Anticoagulants and thrombolytic drugs.ppt

ANTICOAGULANTS AND THROMBOLYTIC DRUGS
Haemostasis
 Vascular injury results firstly in vasoconstriction and formation of platelet plug at
the site of injury (primary haemostasis).
 The platelet plug is then stabilized by the formation of a fibrin meshwork,
resulting from activation of the coagulation cascade.
 Fibrin is eventually cleared through digestion by fibrinolytic enzymes.

Primary Haemostasis
When endothelial integrity is breached, platelets adhere to exposed subendothelial
collagen. The adherent platelets become activated and result in;
1) Exposure of fibrinogen receptors, allowing fibrinogen to bind and cross-link
adjacent platelets. The process is known as platelet aggregation. The
platelet fibrinogen receptor consists of a complex of glycoproteins IIb and
IIIa on the platelet membrane.
2) Release of contents of secretory granules including substances such as
adenosine diphosphate (ADP) which promote further platelet activation.
3) Synthesis of thromboxane A2 which also acts to promote further platelet
activation and vasoconstriction.

Activation of the coagulation cascade;
The coagulation cascade can be divided into three parts;
1) The common pathway consists of those reactions subsequent to the
generation of factor Xa, culminating in the cleavage of fibrinogen by thrombin,
with subsequent polymerization of fibrin monomers into fibrin strands. Factor
Xa may be generated either by the extrinsic pathway or by the intrinsic
pathway.
2) In the extrinsic pathway, tissue factor is expressed by cells or released
following tissue injury. Binding of tissue factor to factor VII greatly accelerates
the activation of factor VII and also the action of factor VIIa in the activation of
factor X..
3) The intrinsic pathway is initiated by the action of factor XII by contact of blood
with a ‘foreign’ surface. In vivo, this is usually the subendothelial tissues. A
sequence of reactions then results in activation of factor X. most coagulation
factors are synthesized in the liver, and the synthesis of the pro-coagulant
forms of factors II, VII, IX and X is dependent on the availability of vitamin K.

Fibrinolysis
The fibrinolytic system, just like the coagulation cascade, also consists of a series
of enzymatic steps, this time resulting in the breakdown of polymerized fibrin by
plasmin into degradation products (FDP). Plasmin is generated from the plasma
protein plasminogen by the action of tissue plasminogen activator (tPA), which is
most efficient in the activation of plasminogen, when it is bound to fibrin.

Pathophysiology
 Thrombosis is haemostasis in the wrong place.
 When haemostasis proceeds unchecked within a blood vessel, thrombosis
occurs and vascular occlusion may result. Thrombi may also break up into
small pieces and lodge at distant points within the circulation system
(embolism).

 The process of thrombosis in a blood vessel is promoted by one or more of
three underlying pathological events referred to as Virchow’s triad i.e.;
1) Abnormality of the vessel wall
2) Abnormalities of flow within a vessel wall (Stasis)
3) Abnormality of blood constituents
 Thrombosis in arteries usually result from rupture of an atheromatous plaque,
and arterial thrombosis usually consists initially of platelets and subsequently
of fibrin. Venous thrombosis usually occur in the context of stasis of blood flow
e.g. during periods of immobility or during pregnancy when pressure from
gravid uterus may impede venous return.

ANTICOAGULANT DRUGS
HEPARIN
 Anticoagulation can be achieved very rapidly with heparin, and it is therefore
the anticoagulant of choice in many acute thrombotic states such as treatment
of deep venous thrombosis (DVT) or pulmonary embolism and in severe
unstable angina in which it has an additive effect to aspirin.

Chemistry and pharmacology
 Unfractionated heparin is a mixture of naturally occurring glycosaminoglycans with
polysaccharide chains of length and molecular weights ranging from 5000 to
30,000.
 Low molecular weight heparins are manufactured from unfractionated heparin to
produce materials with an average molecular weight of 4000 – 6500.
 All heparins exert their anticoagulant activity by binding to and greatly accelerating
the action of Antithrombin as an inhibitor of thrombin (factor IIa), factor Xa and
other serine protease coagulation factors.

 All heparins must be given parenterally either by the intravenous route or by the
subcutaneous route.
 The half-life of standard heparin following intravenous route is 45-60 minutes.
Heparins however have complex kinetics depending on the dose, molecular
weights and route of administration.
 Low molecular weight heparins demonstrate less to cells and to heparin
neutralizing proteins than the unfractionated heparin. This leads to improved
bioavailability and to a longer half-life. These properties allow a more predictable
anticoagulant response and once daily dosing subcutaneous administration and
there is no need to monitor therapeutic doses with anticoagulation time assays.

Clinical use of unfractionated heparin
 Heparin is used in;
o DVT and pulmonary thromboembolism. In this situation, standard
practice has been to administer 5000 IU unfractionated heparin
intravenously as a loading dose, followed by a continuous infusion of
30,000 IU over 24-hours, and to monitor anticoagulant effect.
o Unstable angina and in myocardial infarction to prevent coronary re-
occlusion following thrombolysis, and in the treatment and prevention of
mural thrombus.

o Prevention of clotting in extracorporeal circulations such;
 Renal dialysis circuits
 Cardiopulmonary bypass
 Flushing of indwelling catheters.
o Perioperative; to reduce incidence of venous thrombosis and pulmonary
embolism following;
 General or orthopaedic surgery
 Acutely ill or immobile medical patients
o It is given subcutaneously at low doses of 5000 IU b.d. for prophylaxis.

Clinical use of low molecular weight heparin
 Prevention of venous thrombosis in patients at risk including;
o DVT and pulmonary thromboembolism
o Patients undergoing general and orthopaedic surgery
o High risk medical patients
 They have been shown to have similar efficacy to unfractionated heparin in all
these situations.
 They however have the advantage of;
o Convenient once daily dosing making their use attractive and allows
savings on hospitalization costs.
o Less bleeding incidence in medical patients.

Monitoring heparin
 Administration of therapeutic doses of unfractionated heparin must be monitored
in the laboratory.
 A prolongation of the activated partial thromboplastin time (APPT) and the
thrombin time are observed.
 APPT which tests the intrinsic and the common pathways of coagulation is the
test usually chosen for therapeutic heparin monitoring.
 For thrombosis treatment, aim for an APPT of 2 - 3. An alternative is to measure
plasma heparin levels that are based upon plasma anti-Xa activity.
 It is not usually necessary to monitor heparin given in low doses for prophylaxis
as such regimens do not lead to prolongation of the APPT.
 APPT is insensitive to the effects of low molecular weight heparins. These may
be measured by anti-Xa assays (e.g. in renal failure) but monitoring is usually
unnecessary because of the predictability of the responses.

Adverse effects
 Bleeding;
o A major hazard.
o Not entirely predictable by the APTT and patient related factors are also
important.
 Heparin induced thrombocytopenia;
o Occurs in approximately 3% of patients given full-dose unfractionated
heparin. Mildly early thrombocytopenia may be common and of no clinical
significance.
o Thrombocytopenia occurring 4-14 days following heparin exposure is of
greater significance as potential life-threatening thrombosis occurs in
such patients.

o The thrombocytopenia is induced by a heparin-dependent antibody
that causes platelet aggregation.
o Heparin –induced thrombocytopenia can occur with any dose or
preparation of heparin. Although it appears to be much less common
with low molecular weight heparin, antibody cross-reactivity has been
documented.
o It is mandatory to monitor platelet count during heparin therapy and
prophylaxis from day 5 onwards; a baseline platelet count is useful.
o If heparin-induced thrombocytopenia is suspected, heparin should be
withdrawn immediately.

Osteoporosis;
o Reduction in bone density and bone fractures has been described
following prolonged use of heparin (usually greater than 20-weeks).
People at risk include pregnant women on prolonged anticoagulation
therapy.
o The mechanism is poorly understood. There appears to be a relationship
with dose and duration of treatment, but individual susceptibility is also
likely to be important.
o Monitoring of bone density may be considered in high risk patients.
 Hypersensitivity;
o Local injections at injection sites have been reported and much more
rarely anaphylactoid reactions.

Reversal of anticoagulation with heparin
 Because of the short half-life of heparin, in the absence of bleeding, it is
reasonable simply to withhold therapy temporarily if over anticoagulation has
occurred.
 In the presence of haemorrhage, protamine should be administered
intravenously.
 Protamine 1mg neutralizes the effects of 100 IU of unfractionated heparin.
protamine should never be given in doses greater than 50mg and should always
be administered slowly to avoid hypotension and bradycardia.

Contraindications to heparin
1) Uncorrected major bleeding
2) Uncorrected major bleeding disorder, e.g. thrombocytopenia, haemophilia.
3) Active peptic ulcer, oesophageal varices, aneurysm, proliferative retinopathy or
organ biopsy.
4) Recent surgery; especially neurosurgery or ophthalmic surgery.
5) Severe renal or hepatic impairment (not including patients on renal dialysis)
6) Recent stroke, intracranial or intraspinal bleed.
7) Severe hypertension
8) Previous heparin-induced thrombocytopenia or thrombosis.
9) Documented hypersensitivity.

HEPARANAOIDS AND HIRUDINS
 These do not cross-react with heparin-dependent antibodies; hence they can be
used in heparin-induced thrombocytopenia.
 Danaparoid is a heparanoid.
 Desirudin and lepirudin are recombinant hirudins, the natural anticoagulant of the
medicinal leech.
FONDAPARINUX
This is a pentasaccharide which selectively inhibits factor Xa. It is effective in
prevention and treatment of DVT, but more expensive than heparin.

WARFARIN
 In practice, warfarin a derivative of 4-hydroxycoumarin is by far the most
extensively used oral anticoagulant and is the drug of choice.
 Acenocoumarol (nicoumalone) and phenindione are also available but are
rarely used.
 All these drugs act as vitamin K antagonists and share the same
pharmacological principles.

Pharmacology
 The coagulation factors II, VII, IX and X require gamma carboxylation on glutamic
acid residues in order to bind calcium during coagulation reactions.
 Vitamin K is required for this carboxylation reaction, which is essential for
procoagulant activity.
 Whilst acting as a cofactor, vitamin K is converted to vitamin K epoxide. The
epoxide is then recycled via reductase reactions to active forms of vitamin K.
 Warfarin inhibits the reductase enzymes involved in the recycling of vitamin K,
thus leading to the deficiency of procoagulant forms of factors II, VII, IX and X.

 Because some of these cofactors have prolonged half-lives, anticoagulation is
not achieved for several days after initiating warfarin therapy. In acute situations,
it is necessary to overlap heparin and warfarin therapy.
 Warfarin is rapidly absorbed from the gut and is extensively bound to plasma
albumin.
 Elimination of warfarin is by oxidative metabolism in the liver, with a half-life of
15-50 hours.

Monitoring warfarin therapy
 Warfarin therapy is monitored by the prothrombin time (PTI) which assesses the
extrinsic and the common pathways of coagulation.
 Standardization is achieved by calibrating laboratory reagents used for
measuring the prothrombin time against an internationally sensitive index (ISI) to
each reagent. This allows the prothrombin time of each patient on treatment to
be converted to an international normalized ratio (INR).
 The INR is the ratio of the patient’s prothrombin time over the mean value in a
normal reference population determined using the same batch of reagent and
corrected for the ISI of the reagent.
 The development of the INR system of monitoring oral anticoagulation has
allowed comparability of results between laboratories.

Clinical use of oral anticoagulants
 Venous Thromboembolism; prophylaxis, treatment and maintenance.
 Atrial fibrillation (high risk patient)
 Valvular heart disease and prosthetic valve replacements, cardiomyopathy
 Mural thrombus.

Warfarin use in pregnancy
 Warfarin crosses the placenta barrier and is contraindicated in the first trimester
of pregnancy because of teratogenicity, and in the last few weeks of pregnancy
because of fatal bleeding at delivery.
 Placental passage of warfarin leads to fetal anticoagulation at any stage in
pregnancy, and so warfarin is not generally recommended in the management
and prevention of venous thromboembolism during pregnancy.
 Because of the high risk and potentially catastrophic consequences of
embolization from artificial valves, warfarin is still the anticoagulant of choice
from 12-36 weeks of pregnancy in patients with mechanical prosthetic valve.

How to initiate anticoagulation with warfarin
 Because of the kinetics considerations described, anticoagulation with warfarin
is not achieved for several days after initiating therapy.
 In acute thrombosis, loading doses are given at the start of the treatment;
usually 5-10mg warfarin on two consecutive days and to check the INR on the
third day.
 Lower doses are used in;
o Congestive cardiac failure
o Presence of abnormalities of the liver function
o Prolongation of baseline prothrombin time
o Elderly
o Familial protein C or protein S disfunction

 A baseline coagulation screen should be checked prior to initiating treatment.
 Maintenance doses usually lie between 3 and 9mg of warfarin (2.5 – 5.0mg
depending on the warfarin preparation). Daily or alternate-day monitoring of the
INR should be carried out until steady values are achieved within the target
range.
 When overlapping heparin with warfarin, it is important to continue heparin until a
therapeutic INR is achieved with warfarin.

Target ranges for oral anticoagulants
INR Clinical condition
2.0 – 2.5
 Prophylaxis of DVT
 Pulmonary embolism
2.0 – 3.0
 Treatment of DVT
 Prophylaxis in atrial fibrillation and other cardiac sources of
embolism
 Bioprosthetic heart valves
 Post-myocardial infarction
3.0 – 4.5
 Mechanical prosthetic heart valves
 Recurrent thrombosis in patients with antiphospholipid
syndrome

Drug Potentiation Antagonism
Analgesic (NSAIDs) Azapropazone
Phenylbutazone
Aspirin
Ketorolac
Antibiotics Co-trimoxazole
Metronidazole
Ampicillin
Cephalosporins
Erythromycin
Aminoglycosides
Tetracycline
Miconazole
Rifampicin
griseofulvin
Cardiovascular drugs Amiodarone
Fibrates
Spironolactone
Cholestyramine
Endocrine agents Corticosteroids
Thyroxine
Tamoxifen
Anabolic steroids
Glucagon
Gastrointestinal drugs Cimetidine
Omeprazole
CNS Drugs Barbiturates
Antihistamines
Tricyclic antidepressants
Chlorpromazine
Carbamazepine
Phenytoin
Others Allopurinol
Alcohol
Vitamin K
Drug Interactions with
warfarin
Drugs either potentiate or
antagonize the effects of
warfarin;

Adverse effects
 Bleeding;
o This is the most common adverse effect encountered in patients on oral
anticoagulant.
o Bleeding is usually related to prolongation of the INR above the
therapeutic range. Underlying causes should be sought if bleeding occurs
at therapeutic levels.
 Alopecia
 Skin rash; skin reaction seen a lot more with phenindione.
 Skin necrosis susceptibility in patients with protein C or S disfunction

Treatment of haemorrhage and reversal of oral anticoagulation
 For elective situations such as surgery including tooth extractions, warfarin
should be stopped at least 48-hours in advance of the procedure and the INR
monitored, with the option of substituting with heparin if there is high risk of
thrombosis e.g. mechanical valves.
 Vitamin K takes 6-hours to have any effect and in an emergency fresh frozen
plasma or coagulation factor concentrate must be administered to provide an
immediate source of vitamin K dependent factors.
 Small doses of phytomenadione i.e. vitamin K (0.5 – 2mg) are sufficient for the
reversal of warfarin effects in all but the most extreme cases. Administration of
large doses of vitamin K e.g. 10mg makes further use of oral anticoagulation
impossible for several weeks.

Anticoagulants and thrombolytic drugs.ppt

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