• Classification of heparins: Unfractioned heparin, Low Molecular Weight Heparin and Fondaparinux
• Chemical properties
• Fondaparinux
• Mechanism of action of heparin
• Heparin and the coagulation cascade
• Pharmacokinetics of unfractioned heparin
• Clinical uses and drawbacks

• Mechanism of Action
• Dosing/Target INRs
• Drug/Food Interactions
• Managing Elevated INRs
• Patient Counseling
• Other Considerations

Coagulation cascade: extrinsic, intrinsic and common pathways differentiation

Video animation contents:

• Intrinsic pathway
• Extrinsic pathway (endothelium exposure to VIIa factor).
• Common pathway

Extrinsic, intinsic and common pathways

Hemostasis overview

The following animation depicts the process of hemostasis after endothelial damage (vasoconstriction, platelet adhesion, activation, interaction between coagulation factors and thrombin activation).

Hemostasis

Coagulation cascade learning module

This tutorial features interactive exercises and animations that help understand the role of coagulation cascade factors and physiological hemostatic processes.

It highlights clinical disorders on intrinsic and extrinsic pathways, with a special section overviewing Von Willebrand’s disease.

Clotting cascade learning module

Coagulation factors commented

This animation focuses exclusively on the coagulation cascade factors and its sequence of activation. It emphasises biochemical and laboratory aspects.

Coagulation factors

Clopidogrel chemical structur

Pharmamotion has now a new page containing updates on  clopidogrel PPI interactions.

According to the results of the COGENT trial, the combination of the antiplatelet clopidogrel and the PPI omeprazole does not produce clinically relevant cardiovascular interactions. The investigators also suggest that prophylactic PPIs seem to be a very promising strategy to reduce GI events in patients on antithrombotic therapy.

These results were presented at the 21st annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium, sponsored by the Cardiovascular Research Foundation (CRF).

Also of clinical importance: prasugrel was approved this  year for prevention of atherothrombotic events in patients with acute coronary syndromes undergoing primary or delayed percutaneous coronary intervention (PCI).

Further reading

COGENT: No CV events but significant GI benefits of PPI omeprazole. TheHeart.org

Classification of antiplatelet agents

The figure below shows how antiplatelet drugs can be classified according to their mechanism of action. Drug classes include: ADP antagonists (Thienopyridines), COX-1 inhibitors (the only member of this class is aspirin), phosphodiestherase inhibitors and GPIIb/IIIa antagonists.

Classification of antiplatelet agents

Aspirin

Mechanism of action

As shown in the figure, aspirin inhibits platelet cyclooxygenase, a key enzyme in thromboxane A2 (TXA2) generation. Thromboxane A2 triggers reactions that lead to platelet activation and aggregation, aspirin acts as a potent antiplatelet agent by inhibiting generation of this mediator. These effects last for the life of the anucleate platelet, approximately 7 to 10 days.

Aspirin inhibition of COX-1 decreases TXA2 production. Source: Gasparyan, A. Y. et al. J Am Coll Cardiol 2008;51:1829-1843

Therapeutic considerations

Aspirin is indicated as prophylaxis against transient ischemic attacks, myocardial infarction and thromboembolic disorders. It is also used for the treatment of acute coronary syndromes and in the prevention of reoclusion in coronary revascularization procedures. Since side effects such as GI bleeding and acute renal insufficiency are dose dependent, the recommended antiplatelet dose ranges from 75 mg to 325 mg. A related post in this blog reviews some relevant aspects about aspirin pharmacokinetics.

ADP-receptor blockers: thienopyridines

Mechanism of action

Thienopyridines block ADP receptors. Source:Harvey, R; Champe, P “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

Thienopyridines act by inhibiting the ADP-dependent pathway of platelet activation. These drugs have no direct effect on prostaglandin metabolism.

Therapeutics

Ticlopidine is the oldest thienopyridine currently available. It is approved for secondary prevention of thrombotic strokes in patients intolerant of aspirin and for prevention of stent thrombosis in combination with aspirin.  Serious adverse effects of ticlopidine therapy are mainly hematologic and include: neutropenia, thrombocytopenia and thrombotic thrombocytopenic purpura.

Clopidogrel is approved for prevention of atherosclerotic events following recent myocardial infarction, stroke or established peripheral arterial disease. It is also approved for use in acute coronary syndromes that are treated with either PCI  or coronary artery bypass grafting. It has a better safety profile than ticlopidine. Recent studies have shown that PPIs interact with clopidogrel, leading to a reduced effectiveness of the latter.

New antiplatelet drugs: Prasugrel is a recently approved  ( July 2009) agent in this class. Like ticlopidine and clopidogrel, prasugrel requires a loading dose to achieve a maximal antiplatelet effect rapidly.

Phosphodiesterase inhibitors

Dipyridamole is acts as vasodilator and antiplatelet agent. It inhibits adenosine uptake and cyclic GMP phosphodiesterase activity, this decreases platelet aggregability.  Dipyridamole alone has  little antiplatelet effect, it is currently used in combination with aspirin or warfarin in the prophylaxis of thromboembolic disorders.  It is also used in stress testing for myocardial perfusion imaging.

GPIIb/IIIa inhibitors

The glycoprotein IIb/IIIa inhibitors are used parenterally in patients with acute coronary syndromes by specialists, this class of drugs is not used in an outpatient setting by non-specialists.

Mechanism of action

IIb/IIIa receptor binding to fibrinogen. Source: www.integrilin.com

Platelet membrane GPIIb-IIa receptors constitute the final common pathway of platelet aggregation, the  integrin GPIIb/IIIa antagonists prevent cross-linking of platelets. Their action is independent of the aggregation-inducing stimulus.

Therapeutic considerations

Abciximab is a chimeric human-murine monoclonal antibody directed against GPIIb/IIIa, current indications include unstable angina that does not respond to conventional therapy in patients that undergo percutaneous coronary intervention. The peptide derivatives, eptifibatide  and  tirofiban  are  more selective towards the GPIIb/IIIa receptor and have a shorter effect than abciximab.

The most serious adverse effects of GPIIB-IIIa antagonists include major bleeding, intracerebral hemorrhage and thrombocytopenia.

Video review on antiplatelet drugs

Dr. Paul, from www.usmlevideos.net reviews antiplatelet therapy, focusing on ticlopidine and clopidogrel.

References and further reading on antiplatelet therapy

Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.

Harvey, R; Champe, P (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

Brunton, L.B., Lazo, J.S., & Parker, K.L. (Eds.). “Goodman & Gilman’s the pharmacological basis of therapeutics“, 11th edition. New York: McGraw-Hill:2005.

The antiplatelet agent prasugrel (Effient in the US, Efient in the EU) was approved by the FDA on July 10, 2009. Like clopidogrel and ticlopidine, prasugrel is a platelet inhibitor of the thienopyridine class. All drugs in this class act as ADP receptor antagonists,  what makes them different is their safety profile and pharmacokinetic properties. Although clopidogrel is a widely prescribed agent, it has limitations such as: a modest antiplatelet effect, a delayed onset of action and considerable interpatient variability in drug response. All these disadvantages motivated the development of more effective and predictable agents, such as the novel prasugrel.

Much controversy has surrounded the approval of prasugrel . There is uncertainty about the role this drug will play in the prevention of myocardial infarction, as well as its optimal dosing and adverse effects profile.

Mechanism of action

Prasugrel is a prodrug, oxidation by intestinal and hepatic cytochrome P-450 enzymes convert prasugrel into its active metabolite. Prasugrel has a rapid and almost complete absorption after oral ingestion of a loading dose. Its active form binds irreversibly to the adenosine diphosphate (ADP) P2Y12 receptor on platelets for their lifespan, thereby inhibiting their activation and decreasing subsequent platelet aggregation.

Prasugrel has a greater antiplatelet effect than clopidogrel because it is metabolized more efficiently.  Some of the differences in metabolism between clopidogrel and prasugrel may be explained by genetic polymorphisms affecting the cytochrome P-450 system.

Indications

Co-administered with aspirin,  prasugrel is approved by the European Commission for the prevention of atherothrombotic events in patients with acute coronary syndromes (unstable angina, non-ST segment elevation myocardial infarction or ST segment elevation myocardial infarction) undergoing primary or delayed percutaneous coronary intervention (PCI).

Adverse effects and limitations

Prasugrel will include a boxed warning alerting prescribers that the drug can cause significant, sometimes fatal, bleeding.

The drug should not be used in patients with active pathological bleeding, a history of TIAs (transient ischemic attacks) or stroke, or urgent need for surgery, including coronary artery bypass graft surgery.

Some have argued that this boxed warning will make much harder for prasugrel to become a successful drug (in marketing terms).

Which trials lead to prasugrel approval?

TRITON – TIMI 38 is the name of the trial that lead to the approval of prasugrel. TRITON-TIMI 38 was a head to head (prasugrel vs. clopidogrel), randomized, double blind  trial; instead of prasugrel vs. placebo. You can read further details on the official presentation below.

Download: “TRITON TIMI 38 Stent Analysis” PPT

Dr. Victor Serebruany, who is a patent application holder for prasugrel and who worked on early clinical studies for the drug, issued a letter urging the FDA to halt its review of prasugrel. In that letter he requested the FDA to halt its review for prasugrel until a “properly-designed Phase 3 study has been performed with a lower, safer dose of prasugrel and properly defined clinical outcomes”.

MTRAC verdict on prasugrel

The Midlands Therapeutics Review and Advisory Committee (MTRAC) is a UK based independent professional committee of GPs and representatives of other key decision-makers in the use of medicines in primary care.  They conclude that:

Treatment with prasugrel should be initiated in secondary care. It is then appropriate for continued prescribing in primary care. Prasugrel may be suitable for a limited number of patients(e.g. patients who require immediate percutaneous coronary intervention or patients who have experienced stent thrombosis despite previous clopidogrel treatment). However, for each individual, the potential benefits of prasugrel must be carefully balanced against the risk of bleeding. Prasugrel is not recommended for patients over the age of 75 years or patients weighing less that 60 kg because these patients have a high risk of bleeding. It is contraindicated in patients with a history of stroke or transient ischemic attack.

Download PDF: MTRAC, Medicines Management, Keele University. Verdict and summary: Prasugrel

Interview with Steve D. Wiviott, MD, FACC; from the TIMI Study Group

Dr. Cannon, editor in Chief of Cardiosource, interviews one of the TRITON-TIMI 38 investigators: Dr. Steve D. Wiviott.

References and further reading

Wallentin L., P2Y₁₂ inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. European Heart Journal Advance Access published on July 24, 2009
Bhatt, D. L. & Topol, E. J. Scientific and therapeutic advances in antiplatelet therapy. Nature Rev. Drug Discov. 2, 15–28 (2003).

Wiviott SD, Braunwald E, McCabe CH, et al. ; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015. FREE Full Text.

European Medicines Agency (EMEA). European Public Assessment Report — Efient. EMEA website (2009).

Huber, K. Fresh from the pipeline: Prasugrel. Nature Reviews Drug Discovery 8, 449-450 (June 2009).

Bhatt DL. Prasugrel in Clinical Practice. N Engl J Med Published at www.nejm.org July 15, 2009. Free full text.

Finally, it compares normal platelet aggregation with the mechanism of action of Gp IIa/IIIb inhibitors.

Click here to see the full size movie

Some excerpts on the pharmacology of GP IIb/IIIa blockers, including their mechanism of action. From: Lippincott Illustrated Reviews: Pharmacology, 4 ed.

Eptifibatide and tirofiban

These two antiplatelet drugs act similarly to abciximab—namely, blocking the GP IIb/IIIa receptor . Eptifibatide [ep-ti-FIB-ih-tide] is a cyclic peptide that binds to GP IIb/IIIa at the site that interacts with the arginine-glycine-aspartic acid sequence of fibrinogen. Tirofiban [tye-roe-FYE-ban] is not a peptide, but it blocks the same site as eptifibatide. These compounds, like abciximab, can decrease the incidence of thrombotic complications associated with acute coronary syndromes. When intravenous infusion is stopped, these agents are rapidly cleared from the plasma, but their effect can persist for as long as 4 hours. [Note: Only intravenous formulations are available, because oral preparations of GP IIb/IIIa blockers are too toxic.] Eptifibatide and its metabolites are excreted by the kidney. Tirofiban is excreted unchanged by the kidney. The major adverse effect of both drugs is bleeding

In this image you can see an integration of the mechanism of action of antiplatelet agents and the role of IIb/IIIa antagonists. Source: Australian Prescriber.

Further reading:

Antiplatelet therapy after coronary occlusion. Aust Prescr 2007;30:92-6.

One important issue in warfarin therapy is the enormous difference that may exist between patients in the dosing needed to achieve therapeutic levels. A recent study published in PLoS Genetics diggs deep into the basis of the genetic variability in the response to warfarin. They have found that three genes are responsible for this: VKORC1, CYP2C9, CYP4F2.

Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, et al. 2009. A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose. PLoS Genet 5(3)

Warfarin is widely prescribed to reduce blood clotting in order to protect high-risk patients from stroke, thrombosis, and heart attack. But patients vary widely (20-fold) in the warfarin dose needed for proper blood thinning, which means that initial doses in some patients are too high (risking severe bleeding) or too low (risking serious illness). Our GWAS detected two genes (VKORC1, CYP2C9) already known to cause ~40% of the variability in warfarin dose and discovered a new gene (CYP4F2) contributing 1%–2% of the variability. Since our GWAS searched the entire genome, additional genes having a major influence on warfarin dose might not exist or be found in the near-term. Hence, clinical trials assessing patient benefit from individualized dose forecasting based on a patient’s genetic makeup at VKORC1, CYP2C9 and possibly CYP4F2 could provide state-of-the-art clinical benchmarks for warfarin use during the foreseeable future.

Dr. Dan Jonas, from the UNC School of Medicine, reviewed the role of genetic testing in warfarin therapy. He makes clear that “pharmacogenomics is useful in choosing the initial dosing of warfarin. Subsequent dosage adjustments will still be primarily guided by following INRs”

Pharmacogenomics: Using Genetic Testing to Guide Warfarin Therapy

Download PPT file

Slideshow outline:

• Genetic Polymorphisms A Key to Human Individuality
• Single Nucleotide Polymorphisms (SNPs)
• Single Nucleotide Polymorphisms (SNPs)
• Individualized Medicine
• Warfarin is THE example of a narrow therapeutic index
• Factors that Correlate w/ Warfarin Dose
• Genes important for Warfarin Pharmacogenetics: CYP2C9, CYP1A1, VKORC1
• Pharmacogenomics at UNC to Guide Warfarin Therapy
• When Starting Warfarin… consider Genotype!

Some excerpts from the press release:

The U.S. Food and Drug Administration today issued its first approval for a biological product produced by genetically engineered (GE) animals.

The approval is for ATryn, an anticoagulant used for the prevention of blood clots in patients with a rare disease known as hereditary antithrombin (AT) deficiency.

ATryn is a therapeutic protein derived from the milk of goats that have been genetically engineered by introducing a segment of DNA into their genes (called a recombinant DNA or rDNA construct) with instructions for the goat to produce human antithrombin in its milk. Antithrombin is a protein that naturally occurs in healthy individual and helps to keep blood from clotting in the veins and arteries.

Because hereditary AT deficiency occurs in a small population (approximately 1 in 5,000 people in the United States), the FDA granted ATryn an orphan drug designation. The orphan drug designation system encourages the development of medications for patients with a rare disease or condition.

A diagram explaining the process. Source: NYT

A review of the role of antithrombin in the coagulation cascade:

Genetic Variants Linked to Decreased Response to Clopidogrel, Increased Cardiovascular Risk

Polymorphisms in the gene encoding the cytochrome P-450 2C19 enzyme (CYP2C19) not only confer reduced response to clopidogrel, but also are associated with increased risk for cardiovascular events, according to three studies published online by the New England Journal of Medicine and Lancet.

In the first NEJM study, healthy adults exposed to clopidogrel who carried at least one CYP2C19 reduced-function allele had lower plasma concentrations of the drug’s active metabolite and decreased platelet aggregation, relative to noncarriers. In addition, among nearly 1500 patients with acute coronary syndromes who received clopidogrel, carriers of CYP2C19 alleles — primarily CYP2C19*2 — faced greater risk for major cardiovascular events than did noncarriers.

Similarly, the second NEJM study, conducted among some 2200 patients given clopidogrel after MI, found that CYP2C19 reduced-function polymorphisms were associated with higher risk for cardiovascular outcomes.

And in Lancet, researchers again found that CYP2C19*2 was associated with a greater incidence of cardiovascular events among MI patients on clopidogrel. The author of an accompanying commentary calls this observation “fascinating,” but concludes that genotyping cardiac patients “is not necessarily the appropriate solution without further work to validate such an approach.”

NEJM article 1 (Free)

NEJM article 2 (Free)

Lancet article (Free abstract; full text requires subscription)

Lancet comment (Subscription required)

Clopidogrel is marketed under the trade names of: Iscover, Plavix, Clopilet and Ceruvin.