Black Box Warning: Iron Dextran
This preparation should be used for treatment of iron deficiency only in patients in whom oral administration is infeasible or ineffective due to increased risk for anaphylaxis. A test dose is required before administration.
Indications
Iron dextran is reserved for patients with a clear diagnosis of iron deficiency and for whom oral iron is either ineffective or intolerable. Primary candidates for parenteral iron are patients who, because of intestinal disease, are unable to absorb iron taken orally. Iron dextran is also indicated when blood loss is so great (500–1000 mL/wk) that oral iron cannot be absorbed fast enough to meet hematopoietic needs. Parenteral iron may also be employed when there is concern that oral iron might exacerbate preexisting disease of the stomach or bowel. Lastly, parenteral iron can be given to the rare patient for whom the gastrointestinal (GI) effects of oral iron are intolerable.
Adverse Effects
Anaphylactic Reactions.
Potentially fatal anaphylaxis is the most serious adverse effect. Anaphylactic reactions are triggered by dextran in the product, not by the iron. Although these reactions are rare, their possibility demands that iron dextran be used only when clearly required. Furthermore, whenever iron dextran is administered, injectable epinephrine and facilities for resuscitation should be at hand. To reduce risk, each full dose must be preceded by a small test dose. However, be aware that even the test dose can trigger anaphylactic and other hypersensitivity reactions. In addition, even when the test dose is uneventful, patients can still experience anaphylaxis.
Other Adverse Effects.
Hypotension is common in patients receiving parenteral iron. In addition, iron dextran can cause headache, fever, urticaria, and arthralgia. More serious reactions—circulatory failure and cardiac arrest—may also occur. When administered intramuscularly, iron dextran can cause persistent pain and prolonged, localized discoloration. Very rarely, tumors develop at sites of intramuscular (IM) injection. Intravenous (IV) administration may result in lymphadenopathy and phlebitis.
Preparations, Dosage, and Administration
Preparations.
Iron dextran [INFeD, Dexferrum, Infufer, Dexiron] is available in single-dose vials (1 and 2 mL) that contain 50 mg/mL of elemental iron.
Dosage.
Dosage determination is complex. Dosage depends on the degree of anemia, the weight of the patient, and the presence of persistent bleeding. A suggested calculation is [0.0442 × (desired Hgb – observed Hgb) × LBW] = (0.26 × LBW), where Hgb is hemoglobin and LBW is lean body weight in kilograms. The maximal safe dose is 100 mg.
Administration.
Iron dextran may be administered by IM or IV route. IV administration is preferred. This route is just as effective as IM administration but causes fewer anaphylactic reactions and other adverse effects.
Intravenous.
To minimize anaphylactic reactions, IV iron dextran should be administered by the following protocol: (1) administer a small test dose (25 mg over 5 minutes) and observe the patient for at least 15 minutes; (2) if the test dose appears safe, slowly administer a larger dose (over a 10- to 15-minute interval); and (3) additional doses may be given as needed on a daily basis.
Intramuscular.
IM iron dextran has significant drawbacks and should be avoided. Disadvantages include persistent pain and discoloration at the injection site, possible development of tumors, and a greater risk for anaphylaxis. As with IV iron dextran, a small test dose should precede the full therapeutic dose.
Sodium–Ferric Gluconate Complex, Iron Sucrose, and Ferumoxytol
Sodium–ferric gluconate complex (SFGC), iron sucrose, and ferumoxytol represent alternatives to iron dextran for parenteral iron therapy. With all three drugs, the risk for anaphylaxis is very low, so there is little or no need for giving test doses. As a result, these drugs are more convenient than iron dextran. Unfortunately, indications for these drugs are limited to treatment of iron deficiency anemia in patients with chronic kidney disease (CKD). They are not approved for iron deficiency from other causes.
Sodium–Ferric Gluconate Complex
SFGC, sold under the trade name Ferrlecit, is a parenteral iron product indicated for iron deficiency anemia in patients with CKD who are undergoing chronic hemodialysis. The drug is always used in conjunction with erythropoietin, an agent that stimulates RBC production.
SFGC can cause transient flushing and hypotension, associated with lightheadedness, malaise, fatigue, weakness, and severe pain in the chest, back, flanks, or groin. This reaction can be minimized by infusing the drug slowly. In contrast to iron dextran, SFGC poses little risk for anaphylaxis. SFGC is supplied in 5-mL ampules that contain 62.5 mg of elemental iron. For most patients, a single dose consists of 125 mg. The typical patient requires a cumulative dose of 1 g (eight 125-mg infusions on separate days). Every time the drug is administered, facilities for cardiopulmonary resuscitation should be immediately available.
Iron Sucrose
Like SFGC, iron sucrose [Venofer] is a parenteral form of iron indicated for iron deficiency anemia in patients with CKD. However, in contrast to SFGC, whose indications are limited to CKD patients undergoing hemodialysis in conjunction with erythropoietin therapy, iron sucrose is indicated for a broader range of CKD patients, specifically the following:
• Non–dialysis-dependent (NDD) patients receiving erythropoietin
• NDD patients not receiving erythropoietin
• Hemodialysis-dependent (HDD) patients receiving erythropoietin
• Peritoneal dialysis–dependent (PDD) patients receiving erythropoietin
The most common adverse effects of iron sucrose are hypotension and cramps. The drug has also been associated with heart failure (HF), sepsis, and taste perversion. Life-threatening hypersensitivity reactions are very rare: no cases were observed during clinical trials, and only 27 cases (out of 450,000 patients) were reported during postmarketing surveillance. Nonetheless, facilities for cardiopulmonary resuscitation should be available during administration. However, in contrast to iron dextran, no test dose is needed.
Iron sucrose is supplied in 2.5-, 5-, and 10-mL single-dose vials. Administration is IV, either by (1) slow injection (1 mL/min) or (2) infusion. Iron sucrose should not be mixed with other drugs or with parenteral nutrition solutions. All patients should receive a total dose of 1000 mg, but the dosing schedule and administration technique depend on the patient as follows:
• HDD patients—Give ten 100-mg doses during each of 10 consecutive dialysis sessions. Administer by slow IV injection or IV infusion.
• NDD patients—Give five 200-mg doses on separate occasions over a 14-day span. Administer by slow IV injection.
• PDD patients—Give two 300-mg doses 14 days apart, then one 400-mg dose 14 days later. Administer by slow IV infusion.
Ferumoxytol
Ferumoxytol [Feraheme] is a parenteral form of iron indicated for iron deficiency anemia in all patients with CKD, whether or not they are on dialysis or using erythropoietin. Compared with SFGC and iron sucrose, ferumoxytol is much more convenient because it requires only 2 doses (given over 3–8 days), whereas SFGC and iron sucrose require 3 to 10 doses (given over several weeks).
Ferumoxytol is generally well tolerated. The most common adverse effects are nausea, dizziness, hypotension, headache, vomiting, and edema. In clinical trials, about 0.2% of patients experienced serious hypersensitivity reactions. Accordingly, facilities for cardiopulmonary resuscitation should be immediately available. However, in contrast to iron dextran, no test dose is needed.
Because of its unique composition (ferumoxytol is a superparamagnetic form of iron oxide), the drug can interfere with magnetic resonance imaging studies. This interference is most profound 1 to 2 days after dosing but can persist for up to 3 months. Fortunately, ferumoxytol does not interfere with other forms of diagnostic imaging, including x-rays, computed tomography, positron emission tomography, ultrasound, or nuclear medicine imaging.
Ferumoxytol [Feraheme] is supplied in 17-mL single-dose vials (30 mg elemental iron/mL). Administration is by slow IV injection. The usual dosage is 510 mg on day 1, followed by another 510 mg 3 to 8 days later. Additional doses may be given as needed. After each injection, patients should be monitored for at least 30 minutes for hypotension and hypersensitivity reactions. For patients on dialysis, dosing should be done at least 1 hour after starting dialysis, and only after blood pressure (BP) has stabilized.
Inpatient Anesthesia
Intravenous Regional Anesthesia
IV regional anesthesia is employed to anesthetize the extremities—hands, feet, arms, and lower legs, but not the entire leg (because too much anesthetic would be needed). Anesthesia is produced by injection into a distal vein of an arm or leg. Before giving the anesthetic, blood is removed from the limb (by gravity or by application of an Esmarch bandage), and a tourniquet is applied to the limb (proximal to the site of anesthetic injection) to prevent anesthetic from entering the systemic circulation. To ensure complete blockade of arterial flow throughout the procedure, a double tourniquet is used. After injection, the anesthetic diffuses out of the vasculature and becomes evenly distributed to all areas of the occluded limb. When the tourniquet is loosened at the end of surgery, about 15% to 30% of administered anesthetic is released into the systemic circulation. Lidocaine—without epinephrine—is the preferred agent for this type of anesthesia.
Alfentanil and Sufentanil
Alfentanil [Alfenta] and sufentanil are IV opioids related to fentanyl. Both drugs are used for induction of anesthesia, for maintenance of anesthesia (in combination with other agents), and as sole anesthetic agents. Pharmacologic effects are like those of morphine. Sufentanil has an especially high milligram potency (about 1000 times that of morphine). Alfentanil is about 10 times more potent than morphine. Both drugs have a rapid onset, and both are Schedule II agents.
Remifentanil
Remifentanil [Ultiva] is an IV opioid with a rapid onset and brief duration. The brief duration results from rapid metabolism by plasma and tissue esterases, and not from hepatic metabolism or renal excretion. Like fentanyl, remifentanil is about 100 times more potent than morphine. Remifentanil is approved for analgesia during surgery and during the immediate postoperative period. Administration is by continuous IV infusion. Effects begin in minutes and terminate 5 to 10 minutes after the infusion is stopped. For surgical analgesia, the infusion rate is 0.05 to 2 mcg/kg/min. For postoperative analgesia, the infusion rate is 0.025 to 0.2 mcg/kg/min. Adverse effects during the infusion include respiratory depression, hypotension, bradycardia, and muscle rigidity sufficient to compromise breathing. Postinfusion effects include nausea, vomiting, and headache. Remifentanil is regulated as a Schedule II substance.
Dexmedetomidine
Actions and Therapeutic Use
Dexmedetomidine [Precedex], like clonidine, is a selective alpha2-adrenergic agonist. The drug acts in the central nervous system (CNS) to cause sedation and analgesia. The drug has two approved indications: (1) short-term sedation in critically ill patients who are initially intubated and undergoing mechanical ventilation and (2) sedation for nonintubated patients before and/or during surgical and other procedures. However, in addition to these approved uses, dexmedetomidine has a variety of off-label uses, including sedation during awake craniotomy, prevention and treatment of postanesthetic shivering, and enhancement of sedation and analgesia in patients undergoing general anesthesia. In contrast to clonidine, which is administered by epidural infusion, dexmedetomidine is administered by IV infusion.
Pharmacokinetics
With IV infusion, dexmedetomidine undergoes wide distribution to tissues. In the blood, the drug is 94% protein bound. Dexmedetomidine undergoes rapid and complete hepatic metabolism, followed by excretion in the urine. The elimination half-life is 2 hours.
Adverse Effects
The most common adverse effects are hypotension and bradycardia. The mechanism is activation of alpha2-adrenergic receptors in the CNS and periphery, which results in decreased release of norepinephrine from sympathetic neurons innervating the heart and blood vessels. If these cardiovascular effects are too intense, they can be managed in several ways, including (1) decreasing or stopping the infusion, (2) infusing fluid, and (3) elevating the lower extremities. Giving a muscarinic antagonist (e.g., atropine) can increase heart rate.
Additional adverse effects include nausea, dry mouth, and transient hypertension. Importantly, dexmedetomidine does not cause respiratory depression.
Drug Interactions
Dexmedetomidine can enhance the actions of anesthetics, sedatives, hypnotics, and opioids. Excessive CNS depression can be managed by reducing the dosage of dexmedetomidine or the other agents.
Preparations, Dosage, and Administration
Dexmedetomidine [Precedex] is supplied in solution (100 mcg/mL), which must be diluted to 4 mcg/mL before use. Administration is by IV infusion. For intensive care sedation, treatment consists of a loading dose (1 mcg/kg infused over 10 minutes) followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hr for no more than 24 hours. For procedural sedation, treatment typically consists of a loading dose (1 mcg/kg infused over 10 minutes) followed by a maintenance infusion of 0.2 to 1 mcg/kg/hr.
Epidural Anesthesia
Epidural anesthesia is achieved by injecting a local anesthetic into the epidural space (i.e., within the spinal column but outside the dura mater). A catheter placed in the epidural space allows administration by bolus or by continuous infusion. After administration, diffusion of anesthetic across the dura into the subarachnoid space blocks conduction in nerve roots and in the spinal cord. Diffusion through intervertebral foramina blocks nerves located in the paravertebral region. With epidural administration, anesthetic can reach the systemic circulation in significant amounts. As a result, when the technique is used during delivery, neonatal depression may result. Lidocaine and bupivacaine are popular drugs for epidural anesthesia. Because of the risk for death from cardiac arrest, the concentrated (0.75%) solution of bupivacaine must not be used in obstetric patients.
Spinal (Subarachnoid) Anesthesia
Technique
Spinal anesthesia is produced by injecting local anesthetic into the subarachnoid space. Injection is made in the lumbar region below the termination of the cord. Spread of anesthetic within the subarachnoid space determines the level of anesthesia achieved. Movement of anesthetic within the subarachnoid space is determined by two factors: (1) the density of the anesthetic solution and (2) the position of the patient. Anesthetics employed most commonly are bupivacaine, lidocaine, and tetracaine. All must be free of preservatives.
Adverse Effects
The most significant adverse effect of spinal anesthesia is hypotension. Blood pressure is reduced by venous dilation secondary to blockade of sympathetic nerves. (Loss of venous tone decreases the return of blood to the heart, causing a reduction in cardiac output and a corresponding fall in BP.) Loss of venous tone can be compensated for by placing the patient in a 10- to 15-degree head-down position, which promotes venous return to the heart. If BP cannot be restored through head-down positioning, drugs may be indicated; ephedrine and phenylephrine have been employed to promote vasoconstriction and enhance cardiac performance.
Autonomic blockade may disrupt function of the intestinal and urinary tracts, causing fecal incontinence and either urinary incontinence or urinary retention. The prescriber should be notified if the patient fails to void within 8 hours of the end of surgery.
Spinal anesthesia frequently causes headache. These “spinal” headaches are posture dependent and can be relieved by having the patient assume a supine position.
Anticoagulants and Thrombolytics
Continuous Unfractionated Heparin Intravenous Infusion
IV infusion provides steady levels of heparin and therefore is preferred to intermittent injections. Indications for the use of heparin infusion include treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), or in patients with myocardial ischemia or infarction. Dosing may consist of an initial weight-based bolus followed by a weight-based infusion titrated to laboratory results. Whether or not a bolus is indicated depends on the indication for treatment and the facility policy. During the initial phase of treatment, the activated partial thromboplastin time (aPTT) should be measured once every 4 to 6 hours and the infusion rate adjusted accordingly. For additional information on unfractionated heparin, see Chapter 44.
Low-Dose Unfractionated Heparin Therapy
Heparin in low doses is given for prophylaxis against thromboembolism in hospitalized patients. Doses of 5000 units are given subcutaneously every 8 to 12 hours depending on patient weight. During low-dose therapy, monitoring of the aPTT is not usually required.
Protamine Sulfate for Heparin Overdose
Protamine sulfate is an antidote to severe heparin overdose. Protamine is a small protein that has multiple positively charged groups. These groups bond ionically with the negative groups on heparin, thereby forming a heparin-protamine complex that is devoid of anticoagulant activity. Neutralization of heparin occurs immediately and lasts for 2 hours, after which additional protamine may be needed. Protamine is administered by slow IV injection. Dosage is based on the fact that 1 mg of protamine will inactivate 100 units of heparin. Hence, for each 100 units of heparin in the body, 1 mg of protamine should be injected.
Direct Thrombin Inhibitors
Bivalirudin
Bivalirudin [Angiomax], an IV direct thrombin inhibitor, has actions like those of dabigatran (see Chapter 44). The drug is a synthetic drug chemically related to hirudin, an anticoagulant isolated from the saliva of leeches.
Bivalirudin is given in combination with aspirin, clopidogrel, or prasugrel to prevent clot formation in patients undergoing coronary angioplasty. At this time, the standard therapy for these patients is aspirin combined with a platelet glycoprotein (GP) IIb/IIIa inhibitor combined with low-dose, unfractionated heparin. Bivalirudin, an alternative to heparin in this regimen, has been studied in combination with aspirin as well as GP IIb/IIIa inhibitors. In one trial—the Hirulog Angioplasty Study—bivalirudin plus aspirin was compared with heparin plus aspirin. Bivalirudin was at least as effective as heparin at preventing ischemic complications (myocardial infarction [MI], abrupt vessel closure, death) and caused fewer bleeding complications. In a subgroup of patients—those with postinfarction angina—bivalirudin was significantly more effective than heparin.
Adverse Effects
The most common side effects are back pain, nausea, hypotension, and headache. Other relatively common effects (incidence greater than 5%) include vomiting, abdominal pain, pelvic pain, anxiety, nervousness, insomnia, bradycardia, and fever.
Bleeding is the effect of greatest concern. However, compared with heparin, bivalirudin causes fewer incidents of major bleeding (3.7% vs. 9.3%), and fewer patients require transfusions (2% vs. 5.7%). Coadministration of bivalirudin with heparin, warfarin, or thrombolytic drugs increases the risk for bleeding.
Pharmacokinetics
With IV dosing, anticoagulation begins immediately. Drug levels are maintained by continuous infusion. Bivalirudin is eliminated primarily by renal excretion and partly by proteolytic cleavage. The half-life is short (25 minutes) in patients with normal renal function but may be longer in patients with renal impairment. Coagulation returns to baseline about 1 hour after stopping the infusion. Anticoagulation can be monitored by measuring activated clotting time.
Comparison With Heparin
Bivalirudin is just as effective as heparin and has several advantages: it works independently of antithrombin (AT), inhibits clot-bound thrombin as well as free thrombin, and causes less bleeding and fewer ischemic events. However, the drug has one disadvantage: bivalirudin is more expensive than heparin. One single-use vial, good for a full course of treatment, costs about $1000, compared with $10 for an equivalent course of heparin. However, the manufacturer estimates that reductions in bleeding and ischemic complications would save, on average, $1000 per patient, which would offset the greater cost of bivalirudin. The bottom line? Bivalirudin works as well as heparin, is safer, and may be equally cost effective—and hence is considered an attractive alternative to heparin for use during angioplasty.
Preparations, Dosage, and Administration
Bivalirudin [Angiomax] dosing consists of an initial IV bolus (0.75 mg/kg) followed by continuous infusion (1.75 mg/kg/hr) for the duration of the procedure and up to 4 hours after. If necessary, bivalirudin may be infused for up to 20 additional hours at a rate of 0.2 mg/kg/hr. Treatment should begin just before angioplasty. Dosage should be reduced in patients with severe renal impairment. All patients should take aspirin (300–325 mg).
Argatroban
Like bivalirudin, argatroban is an IV anticoagulant that works by direct inhibition of thrombin. The drug is indicated for prophylaxis and treatment of thrombosis in patients with heparin- induced thrombocytopenia (HIT). In clinical trials, argatroban reduced development of new thrombosis and permitted restoration of platelet counts. Like other anticoagulants, argatroban poses a risk for hemorrhage. About 12% of patients experience hematuria. Allergic reactions (dyspnea, cough, rash), which develop in 10% of patients, occur almost exclusively in those receiving either thrombolytic drugs (e.g., alteplase) or contrast media for coronary angioplasty. Argatroban has a short half-life (about 45 minutes), owing to rapid metabolism by the liver. Treatment is monitored by measuring the aPTT. When infusion of argatroban is discontinued, the aPTT returns to baseline in 2 to 4 hours.
Argatroban dosage depends on the setting as follows:
• For prophylaxis and treatment of thrombosis in patients with HIT and normal liver function (but who are not undergoing percutaneous coronary intervention [PCI])—The initial infusion rate is 2 mcg/kg/min. In patients with liver dysfunction, the initial rate is only 0.5 mcg/kg/min. Dosage is adjusted to maintain the aPTT at 1.5 to 3 times the baseline value.
• For prevention of thrombosis in patients with or at risk for HIT who are undergoing PCI—Give an IV bolus (350 mcg/kg) followed by continuous IV infusion (25 mcg/kg/min). Adjust the infusion rate (and perhaps give a second IV bolus) to achieve the desired activated clotting time.
Antithrombin
AT is an endogenous compound that suppresses coagulation, primarily by inhibiting thrombin and factor Xa. Clinically, AT is used to prevent thrombosis in patients with inherited AT deficiency. Currently, we have two AT preparations, marketed as ATryn and Thrombate III. Atryn is made by recombinant DNA technology; Thrombate III is made by extraction from human plasma. Nonetheless, the actions of both products are the same: suppression of coagulation mediated by thrombin and factor Xa.
Recombinant Human Antithrombin
Production.
Recombinant human AT (rhAT), sold as ATryn, is produced in goats that have been given the DNA sequence for human AT, along with genetic instructions that cause the AT to be expressed into their milk. The rhAT produced in goats is nearly identical to endogenous AT.
Therapeutic Use.
rhAT is approved for prevention of perioperative or peripartum thromboembolic events in patients with inherited AT deficiency, a disorder that puts these people at high risk for VTE. In fact, to protect against thromboembolism, these people typically require lifelong therapy with an anticoagulant, usually warfarin. During surgery or childbirth, the risk for thrombosis increases. However, there is also an obvious increase in the risk for serious bleeding. Accordingly, when patients with hereditary AT deficiency are facing childbirth or surgery, anticoagulant therapy is usually discontinued—reducing the risk for bleeding but increasing the risk for thrombosis. To reduce the risk for thrombosis, rhAT is given until anticoagulant therapy can be safely resumed. In clinical trials, rhAT prevented thromboembolism associated with childbirth or surgery in 30 of 31 patients with inherited AT deficiency.
Adverse Effects.
The principal concern is hemorrhage. To minimize risk, AT activity should be monitored and, if it rises too high, the rhAT dosage should be reduced. In addition to causing outright hemorrhage, rhAT may cause hematoma, hematuria, and hemarthrosis. Infusion-site reactions are common.
Because rhAT is derived from goats’ milk, there is a risk for hypersensitivity reactions. Accordingly, patients should be closely observed during the infusion period. If signs of a hypersensitivity reaction develop (e.g., hives, generalized urticaria, wheezing, hypotension), rhAT should be discontinued immediately.
Interaction With Heparin.
As discussed in Chapter 44, heparin produces its anticoagulant effects by enhancing the actions of AT. Accordingly, if rhAT is given to a patient taking heparin, anticoagulation will be greatly increased, thereby posing a risk for bleeding. Accordingly, if heparin is used with rhAT, tests for anticoagulation should be performed often, especially during the first hours after the initiation or termination of rhAT use.
Preparations, Dosage, and Administration.
Treatment consists of a 15-minute loading infusion followed immediately by a continuous maintenance infusion. The loading infusion should begin before delivery or 24 hours before surgery and should continue until normal maintenance coagulation can be reestablished. Dosage size is based on the patient’s AT activity and body weight. The goal is to maintain AT activity between 80% and 120% of normal. During the maintenance infusion, AT activity should be monitored periodically and the dosage adjusted accordingly. Treatment with rhAT is hugely expensive: the drug costs $2.34/unit, and a full course of treatment may require 40,000 units to more than 250,000 units. Financial assistance is available from the manufacturer.
Plasma-Derived Antithrombin.
Plasma-derived AT [Thrombate III] is made by extraction from the plasma of human volunteers. Thrombate III is like rhAT in most regards: Both drugs share the same indication (prevention of thromboembolic events associated with surgery or childbirth in patients with inherited AT deficiency), both pose a risk for hemorrhage, both increase the anticoagulant effects of heparin, and both are given by IV infusion. The drugs differ primarily in that plasma-derived AT carries a risk for hepatitis C and other infections, whereas rhAT does not. As with rhAT, dosage is based on AT activity and body weight.
Glycoprotein IIb/IIIa Receptor Antagonists
Group Properties
The GP IIb/IIIa receptor antagonists, sometimes called “super aspirins,” are the most effective antiplatelet drugs on the market. Three agents are available: abciximab, tirofiban, and eptifibatide. All three are administered intravenously, usually in combination with aspirin and low-dose heparin. Dosages are shown in Table 89.1.
TABLE 89.1
Dosages for Glycoprotein IIb/IIIa Receptor Antagonists
| Application | Tirofiban [Aggrastat] | Eptifibatide [Integrilin] | Abciximab [ReoPro] |
| Acute coronary syndrome (ACS) | 0.4 mcg/kg/min for 30 min, then 0.1 mcg/kg/min for 48–108 hr | 180-mcg/kg bolus, then 2 mcg/kg/min for up to 72 hr | 0.25-mg/kg bolus, then 10 mcg/kg/min for 18–24 hr |
| Percutaneous coronary intervention* (PCI) after treatment for ACS | Continue 0.1 mcg/kg/min for the procedure and 12–24 hr after | Consider decreasing the infusion rate to 0.5 mcg/kg/min for the procedure and 20–24 hr after | Continue 10 mcg/kg/min for the procedure and 1 hr after |
| PCI without prior treatment for ACS | Not FDA approved for this application | 135-mcg/kg bolus before procedure, then 0.5 mcg/kg/min for 20–24 hr | 0.25-mg/kg bolus 10–60 min before procedure, then 0.125 mcg/kg/min (max.,10 mcg/min) for 12 hr |
Actions
The GP IIb/IIIa antagonists cause reversible blockade of platelet GP IIb/IIIa receptors and thereby inhibit the final step in aggregation. As a result, these drugs can prevent aggregation stimulated by all factors, including collagen, thromboxane A2 adenosine diphosphate, thrombin, and platelet activation factor.
Therapeutic Use
The GP IIb/IIIa antagonists are used short term to prevent ischemic events in patients with acute coronary syndrome (ACS) and those undergoing PCI.
Acute Coronary Syndromes
ACSs have two major manifestations: unstable angina and non−ST-segment elevation myocardial infarction (non-STEMI). In both cases, symptoms result from thrombosis triggered by disruption of atherosclerotic plaque. When added to traditional drugs for ACS (heparin and aspirin), GP IIb/IIIa antagonists reduce the risk for ischemic complications.
Percutaneous Coronary Intervention
GP IIb/IIIa antagonists reduce the risk for rapid reocclusion after coronary artery revascularization with PCI (balloon or laser angioplasty, or atherectomy using an intraarterial rotating blade). Reocclusion is common because PCI damages the arterial wall, encouraging platelet aggregation.
Properties of Individual Glycoprotein IIb/IIIa Antagonists
Abciximab
Description and Use.
Abciximab [ReoPro] is a purified Fab fragment of a monoclonal antibody. The drug binds to platelets in the vicinity of GP IIb/IIIa receptors and thereby prevents the receptors from binding fibrinogen. Abciximab, in conjunction with aspirin and heparin, is approved for IV therapy of ACS and for patients undergoing PCI. In addition, studies indicate it can accelerate revascularization in patients undergoing thrombolytic therapy for acute MI. Antiplatelet effects persist for 24 to 48 hours after stopping the infusion.
Adverse Effects and Interactions.
Abciximab doubles the risk for major bleeding, especially at the PCI access site in the femoral artery. The drug may also cause GI, urogenital, and retroperitoneal bleeds. However, it does not increase the risk for fatal hemorrhage or hemorrhagic stroke. In the event of severe bleeding, infusion of abciximab and heparin should be discontinued. Other drugs that impede hemostasis will increase bleeding risk.
Eptifibatide
Eptifibatide [Integrilin] is a small peptide that causes reversible and highly selective inhibition of GP IIb/IIIa receptors. The drug is approved for patients with ACS and those undergoing PCI. Antiplatelet effects reverse within 4 hours of stopping the infusion. The most important adverse effect is bleeding, which occurs most often at the site of PCI catheter insertion, and in the GI and urinary tracts. As with other GP IIb/IIIa inhibitors, the risk for bleeding is increased by concurrent use of other drugs that impede hemostasis.
Tirofiban
Tirofiban [Aggrastat] causes selective and reversible inhibition of GP IIb/IIIa receptors. The drug—neither an antibody nor a peptide—was modeled after a platelet inhibitor isolated from the venom of the saw-scaled viper, a snake indigenous to Africa. Like other GP IIb/IIIa inhibitors, tirofiban is used to reduce ischemic events associated with ACS and PCI. Platelet function returns to baseline within 4 hours of stopping the infusion. Bleeding is the primary adverse effect. The risk for bleeding can be increased by other drugs that suppress hemostasis.
Thrombolytic (Fibrinolytic) Drugs
As their name implies, thrombolytic drugs are given to remove thrombi that have already formed. This contrasts with the anticoagulants, which are given to prevent thrombus formation. In the United States three thrombolytic drugs are available: alteplase, reteplase, and tenecteplase. These drugs are employed acutely and only for severe thrombotic disease: acute MI, PE, and ischemic stroke. Principal differences among the drugs concern specific uses, duration of action, and ease of dosing. All thrombolytics pose a risk for serious bleeding and hence should be administered only by clinicians skilled in their use. Because of their mechanism, thrombolytic drugs are also known as fibrinolytics (and informally as clot busters). Properties of individual agents are shown in Table 89.2.
TABLE 89.2
Properties of Thrombolytic (Fibrinolytic) Drugs
| Alteplase (tPA) | Tenecteplase | Reteplase | |
| Trade name | Activase, Cathflo Activase | TNKase | Retavase |
| Description | A compound identical to human tPA | Modified form of tPA with a prolonged half-life | A compound that contains the active sequence of amino acids present in tPA |
| Source | All three drugs are made using recombinant DNA technology | ||
| Mechanism | All three drugs promote conversion of plasminogen to plasmin, an enzyme that degrades the fibrin matrix of thrombi | ||
| INDICATIONS: | |||
| Acute MI | Yes | Yes | Yes |
| Acute ischemic stroke | Yes | No | No |
| Acute pulmonary embolism | Yes | No | No |
| Clearing a blocked central venous catheter | Yes | No | No |
| Adverse effect: bleeding | With all three drugs, bleeding is the primary adverse effect | ||
| Half-life (min) | 5 | 20–24 | 13–16 |
| Dosage and administration for acute MI | Intravenous: 15-mg bolus, then 50 mg infused over 30 min, then 35 mg infused over 60 min* | Intravenous: Single bolus based on body weight (see text) | Intravenous: 10-unit bolus 2 times, separated by 30 min |
Alteplase (Tissue Plasminogen Activator)
Alteplase [Activase, Cathflo Activase]—also known as tissue plasminogen activator (tPA)—is identical to naturally occurring human tPA. The drug is manufactured using recombinant DNA technology.
The drug first binds with plasminogen to form an active complex. The alteplase-plasminogen complex then catalyzes the conversion of other plasminogen molecules into plasmin, an enzyme that digests the fibrin meshwork of clots. In addition to digesting fibrin, plasmin degrades fibrinogen and other clotting factors. These actions don’t contribute to lysis of thrombi, but they do increase the risk for hemorrhage.
Therapeutic Uses
Alteplase has three major indications: (1) acute MI, (2) acute ischemic stroke, and (3) acute massive PE. In all three settings, timely intervention is essential: the sooner alteplase is administered, the better the outcome.
The importance of early intervention was first demonstrated in GUSTO-I (Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries), a huge trial that evaluated the benefits of two thrombolytic drugs—alteplase (tPA) and streptokinase—in patients with acute MI. Results for alteplase were as follows: among patients treated within 2 hours of symptom onset, the death rate was only 5.4%; among those treated 2 to 4 hours after symptom onset, the rate increased to 6.6%; and among those treated 4 to 6 hours after symptom onset, the rate jumped to 9.4%. Clearly, outcomes are best when thrombolytic therapy is started quickly, preferably within 2 to 4 hours of symptom onset, and even earlier if possible. Thrombolytic therapy of acute MI is discussed further in Chapter 88.
In addition to its use for acute thrombotic disease, alteplase can be used to restore patency in a clogged central venous catheter.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
