Hematology Lecture 2 Drugs Only - Jake Prieto Pt - 2

Hematology Exam 1

Introduction to Drugs Affecting Hemostasis

1. Anticoagulants

2. Thrombolytics/Fibrinolytics

3. Antiplatelets

4. Antifibrinolytics

Anticoagulants (Broad)

Substances that prevent the synthesis of a fibrin network which inhibits

coagulation and the formation of thrombi

Thrombolytics/Fibrinolytics (Broad)

Substances that promote the destruction of already formed blood clots or

thrombi (i.e. – lyse thrombi) by disrupting the fibrin mesh

Antiplatelets (Broad)

Drugs that reduce the adhesion and aggregation of platelets

Antifibrinolytics (Broad)

Drugs that promote the formation of clots and prevent excessive bleeding

Anticoagulants (5 Key Points)

Anticoagulants all inhibit the action or formation of one or more of

the clotting factors.

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They create an immediate defect (minutes when given IV, hours

when given orally) in the clotting mechanism and should be treated

with caution.

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The range between sufficient therapy and hemorrhagic risk is narrow

and varies considerably from patient to patient.

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A large number of unrelated drugs also affect the dose of the

anticoagulant needed to produce a desired effect.

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Individual treatment and frequent laboratory tests are imperative.

Anticoagulants are generally divided into: (4)

1. “Indirect” Thrombin Inhibitors (basically HEPARIN)

2. Coumarin Anticoagulants (basically WARFARIN)

3. Direct Thrombin Inhibitors

4. Direct Active Factor X (Xa) Inhibitors

NOAC (Stands for and which drugs)

Non- vitamin K

Oral

Anti

Coagulant

Heparin

“Indirect” Thrombin Inhibitors (basically HEPARIN)

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Commercial heparin is actually a mixture of heparins (protein molecules) with a wide range of molecular weights.

The three most common preparations of Heparin are:

1) Unfractionated heparin (UFH) -- Heparin Sodium

2) Low-molecular-weight heparin (LMWH)

3) Fondaparinux

Heparin: How Does It Work?

Heparin stimulates antithrombin- III, which in turn, neutralizes the activity of factor X (and other clotting factors as well).

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Bottom line: Without factor X, prothrombin cannot be converted into thrombin, which ultimately prevents fibrin formation from fibrinogen.

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Heparin also stimulates heparin cofactor II, which inhibits thrombin

Unfractionated Heparin (UFH)

Contains fractions with high molecular weights ranging from 5000 to 30,000.

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Only given IV (bolus or infusion).

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In the circulation, UFH binds to a number of plasma proteins, which reduces its anticoagulation activity and causes a rather large variability of anticoagulant response among patients.

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UFH also binds to endothelial cells & macrophages which further adds to this variability.

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Bottom line: the relationship between UFH dose and UFH response can be a bit tricky ….. hence, the need to monitor with aPTT.

Unfractionated Heparin (UFH) → Use of the Drug (4)

Treatment of acute thromboembolic disorders (e.g., pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation).

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Prophylaxis to prevent clotting in cardiac surgery, during blood transfusions, during renal dialysis and blood sample collection.

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Prevention of indwelling catheter clotting (“heparin lock flush”).

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Prevention of embolization of thrombi with patients with atrial fibrillation.

Monitoring UFH Therapy

Since the anti-coagulant response to UFH varies among patients, it is standard practice to adjust the dose of UFH and monitor its clinical effectiveness with the activated partial thromboplastin time (APTT).

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Normal APTT is approximately 25-36 seconds.

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Therapeutic levels of UFH will typically prolong the aPTT to 2-2.5 times that of the normal value.

Unfractionated Heparin (UFH) Adverse Side Effects

The major adverse effect of UFH is spontaneous bleeding, particularly from a

previously unsuspected lesion – this risk can be reduced by careful patient

selection, careful control of dosage and careful monitoring of the aPTT.

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Rare side effect → HIT = heparin-induced thrombocytopenia

Unfractionated Heparin (UFH) Adverse Risk Factors

Risk factors include:

• Higher total dose & longer duration of therapy

• Age > 60 years

• Liver disease

• Renal disease

• Concomitant medications that increase risk of bleeding (e.g., ASA)

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Common bleeding sites include mucous membranes, GI, GU, wounds and areas of tissue trauma – monitor stool (occult blood), urine, gums for bleeding

HIT = heparin-induced thrombocytopenia (2 Types)

UFH causes transient (mild or type 1) thrombocytopenia (HIT =

heparin-induced thrombocytopenia) in approx. 25% of patients

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severe HIT (type 2) in approx. 5% -- platelet counts should be

performed daily

Do not take Unfractionated Heparin (UFH) if …

UFH is contraindicated in patients who are/have:

• hypersensitive to the drug

• actively bleeding (e.g. -- intracranial hemorrhage, ulcerative lesions of GI tract)

• hemophilia

• significant thrombocytopenia

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Generally safe to take during pregnancy, although LMWHs are

considered safer

Reversal of UFH Action (1 Drug)

D/C the heparin.

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Overdose is typically treated with IV PROTAMINE SULFATE, which is a positively-charged chelating-antagonist to the negatively-charged heparin.

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Measurement of the aPTT 2 to 4 hours after protamine administration is used to guide the need for further protamine treatment.

Low Molecular Weight Heparins (LMWHs)

Contains fractions with low molecular weights ranging from 2000 to 9000.

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Tends to work on AT-III in such a way that there is more inactivation of factor X than inactivation of thrombin.

Low Molecular Weight Heparins (LMWHs) Admistration Method

Can be used in either the in-hospital or out-patient setting because they can be

administered subcutaneously on a body weight basis without the need

for aPTT laboratory monitoring

Low Molecular Weight Heparins (LMWHs) (3 Drugs)

1. Enoxaparin (Lovenox)

2. Dalteparin (Fragmin)

3. Tinzaparin (Innohep) was withdrawn from the US market in 2011.

Low Molecular Weight Heparins (LMWHs) (3 Benefits)

They have a longer duration of action than UFH, which often

allows once-daily administration

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• There is evidence that LMWHs produce fewer cases of

heparin-induced thrombocytopenia (HIT) [LMWHs

should not be used in patients that have HIT with UFH]

• LMWHs do not cross the placenta and do not cause fetal

anticoagulation

Low Molecular Weight Heparins (LMWHs) (Use of the Drug)

Treatment of venous thromboembolism associated with abdominal surgery, knee or hip-replacement surgery and in other conditions that place patients at risk for thrombosis (typically administered once before surgery and for 5 to 10 days after surgery).

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Prevent ischemic complications of unstable angina or NSTEMI.

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LMWHs have similar adverse effects, precautions and contraindications to UFH.

Fondaparinux (Arixtra)

A synthetic low molecular weight heparin (LMWH).

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Similar to “natural” LMWHs, tends to work on AT-III in such a way that there is more inactivation of factor X than inactivation of thrombin.

Fondaparinux (Use of Drug)

• Prophylaxis of DVT in patients undergoing hip fracture surgery, or hip or knee replacement, or abdominal surgery with risk of thromboembolic complications.

• acute PE or DVT.

Similar adverse effects, precautions and contraindications to other LMWHs.

Coumarin Anticoagulants

The only major coumarin anticoagulant in the USA is warfarin (Coumadin).

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As a side note, coumarins are the main active ingredient in many rodent poisons & is added to foods that are ingested by rodents, leading to death by hemorrhage or internal bleeding.

Warfarin (How to take?)

Excellent oral absorption – nearly 100% bioavailability.

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Extensively metabolized by the liver.

Onset of action is slower compared to heparin – minimum of 8-12 hours; may take up to 3-5 days to see maximal effect.

3-5 days is also required for clotting factor levels to return to normal after warfarin is discontinued (washout).

Warfarin (When to use the drug)

• Venous thrombosis.

• - PE

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Post-MI and post-op (e.g. – after cardiac, vascular surgery) patients to reduce risk of thromboembolic events such as stroke.

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For prevention of systemic thromboembolism in patients with prosthetic heart valves or atrial fibrillation.

Warfarin: How Does It Work?

Inhibits blood clotting mechanisms by interfering:

• Hepatic synthesis of the vitamin K-dependent clotting factors

• (II, VII, IX & X), whose carboxylation requires reduced vitamin K.

Monitoring Warfarin Therapy

The therapeutic range for oral anticoagulation therapy is defined in terms of the international normalized ratio (INR).

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For most patients, therapeutic levels of warfarin should be adjusted to achieve an INR of 2.0–3.0.

Warfarin Negative Side Effects

Bleeding is the most common side effect and occurs most often from the mucous membranes of the gastrointestinal tract and the genitourinary tract.

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Patients should be instructed to report any signs of bleeding, including nosebleeds, hematuria and bleeding into the skin (ecchymoses).

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Warfarin should never be used in pregnancy (category X under the old FDA pregnancy categories) because it crosses the placenta and is teratogenic (fetal warfarin syndrome).

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Breast feeding should also be avoided during warfarin therapy.

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Defects include malformation of ears and eyes, mental retardation and skeletal deformities.

Warfarin

Some of the more common agents that inhibit warfarin metabolism

(CYP450 inhibition):

Many antimicrobials afhgagafdgasg

Warfarin Key Drug interactions

Some of the more common agents that enhance the effects of warfarin, BUT NOT by inhibiting its metabolism:

• Synthetic thyroid hormones increase the catabolism of many clotting factors and can potentiate the effects of warfarin.

• 2nd and 3rd generation cephalosporins themselves inhibit the production of vitamin K-dependent clotting factors.

• Tetracyclines – mechanism unknown.

• SSRIs – mechanism unknown.

• Herbal products (ginkgo biloba, St. John’s wort, ginseng, echinacea, green tea) – mechanism unknown.

• Corticosteroids – mechanism unknown.

• Other anticoagulants or antiplatelets.

Key Drug-Drug Interactions

The following stimulate warfarin metabolism (CYP450 induction) and

may diminish the desired effects:

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• Griseofulvin

• Rifampin

• Anti-thyroid agents (methimazole, PTU)

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Oral contraceptives increase the synthesis of many clotting factors

and can reduce the effects of warfarin.

Warfarin (Drug-Food Interaction)

Interactions involving warfarin and foods rich in vitamin K result in decreased warfarin effects by stimulating the synthesis of vitamin K-dependent clotting factors.

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Often times, the "culprit" is green, leafy vegetables.

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It's not essential to avoid these, but rather to maintain consistent daily intake.

Phytonadione

Phytonadione (vitamin K1) directly antagonizes the effect of warfarin on clotting factor synthesis.

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It is used to treat:

• Severe hemorrhage caused by warfarin overdose

• Withholding warfarin or decreasing its dose.

Direct Thrombin Inhibitors

The first oral direct thrombin inhibitor came to market in 2010 → Dabigatran

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It offers an alternative to warfarin as an orally administered anticoagulant.

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It does not require frequent blood tests for INR.

Direct Thrombin Inhibitors (How it Works)

As the name implies, dabigatran does not work through AT-III (like heparin), but rather DIRECTLY inhibits thrombin

Dabigatran (Pharmacokinetics)

Converted to active dabigatran once in the body.

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Half-life → 12–13 hours, eliminated renally unchanged (this can be greatly prolonged in patients with renal impairment).

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Does not affect CYP450 enzymes.

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No drug-food interactions.

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3 dosage strengths: 75 mg, 110 mg and 150 mg.

Dabigatran (Used for …) (4)

• To reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

• For the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5–10 days.

• To reduce the risk of recurrence of DVT and PE in patients who have been previously treated with warfarin.

• For the prophylaxis of DVT and PE in patients who have undergone hip replacement surgery.

Bottom line → LOTS of patients are being started on dabigatran instead of warfarin.

Idarucizumab

In October 2015, the FDA approved idarucizumab , which is indicated for patients treated with dabigatran etexilate, when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding.

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• Idarucizumab binds directly to Dabigatran to inactivate it.

Dabigatran (Side Effects)

Increased risk of thrombotic events after premature discontinuation.

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Increases the risk of bleeding (just like other anticoagulants).

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GI complaints → dyspepsia and gastritis-like symptoms (including GERD, esophagitis and gastrointestinal ulcer).

Contraindicated in patients with active pathological bleeding.

Direct Active Factor X (Xa) Inhibitors (3)

• Rivaroxaban

• Apixaban (Eliquis).

• Edoxaban (Savaysa).

Direct Active Factor X (Xa) Inhibitors (How they are absorbed)

Well-absorbed from the intestine with 80–100% bioavailability.

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Metabolized by CYP3A4 enzymes in the liver.

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Metabolites excreted in the urine.

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No drug-food interactions.

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All are administered orally and do not require frequent blood tests for INR.

Indications – Rivaroxaban (Xarelto) and Apixaban (Eliquis)

To reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

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For the treatment of DVT, PE, and for the reduction in the risk of recurrence of DVT and PE.

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For the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

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Edoxaban is only indicated for the first condition on the list above.

Direct Active Factor X (Xa) Inhibitors (Side Effects)

Increased risk of bleeding (that has been the theme with all anticoagulants) → No specific antidote yet.

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Increased risk of thrombotic events after premature discontinuation.

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Use caution in those with hepatic or renal impairments.

Antiplatelets (3 Classes)

1) Cyclooxygenase Inhibitors (mainly aspirin)

2) Thienopyridines (ADP Inhibitors)

3) GP IIb/IIIa Inhibitors

Aspirin

Aspirin acts on platelets by inhibiting the synthesis of TXA₂, one of the substances that helps make the platelets sticky and more likely to aggregate.

• Low doses (81 mg; “baby” aspirin) achieve this effect, but the dose can be increased in certain patients.

• Unlike other NSAIDs, aspirin irreversibly inhibits cyclooxygenase (COX).

• For this reason, aspirin inhibits platelet aggregation for the life of the platelet and effectively reduces platelet aggregation when administered once a day or every other day.

Uses for Aspirin (5)

• To reduce risk of death after ischemic stroke or TIA.

• To reduce risk of vascular mortality in suspected acute MI.

• To reduce risk of death after MI or unstable angina pectoris.

• To reduce risk of MI or sudden death in chronic stable angina.

• Just prior to or following PTCA or CABG to reduce risk of thrombosis.

Aspirin → Side Effects

Can cause GI upset and/or bleeding

Monitor for signs of salicylism.

Effects of ASA can be potentiated (INCRESED) by anticoagulants or other antiplatelets.

Can increase risk of renal dysfunction.

ADP Inhibitors

These drugs act by preventing the binding of ADP to its

receptors (ADP-P2Y12 receptors) on platelets, thereby

inhibiting an important pathway that leads to platelet

aggregation

ADP Inhibitors (4 Examples)

1) Clopidogrel

2) Prasugrel

3) Ticagrelor

4) Ticlopidine (Least Used)

ADP Inhibitors (The blockage of ADP-P2Y12 receptors on platelets does 2 things:)

Reduces the “attraction” of platelets to the scene of the injury.

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Inhibits the expression of GP IIb/IIIa receptors

ADP Inhibitors (Used for …)

To reduce the rate of thrombotic events in patients with unstable angina, STEMI, Non-STEMI.

To reduce risk of stroke (clopidogrel and ticlopidine).

ADP inhibitors can be used in combination with ASA to enhance anti-platelet effects in some patients ….. but this can also enhance the risk of bleeding.

GP IIb/IIIa Inhibitors

This class of drugs inhibits the activation of glycoprotein IIb/IIIa receptors on platelets, thereby inhibiting the “final common pathway” for platelet aggregation (cross-linking of platelets by fibrinogen).

GP IIb/IIIa Inhibitors (3 Examples)

1. Abciximab – irreversible inhibitor

2. Tirofiban – reversible inhibitor

3. Eptifibatide – reversible inhibitor

GP IIb/IIIa Inhibitors (How to take the drug)

These agents are administered IV, typically with an initial bolus (loading dose)

followed by constant (maintenance) infusion.

Abciximab

FDA-approved medication for patients undergoing elective PTCA with a stent, or with unstable angina or non-STEMI.

It can be co-administered with ASA and UFH or LMWH in these settings.

It has also been used as an adjunct to thrombolysis with alteplase and other thrombolytics.

The most common adverse effect is bleeding.

Other adverse reactions include thrombocytopenia, hypotension, and bradycardia.

Eptifibatide

Eptifibatide → derived from southeastern pygmy rattlesnake (

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Tirofiban and eptifibatide are primarily used in patients with unstable angina and MI, often in combination with LMWH.

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They also are used to prevent thrombosis in persons having coronary angioplasty or stent placement for STEMI.

No surprise → Bleeding is the major adverse effect.

Tirofiban

Tirofiban → synthetic compound.

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Tirofiban and eptifibatide are primarily used in patients with unstable angina and MI, often in combination with LMWH.

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They also are used to prevent thrombosis in persons having coronary angioplasty or stent placement for STEMI.

No surprise → Bleeding is the major adverse effect.

Thrombolytics / Fibrinolytics

Thrombolytics rapidly lyse thrombi when administered intravenously (either as a bolus or infusion)

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by catalyzing the formation of plasmin from plasminogen.

Thrombolytics / Fibrinolytics (Three Examples)

• Streptokinase (from streptococci).

• Urokinase (from neonatal kidney cells).

• Synthetic (recombinant) tPA → alteplase , reteplase, tenecteplase.

Thrombolytics / Fibrinolytics (Uses)

Indications include acute MI, acute ischemic (thrombotic, not hemorrhagic) stroke and PE.

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For best results, thrombolytics work best the sooner they are initiated from the onset of the event …………

In the case of acute ischemic stroke:

• Within 3 hours: r-tPA → better functional recovery, but little/no effect on mortality.

• 3–4.5 hours: r-tPA → better functional recovery; effect on mortality is unclear.

• 4.5–6 hours: r-tPA → increased risk of death.

Recombinant tPA vs. Streptokinase/Urokinase

Lower incidence of allergic reaction.

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Recombinant tPA is “clot-specific” → it mainly activates plasminogen attached to fibrin (the clot) rather than free plasminogen.

• This causes less bleeding and greater restoration of blood flow.

• The major concern with all thrombolytics given systemically is the risk of major bleeding

Antifibrinolytics (1 example)

Anti-fibrinolytics promote clot formation and/or prevent excessive bleeding.

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Tranexamic acid prevents plasmin from binding to fibrin.

Uses:

• Dentistry: 5% mouth rinse after extractions/surgery in patients with prolonged bleeding.

• Oral OTC: Used for heavy menstrual bleeding.

Tranexamic Acid — Major Adverse Effect

Major adverse effect: Risk of thrombosis.

Use extra caution in women who:

• Use estrogen-based OCs.

• Smoke.

• Are obese.

Aminocaproic Acid — Mechanism & Uses

Aminocaproic acid prevents plasminogen → plasmin activation.

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Indicated to prevent bleeding in patients with:

• Hemophilia.

• Patients recovering from certain minor surgeries.

Can be administered IV or orally.

Aminocaproic Acid — Adverse Effects (3)

Major adverse effects:

• Thrombosis.

• Hypotension.

• Arrhythmias.

Where in the body does Warfarin Act

• The LIVER

What binds to Gllb/GPllla initially

Fibrinogen

What helps stimulate vasoconstriction

Norepinephrine

Why do you not inject low density heparin in the same spot

To prevent scar tissue & scar tissue buildup

If Blood is alkiline what process occurs

Monohexane Phosphate goes up