Pharmacology of
anticoagulant
Semester I
Semester II
Doaa Abd elfatah Hellal
MD,PhD
ta ct
Con
: [email protected]
: [email protected]
: 01068381663
Learning Outcomes
By the end of the lecture, the students will be able to:
1. Describe different types of anticoagulant drugs
2. Identify kinetics, mechanism of action , uses and adverse effects of heparin &
LMWH.
3. Identify different newer anticoagulant.
4. Identify kinetics, mechanism of action , uses &adverse effects of warfarin.
Anticoagulants
Antithrombotic and Thrombolytic Drugs
Brenner, George M., PhD, Brenner and Stevens’ Pharmacology, Chapter 16, 171-184
Blood coagulation and sites of drug action. Blood coagulation involves the sequential activation of proteolytic clotting factors. The intrinsic
pathway can be activated by surface contact with a foreign body, whereas the extrinsic pathway is activ...
Copyright © 2018 Copyright © 2018 by Elsevier, Inc. All rights reserved.
5
Anticoagulants
Classification
▪ Heparin & low molecular weight heparin
▪ Warfarin
▪ Direct factor Xa inhibitor
▪ Direct thrombin (factor II) inhibitor
Heparin 6
(unfractionated heparin (HMWH).
Source & chemistry
▪
s
Natural sulfated polysaccharide present in mast cells
▪ Carries –ve charge
▪ It is high molecular weight 30000 Dalton (wide range)
Absorption & Distribution
▪ Not taken orally as it precipitated by gastric HCl (given by IV, SC)
▪ Cannot cross BBB or placenta (safe in pregnancy).
▪ Rapid onset & short duration (t1/2 60 min.)
7
Mechanism of action
▪ Its action depends on the presence of a natural
clotting inhibitor called antithrombin III.
▪ Small quantities of heparin can activate antithrombin
III
inhibition of several clotting factors especially
[factor X & thrombin (factor II)].
▪ Anticoagulant in vivo & in vitro
8
Therapeutic uses
▪ Treatment of established thrombosis
▪ Prevention of thrombosis
▪ Keep coagulation time & activated partial
thromboplastin time (APTT) at 2-3 times of its normal
value (for Control of therapy).
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Adverse effects
1. Bleeding is the most common and dangerous SE
▪ can be reversed by antidote protamine sulfate
a basic +ve charged protein that combines with heparin
2. Heparin-induced Thrombocytopenia (HIT) (autoimmune).
▪ Arises from the development of antibodies to the heparin–platelet factor 4
complex.
2. Hematoma if given IM
4. Osteoporosis
5. Alopecia
Low molecular weight heparin (LMWH) (Enoxaparin)
Haemostasis and thrombosis
Ritter, James M., DPhil FRCP HonFBPhS FMedSci, Rang & Dale's Pharmacology, 25, 319-333
Action of heparins. The schematic shows interactions of heparins, antithrombin III (AT III) and clotting factors. To increase the
inactivation of thrombin (IIa) by AT III, heparin needs to interact with both substances (top), but to speed up its e...
Copyright © 2020 © 2020, Elsevier Ltd. All rights reserved.
Unfractionated heparin LMWH (Enoxaparin) 11
Molecular weight range High Low
Anti-factor Xa activity Less specific More specific
Non-specific binding to
High Low
plasma proteins
Low
Bioavailability after s. c.
(due to binding to s.c. High
injection
tissue)
Half-life Short (given 3 times/d) Long (given once/d)
Less common (<2%) less
Thrombocytopenia Common (10%)
affinity for platelet factor 4
Risk of bleeding High Low
APTT Extent of inhibition of factor
Lab monitoring
(Essential) Xa,(May be unnecessary)
LMWH (Enoxaparin)
s
13
Review Q1
s
The primary advantage of enoxaparin over heparin is that it?
A. More effectively inhibits the synthesis of clotting factors
B. Has a more rapid onset
C. Does not cause thrombocytopenia
D. Has a shorter half-life
Review Q 2 14
A 22-year-old woman with deep vein thrombosis in her first trimester of
s
pregnancy, was treated for 7 days with intravenous unfractionated heparin. Which
one of the following drugs would be most appropriate for follow-up therapy for
this patient?
A. Warfarin.
B. Aspirin.
C. Alteplase.
D. Unfractionated heparin (HMWH).
E. Low-molecular-weight heparin (LMWH).
Synthetic factor Xa inhibitors 15
Fondaparinux
s
▪ Synthetic pent-saccharide that have the same mechanism like LMWH (i.e.
selective inhibitor of factor Xa).
▪ It is given by s.c. injection once daily (has long t½).
Rivaroxaban
▪ Oral inhibitor of factor Xa).
▪ Bind to the active site of factor Xa Preventing its
ability to convert prothrombin to thrombin
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Direct thrombin inhibitors (DTIs)
A selective direct competitive thrombin inhibitor that binds to and inhibits both
circulating and thrombus-bound thrombin (factor II a).
Use : alternative to heparin to treat patients with heparin-induced
thrombocytopenia
▪ Argatroban (parenteral)
▪ Dabigatran (Oral)
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Review Q3
Which of the following is direct thrombin inhibitor ?
A. Warfarin.
s
B. Fondaparinux
C. Alteplase.
D. Unfractionated heparin (HMWH).
E. Argatroban.
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Warfarin (Oral anticoagulant)
Source & chemistry
s
Synthetic coumarin compound
Absorption & Distribution
▪ Good (bioavailability is 100%).
▪ Can cross BBB and placenta
▪ Highly bound to the plasma proteins
▪ Metabolized by hepatic CYP450.
Warfarin – drug interactions: look at this link for identification
https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702071676000117#hl0000607
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Warfarin (Oral anticoagulant)
Mechanism of Action
s
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Warfarin (Oral anticoagulant)
Mechanism of Action
s
▪ Warfarin inhibits vitamin K epoxide reductase enzyme in the liver
leading to inhibition of formation of the active form of vitamin K →
↓ synthesis of vitamin K-dependent clotting factors (II, VII, IX, and
X).
▪ The action of warfarin could be antagonized by vitamin K.
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Warfarin (Oral anticoagulant)
Therapeutic uses
▪ Warfarin is given oral 2-10 mg/day for prevention and treatment of thrombosis.
Monitoring
▪ Monitoring is by prothrombin time (PT) or International Normalized Ratio
(INR):
▪ It is the ratio of the PT in the patient to that of normal person.
▪ It must be kept 2-3 times as the normal value.
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Warfarin (Oral anticoagulant)
Adverse effects
1.
s
Bleeding: gingival bleeding, nose bleeding…
▪ It could be treated by the following:
i. Stopping of the drug.
ii. Fresh frozen plasma (FFP).
iii. Vitamin K1(phytomenadione): to enhance synthesis of clotting factors.
2. Teratogenicity: serious birth abnormalities
3. Serious thrombosis: on sudden withdrawal
Brainstorming quesion
What is the proper anticoagulant that can be used in the second trimester of
pregnancy?
Heparin Warfarin
Source Natural. Synthetic
Action In vivo and in vitro In vivo.
Kinetics Ineffective by mouth , not cross the placenta or Absorbed from GIT , Cross the
milk placenta and milk
Mech It activates antithrombin III They compete with Vit. K. on vit
K epoxide reductase
Route S.C oral
Control Blood coagulation time APTT prothrombin time , INR
Onset Immediate Delayed 1-3 days
Duration Short 2-4 hrs Long 4-7 days
Antidote Protamine sulphate + Fresh blood transfusion Vitamin K +Fresh blood
transfusion
Summary
▪ Anticoagulants include heparins, warfarin, Direct thrombin (II) inhibitor, Direct
Xa inhibitor
▪ LMWH is more selective at factor Xa, risks of bleeding and thrombocytopenia
are lower than with HMWH.
▪ Warfarin act by inhibition of vit K epoxide reductase enzyme.
▪ New anticoagulants are more selective cause less bleeding.
▪ New anticoagulants act either on factor (II) or factor X
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References
s
▪ USMLE Step 1 Lecture Notes 2018-Pharmacology (Dec
5,2017)_(1506221173)_ (Kaplan Publishing)
▪ Lippincott’s illustrated review: Pharmacology, 7th edition 2020
▪ Wecker, L. Brody's Human Pharmacology. [ClinicalKey Student]. Retrieved
from https://clinicalkeymeded.elsevier.com/#/books/9780323476522/
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thanks
For W a t ch i n g
