antiplatelets anticoagulants thrombolytics pharmacology mechanism of action pharmacokinetics side effects

1. Anticoagulants and
Anti platelet Agents
Minel Aşcıoğlu
220i-2A
Pharmacology

3. Irreversible COX Inhibitor: Aspirin
• Aspirin is the only antiplatelet agent that irreversibly inhibits platelet
function.
• Therapeutic use: Aspirin is used in the prophylactic treatment of
transient cerebral ischemia, to reduce the incidence of recurrent Ml, and
to decrease mortality in the setting of primary and secondary prevention
of MI.
• Adverse effects: Higher doses of aspirin increase drug-related toxicities
• Causing complications that include an increased incidence of hemorrhagic
stroke and gastrointestinal (GI) bleeding, especially at higher doses of the
drug.
• Nonsteroidal anti-inflammatory drugs, such as ibuprofen, inhibit COX-1 by
transiently competing at the catalytic site. Ibuprofen, if taken within the 2
hours prior to aspirin, can antagonize platelet inhibition by aspirin.
Therefore, immediate-release aspirin should be taken at least 60 minutes
before or at least 8 hours after ibuprofen.

5. P2Y12 Receptor Antagonists
• Clopidogrel, prasugrel , ticagrelor and ticlopidine are P2Y12 ADP receptor inhibitors that also
block platelet aggregation but by a mechanism different from that of aspirin. All of these
agents are administered orally.
• Mechanism of action: These drugs inhibit the binding of ADP to the P2Y12 receptor on
platelets and, thereby, inhibit the activation of the GP lib/lila receptors required for platelets
to bind to fibrinogen and to each other.
• Therapeutic use: Clopidogrel is approved for prevention of atherosclerotic events and in
those with established peripheral arterial disease. It is also approved for prophylaxis of
thrombotic events in acute coronary syndromes
• Ticlopidine is similar in structure to clopidogrel. It is indicated for the prevention of transient
ischemic attacks (TIA) and strokes in patients with a prior cerebral thrombotic event.
However, due to life-threatening hematologic adverse reactions, ticlopidine is generally
reserved for patients who are intolerant to other therapies. Prasugrel is approved to
decrease thrombotic cardiovascular events in patients with acute coronary syndromes
(unstable angina, non-ST-elevation Ml, and ST-elevation Ml managed with PC I). Ticagrelor is
approved for the prevention of arterial thromboembolism in patients with unstable angina
and acute Ml, including those undergoing PCI.

6. • Adverse effects: These agents can cause
prolonged bleeding for which there is no antidote.
• Ticlopidine is associated with severe hematologic
reactions that limit its use, such as
agranulocytosis, thrombotic thrombocytopenic
purpura (TTP), and aplastic anemia.
• Clopidogrel causes fewer adverse reactions, and
the incidence of neutropenia is lower. However,
TTP has been reported as an adverse effect for
both clopidogrel and prasugrel (but not for
ticagrelor).
• Prasugrel is contraindicated in patients with
history of TIA or stroke. Prasugrel and ticagrelor
has black box warnings for bleeding.

7. Glycoprotein IIb/IIIa inhibitors
• Mechanism of action: Abciximab, Tirofiban,
Eptifibatide inhibits the GP 2b/3a receptor complex. By
binding to GP 2b/3a, they block the binding of
fibrinogen and von Willebrand factor and, consequently,
aggregation does not occur.
• Therapeutic use: These agents are given
intravenously, along with heparin and aspirin, as an
adjunct to PCI for the prevention of cardiac ischemic
complications.
• Adverse effects: The major adverse effect of these
agents is bleeding, especially if used with
anticoagulants.

8. Dipyridamole
• Dipyridamole, a coronary vasodilator, increases intracellular levels of cAMP by inhibiting
phosphodiesterase, thereby resulting in decreased thromboxane A2 synthesis.
• The drug may potentiate the effect of prostacyclin and, therefore, decrease platelet adhesion to
thrombogenic surfaces. Dipyridamole is used for stroke prevention and is usually given in combination
with aspirin.
• Patients with unstable angina should not use dipyridamole because of its vasodilating properties, which
may worsen ischemia (coronary steal phenomenon). Dipyridamole commonly causes headache and
dizziness and can lead to orthostatic hypotension (especially if administered IV).

9. Cilostazol
• Cilostazol also has vasodilating activity.
• inhibit phosphodiesterase type Ill, increasing levels of cAMP in platelets and
vascular tissues. The increase in cAMP prevents platelet aggregation and
promotes vasodilation of blood vessels, respectively.
• Cilostazol is approved to reduce the symptoms of intermittent claudication.
Cilostazol is extensively metabolized in the liver by the CYP 3A4 and 2C19
isoenzymes. As such, this agent has many drug interactions that require dose
modification. The primary route of elimination is via the kidney.
• Headache and Gl side effects (diarrhea, abnormal stools, dyspepsia, and
abdominal pain) are the most common adverse effects observed with cilostazol.
Rarely, thrombocytopenia or leukopenia has been reported.
• Phosphodiesterase type Ill inhibitors have been shown to increase mortality in
patients with advanced heart failure. As such, cilostazol is contraindicated in
patients with heart failure.

11. PARENTERAL ANTICOAGULANTS
• The anticoagulant drugs inhibit either the action of the coagulation
factors (for example, heparin) or interfere with the synthesis of the
coagulation factors (warfarin).
• A. Heparin and low molecular weight heparins
• Heparin [HEP-a-rin] is an injectable, rapidly acting anticoagulant that
is often used acutely to interfere with the formation of thrombi.
• Mechanism of action: Heparin acts at a number of molecular
targets, but its anticoagulant effect is a consequence of binding to
antithrombin Ill, with the subsequent rapid inactivation of
coagulation factors. Antithrombin Ill is an a globulin that inhibits
serine proteases of thrombin (factor lla) and factor Xa. In the
absence of heparin, antithrombin Ill interacts very slowly with
thrombin and factor Xa. When heparin molecules bind to
antithrombin Ill, a conformational change occurs that catalyzes the
inhibition of thrombin about 1 000-fold.

12. • LMWHs complex with antithrombin Ill and inactivate factor Xa (including that located on
platelet surfaces) but do not bind as avidly to thrombin.
• Therapeutic use: Heparin and the LMWHs limit the expansion of thrombi by preventing
fibrin formation. These agents are used for the treatment of acute venous
thromboembolism (DVT or PE). Heparin and LMWHs are also used for prophylaxis of
postoperative venous thrombosis in patients undergoing surgery and those with acute MI.
These drugs are the anticoagulants of choice for treating pregnant women, because they do
not cross the placenta, due to their large size and negative charge.

13. • Adverse effects: The chief complication of heparin and LMWH therapy is bleeding. Careful
monitoring of the patient and laboratory parameters is required to minimize bleeding.
Excessive bleeding may be managed by discontinuing the drug or by treating with protamine
sulfate.
• Heparin preparations are obtained from porcine sources and, therefore, may be antigenic.
Possible adverse reactions include chills, fever, urticaria, and anaphylactic shock.
• Heparin-induced thrombocytopenia {HIT} is a serious condition, in which circulating blood
contains an abnormally low number of platelets. This reaction is immune mediated and
carries a risk of venous and arterial embolism. Heparin therapy should be discontinued when
patients develop HIT or show severe thrombocytopenia.
• In cases of HIT, heparin can be replaced by another anticoagulant, such as argatroban.
• [Note: LMWHs can have cross-sensitivity and are not recommended in patients with HIT.]
• In addition, osteoporosis has been observed in patients on long-term heparin therapy.
• Heparin and LMWHs are contraindicated in patients who have hypersensitivity to heparin,
bleeding disorders, alcoholism, or who have had recent surgery of the brain, eye, or spinal
cord.

14. •Fondaparinux
• Selectively inhibits factor Xa by selectively binding to antithrombin III.
• Fondaparinux is approved for use in the treatment of DVT and PE and for the
prophylaxis of venous thromboembolism in the setting of orthopedic and
abdominal surgery.
• The drug is well absorbed from the subcutaneous route with a predictable
pharmacokinetic profile and, therefore, requires less monitoring than heparin.
• Fondaparinuxis is contraindicated in patients with severe renal impairment.
• Bleeding is the major side effect of fondaparinux. There is no available agent
for the reversal of bleeding associated with fondaparinux.
• HIT is less likely with fondaparinux than with heparin but is still a possibility.

15. DIRECT ORAL ANTICOAGULANTS
• A. Dabigatran
• Mechanism of action: Dabigatran etexilate [da-bi-GAT-ran e-TEX-i-late] is the pro drug of
the active moiety dabigatran, which is an oral direct thrombin inhibitor. Both clot-bound
thrombin and free thrombin are inhibited by dabigatran.
• Therapeutic use: Dabigatran is approved for the prevention of stroke and systemic
embolism in patients with nonvalvular atrial fibrillation. It may also be used in the treatment
of DVT and PE. The drug is contraindicated in patients with mechanical prosthetic heart
valves and is not recommended in patients with bioprosthetic heart valves.
• Adverse effects: The major adverse effect, like other anticoagulants, is bleeding.
Dabigatran should be used with caution in renal impairment or in patients over the age of 75,
as the risk of bleeding is higher in these groups. ldarucizumab may be used to reverse
bleeding in severe cases. Gl adverse effects are common with dabigatran and may include
dyspepsia, abdominal pain, esophagitis, and Gl bleeding. Abrupt discontinuation should be
avoided, as patients may be at increased risk for thrombotic events.

16. • B. Direct oral factor Xa inhibitors
• Mechanism of action: Apixaban, rivaroxaban, edoxaban, betrixaban are oral inhibitors
of factor Xa. Inhibition of factor Xa reduces the production of thrombin (lla) from
prothrombin.

17. • Therapeutic use: With the exception of betrixaban, these
agents are approved for prevention of stroke in nonvalvular atrial
fibrillation, as well as the treatment of DVT and PE.
• Rivaroxaban and apixaban are also used as prophylaxis to prevent
or reduce the risk of recurrence of DVT and PE.
• Adverse effects: Bleeding is the most serious adverse effect.
Currently there is no antidote, but recombinant factor Xa
products are in development.
• Declining kidney function can prolong the effect of these drugs
and, therefore, increase the risk of bleeding. Renal dosage
adjustments are recommended for these agents. Abrupt
discontinuation of the factor Xa inhibitors should be avoided.

18. • Argatroban
• Argatroban is a direct thrombin (Factor IIa) inhibitor. Argatroban is used for the prophylaxis
or treatment of venous thromboembolism in patients with HIT, and it is also approved for
use during PCI in patients who have or are at risk for developing HIT. Anticoagulant effects
are immediate. Argatroban is metabolized in the liver. Dose reduction is recommended for
patients with hepatic impairment. As with other anticoagulants, the major side effect is
bleeding.
• Bivalirudin and desirudin
• Bivalirudin] and desirudin are selective direct thrombin inhibitors that reversibly inhibit the
catalytic site of both free and clot-bound thrombin.
• Bivalirudin is an alternative to heparin in patients undergoing PCI who have or are at risk
for developing HIT and also in patients with unstable angina undergoing angioplasty.
• In patients with normal renal function, the half-life of bivalirudin is 25 minutes. Dosage
adjustments are required in patients with renal impairment.
• Desirudin is indicated for the prevention of DVT in patients undergoing hip replacement
surgery. Like the others, bleeding is the major side effect of these agents.

19. VITAMIN K ANTAGONISTS
• Coumarin anticoagulants owe their action to the ability to
antagonize the cofactor functions of vitamin K. The only
coumarin anticoagulant available in the United States is
warfarin.
• The international normalized ratio (INR) is the standard by
which the anticoagulant activity of warfarin therapy is
monitored.
• Warfarin has a narrow therapeutic index. Therefore, it is
important that the INR is maintained within the optimal range
as much as possible, and frequent monitoring may be
required.

21. • Unlike heparin, the anticoagulant effects of warfarin are not observed immediately after drug
administration. lnstead, peak effects may be delayed for 72 to 96 hours, which is the time
required to deplete the pool of circulating clotting factors.
• The anticoagulant effects of warfarin can be overcome by the administration of vitamin K.
However, reversal following administration of vitamin K takes approximately 24 hours (the
time necessary for degradation of already synthesized clotting factors).
• Therapeutic use: Warfarin is used in the prevention and treatment of DVT and PE, stroke
prevention, stroke prevention in the setting of atrial fibrillation and/or prosthetic heart
valves, protein C and S deficiency, and antiphospholipid syndrome. It is also used for
prevention of venous thromboembolism following orthopedic surgery.
• Adverse effects: The principal adverse effect of warfarin is bleeding. Minor bleeding may
be treated by withdrawal of the drug or administration of oral vitamin K, but severe bleeding
may require greater doses of vitamin K given intravenously. Whole blood, frozen plasma, and
plasma concentrates of blood factors may also be used for rapid reversal of warfarin.
• Purple toe syndrome, a rare, painful, blue-tinged discoloration of the toe caused by
cholesterol emboli from plaques, has also been observed with warfarin therapy. Warfarin is
teratogenic and is contraindicated in pregnancy.

23. Alteplase and tenecteplase
• Alteplase (formerly known as tissue plasminogen activator or
TPA) obtained as a product of recombinant DNA technology.
Tenecteplase [ten-EK-te-place] is recombinant TPA with a
longer half-life and greater binding affinity for fibrin than
alteplase.
• Alteplase has a low affinity for free plasminogen in the
plasma, but it rapidly activates plasminogen that is bound to
fibrin in a thrombus or a hemostatic plug. Thus, alteplase is
said to be "fibrin selective" at low doses. Alteplase is
approved for the treatment of Ml, massive PE, and acute
ischemic stroke.
• Tenecteplase is approved only for use in acute MI. Alteplase
has a very short half life. Tenecteplase has a longer half-life.
• Alteplase may cause angioedema, and there may be an
increased risk of this effect when combined with angiotensin-
converting enzyme (ACE) inhibitors.

24. • Therapeutic use:
• Originally used for the treatment of DVT and serious PE, thrombolytic drugs are
currently used less frequently because of tendency to cause serious bleeding.
• For Ml, intracoronary delivery of the drugs is the most reliable in terms of
achieving recanalization. However, cardiac catheterization may not be possible in
the 2- to 6-hour "therapeutic window," beyond which significant myocardial
salvage becomes less likely. Thus, thrombolytic agents are usually administered
intravenously.
• Thrombolytic agents are helpful in restoring catheter and shunt function, by
lysing clots causing occlusions.
• They are also used to dissolve clots that result in strokes.

26. REFERENCE:
•Lippincott Pharmacology 7TH edition

27. THANK YOU!