Pharmacology_Katzung

Pharmacology_Katzung. The most serious interactions with warfarin are those that increase the anticoagulant effect and the risk of bleeding. The most dangerous of these interactions are the pharmacokinetic interactions with the mostly obsolete pyrazolones phenylbutazone and sulfinpyrazone. These drugs not only augment the hypoprothrombinemia but also inhibit platelet function and may induce peptic ulcer disease (see Chapter 36). The mechanisms interactions with oral anticoagulants. 1Stereoselectively inhibits the oxidative metabolism of the S-warfarin enantiomorph of racemic warfarin.


Pharmacology_Katzung

Pharmacology_Katzung. for their hypoprothrombinemic interaction are a stereoselective inhibition of oxidative metabolic transformation of S-warfarin (the more potent isomer) and displacement of albumin-bound warfarin, increasing the free fraction. For this and other reasons, neither phenylbutazone nor sulfinpyrazone is in common use in the United States. Metronidazole, fluconazole, and trimethoprimsulfamethoxazole also stereoselectively inhibit the metabolic transformation of S-warfarin, whereas amiodarone, disulfiram, and cimetidine inhibit metabolism of both enantiomorphs of warfarin (see Chapter 4). Aspirin, hepatic disease, and hyperthyroidism augment warfarin’s effects—aspirin by its effect on platelet function and the latter two by increasing the turnover rate of clotting factors. The third-generation cephalosporins eliminate the bacteria in the intestinal tract that produce vitamin K and, like warfarin, also directly inhibit vitamin K epoxide reductase.


Pharmacology_Katzung

Pharmacology_Katzung. Barbiturates and rifampin cause a marked decrease of the anticoagulant effect by induction of the hepatic enzymes that transform racemic warfarin. Cholestyramine binds warfarin in the intestine and reduces its absorption and bioavailability. Pharmacodynamic reductions of anticoagulant effect occur with increased vitamin K intake (increased synthesis of clotting factors), the diuretics chlorthalidone and spironolactone (clotting factor concentration), hereditary resistance (mutation of vitamin K reactivation cycle molecules), and hypothyroidism (decreased turnover rate of clotting factors). Drugs with no significant effect on anticoagulant therapy include ethanol, phenothiazines, benzodiazepines, acetaminophen, opioids, indomethacin, and most antibiotics. Reversal of Warfarin Action


Pharmacology_Katzung

Pharmacology_Katzung. Reversal of Warfarin Action Excessive anticoagulant effect and bleeding from warfarin can be reversed by stopping the drug and administering oral or parenteral vitamin K1 (phytonadione), fresh-frozen plasma, prothrombin complex concentrates, and recombinant factor VIIa (rFVIIa). A four-factor concentrate containing factors II, VII, IX, and X (Prothrombin Complex Concentrate, [Human]; Kcentra) (4F PCC) is available. The disappearance of excessive effect is not correlated with plasma warfarin concentrations but rather with reestablishment of normal activity of the clotting factors. A modest excess of anticoagulant effect without bleeding may require no more than cessation of the drug. The warfarin effect can be rapidly reversed in the setting of severe bleeding with the administration of prothrombin complex or rFVIIa coupled with intravenous vitamin K. It is important to note that due to the long half-life of warfarin, a single dose of vitamin K or rFVIIa may not be sufficient.


Pharmacology_Katzung

Pharmacology_Katzung. Oral Xa inhibitors, including rivaroxaban, apixaban, and edoxaban represent a new class of oral anticoagulant drugs that require no monitoring. Along with oral direct thrombin inhibitors (discussed below) this new class of direct oral anticoagulant (DOAC) drugs is having a major impact on antithrombotic pharmacotherapy. Rivaroxaban, apixaban, and edoxaban inhibit factor Xa, in the final common pathway of clotting (see Figure 34–2). These drugs are given as fixed doses and do not require monitoring. They have a rapid onset of action and shorter half-lives than warfarin.


Pharmacology_Katzung

Pharmacology_Katzung. Rivaroxaban has high oral bioavailability when taken with food. Following an oral dose, the peak plasma level is achieved within 2–4 hours; the drug is extensively protein-bound. It is a substrate for the cytochrome P450 system and the P-glycoprotein transporter. Drugs inhibiting both CYP3A4 and P-glycoprotein (eg, ketoconazole) result in increased rivaroxaban effect. One third of the drug is excreted unchanged in the urine and the remainder is metabolized and excreted in the urine and feces. The drug half-life is 5–9 hours in patients age 20–45 years and is increased in the elderly and in those with impaired renal or hepatic function.


Pharmacology_Katzung

Pharmacology_Katzung. Apixaban has an oral bioavailability of 50% and prolonged absorption, resulting in a half-life of 12 hours with repeat dosing. The drug is a substrate of the cytochrome P450 system and P-glycoprotein and is excreted in the urine and feces. As with rivaroxaban, drugs inhibiting both CYP3A4 and P-glycoprotein, as well as impairment of renal or hepatic function, result in increased drug effect. Edoxaban is a once-daily Xa inhibitor with a 62% oral bioavailability. Peak drug concentrations occur 1–2 hours after dosage and are not affected by food. The drug half-life is 10–14 hours. Edoxaban does not induce CYP450 enzymes. No dose reduction is required with concurrent use of P-glycoprotein inhibitors. Edoxaban is primarily excreted unchanged in the urine.


Pharmacology_Katzung

Pharmacology_Katzung. Rivaroxaban is approved for prevention of embolic stroke in patients with atrial fibrillation without valvular heart disease, prevention of venous thromboembolism following hip or knee surgery, and treatment of venous thromboembolic disease (VTE). The prophylactic dosage is 10 mg orally per day for 35 days for hip replacement or 12 days for knee replacement. For treatment of DVT/PE the dosage is 15 mg twice daily for 3 weeks followed by 20 mg/d. Depending on clinical presentation and risk factors, patients with VTE are treated for 3–6 months; rivaroxaban is also approved for prolonged therapy in selected patients to reduce recurrence risk at the treatment dose. Apixaban is approved for prevention of stroke in nonvalvular atrial fibrillation, for prevention of VTE following hip or knee surgery, and for treatment and long-term prevention of VTE. The dosage for atrial fibrillation is 5 mg twice daily; the dose for VTE is 10 mg twice a day for the first week, followed by 5 mg twice a day.


Pharmacology_Katzung

Pharmacology_Katzung. and for treatment and long-term prevention of VTE. The dosage for atrial fibrillation is 5 mg twice daily; the dose for VTE is 10 mg twice a day for the first week, followed by 5 mg twice a day. The prophylactic dose for prevention of VTE following hip or knee surgery or long-term prevention of VTE following initial therapy is 2.5 mg twice a day. The recommended duration of therapy in hip and knee replacement is the same as for rivaroxaban. Edoxaban is approved for prevention of stroke in nonvalvular atrial fibrillation, and to treat VTE following treatment with heparin or LMWH for 5–10 days. The dose for atrial fibrillation and VTE treatment is 60 mg once daily. For patients with creatinine clearance of 15–50 mL/min or those taking concomitant P-glycoprotein inhibitors, the dose is


Pharmacology_Katzung

Pharmacology_Katzung. CHAPTER 34 Drugs Used in Disorders of Coagulation 617 30 mg once daily. Edoxaban is contraindicated in patients with atrial fibrillation and creatinine clearance >95 mL/min, due to the increased rate of ischemic stroke in this group compared with patients taking warfarin. Assessment of and Reversal of Anti-Xa Drug Effect


Pharmacology_Katzung

Pharmacology_Katzung. Assessment of and Reversal of Anti-Xa Drug Effect Measurement of anti-Xa drug effect is not needed in most situations but can be accomplished by anti-Xa assays calibrated for the drug in question. Andexanet alfa is a factor Xa “decoy” molecule without procoagulant activity that competes for binding to anti-Xa drugs. In clinical trials involving apixaban and rivaroxaban, andexanet given by IV infusion resulted in rapid decrease in anti-Xa effect. Non-neutralizing antibodies occurred in 17% of those treated; the effect of these antibodies with drug re-exposure is not known. Based on the available data, andexanet is likely to be the first antidote approved for use in patients treated with anti-Xa agents who require rapid reversal for surgery or uncontrolled bleeding.


Pharmacology_Katzung

Pharmacology_Katzung. The direct thrombin inhibitors (DTIs) exert their anticoagulant effect by directly binding to the active site of thrombin, thereby inhibiting thrombin’s downstream effects. This is in contrast to indirect thrombin inhibitors such as heparin and LMW heparin (see above), which act through antithrombin. Hirudin and bivalirudin are large, bivalent DTIs that bind at the catalytic or active site of thrombin as well as at a substrate recognition site. Argatroban and melagatran are small molecules that bind only at the thrombin active site.


Pharmacology_Katzung

Pharmacology_Katzung. Leeches have been used for bloodletting since the age of Hippocrates. More recently, surgeons have used medicinal leeches (Hirudo medicinalis) to prevent thrombosis in the fine vessels of reattached digits. Hirudin is a specific, irreversible thrombin inhibitor from leech saliva that for a time was available in recombinant form as lepirudin. Its action is independent of antithrombin, which means it can reach and inactivate fibrin-bound thrombin in thrombi. Lepirudin has little effect on platelets or the bleeding time. Like heparin, it must be administered parenterally and is monitored by aPTT. Lepirudin was approved by the U.S. Food and Drug Administration (FDA) for use in patients with thrombosis related to heparin-induced thrombocytopenia (HIT). Lepirudin is excreted by the kidney and should be used with great caution in patients with renal insufficiency as no antidote exists. Up to 40% of patients who receive long-term infusions develop an antibody directed against the


Pharmacology_Katzung

Pharmacology_Katzung. kidney and should be used with great caution in patients with renal insufficiency as no antidote exists. Up to 40% of patients who receive long-term infusions develop an antibody directed against the thrombin-lepirudin complex. These antigen-antibody complexes are not cleared by the kidney and may result in an enhanced anticoagulant effect. Some patients re-exposed to the drug developed life-threatening anaphylactic reactions. Lepirudin production was discontinued by the manufacturer in 2012.


Pharmacology_Katzung

Pharmacology_Katzung. Bivalirudin, another bivalent inhibitor of thrombin, is administered intravenously, with a rapid onset and offset of action. The drug has a short half-life with clearance that is 20% renal and the remainder metabolic. Bivalirudin also inhibits platelet activation and has been FDA-approved for use in percutaneous coronary angioplasty.


Pharmacology_Katzung

Pharmacology_Katzung. Argatroban is a small molecule thrombin inhibitor that is FDA-approved for use in patients with HIT with or without thrombosis and coronary angioplasty in patients with HIT. It, too, has a short half-life, is given by continuous intravenous infusion, and is monitored by aPTT. Its clearance is not affected by renal disease but is dependent on liver function; dose reduction is required in patients with liver disease. Patients on argatroban will demonstrate elevated INRs, rendering the transition to warfarin difficult (ie, the INR will reflect contributions from both warfarin and argatroban). (INR is discussed in detail in the section on warfarin administration.) A nomogram is supplied by the manufacturer to assist in this transition.


Pharmacology_Katzung

Pharmacology_Katzung. Advantages of oral direct thrombin inhibition include predictable pharmacokinetics and bioavailability, which allow for fixed dosing and predictable anticoagulant response and make routine coagulation monitoring unnecessary. Similar to the direct oral anti-Xa drugs described above, the rapid onset and offset of action of these agents allow for immediate anticoagulation. Dabigatran etexilate mesylate is the only oral direct thrombin inhibitor approved by the FDA. Dabigatran is approved for reduction in risk of stroke and systemic embolism with nonvalvular atrial fibrillation, treatment of VTE following 5–7 days of initial heparin or LMWH therapy, reduction of the risk of recurrent VTE, and VTE prophylaxis following hip or knee replacement surgery.


Pharmacology_Katzung

Pharmacology_Katzung. Dabigatran and its metabolites are direct thrombin inhibitors. Following oral administration, dabigatran etexilate mesylate is converted to dabigatran. The oral bioavailability is 3–7% in normal volunteers. The drug is a substrate for the P-glycoprotein efflux pump; P-glycoprotein inhibitors such as ketoconazole should be avoided in patients with impaired renal function. The half-life of the drug in normal volunteers is 12–17 hours. Renal impairment results in prolonged drug clearance. For prevention of stroke and systemic embolism in nonvalvular atrial fibrillation, the dosage is 150 mg twice daily for patients with creatinine clearance greater than 30 mL/min. For decreased creatinine clearance of 15–30 mL/min, the dosage is 75 mg twice daily. No monitoring is required. Assessment of and Reversal of Antithrombin Drug Effect


Pharmacology_Katzung

Pharmacology_Katzung. Assessment of and Reversal of Antithrombin Drug Effect As with any anticoagulant drug, the primary toxicity of dabigatran is bleeding. Dabigatran will prolong the PTT, thrombin time, and ecarin clotting time, which can be used to estimate drug effect if necessary. The ecarin clotting time [ECT] is another clotting test based on the use of a protein isolated from viper venom. Idarucizumab is a humanized monoclonal antibody Fab fragment that binds to dabigatran and reverses the anticoagulant effect. The drug is approved for use in situations requiring emergent surgery or for life-threatening bleeding. The recommended dose is 5 g given intravenously. If bleeding re-occurs a second dose may be given. The drug is primarily excreted by the kidneys. The half-life in patients with normal renal function is approximately 1 hour. Summary of the Direct Oral Anticoagulant Drugs


Pharmacology_Katzung

Pharmacology_Katzung. Summary of the Direct Oral Anticoagulant Drugs The direct oral anticoagulant drugs have consistently shown equivalent antithrombotic efficacy and lower bleeding rates when compared with traditional warfarin therapy. In addition, these drugs offer the advantages of rapid therapeutic effect, no monitoring requirement, and fewer drug interactions in comparison with warfarin, which has a narrow therapeutic window, is affected by diet and many drugs, and requires monitoring for dosage optimization. However, the short half-life of the newer anticoagulants has the important consequence that patient noncompliance will quickly lead to loss of anticoagulant effect and risk of thromboembolism. Given the convenience of onceor twice-daily oral dosing, lack of a monitoring requirement, and fewer drug and dietary interactions documented thus far, the new direct oral anticoagulants represent a significant advance in the prevention and therapy of thrombotic disease.


Pharmacology_Katzung

Pharmacology_Katzung. Fibrinolytic drugs rapidly lyse thrombi by catalyzing the formation of the serine protease plasmin from its precursor zymogen, plasminogen (Figure 34–3). These drugs create a generalized lytic state when administered intravenously. Thus, both protective hemostatic thrombi and target thromboemboli are broken down. The Box: Thrombolytic Drugs for Acute Myocardial Infarction describes the use of these drugs in one major application.


Pharmacology_Katzung

Pharmacology_Katzung. Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the proactivator plasminogen. This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin. Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin. Plasmin itself cannot be used because naturally occurring inhibitors (antiplasmins) in plasma prevent its effects. However, the absence of inhibitors for urokinase and the streptokinase-proactivator complex permits their use clinically. Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins; this allows it to lyse the thrombus from within.


Pharmacology_Katzung

Pharmacology_Katzung. The paradigm shift in 1980 on the causation of acute myo-cardial infarction to acute coronary occlusion by a thrombus created the rationale for thrombolytic therapy of this com-mon lethal disease. At that time—and for the first time— intravenous thrombolytic therapy for acute myocardial infarction in the European Cooperative Study Group trial was found to reduce mortality. Later studies, with thousands of patients in each trial, provided enough statistical power for the 20% reduction in mortality to be considered statisti-cally significant. Although the standard of care in areas with adequate facilities and experience in percutaneous coronary intervention (PCI) now favors catheterization and placement of a stent, thrombolytic therapy is still very important where PCI is not readily available. The proper selection of patients for thrombolytic therapy is critical. The diagnosis of acute myocardial infarction is made clinically and is confirmed by electrocardiography. Patients with


Pharmacology_Katzung

Pharmacology_Katzung. The proper selection of patients for thrombolytic therapy is critical. The diagnosis of acute myocardial infarction is made clinically and is confirmed by electrocardiography. Patients with ST-segment elevation and bundle branch block on electrocardi-ography have the best outcomes. All trials to date show the great-est benefit for thrombolytic therapy when it is given early, within 6 hours after symptomatic onset of acute myocardial infarction. Thrombolytic drugs reduce the mortality of acute myocardial infarction. The early and appropriate use of any thrombolytic drug probably transcends possible advantages of a particular drug.


Pharmacology_Katzung

Pharmacology_Katzung. Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs). These activators preferentially activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation. Recombinant human t-PA is manufactured as alteplase. Reteplase is another recombinant human t-PA from which several amino acid sequences have been deleted. Tenecteplase is a mutant form of t-PA that has a longer half-life, and it can be given as an intravenous bolus. Reteplase and tenecteplase are as effective as alteplase and have simpler dosing schemes because of their longer half-lives.


Pharmacology_Katzung

Pharmacology_Katzung. Administration of fibrinolytic drugs by the intravenous route is indicated in cases of pulmonary embolism with hemodynamic instability, severe deep venous thrombosis such as the superior vena caval syndrome, and ascending thrombophlebitis of the iliofemoral vein with severe lower extremity edema. These drugs are also given intra-arterially, especially for peripheral vascular disease.


Pharmacology_Katzung

Pharmacology_Katzung. Thrombolytic therapy in the management of acute myocardial infarction requires careful patient selection, the use of a specific thrombolytic agent, and the benefit of adjuvant therapy. Streptokinase is administered by intravenous infusion of a loading dose of 250,000 units, followed by 100,000 units/h for 24–72 hours. Patients with antistreptococcal antibodies can develop fever, allergic reactions, and therapeutic resistance. Urokinase requires a loading dose of 300,000 units given over 10 minutes and a maintenance dose of 300,000 units/h for 12 hours. Alteplase (t-PA) is given as a 15-mg bolus followed by 0.75 mg/kg (up to 50 mg) over 30 minutes and then 0.5 mg/kg (up to 35 mg) over 60 minutes. Reteplase is given as two 10-unit bolus injections, the second administered 30 minutes after the first injection.


Pharmacology_Katzung

Pharmacology_Katzung. Tenecteplase is given as a single intravenous bolus ranging from 30 to 50 mg depending on body weight. Recombinant t-PA has also been approved for use in acute ischemic stroke within 3 hours of symptom onset. In patients without hemorrhagic infarct or other contraindications, this therapy has been demonstrated to provide better outcomes in several randomized clinical trials. The recommended dose is 0.9 mg/kg, not to exceed 90 mg, with 10% given as a bolus and the remainder during a 1-hour infusion. Streptokinase has been associated with increased bleeding risk in acute ischemic stroke when given at a dose of 1.5 million units, and its use is not recommended in this setting.


Pharmacology_Katzung

Pharmacology_Katzung. Platelet function is regulated by three categories of substances. The first group consists of agents generated outside the platelet that interact with platelet membrane receptors, eg, catecholamines, collagen, thrombin, and prostacyclin. The second category contains agents generated within the platelet that interact with membrane receptors, eg, ADP, prostaglandin D2, prostaglandin E2, and serotonin. A third group comprises agents generated within the platelet that act within the platelet, eg, prostaglandin endoperoxides and thromboxane A2, the cyclic nucleotides cAMP and cGMP, and calcium ion. From this list of agents, several targets for platelet inhibitory drugs have been identified (Figure 34–1): inhibition of prostaglandin synthesis (aspirin), inhibition of ADP-induced platelet aggregation (clopidogrel, prasugrel, ticlopidine), and blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelets (abciximab, tirofiban, and eptifibatide). Dipyridamole and cilostazol are


Pharmacology_Katzung

Pharmacology_Katzung. aggregation (clopidogrel, prasugrel, ticlopidine), and blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelets (abciximab, tirofiban, and eptifibatide). Dipyridamole and cilostazol are additional antiplatelet drugs.


Pharmacology_Katzung

Pharmacology_Katzung. The prostaglandin thromboxane A2 is an arachidonate product that causes platelets to change shape, release their granules, and aggregate (see Chapter 18). Drugs that antagonize this pathway interfere with platelet aggregation in vitro and prolong the bleeding time in vivo. Aspirin is the prototype of this class of drugs. As described in Chapter 18, aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase. Other salicylates and nonsteroidal anti-inflammatory drugs also inhibit cyclooxygenase but have a shorter duration of inhibitory action because they cannot acetylate cyclooxygenase; that is, their action is reversible.


Pharmacology_Katzung

Pharmacology_Katzung. In 2014, following a review of the available data, the FDA reversed course and concluded that aspirin for primary prophylaxis (patients without a history of myocardial infarction or stroke) was not supported by the available data but did carry significant bleeding risk. In contrast, meta-analysis of many published trials of aspirin and other antiplatelet agents have demonstrated the utility of aspirin in the secondary prevention of vascular events among patients with a history of vascular events. THIENOPYRIDINES: TICLOPIDINE, CLOPIDOGREL, & PRASUGREL


Pharmacology_Katzung

Pharmacology_Katzung. THIENOPYRIDINES: TICLOPIDINE, CLOPIDOGREL, & PRASUGREL Ticlopidine, clopidogrel, and prasugrel reduce platelet aggregation by inhibiting the ADP pathway of platelets. These drugs irreversibly block the ADP P2Y12 receptor on platelets. Unlike aspirin, these drugs have no effect on prostaglandin metabolism. Use of ticlopidine, clopidogrel, or prasugrel to prevent thrombosis is now considered standard practice in patients undergoing placement of a coronary stent. As the indications and adverse effects of these drugs are different, they will be considered individually.


Pharmacology_Katzung

Pharmacology_Katzung. Ticlopidine is approved for prevention of stroke in patients with a history of a transient ischemic attack (TIA) or thrombotic stroke, and in combination with aspirin for prevention of coronary stent thrombosis. Adverse effects of ticlopidine include nausea, dyspepsia, and diarrhea in up to 20% of patients, hemorrhage in 5%, and, most seriously, leukopenia in 1%. The leukopenia is detected by regular monitoring of the white blood cell count during the first 3 months of treatment. Development of thrombotic thrombocytopenic purpura has also been associated with the ingestion of ticlopidine. The dosage of ticlopidine is 250 mg twice daily orally. Because of the significant side effect profile, the use of ticlopidine for stroke prevention should be restricted to those who are intolerant of or have failed aspirin therapy. Dosages of ticlopidine less than 500 mg/d may be efficacious with fewer adverse effects.


Pharmacology_Katzung

Pharmacology_Katzung. Clopidogrel is approved for patients with unstable angina or non-ST-elevation acute myocardial infarction (NSTEMI) in combination with aspirin; for patients with ST-elevation myocardial infarction (STEMI); or recent myocardial infarction, stroke, or established peripheral arterial disease. For NSTEMI, the dosage is a 300-mg loading dose orally followed by 75 mg daily of clopidogrel, with a daily aspirin dosage of 75–325 mg. For patients with STEMI, the dosage is 75 mg daily of clopidogrel orally, in association with aspirin as above; and for recent myocardial infarction, stroke, or peripheral vascular disease, the dosage is 75 mg/d.


Pharmacology_Katzung

Pharmacology_Katzung. Clopidogrel has fewer adverse effects than ticlopidine and is rarely associated with neutropenia. Thrombotic thrombocytopenic purpura has been reported. Because of its superior adverse effect profile and dosing requirements, clopidogrel is frequently preferred over ticlopidine. The antithrombotic effects of clopidogrel are dose-dependent; within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited. The maintenance dosage of clopidogrel is 75 mg/d, which achieves maximum platelet inhibition. The duration of the antiplatelet effect is 7–10 days. Clopidogrel is a prodrug that requires activation via the cytochrome P450 enzyme isoform CYP2C19. Depending on the single nucleotide polymorphism (SNP) inheritance pattern in CYP2C19, individuals may be poor metabolizers of clopidogrel, and these patients may be at increased risk of cardiovascular events due to inadequate drug effect. The FDA has recommended CYP2C19 genotyping to identify such patients and


Pharmacology_Katzung

Pharmacology_Katzung. of clopidogrel, and these patients may be at increased risk of cardiovascular events due to inadequate drug effect. The FDA has recommended CYP2C19 genotyping to identify such patients and advises prescribers to consider alternative therapies in poor metabolizers (see Chapter 5). However, more recent studies have questioned the impact of CYP2C19 metabolizer status on outcomes. Drugs that impair CYP2C19 function, such as omeprazole, should be used with caution.


Pharmacology_Katzung

Pharmacology_Katzung. Prasugrel, similar to clopidogrel, is approved for patients with acute coronary syndromes. The drug is given orally as a 60-mg loading dose and then 10 mg/d in combination with aspirin as outlined for clopidogrel. The Trial to assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI38) compared prasugrel with clopidogrel in a randomized, double-blind trial with aspirin and other standard therapies managed with percutaneous coronary interventions. This trial showed a reduction in the primary composite cardiovascular endpoint (cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) for prasugrel in comparison with clopidogrel. However, the major and minor bleeding risk was increased with prasugrel. Prasugrel is contraindicated in patients with history of TIA or stroke because of increased bleeding risk. In contrast to clopidogrel, cytochrome P450 genotype status is not an important factor in prasugrel pharmacology.


Pharmacology_Katzung

Pharmacology_Katzung. Ticagrelor is a newer type of ADP inhibitor (cyclopentyl triazolopyrimidine) and is also approved for oral use in combination with aspirin in patients with acute coronary syndromes. Cangrelor is a parenteral P2Y12 inhibitor approved for IV use in coronary interventions in patients without previous ADP P2Y12 inhibitor therapy.


Pharmacology_Katzung

Pharmacology_Katzung. The reported incidence of resistance to these drugs varies greatly, from less than 5% to 75%. In part this variation reflects the definition of resistance (recurrent thrombosis while on antiplatelet therapy versus in vitro testing), methods by which drug response is measured, and patient compliance. Several methods for testing aspirin and clopidogrel resistance in vitro are now FDA-approved. However, the measures of drug resistance vary considerably by testing method. These tests may be useful in selected patients to assess compliance or identify patients at increased risk of recurrent thrombotic events. However, their utility in routine clinical decision-making outside of clinical trials remains controversial. A recent randomized prospective trial found no benefit over standard therapy when information obtained from monitoring antiplatelet drug effect was used to alter therapy.


Pharmacology_Katzung

Pharmacology_Katzung. The platelet GP IIb/IIIa (integrin αIIbβ3) receptor functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor. Activation of this receptor complex is the final common pathway for platelet aggregation. Ligands for GP IIb/IIIa contain an Arg-Gly-Asp (RGD) sequence motif important for ligand binding, and thus RGD constitutes a therapeutic target. There are approximately 50,000 copies of this complex on the surface of each platelet. Persons lacking this receptor have a bleeding disorder, Glanzmann’s thrombasthenia.


Pharmacology_Katzung

Pharmacology_Katzung. The GP IIb/IIIa antagonists are used in patients with acute coronary syndromes. These drugs target the platelet GP IIb/IIIa receptor complex shown in Figure 34–1. Abciximab, a chimeric monoclonal antibody directed against the IIb/IIIa complex including the vitronectin receptor, was the first agent approved in this class of drugs. It has been approved for use in percutaneous coronary intervention and in acute coronary syndromes. Eptifibatide is a cyclic peptide derived from rattlesnake venom that contains a variation of the RGD motif (KGD). Tirofiban is a peptidomimetic inhibitor with the RGD sequence motif. Eptifibatide and tirofiban inhibit ligand binding to the IIb/IIIa receptor by their occupancy of the receptor but do not block the vitronectin receptor. Because of their short half-lives, they must be given by continuous infusion. Oral formulations of GP IIb/IIIa antagonists are in various stages of development.


Pharmacology_Katzung

Pharmacology_Katzung. Dipyridamole is a vasodilator that also inhibits platelet function by inhibiting adenosine uptake and cGMP phosphodiesterase activity. Dipyridamole by itself has little or no beneficial effect. Therefore, therapeutic use of this agent is primarily in combination with aspirin to prevent cerebrovascular ischemia. It may also be used in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves. A combination of dipyridamole complexed with 25 mg of aspirin is now available for secondary prophylaxis of cerebrovascular disease. Cilostazol is a phosphodiesterase inhibitor that promotes vasodilation and inhibition of platelet aggregation. Cilostazol is used primarily to treat intermittent claudication.


Pharmacology_Katzung

Pharmacology_Katzung. Cilostazol is a phosphodiesterase inhibitor that promotes vasodilation and inhibition of platelet aggregation. Cilostazol is used primarily to treat intermittent claudication. Vitamin K confers biologic activity upon prothrombin and factors VII, IX, and X by participating in their postribosomal modification. Vitamin K is a fat-soluble substance found primarily in leafy green vegetables. The dietary requirement is low because the vitamin is additionally synthesized by bacteria that colonize the human intestine. Two natural forms exist: vitamins K1 and K2. Vitamin K1 (phytonadione; Figure 34–5) is found in food. Vitamin K2 (menaquinone) is found in human tissues and is synthesized by intestinal bacteria.


Pharmacology_Katzung

Pharmacology_Katzung. Vitamins K1 and K2 require bile salts for absorption from the intestinal tract. Vitamin K1 is available clinically in oral and parenteral forms. Onset of effect is delayed for 6 hours but the effect is complete by 24 hours when treating depression of prothrombin activity caused by excess warfarin or vitamin K deficiency. Intravenous administration of vitamin K1 should be slow, as rapid infusion can produce dyspnea, chest and back pain, and even death. Vitamin K repletion is best achieved with intravenous or oral administration because its bioavailability after subcutaneous administration is erratic. Vitamin K1 is currently administered to all newborns to prevent the hemorrhagic disease of vitamin K deficiency, which is especially common in premature infants.


Pharmacology_Katzung

Pharmacology_Katzung. The water-soluble salt of vitamin K3 (menadione) should never be used in therapeutics. It is particularly ineffective in the treatment of warfarin overdosage. Vitamin K deficiency frequently occurs in hospitalized patients in intensive care units because of poor diet, parenteral nutrition, recent surgery, multiple antibiotic therapy, and uremia. Severe hepatic failure results in diminished protein synthesis and a hemorrhagic diathesis that is unresponsive to vitamin K.


Pharmacology_Katzung

Pharmacology_Katzung. Deficiencies in plasma coagulation factors can cause bleeding (Table 34–3). Spontaneous bleeding occurs when factor activity is less than 5–10% of normal. Factor VIII deficiency (classic hemophilia, or hemophilia A) and factor IX deficiency (Christmas disease, or hemophilia B) account for most of the heritable coagulation defects. Concentrated plasma fractions and recombinant protein preparations are available for the treatment of these deficiencies. Administration of plasma-derived, heator detergent-treated factor concentrates and recombinant factor concentrates are the standard treatments for prevention and treatment of bleeding associated with hemophilia. Lyophilized factor VIII concentrates are prepared from large pools of plasma. Transmission of viral diseases such as hepatitis B and C and HIV is reduced or eliminated by pasteurization and by extraction of plasma with solvents and detergents. However, this treatment does not remove other potential causes of transmissible diseases


Pharmacology_Katzung

Pharmacology_Katzung. C and HIV is reduced or eliminated by pasteurization and by extraction of plasma with solvents and detergents. However, this treatment does not remove other potential causes of transmissible diseases such as prions. For this reason, recombinant clotting factor preparations are recommended whenever possible for factor replacement. The best use of these therapeutic materials requires diagnostic specificity of the deficient factor and quantitation of its activity in plasma. Recently, several longer-acting factor VIII and IX preparations have been developed. Eloctate is a factor VIII-Fc domain conjugate that prolongs the factor VIII half-life and allows twice-weekly dosing in many cases. Idelvion is a factor IX-albumin conjugate with a half-life of 100 hours (native factor IX has a half-life of 16 hours) and is FDA-approved for prophylaxis or treatment of bleeding in hemophilia B patients, offering the possibility of once-weekly


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 34–3 Therapeutic products for the treatment of coagulation disorders.1 FFP, fresh frozen plasma; DDAVP, 1-deamino-8-D-arginine vasopressin. 1For warfarin overdose or coumarin rodenticide poisoning, a four-factor concentrate (II, VII, IX, X) is available. Antithrombin concentrates are available for patients with thrombosis in the setting of antithrombin deficiency. Activated protein C concentrates were approved for treatment of sepsis but withdrawn from the market in 2011 following publication of a study demonstrating no benefit in sepsis and increased bleeding risk. 2Cryoprecipitate should be used to treat bleeding in the setting of factor VIII deficiency and von Willebrand disease only in an emergency in which pathogen-inactivated products are not available.


Pharmacology_Katzung

Pharmacology_Katzung. 2Cryoprecipitate should be used to treat bleeding in the setting of factor VIII deficiency and von Willebrand disease only in an emergency in which pathogen-inactivated products are not available. dosing in the case of Idelvion. Intermediate purity factor VIII concentrates (as opposed to recombinant or high purity concentrates) contain significant amounts of von Willebrand factor. Humate-P is a factor VIII concentrate that is approved by the FDA for the treatment of bleeding associated with von Willebrand disease. Vonicog alfa is a recombinant von Willebrand factor product approved for treatment and control of bleeding in adults with von Willebrand disease. Fresh frozen plasma is used for factor deficiencies for which no recombinant form of the protein is available. A four-factor plasma replacement preparation containing vitamin K–dependent factors II VII, IX, and X (4F PCC, Kcentra) is available for rapid reversal of warfarin in bleeding patients.


Pharmacology_Katzung

Pharmacology_Katzung. Hemophilia A and B patients are given factor VIII and IX replacement, respectively, as prophylaxis to prevent bleeding, and in higher doses to treat bleeding events or to prepare for surgery. Desmopressin acetate increases the factor VIII activity of patients with mild hemophilia A or von Willebrand disease. It can be used in preparation for minor surgery such as tooth extraction without any requirement for infusion of clotting factors if the patient has a documented adequate response. High-dose intranasal desmopressin (see Chapter 17) is available and has been shown to be efficacious and well tolerated by patients.


Pharmacology_Katzung

Pharmacology_Katzung. Freeze-dried concentrates of plasma containing prothrombin, factors IX and X, and varied amounts of factor VII (Proplex, etc) are commercially available for treating deficiencies of these factors (Table 34–3). Each unit of factor IX per kilogram of body weight raises its activity in plasma 1.5%. Heparin is often added to inhibit coagulation factors activated by the manufacturing process. However, addition of heparin does not eliminate all thromboembolic risk. Some preparations of factor IX concentrate contain activated clotting factors, which has led to their use in treating patients with inhibitors or antibodies to factor VIII or factor IX.


Pharmacology_Katzung

Pharmacology_Katzung. Two products are available expressly for this purpose: Autoplex (with factor VIII correctional activity) and FEIBA (Factor Eight Inhibitor Bypass Activity). These products are not uniformly successful in arresting hemorrhage, and the factor IX inhibitor titers often rise after treatment with them. Acquired inhibitors of coagulation factors may also be treated with porcine factor VIII (for factor VIII inhibitors) and recombinant activated factor VII. Recombinant activated factor VII (NovoSeven) increasingly is being used to treat coagulopathy associated with liver disease and major blood loss in trauma and surgery. These recombinant and plasma-derived factor concentrates are very expensive, and the indications for them are very precise. Therefore, close consultation with a hematologist knowledgeable in this area is essential.


Pharmacology_Katzung

Pharmacology_Katzung. Cryoprecipitate is a plasma protein fraction obtainable from whole blood. It is used to treat deficiencies or qualitative abnormalities of fibrinogen, such as that which occurs with disseminated intravascular coagulation and liver disease. A single unit of cryoprecipitate contains 300 mg of fibrinogen.


Pharmacology_Katzung

Pharmacology_Katzung. Cryoprecipitate may also be used for patients with factor VIII deficiency and von Willebrand disease if desmopressin is not indicated and a pathogen-inactivated, recombinant, or plasma-derived product is not available. The concentration of factor VIII and von Willebrand factor in cryoprecipitate is not as great as that found in the concentrated plasma fractions. Moreover, cryoprecipitate is not treated in any manner to decrease the risk of viral exposure. For infusion, the frozen cryoprecipitate unit is thawed and dissolved in a small volume of sterile citrate-saline solution and pooled with other units. Rh-negative women with potential for childbearing should receive only Rh-negative cryoprecipitate because of possible contamination of the product with Rh-positive blood cells.


Pharmacology_Katzung

Pharmacology_Katzung. Recombinant factor VIIa is approved for treatment of inherited or acquired hemophilia A or B with inhibitors, treatment of bleeding associated with invasive procedures in congenital or acquired hemophilia, or factor VII deficiency. In the European Union, the drug is also approved for treatment of Glanzmann’s thrombasthenia. Factor VIIa initiates activation of the clotting pathway by activating factor IX and factor X in association with tissue factor (see Figure 34–2). The drug is given by bolus injection. For hemophilia A or B with inhibitors and bleeding, the dosage is 90 mg/kg every 2 hours until hemostasis is achieved, and then continued at 3to 6-hour intervals until stable. For congenital factor VII deficiency, the recommended dosage is 15–30 mg/kg every 4–6 hours until hemostasis is achieved.


Pharmacology_Katzung

Pharmacology_Katzung. Factor VIIa has been widely used for off-label indications, including bleeding with trauma, surgery, intracerebral hemorrhage, and warfarin toxicity. A major concern of off-label use has been the possibility that thrombotic events may be increased. A recent study examined rates of thromboembolic events in 35 placebo-controlled trials where factor VIIa was administered CHAPTER 34 Drugs Used in Disorders of Coagulation 623 for nonapproved indications. This study found an increase in arterial, but not venous, thrombotic events, particularly among elderly individuals. Orphan drug status is a designation given by the FDA to promote development of therapies for rare disorders (see Chapter 1). Factor XIII is a transaminase that crosslinks fibrin within a clot, thereby stabilizing it. Congenital factor XIII deficiency is a rare bleeding disorder. Recombinant factor XIII A-subunit is FDA-approved for prevention of bleeding in patients with factor XIII deficiency.


Pharmacology_Katzung

Pharmacology_Katzung. Factor X concentrate is a plasma-derived factor X preparation that is FDA-approved for control of bleeding in patients with factor X deficiency and for perioperative management of patients with mild factor X deficiency. Protein C concentrate is a plasma-derived protein C preparation approved for treatment of life-threatening thrombosis or purpura fulminans, a life-threatening disorder involving thrombosis in skin and systemic circulation. Recombinant antithrombin is FDA-approved for prevention of perioperative and peripartum thromboembolic events in patients with hereditary antithrombin deficiency. FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID


Pharmacology_Katzung

Pharmacology_Katzung. FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID Aminocaproic acid (EACA), which is chemically similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis. It competitively inhibits plasminogen activation (Figure 34–3). It is rapidly absorbed orally and is cleared from the body by the kidney. The usual oral dosage of EACA is 6 g four times a day. When the drug is administered intravenously, a 5-g loading dose should be infused over 30 minutes to avoid hypotension. Tranexamic acid is an analog of aminocaproic acid and has the same properties. It is administered orally with a 15-mg/kg loading dose followed by 30 mg/kg every 6 hours.


Pharmacology_Katzung

Pharmacology_Katzung. Clinical uses of EACA are as adjunctive therapy in hemophilia, as therapy for bleeding from fibrinolytic therapy, and as prophylaxis for rebleeding from intracranial aneurysms. Treatment success has also been reported in patients with postsurgical gastrointestinal bleeding and postprostatectomy bleeding and bladder hemorrhage secondary to radiationand drug-induced cystitis. Adverse effects of the drug include intravascular thrombosis from inhibition of plasminogen activator, hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness. The drug should not be used in patients with disseminated intravascular coagulation or genitourinary bleeding of the upper tract, eg, kidney and ureters, because of the potential for excessive clotting. DRUGS REMOVED FROM MARKET FOR LACK OF EFFICACY OR SAFETY: APROTININ AND ACTIVATED PROTEIN C


Pharmacology_Katzung

Pharmacology_Katzung. DRUGS REMOVED FROM MARKET FOR LACK OF EFFICACY OR SAFETY: APROTININ AND ACTIVATED PROTEIN C Aprotinin is a serine protease inhibitor (serpin) that inhibits fibrinolysis by free plasmin and may have other antihemorrhagic effects as well. It also inhibits the plasmin-streptokinase complex in patients who have received that thrombolytic agent. Aprotinin was shown to reduce bleeding—by as much as 50%—from many types of surgery, especially that involving extracorporeal circulation for open-heart procedures and liver transplantation. However, clinical trials and internal data from the manufacturer suggested that use of the drug was associated with an increased risk of renal failure, heart attack, and stroke. A prospective trial was initiated in Canada but halted early because of concerns that use of the drug was associated with increased mortality. The drug was removed from the market in 2007.


Pharmacology_Katzung

Pharmacology_Katzung. Drotrecogin alfa is a recombinant form of activated protein C that was initially approved by the FDA in 2001 for reduction of mortality in adults with sepsis associated with acute organ dysfunction and high mortality. The drug was voluntarily withdrawn from the market in 2011 after a follow-up study showed no survival benefit in sepsis. Aminocaproic acid Generic, Amicar Antihemophilic factor Alphanate, Bioclate, Helixate, Hemofil [factor VIII, AHF] M, Koate-HP, Kogenate, Monoclate, Recombinate, others Anti-inhibitor coagulant complex Autoplex T, Feiba VH Immuno Antithrombin III Thrombate III, ATryn Bivalirudin Generic, Angiomax Cilostazol Generic, Pletal Clopidogrel Generic, Plavix Dipyridamole Generic, Persantine Enoxaparin (low-molecular-Generic, Lovenox weight heparin)


Pharmacology_Katzung

Pharmacology_Katzung. Bivalirudin Generic, Angiomax Cilostazol Generic, Pletal Clopidogrel Generic, Plavix Dipyridamole Generic, Persantine Enoxaparin (low-molecular-Generic, Lovenox weight heparin) January C et al: 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1. Li A, Lopes RD, Garcia DA: Use of direct oral anticoagulants in special populations. Hematol Oncol Clin North Am 2016;30:1053. Samuelson BT, Cuker A: Measurement and reversal of the direct oral anticoagulants. Blood Rev 2016;31:77. Dahlback B: Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008;112:19. Factor IX complex, human AlphaNine SD, Bebulin VH, BeneFix, Konyne 80, Mononine, Profilnine SD, Proplex T, Proplex SX-T Fondaparinux Generic, Arixtra Heparin sodium Generic, Liquaemin


Pharmacology_Katzung

Pharmacology_Katzung. Factor IX complex, human AlphaNine SD, Bebulin VH, BeneFix, Konyne 80, Mononine, Profilnine SD, Proplex T, Proplex SX-T Fondaparinux Generic, Arixtra Heparin sodium Generic, Liquaemin Ticlopidine Generic, Ticlid Tranexamic acid Generic, Cyklokapron, Lysteda Urokinase Abbokinase, Kinlytic Vitamin K Generic, various Warfarin Generic, Coumadin Mannucci PM, Levi M: Prevention and treatment of major blood loss. N Engl J Med 2007;356:2301. Furie B: Do pharmacogenetics have a role in the dosing of vitamin K antagonists? N Engl J Med 2013;369:2345. Kearon C et al: Antithrombotic therapy for VTE disease: Chest guideline and expert panel report. Chest 2016;149:315.


Pharmacology_Katzung

Pharmacology_Katzung. Kearon C et al: Antithrombotic therapy for VTE disease: Chest guideline and expert panel report. Chest 2016;149:315. This patient has pulmonary embolism secondary to a deep venous thrombosis (DVT). Options for treating this patient include unfractionated heparin or low-molecular-weight heparin followed by warfarin, with INR goal of 2–3; parenteral anticoagulation for 5–7 days followed by edoxaban; or rivaroxaban, apixaban, or dabigatran alone without monitoring. As this situation can be considered a provoked event given the history of oral contraceptive use, the recommended duration of therapy would be 3–6 months depending on individual risk factors and preferences. The patient should be counseled to use an alternative form of contraception. Mary J. Malloy, MD, & John P. Kane, MD, PhD


Pharmacology_Katzung

Pharmacology_Katzung. A 42-year-old woman has heterozygous familial hyper-cholesterolemia (HeFH) but is otherwise well and has no symptoms of coronary or peripheral vascular disease. A carotid ultrasound was normal. Her mother had a myo-cardial infarction at age 51 and had no known risk factors other than her presumed HeFH. The patient also has ele-vated lipoprotein (a) at 2.5 times normal and low HDL-C (43 mg/dL). She developed muscle symptoms with each of 3 statins (atorvastatin, rosuvastatin, and simvastatin) so they were discontinued although she did not develop elevated levels of creatine kinase. Her untreated LDL-C is 235 mg/dL and triglycerides 125 mg/dL. Her LDL-C goal for primary prevention of arteriosclerotic vascular disease is in the 70-mg/dL range because of her multiple lipopro-tein risk factors and her mother’s history of premature coronary artery disease. She has no other risk factors and her diet and exercise habits are excellent. How would you manage this patient?


Pharmacology_Katzung

Pharmacology_Katzung. Plasma lipids are transported in complexes called lipoproteins. Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias. Hyperlipemia denotes increased levels of triglycerides. The major clinical sequelae of hyperlipidemias are acute pancreatitis and atherosclerosis. The former occurs in patients with marked hyperlipemia. Control of triglycerides can prevent recurrent attacks of this life-threatening disease. Atherosclerosis is the leading cause of death for both genders in the USA and other Western countries. Lipoproteins that contain apolipoprotein (apo) B-100 convey lipids into the artery wall. These are low-density (LDL), intermediate-density (IDL), very-low-density (VLDL), and lipoprotein(a) (Lp[a]). Remnant lipoproteins formed during the catabolism of chylomicrons that contain the B-48 protein (apo B-48) can also enter the artery wall, contributing to atherosclerosis.


Pharmacology_Katzung

Pharmacology_Katzung. Cellular components in atherosclerotic plaques (atheromas) include foam cells, which are transformed macrophages, and smooth muscle cells filled with cholesteryl esters. These cellular alterations result from endocytosis of modified lipoproteins via at least four species of scavenger receptors. Chemical modification of lipoproteins by free radicals creates ligands for these receptors. The atheroma grows with the accumulation of foam cells, collagen, fibrin, and frequently calcium. Whereas such lesions can slowly occlude coronary vessels, clinical symptoms are more frequently precipitated by rupture of unstable atheromatous plaques, leading to activation of platelets and formation of occlusive thrombi.


Pharmacology_Katzung

Pharmacology_Katzung. Although treatment of hyperlipidemia can cause slow physical regression of plaques, the well-documented reduction in acute coronary events that follows vigorous lipid-lowering treatment is attributable chiefly to mitigation of the inflammatory activity of macrophages and is evident within 2–3 months after starting therapy. High-density lipoproteins (HDL) exert several antiatherogenic effects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. Low levels of HDL (hypoalphalipoproteinemia) are an independent risk factor for atherosclerotic disease and thus are a potential target for intervention.


Pharmacology_Katzung

Pharmacology_Katzung. Cigarette smoking is a major risk factor for coronary disease. It is associated with reduced levels of HDL, impairment of cholesterol retrieval, cytotoxic effects on the endothelium, increased oxidation of lipoproteins, and stimulation of thrombogenesis. Diabetes, also a major risk factor, is another source of oxidative stress. Normal coronary arteries can dilate in response to ischemia, increasing delivery of oxygen to the myocardium. This process is mediated by nitric oxide, acting on smooth muscle cells of the arterial media. The release of nitric oxide from the vascular endothelium is impaired by atherogenic lipoproteins, thus aggravating ischemia. Reducing levels of atherogenic lipoproteins and inhibiting their oxidation restores endothelial function.


Pharmacology_Katzung

Pharmacology_Katzung. Because atherogenesis is multifactorial, therapy should be directed toward all modifiable risk factors. Atherogenesis is a dynamic process. Quantitative angiographic trials have demonstrated net regression of plaques during aggressive lipid-lowering therapy. Primary and secondary prevention trials have shown significant reduction in mortality from new coronary events and in all-cause mortality.


Pharmacology_Katzung

Pharmacology_Katzung. Lipoproteins have hydrophobic core regions containing cholesteryl esters and triglycerides surrounded by unesterified cholesterol, phospholipids, and apoproteins. Certain lipoproteins contain very high-molecular-weight B proteins that exist in two forms: B-48, formed in the intestine and found in chylomicrons and their remnants; and B-100, synthesized in liver and found in VLDL, VLDL remnants (IDL), LDL (formed from VLDL), and Lp(a) lipoproteins. HDL consist of at least 20 discrete molecular species containing apolipoprotein A-I (apo A-I). About 100 other proteins are known to be distributed variously among the HDL species. A. Chylomicrons Chylomicrons are formed in the intestine and carry triglycerides of dietary origin, unesterified cholesterol, and cholesteryl esters. They transit the thoracic duct to the bloodstream.


Pharmacology_Katzung

Pharmacology_Katzung. Chylomicrons are formed in the intestine and carry triglycerides of dietary origin, unesterified cholesterol, and cholesteryl esters. They transit the thoracic duct to the bloodstream. Triglycerides are removed from the chylomicrons in extrahepatic tissues through a pathway shared with VLDL that involves hydrolysis by the lipoprotein lipase (LPL) system. Decrease in particle diameter occurs as triglycerides are depleted. Surface lipids and small apoproteins are transferred to HDL. The resultant chylomicron remnants are taken up by receptor-mediated endocytosis into hepatocytes. B. Very-Low-Density Lipoproteins


Pharmacology_Katzung

Pharmacology_Katzung. B. Very-Low-Density Lipoproteins VLDL are secreted by liver and export triglycerides to peripheral tissues (Figure 35–1). VLDL triglycerides are hydrolyzed by LPL, yielding free fatty acids for storage in adipose tissue and for oxidation in tissues such as cardiac and skeletal muscle. Depletion of triglycerides produces remnants (IDL), some of which undergo endocytosis directly into hepatocytes. The remainder are converted to LDL by further removal of triglycerides mediated by hepatic lipase. This process explains the “beta shift” phenomenon, the increase of LDL (beta-lipoprotein) in serum as hypertriglyceridemia subsides. Increased levels of LDL can also result from increased secretion of VLDL and from decreased LDL catabolism. C. Low-Density Lipoproteins


Pharmacology_Katzung

Pharmacology_Katzung. C. Low-Density Lipoproteins LDL are catabolized chiefly in hepatocytes and other cells after receptor-mediated endocytosis. Cholesteryl esters from LDL are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. Cells also obtain cholesterol by synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase. Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell. Normally, about 70% of LDL is removed from plasma by hepatocytes. Even more cholesterol is delivered to the liver via IDL and chylomicrons. Unlike other cells, hepatocytes can eliminate cholesterol by secretion in bile and by conversion to bile acids. D. Lp(a) Lipoprotein


Pharmacology_Katzung

Pharmacology_Katzung. D. Lp(a) Lipoprotein Lp(a) lipoprotein is formed from LDL and the (a) protein, linked by a disulfide bridge. The (a) protein is highly homologous with plasminogen but is not activated by tissue plasminogen activator. It occurs in a number of isoforms of different molecular weights. Levels of Lp(a) vary from nil to over 2000 nM/L and are determined chiefly by genetic factors. Lp(a) is found in atherosclerotic plaques and contributes to coronary disease by inhibiting thrombolysis. It is also associated with aortic stenosis. Levels are elevated in certain inflammatory states. The risk of coronary disease is strongly related to the level of Lp(a). A common variant (I4399M) in the coding region is associated with elevated levels. E. High-Density Lipoproteins


Pharmacology_Katzung

Pharmacology_Katzung. E. High-Density Lipoproteins The apoproteins of HDL are secreted largely by the liver and intestine. Much of the lipid comes from the surface monolayers of endothelium Lipoprotein lipase FFA HDL VLDL remnant B-100 ApoC VLDL ApoE HDL LDL Peripheral cell Cholesterol Cholesteryl estersLysosome Acetyl-CoA HMG-CoA reductase Lysosome Cholesterol Mevalonic acid ApoB, ApoE, ApoC RER Golgi vesicle LDL receptor * * Cholesterol biosynthetic pathway


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 35–1 Metabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via the Golgi apparatus. They acquire additional apo C lipoproteins and apo E from HDL. Very-low-density lipoproteins (VLDL) are converted to VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the apo E are given back to high-density lipoproteins (HDL). Some of the VLDL remnants are converted to LDL by further loss of triglycerides and loss of apo E. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apo E; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic


Pharmacology_Katzung

Pharmacology_Katzung. triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apo E; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic reticulum. (Adapted, with permission, from Kane J, Malloy M: Disorders of lipoproteins. In: Rosenberg RN et al [editors]: The Molecular and Genetic Basis of Neurological Disease. 2nd ed. Butterworth-Heinemann, 1997.) chylomicrons and VLDL during lipolysis. HDL also acquires cholesterol from peripheral tissues, protecting the cholesterol homeostasis of cells. Free cholesterol is chiefly exported from the cell membrane by a transporter, ABCA1, acquired by a small particle termed prebeta-1 HDL, and then esterified by lecithin:cholesterol acyltransferase (LCAT), leading to the formation of larger HDL species. Cholesterol is also exported by the ABCG1 transporter and the scavenger receptor, SR-BI, to large HDL particles. The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron


Pharmacology_Katzung

Pharmacology_Katzung. HDL species. Cholesterol is also exported by the ABCG1 transporter and the scavenger receptor, SR-BI, to large HDL particles. The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via SR-BI that does not cause endocytosis of the lipoproteins. At the population level, HDL cholesterol (HDL-C) levels relate inversely to atherosclerosis risk. Among individuals, the capacity to accept exported cholesterol can vary widely at identical levels of HDL-C. The ability of peripheral tissues to export cholesterol via the transporter mechanism and the acceptor capacity of HDL are emerging as major determinants of coronary atherosclerosis.


Pharmacology_Katzung

Pharmacology_Katzung. Lipoprotein disorders are detected by measuring lipids in serum after a 10-hour fast. Risk of heart disease increases with concentrations of the atherogenic lipoproteins, is inversely related to levels of HDL-C, and is modified by other risk factors. Evidence from clinical trials suggests that an LDL cholesterol (LDL-C) level of 50-60 mg/dL is optimal for patients with coronary disease. Ideally, triglycerides should be below 120 mg/dL. Although LDL-C is still the primary target of treatment, reducing the levels of VLDL and IDL also is important. Calculation of non-HDL cholesterol provides a means of assessing levels of all the lipoproteins in the VLDL to LDL cascade. Differentiation of the disorders requires identification of the lipoproteins involved (Table 35–1). Diagnosis of a primary disorder usually requires further clinical and TABLE 35–1 The primary hyperlipoproteinemias and their treatment.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 35–1 The primary hyperlipoproteinemias and their treatment. 1Single-drug therapy with marine omega-3 dietary supplement should be evaluated before drug combinations are used. 2Select pharmacologically compatible reductase inhibitor (see text). genetic data as well as ruling out secondary hyperlipidemias (Table 35–2). Phenotypes of abnormal lipoprotein distribution are described in this section. Drugs mentioned for use in these conditions are described in the following section on basic and clinical pharmacology. TABLE 35–2 Secondary causes of hyperlipoproteinemia.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 35–2 Secondary causes of hyperlipoproteinemia. Hypertriglyceridemia is associated with increased risk of coronary disease. Chylomicrons, VLDL, and IDL are found in atherosclerotic plaques. These patients tend to have cholesterol-rich VLDL of small particle diameter and small, dense LDL. Hypertriglyceridemic patients with coronary disease or risk equivalents should be treated aggressively. Patients with triglycerides above 700 mg/dL should be treated to prevent acute pancreatitis because the LPL clearance mechanism is saturated at about this level.


Pharmacology_Katzung

Pharmacology_Katzung. Hypertriglyceridemia is an important component of the metabolic syndrome, which also includes insulin resistance, hypertension, and abdominal obesity. Reduced levels of HDL-C are usually observed due to transfer of cholesteryl esters to the triglyceride-rich lipoprotein particles. Hyperuricemia is frequently present. Insulin resistance appears to be central to this disorder. Management of these patients frequently requires, in addition to a fibrate, the use of metformin, another antidiabetic agent, or both (see Chapter 41). The severity of hypertriglyceridemia of any cause is increased in the presence of the metabolic syndrome or type 2 diabetes.


Pharmacology_Katzung

Pharmacology_Katzung. Chylomicrons are not present in the serum of normal individuals who have fasted 10 hours. The recessive traits of deficiency of LPL, its cofactor apo C-II, the LMF1 or GPIHBP1 proteins, or ANGPTL4 and Apo A-V, are usually associated with severe lipemia (2000 mg/dL of triglycerides or higher when the patient is consuming a typical American diet). These disorders might not be diagnosed until an attack of acute pancreatitis occurs. Patients may have eruptive xanthomas, hepatosplenomegaly, hypersplenism, and lipid-laden foam cells in bone marrow, liver, and spleen. The lipemia is aggravated by estrogens because they stimulate VLDL production, and pregnancy may cause marked increases in triglycerides despite strict dietary control. Although these patients have a predominant chylomicronemia, they may also have moderately elevated VLDL, presenting with a pattern called mixed lipemia (fasting chylomicronemia and elevated VLDL). Deficiency of lipolytic activity can be diagnosed after


Pharmacology_Katzung

Pharmacology_Katzung. they may also have moderately elevated VLDL, presenting with a pattern called mixed lipemia (fasting chylomicronemia and elevated VLDL). Deficiency of lipolytic activity can be diagnosed after intravenous injection of heparin. A presumptive diagnosis is made by demonstrating a pronounced decrease in triglycerides 72 hours after elimination of daily dietary fat. Marked restriction of total dietary fat and abstention from alcohol are the basis of effective long-term treatment. Niacin, a fibrate, or marine omega-3 fatty acids may be of some benefit if VLDL levels are increased. Apo C-III antisense is a potential adjunct to therapy.


Pharmacology_Katzung

Pharmacology_Katzung. The primary hypertriglyceridemias probably reflect a variety of genetic determinants. Many patients have centripetal obesity with insulin resistance. Other factors, including alcohol and estrogens, that increase secretion of VLDL aggravate the lipemia. Impaired removal of triglyceride-rich lipoproteins with overproduction of VLDL can result in mixed lipemia. Eruptive xanthomas, lipemia retinalis, epigastric pain, and pancreatitis are variably present depending on the severity of the lipemia. Treatment is primarily dietary, with restriction of total fat, avoidance of alcohol and exogenous estrogens, weight reduction, exercise, and supplementation with marine omega-3 fatty acids. Most patients also require treatment with a fibrate. If insulin resistance is not present, niacin may be useful.


Pharmacology_Katzung

Pharmacology_Katzung. In this common disorder, which is associated with an increased incidence of coronary disease, individuals may have elevated levels of VLDL, LDL, or both, and the pattern may change with time. Familial combined hyperlipoproteinemia involves an approximate doubling in VLDL secretion and appears to be transmitted as a dominant trait. Triglycerides can be increased by the factors noted above. Elevations of cholesterol and triglycerides are generally moderate, and xanthomas are absent. Diet alone does not normalize lipid levels. A reductase inhibitor alone, or in combination with niacin or fenofibrate, is usually required to treat these patients. When fenofibrate is combined with a reductase inhibitor, either pravastatin or rosuvastatin is recommended because neither is metabolized via CYP3A4. Marine omega-3 fatty acids may be useful.


Pharmacology_Katzung

Pharmacology_Katzung. In this disorder, remnants of chylomicrons and VLDL accumulate and levels of LDL are decreased. Because remnants are rich in cholesteryl esters, the level of total cholesterol may be as high as that of triglycerides. Diagnosis is confirmed by the absence of the ε3 and ε4 alleles of apo E, the ε2/ε2 genotype. Other apo E isoforms that lack receptor ligand properties can also be associated with this disorder. Patients often develop tuberous or tuberoeruptive xanthomas, or characteristic planar xanthomas of the palmar creases. They tend to be obese, and some have impaired glucose tolerance. These factors, as well as hypothyroidism, can aggravate the lipemia. Coronary and peripheral atherosclerosis occurs with increased frequency. Weight loss, together with decreased fat, cholesterol, and alcohol consumption, may be sufficient, but a fibrate or niacin is usually needed to control the condition. These agents can be given together in more resistant cases. Reductase inhibitors are also


Pharmacology_Katzung

Pharmacology_Katzung. alcohol consumption, may be sufficient, but a fibrate or niacin is usually needed to control the condition. These agents can be given together in more resistant cases. Reductase inhibitors are also effective because they increase hepatic LDL receptors that participate in remnant removal.


Pharmacology_Katzung

Pharmacology_Katzung. This is an autosomal dominant trait. Although levels of LDL tend to increase throughout childhood, the diagnosis can often be made on the basis of elevated umbilical cord blood cholesterol. In most heterozygotes, cholesterol levels range from 260 to 500 mg/dL. Triglycerides are usually normal. Tendon xanthomas are often present. Arcus corneae and xanthelasma may appear in the third decade. Coronary disease tends to occur prematurely. In homozygous familial hypercholesterolemia, which can lead to coronary disease in childhood, levels of cholesterol often exceed 1000 mg/dL and early tuberous and tendinous xanthomas occur. These patients may also develop elevated plaque-like xanthomas of the aortic valve, digital webs, buttocks, and extremities.


Pharmacology_Katzung

Pharmacology_Katzung. Some individuals have combined heterozygosity for alleles producing nonfunctional and kinetically impaired receptors. In heterozygous patients, LDL can be normalized with reductase inhibitors or combined drug regimens (Figure 35–2). Homozygotes and those with combined heterozygosity whose receptors retain even minimal function may partially respond to niacin, ezetimibe, and reductase inhibitors. Emerging therapies for these patients include mipomersen, employing an antisense strategy targeted at apo B-100, and lomitapide, a small molecule inhibitor of microsomal triglyceride transfer protein (MTP), and monoclonal antibodies directed at PCSK9. LDL apheresis is effective in medication-refractory patients.


Pharmacology_Katzung

Pharmacology_Katzung. Defects in the domain of apo B-100 that binds to the LDL receptor impair the endocytosis of LDL, leading to hypercholesterolemia of moderate severity. Tendon xanthomas may occur. Response to reductase inhibitors is variable. Upregulation of LDL receptors in liver increases endocytosis of LDL precursors but does not increase uptake of ligand-defective LDL particles. Fibrates or niacin may have beneficial effects by reducing VLDL production. B-100 B-100 VLDL LDL BloodR HepatocyteAcetyl-CoA HMG-CoA reductase inhibitors Cholesterol Bile acids Niacin GutResins Ezetimibe HMG-CoA FIGURE 35–2 Sites of action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-density lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. VLDL, very-low-density lipoproteins; R, LDL receptor.


Pharmacology_Katzung

Pharmacology_Katzung. Some persons with familial combined hyperlipoproteinemia have only an elevation in LDL. Serum cholesterol is often less than 350 mg/dL. Dietary and drug treatment, usually with a reductase inhibitor, is indicated. It may be necessary to add niacin or ezetimibe to normalize LDL. This familial disorder, which is associated with increased atherogenesis and arterial thrombus formation, is determined chiefly by alleles that dictate increased production of the (a) protein moiety. Lp(a) can be secondarily elevated in patients with severe nephrosis and certain other inflammatory states. Niacin reduces levels of Lp(a) in many patients. Reduction of levels of LDL-C below 100 mg/dL decreases the risk attributable to Lp(a), as does the administration of low-dose aspirin. PCSK9 monoclonal antibodies also reduce levels of Lp(a) by about 25%.


Pharmacology_Katzung

Pharmacology_Katzung. Individuals lacking activity of lysosomal acid lipase (LAL) accumulate cholesteryl esters in liver and certain other cell types leading to hepatomegaly with subsequent fibrosis, elevated levels of LDL-C, low levels of HDL-C, and often modest hypertriglyceridemia. Rarely, a totally ablative form, Wolman disease, occurs in infancy. A recombinant replacement enzyme therapy, sebelipase alfa, effectively restores the hydrolysis of cholesteryl esters in liver, normalizing plasma lipoprotein levels.


Pharmacology_Katzung

Pharmacology_Katzung. Deficiency of cholesterol 7α-hydroxylase can increase LDL in the heterozygous state. Homozygotes also can have elevated triglycerides, resistance to reductase inhibitors as a single agent, and increased risk of gallstones and coronary disease. A combination of niacin with a reductase inhibitor appears to be effective. Autosomal recessive hypercholesterolemia (ARH) is due to mutations in a protein that normally assists in endocytosis of LDL. High-dose reductase inhibitor plus ezetimibe is effective. The receptor chaperone PCSK9 normally conducts the receptor to the lysosome for degradation. Gain-of-function mutations in PCSK9 are associated with elevated levels of LDL-C and could be managed with a PCSK9 antibody. The ABCG5 and ABCG8 half-transporters act together in enterocytes and hepatocytes to export phytosterols into the intestinal lumen and bile, respectively. Homozygous or combined heterozygous ablative mutations in either transporter result in elevated levels of LDL enriched in


Pharmacology_Katzung

Pharmacology_Katzung. to export phytosterols into the intestinal lumen and bile, respectively. Homozygous or combined heterozygous ablative mutations in either transporter result in elevated levels of LDL enriched in phytosterols, tendon and tuberous xanthomas, and accelerated atherosclerosis. Ezetimibe is a specific therapeutic for this disorder.


Pharmacology_Katzung

Pharmacology_Katzung. Rare genetic disorders, including Tangier disease and LCAT (lecithin:cholesterol acyltransferase) deficiency, are associated with extremely low levels of HDL. Familial hypoalphalipoproteinemia is a more common disorder with levels of HDL cholesterol usually below 35 mg/dL in men and 45 mg/dL in women. These patients tend to have premature atherosclerosis, and the low HDL may be the only identified risk factor. Management should include special attention to avoidance or treatment of other risk factors. Niacin increases HDL in many of these patients but the effect on outcome is unknown. Reductase inhibitors and fibric acid derivatives exert lesser effects. Aggressive LDL reduction is indicated. In the presence of hypertriglyceridemia, HDL cholesterol is low because of exchange of cholesteryl esters from HDL into triglyceride-rich lipoproteins. Treatment of the hypertriglyceridemia increases the HDL-C level.


Pharmacology_Katzung

Pharmacology_Katzung. Before primary disorders can be diagnosed, secondary causes of the phenotype must be considered. The more common conditions are summarized in Table 35–2. The lipoprotein abnormality usually resolves if the underlying disorder can be treated successfully. These secondary disorders can also aggravate a primary genetic disorder. Dietary measures are initiated first—unless the patient has evident coronary or peripheral vascular disease—and may obviate the need for drugs. Patients with the familial hypercholesterolemias always require drug therapy in addition to diet. Cholesterol and saturated and trans-fats are the principal factors that increase LDL.


Pharmacology_Katzung

Pharmacology_Katzung. Total fat, sucrose, and especially fructose increase VLDL. Alcohol can cause significant hypertriglyceridemia by increasing hepatic secretion of VLDL. Synthesis and secretion of VLDL are increased by excess calories. During weight loss, LDL and VLDL levels may be much lower than can be maintained during neutral caloric balance. The conclusion that diet suffices for management can be made only after weight has stabilized for at least 1 month. General recommendations include limiting total calories from fat to 20–25% of daily intake, saturated fats to less than 7%, and cholesterol to less than 200 mg/d. Reductions in serum cholesterol range from 10% to 20% on this regimen. Use of complex carbohydrates and fiber is recommended, and cis-monounsaturated fats should predominate. Weight reduction, caloric restriction, and avoidance of alcohol are especially important for patients with elevated triglycerides.


Pharmacology_Katzung

Pharmacology_Katzung. The effect of dietary fats on hypertriglyceridemia is dependent on the disposition of double bonds in the fatty acids. Omega-3 fatty acids found in fish oils, but not those from plant sources, activate peroxisome proliferator-activated receptor-alpha (PPAR-α) and can induce profound reduction of triglycerides in some patients. They also have anti-inflammatory and antiarrhythmic activities. Omega-3 fatty acids are available over the counter as triglycerides from marine sources or as a prescription medication containing ethyl esters of omega-3 fatty acids. It is necessary to determine the content of docosahexaenoic acid and eicosapentaenoic acid in over-the-counter preparations. Appropriate amounts should be taken to provide up to 3–4 g of these fatty acids (combined) daily. It is important to select preparations free of mercury and other contaminants. The omega-6 fatty acids present in vegetable oils may cause triglycerides to increase.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with primary chylomicronemia and some with mixed lipemia must consume a diet severely restricted in total fat (10–20 g/d, of which 5 g should be vegetable oils rich in essential fatty acids), and fat-soluble vitamins should be given. Homocysteine, which initiates proatherogenic changes in endothelium, can be reduced in many patients by restriction of total protein intake to the amount required for amino acid replacement. Supplementation with folic acid plus other B vitamins, and administration of betaine, a methyl donor, is indicated in severe homocysteinemia. Reduction of high levels of homocysteine is especially important in individuals with elevated levels of Lp(a). Consumption of red meat should be minimized to reduce the production by the intestinal biome of tetramethyl amine oxide, a compound injurious to arteries.


Pharmacology_Katzung

Pharmacology_Katzung. The decision to use drug therapy for hyperlipidemia is based on the specific metabolic defect and its potential for causing atherosclerosis or pancreatitis. Suggested regimens for the principal lipoprotein disorders are presented in Table 35–1. Diet should be continued to achieve the full potential of the drug regimen. These drugs should be avoided in pregnant and lactating women and those likely to become pregnant. All drugs that alter plasma lipoprotein concentrations potentially require adjustment of doses of anticoagulants. Children with heterozygous familial hypercholesterolemia may be treated with a resin or reductase inhibitor, usually after 7 or 8 years of age, when myelination of the central nervous system is essentially complete. The decision to treat a child should be based on the level of LDL, other risk factors, the family history, and the child’s age. Drugs are usually not indicated before age 16 in the absence of multiple risk factors or compound genetic dyslipidemias.


Pharmacology_Katzung

Pharmacology_Katzung. COMPETITIVE INHIBITORS OF HMG-COA REDUCTASE (REDUCTASE INHIBITORS: “STATINS”) These compounds are structural analogs of HMG-CoA (3-hydroxy3-methylglutaryl-coenzyme A, Figure 35–3). Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, rosuvastatin, and pitavastatin belong to this class. They are most effective in reducing LDL. Other effects include decreased oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions. It has become standard practice to initiate reductase inhibitor therapy immediately after acute coronary syndromes, regardless of lipid levels.


Pharmacology_Katzung

Pharmacology_Katzung. Lovastatin and simvastatin are inactive lactone prodrugs that are hydrolyzed in the gastrointestinal tract to the active β-hydroxyl derivatives, whereas pravastatin has an open, active lactone ring. Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing congeners that are active as given. Absorption of the ingested doses of the reductase inhibitors varies from 40% to 75% with the exception of fluvastatin, which is almost completely absorbed. All have high first-pass extraction by the liver. Most of the absorbed dose is excreted in the bile; 5–20% is excreted in the urine. Plasma half-lives of these drugs range from 1 to 3 hours except for atorvastatin (14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours). Mechanism of Action HMG-CoA reductase mediates the first committed step in sterol biosynthesis. The active forms of the reductase inhibitors are structural analogs of the HMG-CoA intermediate (Figure 35–3)


Pharmacology_Katzung

Pharmacology_Katzung. HMG-CoA reductase mediates the first committed step in sterol biosynthesis. The active forms of the reductase inhibitors are structural analogs of the HMG-CoA intermediate (Figure 35–3) FIGURE 35–3 Inhibition of HMG-CoA reductase. Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom: The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas).


Pharmacology_Katzung

Pharmacology_Katzung. that is formed by HMG-CoA reductase in the synthesis of mevalonate. These analogs cause partial inhibition of the enzyme and thus may impair the synthesis of isoprenoids such as ubiquinone and dolichol and the prenylation of proteins. It is not known whether this has biologic significance. However, the reductase inhibitors clearly induce an increase in high-affinity LDL receptors. This effect increases both the fractional catabolic rate of LDL and the liver’s extraction of LDL precursors (VLDL remnants) from the blood, thus reducing LDL (Figure 35–2). Because of marked first-pass hepatic extraction, the major effect is on the liver. Preferential activity in liver of some congeners appears to be attributable to tissue-specific differences in uptake. Modest decreases in plasma triglycerides and small increases in HDL also occur.


Pharmacology_Katzung

Pharmacology_Katzung. Clinical trials involving many of the statins have demonstrated significant reduction of new coronary events and atherothrombotic stroke. Mechanisms other than reduction of lipoprotein levels appear to be involved. The availability of isoprenyl groups from the HMG-CoA pathway for prenylation of proteins is reduced by statins, resulting in reduced prenylation of Rho and Rab proteins. Prenylated Rho activates Rho kinase, which mediates a number of mechanisms in vascular biology. The observation that reduction in new coronary events occurs more rapidly than changes in morphology of arterial plaques suggests that these pleiotropic effects may be important. Likewise, decreased prenylation of Rab reduces the accumulation of Aβ protein in neurons, possibly mitigating the manifestations of Alzheimer’s disease.


Pharmacology_Katzung

Pharmacology_Katzung. Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of LDL. Women with hyperlipidemia who are pregnant, lactating, or likely to become pregnant should not be given these agents. Use in children is restricted to selected patients with familial hypercholesterolemias.


Pharmacology_Katzung

Pharmacology_Katzung. Because cholesterol synthesis occurs predominantly at night, reductase inhibitors—except atorvastatin, rosuvastatin, and pitavastatin—should be given in the evening. Absorption generally (with the exception of pravastatin and pitavastatin) is enhanced by food. Daily doses of lovastatin vary from 10 to 80 mg. Pravastatin is nearly as potent on a mass basis as lovastatin with a maximum recommended daily dose of 80 mg. Simvastatin is twice as potent and is given in doses of 5–80 mg daily. Because of increased risk of myopathy with the 80-mg/d dose, the U.S. Food and Drug Administration (FDA) issued labeling for scaled dosing of simvastatin and combined ezetimibe/simvastatin in 2011. Pitavastatin is given in doses of 1–4 mg daily. Fluvastatin appears to be about half as potent as lovastatin on a mass basis and is given in doses of 10–80 mg daily. Atorvastatin is given in doses of 10–80 mg/d, and rosuvastatin at 5–40 mg/d. The dose-response curves of pravastatin and especially of


Pharmacology_Katzung

Pharmacology_Katzung. on a mass basis and is given in doses of 10–80 mg daily. Atorvastatin is given in doses of 10–80 mg/d, and rosuvastatin at 5–40 mg/d. The dose-response curves of pravastatin and especially of fluvastatin tend to level off in the upper part of the dosage range in patients with moderate to severe hypercholesterolemia. Those of other statins are somewhat more linear.


Pharmacology_Katzung

Pharmacology_Katzung. Elevations of serum aminotransferase activity (up to three times normal) occur in some patients. This is often intermittent and usually not associated with other evidence of hepatic toxicity. Therapy may be continued in such patients in the absence of symptoms if aminotransferase levels are monitored and stable. In some patients, who may have underlying liver disease or a history of alcohol abuse, levels may exceed three times normal. This finding portends more severe hepatic toxicity. These patients may present with malaise, anorexia, and precipitous decreases in LDL. Medication should be discontinued immediately in these patients and in asymptomatic patients whose aminotransferase activity is persistently elevated to more than three times the upper limit of normal. These agents should be used with caution and in reduced dosage in patients with hepatic parenchymal disease, north Asians, and the elderly. Severe hepatic disease may preclude their use. In general, aminotransferase


Pharmacology_Katzung

Pharmacology_Katzung. be used with caution and in reduced dosage in patients with hepatic parenchymal disease, north Asians, and the elderly. Severe hepatic disease may preclude their use. In general, aminotransferase activity should be measured at baseline, at 1–2 months, and then every 6–12 months (if stable). Monitoring of liver enzymes should be more frequent if the patient is taking other drugs that have potential interactions with the statin. Excess intake of alcohol tends to aggravate hepatotoxic effects of statins. Fasting plasma glucose levels tend to increase 5–7 mg/dL with statin treatment. Long-term studies have shown a small but significant increase in the incidence of type 2 diabetes in statin-treated patients, most of whom had findings of prediabetes before treatment.


Pharmacology_Katzung

Pharmacology_Katzung. Minor increases in creatine kinase (CK) activity in plasma are observed in some patients receiving reductase inhibitors, frequently associated with heavy physical activity. Rarely, patients may have marked elevations in CK activity, often accompanied by generalized discomfort or weakness in skeletal muscles. If the drug is not discontinued, myoglobinuria can occur, leading to renal injury. Myopathy may occur with monotherapy, but there is an increased incidence in patients also receiving certain other drugs. Genetic variation in an anion transporter (OATP1B1) is associated with severe myopathy and rhabdomyolysis induced by statins. Variants in the gene (SLCO1B1) coding for this protein can now be assessed (see Chapter 5).


Pharmacology_Katzung

Pharmacology_Katzung. The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin, and to a lesser extent pitavastatin, is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, some HIV protease inhibitors, tacrolimus, nefazodone, fibrates, paroxetine, venlafaxine, and others (see Chapters 4 and 66). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy.


Pharmacology_Katzung

Pharmacology_Katzung. Conversely, drugs such as phenytoin, griseofulvin, barbiturates, rifampin, and thiazolidinediones increase expression of CYP3A4 and can reduce the plasma concentrations of the 3A4-dependent reductase inhibitors. Inhibitors of CYP2C9 such as ketoconazole and its congeners, metronidazole, sulfinpyrazone, amiodarone, and cimetidine may increase plasma levels of fluvastatin and rosuvastatin. Pravastatin and rosuvastatin appear to be the statins of choice for use with verapamil, the ketoconazole group of antifungal agents, macrolides, and cyclosporine. Doses should be kept low and the patient monitored frequently. Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily. All statins undergo glycosylation, thus creating an interaction with gemfibrozil.


Pharmacology_Katzung

Pharmacology_Katzung. Creatine kinase activity should be measured in patients receiving potentially interacting drug combinations. In all patients, CK should be measured at baseline. If muscle pain, tenderness, or weakness appears, CK should be measured immediately and the drug discontinued if activity is elevated significantly over baseline. The myopathy usually reverses promptly upon cessation of therapy. If the association is unclear, the patient can be rechallenged under close surveillance. Myopathy in the absence of elevated CK can occur. Rarely, hypersensitivity syndromes have been reported that include a lupus-like disorder, dermatomyositis, peripheral neuropathy, and autoimmune myopathy. The latter presents as severe pain and weakness in proximal muscles that does not remit when the statin is discontinued. It is HMG-CoA reductase antibody positive and requires immunosuppressive treatment.


Pharmacology_Katzung

Pharmacology_Katzung. Reductase inhibitors may be temporarily discontinued in the event of serious illness, trauma, or major surgery to minimize the potential for liver and muscle toxicity. Use of red yeast rice, a fermentation product that contains statin activity, is not recommended because the statin content is highly variable and some preparations contain a nephrotoxin, citrinin. The long-term safety of these preparations, which often contain a large number of poorly studied organic compounds, has not been established. Gemfibrozil and fenofibrate decrease levels of VLDL and, in some patients, LDL as well. Another fibrate, bezafibrate, is not yet available in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Gemfibrozil and fenofibrate decrease levels of VLDL and, in some patients, LDL as well. Another fibrate, bezafibrate, is not yet available in the USA. Gemfibrozil is absorbed quantitatively from the intestine and is tightly bound to plasma proteins. It undergoes enterohepatic circulation and readily passes the placenta. The plasma half-life is 1.5 hours. Seventy percent is eliminated through the kidneys, mostly unmodified. The liver modifies some of the drug to hydroxymethyl, carboxyl, or quinol derivatives. Fenofibrate is an isopropyl ester that is hydrolyzed completely in the intestine. Its plasma half-life is 20 hours. Sixty percent is excreted in the urine as the glucuronide, and about 25% in feces. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Fibrates function primarily as ligands for the nuclear transcription receptor PPAR-α. They transcriptionally upregulate LPL, apo A-I, and apo A-II, and they downregulate apo C-III, an inhibitor of lipolysis. A major effect is an increase in oxidation of fatty acids in liver and striated muscle (Figure 35–4). They increase lipolysis of lipoprotein triglyceride via LPL. Intracellular lipolysis in adipose tissue is decreased. Levels of VLDL decrease, in part as a result of decreased secretion by the liver. Only modest reductions of LDL occur in most patients. In others, especially those with combined hyperlipidemia, LDL often increases as triglycerides are reduced. HDL cholesterol increases moderately. Part of this apparent increase is a consequence of lower triglyceride in plasma, resulting in reduction in the exchange of triglycerides into HDL in place of cholesteryl esters.


Pharmacology_Katzung

Pharmacology_Katzung. Fibrates are useful drugs in hypertriglyceridemias in which VLDL predominate and in dysbetalipoproteinemia. They also may be of benefit in treating the hypertriglyceridemia that results from treatment with antiviral protease inhibitors. The usual dose of gemfibrozil is 600 mg orally once or twice daily. The dosage of fenofibrate as Tricor is one to three 48-mg tablets (or a single 145-mg tablet) daily. Dosages of other preparations vary. Absorption of gemfibrozil is improved when the drug is taken with food.


Pharmacology_Katzung

Pharmacology_Katzung. Rare adverse effects of fibrates include rashes, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and high blood levels of aminotransferases or alkaline phosphatase. A few patients show decreases in white blood count or hematocrit. Both agents may potentiate the action of anticoagulants, and doses of these agents should be adjusted. Rhabdomyolysis has occurred rarely. Risk of myopathy increases when fibrates are given with reductase inhibitors. Fenofibrate is the fibrate of choice for use in combination with a statin. Fibrates should be avoided in patients with hepatic or renal dysfunction. There appears to be a modest increase in the risk of cholesterol gallstones, reflecting an increase in the cholesterol content of bile. Therefore, fibrates should be used with caution in patients with biliary tract disease or in those at higher risk such as women, obese patients, and Native Americans.


Pharmacology_Katzung

Pharmacology_Katzung. Skeletal muscle Fatty acid oxidation Lipoprotein lipase Endothelium Liver Apo Clll synthesis Apo Al and Apo AII synthesis Fatty acids VLDL, Chylomicron Transcription of LPL vessels Hydrolysis of VLDL and chylomicron triglycerides FIGURE 35–4 Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-α, which decreases the secretion of VLDL and increases its peripheral metabolism. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins. Niacin (but not niacinamide) decreases triglycerides and LDL levels, and Lp(a) in most patients. It often increases HDL levels significantly. Historically, combination therapy including niacin has been associated with regression of atherosclerotic coronary lesions in three angiographic trials and with extension of lifespan in one large trial in which patients received niacin alone.


Pharmacology_Katzung

Pharmacology_Katzung. In its role as a vitamin, niacin (vitamin B3) is converted in the body to the amide, which is incorporated into niacinamide adenine dinucleotide (NAD), which in turn has a critical role in energy metabolism. In pharmacologic doses, it has important effects on lipid metabolism that are poorly understood. It is excreted in the urine unmodified and as several metabolites. One, N-methyl nicotinamide, creates a draft on methyl groups that can occasionally result in erythrocyte macrocytosis, similar to deficiency of folate or vitamin B12. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Niacin inhibits VLDL secretion, in turn decreasing production of LDL (Figure 35–2). Increased clearance of VLDL via the LPL pathway contributes to reduction of triglycerides. Excretion of neutral sterols in the stool is increased acutely as cholesterol is mobilized from tissue pools and a new steady state is reached. The catabolic rate for HDL is decreased. Fibrinogen levels are reduced, and levels of tissue plasminogen activator appear to increase. Niacin inhibits the intracellular lipase of adipose tissue via receptor-mediated signaling, possibly reducing VLDL production by decreasing the flux of free fatty acids to the liver. Sustained inhibition of lipolysis has not been established, however.


Pharmacology_Katzung

Pharmacology_Katzung. In combination with a resin or reductase inhibitor, niacin normalizes LDL in most patients with heterozygous familial hypercholesterolemia and other forms of hypercholesterolemia. These combinations are also indicated in some cases of nephrosis. In severe mixed lipemia that is incompletely responsive to diet, niacin often produces marked reduction of triglycerides, an effect enhanced by marine omega-3 fatty acids. It is useful in patients with combined hyperlipidemia and in those with dysbetalipoproteinemia. Niacin is clearly the most effective agent for increasing HDL and reduces Lp(a) in most patients. For treatment of heterozygous familial hypercholesterolemia, 2–6 g of niacin daily is usually required; more than this should not be given. For other types of hypercholesterolemia and for hypertriglyceridemia, 1.5–3.5 g daily is often sufficient. Crystalline niacin should be given in divided doses with meals, starting with 100 mg two or three times daily and increasing gradually.