2.1 Pharm Exam2: Anticoagulants

Front 1

Hemostasis

Back 1

Cessation of blood loss from a damaged vessel

Front 2

Thrombosis

Back 2

Pathological formation of a "hemostaic plug"

Front 3

Thrombus

Back 3

A blood clot that forms in a vessel and stays there.
Arterial thrombus - consists mainly of platelets and leukocytes in a fibrin mesh
Venous thrombus - similar in composition to a blood clot, with a jelly-like red tail

*platelet rxns + blood coagulation= thrombus formation

Front 4

Embolism

Back 4

all or part of a thrombus that had become dislodged and moves to a distant site

Front 5

Fibrinolysis

Back 5

A normal body process that prevents blood coagulation from growing and causing problems.

Front 6

Coagulation:

Platelet Reactions lead to ........

What do they release?

Back 6

Generally lead to platelet activation & aggregation & stimulates blood coagulation

Release: ADP*, thromboxane A2*, Ca2+, platelet factors

Front 7

Coagulation:

Platelet activation exposes _____________, allowing platelets to interact with platelet factors

(necessary for the coagulation cascade to progress)

Back 7

acidic phospholipids

Front 8

Coagulation:

Blood coagulation occurs via the extrinsic (faster) & intrinsic (slower) pathways.

How does each begin?

What do BOTH lead to?

Back 8

Extrinsic pathway:
Begins with release of tissue factor & activation of factor VIIa and Ca2+

Intrinsic pathway:
Begins with activation of pro-enzymes (XII or XI) through contact with thrombin (or with glass in a laboratory)

*BOTH result in the proteolytic conversion of prothrombin to thrombin

Front 9

Coagulation:

The coagulation cascade begins w/ either the conversion of prothrombin to thrombin,

then thrombin converts soluble fibrinogen to ......

What does this lead to?

Back 9

Soluble fibrinogen--(thrombin)-->insoluble fibrin

--> fibrin precipitates & forms mesh network that collects aggregated platelets & forms a thrombus

Front 10

Coagulation:

The process of thrombus formation is highly regulated (to prevent too much clotting)

What occurs simultaneously?

Back 10

Antithrombin (a serine protease inhibitor) inactivates thrombin (factor IIa), IXa, and Xa

Aided by Protein C & S (other anticoagulants)

*clot degradation occurs w/ wound healing

Front 11

Coagulation:

what is Vitamin K necessary for?

When might it be deficient?

Back 11

Vitamin K must be converted from epoxide form back to a reactive hydroquinone

Required for the γ-carboxylation--> activation of coagulation factors II, VII, IX, & X in the liver

Vit K is fat soluble so it may be deficient in malnourished & cause excessive bleeding (dec coagulation)

Front 12

Three ways drugs affect hemostasis and thrombosis:

Back 12

- Blood coagulation (fibrin formation)
-- rarely to promote hemostasis, usually to prevent coagulation--> anti-caogulants

- Platelet function--> anti-platelets

--prevent platelet activation/aggregation

- Fibrin removal (fibrinolysis)--> fibrinolytics

--remove fibrin clots

Front 13

Anti-coagulant Drug Types

Back 13

Heparins (indirect thrombin inhibitors)

Vitamin K antagonists (oral)

Direct Thrombin inhibitors (dabigatran in oral)

Factor Xa Inhibitors (oral)

Front 14

Indirect thrombin Inhibitors: Heparins- Drugs

Back 14

Low-molecular-weight (LMW) heparin (Enoxaparin)

Unfractionated (UF) Heparin (Heparin sodium)

Fondaparinux (synthetic pentasaccharide)

Front 15

Heparins (sulfated mucopolysaccharides) are found in granules of basophils & mast cells

How do LMW & UF heparins differ?

Back 15

in molecular weight;

- UF heparin has a MW range of 5,000-30,000
- LMW heparin are enzymatically produced fragments of UFH, w an average MW of 6,000

Front 16

Heparin (indirect thrombin inhibitors): MOA

Back 16

- Heparin acts as a catalyst to Anti-thrombin

(enhances anti-thrombin activity 1000 fold)

-->binds anti-thrombin--> exposing motif that rapidly inactivates coagulation factors

- Anti-thrombin is a suicide inhibitor, forming a 1:1 complex with thromin & inactivating thrombin (& inactivating self in process)

*heparins do NOT have innate antithrombotic activity (do NOT interact directly w/ thrombin)

Front 17

Heparin:

How does LMW & UF heparin differ in MOA

Back 17

-LMW heparin inactivates factor Xa ONLY

(shorter, lacks binding motif for other factors)

-UF heparin inactivates coagulation factors IIa (thrombin), IXa, & Xa

(UF and LMW heparin ar extracted from beef lung, or hog intestine)

Front 18

Heparin: Therapeutic uses

Back 18

-Initiate treatment of venous thrombosis & pulmonary embolism (Oral anticoagulant is initiated concurrently)
-Thrombosis on prosthetic heart valves
-Thrombosis & embolization in patients with atrial fibrillation
-Myocardial infarction in patients with unstable angina

Front 19

Heparin: Pharmacokinetics

Back 19

(all heparins have equal efficacy)
UFH:
- IV admin is more rapid & predictable, but maintenance doses may be given subcutaneously-but absorption variable (no IM)
- Dosing based on weight is most effective
LMWH:
- Subcutaneous absorption more predictable than for UFH

BEST (easiest, most predictable)

Metabolism
- Cleared by reticuloendothelial system (liver), some active heparin is excreted in the urine

Front 20

Heparin: Toxicity (side effects)

Back 20

-Bleeding = The major adverse effect
^ Minimized ww tight control of dosage, patient selection (recent surgery, peptic ulcer,elderly, renal failure most prone to hemorrhage), & monitoring

-Allergic reaction due to animal origin of heparin preparations (cow & pig)

-Osteoporosis

-Heparin-induced thrombocytopenia (HIT)

Front 21

What is Heparin Induced Thrombocytopenia (HIT)?

Back 21

- Rare but serious increased risk for thrombosis due to the formation of antibodies to heparin and platelet factor 4

(Generally occurs 2-14 days after beginning therapy – usually with UF Heparin)

- Observed as decreased platelet counts, may lead to thrombosis

Front 22

Heparin: Treating Overdose

Back 22

- IV injection of protamine which forms a stable, inert complex

- calculate amount of protamine based on the dose of heparin

Front 23

Heparin: Contraindications

Back 23

- Hypersensitivity to LMWH or UFH
- Allergy (hypersensitivity) to beef /pork products

- Hypersensitivity to methylparaben
- History of HIT

Front 24

Direct thrombin inhibitors- Drugs

Back 24

-Hirudin (isolate from leach saliva)

Recombinant hirudin- Bivalents:

-Lepirudin
-Bivalirudin (semisynthetic)

Synthetic- Monovalents:

-Argatroban

-Dabigatran etexilate (oral)

Front 25

Direct Thrombin Inhibitors: MOA

Back 25

* interact DIRECTLY w thrombin

Bivalent Agents: Lepirudin & Bivalirudin
- Binds both substrate recognition & catalytic site of thrombin (factor IIa) to inhibit the coagulation cascade

Monovalent Agents: Argatroban & Dabigatran
- Binds to & blocks the catalytic site on thrombin

-Dabigatran speficially inhibits Factor IIa (thrombin)

Front 26

Direct Thrombin Inhibitors: Adverse effects & contraindications

Back 26

Hemorrhage – most serious/common

Gi bleeding & dyspepsia (Dabigatran)

Lepirudin – contraindicated in renal insufficiency
Argatroban – contraindicated in hepatic insufficiency

Dabigatran- contraindicated in pregnancy & A fib w/ artificial valves, p-glycoprotein inducers (rifampin) (dec exposure) & renal dysfunction(GFR > 30) (toxicity)

Front 27

Direct thrombin Inhibitors: Therapeutic use

Back 27

Primary use is treatment of HIT

Dabigatran- reduce stroke in patients w/ non-valvular atrial fibrilation, prevent DVT in hip & knee replacement

(Drug selection often based on presence of renal/hepatic insufficiency)

Front 28

Factor Xa inhibitors (oral) Drugs

Back 28

Rivaroxaban

Apixaban

Front 29

Rivaroxaban (factor Xa inhibitor):

toxicity & contraindications

Back 29

toxicity:

bleeding

epidural or spinal hematoma--> paralysis

contraindications:

pregnancy (class C)

renal or hepatic dysfunction (toxicity)

CYP3A4 inhibitor

neuraxial anethesia or spinal puncture**

-->hematoma --> paralysis

Front 30

Rivaroxaban therapeutic use

Back 30

-prevention of DVT in hip or knee replacement

Front 31

Apixaban (factor Xa inhibitor): therapeutic use

Back 31

-DVT & pulmonary embolism treatment

*less adverse side effects than rivaroxaban (mostly bleeding), in both you should adjust dose for renal impairments & not use in combo w other CYP3A4 inhibitors

Front 32

Vitamin K antagonists:

Oral Agents (drugs)

Back 32

Warfarin (Coumadin – generics)

(Wisconsin Alumni Research Foundation + “arin”) – bishydroxycoumarin

Front 33

Warfarin: Pharmacokinetics

Back 33

- Isolated from spoiled sweet clover silage
- 100% bioavailability, over 99% is bound to plasma albumin (high toxicity)
- Effects delayed 12-16 hours no effect on circulating clotting factors
- Full clotting effect not seen for 8-16 days
- t½ is 36 hours

Front 34

Warfarin: MOA

Back 34

Warfarin inhibits hydroxylation of Vit K-->

Vit K necessary for y-carboxyylation-->
Blocks γ-carboxylation of glutamate residues in prothrombin, factors VII, IX, & X-->

Prevents activation of coagulation factors (remain biologically inactive)

Front 35

Warfarin: Toxicity

Back 35

- Hemorrhage of the bowel or brain

(main adverse effect)

-Purple toe syndrome:

painful discoloration of toe due to cholesterol

- Significant interpatient variability in toxicity
- Correct dosing requires continual monitoring

Contraindicated in Pregnancy:
- Freely crosses the placenta to cause birth defects

Front 36

Warfarin: Drug Interactions

Back 36

Drug interactions
- Certain drugs decrease metabolism of warfarin and lead to increased risk of bleeding (pharmacokinetic interactions)

- Other factors such as asprin or hyperthyroidism may increase the risk of bleeding through altered pharmacodynamic effects

Altered vitamin K intake (diet or through antibiotics)
- Green tea, broccoli, liver are high in vitamin K

**Reversal of warfarin actions may be accomplished by administering vitamin K or Kcentra

Front 37

Clinical Use: Warfarin, Heparin (anti-coagulants)

Back 37

Heparin is used acutely, warfarin is used for prolonged therapy
Anticoagulants are used to prevent:
- Deep vein thrombosis
- Pulmonary embolus
- Thrombosis and embolisation in patients with atrial fibrillation
- Thrombosis on prosthetic heart valves
- Clotting in extracorporeal circulations (e.g. during hemodialysis)
- Myocardial infarction in patients with unstable angina

Front 38

Contraindications to anticoagulation therapy

Back 38

General
- Active bleeding
- Hemophilia
- Severe liver disease
- Severe thrombocytopenia
- Inability to meticulously supervise and monitor treatment
Heparin
- History or suspected HIT
Warfarin
- Pregnancy

Front 39

Fibrinolysis (Thrombolysis)

Back 39

Fibrinolysis system
- Activated along with the coagulation cascade
- Plasminogen activators – convert plasminogen to plasmin
- Tissue plasminogen activator (tPA)
- Urokinase-type plasminogen activator
- Kallikrein, neutrophil elastase

Plasminogen is deposited along with fibrin in the thrombus, activities are localized to the clot

Front 40

Fibrinolytic Drugs: MOA

Back 40

Enzymatically convert plasminogen to plasmin
*increase half life of enzyme

All have similar efficacy

Front 41

Contraindications to Thromblytic Therapy

Back 41

- Surgery within last 10 days
- Serious GI bleeding w/in 3 months
- History of hypertension
- Active bleeding or hemorrhagic disorder
- Previous cerebrovascular accident or active intracranial process
- Aortic dissection
- Acute pericarditis

Front 42

Fibrinolytic Drugs: Therapeutic Uses

Back 42

Therapeutic Uses – time is critical element
- Pulmonary embolism with hemodynamic instability
- Severe deep venous thrombosis
- Ischemic stroke – tPAs (use w/i 3 hrs)
-- AHA recommends fibrin-specific over nonspecific agents
- Acute myocardial infarction (20% reduction in mortality)
- The choice- the recombinant proteins are expensive (>12x the cost of streptokinase)

Front 43

Fibrinolytic Drugs: Side Effects

Back 43

- Hemorrhage due to the lysis of fibrin in “physiological thrombi”

Front 44

Resting platelet state:

Back 44

Resting platelets
- Intact endothelial cells release substances that inhibit platelet activation (NO, prostaglandin I2)
- Activation of the prostacyclin receptor by PGI2, a Gs-coupled receptor --> ↑ cAMP and decreased release of Ca2+ from the ER
- The GP IIb and IIIa receptors inactive (unable to bind fibrinogen)

Front 45

Injured endothelium platelet state:

Back 45

- Injury to the endothelium the underlying basal lamina is exposed to the blood stream, and decreased PGI2 release  ↓ cAMP and release of Ca2+ from the ER
- Activation of platelets begins, subsequent interaction of GPIa/IIa receptors with collagen initiate intracellular activity.
- Activation of COX-1 leading to production and release of TxA2, ADP, Ca2+, and other molecules involved in coagulation.

--> Formation of bonds btwn GPIIB/IIIa & fibrinogen necessary for platelet aggregation

-->thrombus formation

Front 46

Autocrine and paracine actions that lead to platelet aggregation

Back 46

Autocrine and paracrine actions of ADP further stimulate the activation of GPIIb/IIIa by inducing a conformational change-->

(ADP is one of the most important signaling

molecules leading to platelet aggregation)

ADP Stimulates the P2Y12 receptor-Gi-coupled

-->↓ cAMP
(mainly found on platelets)

Front 47

Antiplatelet Agents: Aspirin MOA

Back 47

Mechanism of action
- Thromboxane A2 is a platelet product that causes platelets to change shape, release granules and aggregate
- Aspirin irreversibly acetylates the active site of COX1, preventing the formation of a precursor of thromboxane A2 production
- The inhibition of COX1 is irreversible and results in permanent inhibition in each platelet because the COX1 enzyme cannot be regenerated

Front 48

Aspirin: Therapeutic Use

Back 48

Therapeutic Use
- Prevention of myocardial infarction Decreases “stickiness” of platelets
- Transient cerebral ischemia
- May be combined with other anticlotting drugs to increase benefits different MOA

Front 49

Aspirin: Adverse Effects

Back 49

Bleeding, salicylism – generally with larger doses than used for this indication

Front 50

Antiplatelet Agents – 
ADP antagonists

Back 50

Clopidogrel (Plavix®)

Ticagrelor
Prasugrel (Effient®)

Front 51

Antiplatelet Agents – 
ADP antagonists: MOA

Back 51

Mechanism of Action
- Irreversibly bind to and inhibit (non-competitive antagonists) the P2Y12 receptor (Gi-coupled), the receptor for ADP release from the platelet
- Receptor blockade prevents platelet aggregation

Front 52

Antiplatelet Agents – 
ADP antagonists: Therapeutic Use

Back 52

- Used alone or in combination with aspirin (synergistic effect)
- Clopidogrel
-- Reduce the rate of stroke and MI in individuals with recent MI, peripheral artery disease or acute coronary syndrome
- Prasugrel approved to reduce risk of heart attack following angioplasty
-- Higher incidence of stroke in those that have had a stroke previously

Front 53

Antiplatelet Agents: Vorapaxar

MOA

contraindication

Back 53

MOA:

blocks PAR1 receptor tail on platelet from being cleaved & activated by thrombin---> preventing platelet activation

contraindication:

pt w history of stroke, TIA, ICH

Front 54

Antiplatelet Agents – 
ADP antagonists: Adverse Effects

Back 54

-Bleeding
- Thrombotic thrombocytopenic purpura

Front 55

Antiplatelet Agents – 
Gycoprotein IIB/IIIA Receptor Blockade

Back 55

Abciximab (ReoPro®) – Humanized monoclonal antibody that binds glycoprotein IIb/IIIa
Eptifibadine (Integrilin®) – Antagonist of glycoprotein IIb/IIIa
Tirofiban (Aggrastat®) – Antagonist of glycoprotein IIb/IIIa

Front 56

Antiplatelet Agents – 
Gycoprotein IIB/IIIA Receptor Blockade: MOA

Back 56

prevent interaction of the glycoprotein IIB/IIIA to fibrinogen-->
prevents platelet aggregation

Front 57

Antiplatelet Agents – 
Gycoprotein IIB/IIIA Receptor Blockade: Therapeutic Uses

Back 57

Acute coronary syndromes

Front 58

Antiplatelet Agents – 
Gycoprotein IIB/IIIA Receptor Blockade: Adverse Effects

Back 58

Bleeding

Front 59

Treatment of Bleeding Disorders: Hereditary

Back 59

Hereditary clotting defects
- Lack of factor VIII, IX, others.
- Missing factors can be supplied by fresh or concentrated plasma preparations
-- Potential for transmission of disease
-- Recombinant factors are now available, but expensive

Front 60

Treatment of Bleeding Disorders: Acquired

Back 60

- more common, esp in hospitals

- Liver disease, vitamin K deficiency, excessive oral anticoagulant therapy (anything reduce fat soluble vit--> K)

-Digestive disorders

TX:
-- May require vitamin K replacement
-- Replacement may be administered orally or parenterally
-- Commonly administered to newborns & premis to prevent the hemorrhagic disease of vitamin K deficiency