Anticoagulants

Dr Sourya Mohapatra
DEPT.OF PHARMACOLOGY
S.C.B MCH
ANTICOAGULANTS((PARE
NTERAL)

INTRODUCTION
• Drugs that inhibit the clotting process.
• Necessary to inhibit thrombus formation.(arterial or
venous thrombi)e.g in DVT
• Prevents formation of emboli .e.g in
Thromboembolism.

CLASSIFICATION:
I. Used in vivo
A. Parenteral anticoagulants
( i) Indirect thrombin inhibitors:
1.Unfractionated Heparin(UFH)
2.Low molecular weight heparins : enoxaparin ,dalteparin ,reviparin ,nadroparin,
ardeparin, parnaparin
3.Selective factorXa inhibitor: Fondaparinux,
4.Heparinoids: Danaparoid
(ii) Direct thrombin inhibitors: Lepirudin, Bivalirudin, Argatroban
B. Oral anticoagulants
(i) Coumarin derivatives: Bishydroxycoumarin( dicumarol), Warfarin sod,
Acenocoumarol (Nicoumalone), Ethylbiscoumacetate
(ii) Indandione derivative: Phenindione.
(iii) Direct factor Xa inhibitors: Rivaroxaban
(iv) Oral direct thrombin inhibitor: Dabigatran etexilate

Cont..
II. Used in vitro
A. Heparin: 150 U to prevent clotting of 100 ml blood.
B. Calcium complexing agents:
• Sodium citrate: 1.65 g for 350 ml of blood; used to
keep blood in the fluid state for transfusion;
(ANTICOAGULANT ACID CITRATE DEXTROSE SOLUTION)
2.2 g/100 ml (75 ml is used for 1 unit of blood).
• Sodium oxalate: 10 mg for 1 ml blood
• Sodium edetate: 2 mg for 1 ml blood

DRUGS USED IN VIVO
INDIRECT THROMBIN INHIBITORS(parenteral):
HEPARIN:
CHEMISTRY AND OCCURRENCE:
• Heparin is a non-uniform mixture of straight chain muco
polysaccharides with MW 10,000 to 20,000.
• It is the strongest organic acid present in the body.
Occurrence: in mast cells (MW ~75,000) loosely bound to the
granular protein.
Commercially : ox lung and pig intestinal mucosa.
TYPES:
A.High Molecular Wt(HMW) or unfractioned heparin(UFH)
B. Low Mol.Wt.(LMWH)

MECHANISM OF ACTION
1.Anticoagulant action

CONT..
• Factors XII,XI, IX,X,II are inactivated by Antithrombin
III(Natural anticoagulant)
• Antithrombin III---Binds with the protease(clotting factors) to
form a stable complex .
• However, in the absence of heparin, the two interact very
slowly.
Heparin enhances the action of AT III in two ways:
a. Long heparin molecule provides a scaffolding for the clotting
factors (mainly Xa and IIa) as well as AT III to get bound and
interact with each other.
b. Heparin induces conformational change in AT III to expose
its interactive sites.

CONT..
• Inhibition of IIa (thrombin) requires a and b, but Xa
inhibition can occur by mechanism ‘b’ alone.
• At low concentrations of heparin, factor Xa mediated
conversion of prothrombin to thrombin is selectively
affected.

2. Antiplatelet action
• Heparin in higher doses inhibits platelet aggregation and
prolongs bleeding time.
3. Lipaemia clearing
• Inj heparin clears turbid post-prandial lipaemic plasma by
releasing a lipoprotein lipase from the vessel wall and tissues----
hydrolyses triglycerides and VLDLs to FFAs---- pass into
tissues ---- plasma looks clear.
• This action requires lower concentration of heparin than that
needed for anticoagulation.
.

PHARMACOKINETICS
Absorption:
Heparin is a large, highly ionized molecule--- not absorbed orally.
• Injected i.v. --- acts instantaneously, but after s.c. injection anticoagulant
effect develops after ~60 min. .
• Does not cross blood-brain barrier or placenta (anticoagulant of choice
during pregnancy).
• After i.v. injection of doses < 100 U/kg, the t½ averages 1 hr. Beyond this,
dose-dependent inactivation is seen and t½ --prolonged to 1–4 hrs.
• The t½ is longer in cirrhotics and renal failure patients, and shorter in
patients with pulmonary embolism.
Metabolism:
• Liver by heparinase .
• Heparin released from mast cells is degraded by tissue macrophages.
Excretion: urine.

UNITAGE AND ADMINISTRATION
• 1 U is the amount of heparin that will prevent 1 ml of citrated sheep
plasma from clotting for 1 hour after the addition of 0.2 ml of 1% CaCl2
solution.
• Heparin sod. 1 mg has 120–140 U of activity.
• Prep available: HEPARIN SOD., BEPARINE, NUPARIN 1000 and
5000 U/ ml in 5 ml vials for injection.
• Heparin should not be mixed with penicillin, tetracyclines,
hydrocortisone or NA in the same syringe or infusion bottle.

CONT..
Dosage :
• Heparin is conventionally given i.v. in a bolus dose of 5,000–10,000
U (children 50–100 U/kg), followed by continuous infusion of 750–
1000 U/hr.
• Intermittent i.v. bolus doses of UFH are no longer recommended.
• The rate of infusion is controlled by aPTT measurement .If not
available---- whole blood clotting time measured and kept at ~2
times the normal value.

CONT..
Deep s.c. injection of 10,000–20,000 U every 8–12 hrs can be given if i.v.
infusion is not possible.
• Avoid hematoma formation-----more common with i.m route—DONOT
USE.
Low dose (s.c.) regimen:
5000 U is injected s.c. every 8–12 hours, started before surgery and continued
for 7–10 days or till the patient starts moving about.
• This regimen ---- prevents postop DVT without increasing surgical bleeding.
• NO aPTT or clotting time prolongation.
• However, it should not be used in case of neurosurgery or in spinal
anaesthesia cases(risk of hematoma ). Or in the patients receiving aspirin or
oral anticoagulants.
• It is ineffective in high-risk situations, e.g. hip joint or pelvic surgery.

ADVERSE EFFECTS
1.Bleeding: due to overdose is the most serious complication of heparin therapy.
• Haematuria is generally the first sign. With proper monitoring, serious bleeding occurs
only in 1–3% patients.
2. Heparin induced Thrombocytopenia
• common problem ----(5-10d)of the therapy.
• Generally --- mild and transient----due to aggregation of platelets.
• Occasionally serious thromboembolic events result(limb ischemia, b/l adrenal
hemorrhage).
• In some patients antibodies are formed to the heparin platelet complex and marked
depletion of platelets occurs----heparin should be discontinued in such cases.
• Even low molecular weight (LMW) heparins are not safe in such patients.
• Warfarin may precipitate venous limb gangrene or skin necrosis in patients with
heparin-induced thrombocytopenia and should not be used until the platelet
count returns to normal.
.

Cont..
3. Osteoporosis may develop on long-term use of
relatively high doses.(increases osteoclast action).
4. Transient and reversible alopecia is infrequent
5. Hypersensitivity reactions are rare; manifestations are
urticaria, rigor, fever and anaphylaxis.

CONTRAINDICATIONS
1.Bleeding disorders, history of heparin induced thrombocytopenia.
2. Severe hypertension (risk of cerebral haemorrhage), threatened
abortion, piles, g.i. ulcers (risk of aggravated bleeding).
3. Subacute bacterial endocarditis (risk of embolism), large
malignancies (risk of bleeding in the central necrosed area of the
tumour), tuberculosis (risk of hemoptysis).
4. Ocular and neurosurgery, lumbar puncture.
5. Chronic alcoholics, cirrhosis, renal failure.
6. Aspirin and other antiplatelet drugs should be used very cautiously
during heparin therapy.

HEPARIN ANTAGONIST
Protamine sulfate
• It is a strongly basic, low molecular weight protein obtained from fish.
• Given i.v. it neutralises heparin weight for weight, i.e. 1 mg is needed for every 100 U
of heparin.
• Needed infrequently ------ as heparin action disappears by itself in a few hours, and
whole blood transfusion is needed to replenish the loss when bleeding occurs.
• Uses: when heparin action needs to be terminated rapidly, e.g. after cardiac or
vascular surgery.
• Protamine does not neutralize fondaparinux, and it only partially reverses the
anticoagulant effect of LMW heparins.
• S/E: hypersensitivity reactions.
Rapid i.v. injection causes flushing and breathing difficulty.
• Prep: PROTA, PROTAMINE SULFATE 50 mg in 5 ml inj.

LMW HEPARINS
• Heparin has been fractionated into LMW forms (MW
3000–7000) by different techniques.
• LMW heparins have a different anticoagulant profile; i.e.
selectively inhibit factor Xa with little effect on IIa.

PHARMACOKINETIC PARAMETERS
• Given s.c.
• Excretion: renal(not to be used in patients with renal
failure).
• aPTT/clotting times are not prolonged, lab monitoring
is not needed; dose is calculated on body weight
basis.

INDICATIONS OF LMW HEPARINS
1. Prophylaxis of deep vein thrombosis and pulmonary
embolism in high-risk patients undergoing surgery; stroke or other
immobilized patients.
2. Treatment of established deep vein thrombosis.
3. Unstable angina and MI: they have largely replaced
continuous infusion of UFH.
4. To maintain patency of cannulae and shunts in dialysis
patients.

PREPARATIONS AVAILABLE
• Enoxaparin: CLEXANE 20 mg (0.2 ml) and 40 mg (0.4ml)
prefilled syringes; 20–40 mg OD, s.c. (start 2 hour before
surgery).
• Reviparin: CLIVARINE 13.8 mg (eq. to 1432 anti Xa IU) in
0.25 ml prefilled syringe; 0.25 ml s.c. once daily for 5-10 days.
• Nadroparin: FRAXIPARINE 3075 IU (0.3 ml) and 4100 IU (0.4
ml) inj., CARDIOPARIN 4000 anti Xa IU/0.4 ml, 6000 anti Xa
IU/0.6 ml, 100, 000 anti Xa IU/10 ml inj.
• Dalteparin: 2500 IU OD for prophylaxis; 100 U/Kg 12 hourly or
200 U/Kg 24 hourly for treatment of deep vein thrombosis.
FRAGMIN 2500, 5000 IU prefilled syringes.
• Parnaparin: 0.6 ml s.c. OD for unstable angina and
prophylaxis of DVT; FLUXUM 3200 IU (0.3 ml), 6400 IU (0.6
ml) inj.
• Ardeparin: 2500-5000 IU OD; INDEPARIN 2500 IU, 5000 IU
prefilled syringes.

SELECTIVE FACTOR Xa INHIBITOR
FONDAPARINUX
• a synthetic pentasaccharide and selective Factor Xa inhibitor .
• Given by s.c injection, reaches peak plasma levels in 2 h, has a t1/2 of 17
h and BA=100%.
• No necessity of lab monitoring(aPTT).
• Longer acting alternative to LMWHs.
• EXCRETION: urine.
• CONTRAINDICATION: Because of the risk of accumulation and
subsequent bleeding------ not to be used in patients with a creatinine
clearance less than 30 mL/min.

USES OF FONDAPARINUX
:
1. Approved for thromboprophylaxis in patients undergoing hip or knee
surgery or surgery for hip fracture .
2. For initial therapy of patients with deep vein thrombosis or pulmonary
embolism.
3. Alternative to heparin or LMWH in patients with acute coronary
syndrome. For this indication and for thromboprophylaxis :given s.c O.D
at a dose of 2.5 mg.
4.Heparin induced thrombocytopenia.
• Prep available: FONDAPARINUX, ARIXTRA 5 mg/0.4 ml, 7.5 mg/0.6
ml and 10 mg/0.8 ml prefilled single dose syringe.
• Dose: 5–10 mg s.c. once daily.

SUMMARY OF UFH,LMWH,FONDAPARINUX
LAB MONITORING aPTTMonitoring
done
No monitoring
required
No monitoring
required
OSTEOPOROSIS Risk is high Less or no no

HEPARINOIDS
DANAPAROID
• Low molecular wt. heparinoid.
• preparation containing mainly heparan sulfate which
is a heparin-like substance found in many tissues,
having less potent anticoagulant action than heparin.
• Danaparoid is obtained from pig gut mucosa, and is
used in cases with heparin induced
thrombocytopenia

DIRECT THROMBIN INHIBITORS
( invivo PARENTERAL)
• The direct thrombin inhibitors (DTIs) exert their
anticoagulant effect by directly binding to the active site of
thrombin, thereby inhibiting thrombin’s downstream effects.
• Hirudin and Bivalirudin are large, bivalent DTIs that bind at the
catalytic or active site of thrombin as well as at a
substrate recognition site.

1.Lepirudin
• Recombinant preparation of hirudin (a polypeptide anticoagulant secreted by
salivary glands of leech).
• Binds firmly to the catalytic as well as the substrate recognition sites of
thrombin and inhibits it directly.
• Eliminated : kidneys
• t1/2 is about 2 h after s.c administration and about 10 min after i.v infusion.
• Injected i.v., it is indicated only in patients who are at risk of heparin induced
thrombocytopenia.
• On repeated/prolonged administration----prolonged anticoagulant effect -----
possibility of anaphylaxis.
• Its action cannot be reversed by protamine or any other antidote

2.BIVALIRUDIN
• smaller peptide prepared synthetically.
• The t1/2 of bivalirudin is 25 min; dosage reductions are recommended for
patients with renal impairment.
• Is used as an alternative to heparin in patients undergoing coronary
angioplasty or cardiopulmonary bypass surgery.
3.ARGATROBAN
• Synthetic compound based on the structure of l-arginine,.
• Binds reversibly to the catalytic site of thrombin, but not to the
substrate recognition site.
• Has rapid and short-lasting antithrombin action.
• Is given i.v and has a t1/2 of 40–50 min. It is metabolized in the liver and
excreted in the bile.
• Administered by i.v. infusion, it can be used in place of lepirudin for short-
term indications in patients with heparin induced thrombocytopenia

Anticoagulants

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