COAGULANTS AND ANTICOAGULANTS

BY
DR. O. A. ELUWOLE
DEPARTMENT OF MEDICAL PHARMACOLOGY AND THERAPEUTICS,
FACULTY OF BASIC MEDICAL SCIENCES
OBAFEMI AWOLOWO UNIVERSITY,
ILE – IFE, OSUN STATE
NIGERIA.
OUTLINES
 Physiology of coagulation (Haemostasis and
thrombosis)
 Prototype of coagulant and its pharmacology
 Prototype of anticoagulants and its pharmacology
 Factors affecting anticoagulants
HAEMOSTASIS
Haemostasis is the arrest of blood loss from damaged vessels and is
essential to survival.
The main phenomena are:
– platelet adhesion and activation
– blood coagulation (fibrin formation).
• Thrombosis is a pathological condition resulting from inappropriate
activation of haemostatic mechanisms:
-venous thrombosis is usually associated with stasis of blood; a
venous thrombus has a small platelet component and a large
component of fibrin
– arterial thrombosis is usually associated with atherosclerosis,
and the thrombus has a large platelet component.
• A portion of a thrombus may break away, travel as an embolus and
lodge downstream, causing ischaemia and/or infarction.
PHYSIOLOGY OF BLOOD COAGULATION

 Blood coagulation means the conversion of liquid blood toa gel or

clot. The main event is the conversion by thrombin of soluble
fibrinogen to insoluble strands of fibrin, the last step in a complex
enzyme cascade.
 The components (called factors) are present in blood as inactive
precursors(zymogens) of proteolytic enzymes and co-factors. They
are activated by proteolysis, the active forms being designated by the
suffix ‘a’. Factors XIIa, XIa, Xa, IXa and thrombin (IIa) are all serine
proteases.
 PHYSIOLOGY OF BLOOD COAGULATION
 Activation of a small amount of one factor
catalyses the formation of larger amounts of the
next factor, which catalyses the formation of still
larger amounts of the next, and so on;
consequently, the cascade provides a mechanism
of amplification.
 accelerating enzyme cascade has to be controlled
by inhibitors, because otherwise all the blood in
the body would solidify within minutes of the
initiation of haemostasis.
 PHYSIOLOGY OF BLOOD COAGULATION

 One of the most important inhibitors is antithrombin III, which

neutralises all the serine proteases in the cascade. Vascular
endothelium also actively limits thrombus extension .
 Two pathways of fibrin formation were described traditionally
(termed ‘intrinsic’—because all the components are present in
the blood—and ‘extrinsic’—because some components come
from outside the blood).
 The intrinsic or ‘contact’ pathway is activated when shed blood
comes into contact with an artificial surface such as glass, but
physiologically the system functions as a single in vivo pathway.
 Drugs are used to modify the cascade either when there is a defect
in coagulation or when there is unwanted coagulation.
COAGULATION DEFECTS
 Genetically determined deficiencies of clotting factors are not
common. Examples are classic haemophilia caused by lack of
factor VIII, and an even rarer form of haemophilia (haemophilia
B or Christmas disease) caused by lack of factor IX (also called
Christmas factor). Missing factors can be supplied by giving
fresh plasma or concentrated preparations of, respectively,
factor VIII or factor IX.

 Acquired clotting defects are more common than hereditary

ones. The causes include liver disease, vitamin K deficiency
(universal in neonates) and excessive oral anticoagulant therapy,
each of which may require treatment with vitamin K.
 PROCOAGULANT DRUGS: VITAMIN K

• Reduced vitamin K is a co-factor in the posttranslational

γ-carboxylation of glutamic acid (Glu) residues in factors
II, VII, IX and X. The γ-carboxylated glutamic acid (Gla)
residues are essential for the interaction of these factors
with Ca2+ and negatively charged phospholipid.
 VITAMIN K ANTAGONISTS: WARFARIN
 Oral anticoagulants were discovered as an indirect result of a
change in agricultural policy in North America in the 1920s.
Sweet clover was substituted for corn in cattle feed, and an
epidemic of deaths of cattle from haemorrhage ensued.

 Warfarin is the most important oral anticoagulant; alternatives

with a similar mechanism of action, for example phenindione,
are now used only in rare patients who experience idiosyncratic
adverse reactions to warfarin.

 Warfarin and other vitamin K antagonists require frequent blood

tests to individualise dose, and are consequently inconvenient as
well as having a low margin of safety.
PHARMACOKINETICS
 The dose of warfarin is usually adjusted to give an
INR of 2–4, the precise target depending on the
clinical situation.
 The duration of treatment also varies, but for
several indications (e.g. to prevent
thromboembolism in chronic atrial fibrillation),
treatment is long term, with the logistical challenge
of providing a worldwide network of anticoagulant
clinics and demands on the patient in terms of
repeat visits and blood tests.
 ORAL ANTICOAGULANTS
Oral anticoagulants (e.g. warfarin)
Act on vitamin K epoxide reductase component 1 (VKORC1) to
inhibit the reduction of vitamin K epoxide, thus inhibiting the γ-
carboxylation of Glu in II, VII, IX and X.
• Act only in vivo, and their effect is delayed until preformed clotting
factors are depleted.
• Many factors modify their action; genetic factors (polymorphisms of
CYP2C6 and VKORC1) and drug interactions are especially
important.
• There is wide variation in response; their effect is monitored by
measuring the international normalized ratio (INR) and the dose
individualised accordingly.
• Orally active direct thrombin inhibitors (e.g. dabigatran etexilate) or
factor Xa inhibitors (e.g. rivaroxaban) are used increasingly and do not
require monitoring/dose individualisation.
 USES OF ANTICOAGULANTS
 Treatment and/or prevention of bleeding:
– from excessive oral anticoagulation (e.g. by warfarin)
– in babies: to prevent haemorrhagic disease of the newborn.
• For vitamin K deficiencies in adults:
– sprue, coeliac disease, steatorrhoea
– lack of bile (e.g. with obstructive jaundice).
 FACTORS THAT LESSEN THE EFFECT OF ORAL
ANTICOAGULANTS
 Physiological state/disease
There is a decreased response to warfarin in conditions (e.g. pregnancy) where
there is increased coagulation factor synthesis. Similarly, the effect of oral
anticoagulants is lessened in hypothyroidism, which is associated with reduced
degradation of coagulation factors.
 Drugs : Several drugs reduce the effectiveness of warfarin; this leads to increased
doses being used to achieve the target INR. Furthermore, the dose of warfarin
must be reduced when the interacting drug is discontinued, to avoid haemorrhage.
 Vitamin K. This vitamin is a component of some parenteral feeds and vitamin
preparations.
 Drugs that induce hepatic P450 enzymes.
Enzyme induction (e.g. by rifampicin, carbamazepine) increases the rate of
degradation of warfarin. Induction may wane only slowly after the inducing drug is
discontinued, making it difficult to adjust the warfarin dose appropriately.
 Drugs that reduce absorption.
 Drugs that bind warfarin in the gut
 UNWANTED EFFECTS OF ORAL ANTICOAGULANTS

 Haemorrhage (especially into the bowel or the brain) is the main

hazard.
Depending on the urgency of the situation, treatment may consist of
withholding warfarin (for minor problems), administration of vitamin
K, or fresh plasma or coagulation factor concentrates (for life-
threatening bleeding).
 Oral anticoagulants are teratogenic, causing disordered bone
development which is believed to be related to binding to the
vitamin K-dependent protein osteocalcin.
 Hepatotoxicity occurs but is uncommon.
 Necrosis of soft tissues (e.g. breast or buttock)
 PRECAUTIONS
The therapeutic use of warfarin requires a careful balance
between giving too little, leaving unwanted coagulation
unchecked, and giving too much, thereby causing
haemorrhage.
Therapy is complicated not only because the effect of each
dose is maximal some 2 days after its administration, but
also because numerous medical and environmental
conditions modify sensitivity to warfarin, including
interactions with other drugs.
The effect of warfarin is monitored by measuring PT,
which is expressed as an international normalised ratio
(INR).
 THROMBOSIS
Thrombotic and thromboembolic disease is common and has severe
consequences, including myocardial infarction, stroke, deep vein
thrombosis and pulmonary embolus.
The main drugs used for platelet-rich ‘white’ thrombi are the
antiplatelet drugs and fibrinolytic drugs.
The main drugs used to prevent or treat ‘red’ thrombus are: injectable
anticoagulants (heparin and newer thrombin inhibitors)
ANTICOAGULANTS
Injectable anticoagulants (e.g. heparin, low-
molecular-weight heparins)
 • Potentiate antithrombin III, a natural inhibitor that inactivates Xa and
thrombin.
• Act both in vivo and in vitro. • Anticoagulant activity results from a
unique pentasaccharide sequence with high affinity for antithrombin
III.
• Heparin therapy is monitored via activated partial thromboplastin time
(APTT), and dose individualised. Unfractionated heparin (UFH) is used
for patients with impaired renal function.
• Low-molecular-weight heparins (LMWHs) have the same effect on
factor X as heparin but less effect on thrombin; therapeutic efficacy is
similar to heparin but monitoring and dose individualisation are not
needed. Patients can administer them subcutaneously at home. They are
preferred over UFH except for patients with impaired renal function.
 ADMINISTRATION AND
PHARMACOKINETIC ASPECTS
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 haematomas).
After intravenous injection of a bolus dose, there is a phase of rapid elimination
followed by a more gradual disappearance owing both to saturable processes
(involving binding to sites on endothelial cells and macrophages) and to slower
non-saturable processes including renal excretion.
As a result, once the dose exceeds the saturating concentration, a greater
proportion is dealt with by these slower processes, and the apparent half-life
increases with increasing dose (saturation kinetics).
Heparin acts immediately following intravenous administration but the onset is
delayed by up to 60 min when it is given subcutaneously. The elimination half-
life is approximately 40–90 min. In urgent situations, it is therefore usual to
start treatment with a bolus intravenous dose, followed by a constant-rate
infusion. The activated partial thromboplastin time (APTT), or some other in
vitro clotting test.
Anticoagulants and drug
interaction
 Drugs that displace warfarin from binding sites on plasma albumin.
 Some of the NSAIDs and chloral hydrate cause a transient increase
in the concentration of free warfarin in plasma by competing with it
for binding to plasma albumin. This mechanism seldom causes
clinically important effects, unless accompanied by inhibition of
warfarin metabolism, as with phenylbutazone.
 Drugs that inhibit reduction of vitamin K.
Such drugs include the cephalosporins.
 Drugs that decrease the availability of vitamin K.
 Broad spectrum antibiotics and some sulfonamides depress the
intestinal flora that normally synthesise vitamin K2; this has little
effect unless there is concurrent dietary deficiency.
 ANTICOAGULANTS AND DRUG INTERACTION
Agents that inhibit hepatic drug metabolism. Examples
include co-trimoxazole, ciprofloxacin, metronidazole,
amiodarone and many antifungal azoles.
Stereo-selective effects (warfarin is a racemate, and its isomers are
metabolised differently from one another)
Drugs that inhibit platelet function.
Aspirin increase the risk of bleeding if given during warfarin therapy,
although this combination can be used safely with careful monitoring.
Other non-steroidal anti-inflammatory drugs (NSAIDs) also increase
the risk of bleeding, partly by their effect on platelet thromboxane
synthesis and, in the case of some NSAIDs, also by inhibiting
warfarin metabolism as above.
Some antibiotics, including moxalactam and carbenicillin, inhibit
platelet function.
Heparin inhibits coagulation, both in vivo and in vitro, by activating
antithrombin III.
Antithrombin III inhibits thrombin and other serine proteases by
binding to the active serine site. Heparin modifies this interaction by
binding, via a unique pentasaccharide sequence to antithrombin III,
changing its conformation and increasing its affinity for serine
proteases.
Thrombin is considerably more sensitive to the inhibitory effect of the
heparin–antithrombin III complex than is factor Xa. To inhibit
thrombin, it is necessary for heparin to bind to the enzyme as well as to
antithrombin III; to inhibit factor Xa, it is necessary only for heparin to
bind to antithrombin III.
Antithrombin III deficiency is very rare but can cause thrombophilia
and resistance to heparin therapy. The LMWHs increase the action of
antithrombin III on factor Xa but not its action on thrombin, because
the molecules are too small to bind to both enzyme and inhibitor,
essential for inhibition of thrombin but not for that of factor Xa.