Term 2 Pharm - Anti-Coagulation Drugs Flashcards
(47 cards)
1
Q
What are the major adverse effects of anti-coagulants?
A
- Major adverse effect is bleeding (frequently life-threatening or fatal)
- Account for the highest number of adverse events of all drug classes
- But they are still lifesaving
2
Q
What are the Anti-platelet agents?
A
- Cyclooxygenase inihibitors
- ADP-receptor inhibitors
- GPIIb/IIIa antagonists
3
Q
What are the Anticoagulants?
A
- Heparin
- Vitamin K antagonists
- Parenteral direct thrombin inhibitors
- Target specific oral agents (TSOACs)
4
Q
What causes Thrombosis?
A
Thrombosis occurs when there is a breakdown in the balance between thrombogenic factors and protective mechanisms
5
Q
What are common Thrombogenic Factors?
A
- Endothelial cell disruption
- Activation of platelets
- Activation of blood
- coagulation
- Inhibition of fibrinolysis
- Stasis
6
Q
What are some Protective Mechanisms against thrombosis?
A
- Intact endothelium
- Neutralization of coag factors by endogenous - factors
- Dilution of clotting factors by blood flow
- Clearance of activated factors by the liver
- Fibrinolysis
7
Q
Definition of a Thrombus
A
Thrombus = Blood Cells + Fibrin Clot
8
Q
Definition of an Embolus
A
Embolus = Thrombus far from home (Thrombus = Blood Cells + Fibrin Clot)
9
Q
Arterial Thrombus
A
- Occurs in association with pre-existing vascular disease, e.g., atherosclerosis in areas of disturbed flow
- Occurs under conditions of high flow
- Predominantly platelet aggregates bound by fibrin strands
- Causes tissue ischemia by obstructing flow or embolizing to distal circulation
*Arterial clots are usually formed by vascular damage
10
Q
Venous
A
- Generally lower limbs; other sites especially with associated thrombophilia
- Occurs under conditions of low flow, stasis
- Composed of red cells and fibrin with relatively fewer platelets
- Obstruct venous return; venous inflammation; pulmonary emboli
*Venous clots are usually formed by stasis
11
Q
Common Indications for Anticoagulation
A
Primary prevention of thrombosis (Venous) - Hospitalization - Surgery - Immobilization - Cancer
(Arterial)
- Stroke in atrial fibrillation
- Myocardial infarction
- Mechanical heart valves
- Peripheral arterial occlusion
Secondary prevention
Treatment of acute thrombosis
Choice of agent depends on mechanism of thrombosis
12
Q
Type of anti-coag depends on venous or arterial thrombosis, explain…
A
For Arterial – anti-platelets
For Venous – down regulation of coag
13
Q
Describe Primary Hemostasis (Primary Hemostatic Plug)
A
- Platelet Adhesion
- To sub endothelium
- Via collagen – vWF – platelet receptor GpIb - Activation/degranulation/shape change
- Collagen
- Soluble agonists - Aggregation
- Via fibrinogen -platelet receptor GpIIb/IIIa - Support of coagulation
- Exposure of PS/PE
14
Q
Anti-Platelet Agents
A
Agents
- COX inhibitors
- ADP P2Y12 receptor antagonists
- Clopidogrel
- Prasugrel
- Ticagrelor
- Dipyridimole
Indicated for prevention of arterial thrombosis
Prolong bleeding time/PFA-100
15
Q
Acetylsalicylic Acid (Aspirin: ASA)
A
- Aspirin inhibits platelet aggregation by irreversible
acetylation of platelet cyclo-oxygenase (COX) - Aspirin prevents formation of thromboxane A2 and therefore inhibits TXA2 mediated platelet aggregation
- Rapid absorption, peak platelet effect at 1 hour (3-4 hours for enteric coated)
- Half-life is 15-20 minutes BUT effect on platelets is IRREVERSIBLE
(Lasts for entire 7-10 day lifespan of platelets. 10-15% of circulating platelets are replaced every 24 hours. Must discontinue the drug 10 days in advance of invasive procedures for complete restoration of normal platelet function) - No effect on platelet adhesion
16
Q
Aspirin Adverse Effects
A
B/c irreversible COX (cyclooxygenase) inhibitor
inhibitor!
- Major side effects are gastrointestinal and are dose-related
(GI upset, ulcer, bleed) - Not associated with major bleeding in patients with normal baseline hemostasis
- Bleeding is increased with concurrent use of anticoagulants, some supplements
- Exacerbates bleeding tendency in patient with bleeding disorders (be careful for surgery)
- Elderly are more susceptible
17
Q
Reversible COX Inhibitors
A
- Nonsteroidal anti-inflammatory agents
(Ibuprofen)
(Naproxen) - Reversible inhibition of COX
- Platelet function is restored when the drug is cleared
For ibuprofen
- Rapid absorption of oral dose; peak effect 1-2 hours
- Half-life is ~2 hours
- Essentially all of the drug is excreted (urine) 24 hours after the last dose
- Holding the drug for 1-2 days preoperatively is sufficient
For naproxen
- Half life is 12-17 hours
- Must discontinue several days before surgery
18
Q
Uses for Aspirin as an Antithrombotic Agent
A
- Primary and secondary prevention of arterial thrombosis
- Inferior to anticoagulants for stroke prevention in atrial fibrillation, mechanical heart valves
- Reduces disorders associated with placental insufficiency (e.g., preeclampsia)
- Efficacious for prevention of venous thromboembolism in limited situations (e.g., hip fracture surgery)
19
Q
(ADP) P2Y12 Receptor Antagonists
A
Examples
- Thienopyridines = They Inhibit ADP-induced platelet aggregation via irreversible (but partial) alterations of ADP receptor P2Y12
(Clopidogrel)
(Prasugrel)
- Ticagrelor
(First cyclopentyl-triazolopyrimidine)
(First reversible oral antagonist of ADP receptor P2Y12) - Cangrelor (IV)
Defects in platelet P2Y12 receptor are associated with bleeding disorders
20
Q
Clopidogrel
Type of thienopyridines = They Inhibit ADP-induced platelet aggregation via irreversible (but partial) alterations of ADP
A
Rapidly absorbed and metabolized to SR 26334
- Processed by CYP3A4***
- Metabolism inhibited by concurrent use of atorvastatin
- Maximum inhibition of platelet aggregation by 4-6 hours after oral dose
- Plasma elimination half-life 8 hours
- Steady state platelet inhibition (50-60% inhibition) achieved by 4-7 days
- Individual response is variable; some are resistant to anti-platelet effects
Uses of clopidogrel
- Secondary prevention of arterial thrombosis
- Prevention of coronary stent thrombosis (with aspirin)
Adverse effects
- Similar to aspirin with respect to bleeding
- Increased bleeding complications when both aspirin and clopidogrel are used together
- Thrombotic thrombocytopenic purpura (TTP)
- Rash and diarrhea
21
Q
Prasugrel
Type of thienopyridines = They Inhibit ADP-induced platelet aggregation via irreversible (but partial) alterations of ADP
A
Orally administered prodrug
- Rapidly absorbed; requires activation by enzymatic metabolism (predominantly CYP3A & CYP2B6)
- Peak effect 1-2 hours after oral dose; elimination half life ~7 hours
- Steady state platelet inhibition (70% inhibition) achieved by 3-5 days
- Little resistance reported
Uses of prasugrel
- Management of acute coronary syndromes with percutaneous coronary interventions
- Prevention of coronary stent thrombosis (with aspirin)
Adverse effects
- Similar to aspirin, clopidogrel with respect to bleeding
- Increased bleeding when aspirin & prasugrel are used together
- Increased risk of stroke (both hemorrhagic and ischemic)
- Contraindicated in patients with history of TIA or stroke
TTP is class effect
22
Q
Ticagrelor
A
Reversible P2Y12 receptor antagonist
- Rapidly absorbed; active metabolite generated by CYP3A4 but parent drug active also
- Peak effect 2 hours after oral dose; elimination half life 7-9 hours
- Steady state platelet inhibition achieved by 3-5 days
- Resistance not expected because it is active as parent drug
Uses of ticagrelor
- Prevention of thrombotic cardiovascular events in patients with acute coronary syndromes
Adverse effects
- Similar to other antiplatelet agents with respect to bleeding
- Dyspnea & bradycardia (similar structurally to adenosine)
- Gynecomastia in men
(First cyclopentyl-triazolopyrimidine)
(First reversible oral antagonist of ADP receptor P2Y1
23
Q
Selection of an Oral Anti-Platelet Agent
A
1st line = Aspirin
- Coronary artery disease/angina/MI
- Thrombotic stroke/Transient cerebral ischemia
- Peripheral arterial disease
- Added to warfarin in patients with prosthetic heart valves who develop systemic embolism on warfarin alone
- Atrial fibrillation in patients with contraindication to warfarin, TSOACs
2nd line = Clopidogrel (ADP antagonists)
- Transient cerebral ischemia
- Prevention of arterial thrombosis where aspirin contraindicated
- With aspirin for coronary stent thromboprophylaxis
- Recurrent arterial thromboembolism despite treatment with aspirin
Acute coronary syndromes = Prasugrel, Ticagrelor
24
Q
How does Heparin work?
A
Heparin works through anti-thrombin (accelerates its inhibition of factors 10a and 2a)
- Highly sulfated family of glycosaminoglycans
- Found in all animals above the horseshoe crab
- Produced by mast cells
- Extracted from beef or porcine gut or lung
- 1 billion pigs per year worldwide
- Accelerates inhibition coagulation factors by antithrombin
25
Heparin Pharmacology
(Bioavailability by route of administration)
- Intravenous: 100% bioavailable; anticoagulant effect is immediate
- Much individual variation in bioavailability
- Binds widely to plasma proteins
- Ineffectiveness of fixed dose
- Heparin resistance
(Subcutaneous)
- Poor bioavailability
- Acceptable anticoagulant effect 1-3 hours after injection
- Must use higher doses than IV
- Less frequent dosing
Oral: NO; Zero bioavailability
Intramuscular: NO; Risk for hematoma
Does not cross the placenta and is anticoagulant of choice in pregnancy
26
Heparin Clearance
Complicated, nonlinear pharmacokinetics
Two phases:
(Initial - rapid)
- Binds to receptors on endothelial cells and macrophages where it is internalized and metabolized to smaller forms
- Binds to plasma proteins
(Second - slow)
- Renal
Half life is dose-dependent
25 U/kg 30 min
100 U/kg 60 min
400 U/kg 150 min
27
Heparin Dosing
Two general dosing regimens
(“Mini” dose)
- Subcutaneous
- Generally used for thromboprophylaxis
- 5000 units, two to three times per day
- No lab monitoring
(Therapeutic, adjusted “full” dose)
- Intravenous
- Bolus dose followed by
- Continuous infusion; dose adjusted according to effect on aPTT (goal 80 – 114 sec)
- Generally used for treatment of acute thrombosis
- Dose adjustments made after 4 to 6 hours at steady state
28
Side Effects of Heparin
Bleeding
- Occurs in up to 21% of patients receiving full dose heparin
- Most is minor; major bleeding is dose dependent
- Beware other risk factors for bleeding (including concomitant antithrombotic agents)
Osteoporosis
- Greatest risk at > 3 months of treatment
- Mechanism unknown; may affect osteoclasts or vit D metabolism
Skin lesions
- Urticaria
- Papules and plaques
- Necrosis (immune mediated)
Hypoaldosteronism
- Interferes with biosynthesis of aldosterone
- Rare, usually not clinically important; hyperkalemia reported
29
Heparin Induced Thrombocytopenia
| Type II HIT
Immune-mediated
- IgG directed against heparin/PF4 antigen on platelet surface
Occurs within 5-15 days of initiation of therapy
- May occur earlier if previous heparin exposure within the last 3 mo (due to pre-existing IgG rather than amnestic response)
Thrombocytopenia generally modest
- Median platelet nadir ~50,000/uL
- Typical range 25-100K (Contrast to ITP or other drug induced thrombocytopenias which tend to have lower nadirs, typically 20K)
- Platelet count may be “normal” (e.g., 50% drop within normal range)
Highly thrombotic state: arterial or venous thrombosis in 50%
- Bleeding uncommon
Diagnosis is best made on clinical grounds
- Sensitive antibody test is available (but not specific; many false +)
*Heparin binds to PF4 triggers production of IgG causes activation of platelets --> 2 things: 1) generation of a potent hypercoaguable state/induced coagualtion + 2) triggers clearing of platelets by reticular endothelial system --> Heparin Induced Thrombocytopenia
30
Unfractioned Heparin vs Fractioned Heparin
Unfractioned Heparin binds to plasma proteins but fractioned (or low molecular weight heparin) does not bind to plasma proteins (almost 100% bioavailability & reliable… and this takes out initial 1st phase or normal heparin)
31
Low Molecular Weight Heparins
Peak anticoagulant effect 4-6 hours after dose
FDA approved
- Dalteparin
- Enoxaparin
- Tinzaparin
- Fondaparinux
Advantages over unfractionated heparin
- Fixed, weight-based dose (subcutaneous administration)
- Allows for self injection at home
- No routine laboratory monitoring required in majority of cases
- More predictable anticoagulant response
- Less HIT
Disadvantages
- Long half life may be a problem in bleeding patients as there is no good antidote
- Renal excretion makes use in renal insufficiency difficult
32
Indications for Heparins/Low Molecular Weight Heparins
Primary prevention of venous and arterial thrombosis
“Treatment” of acute venous and arterial thrombosis
- Treatment is misnomer
- Heparin does not degrade thrombus
- Heparin prevents thrombus propagation and new clot formation while endogenous fibrinolytic system hydrolyzes established clot
- “Treatment” is therefore more appropriately described as secondary prophylaxis
33
Reversing Heparin Effect
- Short half life allows discontinuation shortly before invasive procedures
- In severe bleeding, treat with protamine sulfate
- Protamine sulfate is an anticoagulant so overdose will exacerbate bleeding
- Minimally effective for reversing LMWH effect
- Ineffective for reversing fondaparinux (= REALY low weight synthetic heparin)
34
How does Warfarin work?
Brand name COUMADIN
Warfarin is a vitamin K antagonist (inhibits activation of factors 2,7,9,10)
Moldy silage made from sweet clover hay contained a potent anticoagulant
Anticoagulant later identified as dicoumarol, a member of coumarin family of compounds
Warfarin prolongs the PT and aPTT
- Dose is adjusted according to effect on PT/INR
Goal for most indications: INR 2.5, range 2.0 - 3.0
Some heart valves have higher target INR
35
Warfarin Mechanism of Action
- Warfarin is a vitamin K antagonist
- Vitamin K is required as a cofactor in the pathway that effects gamma carboxylation on coagulation factors II, VII, IX and X
- Gamma carboxylation is required for coagulation factor binding to phospholipid surfaces
- Gamma carboxylation is also required for activity of the endogenous anticoagulants protein C, protein S and protein Z
- WARFARIN INHIBITS THE SYNTHESIS OF ACTIVE COAGULATION FACTORS (inhibits epoxide reductase)
- Distinguish from heparin, which inhibits activity of preformed coagulation factors
36
Warfarin Pharmacology
Oral dose is rapidly and extensively absorbed from the GI tract
Peak levels reached in 90 minutes after ingestion
Food slows absorption, but does not alter bioavailability
Extensively protein-bound in plasma, especially to albumin
Crosses the placenta; active form does not enter breast milk
Metabolized in liver by cytochrome P450 enzyme pathways
Metabolites excreted in urine
2% of warfarin excreted unchanged in urine
Warfarin clearance declines with age
Clearance of active drug NOT affected by renal dysfunction, but clearance is increased in patients on dialysis
Genetic polymorphisms affect warfarin metabolism and dosing
Half-life is approximately 33 hours
Steady state anticoagulation is reached in 7-10 days
NOT good for acute use (start with Heparin and then continue with Warfarin)
Slow onset of action usually demands that warfarin be started concurrently with a fast-acting anticoagulant (e.g., heparin, LMWH)
Important to overlap heparin and warfarin by two days once therapeutic INR achieved
37
Conditions that Alter Warfarin Effect on Anticoagulation
Medications
- Drug interactions are many
Foods rich in vitamin K
- Vegetables, especially leafy greens; also green tea leaves
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Medical conditions
- Liver disease
- CHF
- Malnutrition
- Hypermetabolic states
(Fever)
(Hyperthyroidism)
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Warfarin resistance
- Gastric bypass surgery
- Pharmacogenetics
38
After Initiation of Warfarin Therapy
Anticoagulant effect parallels decrease in active coagulation factors, which are cleared from plasma according to well defined half-lives
- PT/INR effect depends on clearance of factor VII, which has the shortest half life
- Anticoagulant effect depends on clearance of factors IIa and Xa
- Can induce transient hypercoagulable state
39
Indications for Warfarin
Primary and secondary prevention of venous thromboembolism
Primary and secondary prevention of arterial thrombosis in some circumstances
- Stroke prevention in atrial fibrillation, mechanical heart valves
- Failure of antiplatelet therapy
- In addition to antiplatelet therapy in high risk patients
40
Warfarin Side Effects
Bleeding
- Related to intensity of anticoagulation; elderly more prone
- Especially likely to happen in patient on stable dose whose clinical situation changes
Skin necrosis
- Generally occurs between day 3 and 8 of therapy
- Thrombosis of venules & capillaries in subcutaneous fat
- Pathogenesis unknown; related to transient hypercoagulable state at initiation of therapy
- Protein C and protein S deficiencies pre-dispose; also occurs in patients without risk factors
Teratogenic during early fetal development
41
Reversing Warfarin Effect
Vitamin K
- Oral dose ranging from 2.5 to 10 mg depending on degree of reversal required
- Effect seen within hours
- Reversal of rodenticide effect requires months of treatment
Fresh frozen plasma
- Contains coagulation factors
- Used when immediate reversal of anticoagulation is needed (e.g., life-threatening bleeding or immediate surgery)
- Short duration of action due to short half-life of factor VII
- Administer vitamin K concomitantly
Prothrombin complex concentrates
- Plasma-derived concentrates containing vitamin K dependent factors
- Used when immediate reversal required
42
Parenteral Direct Thrombin Inhibitors
Used when heparins are contraindicated (HIT)
Two IV forms are currently available in the US
- Argatroban (small molecule); hepatic clearance
- Bivalirudin (peptide)
Mechanism of action
- Bind and inactivate thrombin
Administered by continuous IV infusion
No antidote but short half-lives (~0.5 – 2 hours)
Will prolong both PT and aPTT but anticoagulant effect monitored by aPTT prolongation
Argatroban approved for rx and prevention of thrombosis in HIT
Bivalirudin & argatroban approved for anticoagulation during percutaneous coronary interventions in patients with HIT
Argatroban is main drug used for replacement of heparin when heparin induced thrombocytopenia occurs(monitor use by aPTT)… not for primary use b/c hella expensive
43
Target Specific Oral Anticoagulants
- Dabigatran (Pradaxa):
- Rivaroxaban (Xarelto):
- Apixaban (Eliquis):
Target Specific Oral Anticoagulants
- Dabigatran (Pradaxa): Thrombin (IIa)
- Rivaroxaban (Xarelto): Xa
- Apixaban (Eliquis): Xa
44
Dabigatran
Inhibits thrombin directly
Oral prodrug rapidly converted to active drug by liver
- Does not involve cytochrome p450 system
Peak level at ~2 hours after ingestion
Half-life 14-17 hours after reaching steady state
Bioavailability ~7%
Active drug cleared predominantly by renal excretion
- Dose reduction in moderate renal dysfunction
- Do not use in severe renal dysfunction
Few drug, food interactions
- Verapamil, quinidine
No laboratory monitoring
- Prolongs thrombin time and aPTT to lesser extent
New antidote approved
Side effects
- Bleeding
- Gastrointestinal
Approved for stroke prevention in atrial fibrillation, acute VTE rx
45
Rivaroxaban
Inhibits activated factor X (Xa) directly
Peak level at ~3 hours after ingestion
Half-life 4-9 hours after reaching steady state (longer in elderly)
Bioavailability 80-100%
Active drug metabolized by CYP3A4
- Concurrent use with inhibitors increased drug exposure
(Ritonavir, clarithromycin, erythromycin, ketoconazole)
- Concurrent use with inducers decreased drug exposure
Active drug cleared predominantly by renal excretion
- Dose reduction in moderate renal dysfunction
- Do not use in severe renal dysfunction
No significant food interactions
No laboratory monitoring
- Prolongs prothrombin time
No antidote
Side effects
- Bleeding
Approved for prevention, treatment of acute VTE & stroke prevention in atrial fibrillation
46
Fibrinolytic Agents
“Clot buster” drugs
Anticoagulant and antiplatelet agents prevent thrombus formation and extension
Fibrinolytic agents break down thrombi
Mechanisms of action
- Convert plasminogen to plasmin which degrades fibrin
(Recombinant tissue plasminogen activator... rTPA; Alteplase)
(Urokinase plasminogen activator)
- Binds to plasminogen and the complex degrades fibrin
(Streptokinase)
Uses
- Acute ischemic stroke, coronary or peripheral arterial occlusion
- Massive pulmonary embolism, extensive iliofemoral DVT
- Clear occluded central venous catheters
Major adverse event is bleeding
47
Herbs/Supplements/Others for Anticoagulation
```
- Selective serotonin reuptake inhibitors (SSRI)
(Increased GI bleeding in combination with NSAID, anticoagulants)
- Feverfew/willow bark – contain salicin
- Gingko
- Garlic
- Ginger
- Fish oil
- PC-SPES
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