General Pharmacology

Pharmacology of the blood

Done by: Abeer Khasawneh

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Today we will talk about the pharmacology of the blood, we will mainly concern about the treatment of anemia as well as some problems seen in blood like thromboembolic disorders, MI and DVT. These thromboembolic disorders can be controlled by antiplatelet, anticoagulant or hemolytic agents. Blood coagulation It's an important physiological process needed to arrest bleeding. How does it occur? It's mainly seen or mediated by intrinsic and extrinsic pathways. So, blood coagulation is the process that generates thrombin and consists of two interrelated pathways: the extrinsic and the intrinsic systems. In general, activated factor X is important for the conversion of prothrombin into thrombin (factor II), then once thrombin is formed, it will convert fibrinogen into fibrin which is the mesh like matrix of the blood clot, so the blood clot is mainly composed of fibrin. At the same

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time, platelets are activated in which there will be an increase in the platelets aggregation and adhesion. Now, some definitions which are important to know:

Hemostasis.
It is what occurs physiologically in order to arrest bleeding. How does it occur? I. Vascular spasm (vasoconstriction) of the damaged blood vessels to minimize blood loss. II. Platelet plugs formation due to platelets aggregation & adhesion. III. Blood coagulation or clotting which is seen by formation of fibrin. So, you will see that any clot is rich in fibrin as well as platelets. But we still have some differences; the thrombus that is formed in the arterial side is mainly rich in platelets, while in the venous side it's mainly rich in fibrin. And this may be considered as a part of the treatment of some diseases, for example, antiplatelets are ineffective to treat thrombosis that occurs in the venous side.

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 Thrombosis
It's a pathological condition results from formation of haemostatic plug within the vasculature in the absence of bleeding.

Thrombus
It's a clot that adheres to blood vessels, but in some cases, it may become detached to form an embolus that may lodge downstream causing ischemia and infarction at the site of occlusion. Thrombus and embolus have a high chance to occlude the blood vessels and limit blood flow. So in our treatment, by using of anticoagulants, antiplatelets mainly in the arterial side and fibrinolytic agents, we are looking to prevent or to decrease the extension or to make a lysis of already formed thrombus.
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The most important type of embolism is called pulmonary embolism. In which the sites of occlusion are the pulmonary arteries and any branch related to them. This condition may cause a fatal situation. There are many reasons for thrombosis to occur: 1. Blood stasis. - For example, patients who had a surgery like knee or hip replacements, will stay immobile for a long period of time, maybe for 4 or 6 months, so this immobility will increase the risk of thrombosis. 2. Pregnancy. - Because during pregnancy this female is presented in a hypercoagulable state. 3. Smoking. 4. Hyperlipidemia. - Because it will increase the risk of arthrosclerosis of blood vessels. 5. using of contraceptives. Drugs used in coagulation disorders are Anticoagulant, Antiplatelet, or Thrombolytics.

Anticoagulant drugs.
A drug that is used to prevent the propagation and extension of the thrombus.

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 Antiplatelets
Drugs that inhibit platelets aggregation and adhesion. An example is Aspirin.

Thrombolytic or fibrinolytic agents.

Drugs that cause lysis of already formed thrombus. And they promote removing the products of coagulation (fibrin removal).

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What you have to know from the previous figure is that: - Platelets play an important role in the coagulation process, so we will use antiplatelets drugs. - The most important clotting factors are II and X (that will lead to the formation of fibrin). So, Anticoagulants will interfere with these clotting factors, either by inactivating them or inhibiting the activation or the synthesis of active clotting factors. - If the thrombus (fibrin) is already formed, then we will use fibrinolytic agents that will cause lysis of fibrin.

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So here, you can see that the vascular injury is prevented by reducing the risk factors. Platelets aggregation and adhesion are prevented by antiplatelet. Thrombin generation and fibrin formation are prevented by anticoagulant. And plasmin generation is prevented by fibrinolytic agents (fibrinolysis).

In our body, we already have some endogenous compounds or proteins that will prevent clot or fibrin formation, like protein S, protein C, antithrombin III and prostacyclins or prostaglandins I2. These endogenous compounds will inhibit platelets aggregation or thrombus formation. So some drugs as you will see may increase the activity of already presented anticoagulant proteins or endogenous compounds.

Anticoagulants
Can be classified into 2 groups, either orally active anticoagulants or parenterally used anticoagulants (most common example is heparin). Heparin. - It is a large sulfated polysaccharide polymer that has a large molecular weight. - Not absorbed orally. Used intravenously in which this will produce an immediate effect, especially for acute cases like acute MI, or can be used subcutaneously in which its onset of action begins after 1 or 2 4 hours after administration (mostly after 60 min).

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- Shouldn't be used intramuscularly because it will increase the risk of hematoma (bleeding in the muscles). - It's active in vivo (inside the body) and vitro (outside the body).

What is the mechanism of action of heparin?

We have an endogenous anticlotting protein known as antithrombin III that will irreversibly inhibit factor II (thrombin) as well as factor X. Now, the activity of antithrombin III will be about 1000 fold by using of heparin. So, we can say that the antiheparin mechanism of action is done by the activation of antithrombin III which will mainly inactivate thrombin factors II and X so that this enzymatic activity is accelerated by using of heparin.

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As you can notice from the picture. If I use heparin, the interaction will be more, faster than in the absence of heparin. This antithrombin III will arrest thrombin and factor X. Thrombin is important as we said to convert fibrinogen into fibrin (the clot), so if I inhibit thrombin, I will inhibit the activation of fibrin. Therapeutic uses of heparin: Anticoagulants are effective in the treatment of thrombosis in the arteries as well as in the veins. 1. it's used in the treatment of deep venous thrombosis. From its name; we will have a thrombus that occurs in the deep veins. Most commonly in the lower legs, or sometimes in the pelvis.

2. Acute MI. In which I will use the intravenous root of administration. So intravenous heparin is administered.
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3. Pulmonary embolism. Which is an embolic disorder that will cause occlusion of the pulmonary artery. 4. Can be used prophylactically to prevent post operative thrombosis. 5. The drug of choice to control thrombosis in a pregnant female who is presented in a hypercoagulable state (have a high recurrence toward thrombosis). o Question: Why is heparin considered to be the drug of choice to control thrombosis in a pregnant female? - Because once you give a drug during pregnancy, you are looking for its safety in which it can be determined by the drug ability to cross the placenta. If this drug minimally crosses the placenta, this means it's safe. So the large molecular weight heparin mostly doesn't cross the placenta to produce any fetal adverse effects. 6. in patients who have prosthetic heart valves. How to monitor heparin effect? Overdose will lead to bleeding and subtherapeutic dose will lead to thrombosis. So to monitor heparin effect we do a lab test known as aPTT (activated partial thromboplastin time) and it's measured in seconds. It should be 1.5 -2.5 above or fold the normal control which is 23-31 seconds.

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 Adverse effects of heparin. 1. the most important adverse effect of heparin or any other anticoagulant is bleeding. If bleeding is developed due to heparin use, what will you do? - First of all, you should stop the drug. - And then we will use the antidote. The antidote of heparin is protamine sulphate. - We may use also blood transfusion or fresh frozen plasma. The interaction between heparin and sulphate is a chemical interaction (Chemical antagonism); the protamine is highly positively charged compound (basic drug) that will interact with the negatively charged heparin.

The protamine is also given intravenously (infusion). It should be given in an accurate calculated dose; because overdose of protamine will cause bleeding (it has a weak anticoagulant effect). So, 1mg of protamine sulphate is used for each 1oo unit of heparin.

2. Long term use of heparin will lead to osteoporosis. 3. It may lead to thrombocytopenia (decrease in platelets number). Once it's developed, it's preferred to stop the drug,

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Now, what we talked about earlier was the large sulfated polysaccharide polymer or what we call the unfractionated heparin. Better than the unfractionated heparin is the low molecular one. So we did chemical / enzymatic depolymerisation, to get a small polymer, known as low molecular weight heparin. This low molecular weight heparin has many advantages compared with the large or unfractionated one: 1. First of all, the mechanism of action is mostly the same. Both of them will activate antithrombin III that will inactivate factor X as well as factor II (thrombin). But the low molecular weight heparin will activate antithrombin III that mainly inactivates factor X more than factor II (thrombin). So it selectively accelerates the interaction between antithrombin III and factor X (Reduced activity against thrombin relative to factor Xa), so that, it can be used in lower doses compared with unfractionated heparin.

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2. The low molecular weight heparin has more predictable anticoagulant effects. 3. Can be used in lower doses as we said earlier. 4. given only subcutaneously, so it can be used for in and outpatients. 5. Have a good bioavailability compared with the unfractionated heparin. 6. As well as there is no need to be monitored by using the aPTT test. So this will save money and effort. 7. It can be used in pregnancy because it can't cross the placenta. It's preferred to be used in pregnancy, given subcutaneously so that it can be used by the female herself. 8. Less thrombocytopenia. 9. Less bone loss. 10. No antidote. An example is Enoxaparin. It has a long duration of action, by that it can be used once or twice daily. o Question: Do you prefer to use the low molecular weight heparin or the unfractionated one? - We prefer to use the low molecular weight heparin. But in emergency cases like in the case of acute MI, I will use the unfractionated heparin intravenously.

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o Question: How can I treat bleeding caused by the low molecular weight heparin? - I'll stop using the drug itself and I will not use any antidote. This criterion (having no antidote) is not considered as a disadvantage, because the tendency to bleeding or what we call bleeding risk is already less.

Oral anticoagulants (Warfarin) Beginning with the differences between heparin and warfarin. Warfarin is given orally, while heparin is given parenterally. In structure, warfarin is related to vitamin k, in which its mechanism of action is done by inhibiting the activation or synthesis of vitamin k dependent clotting factors (II, VII, IX, X). Or what is known as 1972. This drug is contraindicated during pregnancy. Because it can cross the placenta and leads to fetal malformations and may induce abortion
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(teratogenicity). While heparin is safe in pregnancy. Heparin has a rapid onset of action while warfarin has a delayed onset of action; it needs 812 hours to produce its effect. o Question: Can you explain why does warfarin has a delayed onset of action? - Warfarin will not inhibit the already presented clotting factors. It inhibits the synthesis of new ones. So by that it has a delayed onset of action. It will go to the liver to inhibit the synthesis of new clotting factors. This is seen after the depletion of the older ones. So after the depletion of the old clotting factors, it will inhibit the synthesis of new ones. By that, it can't be used for emergency situations. It's only active in vivo, why? Because the synthesis is mainly done in the liver. They inhibit the synthesis of vitamin k dependent clotting factors in the liver so it's only active in vivo. This drug has a narrow therapeutic index, as well as having many drugs interactions. Therapeutic uses of warfarin 1. It inhibits vitamin k epoxide reductase enzyme in the liver which is important for the synthesis of vitamin k dependant clotting factors (1972). 2. it's used prophylactically, when? I. in prevention of thromboembolic disorders during orthopedic organological surgery or gynecologic surgery. II. In patients with history of MI. III. Patients with prosthetic heart valves. IV. as well as patients with chronic atrial fibrillation which is a type of supraventricular arrhythmia.
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3. it's used also in the treatment or prevention of progression or recurrence of deep venous thrombosis. Usually, we will begin with heparin because of its rapid onset of action, and then we switch to warfarin. How to monitor warfarin? In order to prevent the risk of bleeding, warfarin is controlled by a lab test called PT (prothrombin time). Each case has a specific prothrombin time measured daily and the dose is adjusted until INR is stabilized We have some variations between hospital and lab. To overcome the variations in the prothrombin time we make what we call INR (international normalized ratio and should be between 2-3.5). Adverse effects of warfarin The most important side effect is bleeding. To overcome bleeding, what we will use? - First of all, stop the drug. - Then use Antidote which is vitamin k (phytomenadione). But this vitamin K has a delayed onset of action; it needs about 24 hours to produce its effect. - In some cases we will use fresh frozen plasma which contains the clotting factors. o Question: If someone taking warfarin got injured, in this case, will he/she have bleeding or not? - There will be prolonging of the bleeding time.

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o Question: Why do injuries of people with diabetes mellitus take a long time to heal? - Answer: you have to know that DM is not related to hemostasis. Those patients have what we call neuropathy as well as ischemia (decreased blood supply to the site of injury). So in this case, we will be afraid that the patient might get infected in the area of injury. o Question: What is the effect of increasing the dose of vitamin K on its onset of action? - Answer: Even if we increase the dose of vitamin K, it will still have a delayed onset of action. Because it needs time to inhibit the action of warfarin and the inhibition of the synthesis of vitamin k dependent anticlotting factors. Contraindications of Anticoagulants Chronic use of anticoagulants may increase the risk of bleeding. Because of that, anticoagulants are contraindicated in: 1. Patients with bleeding tendency. 2. Recent surgery. 3. Uncontrolled hypertension. 4. Patients with peptic ulcer. 5. Patients with renal or hepatic disease. 6. Patients with intracranial hemorrhage.

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So, before you make any dental procedure for any patient, you should ask him/her if he/she uses an anticoagulant or antiplatelet. And looking for the dose, because they may have a chance of bleeding.

We have a high drug-drug interaction with warfarin and other drugs. Some drugs may increase the level and action of warfarin, thus increasing the risk of bleeding. Some drugs may inhibit warfarin metabolism, like erythromycin antibiotic. Other drugs may accelerate warfarin metabolism, thus inhibiting its therapeutic response. An example is the hepatic enzyme inducers, like rifampicin and Barbiturates.

Warfarin is highly protein bound. Some drugs may displace warfarin from its binding sites. So this will increase the free warfarin concentration, by that increasing its therapeutic response or effectiveness. Antiplatelets. We said that the most common and cheapest example is Aspirin. This drug is effective to prevent thrombosis in the arterial side (vessels). It inhibits platelets aggregation and adhesion. Mechanism of action As we said before, it inhibits the synthesis of thromboxane A2 which is important for platelets activation and aggregation. The most important adverse effect is bleeding and the most common antiplatelet to cause bleeding is Aspirin.
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 Fibrinolytic agents or thrombolytic agents. Drugs that will cause lysis of already formed thrombus, in which their activity will decrease if the thrombus becomes aged. So their activity will be less if we have an old or aged thrombus. How do they work? (mechanism of action) As we said before, prothrombin is converted into thrombin. Then thrombin will convert fibrinogen into fibrin (clot). An example is the tissue plasminogen activator (tPA). It's expensive and has less antigenic reactions or immune response. It will accelerate the conversion of plasminogen into plasmin. Plasmin will cause degradation of the fibrin clot giving more fibrin degradation products. So we can say that fibrinolytic agents are plasminogen activator. . .)MI( These drugs are expensive. Their injection may cost 1000 JD. They can save the patient's life. Epinephrine can be used as a saver only in the anaphylactic shock but not in the thromboembolic disorders. The cheapest plasminogen activator is Streptokinase. It's obtained from bacteria (Hemolytic petus streptococcus). Because of that, continuous use of these drugs will lead to allergic or antigenic reactions. Clinical uses 1. To treat acute MI, in which they will be given within 12 hours from the onset of symptoms. The earlier the better.

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2. In ischemic stroke within 3 hours from the onset of symptoms and as earlier, as it will give better response. Now, stroke could be either hemorrhagic or ischemic one. So, before you give fibrinolytic agents, you should exclude the hemorrhagic stroke. If it's ischemic, then you should use those fibrinolytic agents. But if it's hemorrhagic, they are contraindicated. If serious bleeding developed, we will use Tranexamic acid, which is plasminogen inhibitor that inhibits the action of plasmin (inhibits the activation of plasminogen into plasmin). Or we use fresh frozen plasma. Now, you should be able to compare between heparin and warfarin: Root of comparison 1. route of administration 2. onset of action 3. mechanism of action heparin warfarin

Parenterally (IV or SC) orally faster Slower (delayed onset of action).

Activates antithrombin Inhibits the synthesis III. of vitamin K factors. dependent clotting No (contraindicated). By aPT Vitamin K

4. use during pregnancy 5. Monitoring 6. The use of antidote in the case of overdose.

yes By aPTT Protamine sulphate

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 Anemia
It has different causes. Now, when we can say it's anemia? When the Hb level is below than the normal, referring to the age and sex. In males, the Hb level should be (13.5 or14-17.5). In females, it should be (11.5 or 12.5 -15.5). The Hb is the site in the RBC that is important for oxygen carrying. The clinical features of Anemia (general symptoms) - Pallor, fatigue, shortness of breath (Dyspnea) and palpitations. These are called unspecific symptoms. It's classified depending on the RBCs size into different classes: 1. Microcytic anemia. When the RBCs size becomes smaller. It's seen due to Iron deficiency.

2. Macrocytic anemia. When we have large RBCs size. It's seen in Megaloblastic anemia which is due to B12 or folic acid deficiencies. 3. Normocytic anemia. We have normal RBCs size. And it occurs due to chronic disease. The most common cause is Iron deficiency anemia. And it's highly seen in developing countries.))

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 IRON DEFICIENCY ANEMIA

The iron is important for Hb production. Low hemoglobin synthesis will decrease the capacity of RBC to carry oxygen. We get Iron from diet. It's mainly absorbed in the GIT in the duodenum. It's absorbed from the intestinal surface to be transported in the blood by a protein carrier known as transferrin. Excess iron is stored in the bone marrow, the liver, the spleen as well as in the muscles. The dietary iron is represented in the form of heme (Fe+2) (Ferrous form). Non heme iron (ferric form), should be used by gastric HCl to form the heme one in order to be absorbed. So, some doctors advise that once you have an iron deficiency anemia, it's preferred to increase vitamin C intake by using for example, citrus juice or citrus fruits (lemon and orange). Vitamin C will increase the reduction of ferric form to ferrous one in order to be absorbed. And it's important to know, that if we have an iron poisoning, you should avoid using vitamin C, like juice or any other thing that contains vitamin C. So vitamin C is important to accelerate the absorption of Iron. For example, assume that we have a patient with cancer and Gastrectomy (he/she had removed his/her stomach) and there is no HCl secretion. Then those individuals are suspected to develop iron deficiency anemia.

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Pathophysiology Once the iron stores are decreased, the Hb synthesis will decrease, this will cause gradual fall in RBC production in the bone marrow. Newly formed RBC will look small. So that they are microcytic as well as the Hb concentration inside this RBC is very low. We can say that iron deficiency anemia is microcytic hypochromic anemia. Microcytic (small RBC). Hypochromic (low Hb concentration inside the RBC). So, how do we diagnose iron deficiency anemia? By using the generalized signs and symptoms. For example, in blood film the RBC is microcytic. And we also measure the Hb level. Sometimes we measure the ferritin level (stored form of Iron).

This figure represents koilonychia, which is a cup shaped nails. They are convex and most common in children. There will be Spooning of the fingernails.
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Iron deficiency anemia is common in females more than males because of blood loss during menstruation or high demand during pregnancy. The common causes of Iron deficiency anemia are: 1. Dietary deficiency poverty for example or they are vegetarians, or have Malabsorption 2. Chronic blood loss for example Menorrhagia 3. Increased demand Pregnancy. 4. Inadequate absorption- Gastrectomy.

Treatment of Iron deficiency anemia 1. You should remove the cause if it's possible. For example, in pregnancy there is a high blood demand, so we should administer iron. If there is bleeding or hemorrhage, then we should control it. 2. Then, we need iron supplement that will extend also for 3 months to increase the concentration of the stored iron. Iron is given either orally or parenterally. Oral Iron Preparations. Examples are: ferrous sulphate and ferrous gluconate in the form of tablets and ferrous fumarate in the form of syrup. The tablet looks like candy. So it will cause common toxicity in children. Any iron supplement will cause GIT adverse effects: nausea, vomiting and constipation.

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It's the best to take the iron supplement before meal, about half an hour before meal. But some patients, because they can't tolerate these adverse effects, they take them after or during meal. And you know that some types of food may affect the iron absorption, like Calcium containing food (milk) and oxalic acid containing food (tea). o Question: which one do you prefer to use? The ferrous sulphate tablet which is 200 mg or the ferrous gluconate tablet which is 300 mg? - Both of them are effective and are used orally to control iron deficiency anemia. But here, you shouldn't look to the total concentration of the tablet; you should look to the concentration of iron element itself. Now, the ferrous sulphate although it's 200 mg, but it contains Iron in a higher level than the ferrous gluconate. So, we will use the tablet and we will continue at least for 3 months to replenish stores. Failure to respond to oral iron preparation causes: 1. Patients noncompliance (due to development of Iron adverse effects: Nausea, Vomiting, and GI irritation) 2. Continued blood loss 3. Malabsorption By that, I will switch to the parentral Iron supplement.

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 Iron parentral preparation can be used when: 1. Intolerance to oral preparation 2. Rapid response is required 3. Iron cannot be absorbed from GIT Parentral rout of administration has some adverse effects; an example is the Iron Sorbitol Citrate given IM, it will cause staining of the skin. And this is actually painful. Megaloblastic anemia It's developed because of either Vitamin B12 deficiency (more common) or Folate deficiency. Both of them are important for the synthesis of DNA and RNA nucleotides. B12 Deficiency The less common cause is seen in vegetarians. Because the main source of B12 is an animal one. So there will be higher chance of developing B12 deficiency anemia. The most common cause is pernicious anemia that occurs due to deficiency of Intrinsic factors secreted by the parietal cells which are important for B12 absorption. This B12 is mainly stored in the liver. The source may be sufficient for 3 years. This disease used to be rare, but nowadays it's very common. Any one that looks fatigue, pale, having impairment in memory and dementia, should go and measure the B12 level.

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You as a dentist may face such cases, so you have to know the general symptoms or criteria for iron deficiency anemia like mucosal change or glossitis (beefy red tongue).

B12 is not only important for RBC or hemoglobin production. It's also important for neurons. So B12 deficiency may lead to neurological symptoms. The early one is paresthesia, and the late one is difficulty in balance. How is it treated? 1. By B12 supplement if we have no malabsorption and it's not a pernicious anemia. 2. If no then I can give IV or IM B12. Examples are Hydroxycobalamin and Cyanocobalamin.

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So 1 mg is given twice weekly for 3 weeks. Then 1mg is given monthly as a maintenance dose therapy. Sometimes we don't have only B12; but we might have a B complex like B1 and B6. Megaloblastic anemia is a macrocytic one as we said before and occurs due to B12 or folic acid deficiencies which are hematologically indistinguishable. Folic acid o Question: Treatment of B12 deficiency anemia can be corrected or improved by administration of folic acid. But, can we use folic acid alone to treat Megaloblastic anemia? - If we have macrocytic anemia, it's either due to B12 or folic acid deficiency, so if we use folic acid alone, it can correct or improve the anemia, but it will not improve the neurological manifestations due to B12 deficiency and they may become irreversible. So the best choice of treatment is either B12 or B12+folic acid. The main source of Folic acid is green vegetables. It's Important for RBC production. Now, Folic acid to be active it should be activated to tetrahydrofolate which is important for DNA and RNA synthesis. Causes of folate deficiency: 1. Poor intake-old age, alcohol excess. 2. Malabsorption. 3. Excess utilization-pregnancy.

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4. Drugs-phenytoin. Treatment of FA deficiency Folic acid deficiency anemia is corrected by folic acid, 5mg is taken daily. It's very important to correct or treat this anemia especially in pregnant females. Deficiency in folic acid during pregnancy will lead to a disease known as spina bifida (neural tube defects) and Malformations in the baby. This baby will have openings in his/her back. So any married female that is planning to have a baby, should take folic acid one month before and 2 months after pregnancy (the 1st 2 months of the 1st trimester). She needs a high supplement of folic acid, 5mg is sufficient for her taken daily to prevent the development of neural tube defects in the baby. Erythropoietin It's a hormone secreted by the kidney to stimulate RBC production in the bone marrow. Patients with renal failure, can't produce or secret Erythropoietin by that they need a replacement therapy. We can use Erythropoietin exogenously, given intravenously or subcutaneously to treat anemia due to renal failure.

-The End-

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