Pharmacology of The Blood

7/30/2019 Pharmacology of The Blood

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Pharmacology of the blood

Anticoagulants

Last lecture we talked about thromboembolic disorders (pathologicdisorders).

Physiological thrombus: is important to stop bleeding. Pathological thrombus: diseases like:o DVT (deep venous thrombosis).o PE (pulmonary embolism).o Ischemic stroke.o 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. Plateletsplay 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 typeof 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.

Heparin WarfarinOnset of action Rapid Delayed

During pregnancy Safe Teratogenicity

Root of administration Parenterally Orally

Active in vivo and vitro vivo

Monitored by Lab test aptt PT prothrombin time

MOA Activates antithrombin III Inhibits synthesis of vitamin k

Site of action - Liver

Antiplatelet drugs

Antiplateletdrug (slide#30) will just remind you of aspirin

Exam question: NSAIDs inhibit the synthesis ofprostaglandins. How?

They inhibit the enzyme COX (cyclo-oxygenase). Most of them are non-

selective, so they inhibit both COX1 and COX2.

Aspirin has a major peculiar effect; it has anantiplatelet 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 antiplateleteffect?

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 thanaspirin, and their adverse effects of bleeding are less than aspirin.

Another example is tropix (Plavix, Ticlid).


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Fibrinolytic (thromboembolic) agents

Venous thrombosis is treated either by fibrinolytic agents or by

anticoagulants including heparin or warfarin. In the venous sidethrombus 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 isthat 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 streptococcalinfection 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.

In which cases are they used in treatment of bleeding?1.

Dental extraction.

2. Menorrhagia.3. Epistaxisis.4. 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.


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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 patientsage and the patients gender (reduction of

the oxygen carrying capacity of hemoglobin).

The generalized symptoms of anemia:1. Pain, palpitations.2. Shortness of breath.3. Generalized fatigue.4. 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.

Theanemia 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 isknown 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.


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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 todiagnose 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.)


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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 ironto 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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What are the causes of iron deficiency anemia?1. Depending on importance of HCL, in case ofachlorhydria 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).

2. The most important cause of iron deficiency anemia is dietarydeficiency. (E.g., low social class, poverty, vegetarians). The sourcethat contains the highest iron content is the diary food and meat,

so we will see the iron deficiency most commonly in vegetarian

people.

3. Chronic blood loss (E.g., menorrhagia). This explains why irondeficiency anemia is more common in females than males.

4. Increasing demand like in pregnancy. A pregnant female has ahigher 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 anemiais corrected in order to replenish the stores of iron. Oral iron

supplements (E.g., ferrous sulfate, ferrous gluconate and ferrousfumarate). 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 takethem 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?1. That is because of patients noncompliance. This female patient

doesnt take her oral iron supplement. Why? The most commoncause is the adverse effects (nausea, vomiting, constipation).

2. Theres a continued blood loss.3. Theres malabsorption.


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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 anemiaAs 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 andpoverty, 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 beactivated 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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The causes of folic acid anemia:1. Poor intake-old age, alcohol excess.2. Excess utilization during pregnancy.3. Malabsorption.4. 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 4months, 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.

Pharmacology of The Blood

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