1. Anticoagulant Drugs Dr. : Asmaa Fady MD., MSC, M.B, B.Ch
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2. Learning Objectives:
To describe different classes of anticoagulant drugs and their mechanism of action
To explain the pharmacological effects, pharmacokinetics, clinical uses and adverse effects of anticoagulant drugs
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3. Definition & target of anticoagulants:
An anticoagulant is substance that prevents coagulation or clotting of blood via its action on clotting factor.
Uses:
Storage of blood for blood transfusion or hematological testing
Therapeutic uses (venous thrombi).
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4. Indirect thrombin inhibitors Direct thrombin inhibitors DTIs
Anticoagulant drugs are classified according to the method of administration into
Anticoagulants
Parenteral
Indirect thrombin inhibitors
HMWH.
LMWH
Direct thrombin inhibitors DTIs
Argatroban
oral
Direct thrombin inhibitors:
Dabigatran
Direct Xa inhibitors:
Rivaroxaban Apixaban
Warfarin
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5. A) Parenteral Anticoagulants
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6. A) Parenteral Anticoagulants: 1. Indirect thrombin inhibitors
(un-fractioned heparin UFH): high molecular weight heparin.
(fractioned heparin FH): low Molecular Weight Heparin
Mechanism of action:
binding to anti-thrombin III (natural circulating anti coagulant in the blood) and accelerating its action.
The function of anti thrombin involves the inactivation of factor X and thrombin.
factor X and thrombin (UFH)
factor X only (LMWH)
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7. A) Parenteral Anticoagulants: 1
A) Parenteral Anticoagulants: 1. Indirect thrombin inhibitors: Mechanism of action:
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8. A) Parenteral anticoagulants: 1- Indirect thrombin inhibitors
A) Parenteral anticoagulants: 1- Indirect thrombin inhibitors * UFH: large molecular weight heparin pharmacokinetics -
Heparin is derived from animal source, It is a strong acid and carries strong electronegative charge.
Heparin is not absorbed from the gut because of its charge and high molecular weight, and it is therefore given intravenously or subcutaneously (intramuscular injections would cause hematoma).
Rapid onset and short duration.
Doesn’t cross blood placental barrier. (safe during pregnancy & lactation).
In the blood, heparin binds to many proteins & cells causing unpredictable pharmacokinetics, so monitoring is mandatory.
Renal Excretion.
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9. A) Parenteral anticoagulants: 1- Indirect thrombin inhibitors
A) Parenteral anticoagulants: 1- Indirect thrombin inhibitors * UFH: large molecular weight heparin: pharmacodynamics
The active heparin molecules bind tightly to antithrombin III and cause a conformational change in this inhibitor. The conformational change of antithrombin exposes its active site for more rapid interaction with the activated clotting factors. (thrombin and Xa mainly)
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10. A) Parenteral anticoagulants: 1- Indirect thrombin inhibitors
A) Parenteral anticoagulants: 1- Indirect thrombin inhibitors * UFH: large molecular weight heparin:
Monitoring of Heparin Effect:
Activated partial thromboplastin time (a PTT): not exceed normal.
Clotting time to be normal.
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11. Heparin (UFH) Toxicity
1. Bleeding. 2. Allergy (animal source) 3. Transient loss of hair and reversible alopecia. 4. Long term use is associated with osteoporosis & spontaneous fracture. 5.Heparin-induced thrombocytopenia (HIT) is a systemic hypercoagulable state that occurs in 1–4% of individuals treated with UFH. This is caused by IgM or IgG antibodies against complexes of heparin and platelet factor 4. (Paradoxical action). Ttt: discontinue heparin & use Argatroban.
PF4 YY
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12. Heparin (UFH) Contraindications
1. Hypersensitivity to the drug (animal source) 2. In patients with Heparin Induce Thrombocytopenia. 3. Hypertension, intracranial hemorrhage. 4. Active bleeding cases hemophilia, thrombocytopenia, Active TB, ulcerative lesion, threatened abortion. 7. Advanced liver or renal diseases. 8. During or after brain, spinal cord or eye surgery.
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13. Reversal of (UFH) heparin action
-Discontinuation of heparin. -Fresh blood transfusion. -specific antagonist (antidote): Protamine sulfate is indicated. Protamine is a highly basic, positively charged peptide that combines with negatively charged heparin as an ion pair to form a stable complex devoid of anticoagulant activity.
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14. A) Parenteral anticoagulants: 1- Indirect thrombin inhibitors
A) Parenteral anticoagulants: 1- Indirect thrombin inhibitors ** FH: low molecular weight heparin:
Semisynthetic agents, potentiate the effect of antithrombin III selectively on activated factor X (Xa) and have less effect on other coagulation factor.
No specific antidote.
Needs dose adjustment in renal patients.
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15. LMWHs have replaced UFH for most clinical indications for the following reasons:
MWHs are administered SC.
Less frequent dosing requirements (once or twice daily is sufficient) [have a longer half-life than heparin]
No need for laboratory monitoring [predictable pharmacokinetic and pharmacodynamic - Less likely to cause thrombocytopenia].
LMWH are as effective as and safer than UFH.
Less frequent hemorrhage.
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16. Therapeutic uses of (UFH) Heparin and the LMWHs
Treatment of acute venous thromboembolism (DVT or Pulmonary Embolism).
Prophylaxis of postoperative venous thrombosis in patients undergoing surgery (for example, hip replacement) and those with acute MI.
They are the anticoagulants of choice for treating pregnant women, because they do not cross the placenta, due to their large size and negative charge
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17. A) Parenteral Anticoagulants: 2) Direct thrombin inhibitors (DTIs) Argatroban
Mechanism of action:
directly binding to the active site of thrombin, thereby inhibiting thrombin’s effects.
Given SC and IV
It has a short half-life, is given by continuous intravenous infusion, and is monitored by a PTT.
Its clearance is not affected by renal disease but is dependent on liver function; dose reduction is required in patients with liver disease.
Argatroban is used for the prophylaxis or treatment of venous thromboembolism in patients with HIT (Heparin induced thrombocytopenia)
Because Argatroban is metabolized in the liver, it may be used in patients with renal dysfunction
major side effect is bleeding.
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18. B) Oral anticoagulants
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19. B) Oral anticoagulants 1) Vitamin K antagonist “Warfarin”
Pharmacokinetics: synthetic drugs • It is given orally. • It has 100% bioavailability. • 99 % bound to plasma albumin but with small affinity, so it has small volume of distribution. • It passes the placenta and is excreted in milk. • long t1/2 ≈36 hours. Delayed onset (start with both heparin & warfarin, then when the warfarin effect appeared, stop heparin and continue with warfarin). & prolonged duration of action (lasts for 4-5 days after stoppage to the drug). • It lacks urinary excretion. • Narrow therapeutic index.
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20. Rule of Vitamin K in blood coagulation
Source: leavy green vegetables & from bacteria flora.
Absorbed from the intestine in the presence of bile.
Absorbed Vit. K goes into the liver, to be activated and utilized.
Vit. K vitamin K H2 (active form): its function is gamma carboxylation (activation) of clotting factors II, VII, IX, X.
After this activation, Vit K is converted into the inactive form (Vit. K epoxide).
Vit K epoxide is re activated again by vitamin K epoxide reductase enzyme: gamma carboxylation of clotting factors.
Warfarin block both enzymes (prevent synthesis of these clotting factors)
Observe some drugs have warfarin like effect like
Aspirin in very large dose.
3rd generation Cephalosporins.
Vit k reductase
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21. B) Oral anticoagulants 1) Vitamin K antagonist “Warfarin”
Mechanism of action:
vitamin k is required for the synthesis of clotting factors II, VII, IX, and X.
These clotting factors are pharmacologically inactive until they are decarboxylated by vitamin k.
The decarboxylation reaction proceeds when we have reduced form of Vit K.
Reduced Vit K is oxidized to vitamin k epoxide yielding caboxylated fully active clotting factors
Oxidized form of Vit K is recycled back to the reduced form by Vit K epoxide reductase enzyme
Warfarin inhibits Vit K epoxide reductase enzyme.
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22. Monitoring of warfarin Effect:
Prothrombin time (PT): it should increase of normal.
International Normalized Ratio (INR): INR is the prothrombin time ratio .The dose of warfarin is usually adjusted to give an INR of 2– 4.
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23. Toxicity (adverse effects) of warfarin
It has a narrow therapeutic index
Pass placenta causing hemorrhagic disorder in fetus. Also it can affect protein synthesis in bone of fetus leading to abnormal bone formation (teratogenic).
Bleeding, nausea, vomiting & anorexia.
Hypersensitivity reaction. (less frequent than heparin).
Sometimes it can cause cutaneous necrotic rash.
Multiple drug interactions
Reversal of Warfarin Action:
1. Stop drug.
2. Large dose of vitamin K1 (Phytonadione).
3. Fresh frozen plasma.
4- recently approved: four-factor concentrate containing factors II, VII, IX, and X.
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24. Drug interactions with warfarin
Pharmacokinetic drug interactions:
Absorption: cholestyramine decreases absorption of warfarin.
Distribution: plasma protein binding.: 99% attached to plasma albumin by low affinity, can be easily displaced from pp. by other drugs (NSAIDs, sulfonamides, loop diuretics, fibrates and statins): free active form of drug toxicity of warfarin.
Metabolism: it is metabolized by CYP450, so hepatic microsomal enzyme inducers or inhibitors will affect its metabolism:
HME Inducers (rifampicin, barbiturates) therapeutic warfarin effect
HME inhibitors: (cimetidine, omeprazole, erythromycin, valporic acid, ketoconazole, allopurinol) warfarin toxicity.
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25. Drug interactions with warfarin
Pharmacodynamic drug interactions:
Aspirin in small dose (antiplatelet) and large dose (warfarin like action) bleeding.
Heparin and other anticoagulants bleeding.
Drugs inducing Reduction of vitamin K production like broad spectrum antimicrobial Cephalosporins (third generation) bleeding.
Excessive Vit. K food supplements inhibits warfarin action thrombosis.
Drugs with no significant effect on anticoagulant therapy include ethanol, Phenothiazines, benzodiazepines, acetaminophen, opioids, indomethacin, and most antibiotics.
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26. B) Oral anticoagulants 2) Oral Direct thrombin inhibitors
Mechanism of action:
directly binding to the active site of thrombin, thereby inhibiting thrombin’s effects.
Advantages
Predictable pharmacokinetics and bioavailability, which allow for fixed dosing.
Routine monitoring unnecessary.
No drug- drug interactions.
Rapid onset and offset of action allow for immediate anticoagulation, thus avoiding the need for overlap with additional anticoagulant drugs.
Dabigatran
oral administration.
Renal impairment results in prolonged drug clearance and may require dose adjustment.
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27. B) Oral anticoagulants: 3) Oral Direct Factor Xa inhibitors
Rivaroxaban, apixaban, and edoxaban
Mechanism :
inhibit factor Xa, in the final common pathway of clotting.
These drugs are given as fixed doses and do not require monitoring.
They have a rapid onset of action and shorter half-lives than warfarin.
Adjust dose in cases of renal or hepatic Impairment .
No antidotes exist for direct Xa inhibitors.
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