ANTIPLATELETS

&
ANTICOAGULANTS

MRS. K. GLADYS KALPANA M.PHARM

PREPARED BY MRS. K. GLADYS KALPANA M.PHARM

 INTRODUCTION
• Drugs are often used in therapeutics to prevent blood coagulation and
to arrest blood loss.
• They do that by acting on various stages of coagulation:
• Platelet aggregation
• Clot or fibrin formation; or
• Fibrinolysis
• Hemostasis is the spontaneous arrest of bleeding from damaged
blood vessels.
MRS. K. GLADYS KALPANA M.PHARM
MRS. K. GLADYS KALPANA M.PHARM
MRS. K. GLADYS KALPANA M.PHARM
MRS. K. GLADYS KALPANA M.PHARM
 ANTITHROMBOTIC AGENTS-CLASSIFICATION

I. • Antiplatelet agents
II. • Anticoagulants
III.• Fibrinolytic agents; and
IV.• Hemorrheological agents

MRS. K. GLADYS KALPANA M.PHARM

 ANTIPLATELET AGENTS-CLASSIFICATION

I. Prostacyclin PGI2.
II. Inhibitors of TXA2 formation e.g., Aspirin.
III. ADP receptor (P2Y12) antagonists e.g., Ticlopidine, Clopidogrel,
Prasugrel.
IV. Phosphodiesterase inhibitors e.g., Dipyridamole.
V. Glycoprotein IIb/IIIa antagonists e.g., Abciximab; and
VI. Protease activated receptor (PAR-1) antagonist e.g., Vorapaxar
MRS. K. GLADYS KALPANA M.PHARM
 PROSTACYCLIN

• (PGI2) is naturally produced by the endothelial cells lining the blood vessels.
• It is also present in other tissues such as the brain, the gut and the kidney.
• In man, prostacyclin infusion, in addition to inhibiting platelet aggregation, causes
vasodilatation, resulting in hypotension, tachycardia, headache and intense facial
flushing.
• It causes renin release. The compound is very unstable with a short half life of 3 minutes.
• Epoprostanol, an analogue of PGI2, is available for preventing platelet aggregation
during hemodialysis and to treat primary pulmonary hypertension

MRS. K. GLADYS KALPANA M.PHARM

 ASPIRIN
• Aspirin selectively acetylates platelet cyclo-oxygenase irreversibly.
• The enzyme of vessel walls is less sensitive to aspirin than is that of
platelets.
• Hence, small doses of aspirin selectively inhibit the synthesis of
TXA2 by platelets whereas higher doses also inhibit PGI2
formation in the vessel.

MRS. K. GLADYS KALPANA M.PHARM

 ASPIRIN
• Aspirin in the oral dose of 75-150 mg daily is useful in:
• • Decreasing the incidence of CHD in adults with high risk factors (Primary
prevention).
• • Preventing MI in patients with angina.
• • Acute coronary syndromes (ACS) such as unstable angina. As immediate
platelet inhibition is desirable, the dose of aspirin should be 150-300 mg.
• • Patients undergoing coronary bypass surgery or angioplasty, or other
revascularization procedures.

MRS. K. GLADYS KALPANA M.PHARM

 ASPIRIN
• Preventing stroke in patients with cerebrovascular disease and history of
transient ischemic attacks (TIA).
• Preventing ischemic limb complications in patients with atherosclerotic
peripheral vascular disease.
• Preventing re-infarction in patients with MI and ischemic heart disease.
• Preventing the development of preeclampsia in pregnant women at high risk
of developing that condition; for this purpose, it is started between the 12th
and 16th weeks of pregnancy.

MRS. K. GLADYS KALPANA M.PHARM

 ASPIRIN
• Its routine use in all pregnant women to prevent pre-eclampsia is, however,
not recommended.
• It does not prevent the development of eclampsia if started after the onset of
pre-eclampsia.
• In hypertensive patients, aspirin therapy should not be initiated until the BP
is controlled.
• The low dose aspirin therapy can cause adverse effects including GI
bleeding, and intracranial hemorrhage, though rarely.

MRS. K. GLADYS KALPANA M.PHARM

 DAZOXIBEN AND TICLOPIDINE
• Dazoxiben is a substituted imidazole which selectively blocks production of
TXA2 without affecting the production of PGI2. However, aspirin is safer
and far superior.
• Ticlopidine, a thienopyridine derivative, is a prodrug. Its active metabolites
act as ADP receptor (P2Y12) antagonists and inhibit platelet aggregation.
• Orally, the onset of action is delayed for hours to days and the effect lasts for
a few days after its discontinuation.
• Adverse effects include neutropenia, thrombocytopenia, thrombotic
thrombocytopenic purpura (TTP), rash, diarrhoea and liver dysfunction.
MRS. K. GLADYS KALPANA M.PHARM
 CLOPIDOGREL:
• It is a prodrug, has slow onset of action (t½ 8 hrs).
• It gets metabolised to its active form by CYP2C19 which irreversibly blocks above-
mentioned ADP receptors.
• Its antiplatelet effect lasts for the life of the platelets (5-7 days). The usual dose is 75
mg/day.
• Combination of aspirin and clopidogrel is synergistic.
• Such combination offers no advantage over aspirin for primary prevention of CV disease.
The combination is usually used in patients with ACS (unstable angina, NSTEMI, acute
MI [STEMI]), during percutaneous coronary intervention (PCI) and other vascularisation
procedures.
• Excessive bleeding is a clear hazard of this combination.
MRS. K. GLADYS KALPANA M.PHARM
 DIPYRIDAMOLE:
• This vasodilator reversibly inhibits platelet phosphodiesterase
enzyme and thus, increases cAMP. It has a weak therapeutic effect.
• Its main use is as an adjunct to warfarin in patients with artificial
heart valves. It is used orally in the dose of 100 mg qid. By itself,
it is hardly of any benefit.

MRS. K. GLADYS KALPANA M.PHARM

 ABCIXIMAB:
• This monoclonal antibody blocks platelet receptors and inhibits
platelet aggregation by inhibiting Glycoprotein IIb/IIIa.
• Given as IV bolus, followed by infusion for 12 hours, it produces
an immediate effect which lasts for 18-24 hours after stopping the
infusion.
• Small amounts of the drug can be detected on circulating platelets
for 7-14 days.

MRS. K. GLADYS KALPANA M.PHARM

 ABCIXIMAB:
• It is an effective antithrombotic agent in ACS that requires
percutaneous coronary intervention.
• It acts synergistically with aspirin and heparin. The drug is
effective in refractory unstable angina and has also been used in
ischemic stroke.
• The major adverse effect is thrombocytopenia, which is reversed
by platelet transfusion; monitoring of platelet count is necessary.

MRS. K. GLADYS KALPANA M.PHARM

 ANTICOAGULANTS-CLASSIFICATION
• These are drugs used to reduce the coagulability of blood.
• A. Parenteral anticoagulants
• (i) Indirect thrombin inhibitors: Heparin, Low molecular weight heparins, Fondaparinux,
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
MRS. K. GLADYS KALPANA M.PHARM

• (iv) Oral direct thrombin inhibitor: Dabigatran etexilate

 PHARMACOLOGY OF HEPARIN
• Heparin is an injectable, rapidly acting anticoagulant that is
often used acutely to interfere with the formation of thrombi.
• It occurs as a macromolecule complexed with histamine in mast
cells.
• Commercial heparin is obtained from the lung and the intestinal
mucosa of pigs and cattle.

MRS. K. GLADYS KALPANA M.PHARM

 Mechanism of action
• It acts indirectly by activating plasma antithrombin III.
• The heparin-AT III complex then binds to clotting factors of the intrinsic and common
pathways (Xa, IIa, IXa, XIa, XIIa and XIIIa) and inactivates them but not factor VIIa
operative in the extrinsic pathway.
• At low concentrations of heparin, it affects the conversion of prothrombin to thrombin in
the presence of factor Xa.
• Also inhibits factor Xa as well as thrombin (IIa) mediated conversion of fibrinogen to
fibrin.
• Heparin in higher doses inhibits platelet aggregation and prolongs bleeding time.

MRS. K. GLADYS KALPANA M.PHARM

 Pharmacokinetics and Pharmacodynamics
• It acts instantaneously after i.v. administration (dose < 100 U/kg, the t½
averages 1 hr).
• On s.c. injection, anticoagulant effect develops after ~60 min (dose is
5000 U) 8–12 hours, started before surgery and continued for 7–10 days
or till the patient starts moving about.
• Heparin does not cross blood-brain barrier or placenta.
• It is metabolized in liver by heparinase and excreted in urine.

MRS. K. GLADYS KALPANA M.PHARM

 Therapeutic use
• Prevention of venous thrombosis
• Treatment of a variety of thrombotic diseases, such as pulmonary
embolism and acute myocardial infarction.
• Deep vein thrombosis
• To maintain patency of cannulae and shunts in dialysis patients.

MRS. K. GLADYS KALPANA M.PHARM

 Adverse effect
• Bleeding due to overdose is the most serious complication of
heparin therapy.
• Thrombocytopenia
• Transient and reversible alopecia
• Osteoporosis

MRS. K. GLADYS KALPANA M.PHARM

 Contraindications
• Bleeding disorders
• Severe hypertension
• Subacute bacterial endocarditis
• Threatened abortion
• Ocular and neurosurgery, lumbar puncture
• Chronic alcoholics, cirrhosis, renal failure.
• Aspirin and other antiplatelet drugs should be used very cautiously
during heparin therapy.
MRS. K. GLADYS KALPANA M.PHARM
 LOW MOLECULAR WEIGHT HEPARINS
•Enoxaparin:
•Reviparin:
•Nadroparin:.
•Dalteparin:.
•Parnaparin:
•Ardeparin:
MRS. K. GLADYS KALPANA M.PHARM
• Fondaparinux: Synthetic heparin which has 100%
bioavailability with less thrombocytopenic effect
compared to LMW heparin.
• Danaparoid is a preparation containing mainly
heparin sulfate which is a heparin-like substance found
in many tissues.
• Synthetically obtained from pig gut mucosa, and is
used in cases with heparin induced thrombocytopenia.
MRS. K. GLADYS KALPANA M.PHARM
 DIRECT THROMBIN INHIBITORS
• Lepirudin This 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.
• Injected i.v., it is indicated only in patients who are at risk of heparin
induced thrombocytopenia.
• Bivalirudin It is a smaller peptide prepared synthetically which has
actions and uses similar to lepirudin.

MRS. K. GLADYS KALPANA M.PHARM

 DIRECT THROMBIN INHIBITORS
• Argatroban This is a synthetic nonpeptide compound which binds
reversibly to the catalytic site of thrombin.
• It produces a rapid and short-lasting antithrombin action.
Administered by i.v. infusion, it can be used in place of lepirudin for
short-term indications in patients with heparin induced
thrombocytopenia.

MRS. K. GLADYS KALPANA M.PHARM

 HEPARIN ANTAGONIST
• Protamine sulfate
• It is a strongly basic, low molecular weight
protein obtained from the sperm of certain fish.
• Given i.v. it neutralises heparin weight for
weight, i.e. 1 mg is needed for every 100 U of
heparin.
MRS. K. GLADYS KALPANA M.PHARM
• Bishydroxycoumarin (Dicumarol)
• It is slowly and unpredictably absorbed orally.
• Its metabolism is dose dependent—t½ is prolonged at higher doses. Has
poor g.i. tolerance; not preferred now.
• DICOUMAROL 50 mg tab.
• Acenocoumarol (Nicoumalone)
• The t½ of acenocoumarol as such is 8 hours, but an active metabolite is
produced so that overall t½ is about 24 hours.
• Acts more rapidly.
MRS. K. GLADYS KALPANA M.PHARM
 ORAL ANTICOAGULANTS

MRS. K. GLADYS KALPANA M.PHARM

 WARFARIN
• Warfarin and its congeners act as anticoagulants only in vivo.
• Act indirectly by interfering with the synthesis of vit K dependent clotting
factors in liver.
• competitive antagonists of vit K and lower the plasma levels of functional
clotting factors by inhibiting the enzyme vit K epoxide reductase (VKOR)
and interfere with regeneration of the active hydroquinone form of vit K.
• Warfarin is rapidly and completely absorbed from intestines and is 99%
plasma protein bound.
• It crosses placenta and is secreted in milk
MRS. K. GLADYS KALPANA M.PHARM
 PHARMACOLOGY OF WARFARIN
• Warfarin is rapidly and completely absorbed from intestines and is
99% plasma protein bound.
• It crosses placenta and is secreted in milk.
• S-warfarin is transformed into inactive metabolites by CYP2C9 and
R-warfarin is transformed by CYP1A2, CYP2C19 (minor pathway),
and CYP3A4 (minor pathway).
• The inactive metabolites of warfarin are excreted in urine and stool.
• The t1/2 ranges from 25 to 60 hours (mean ~40 hours); the duration
of action of warfarin is 2–5 days.
MRS. K. GLADYS KALPANA M.PHARM
 Drug-Drug interaction
• Warfarin interferes in uptake or metabolism of the oral anticoagulant or vit K;
• Patients must be educated to report the addition or deletion of any medication, including
non-prescription drugs, herbal remedies and food supplements.
• Reduced absorption of drug caused by binding to cholestyramine in the GI tract;
• Increased volume of distribution and a short t1/2 secondary to hypoproteinemia, as in
nephrotic syndrome;
• increased metabolic clearance of drug secondary to induction of hepatic enzymes,
especially CYP2C9, by barbiturates, carbamazepine, or rifampin; ingestion of large
amounts of vitamin K–rich foods or supplements; and increased levels of coagulation
factors during pregnancy. Hence, the PT can be shortened in any of these cases.
MRS. K. GLADYS KALPANA M.PHARM
 DRUG INTERACTION
• Include decreased metabolism due to CYP2C9 inhibition by amiodarone, azole antifungals,
cimetidine, clopidogrel, cotrimoxazole, disulfiram, fluoxetine, isoniazid, metronidazole,
sulfinpyrazone, tolcapone, or zafirlukast
• Displacement from protein binding sites caused by loop diuretics or valproate.
• Relative deficiency of vitamin K may result from inadequate diet (e.g., postoperative
patients on parenteral fluids), especially when coupled with the elimination of intestinal
flora by antimicrobial agents.

MRS. K. GLADYS KALPANA M.PHARM

 Adverse effects
• Bleeding, ecchymosis, epistaxis, haematuria, bleeding in the g.i.t.
• Intracranial or other internal haemorrhages may even be fatal.
• Bleeding is more likely if therapy is not properly monitored, or when
INR exceeds 4, or interacting drugs /contraindications are present.

MRS. K. GLADYS KALPANA M.PHARM

• Factors enhancing effect of oral anticoagulants are:
• Debility, malnutrition, malabsorption and prolonged antibiotic
therapy: the supply of vit K to liver is reduced in these conditions.
• Liver disease, chronic alcoholism: synthesis of clotting factors may be
deficient.
• Hyperthyroidism: the clotting factors are degraded faster.
• New-borns: have low levels of vit K and clotting factors (there should
be no need of these drugs in neonates anyway).

MRS. K. GLADYS KALPANA M.PHARM

• Factors decreasing effect of oral anticoagulants are:
• Pregnancy: plasma level of clotting factors is higher.
• Nephrotic syndrome: drug bound to plasma protein is lost in urine.
• Genetic warfarin resistance:
• the affinity of warfarin (as well as of vit K epoxide) to bind to the reductase
(VKOR) enzyme, which generates the active vit K hydroquinone, is low.
• Dose of oral anticoagulant is 4–5 times higher.

MRS. K. GLADYS KALPANA M.PHARM

• A standardized system called the International Normalized Ratio (INR) based on the use of human
brain TP has been developed by WHO and adopted in all countries.

MRS. K. GLADYS KALPANA M.PHARM

 THERAPEUTIC USES

• Deep vein thrombosis (DVT) and pulmonary embolism (PE)

• Myocardial infarction (MI)
• Unstable angina
• Rheumatic heart disease; Atrial fibrillation (AF)
• Cerebrovascular disease
• Vascular surgery, prosthetic heart valves, retinal vessel
thrombosis, extracorporeal circulation, haemodialysis
• Defibrination syndrome
MRS. K. GLADYS KALPANA M.PHARM
 ANTIPLATELET DRUGS (ANTITHROMBOTIC DRUGS)

• These are drugs which interfere with platelet function and are useful in
the prophylaxis of thromboembolic disorders.
• Aspirin, Dipyridamole

MRS. K. GLADYS KALPANA M.PHARM

 FIBRINOLYTICS (THROMBOLYTICS)

• These are drugs used to lyse thrombi/clot to recanalize occluded blood

vessels (mainly coronary artery).
• Fibrinolysis: Endothelial cells secrete tissue plasminogen activator (t-
PA) at sites of injury. t-PA binds to fibrin and cleaves plasminogen to
plasmin, resulting in fibrin digestion.
• Plasminogen activator inhibitors-1 and -2 (PAI-1, PAI-2) inactivate t-
PA; a2-antiplasmin (a2-AP) inactivates plasmin.

MRS. K. GLADYS KALPANA M.PHARM

• Streptokinase
• Alteplase (rt-PA)
• Urokinase Reteplase
• Tenecteplase

MRS. K. GLADYS KALPANA M.PHARM

 STREPTOKINASE
• It is a 47,000 Da protein produced by b-haemolytic streptococci.
• It forms a stable, noncovalent 1:1 complex with plasminogen, to form
free plasmin.
• Streptokinase is rarely used clinically for fibrinolysis since the advent
of newer agents.
• Plasma t½ is estimated to be 30–80 min.

MRS. K. GLADYS KALPANA M.PHARM

 DOSAGE
• For MI: 7.5–15 lac IU infused i.v. over 1 hr.
• For deep vein thrombosis and pulmonary
embolism: 2.5 lac IU loading dose over ½–1 hr,
followed by 1 lac IU/hr for 24 hr.

MRS. K. GLADYS KALPANA M.PHARM

• TISSUE PLASMINOGEN
ACTIVATOR (t-PA)
• t-PA is a serine protease that is
a poor plasminogen activator in
the absence of fibrin.

MRS. K. GLADYS KALPANA M.PHARM

 FREQUENTLY ASKED FRIENDS
• Classification of coagulants and anticoagulants.

MRS. K. GLADYS KALPANA M.PHARM