Pharm Friday – Antiplatelet Agents Overview

Another home run from our friends at Pharmamotion:

Classification:

• ADP Antagonists: thienopyridines act by inhibiting the ADP-dependent pathway of platelet activation. These drugs have no direct effect on prostaglandin metabolism.
  • Ticlopidine …is approved for secondary prevention of thrombotic strokes in patients intolerant of aspirin and for prevention of stent thrombosis in combination with aspirin.  adverse effects [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.

• Aspirin: 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… indicated as prophylaxis against transient ischemic attacks, myocardial infarction and thromboembolic disorders. It is also used for the treatment of acute coronary syndromes

• Phosphodiesterase inhibitors: Dipyridamole acts as vasodilator and antiplatelet agent. It inhibits adenosine uptake and cyclic GMP phosphodiesterase activity, this decreases platelet aggregability  …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: used parenterally in patients with acute coronary syndromes…  the integrin GPIIb/IIIa antagonists prevent cross-linking of platelets… current indications include unstable angina that does not respond to conventional therapy in patients that undergo percutaneous coronary intervention.

Antiplatelet agents: mechanisms of action and general overview [Pharmamotion]

Generic Versus Branded Drugs: Concerns Amidst Limited Evidence

Many physicians have found [the switch to generic drugs] particularly problematic in classes of drugs with a narrow therapeutic range, including antiepileptics, psychotropics, antiarrhythmics, and anticoagulants.

although the generic’s mean maximal concentration and area under the concentration-time curve are typically within a few percentage points of the original’s — typically about 4% — the 90% confidence interval for those means can be 20% below or 25% above the branded drug’s mean.

much of the current evidence of problems with generic antiepileptics is anecdotal, or comes from retrospective or case-control studies — not randomized controlled trials.  But all of those studies have come to similar conclusions.

Two retrospective studies published last year in Neurology found that patients who had events like break-through seizures were much more likely to have been switched from a branded product to a generic… “Brand-to-generic seems to be the biggest issue,” Meador said. “But generic-to-generic seems to confer some risk as well.”

some non-SSRI antidepressants aren’t so forgiving, said Jeffrey Lieberman, MD, a psychiatrist at Columbia University in New York City.  He mentioned the tricyclic drug nortriptyline and bupropion (Wellbutrin) as more susceptible than most antidepressants to dosage variations.

Generics versus Brands: How It Plays Out in Practice [Medpage Today]

Serotonin Receptor Antagonists

All 5-HT3 antagonists are identified by the suffix -setron

The following are  5-HT3  antagonists serum half- lives:

• Dolasetron (Anzemet): 7-9 hours.
• Granisetron (Kytril, generic) 9-11 hours.
• Ondansetron (Zofran, generic): 3.9 hours.
• Palonosetron (Aloxi): 40 hours.

At equivalent doses for the prevention of acute emesis, 5-HT3 serotonin receptor antagonists have equivalent safety and efficacy and can be used interchangeably… their clinical use is limited to situations that produce vagal stimulation (eg. surgery) and chemotherapy

5-HT activates 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves. These afferent fibers have projections to the  nucleus tractus solitarius (NTS) and the area postrema (AP).

5HT3 antagonists are superior to metoclopramide, droperidol, and dimenhydrinate in the pharmacologic prophylaxis of postoperative nausea and vomiting. Recently, the FDA added a boxed warning to metoclopramide because of an increased risk of tardive dyskinesia

According to experimental data, these agents have shown to induce minor electrocardiographic changes. It is recommended not to administer dolasetron to patients with prolonged QT or with drugs that may prolong the QT interval.

Serotonin 5-HT3-receptor antagonists: pharmacokinetics, MOA, indications and adverse effects [Pharmamotion]

Lipid Lowering Agent: Crash Course Podcost

The Science of Pharmacy offers a 7 minute review of lipid lowering agents. hosted by a registered pharmacist.  This is a worthwhile and efficient review of very common drugs.

Lipid-Lowering Agents – The top video clips of the week are here

Saxagliptin Approved (DPP4 inhibitor)

[Saxagliptin] which will be sold under the brand name Onglyza, is in a relatively new class, called DPP-4 inhibitors, that can be taken along with older diabetes drugs.

Until now, Merck’s Januvia has been the only drug in the class on the market in this country.

Saxagliptin Approval: Finally, Competition for Merck’s Januvia [WSJ Health Blog

Treating Swine Flu

Can the swine flu be treated with antiviral drugs?
Like some garden-variety flu, this swine flu is resistant to two drugs known as amantadine and rimantadine… CDC says Tamiflu and Relenza work against this strain of swine flu, the WSJ reports.

Does the flu vaccine protect against the swine flu?
The CDC reported earlier this week that the seasonal flu vaccine “might not” provide protection against the flu. The agency says it has created a “seed vaccine” specifically tailored to this swine flu. That could be used to manufacture a targeted vaccine if officials deem it necessary to do so.

Health Blog Q&A: Swine Flu in the U.S. and Mexico [WSJ]

Midwives and Prescriptions

The Pennsylvania Board of Nursing has published regulations implementing a 2007 law which gives nurse midwives the authority to prescribe, administer, and dispense drugs pursuant to collaborative agreement with a physician. The law and regulations also apply to medical devices, immunizing agents, and laboratory tests.  In order to obtain prescriptive authority, nurse midwives must hold a master’s degree or equivalent, have national certification, and complete at least 45 hours of advanced pharmacology coursework and 16 hours of continuing education in pharmacology every two years.

Pennsylvania Gives Nurse Midwives Authority to Prescribe [Physician Law]

The Impact of ALLHAT

Andrew Pollack:

Allhat [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial] began enrolling patients with high blood pressure, age 55 and older, in 1994, with more than 42,000 people eventually participating.

patients receiving the Norvasc [CCB, Pfizer] had a 38 percent greater incidence of heart failure than those on the diuretic. And those receiving the ACE inhibitor… had a 15 percent higher risk of strokes and a 19 percent higher risk of heart failure.

The percentage of hypertension patients receiving a diuretic rose to around 40 percent in the year after the Allhat results were announced, up from 30 to 35 percent beforehand, according to some studies. But use of diuretics has since stayed at that plateau. And over all, use of newer hypertension drugs has grown faster than the use of diuretics since 2002

The aftereffects of the study show how hard it is to change medical practice, even after a government-sanctioned trial costing $130 million produced what appeared to be solid evidence.

A confluence of factors blunted Allhat’s impact. One was the simple difficulty of persuading doctors to change their habits. Another was scientific disagreement

Even before Allhat was finished, and certainly since then, new drugs appeared. Others, meanwhile, became available as generics, reducing the cost advantage of the diuretics. And many doctors have shifted to using two or more drugs together

So Allhat’s main query — which drug to use first — became “an outdated question that doesn’t have huge relevance to the majority of people’s clinical practices,” said Dr. John M. Flack, the chairman of medicine at Wayne State University

The Minimal Impact of a Big Hypertension Study [NYT]

21 Fraudulent Studies Retracted

Baystate Medical Center in Springfield, Mass., has asked several anesthesiology journals to retract the studies, which appeared between 1996 and 2008, the WSJ reports. The hospital says its former chief of acute pain, Scott S. Reuben, faked data used in the studies.

Take a look at Reuben’s work here.

A New Low in Drug Research: 21 Fabricated Studies [WSJ Health Blog]

Fertility Drugs and Ovarian Cancer – No Associations Found

Participants 54 362 women with infertility problems referred to all Danish fertility clinics during 1963-98. 

Main outcome measure Effect of four groups of fertility drugs (gonadotrophins, clomifene citrate, human chorionic gonadotrophin, and gonadotrophin releasing hormone) on overall risk of ovarian cancer after adjustment for potential confounding factors.

Results Analyses within cohort showed no overall increased risk of ovarian cancer after any use of gonadotrophins (rate ratio 0.83, 95% confidence interval 0.50 to 1.37), clomifene (1.14, 0.79 to 1.64), human chorionic gonadotrophin (0.89, 0.62 to 1.29), or gonadotrophin releasing hormone (0.80, 0.42 to 1.51). Furthermore, no associations were found between all four groups of fertility drugs and number of cycles of use, length of follow-up, or parity.

Conclusion No convincing association was found between use of fertility drugs and risk of ovarian cancer.

Use of fertility drugs and risk of ovarian cancer: Danish population based cohort study [BMJ]