Pharmacology of the blood

Anticoagulants
Last lecture we talked about thromboembolic disorders (pathologic disorders). o o o o Physiological thrombus: is important to stop bleeding. Pathological thrombus: diseases like: DVT (deep venous thrombosis). PE (pulmonary embolism). Ischemic stroke. MI (myocardial Infarction).

These are known as thromboembolic disorders in which we try to prevent thrombosis by different mechanisms: 1. Drugs that inhibit platelet aggregation and adhesiveness. Platelets play an important role for thrombus or clot formation. 2. Drugs that inhibit the action of the clotting factors. Either drugs that are given parenterally (E.g., heparin), it will activate antithrombin III which is an endogenous protease which activity is increased by heparin.) Antithrombin III will cause degradation of thrombin IIa and X. Or drugs that are given orally (E.g., warfarin). Another type of anticoagulants and it inhibits the synthesis of vitamin k dependent clotting factors. It has a delayed onset of action because its site of action is in the liver, its effect is seen after the already synthesized clotting factors are depleted, and by that it has a delayed onset of action. It is not used during pregnancy because it can cross the placenta (teratogenicity).
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At the end of the last lecture we talked about the differences between heparin and warfarin.
Onset of action During pregnancy Root of administration Active in Monitored by MOA Site of action Heparin Rapid Safe Parenterally vivo and vitro Lab test aptt Activates antithrombin III Warfarin Delayed Teratogenicity Orally vivo PT prothrombin time Inhibits synthesis of vitamin k Liver

Antiplatelet drugs
Antiplatelet drug (slide#30) will just remind you of aspirin Exam question: NSAIDs inhibit the synthesis of prostaglandins. How? They inhibit the enzyme COX (cyclo-oxygenase). Most of them are nonselective, so they inhibit both COX1 and COX2. Aspirin has a major peculiar effect; it has an antiplatelet effect comparing with other NSAIDs, why? Because it irreversibly inhibits COX1. Cox1 is important in the production of thromboxane A2, which is responsible to cause vasoconstriction, and it will enhance platelet aggregation and adhesiveness. So once I block the synthesis of thromboxane A2 I can inhibit platelet aggregartion and platelet function. Why does a low dose of aspirin have an antiplatelet effect? We have COX1 and COX2, we have thromboxane A2 and prostaglandin i2. The action of thromboxane A2 is opposite to the action of prostaglandin i2. Thromboxane A2 stimulates platelet activation and aggregation as well as vasoconstriction, while prostaglandin i2 or
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prostacyclin inhibits platelet aggregation and induces vasodilatation. Low doses of aspirin will inhibit thromboxane A2, and prostacyclin effect is kept intact, and this is what we need; only inhibition of thromboxane A2 that is responsible for platelet aggregation. We do not want to inhibit prostacyclin because prostacyclin effect is important to inhibit platelet aggregation. Low doses inhibit thromboxane A2 more than prostacyclin or prostaglandin i2. The higher doses of aspirin can inhibit both. We will use its inhibitory effect on thromboxane A2. So it is preferred as an antiplatelet. Most boxes come in a dose between 80 and 150 and some boxes say 80 to 180 mg. This is the dose that will have an antiplatelet effect. It was known in the past as baby aspirin (small dose of aspirin). It is important to be taken daily usually in the elderly people, especially males with a history of smoking, hypertension, diabetes, thromboembolic disorders including MI or stroke. So those individuals have higher chances to develop arterial thrombosis which can be inhibited by aspirin. They should take aspirin as a prophylactic daily (small dose) if aspirin is not contraindicated (peptic ulcer or bronchial asthma). Thromboxane A2 synthesis doesnt recover until the affected platelets are replaced by new ones after 7 to 10 days. The affect of aspirin and other antiplatelets is prevention of arterial thrombosis, because platelets play an important rule for thrombus formation in the arterial side. There are other types of antiplatelets that work with different mechanisms (E.g., ADP receptor antagonists, esterase inhibitors, etc...) The most important adverse effect of antiplatelets will be bleeding. We have another type of antiplatelets that are more expensive than aspirin, and their adverse effects of bleeding are less than aspirin. Another example is tropix (Plavix, Ticlid).

Fibrinolytic (thromboembolic) agents

Venous thrombosis is treated either by fibrinolytic agents or by anticoagulants including heparin or warfarin. In the venous side thrombus is usually due to the action of fibrin and clotting factors. They found that aspirin and other antiplatelets are more effective in controlling of thrombosis in the arterial side like MI and stroke. Fibrinolytic agents are effective in both, arterial and venous side. From their name fibrinolytic, they will cause lysis of the thrombus and degradation of the clot. They will activate endogenous proteases enzyme in which plasminogen is converted to plasmin, and this plasmin will cause degradation of the fibrin or lysis of the clot.

Figure (35) may look difficult. Plasminogen is converted to plasmin. This conversion is activated by using of the activator (E.g., Streptokinase or t-PA), they will accelerate this conversion, at the end this plasmin
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(proteases enzyme) will cause damage or cleavage of fibrin to get fibrin split products, and in the same time may cause lysis of fibrinogen to get the degradation product. At the end of the thrombus formation, fibrinogen is converted to fibrin. This fibrin is the insoluble clot. The action of fibrinolytic agent or thrombolytic agent is that vthey will inhibit the conversion of fibrinogen to fibrin. How? Because they accelerate the action of the protease plasmin that we get from plasminogen, plasminogen is converted to plasmin by the action of fibrinolytic agents. This plasmin will cause degradation of the fibrin clot. This figure shows you that we have a positive effect of streptokinase (activates the conversion of plasminogen to plasmin that will cause damage of the fibrin clot).

Streptokinase is produced by culture of the streptococci bacteria. Its source is bacterial. Comparing with other fibrinolytic agents its price is cheap. Continuous use may produce an allergic or immune reaction. Why? Because its source is bacterial, we had in the past a streptococcal infection so we already have antibodies against streptococci in our bodies. Using streptokinase in a patient already having an infection by spread bacteria, this antibody will invade streptokinase and that will reduce its effectiveness and will produce an allergic response. Not always seen if we already had in the past a streptococcal infection. But also the continuous use of streptokinase will enhance the development or formation of antibodies. Another drug is tissue plasminogen activator (t-PA) or alteplase. It is produced by recombinant DNA technology. Genetically cloned, theres no immune reaction. Its not a form of bacteria and it is more expensive than streptokinase. They are highly complicated with bleeding. They have a high risk to induce bleeding. They are used for example for treatment of MI (myocardial infarction). In acute MI they are given
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within 12 hours from the onset of MI. If we give them earlier we will get better results, because the older the thrombus, the lesser the effectiveness of the drugs. They are also used for the treatment of ischemic strokes, the stroke is two types, either hemorrhagic or ischemic. Before we give the fibrinolytic agent we should distinguish whether its an ischemic stroke or a hemorrhagic stroke. As for the ischemic stroke they are given within 3 hours from the onset of the stroke. If they were given after three hours, that will reduce their effectiveness. The most important adverse effect is bleeding. These drugs are given intravenously (IV infusion). If its severe the drug should be stopped and we will use what is known as tranexamic acid or fresh plasma containing clotting factor. another adverse effect, streptokinase may induce an immune reaction.

Antifibrinolytic drugs
Antifibrinolytic drugs mean that their action is opposite to streptokinase. They will inhibit the conversion of plasminogen to plasmin. 1. 2. 3. 4. In which cases are they used in treatment of bleeding? Dental extraction. Menorrhagia. Epistaxisis. Over dose of fibrinolytic agents.

We have different examples. One example is tranexamic acid. It inhibits plasminogen activation by that this will inhibit fibrinolysis. It is used for the treatment of bleeding. So now you can distinguish between fibrinolytic and antifibrinolytic agents. Fibrinolytic agents are drugs that cause degradation of fibrin by activation of the conversion of plasminogen to plasmin, opposite of their effect is the action of tranexamic acid; it will inhibit this fibrinolytic effect.

 What is the most important effect of tranexamic acid? Thrombosis, because it inhibits the fibrinolytic effect. So the most important adverse effect is thrombosis, unlike the other drugs that are complicated with bleeding.

Treatment of Anemia
High modifying anemia is when we have low HB concentration, depending on the patients age and the patients gender (reduction of the oxygen carrying capacity of hemoglobin). 1. 2. 3. 4. The generalized symptoms of anemia: Pain, palpitations. Shortness of breath. Generalized fatigue. Pallor.

HBs content or amount in the male ranges from (13.5-17.5). In the female it ranges from (11.5-14.5). And sometimes they reach 16.5. The severity of symptoms depends on the onset of anemia and its severity. The anemia depending on the size of RBCs: 1. Microcytic from its name micro which means small. In microcytic anemia the most common cause is iron deficiency anemia, which is the most common cause of anemia in developing countries, IDA (iron deficiency anemia). 2. Macrocytic anemia, in which the RBCs size is large, and it is known as megaloblastic anemia, that is either due to B12 deficiency or due to folic acid deficiency. 3. Normocytic anemia that happens due to malignancy or anemia of chronic disease. Either due to malignancy, or renal disease due rheumatoid arthritis anemia chronic disorders.

Firstly, iron deficiency anemia (IDA) that is the most common type of anemia in developing countries. The RBCs are small and thats why it is named microcytic anemia. They are pale RBCs in which the iron supplement and at the same time the iron store are insufficient for HB production and to maintain normal hemoglobin level. It is common in children between the age of 6 months and 2 years and also in teenagers. It is more common in females than males. What are the investigations that are important to diagnose iron deficiency anemia? It is diagnosed from signs and nonspecific symptoms. But there are some specific symptoms for the iron deficiency anemia like koilonychia (spooning of the finger nails, most commonly seen in children with iron deficiency anemia and they are thin nails that become flat and less concave in their shape.)

Another characterestic is the angular stomatitis, Which is an ulceration on the angles of the mouth and that is a characteristic of iron deficiency anemia.

Other symptoms are pallor skin, irritability, fatigue. The generalized symptoms are lethargy, tachycardia, shortness of breath (dyspnea), headache, hypotension and these are characteristics of iron deficiency anemia. First of all as we said the iron which is the centre of HB that is important for carrying oxygen to the tissue. Iron absorption may be from the small intestine from the duodenum. The intestinal mucosa will regulate iron absorption. Once we have deficiency iron absorption from the intestinal mucosa will be more. This iron is carried in the blood by a protein or carrier known as transferrin and it is stored in the liver, bone marrow, muscles and spleen in the form of ferritin. Dietary iron in the form of ferrous or heme (Fe+2) is easily absorbed, but in the form of ferric (FE+3) its not easily absorbed. This compound should be reduced by the action of HCL or vitamin C. Whys is it important for any individual who takes iron to take citrus juice? Because vitamin C will enhance the absorption of iron, because this acidity of vitamin C will increase the conversion from ferric to ferrous (the absorbable form of iron).
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1.

2.

3. 4.

What are the causes of iron deficiency anemia? Depending on importance of HCL, in case of achlorhydria or gastrectomy. Because of cancer, we may remove the stomach and that will inhibit gastric acid secretion, so there will be no HCL, and that will reduce iron absorption so the patient will develop iron deficiency anemia. So when iron stores are decreased the HB synthesis will be less. And by that there will be a fall in RBCs production from the bone marrow (reduction of oxygen carrying capacity of hemoglobin). And so we will have the generalized signs and symptoms. Inadequate absorption because of malabsorption, (E.g., gastrectomy). The most important cause of iron deficiency anemia is dietary deficiency. (E.g., low social class, poverty, vegetarians). The source that contains the highest iron content is the diary food and meat, so we will see the iron deficiency most commonly in vegetarian people. Chronic blood loss (E.g., menorrhagia). This explains why iron deficiency anemia is more common in females than males. Increasing demand like in pregnancy. A pregnant female has a higher chance of developing iron deficiency anemia .In the second trimester she needs to take iron supplement.

Treatment of iron deficiency anemia

First of all we should correct the cause, and we need an iron replacement therapy. Oral iron type. The treatment will be prolonged even if the anemia is corrected in order to replenish the stores of iron. Oral iron supplements (E.g., ferrous sulfate, ferrous gluconate and ferrous fumarate). The iron tablets shape and color is like candy because it is a sugar coated tablet, and by that theres a high chance of iron poisoning in children, accidentally. They think it is candy and by that they have a high chance of developing iron intoxication or iron poisoning. Ferrous sulfate tablet which is about 200 mg of
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ferrous sulfate is taken 3 times daily from 1 to 2 weeks. This can increase the hemoglobin content by 1 gm/dl. We have ferrous gluconate tablet and we have ferrous fumarate syrup. The ferrous sulfate strength is 200 mg, and the ferrous gluconate strength is 300 mg. Some people may think that the ferrous gluconate will contain more iron than ferrous sulfate, because its concentration or strength will be more. This is wrong! You shouldnt look at the total strength; you should look at the iron element inside the tablet. Most important adverse effects with iron supplement especially if it is taken orally- are the GI tract adverse effects, (E.g., nausea, vomiting, GI tract discomfort and constipation). It is preferred to take the tablet 30 minutes prior to the meal, but because of these adverse effects, we advise the patient to take them within the meal. Keep in mind that calcium containing foods will empire iron absorption. Oxalic acid containing foods like spinach and tannic acid in tea will also empire iron absorption. Once the hemoglobin is corrected we should not stop the treatment, we should continue for at least three months in order to replenish the stores. Parenteral Iron: If a female has iron deficiency anemia, (diagnosed from her HB, ferritin or iron concentration of the plasma. IDA has low MCV and low MCH. It is microcytic because of the low MCV, and low MCH and that causes the RBCs to look pale. We take a blood fill and look into the RBCs color and size). Why do we have failure in the treatment? That is because of patients noncompliance. This female patient doesnt take her oral iron supplement. Why? The most common cause is the adverse effects (nausea, vomiting, constipation). Theres a continued blood loss. Theres malabsorption.

1.

2. 3.

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And by that this patient should be treated by parenteral iron supplements. It is either given intravenously or intramuscularly. We prefer IM, and IV is not commonly used because it has a high risk of anaphylaxis. Parenteral is used in tolerance to the oral preparation. In parenteral iron preparation we need a rapid response, and when we have malabsorption which means iron is poorly absorbed from the GI tract. An example of iron that is given IM is iron sorbitol citrate. The most common adverse effect is the staining of the skin. Theres a preferable way called the z-track procedure, which nurses learn; they hold the skin and insert the syringe in order to avoid the risk of staining.

Megaloblastic anemia
As you know the folic acid and vitamin B12 are important for the synthesis of purines and pyrimidines, for the synthesis of DNA. The maturation of RBCs is arrested but the maturation of the cytoplasm will continue, so we will have a macrocytic anemia in which the RBCs size will be more. We arrest RBCs maturation (nucleus development) but the cytoplasm maturation still continues, so the RBCs size will be more than normal. The most common type is either B12 (cobalamin deficiency) or folic acid (folate deficiency). Causes of B12 deficiency: 1. Most important cause of vitamin B12 deficiency anemia is known as pernicious anemia. As you know from physiology the intrinsic factor which is secreted from the G cells (parietal cells) in the store is important for B12 absorption. Loss of the intrinsic factor will empire B12 absorption. (most common cause) 2. Less common cause is due to low social class, vegetarian diets and poverty, because vitamin B12s highest source is presented in meat, eggs and diary food. They contain high vitamin B12 content.

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Studies say that almost half of the Jordanian population suffers from B12 deficiency. And also other important studies found out that a lot of females have vitamin D deficiency. Vitamin B12 absorption is in the intestine, mainly in the terminal ileum, which requires the intrinsic factor that is secreted from parietal cells. It is stored in the liver (3 years supply). Vitamin B12 deficiency is rare but mostly seen in vegetarian people. Megaloblastic anemia signs and symptoms: Pallor, shortness of breath, generalized fatigue, sore tongue (glossitis). We might also have stomatitis.

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Chronic deficiency, as you know vitamin B12 is not important for DNA synthesis but it is important for neurological functions. Chronic deficiency can lead to paresthesias, blurred vision, numbness (early response) and difficulty in balance, as a late response. Vitamin B12 is important for neauronal function. Once we have a megaloblastic anemia, it should not be treated by folic acid alone, because folic acid alone can correct the anemia , but if the cause is B12 deficiency that means no B12 supplement and by that this will increase neurological deformities or problems because of absence of B12 supplement. Treatment of B12 deficiency anemia with folic acid alone may improve the hematological picture, it will correct the hemoglobin and it will correct this anemia. But it will worsen the neurological picture because the patient will not take a source of B12. Once we have a megaloblastic anemia either B12 with folic acid should be given or B12 alone, it is the best. How do we give B12? It is either given orally or it is given parenterally. If there is no malabsorption problem it may be given orally. It can be given parenterally like hydroxycobalamin, cyanocobalami and they are given IM. Usually 1 mg is given twice weekly, for 3 weeks to replenish the stores, then 1 mg is taken monthly as a maintenance dose.

Lastly, Folic acid anemia, the source of folic acid is mainly from green vegetables. It is absorbed in the upper small intestine. The daily intake is 200 g and it is more during pregnancy and lactation. Folic acid should be activated to tetrahydrofolate (FH4) which is important for purines and pyrimidines synthesis by the action of dihydrofolate reductase enzyme. FH4 or tetrahydrofolate is important for DNA synthesis, (synthesis of purines pyrimidines).
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 1. 2. 3. 4.

The causes of folic acid anemia: Poor intake-old age, alcohol excess. Excess utilization during pregnancy. Malabsorption. Drugs. Just to remind you anticonvulsant drugs like phenytoin will induce folic acid deficiency anemia.

So the causes are either due to low intake, malabsorption, high utilization due to pregnancy, excess alcohol intake, or due to drugs like phenytoin. How is it treated? We should treat the cause if its possible, oral folic acid is given for 4 months, folic acid should be given prophylactically in individuals who have a high chance to develop folic acid deficiency anemia. Like patients that are treated by anticonvulsant drugs (phenytoin), during pregnancy (chronic hemolytic anemia), the folic acid supplement is highly important to prevent development of neural defect known as neuronal tube defect like spina bifida or anencephaly, here a malformation maybe seen due to folic acid deficiency during pregnancy. Once the child is born he has an opening in his back or anencephaly (without a skull), it can cause death and disability. So before a female plans pregnancy, folic acid should be taken one month before and in the first trimester of pregnancy. It is very important to prevent neuronal tube defects.

Good luck and Please forgive me for any mistakes, Sarah Farouk Al-Akhras.

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