Renal Failure while on ACE Inhibitor Therapy

Many chronic conditions can lead to renal failure. Hypertension and diabetes can independently cause renal failure. The effect is compounded in patients who have both. Congestive heart failure can also be present and problematic. Medications have been developed that affect the normal physiologic pathways that maintain blood flow to the kidneys in order to both maintain flow and reduce systemic hypertension. Angiotensin converting enzyme (ACE) inhibitors are one common type.

In order for the kidneys to function, blood is pumped through the aorta which supplies the paired renal arteries. Each artery branches multiple times until it reaches the functional unit of the kidney, the glomerulus. Blood flows into the glomerulus via the afferent arteriole and out via the efferent (e for exiting) arteriole. These arterioles are controlled by a hormonal regulation system that helps control how much blood flow and pressure each glomerulus sees.

The hormonal pathway is called the renin-angiotensin-aldosterone (RAS) system. When renal blood flow (RBF) is reduced, cells near the glomerulus called the juxtaglomerular apparatus convert circulating prorenin into renin. Renin catalyzes the conversion of liver-produced angiotensinogen into angiotensin I. This in turn is a precursor for angiotensin II. The conversion is facilitated by angiotensin converting enzyme (ACE) found on the surface vascular endothelial cells, primarily in the lungs.

Angiotensin II has several functions. First, it causes vasoconstriction, primarily at the efferent arteriole. It also stimulates secretion of aldosterone from the adrenal gland, which helps sodium reabsorption and potassium excretion. It also facilitates antidiuretic hormone secretion from the pituitary gland. Generally, angiotensin II wants to preserve circulating volume and blood flow.

RAAS Schematic
Source: Wikipedia

In normal physiology, renal blood flow (RBF) and glomerular filtration rate are maintained in a narrow range, regardless of blood pressure. Too much RAS activation though can lead to hypertension. Many medications affect particular steps in this pathway to disrupt that activation.

ACE Inhibitors (ACE-i) function by blocking the angiotensin converting enzyme, decreasing the formation of angiotensin II (A-II). This can maintain renal function by decreased vasoconstriction and decreased sodium retention, while increasing renal blood flow. Glomerular filtration rate (GFR) may stay the same or even decrease, due to the differential effects on the afferent and efferent arterioles. Since A-II increases GFR by constricting the efferent arteriole relatively more, blocking A-II will dilate the efferent arteriole to a greater degree. The result is more blood flowing through the kidney overall, but less of it actually being filtered by the glomerulus.

This effect on the kidney is reflected in an expected slight rise in creatinine after initiating ACE inhibitor therapy. The expected rise is usually between 10 and 20%.  Acute kidney insufficiency (AKI) is defined as a rise greater than 0.5 if the serum creatinine was initially less than 2.0 mg/dL or more than 1.0 if the baseline was greater than 2. AKI is exacerbated in patients with congestive heart failure (CHF), and can occur even years after therapy was started.

Four mechanisms have been proposed for how ACE-i cause AKI in this setting. The main mechanism occurs if ACE-i cause the mean arterial pressure to decrease to a point that renal perfusion cannot be maintained. The other causes include: simultaneous diuretic use, NSAID use, or high grade renal artery stenosis.

Presuming the latter three causes have been excluded, ACE inhibitor-induced AKI can be managed with close monitoring of serum creatinine and potassium levels. Hyperkalemia is also common, as blocking A-II causes potassium to accumulate in the circulation. This is exacerbated in patients with diabetes, hyperglycemia, and on beta-blockers (which are common in CHF patients). Once adequately titrated, ACE-i therapy can continue as most induced AKI is reversible and potassium levels can be managed by reducing other potassium-retaining interventions. The long-term benefits of ACE-i should outweigh these short-term issues.  

References:

Schoolwerth AC et al. "Renal Considerations in Angiotensin Converting Enzyme Inhibitor Therapy." Circulation. 2001; 104:1985-1991. 

Federalism and Pharmaceuticals

There's an interesting Supreme Court case coming up. The case deals with whether drug-makers are liable for side-effects of medications that occur, even after the drug label/warning is approved by the FDA. There's an interesting discussion about patients vs. big pharma on the Healthbeat Blog (via KevinMD):

First, the details of the case: In the spring of 2000, Diana Levine of Vermont received treatment for migraines which consisted of the painkiller Demerol and Phenergan, an antihistamine manufactured by Wyeth Pharmaceuticals. Phenergan is typically injected directly into the muscle or dripped into the vein through steady doses (a procedure called an “IV drip”). When administering the drug, clinicians must be careful not to expose it to blood in the arteries; doing so causes “swift and irreversible gangrene,” to use an evocative phrase from a September New York Times article on Levine’s case.

Unfortunately, the physician assistant who attended to Levine administered Phenergan neither through muscular injection nor IV drip, but through a process called “IV push”—a direct intravenous shot in the arm. The assistant missed and hit an artery. Over the next few weeks, Levine, who was an avid guitarist, saw her right hand and forearm turn purple and then black—until both were finally amputated.

The court battle is over whether or not Wyeth Pharmaceuticals sufficiently warned against the dangers of IV push on its packaging for Phenergan—packaging that had been approved by the FDA. The drug’s labeling did warn that it was preferable to give Phenergan through IV drip, and warned that “inadvertent intra-arterial injection”—accidentally injecting the drug into an artery—could cause “gangrene requiring amputation.” But nowhere on the Phenergan label was there an express warning that the method of IV push is extremely risky for this very reason.

The Heparin Mishaps: Would More Technology Help?

Dennis Quaid? Heparin? Confusing, perhaps, but there have been several recent cases of overdoses of the drug heparin. One case unfortunately involved the children of actor Dennis Quaid. Some have proposed that automated systems may have prevented these errors, but the Wall Street Journal's health blog argues otherwise:

There’s just one problem in this case: automation wouldn’t have done much for the tots in Texas. A pharmacist made an error mixing heparin solution, often used to flush IV lines — and IV flushes often aren’t part of physician orders anyway. You can read the statement from Christus Spohn, which also says there’s no indication as yet that heparin contributed to the deaths in the NICU.

Doctors typically prescribe a dose of a particular drug over a particular time, and whether it should be administered intravenously or by mouth, for example. But a pharmacist often decides just how the drug will be prepared, whether by syringe into an IV or pre-mixed with saline. The pharmacist may note that a heparin flush is indicated before and after administration, or the nurse may know that it’s just part of the standard procedure.

The article does go on to note that some advanced systems do exist, but even they have their drawbacks:

Another up-and-coming technology might have helped the Quaids, but not the Texas tykes: Bar Code Medication Administration, or BCMA. Those systems require medications to be labeled with bar codes in the pharmacy identifying drug, dose and patient, and then checked — via scanner and computer — against codes in the medical record and a patient armband. But if the wrong dose is mixed and mislabeled in the pharmacy, overdoses can still occur.

“There still is that interface of human to computer that is always going to be plagued with problems,” Zachary Stacy, an associate professor at the St. Louis College of Pharmacy, tells Health Blog.

Clearly, the human element means these systems will always have some level of error, but I think this should not be used as a strong argument against their use. Any reduction in the rate of errors is an improvement, even if not all errors can be eliminated. What these hospitals really need to do is examine the processes and safeguards they had in place and why they failed to prevent this error. If they have too few techs who are perhaps overworked, the solution may actually lie in hiring more staff rather than switching systems.

Avastin: Worth The Price?

Similar to my recent post on CT Angiograms, the cancer drug Avastin has come under new scrutiny about whether its benefits justify its costs:

Looked at one way, Avastin, made by Genentech, is a wonder drug. Approved for patients with advanced lung, colon or breast cancer, it cuts off tumors’ blood supply, an idea that has tantalized science for decades. And despite its price, which can reach $100,000 a year, Avastin has become one of the most popular cancer drugs in the world, with sales last year of about $3.5 billion, $2.3 billion of that in the United States.

But there is another side to Avastin. Studies show the drug prolongs life by only a few months, if that. And some newer studies suggest the drug might be less effective against cancer than the Food and Drug Administration had understood when the agency approved its uses.

Like the CT Angiograms, the difficulty here is what costs should be paid to improve the quality of life of a terminally ill patient. While compassionate people may think that almost any cost is justifiable, one must recognize that from society's point of view, those dollars could be used to pay for TB drugs or for preventative care or for vaccines for children. As a society, America has seemed to strongly preferred costly tertiary interventions that benefit few patients versus more bland primary interventions that prevent disease across many individuals. Is this right? I am not sure, as ideally both ends of the spectrum would be covered, but I feel that we do tend to lean too far towards costly interventions on patients who may be better off with simply receiving palliative care. What do you think? Feel free to comment.

Geriatrics and Antipsychotics

On the heels of my ground-scuffing post on adolescents and antidepressants, the NYTimes has published a piece on the overuse of antipsychotic medications in the elderly:

The use of antipsychotic drugs to tamp down the agitation, combative behavior and outbursts of dementia patients has soared, especially in the elderly. Sales of newer antipsychotics like Risperdal, Seroquel and Zyprexa totaled $13.1 billion in 2007, up from $4 billion in 2000, according to IMS Health, a health care information company.

Part of this increase can be traced to prescriptions in nursing homes. Researchers estimate that about a third of all nursing home patients have been given antipsychotic drugs.

The increases continue despite a drumbeat of bad publicity. A 2006 study of Alzheimer’s patients found that for most patients, antipsychotics provided no significant improvement over placebos in treating aggression and delusions.

Is there anything psychiatrists won't try to cure with a scrip? Heh, just kidding, but the off-label use of psychiatric medications is disturbing, as I saw on my own psychiatry rotation. Sometimes, I wondered whether we were truly living up to the maxim of "do no harm."

Medical Marvel: Sulfhemoglobinemia (Green Blood)

Sulfhemoglobinemia is:

... a rare condition in which there is excess sulfhemoglobin (SulfHb) in the blood. The pigment is a greenish derivative of hemoglobin which cannot be converted back to normal, functional hemoglobin. It causes cyanosis even at low blood levels.

Sulfhemoglobinemia is usually drug induced. Drugs associated with sulfhemoglobinemia include acetanilid, phenacetin, nitrates, trinitrotoluene and sulfur compounds (mainly sulphonamides). Another possible cause is occupational exposure to sulfur compounds. The condition generally resolves itself with erythrocyte (red blood cell) turnover, although blood transfusions can be necessary in extreme cases.

A case report appeared in The Lancet last year, documenting one instance of this condition:

The man - a 42-year-old white Canadian - had developed a compartment syndrome (localised tissue/nerve damage due to restricted blood flow) in both lower legs after falling asleep in a sitting position. He was a smoker whose medical history included chronic shoulder pain and migraine, and was taking a number of regular medications, including sumatriptan to treat the migranes.

Doctors decided he needed urgent fasciotomies (a limb saving procedure in which tissue is cut into to relieve pressure) and he underwent emergency tests, which determined he was mildly tachycardic (rapid heart beat) but had normal blood pressure and his only initial abnormal blood result was an extremely high creatine kinase concentration.

In the operating theatre, multiple attempts to insert a radial arterial catheter yielded dark greenish-black blood, which was immediately sent away for analysis. Meanwhile the catheter was eventually fully inserted, and the man recovered well.

Sulfhaemoglobinaemia, rather than cyanosis, was diagnosed as the cause of the green-black blood.

Green blood! Who knew?


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Adolescence and Antidepressants

As I was wrapping up my psychiatry rotation, I came across this piece about patients who had come of age on antidepressants. For most drugs, chronic use does not change how people perceive themselves, but with psychotropic drugs, this may not be the case:

“I’ve grown up on medication,” my patient Julie told me recently. “I don’t have a sense of who I really am without it.”

At 31, she had been on one antidepressant or another nearly continuously since she was 14. There was little question that she had very serious depression and had survived several suicide attempts. In fact, she credited the medication with saving her life.

But now she was raising an equally fundamental question: how the drugs might have affected her psychological development and core identity.

It is indeed an interesting question. As the author notes, for patients who are on these drugs whil their brains are still developing may not remember a time when they were not on antidepressants. Their sense of who they are is shaped in part by the medications. This can lead to interesting but distressing side effects:

Beyond these concerns, there are other important issues to consider in long-term use of antidepressants, especially in young people. One patient, a woman in her mid-20s, told me that she felt pressured by her boyfriend to have sex more often than she wanted. “I’ve always had a low sex drive,” she said.

For the past eight years she had been taking Zoloft, which like all the antidepressants in its class is known to lower libido and to interfere with sexual performance. She had understandably mistaken the side effect of the drug for her “normal” sexual desire and was shocked when I explained it: “And I thought it was just me!”

Honestly, sometimes I tend to overlook these "common" side effects as medical students are trained to know the rare / more severe reactions. However, hearing this story makes me realize how little we truly know about these medications and their impact on our patients' lives, especially over the long term.

Books And Resources For USMLE Step 1

Every U.S. medical student must take and pass Step I prior to becoming a licensed physician. Although Step 2 and 3 are also important, Step I ends up being *the* major test since it is the one residency programs look at when a student applies for a particular program. Having recently taken Step I, here are some resources, both online and books, that I found useful:

Books:
First Aid for USMLE Step I 2008 - An ABSOLUTE essential. This book contains the basic information for the entire test. If you can memorize this entire book, you are almost guaranteed a 240+ score.

BRS Physiology - A solid review of all the physiology you need to know for the test

BRS Pathology - A good companion to the physiology book

Microbiology Made Ridiculously Simple - A good review of microbiology. It probably has much more detail than you need for the test, but combine this with First Aid's microbio, and you're golden.

Pharmcards - Probably more detail than you need for pharmacology, and does contain some errors, but overall, if you know these cards, you're set for the pharm parts of the test

There are several other potentially useful books, but if you use the ones listed here and master them, you will do very, very well.

Online:
Ace Step I Without Becoming a Hermit - another guide to books for Step I written by a HMS student

Goljan Notes - the mythical Dr. Goljan apparently runs Step I review courses. His notes and mp3 lectures are heralded by some. I listened to most of the lectures, but looking back on it, they're probably best started early and listened to in one's spare time

Kaplan QBank - Almost every student will end up doing practice questions in addition to studying. There are several QBanks out there, but Kaplan has a reputation for good results. Try it before you buy it:

The Challenge consists of a sample set of questions to let you assess how your studying is going, as well as give you a taste of what Kaplan's questions are like. I used them in my preparation, and definitely found it worthwhile. 


Feel free to comment on other resources you find helpful!

Better Know A District - Glaxo-Smith-Kline

Stephen Colbert has a series called 'Better Know A District,' where he interviews various members of Congress. This week, his piece featured Pennsylvania's 7th Representative Joe Sestak. I just found Colbert's riff in the middle of this clip on the drugs he's on to be funny:

For even more Colbert, you have to read:

Tier 4 Drug Pricing

As a follow-up to my post last week about the economics of drug dosing, the Times has published another piece looking at the growing popularity of Tier 4 drug pricing among insurance plans.

"With the new pricing system, insurers abandoned the traditional arrangement that has patients pay a fixed amount, like $10, $20 or $30 for a prescription, no matter what the drug’s actual cost. Instead, they are charging patients a percentage of the cost of certain high-priced drugs, usually 20 to 33 percent, which can amount to thousands of dollars a month."

As I've previously argued, private insurance fundamentally makes no sense:

"But the new system sticks seriously ill people with huge bills, said James Robinson, a health economist at the University of California, Berkeley. “It is very unfortunate social policy,” Dr. Robinson said. “The more the sick person pays, the less the healthy person pays.”

Traditionally, the idea of insurance was to spread the costs of paying for the sick.

“This is an erosion of the traditional concept of insurance,” Mr. Mendelson said. “Those beneficiaries who bear the burden of illness are also bearing the burden of cost.”"

Any reasonable analysis of the insurance system should have predicted that this would occur. It was only a matter of time.

The Economics of Drug Dosages

I recently read an interesting article on the economics of drug dosing. The article discusses the medication used to treat Gaucher Disease, the most common lysosomal storage disorder. If untreated, the disease can cause many problems, including severe bone/joint damage. The drug costs over $200,000 per year! I must admit I have never really given it much thought, but if a drug can cost, but at those prices, it definitely gives one pause:

The drug in question, Cerezyme, is used to treat a rare inherited enzyme deficiency called Gaucher disease. Some experts say that for most patients, as little as one-fourth the standard top dose would work, saving the health care system more than $200,000 a year per Gaucher patient. “It is economic malpractice to give a much higher dose of an expensive drug than is required,” said Dr. Ernest Beutler, an authority on Gaucher disease at the Scripps Research Institute. Some other Gaucher specialists argue otherwise, saying that skimping on the medicine could endanger patients.

The economics of this drug are staggering:

With Cerezyme, which is made by Genzyme, the profits are sizable. Gaucher disease, which can have complications like ruined joints, is rare; only about 1,500 people in the United States are on the drug and about 5,000 worldwide. Sales of Cerezyme totaled $1.1 billion last year, making it a blockbuster by industry standards.

A BILLION dollars from a drug used by at most 5000 people? I am willing to bet that most of the people outside the U.S. do not get the medication, meaning that in the U.S. the cost of the drug may be even higher than the value quoted above. To be fair, here is Genzyme's defense:

Genzyme, which became a leading biotechnology company because of Cerezyme, says that it has raised the price only once — 3 percent last year — since introducing the drug in 1994. The company says it needs the high price to make a sustainable business of serving such a small number of patients and to pay for research on new products. Genzyme also says it provides the drug free, if necessary, so that no one goes without the product because of its cost. But critics say the company’s development costs were minimal, because the early work on the treatment was done by the National Institutes of Health, which gave Genzyme a contract to manufacture it. And analysts estimate the current cost of manufacturing the drug to be only about 10 percent of its price. Insurers generally cover the drug because there are so few patients. But finding or staying on insurance can be difficult.

The collective costs can be staggering:

Ms. Mangum began treatment in 2000, at a cost of more than $400,000 a year. The next year, the premiums for everyone in her insurance pool went up by $180 a month.

I am not sure what can be done about this under the current system, but if one thinks about the true purpose of insurance, I think it becomes clear that a national healthcare system is necessary to protect and cover the costs for individuals who have these rare but treatable diseases.

A Few Interesting Stories

Whew! Done with Step 1! I've enjoyed a few days off, but it's back to the wards tomorrow, specifically the psych wards. I don't have anything in particular to discuss today, so here's a smattering of links with interesting stories:

When a murderer becomes a medical student - a medical school in Stockholm is faced with a dilemma over what to do when a convicted murderer who has served his time is found to be in the student body.

Do statins really prolong a patient's life? - an interesting look at the issue of how to use a drug for a disease versus as prophylaxis.

Who really gets MRSA? - As reports of a new strain of MRSA among homosexual men appeared, the article notes another group that also has a high incidence of such infections.

Hoarseness on the political trail - Find out what the candidates do in their attempts to not lose their voice while being a "voice for the people."

Seven Common Medical Myths - Haha, I must admit, I have held at least 4 of these.

Does a surgeon's gender matter? - Wow, I never would have considered to research this, but it is something to ponder, especially in gender-based operations (ex. mastectomies, prostate surgery)

The Fibromyalgia Fallacy?

Fibromyalgia has been a mystery to me as a medical student. Luckily, I am not alone as rheumatologists seem perplexed by this entity as well. The recent NYTimes article Drug Approved. Is Disease Real? describes Pfizer's release of the first drug approved to treat fibromyalgia, Lyrica. The piece raises the issue of whether pharmacological treatments should be developed for conditions that are not yet well-defined. The most telling quote in the article came from Dr. Frederick Wolfe:

Dr. Frederick Wolfe, the director of the National Databank for Rheumatic Diseases and the lead author of the 1990 paper that first defined the diagnostic guidelines for fibromyalgia, says he has become cynical and discouraged about the diagnosis. He now considers the condition a physical response to stress, depression, and economic and social anxiety.

“Some of us in those days thought that we had actually identified a disease, which this clearly is not,” Dr. Wolfe said. “To make people ill, to give them an illness, was the wrong thing.”

If the researchers who helped define a disease no longer consider it one, one must wonder about the motives underlying the pharmaceutical industry's push into this area. As interesting as the diseases treated in rheumatology are from a pathophysiological point of view, these endless "clinical criteria conditions" that are diagnosed by criteria instead of by signs/symptoms ultimately make it unappealing to me. While I am sympathetic to people who suffer from the constellation of symptoms we term 'fibromyalgia,' scientists should be careful to not overly define an entity that is not yet fully understood as this may do more harm than good. If the cause of the disease is not well-known, then what exactly are these new drugs targeting in the body? Without having a better idea of how these drugs work, and having other options available, the use of the new pharmaceuticals seems a bit dubious to me.

Tyramine and the Cheese Syndrome

Just a little anecdote about why tyramine can cause a hypertensive crisis:

In humans, if monoamine metabolism is compromised by the use of monoamine oxidase inhibitors (MAOIs) and foods high in tyramine are ingested, a hypertensive crisis can result as tyramine can cause the release of stored monoamines, such as dopamine, norepinephrine, epinephrine. The first signs of this were discovered by a neurologist who noticed his wife, who at the time was on MAOI medication, had severe headaches when eating cheese. For this reason, the crisis is still called the "cheese syndrome," even though other foods can cause the same problem.

Foods high in tyramine include cheese, wine, many meats, chocolate and soy. So yea, basically everything has tyramine in it. Good luck, people on MAO inhibitors.

8 Phun Pharmacology Phacts

Here are some random drug facts/trivia/history I picked up while studying pharmacology. Some of them are well-known; some, perhaps not so much. Anyway, here are 8 "phun pharmacology phacts":

Q: Why do diuretics trigger sulfa allergies?

A: The observation that patients treated with sulfonamides developed a hyperchloremic metabolic acidosis led to the development of acetazolamide and subsequently the thiazide diuretics. (Note: loop diuretics also trigger sulfa allergies, but I am not sure why)



Q: Which drug used to treat hypertension was noted to have a side effect that some middle aged men might find beneficial?

A: Minoxidil was found to cause hypertrichosis (increased hair growth), so a less potent form was marketed as the anti-balding agent Rogaine.



Q: A patient presents with hypotension, weakness, disorientation, psychosis, and a breath that smells like bitter almonds. Which antihypertensive drug might the patient have been on?

A: The bitter almond breath is due to cyanide toxicity, a side effect of nitroprusside. The metabolism of nitroprusside releases cyanide.



Q: Why should people on Viagra not take nitrates?

A: Sildenafil (Viagra) and nitrates act synergistically. Nitrates activate guanylate cyclase to increase cyclic GMP; sildenafil inhibits phosphodiesterase V to inhibit break down of cGMP. Together, the drugs markedly increase cGMP which leads to massive vasodilation and hypotension. Not exactly the best way to rekindle one's marriage, huh?

Quick note: One of the side effects of Viagra is difficulty with blue-green color discrimination, just like the color of the pills.



Q: What are "poppers"?

A: Per PharmCards, poppers are "street forms of amyl nitrates used to produce giddiness and enhance sexual perfomance via release of NO in the corpora cavernosa." The drug is related to nitroglycerin.



Q: What drug was initially discovered by William Wuthering as a treatment for dropsy, an old term for edema?

A: Digoxin is a purified extract of the foxglove plant, also known as digitalis.

Another quick note: One of digoxin's side effects is blurry yellow vision (think Van Gogh).









Q: Why are tricyclic antidepressants sedating?

A: They were first developed as antihistamines.



Q: How was penicillin discovered?

A: Penicillin was included in this list of 10 notable accidental inventions. As the story goes:

Everybody knows the story – or at least, should – the brilliant yet notoriously absent-minded biologist Sir Alexander Fleming was researching a strain of bacteria called staphylococci. Upon returning from holiday one time in 1928, he noticed that one of the glass culture dishes he had accidentally left out had become contaminated with a fungus, and so threw it away. It wasn’t until later that he noticed that the staphylococcus bacteria seemed unable to grow in the area surrounding the fungal mould.
Fleming didn’t even hold out much hope for his discovery: it wasn’t given much attention when he published his findings the following year, it was difficult to cultivate, and it was slow-acting – it wasn’t until 1945 after further research by several other scientists that penicillin was able to be produced on an industrial scale, changing the way doctors treated bacterial infections forever.

Can't get enough? Check out why Italian women love atropine, or the top 5 medical urban legends.

Take Wikipedia With A Grain Of Salt

While doing some Step I practice questions, I learned that furosemide blocks the Na+ transporter of the macula densa along with the Na/K/2CL transporter of the thick ascending limb. Upon discussion with a friend, we realized we had a difference of opinion as to where the macula densa was located. I believed it was in the distal convoluted tubule, whereas they placed it at the distal convoluted tubule. I figured a quick Wikipedia search would resolve this. However, I was surprised at what I saw:

In the kidney, the macula densa is an area of closely packed specialized cells lining the wall of the thick ascending limb of Henle (TALH) at the point of return of the nephron to the vascular pole of its parent glomerulus glomerular vascular pole.

I was a bit chagrined to see this, but the article referenced Junquiera's Basic Histology, so I figured I'd bust out my copy to see what it actually said. Here's what I found:

In this juxtaglomerular region, cells of the distal convoluted tubule usually become columnar and closely packed together. Most of the cells have a Golgi complex in the basal region. This modified segment of the wall of the distal convoluted tubule, which appears darker in microscopic preparations because of the close proximity of its nuclei, is called the macula densa.
Source: Junquiera, LC, Carneiro J. Basic Histology, 11th. ed. 2005, p. 379

I suppose some might argue that this is semantics as I believe the macula densa is located at the end of the TALH and at the beginning of the DCT, so perhaps it is in the transition zone between the two. Obviously, the terms are human definitions, and kidneys could care less about those.


Source: http://kcampbell.bio.umb.edu/December01/Juxtaglo.gif

Still, I'll take the histology book as the authority, so I went ahead fixed the macula densa page on Wikipedia, but it was a little surprising to me. I know Wikipedia is not flawless but I figured the more specialized the article, the more likely someone who knew something about it wrote it, and the less likely there would be an error. Oh well... I'll still use it, but I guess when there's a doubt, I'll still have to go back to the original sources.

Want more? Read about my initial views on Wikipedia or more renal stuff about how colas affect the kidney.

Why Monica Bellucci Might Take Atropine

Q: Why might some Italian women be crazy?

A: Atropine makes them that way! Atropine is an anti-muscarinic agent that acts on M1 receptors in the CNS, M2 receptors in the heart, and M3 receptors in smooth muscle tissue and various glands. The drug can be used to treat bradycardia, cholinesterase inhibitor overdose, and mild cramping and urgent bladder in mild cystitis. The side effects of atropine can be remembered by the mnemonic:

• Red as a beet - Dilation of superficial vessels leads to flushing
• Blind as a bat - Cycloplegia and mydriasis
• Dry as a bone - Decreased lacrimation and salivation
• Hot as a hare - Atropine fever due to decreased perspiration
• Mad as a hatter - Delirium and hallucinations

It was first isolated from the plant Atropa belladonna (right), so named because extracts from the plant were allegedly used by Italian women to dilate their pupils. However, my un-PC hunch is that some of the women OD'ed on the atropine causing them to be "mad as a hatter." Then again, Italy gave us Monica Bellucci, so perhaps that's an acceptable trade-off.

More anecdotes? Find out why the French are a little too familiar with a certain STD and with a certain might-as-well-be an STD.

To be or not to be PharmFree

I recently read an interesting article in the New York Times Magazine entitled Dr. Drug Rep. In it, a psychiatrist Dr. Daniel Carlat describes his experiences as a drug representative for Effexor XR over a year. He describes how he was initially recruited by Wyeth Pharmaceuticals, the producers of Effexor and his feelings about his first trip out as a drug rep. He describes the tactics the drug reps used to convince him to represent their drug, and what points they trained him to use to convince others. Dr Carlat's perspective is intriguing because he seems to be truly a man in the middle, as he neither a paid employee of a pharmaceutical company, nor a shrill PharmFree representative, touting a supposed moral high ground.

As medical students, we are secondary or tertiary targets for most reps (after physicians and residents). We stealthily sneak in to lunches, or are at times openly invited. We eat, casually listen, and sometimes come away with a pen. The reps vary: some ignore us, some politely greet us, and a few even try to make us converts early on. In any case, most medical students find the whole thing a bit comical but mostly harmless.

However, for those of us with a few ethical concerns, I have broken the issue down into point/counterpoints:

Point: Even though we are not the direct targets of the reps, we are still influenced by their pitches. Students will remember those drugs that are described more easily later on when they become practitioners. While we might not think we are being influenced, prescribing practices tend to show the contrary on average. Physicians are more likely to prescribe drugs that are detailed to them than drugs that are not. And the reps know this: Pharma links up drug sales info from local pharmacies to DEA numbers on lists sold to them by the AMA. As the article notes:

The American Medical Association is also a key player in prescription data-mining. Pharmacies typically will not release doctors’ names to the data-mining companies, but they will release their Drug Enforcement Agency numbers. The A.M.A. licenses its file of U.S. physicians, allowing the data-mining companies to match up D.E.A. numbers to specific physicians. The A.M.A. makes millions in information-leasing money.

Also, given the time constraints of such interactions, physicians are more likely to trust the nice-looking pharm rep who brought lunch instead of thoroughly investigating whether or not a particular drug is efficacious.

Counterpoint: Free food

Point: At the end of the day, it is the patients who suffer when they are asked to purchase overpriced or inappropriate medications. As physicians, we have a fiduciary responsibility towards our patients to act in our patients' best interests. They trust us to do so, and their lives depend on it, quite literally in some cases. If we prescribe medications with competing interests at play, we do our patients a disservice.

Counterpoint: Free pens, or even a laser pointer (Thank you, random dialysis dude)

Point: If one were to become involved as a representative for a drug, either by doing lunches or giving lectures, it is easy to lose one's objectivity in light of the significant additional income as well as prestige such events offer. Even by merely receiving gifts, there is some compromise of our integrity due to the norms of reciprocity deeply ingrained in our culture.

Counterpoint: FREE STUFF!!!

Okay, in all honesty, I am still divided on this issue myself. I agree that the free stuff is effective (if it wasn't, why would Pharma spend so much money/time doing it?) and I agree that I most likely will be influenced. However, my economic senses chasten at the thought of limiting the marketing potential of a firm in a capitalist society. We allow gas companies, and car companies, and even alcohol companies to market their products in almost any manner possible. Why are drugs held to a different standard? All the other products I mentioned can also seriously harm individuals. Of course, those products do not involve a "fiduciary agent" like a physician who restricts their purchase, but still, why should that matter for marketing efforts? There seems to be inconsistency here, as we clearly trust physicians to prescribe drugs, yet are wary of how they may be swayed by representatives of the pharmaceutical industry.

To me, it seems like the current system cannot hold. I see one of two solutions. First, either physicians should get serious about this issue. To do so, they should petition the AMA to ban the sale of DEA information to pharmaceutical companies as well as ban detailing as a practice, ie ban pharm reps from entering their offices (as some physicians have done). However, this seems highly unlikely due to the entrenched interests who would have no reason to undergo such a radical change. My other thought would be to have all physicians basically make disclaimers to their patients about which representatives for which drugs have been in their office in the past 3-6 months, much like researchers must make disclaimers at the end of journal articles. By doing so, physicians would be free to decide whether or not to accept reps into their office, pharma companies could continue detailing, but I think the main difference would be that the "consumer" patient would be better informed about how their physician practices medicine and how their physician's prescription choice is or is not being influenced.