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4

Farah Khreisat

Tamara Wahbeh

Malik Al-Zuhlof

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بسم هللا الرحمن الرحيم

Hello guys, hope you're doing well, as you have seen while studying the

previous sheets done by my colleagues, all of them talked about one

topic, which is (Drugs used in clotting disorders), specifically to reduce

clotting. We've finished two of these groups of drugs: (Anti platelets and

Anti coagulants) and today we're going to discuss the 3rd group which is

Thrombolytics in the first half of this sheet.

Before digging deep into the new topic, the doctor mentioned some

notes about anti coagulants:

- One of the main drawbacks that used to frighten us from using

Dabigatran and Rivaroxaban is the absence of antidotes for these two

drugs, but fortunately, both of these drugs have antidotes now!

Dabigatran's antidote was approved by the FDA in 2015, while

Rivaroxaban's antidote was approved by the FDA recently in May, 2018.

So, both factor IIa (Thrombin) inhibitors and factor Xa inhibitors have

antidotes now.

-The main side effect of using Dabigatran and Rivaroxaban is bleeding

(just like any other anti coagulant drug).- similar to bleeding caused by

warfarin - .

-Rivaroxaban has additional side effects such as: Thrombocytopenia in

3% of the patients, pruritus in 1-2% of the patients, and elevation of

liver enzymes in 3-7% of the patients.

Extra note: Pruritusmeans severe itching of the skin.

Now let's start with our new topic:

Thrombolytics (Fibrinolytics)

These are extremely powerful drugs, they directly target thrombi and

they literally dissolve them. Here comes an important question, which

kind of thrombi do these drugs target?

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This is where the main problem of using these drugs lies.. both

protective hemostatic thrombi and target pathogenic thromboemboli

are broken down by these drugs (simply, they lack selectivity =

Thrombolysis all over the body!).

-MOA (Mechanism of action): thrombolytics convert plasminogen to

plasmin which will cause thrombi to dissolve by the degradation of

Fibrin.

-Fibrin degradation products (FDPs) are produced from the degredation

of fibrin by plasmin, useful in diagnosis.

The main difference between these 3 groups of drugs is their selectivity

to plasminogen:

-Some of them (such as t-PA which is the most expensive one) is

selective to plasminogen in clot.

-However, Streptokinase (the strongest thrombolytic drug) is not

selective at all because it activates circulating plasminogen all over the

body, so it acts rapidly but the risk of having side effects "mainly

Thrombolytics

Streptokinase Urokinase t-PA (Tissue

plaminogen

activator)

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bleeding" is much higher. (We'll discuss this in details in the following

pages, don’t worry).

It is important to note that some doctors choose streptokinase over t-PA

although it lacks selectivity, simply because the effect is stronger

regardless of the more severe side effects that could arise (in situations

where benefit outweighs the risk).

Indications: (when to use thrombolytics?)

These drugs are either given intravenously (IV) or intra-arterially (IA).

-We give these drugs intra-arterially for: peripheral vascular disease,

where there is a blockage in peripheral arteries.

-In most of the cases, we give thrombolytics intravenously for:

1- Multiple pulmonary emboli.

2- Central deep venous thrombosis (superior vena cava syndrome,

ascending thrombophlebitis* of iliofemoral vein, femoral vein blockage).

*Thrombophlebitis is a phlebitis (inflammation of a vein) related to

a thrombus (blood clot). "Some people might suggest the administration

of heparin in this case".

3- Acute myocardial infarction (Coronary artery blockage).

4-Acute ischemic stroke: t-PA should be used within 3 hours after onset

of symptoms.

Note: after reading the previous indications, we can deduce that these

drugs are used in emergency situations, and none of the drugs

mentioned in the previous lectures (Heparin, warfarin, aspirin, etc...) can

be used in these urgent situations.

When exactly should we give thrombolytics( after how many

hours/minutes of the incidence should we give thrombolytics)? Each

one of the previously mentioned indications has a specific time at which

we should administer thrombolytics. We start measuring time from the

exact moment at which the incidence happens (not from the moment

the patient reaches the hospital!). In general, the period through which

thrombolytics are effective is 6 hours from the moment at which the

incidence happened, what do we mean by that?

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This means that if we have a patient with myocardial infarction and he

presents to you after 6 hours, you can't give him any thrombolytic agent

(the damage already happened (cardial myocytes are already dead due

to decreased blood flow) and the damage is irreversible and we will only

worsen the situation by giving thrombolytics). However, if he presents to

you any time before 6 hours have passed (after 1 or 2 hours for

example), you should give him thrombolytics as soon as possible (The

earlier the thrombolytic is given the better).

Now let's dig deep into each one of the thrombolytic agents and know

the main differences between them:

1- Streptokinase: a) Its name originates from the fact that it's formed by streptococci

(bacterial product), so it may cause an allergic reaction due to its

bacterial origin.

b) MOA: it combines with plasminogen forming a complex that cleaves

another plasminogen molecule to plasmin, so it will convert all

circulating plasminogen to plasmin, active plasmin will circulate in the

blood affecting fibrin all over the body.

c) It's a very strong and effective drug with serious adverse effects.

2- t-PA (Tissue plasminogen activator): a) An endogenous direct activator of plasminogen (found normally in our

bodies).

b) It preferentially activates plasminogen that is bound to fibrin ( as we

said before, it is selective to plasminogen in clot) meaning that

"theoretically" it confines fibrinolysis to formed thrombi (but it actually

still affects hemostatic thrombi).

That's why it's more expensive than streptokinase.

3- Alteplase: it is recombinant t-PA.

4- Reteplase: a)Genetically-modified recombinantt-PA.

b) Less expensive than t-PA but less fibrin-selective.

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5- Tenecteplase: a)Genetically-modified recombinant t-PA.

b)Long t1/2 (half life).

c)Slightly more fibrin-selective than t-PA.

-This is the best thrombolytic agent ( Long half-life, more selective, less

side effects).

Notes: -Other drugs mentioned in slide 43 and not written in the sheet are not

required.

- The doctor focused mainly on streptokinase and t-PA and he

emphasized many times on the differences between them, let’s recap

them together:

1) Streptokinase is the strongest and most effective thrombolytic agent

(all circulating plasminogen activated).

2) It is more favourable to use t-PA since it's more selective.

3) Streptokinase produces more serious side effects than t-PA due to its

lack of selectivity.

-Important note: (the doctor focused on this point)

After giving a thrombolytic drug, as the clot dissolves the

concentration of thrombin will increase locally leading to increased

platelet aggregation and formation of new thrombi, specifically after

the function of the thrombolytic drug ends (since most of them have a

short half life of only 1-2 hours, that's why we said that tenecteplase is

the best one due to its longer half life).

So, we must give an anti-platelet or anti-coagulant after giving a

thrombolytic agent to prevent thrombosis.

Side effects of thrombolytics:

1- Bleeding: happens because these agents do not distinguish between

the fibrin in an unwanted thrombus and fibrin in a beneficial hemostatic

plug, or fibrinogen in the circulation.

2- Reperfusion arrhythmia: This side effect usually happens in cases

of myocardial infarction where the coronary artery is blocked, after

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treating it with a thrombolytic agent, the perfusion ( التروية) to the heart

will suddenly increase leading to arrhythmia.

3- Hypotension.

4- Hypersensitivity: a side effect of using streptokinase and

anistreplase* due to their bacterial origin.

*anistreplase: an acetylated streptokinase-plasminogen complex that

cleaves plasminogen to plasmin (not required).

Note: remember that streptococci cause strep throat (streptococcal

pharyngitis) which -if left untreated- can lead to rheumatic fever, most

people have experienced a streptococcal infection so they have

circulating antibodies against streptococci in their bodies, so these

people when given streptokinase, the streptokinase-antibody reaction

may lead to fever, hypersensitivity and even failure of therapy! And this

is another reason why streptokinase is less expensive than t-PA other

than its lack of selectivity.

-Important points to take into consideration while using thrombolytics: 1- Monitor IV sites for bleeding, redness and pain.

2- Monitor for bleeding from gums, mucous membrane, nose and

injection sites.

3- Observe for signs of internal bleeding (decreased BP, restlessness,

increased pulse).

This marks the end of the topic of drugs that reduce clotting:

Anti platelets.

Anti coagulants.

Thrombolytics (Fibrinolytics).

Anti Thrombolytic drugs

Anti fibrinolytic (coagulant drugs)

Note: The doctor didn't explain this group of drugs clearly in the lecture,

he was on a hurry so I combined what he said in the lecture with what's

written in the slides and last year's sheet to make everything clear.

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-Please focus of their name (Anti-Thrombolytic drugs), not

Anti-Thrombotic, Anti thrombotic is the same as anti coagulant.

These are drugs that enhance thrombi formation by inhibiting the

thrombolytic pathway. Therefore, they are used to treat extensive

bleeding conditions.

1-Aminocaproic Acid: a) It inhibits enzymes like plasmin that is responsible for fibrolysis, so it's

useful in enhancing hemostasis when fibrinolysis contributes to

bleeding. Therefore, it is effective in treatment of certain bleeding

disorders.

However, in life threatening situations (extensive bleeding), transfusion

of appropriate blood products and other emergency measures may be

required.

b) It's an old drug, marketed as Amicar.

c) Used in postpartum bleeding or heavy menstruation (1g is

administered orally), post major-surgery bleeding (colectomy). You can

see this drug sometimes in sport matches when a player is injured and

they apply a patch on the site of bleeding to reduce it quickly, where

these patches contain aminocaproic acid.

d) Adverse effects: renal failure, edema, headache, malaise.

2- Tranexamic acid: a) Similar MOA to aminocaproic acid, it inhibits enzymes like plasmin

that is responsible for fibrolysis, can be given orally, IV, IM.

b) Uses:

-Tranexamic acid has been found to decrease the risk of death in people

who have significant bleeding due to trauma. (Its main benefit is when

taken within the first three hours).

- It is used to treat heavy menstrual bleeding. When taken orally it

treats regularly occurring heavy menstrual bleeding safely and

effectively. (Note:Tranexamic acid is the only non-hormonal medicine

that is FDA approved for heavy monthly bleeding).

-Dentists may give it as a wash (it will be one of its contents) to stop

gum bleeding or (Aminocaproic Acid can be used).

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c) Common adverse effects include:

-Headaches (50.4 - 60.4%).

-Back aches (20.7 - 31.4%).

-Nasal sinus problem (25.4%).

-Notes:

- Don’t give these two drugs to patients with high risk of thrombosis

(stroke, myocardial infarction, hypercholsteremia, arteriosclerosis…) Or

patients who are allergic to these drugs.

- Tranexamic acid is more expensive than Aminocaproic Acid.

We've finished talking about drugs used in clotting disorders (either to

reduce or facilitate clotting), now we'll start with a completely new topic

related to nutrition.

Iron Deficiency Anemia

First, let's revise some points regarding hematopoiesis (we took most of

the information mentioned in the next 2 pages in details in physiology

and biochemistry, but I had to put them in this sheet since the doctor

read them all).

So don't worry, you know all of this:

-200 billion new blood cells are produced per day!

- The hematopoietic machinery requires a constant supply of: iron,

vitamin B12, and folic acid.

-Iron deficiency results in Iron deficiency anemia.

-Megaloblastic anemia results from either vitamin B12 deficiency or

Folic acid deficiency.

- Hematopoietic growth factors: proteins that regulate the proliferation

and differentiation of hematopoietic cells.

- Inadequate supplies of either the essential nutrients or the growth

factors result in deficiency of functional blood cells.

-Anemia: a deficiency in oxygen-carrying erythrocytes.

-Iron deficiency is the most common cause of chronic anemia.

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How does Iron deficiency anemia occur?

Iron forms the nucleus of the iron-porphyrin heme ring, which together

with globin chains form haemoglobin.

In the absence of adequate iron, small erythrocytes with insufficient

haemoglobin are formed, giving rise to microcytic hypochromic

anaemia.

Note: The cardiovascular adaptations to chronic anaemia include:

1) Tachycardia. 2) Increased cardiac output.

3) Vasodilation.

These adaptations may worsen the situation and lead to CHF (Congestive

heart failure)! So you can't and you shouldn't let the patient stay

anaemic, you have to treat him to avoid all these fatal consequences.

-Total iron in the body is approximately equal to 3.5 g (2.5 g of it is in Hb,

the rest is either in myoglobin or bound to transferrin or stored in

ferritin). -remember iron distribution in the body, we took it in

physiology-.

-Absorbed iron is usually 10 to 25 % of ingested iron, and this percentage

increases up to 30 % in case of iron deficiency anaemia.

Daily iron requirements:

The underlined ones in the picture are the ones mentioned by the

doctor:

Iron absorption:

-In the diet, Iron is found in two forms: Heme Iron (Iron bound to heme),

which is usually found in animal based products such as meat, and Non-

We took them in details in physiology

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heme Iron which is usually found in vegetables, grains and therapeutic

Iron.

- Heme Iron is more easily absorbed (it is absorbed as a whole intact

structure).

- Non-heme Iron needs to be disintegrated from proteins that it is

complexed with, to elemental iron in order to be absorbed.

This figure is really important, it shows us the total iron content in

different sources of iron, and how much of it will actually be absorbed

when we ingest each one of them.

Few notes regarding the figure:

1- Notice that spinach is rich in Iron but it is considered to be a poor

source of iron! Because as we took in physiology, Iron in spinach is

complexed with phytate and the body doesn’t readily disintegrate this

complex, that's why we can't benefit from most of the Iron present in

spinach. (same thing applies for baked beans).

2- However, much higher amounts of Iron are absorbed when we eat

beef (heme iron), so beef (meat in general) is a great source of iron.

3- If you don't like meat, you can eat fortified baby cereal, it's a good

source of iron.

-please look at the figure carefully and compare the total iron content to

the actual absorbed amount for every source.

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Indications for the Use of Iron (when to use Iron

supplements?)

1-Treatment or prevention of iron deficiency anemia.

2-Populations with increased iron requirements:

a) Infants, especially premature infants.

b) Children during rapid growth periods.

c) Pregnant and lactating women.

d) Chronic kidney disease (Important), people with chronic renal disease

(failure) need iron supplements due to two reasons:

Hemodialysis causes loss of erythrocytes at a relatively

high rate.

These patients are treated with the erythrocyte growth

factor erythropoietin (exogenous given by injection), which

will increase the rate of hematopoiesis, increasing the

demand on iron.

3-People with inadequate iron absorption:

a) This is seen frequently after gastrectomy.

b) Severe small bowel disease that results in generalized malabsorption.

Note: groups 2 and 3 are susceptible to develop iron deficiency anaemia.

Oral Iron supplements:

There are 3 preparations:

1- ferrous fumarate: 33% elemental iron (high iron content), it is the

best (new) but is associated with more side effects.

2- Ferrous sulphate: 20%elemental iron, it has lesser amounts of iron

than ferrous fumarate but with lesser side effects.

3- Ferrous gluconate: 12% elemental iron, very low iron content with the

least side effects.

So, we deduce that when the iron content increases in the tablet, the

side effects increase, and that’s why ferrous fumarate causes more

severe side effects than ferrous sulphate and gluconate.

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Important notes:

Treatment with oral iron should be continued for 3–6 months in

order to replenish (rebuild) iron stores.

Iron is absorbed more completely when the stomach is empty, so

patients should take oral iron supplements on an empty stomach

(before food), because food decreases iron absorption by 30 -

50%. But the problem is that it causes severe "and sometimes

intolerable" nausea and vomiting especially in ladies, some

patients can't tolerate these side effects, so they either take it

with food (this will decrease its absorption), or we switch them to

parenteral iron (IV) as a last choice, because it develops other side

effects.

Iron absorption is enhanced by: Vitamin C, orange juice, meat and

fish.

Iron absorption is inhibited by: cereals, tea and milk.

Side effects:

20-25% of patients taking oral iron will suffer from side effects mainly

related to the GI tract :

Nausea

Epigastric pain

Constipation, diarrhea

Heartburn

Abdominal cramps

Patients taking oral iron develop black stool (very important).

Note:

The drug that results in black stool: Oral iron supplements.

The drug that results in black urine: Metronidazole (Flagyl).

-Drug interactions: Tetracycline and Antacids decrease iron absorption.

Parenteral Iron: -IV, might be taken IM (not preferable); it's painful and causes staining

to muscular tissue.

-Indications:

Patients with severe documented iron deficiency.

Patients who are unable to tolerate or absorb oral iron.

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Patients with extensive chronic anemia who cannot be maintained

with oral iron alone. This includes:

1- Patients with advanced chronic renal disease requiring

hemodialysis and treatment with erythropoietin.

2- Various post gastrectomy conditions and previous small bowel

resection, inflammatory bowel disease involving the proximal

small bowel, and malabsorption syndromes.

We've finally reached the end of this lecture, hope it was clear enough.

Best of luck,

Your colleague, Farah Khreisat..