI symptoms are common and dose related: nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea. These signs and symptoms can be reduced by lowering the daily dose.
image Black stool can confound the ability to diagnose GI bleeding.

Intravenous Administration

image Anaphylaxis-like reactions occur in 0.7% of patients taking iron dextran. Chest pain, wheezing, and a fall in blood pressure mandate immediate termination of the infusion and a call for the emergency medical team.

image Iron sucrose results in a much lower incidence of anaphylaxis-like reactions.

Important Notes

image Free inorganic iron is extremely toxic; therefore iron is quickly bound by transferrin and subsequently stored in the body in the form of hemoglobin, myoglobin, ferritin, and, to a small degree, transferrin. Hemoglobin and myoglobin constitute about 80% of all stored iron.
image Iron deficiency is caused by the following:

image Malnutrition
image Any chronic blood loss

• Menstruation, GI bleeding
• Cancers

image Increased utilization:

• Pregnancy
• Recombinant erythropoietin administration: common in patients with renal failure caused by abnormally low erythropoietin production by the peritubular capillary endothelial cells in the kidney

image Iron deficiency results in small, pale RBCs: microcyctic, hypochromic anemia. RBC size is measured by the mean cell volume (MCV).
image A number of laboratory measurements can be used for the diagnosis of iron deficiency. See Table 16-3.
image The goal of iron therapy is twofold: to correct the anemia, and to correct the deficient iron stores in the body. It can take 6 to 12 months of oral iron therapy to correct the iron stores.
image The hemoglobin should increase by about 2 g/dL (20 g/L) after 3 weeks of therapy in a normally responding patient.
image Foods with high iron content include the following:

image Tofu, beans, lentils, asparagus, broccoli, eggs
image Red and white meats: pork, beef, chicken, turkey (livers are very high)
image Many seafoods: clams (highest), oysters, mussels, sardines, shrimp
image Enriched cereals, pastas, oatmeals

image Iron toxicity occurs in iron storage diseases including hemochromatosis and hemosiderosis, as well as iron-loading anemias such as thalassemia.
image Iron toxicity is treated with phlebotomy (removing blood) and iron chelators deferoxamine (parenteral), deferasirox (oral), and deferiprone (oral but not available in the United States). Phlebotomy is not indicated when the patient is anemic or being treating for anemia. Chelators are discussed further in Chapter 7.

TABLE 16-3 Laboratory Measurements Used for Diagnosis of Iron Deficiency

Hemoglobin Low
Serum iron: measure of iron bound to serum ferritin Low
Ferritin: ferritin level correlates with total body iron stores Low
Total iron binding capacity (TIBC): refers to the number of unoccupied binding sites on transferrin and is determined by both the iron levels and the transferrin levels High
Transferrin percent saturation: percent of iron bound to transferrin; a calculated value based on serum iron and TIBC Low
Bone marrow iron Low

Advanced

image Myelodysplastic syndrome (a bone marrow disease resulting in abnormal blood counts) can produce a microcytic hypochromic anemia. However, iron storage measurements are not low, and this is not an iron deficiency state. It is an abnormality of iron utilization in the bone marrow.
image Thalassemia is a hemoglobinopathy (hemoglobin disease) that also results in a microcytic hypochromic anemia with a normal iron profile.
image Transferrin saturation percent is calculated as follows:

image

image Hypothyroidism can lower ferritin levels; infection or states of inflammation can increase ferritin because it is an acute phase reactant.
image Oral iron preparations with other additives, polysaccharide-iron complexes, or enteric coatings or sustained-release forms probably do not offer any advantages beyond those achieved by reducing the dose or timing of administration of plain ferrous salts.

Evidence

Iron Supplementation in Pregnancy

image A Cochrane review in 2009 (49 studies, N = 23,200 women) showed that compared with placebo or no treatment, daily iron supplementation was associated with increased hemoglobin levels in maternal blood both before and after birth and reduced risk of anemia at term.

FYI

image Nomenclature:

image Myelo refers to bone marrow. Dysplasia means abnormal growth.
image Thallasa is Greek for the sea. Mediterranean natives have a high incidence of thalassemia.

image Ferroxidase oxidizes iron from Fe2+ to Fe3+; ferrireductase reduces iron from Fe3+ to Fe2+.
image Dextran is a branched complex polysaccharide made of glucose molecules.
image Deferasirox is a newer treatment for iron overload.
image Hemosiderin-laden macrophages are a finding seen with bronchoalveolar washing, in conditions that cause chronic bleeding in the lungs.

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