Pharmacology - An Illustrated Review
24. Drugs Acting on the Blood
Traumatic injury to blood vessels results in a series of events aimed at achieving hemostasis (cessation of bleeding), including vasoconstriction, platelet aggregation, and the deposition of fibrin (Fig. 24.1).
Undamaged endothelium releases chemical mediators, such as prostacyclin and nitric oxide (NO). These are inhibitors of platelet aggregation. Prostacyclin acts by activating cyclic adensone monophosphate (cAMP). This, in turn, increases intracellular Ca2+ levels causing platelet inactivation and inhibition of platelet aggregation agents.
When there is physical damage to endothelium, platelets adhere to exposed subendothelial collagen fibers. This is bridged by von Willibrand factor (vWF) in the vascular epithelium interacting with glycoprotein 1b receptors on the surface of platelets. This adhesion activates platelets which release several substances: von Willibrand factor promotes adhesiveness and serotonin, platelet-derived growth factor (PDGF) and thromboxane A2 promote vasoconstriction. Other mediators released by platelets enhance platelet activation and attract more platelets, e.g., adenosine diphosphate (ADP), platelet-activating factor (PAF), and thrombin. Activated platelets also change shape and glycoprotein IIb/IIIa (GPIIa/IIIb) receptors on their surface change their conformation which promotes the affinity of platelets for fibrinogen. Fibrinogen binding to GPIIa/IIIb on two separate platelets causes platelet cross-linking and further platelet aggregation.
Endothelial injury also stimulates the coagulation (clotting) cascade via the release of tissue factors and by mediators released by activated platelets. This results in the formation of thrombin (Factor IIa) which then catalyses the hydrolysis of fibrinogen to fibrin. Fibrin forms a meshwork within the platelet plug (aggregated platelets). Overall, a platelet-fibrin clot is produced that achieves hemostasis (Figs. 24.1 and 24.2).
Fig. 24.1 Platelet-mediated hemostasis.
Vascular injury and endothelial defects in vessel walls expose collagen and extracellular matrix. This causes the activation of platelets. Von Willebrand factor in vascular epithelium interacts with glycoprotein 1b in the platelet membrane to cause fast-flowing platelets to slow down at the site of an endothelial defect. The defect exposes collagen, which activates platelets and causes them to change shape and gain an affinity for fibrinogen. The platelets then become linked to each other via fibrinogen bridges, causing thrombus formation.
Fig. 24.2 Aggregation of platelets by glycoprotein IIb/IIIa and fibrinogen.
Glycoprotein IIb/IIIa in the platelet membrane change their conformation when platelets are activated by adhesion to collagen. This causes the platelets to gain an affinity for fibrinogen. Activated platelets release other substances, for example, serotonin and thromboxane A2, which can activate other platelets. (ADP, adenosine diphosphate; PAF, platelet-activating factor.)
Thrombosis and Embolism
Thrombosis is the formation of an unwanted blood clot in a blood vessel or within the heart. It is an inappropriate response of the hemostatic process to alterations in the circulatory system, lesions in vascular walls, or other stimuli (Fig. 24.2).
Embolism occurs when thrombi are dislodged and are carried by the circulation to small vessels, where they may cause occlusions and tissue ischemia.
Thrombosis is treated by pharmaco logical agents designed to inhibit platelet function, inhibit fibrin deposition, or enhance fibrinolysis.
24.1 Antiplatelet Drugs
When platelets are stimulated to aggregate, arachidonic acid is liberated from platelet phospholipids and may be metabolized to thromboxane A2 by the sequential actions of cyclooxygenase and thromboxane synthetase. As this occurs, platelet levels of cyclic adenosine monophosphate (cAMP) decrease, and adenosine diphosphate (ADP) is released. Both ADP and thromboxane A2 are potent stimuli for platelet aggregation.
Role of endothelial cells in preventing thrombus formation
Endothelial cells produce nitric oxide (NO) and prostacyclin, which inhibit platelets from adhering to undamaged, healthy endothelium. Diseases that impair endothelial function (e.g., elevated blood glucose, chronic hypertension, and smoking) therefore increase the tendency for platelets to adhere to epithelium and so predispose an individual to thrombosis.
Aspirin is discussed in more detail in Chapter 33.
Mechanism of action. Aspirin acetylates platelet cyclooxygenase (COX–1) and irreversibly inhibits the enzyme (Fig. 24.3). This reduces the formation of thromboxane A2.
Pharmacokinetics. Aspirin is usually given at a dose of 50 to 100 mg daily for its antithrombic effects.
– Prophylaxis or treatment of stroke or myocardial infarction (MI)
– Also used after vascular surgery, such as percutaneous coronary intervention, carotid endarterectomy or coronary artery bypass surgery, to prevent thrombosis
Stroke is death of brain tissue due to either cerebral ischemia or intercerebral hemorrhage. Ischemic strokes are usually caused by thromboembolism but may rarely be caused by severe hypotension or vasculitis. Hemorrhagic strokes are usually due to rupture of an aneurysm. There are many risk factors for stroke including hypertension, diabetes, heart disease, peripheral vascular disesase, atrial fibrillation, and drugs (e.g., contraceptive steroids), and excess alcohol intake. Symptoms occur shortly after the cerebral event and relate to the area of brain affected. They may include difficulty speaking, understanding language, or walking; vision problems; contralateral paralysis or numbness; and headache. Treatment for ischemic stroke includes aspirin and t-PA anticoagulation. Hemorrhagic strokes require surgical removal of the clot and clipping or coiling of the aneurysm.
Side effects. The major side effects of aspirin are gastrointestinal (GI) distress and bleeding.
Mechanism of action. Dipyridamole inhibits platelet ADP release by increasing cAMP levels through two mechanisms: it increases adenosine concentrations in the blood, which stimulates adenylate cyclase to increase cAMP, and it is a phosphodiesterase inhibitor and slows cAMP catabolism to ADP. Dipyridamole also decreases the adhesion of platelets to artificial surfaces.
Uses. This agent is available in combination with aspirin for prevention of cerebrovascular ischemia.
Side effects. Dipyridamole produces vasodilation that may lead to flushing, headache, dizziness, and hypotension.
Clopidogrel and Ticlopidine
Mechanism of action. Clopidogrel and ticlopidine inhibit ADP-induced platelet fibrinogen binding and subsequent platelet–platelet interactions (Fig. 24.3).
– Used in patients undergoing coronary stent placement to prevent thrombosis and restenosis
– Used for patients who have experienced or are at risk for cerebrovascular or cardiovascular thrombotic events (i.e., stroke or myocardial infarction) and is recommended for patients who cannot take aspirin
Fig. 24.3 Inhibitors of platelet aggregation.
Platelets attach to collagen via glycoprotein VI (GPVI) on platelet membranes. This activates them and causes them to secrete ADP and serotonin, as well as activating the enzyme cyclooxygenase (COX-1). COX-1 causes thromboxane A2 to be produced from arachidonic acid. These substances activate glycoprotein IIb/IIIa (GPIIb/GPIIIa), which cause platelet aggregation via fibrinogen. Acetylsalicylic acid (ASA) inhibits COX-1, which prevents thromboxane formation. Clopidogrel is an ADP-receptor antagonist. Other agents (e.g., abciximab) block the binding of fibrinogen to GPIIb/GPIIIa. P2Y12 is a subtype of purinergic receptor on platelets. TP, thromboxane prostanoid receptor.
Side effects. These drugs are generally well tolerated. Ticlopidine may produce agranulocytosis (acute low white blood cell count), and patients must be monitored for evidence of neutropenia.
Glycoprotein IIb/IIIa Receptor Antagonists
Abciximab, Eptifibatide, and Tirofiban
Abciximab is a monoclonal antibody, eptifibatide is a cyclic peptide, and tirofiban is a small molecule.
Mechanism of action. This class of drugs prevents platelet aggregation by competing with fibrinogen and von Willebrand factor for occupancy of platelet receptors (Figs. 24.2 and 24.3).
Pharmacokinetics. These agents are given intravenously (IV) for acute treatment or prophylaxis.
– Stent placement and coronary angioplasty (abciximab)
– Prevention of thrombosis in acute coronary syndrome (eptifibatide and tirofiban)
– Bleeding at arterial sites
– Acute thrombocytopenia (low platelet count) may occur with abciximab
Thrombocytopenia is the term for a low platelet count. Causes include decreased production of platelets, e.g., due to leukemia or aplastic anemia, or increased breakdown of platelets, e.g., due to autoimmune disease, viruses, drugs (e.g., heparin and sulfa-containing antibiotics), thrombotic thrombocytopenic purpura (tTP), idiopathic thrombocytopenic purpura (ITP), and hypersplenism. Symptoms include nosebleeds, bruising, prolonged bleeding from cuts, and bleeding gums. Treatment may not be required for mild thrombocytopenia. Otherwise, treatment is aimed at the underlying cause.
Heparin is an endogenous sulfated mucopolysaccharide found in mast cells bound to histamine. The drug is commercially prepared from pork stomach and beef lung.
Mechanism of action. Heparin combines with, and catalytically activates, a plasma cofactor named antithrombin III. This complex neutralizes several activated clotting factors, particularly factors IIa (thrombin) and Xa (Figs. 24.4 and 24.5). Heparin is active to a lesser extent against activated forms of factors VIII, IX, XI, and XII. It has no therapeutic effects other than the inhibition of clotting. Heparin causes the release of lipoprotein lipase from tissues, which hydrolyzes plasma triglycerides and has a “clearing” effect on turbid plasma.
– Heparin can be given IV or subcutaneously.
– Dosage is adjusted according to coagulation time (activated partial thromboplastin time) in therapy of acute thrombotic episodes.
– For prophylaxis, low doses of heparin are given, which cause little change in clotting time.
– Percutaneous coronary intervention
– Treatment and prevention of venous thromboembolism
Percutaneous coronary intervention
Percutaneous, meaning “through the skin,” refers to procedures in which access to organs or tissues is achieved via needle puncture of the skin. Percutaneous coronary interventions include balloon angioplasty, implantation of stents, and rotational or laser atherectomy to clear atherosclerotic vessels.
Deep vein thrombosis
Deep vein thrombosis (DVT) is a blood clot (thrombosis) that most commonly occurs in the deep veins of the lower leg. It is precipitated by factors that cause abnormal blood clotting or venous circulation. Risk factors for developing DVT include immobility (e.g., sitting or lying for prolonged periods of time), surgery, obesity, pregnancy, malignancy, and estrogen-containing drugs. DVT is often asymptomatic, but it can present with swollen, hot, painful calves, with distended veins. There may also be increased resistance and pain on dorsiflexion of the foot (Homan sign). DVT is diagnosed by venograph or Doppler ultrasound and is treated by heparin, then warfarin anticoagulation. Deep vein thrombi may break off and cause a pulmonary embolism.
– Thrombocytopenia. This may be mild and transient or severe if antiplatelet antibodies are formed.
– Osteoporosis. This occurs when long-term heparin therapy is necessary.
– Allergy. This probably develops to animal proteins in the solution.
Fig. 24.4 Heparins: origin, structure, and mechanism of action.
Antithrombin III (ATIII) is a glycoprotein that can inactivate clotting factors. Heparin inhibits clotting by massively increasing the production of ATIII. Different chain lengths of heparin are required to inactivate different clotting factors. The inactivation of thrombin (factor IIa) requires that heparin contact it and ATIII simultaneously; to inactivate factor Xa, contact between heparin and ATIII is sufficient. A serious complication of heparin usage is thrombocytopenia. This occurs when antibodies attach to heparin on platelets, causing platelet aggregation. This can lead to thromboembolism or hemorrhage. (MW, molecular weight; SC, subcutaneously.)
Antidote. Protamine sulfate is an antidote for heparin and forms a 1:1 complex with the anticoagulant.
The exact mechanism of heparin-associated osteoporosis is unknown. It is thought that it may be due to the following: overactivation of osteoclasts by parathyroid hormone (PTH), reduced activity of osteoblasts, and/or increased bone resorption due to disruption of vitamin D metabolism and collagen activation. The fact that heparin has an affinity for Ca2+ leading to reduced Ca2+ in the blood and activation of PTH may support the first two theories.
Inhibition of aldosterone by heparin (including low-molecular-weight heparin) can result in hyperkalemia (low plasma K+), especially with prolonged treatment. Patients with diabetes mellitus, chronic renal failure, acidosis, or raised plasma K+ and those taking potassium-sparing diuretics are particularly at risk of hyperkalemia and should have their potassium levels monitored.
Mechanism of action. Enoxaparin is a low-molecular-weight heparin that also binds antithrombin III, but the complex is less effective than the heparin-activated complex against thrombin. As a result, enoxaparin exerts an antithrombotic effect (primarily attributed to inhibition of clotting factor Xa) but has little effect on bleeding time.
Pharmacokinetics. Enoxaparin is given by subcutaneous injection.
– Unstable angina
– Non-ST elevation myocardial infarction (NSTEMI)
Fig. 24.5 Inhibition of clotting cascade in vivo.
The clotting cascade requires the synthesis and activation of many clotting factors, so it can be inhibited at various steps. Coumarin anticoagulants decrease the synthesis of factors II, VII, IX, and X in the liver. Heparin and antithrombin III neutralize the protease activity of activated factors.
– Acute MI with ST elevation
– Percutaneous cardiac intervention
Note: These agents cannot be used interchangeably (unit for unit) with heparin or other low-molecular-weight heparin preparations.
– May produce mild thrombocytopenia; thus, periodic platelet counts should be taken.
– Patients with major bleeding
Heparin therapy in pregnancy
Heparins are used in the treatment of thromboembolic disease in pregnancy because they do not cross the placenta. Low-molecular-weight heparins are preferred because they have a lower risk of heparin-induced thrombocytopenia and osteoporosis.
Direct Thrombin Inhibitors
Bivalirudin, Lepirudin, and Argatroban
Mechanism of action. These agents inhibit clot-bound and circulating thrombin.
Pharmacokinetics. Given IV
– Bivalirudin can be used instead of heparin in patients undergoing coronary angioplasty.
– Lepirudin and argatroban are indicated for use in patients with heparin-induced thrombocytopenia.
Side effects. The main side effect of these agents is bleeding.
Mechanism of action. Warfarin is an coumarin oral anticoagulant drug that antagonizes the hepatic synthesis of the vitamin K–dependent clotting factors II (prothrombin), VII, IX, and X (Figs. 24.5 and 24.6).
Fig. 24.6 Vitamin K antagonists of the coumarin type and vitamin K.
Vitamin K promotes the carboxylation of glutamine residues on factors II, VII, IX, and X in the liver. Carboxyl groups are required for Ca2+-mediated binding of factors to phospholipids. Coumarin anticoagulants (e.g., warfarin) act as “false” vitamin K molecules and prevent the regeneration of active vitamin K from vitamin K epoxide.
Warfarin and International Normalized Ratio
Dosages of warfarin depend on the measurement of prothrombin time, reported as International Normalized Ratio (INR). This is usually measured daily in the early days of treatment and then at appropriate intervals thereafter. A normal INR is 1, and the target INR in oral anticoagulant therapy is different depending on the condition for which anticoagulation is required. For example, for treatment of DVT, an INR of 2.5 may suffice, whereas for patients with a prosthetic heart valve, a target INR of 3.5 is more appropriate.
– Well absorbed after oral administration
– Highly bound to plasma proteins (> 90%)
– Metabolized in liver prior to excretion
– Onset of action of 2 to 3 days, during which time preexisting levels of clotting factors are diminished
– Highly variable effects are seen from patient to patient; dosage is adjusted on the basis of the prothrombin time (a standard clotting test).
– Long-term anticoagulant therapy
– Acute venous thromboembolism
– Atrial fibrillation (to reduce the risk of thromboembolic stroke)
– Teratogenesis, especially during the first trimester. This may be explained by the fact that other vitamin K–dependent functions are affected by warfarin administration.
– Liver and kidney toxicity are seen only with indanedione derivatives which limits the usefulness of this chemical class of anticoagulants.
– Drug interactions occur between the oral anticoagulants and many other drugs (Fig. 24.7).
Antidote. Phytonadione (vitamin K1) is a warfarin antagonist that is used in warfarin poisoning.
Fig. 24.7 Possible interactions of vitamin K antagonists and vitamin K.
Dosages of coumarin anticoagulants must be balanced to protect against thrombosis while minimizing the risk of bleeding. Extrinsic factors, such as pharmacological interactions, may threaten this vitamin K/coumarin balance, so dosage adjustment will be necessary.
There are four tests used to gauge hemostatic activity:
1. Quick test: plasma is made incoagulable with a Ca2+ chelating agent (citrate, oxalate, or ethylenediaminetetraacetic acid [EDTA]). Excessive amounts of Ca2+ and tissue thrombokinase are then added. Clotting time is compared with normal values (70–125%).
2. Partial thromboplastin time (PTT): kephalin, kaolin, and Ca2+ are added to citrated plasma, and clotting time is measured (normal clotting time: 25–38 s).
3. Prothrombin time (PT): thrombin is added to citrated plasma (normal clotting time: 18−22 s).
4. Bleeding time: bleeding time is measured (e.g., prick in earlobe).
Note: Platelet counts are also extremely important in monitoring hemostatic activity.
Mechanism of action. These agents promote the dissolution of thrombi by stimulating the conversion of endogenous plasminogen to plasmin (fibrinolysin). Plasmin limits the growth of a clot and dissolves the fibrin meshwork as the endothelial injury heals (Fig. 24.8). Bleeding is the primary adverse effect of these drugs. Patients may also require anticoagulant therapy to prevent reocclusion of blood vessels.
Uses. These agents are used to degrade existing thrombi in cases of myocardial infarction (MI), stroke, or pulmonary embolism.
Pulmonary embolism (PE) is an obstruction in the pulmonary arterial system, usually caused by blood clots from the periphery, particularly the deep veins of the legs, which are transported to the lung. Symptoms include dyspnea (shortness of breath), chest pain exacerbated by taking a deep breath or coughing, cough +/– hemoptysis. PE decreases the area available for diffusion of gases (increases dead space) and so a ventilation/perfusion (V/Q) scan will show a mismatch. In severe cases pulmonary embolism can cause death due to hypoxia and cor pulmonale (right heart failure due to chronic pulmonary hypertension). Treatment involves the use of the anticoagulants heparin and warfarin or thrombolytics, e.g., streptokinase (not normally required). Surgical clot removal may be necessary for large pulmonary emboli.
Streptokinase is produced from cultures of β-hemolytic streptococci and is therefore antigenic but readily available.
Side effects. Allergic and febrile reactions are the most common nonhemorrhagic side effects.
Myocardial infarction and fibrinolysis
Thrombolytic drugs, such as streptokinase, have been shown to reduce mortality in patients having an acute myocardial infarction (MI). They need to be given within 12 hours of symptom onset but ideally within 1 hour. They should be used with caution if there is a risk of bleeding and are absolutely contraindicated if the patient has had a recent hemorrhage, trauma, or surgery, or has a known bleeding disorder.
Anistreplase is an acylated plasminogen–streptokinase activator complex. It is activated after deacylation in the body. This combination is similar to streptokinase but has a longer duration of thrombolytic action.
Urokinase is obtained from human urine or kidney tissue culture and is not antigenic, but it is quite expensive.
Tissue Plasminogen Activators: Alteplase, Reteplase, and Tenecteplase
Mechanism of action. Tissue plasminogen activator (t-PA) is a human protein that specifically cleaves plasminogen, leading to the formation of plasmin. The activity of t-PA is accelerated in the presence of fibrin. Thus, it preferentially activates plasminogen bound to fibrin, which provides “clot-specific” thrombolytic activity.
– Alteplase is human t-PA produced by recombinant DNA methods.
– Reteplase and tenecteplase are bioengineered recombinant mutant forms of t-PA.
Fig. 24.8 Fibrinolysis.
Fibrinolysis occurs when plasminogen is activated to plasmin under the influence of factors such as kallikrein (a peptidase), urokinase, and tissue plasminogen activator (t-PA). Plasmin then acts on the fibrin meshwork to dissolve the clot into fibrinopeptides. Streptokinase and urokinase act as thrombolytic drugs by activating plasminogen. Some anticoagulant drugs (e.g., tranexamic acid), as well as endogenous substances (α2-antiplasmin), act by inhibiting plasma-mediated fibrinolysis.
– Alteplase has a short plasma half-life (4−5 min) and requires a constant infusion to maintain a therapeutic level.
– The modifications of reteplase result in less fibrin binding, a longer half-life, and greater thrombolytic potency than t-PA. Tenecteplase also has a longer plasma half-life, but it has enhanced fibrin specificity.
Drugs Used in the Treatment of Bleeding
Aminocaproic Acid and Tranexamic Acid
Mechanism of action. These agents inhibit plasmin and plasminogen activator (Fig. 24.8).
Uses. They can be used to prevent bleeding in hemophiliacs undergoing dental extractions, as well as in hemorrhage secondary to aplastic anemia, hepatic cirrhosis, or nephrotic disease.
Desmopressin (Antidiuretic Hormone)
Desmopressin is also discussed on page 190.
Mechanism of action. Desmopressin stimulates the release of clotting factor VIII from the vascular endothelium.
Uses. Desmopressin is used preoperatively in hemophilic patients with low circulating levels of this factor.
Hemophilia A and B
Hemophilia A is an autosomal recessive deficiency of factor VIII causing impairment of blood clotting. Symptoms depend on the severity of the factor VIII deficiency and include extensive nosebleeds, bruising, prolonged bleeding from cuts, bleeding gums, hemarthroses (bleeding into joints), muscle hematomas, and blood in the urine or stool. Hemarthroses may lead to arthritis and hematomas may cause nerve damage. Treatment involves the use of desmopressin and concentrated factor VIII replacement. NSAIDs and intramuscular injections should be avoided in these patients.
Hemophilia B (Christmas disease) is caused by a deficiency of factor IX. Clinically, it behaves the same as hemophilia A.
Von Willebrand disease
Von Willebrand disease is an autosomal dominant deficiency of a protein called Von Willebrand factor and factor VIII that is carried along with this. This causes reduced platelet adherence producing symptoms such as nosebleeds, bruising, prolonged bleeding from cuts, and bleeding gums. However, unlike hemophilia, hemarthroses and muscle hematomas are rare. Treatment is by concentrated Von Willebrand factor and factor VIII replacement, desmopressin, or antifibrinolytic drugs.
Mechanism of action Pentoxifylline is a dimethylxanthine derivative that decreases blood viscosity and increases erythrocyte flexibility.
Uses. Pentoxifylline is indicated for muscle pain during exercise associated with occlusive arterial diseases of the limbs (intermittent claudication).
24.3 Anemia and Antianemia Drugs (Hematinics)
Iron Deficiency Anemia
Iron deficiency anemia is a condition in which there is insufficient hemoglobin in red blood cells due to a lack of iron (which is an essential component of heme). Approximately two thirds of the iron content of the body (women: 2 g, men: 5 g) is bound to hemoglobin.
Iron deficiency anemia is usually caused by blood loss from menses in premenopausal women, but it can also be due to inadequate dietary intake of iron, gastrointestinal (GI) bleeding (e.g., from peptic ulcers, long-term use of nonsteroidal antiinflammatory drugs [NSAIDs], or certain GI cancers), from GI conditions that decrease the absorption of iron (e.g., Crohn disease), or by pregnancy (in which the need for iron is increased due to the increase in maternal blood volume and for fetal hemoglobin synthesis).
Blood smear in anemia
Iron deficiency anemia is referred to as a microcytic, hypochromic anemia because red blood cells are smaller and paler than usual when a blood smear is viewed through a microscope. Megaloblastic anemia is characterized by immature (megaloblastic) red blood cells that are macrocytic and hyperchromic. Flow cytometry is used in laboratories to measure red blood cell count; hemoglobin concentration; mean corpuscular volume (MCV), which reports the size of the red blood cell; and red blood cell distribution width (RDW), which measure the deviation of the volume of red blood cells. These can then be used to calculate the patient's hematocrit (percentage of the blood that is composed of red blood cells); mean corpuscular hemoglobin (MCH), which is the mean hemoglobin content of each red blood cell; and mean corpuscular hemoglobin concentration (MCHC), which is the mean hemoglobin content of a given volume of red blood cells. All of these measurements are used clinically to distinguish the different causes and the severity of anemia.
The hematocrit is the percentage of blood volume that is red blood cells (RBCs). It is normally ~48% for men and ~38% for women. The hematocrit is elevated in polycythemia (a disorder in which the bone marrow produces excessive RBCs), and in diseases which cause hypoxia (e.g., chronic obstructive pulmonary disease [COPD]) as the body attempts to compensate by producing more RBCs. It can also be elevated in dehydration. The hematocrit is lowered in hemorrhage and iron-deficiency anemia.
Signs and symptoms of anemia
Anemia may be asymptomatic, or there may be any of the following signs and symptoms: fatigue, pallor (seen most readily by inspection of the conjunctiva or mucous membranes), dizziness, particularly upon standing (postural hypotension), headache, dyspnea (shortness of breath), coldness of the hands and feet, palpitations, and glossitis (swelling and soreness of the tongue). In severe cases, anemia can cause chest pain (angina due to hypoxia of cardiac muscle) and heart failure (as the heart has to work harder to oxygenate tissues). Iron deficiency anemia also commonly causes brittle nails, cracks at the corner of the mouth, and predilection to infection. Pernicious anemia causes neurologic symptoms, such as numbness, tingling, weakness, and impairment of coordination and memory.
Hemochromatosis is a condition in which there is failure of regulation of iron absorption in the bowel. This leads to excessive iron in the body, which then gets deposited in organs, such as the liver, heart, pancreas, and pituitary. Signs include fatigue, arthralgia (joint pain), changes in skin pigmentation, liver disease, cardiomyopathy, and diabetes. Management is by venesection until the patient is iron deficient.
Drugs Used to Treat Iron Deficiency Anemia
– See Fig. 24.9 for absorption of iron and other pharmacokinetic factors.
– Ferrous sulfate is given orally, three or four times daily, preferably on an empty stomach to increase iron absorption.
– Drug of choice for iron deficiency anemia
Side effects. Side effects involve GI symptoms, resulting from the direct toxic effect of iron. This may cause patient noncompliance and is the most common cause of therapeutic failure. This problem can usually be resolved by an adjustment in dosage.
– Iron dextran may be given by intramuscular or IV (preferred) injection.
– Parenterally administered iron is associated with several adverse effects and is indicated only when the need for iron cannot be met by oral administration.
– Dosages must be carefully calculated so that the body's storage capacity is not exceeded (“iron overload”).
Antidote. Deferoxamine mesylate is a specific chelating agent for iron. It may be administered orally or parenterally for treatment of acute iron poisoning or iron overload.
Erythrocyte sedimentation rate
The erythrocyte sedimentation rate (ESR) is a nonspecific test that is a marker for conditions associated with acute and chronic inflammation. It does not provide a conclusive diagnosis but rather prompts the clinician to do further investigations. It measures the rate of sedimentation of red blood cells in anticoagulated blood over 1 hour. If certain proteins cover red cells, these will stick together and will fall faster. The ESR rises with age and anemia.
Megaloblastic anemia is a condition caused by inhibition of DNA synthesis in red blood cell production. It is caused by a lack of vitamin B12 and/or folic acid.
Folic acid is widely available in the diet, and deficiency due to dietary insufficiency alone is uncommon in the United States. Alcohol and some drugs (e.g., anticonvulsants) are folate antagonists and may exacerbate megaloblastic anemia caused by folate deficiency. Folic acid is necessary for the biosynthesis of thymidylate and subsequent formation of DNA. Orally administered folic acid is usually adequate for all folate-deficiency conditions.
The daily requirement for vitamin B12 is extremely low (2−5 μg), and because this vitamin is found in many foods of animal origin, a deficiency due to dietary insufficiency is rare. However, the absorption of vitamin B12 from the GI tract requires the presence of intrinsic factor, a protein secreted in the stomach. The absence of intrinsic factor, as in pernicious anemia, results in inadequate vitamin B12 absorption.
Fig. 24.9 Iron: possible routes of administration and fate in the organism.
Ferrous iron (Fe2+) and heme are well absorbed in the small bowel, where they are oxidized and deposited as ferritin or transported in the plasma protein transferrin to erythroblasts for hemoglobin synthesis. Macrophages degrade erythrocytes, which liberate iron from hemoglobin. This iron can be stored as ferritin or recycled for erythropoiesis in bone marrow via transferrin. Iron is usually given orally for therapeutic replacement. When this is not possible, parenteral iron is given in the form of Fe3+ (ferric) complexes. This prevents free iron toxicity, as Fe3+ can bind to transferrin or be stored in macrophages.
Folic acid and prevention of neural tube defects
Folic acid supplement taken before and during pregnancy can reduce the occurrence of neural tube defects, such as spina bifida. Dosages of folic acid are different depending on the couple's risk factors for neural tube defects.
Drugs Used to Treat Megaloblastic Anemia
Leucovorin (Folinic Acid)
Mechanism of action. Folinic acid is a folic acid derivative with vitamin activity equal to folic acid. It does not require reduction by dihydrofolate reductase to be converted to tetrahydrofolate.
– Injected to “rescue” normal cells after high-dose methotrexate treatment in cancer chemo-therapy
– Can also be given as a folate supplement if oral therapy is not feasible
Mechanism of action. Vitamin2 B12 is required for the normal metabolism of folic acid, and a vitamin B12 deficiency will cause a pernicious anemia (a type of megaloblastic anemia) because of diminished folate-dependent DNA synthesis. However, neurologic symptoms observed in pernicious anemia apparently develop from defective biosynthesis of myelin, which does not involve folic acid.
Pharmacokinetics. See Fig. 24.10 for the metabolism of vitamin B12 and folate.
– Vitamin B12 is given intramuscularly at monthly intervals for the rest of the patient's life.
– Oral vitamin B12 preparations with intrinsic factor derived from animals give erratic and unreliable results.
– Pernicious anemia
Fig. 24.10 Vitamin B12 and folate metabolism.
Vitamin B12 is absorbed in the small intestine but requires intrinsic factor, produced by parietal cells in the stomach. It is transported in the blood by transcobalamin II to the liver for storage or to erythropoietic cells to facilitate the conversion of methyltetrahydrofolic acid to tetrahydrofolic acid (THF), which is important in DNA synthesis. Therapeutically, vitamin B12 is given parenterally. Folic acid is also absorbed in the small intestine and is taken up into erythropoietic cells. Therapeutically, it can be administered orally.
Vitamin B12 absorption
Vitamin B12 absorption from the gastrointestinal tract involves several steps: B12 is released from dietary proteins by gastric acid. It then binds to R proteins, which are secreted in saliva. In the duodenum, trypsin digests the R protein, liberating B12 which then forms a complex with intrinsic factor (IF), a glycoprotein secreted by gastric parietal cells. This B12-IF complex is resistant to the effects of trypsin and travels to the terminal ileum where it binds to specific receptors and is absorbed via receptor-mediated endocytosis.
24.4 Hematopoietic Growth Factors
Filgrastim and Sargramostim
Granulocyte (G) and granulocyte-macrophage (GM) colony stimulating factors (CSF) are naturally occurring peptide growth factors. Filgrastim is a G-CSF; sargramostim, a GM-CSF.
– Stimulation of bone marrow growth after transplantation or cancer chemotherapy
– Anemia due to renal failure, bone marrow disease, cancer chemotherapy, or in patients with acquired immunodeficiency syndrome (AIDS) receiving AZT (zidovudine, formerly called azidothymidine).
Erythropoietin (epoetin α) is a renal hormone that regulates the production of red blood cells in the bone marrow. Patients with chronic renal failure develop anemia secondary to inadequate levels of erythropoietin. Human recombinant erythropoietin has been shown to be effective in treatment of anemia associated with uremia. There are no direct adverse effects of replacement therapy, although ~25% of patients experience hypertension during treatment (mechanism not understood).
Interleukin II (Opreleukin)
Mechanism of action. Interleukin II stimulates the formation of platelet progenitor cells.
Uses. Interleukin II is used to speed platelet recovery in patients undergoing chemotherapy with nonmyeloid malignancies.
Table 22.2 Summary of Mechanisms of Antianginal Drugs
↓ preload and afterload
↓ myocardial O2 consumption
↓ coronary artery spasm
↑ blood flow to ischemic areas of the heart
Activates guanylate cyclase to ↑ cGMP
↓ heart rate and contractility
↓ myocardial O2 consumption
Blocks sympathetic activation
Calcium channel blockers
↑ coronary blood flow
↓ myocardial O2 consumption
Blocks L-type Ca2+ channels to dilate blood vessels and decrease contractility of cardiac muscles
Abbreviation: cGMP, cyclic guanosine monophosphate.