Wednesday, October 27, 2010

Medication, Prescribing, and Timing

There is an important variable that arises in pharmacology that is rarely addressed: after the choice of an antibiotic, how often a day should it be given, what time of day should it be given, and how do doctors compensate for the fact most patients stop antibiotics before the prescribed time period is up?

Sometimes we just don't know, sometimes we forget that patients stop almost all Rx's too early, and sometimes published clinical results are not followed because they are not in the PDR. One concrete example is malaria prophylaxis. Many of the drugs have to be continued for one to four weeks after the patient leaves the malarious area, and many patients forget about the fourth week. My practice is to have the pharmacist label the bottle: "Take.........until the bottle is empty", and then I emphasize to the patient the importance of following this advice.

If you prescribe antibiotics to be taken three times a day, you are fooling yourself, because most patients forget the midday dose, and only in the hospital can you depend on this schedule being followed (by the floor nurse, not the patient). Just ask your residents the next time you see them how well they complied the last time they were prescribed antibiotics. That is one reason I rather prescribe Augmentin, which can be overkill, rather than Amoxicillin, because the former is 2x/day, the the latter 3x/day. For the same reason I prefer Ceftin at b.i.d. to Keflex, especially when treating abscesses, where constant penetration at a bactericidal level is critical and, occasionally, once a day Levaquin to twice a day Cipro, even though the latter is available as a generic.

A classic study was done at NY Presbyterian's pediatric clinic about 40 years ago. Mothers were prescribed the classic bottle of liquid (yellow) penicillin suspension, with the instructions to give their child 1 tsp. four times a day, and warned about the strep throat/rheumatic fever connection. When the mothers returned with their bottles in 10 days, only 10% of them had empty bottles. Assuming that none emptied the bottles that AM out of embarrassment, this means that at least 90% of the most vitally interested persons did not follow the instructions. Add to this the belief of most patients that the less medicine they take the less sick they are helps us to understand why intelligent drug companies prescribe an antibiotic for longer than is necessary (e.g. 3 days of Zithromax is generally equipotent to 5 days, because of its persistence in the necessary tissues and cells) in order to be sure of observing a positive effect.

We all are aware that as the blood sugar climbs above 200, blood becomes more of a non-Newtonian fluid with an atypical cross-sectional velocity profile, and an enlarged viscosity-dependent boundary layer, so that Schlichting's classical theory does not apply. Two well-known results from this are (a) reduced diapedesis of white blood cells, thereby lessening resistance to containing infection, and (b) a non-linear increase in the pressure required to drive blood through the circulatory system, thereby increasing the amount of heart failure. But does the level of blood sugar affect the bactericidal effect of antibiotics? This question is not answered for most antibiotics, which is unfortunate, because diabetics have difficulty controlling the fasting and the post-prandial glucose level equally well, and that should therefore determine the optimum time of the day to deliver a once daily or twice daily antibiotic.

As far as I am aware, although some anti-cancer drugs are tested AM vs. PM to look for a diurnal variation effect, no antibiotic has been. We do know that for some antibiotics the peak level is important, for others the trough, and for still others the area under the dose-time curve, but it is difficult to translate these results into concepts the patient can understand. And the question of with food or on an empty stomach is often answered theoretically rather than clinically. For instance, does it really matter if Synthroid is taken before or after breakfast so long as the patient is consistent by taking the medicine at the same time each day, to reduce the variation of the blood free T4 level? Should a daily antibiotic be given in the AM, when the serum cortisol is at a peak, or in the PM, when the serum iron is at its peak? One could make a case for AM dosing, because one way the body apparently fights infection is to lower the serum iron, but I am unaware of any studies on this possible effect.

Another important point is to make sure certain drugs are dispensed only in tablet rather than capsule form. This is especially important when prescribing Doxycycline, since if a capsule with a pH of 12 gets stuck in the esophagus and dissolves there, the resulting chemical burn can take two to three weeks to heal. I also routinely give skiers the sunburn warning, because if snow blindness is of concern, then so is sunburn, especially on the lips.

The problem of generics also should be addressed (and I realize that I am drifting from my main topic). The generic and the brand name drug are usually compounded differently, with different binders and dyes to make up the tablet. I have seen several cases where the allergic reaction of the patient was due to the binders or the drug-carrying vehicle, and not to the parent antibiotic or drug, e.g. in a reaction to an IM steroid given to treat an acute allergic reaction.

We still do not know the optimum length of time to treat acute sinusitis or acute otitis media or acute cystitis or acute prostatitis. ENT physicians seem to add a Medrol Dospak to any infection they treat above the neck, and we internists do not, but I am not aware of any definitive comparative studies on this subject, nor does it appear in the Cochrane Report. We don't know if we should treat sub-acute Lyme disease for 14 or 21 days, but if you are concerned over malpractice, then 21 days always wins out.

And despite our encouragement NOT to treat viral infections, and the awareness of the public of the problem of drug resistance, I can tell you that if my wife gets a URI and she is not treated, the number of friends who tell her to see another doctor (not myself in either case) so she can get "put on an antibiotic and be properly treated" is astronomical.

Let me close with a related anecdotal story. When I was an intern in NYC, I admitted a male alcoholic with pneumonia one freezing December PM. We put him straightaway into the ICU because of trilobar pneumonia (in those days the admitting intern also covered his patients in the ICU with the help of the ICU resident, not the ward resident). The patient died within 12 hours of admission, and I filled out the death certificate: "Cause of Death...Acute Pneumonia". The supervising ward manager called me down to his office, telling me that in NYC if the death certificate did not specify either viral or bacterial pneumonia, then it became a ME case due to health law, and the body could not be released to the family for burial until an autopsy was performed to determine if a virus or a bacterium was responsible for the death. He asked me to insert an adjective for the family's sake, and I did. So much for the accuracy of death certificates---patients and their families can and should take priority over accurate facts under certain conditions.

Friday, October 22, 2010

Medical Malpractice

The topic of medical malpractice and its cost in both premiums and extra medical tests has recently been discussed in various places, including the Op-Ed pages of the NY Times, but usually by non-doctors. As a practicing family MD (internist) who has been sued 5 times, (once as ward attending, once as hospital medical consultant, and three times for office visits) and who has had all three cases dismissed with prejudice (i.e. no trial, and no payment), let me describe to you non-doctors and non-sued doctors what is wrong with the system.

First, being sued does not make a doctor a better doctor. We improve through experience and studying, and not making the same mistake twice. But the ever-present threat of malpractice makes us more careful, in that most doctors ask themselves before any medical action: how will this look to 12 jurymen who are not doctors? And if a scenario similar to that which we were sued for ever re-occurs, even if we were dismissed, we make sure the same procedure is never followed, because who wants to be sued? An example is the fact that although the Virgin Islands has a Good Samaritan law for emergency treatment by physicians, a physician was sued for doing dockside CPR on a patient who eventually died. His case of course was dismissed because of the law, but the existence of the law did NOT protect him from being sued. He told the newspapers he will never offer emergency medical assistance to a stranger again, because he doesn't want to be sued.

As an example, I had a female patient with Hodgkin's disease, who was cured. For years, her gynecologist and I both urged her to get a colonoscopy, because people with one cancer are at higher risk for a second. There were seven years documented in both our charts of her refusal to get a colonoscopy, and she even refused to check annual stools for blood. When she died from metastatic colon cancer, her husband sued both me and the gynecologist for failure to diagnose the cancer. Again, this took a lot of time away from us. Both our cases were dismissed with prejudice. But the result is that I "fire" (i.e. discharge from my practice) any patient who refuses to do an annual stool for blood or a colonoscopy every 5 years, because again, who wants to be sued even if you win the case?

So now in addition to asking myself "what can the patient have that can damage or kill him/her if I do not diagnose it?" I also ask myself "What test can I be sued for not doing?". You see, a doctor is never sued for doing a test, but only for not doing it. So if a patient or spouse or relative asks for any test, I always say yes, which I never used to do, but that is what the system wants me to do. And it does no good to follow the "disease guidelines", because if you have a patient with 5 diseases (high blood pressure, GI reflux, heart failure, osteoporosis, and asthma) then some of the guidelines will conflict with others. In addition, the guidelines are not uniform: the USPHS, AMA, American Urological Association, American Cancer Association, and American College of Physicians, have widely differing guidelines on using the PSA test for prostate cancer, and even if it should be used at all.

I think it would reduce costs tremendously if the malpractice cases were taken out of the tort-contingency fee system, and put instead into the no-fault system, as is auto insurance in the State of New Jersey, where doctor's and lawyer's fees are set by the workmen's compensation fee schedule.

We also cannot practice medicine and keep notes as the lawyers would have us do, in part because we cannot bill for telephone time and making notes. We could certainly sharply reduce malpractice suits by telling every patient to either come into the office or go to the ER, and never renew any medicine or give any advice over the phone, because we can be sued for telephone advice. I also once flabbergasted a lawyer at a deposition; when he said "If you haven't written it down, you haven't done it", I answered "And what makes you think that if I did write it down I did do it?". For instance we all warn patients on sleeping pills to be careful when driving, but none of us forbid it. I know one doctor who photocopies the PDR warnings of every drug he prescribes, and gives one copy to the patient and puts the other in the chart.

Some results of the threat of malpractice: in at least two counties near Miami Fla., no neurosurgeon will cover the ER for automobile accidents; virtually no OB's teach or do forceps delivery, e.g. for a transverse lie, but proceed immediately to a C-section, and in 2 counties in Northern West Virginia there are no pediatricians, because they all moved northward across the river to a state with lower malpractice premiums. I was taught to tap the chest ("thoracentesis). In about 1% of the cases, in the best hands, there is a partial collapse of the lung (pneumothorax). So now all internists have pulmonologists or chest surgeons do it, because they do it more frequently, and therefore can defend against the incidence of pneumothorax more easily (and of course the chest surgeon charges more).

So now the doctor's mantra is not to avoid error, but to avoid being sued. This is not synonomous with practicing the best medicine. I even know some doctors who refuse to treat any lawyers or their families at all, just as many landlords in NYC refuse to rent to lawyers.

Again, every doctor wants to take the best possible care of his patient, but if 1/2500 infants is born with a birth defect, and 5% of aortic aneurysm repair patients die, and if 1% of hip replacements get infected, the doctor seems to get sued for every bad result. Although in theory the plaintiff has to show the doctor did something wrong, in practice the doctor has to show that he did everything right, and if he/she did, why was there a bad result? In American jurisprudience, if anyone has a bad result in anything, it is someone's fault (unless, of course you lose a lawsuit, and then it is never the lawyer's fault).

One final note: In NY State, they started keeping a record of the death rate for open heart surgeons (and later, their hospitals). The immediate result, as you might expect, is that cardiac surgeons took on fewer riskier cases where the patient has an estimated less than 10% chance of survival, no matter how the family pleads, because he doesn't want his death rate to go up. Several years ago there was a piteous Op-Ed piece about this in the NY Times, by a columnist who said it took him 10 days to find a cardiac surgeon willing to risk operating on his mother, and the surgery was not done at a major hospital teaching center.

I guess I should close with a repeat of a previous story. About 10 years ago, a California woman refused a pap smear for several years in a row, and her refusal was well-documented in the chart. When she died from cervical cancer, the husband sued the gynecologist. He convinced the jury that if the doctor had warned the patient properly, then any prudent patient would have agreed to the pap smear and found the cervical cancer. The jury agreed (!), and found against the GYN who now, of course, fires from his practice any woman who refuses an annual pap test or mammogram.

Sunday, October 17, 2010

Rx. Drugs, Pharmacology, and Side Effects Part I

I think it is important for the public to understand how and why drugs are used, the studies that are used to test for efficacy and side effects, and the importance of using drugs properly.

For starters, it is not true that the less of a drug you take, the less sick you are. Rather, since using any drug exposes you to its side-effects, which often are NOT dose-dependent, you should always take enough of the drug to get the maximum benefit, rather than see how little of the drug you can get away with. You certainly should not be like some of my patients who skip asthma inhalers to see if they really "need" it. In fact, if I suspect exercised-induced asthma in a patient, rather than going through pulmonary function tests with methacholine challenge, I would prefer to convince the patient that the inhaler is needed. So I ask the patient to use an anti-inflammatory inhaler one-half hour before heavy exercise every other time for the next 20 exercise sessions, and then ask the patient if he/she noticed an increase in stamina or time to fatigue/dyspnea. In this way the patient sees the need for the inhaler.

Treating high blood pressure is more of a challenge, because a patient (usually) cannot feel high blood pressure. However, after I tell them that the one event treating hypertension has been shown to prevent is a stroke, they all become faithful converts. Most patients seem to fear loss of function more than death or cancer.

Now how does the FDA require that drugs be tested? In the old days, human prisoners were used as guinea pigs, with time off their sentence used as an inducement to participate. Then it was decided that this was immoral, so now we first test on animals, such as white lab rats and guinea pigs, and we first look to see (a) if any organs are damaged (usually the liver), or (b) if tumors/cancers are induced. The problem, of course, is that all animals have different physiology and biochemistry than do humans. For instance only the guinea pig, along with humans, needs exogenous Vitamin C. All other mammals have the enzyme necessary to make Vitamin C. So already the internal milieu will be different. Then we try to figure out, experimentally, the LD50, i.e. the dose (mg/kg) that will kill half the experimental animals. Then we will try massive doses of the drug to make sure that the drug is not carcinogenic to animals. Of course, an increased dose for a short period of time is not physiologically equivalent to a lower dose over a longer period of time, but that is what we do. One problem with massive doses is the pure effect of a large dose: 8 glasses of water a day is fine for humans, but 80 glasses of water a day will quickly lead to death from dilutional hyponatremia and secondary brain swelling.

Now we have to see if the drug works, so we test the drug against a placebo, and look for a positive effect. Of course, if we already have a treatment for the disease or condition in question, which we usually do, then we test the drug against a drug that we know "works". The drug company runs the test to see if their new drug is "not inferior" to the standard drug for the condition. Later on, when they want to corner the market, they will run a different comparison drug to show that their drug is superior to their competitor. Still later, once the FDA approves the drug for conditions specified in the PDR (e.g. beta-blockers for hypertension), the manufacturer will look for a unique "off-label" benefit, i.e. a use not specified in the PDR. This is neither illegal nor immoral. So now physicians will also use beta-blockers to prevent or reduce the incidence of migraine headaches, and also give beta-blockers (under most conditions) to survivors of heart attacks to lessen the chance of a second heart attack.

The FDA requires the drug company to list all observed side-effects in the PDR. The side effects can either have been observed, or included because of the class of drugs. Remember, if the drug company warns you about a possible side effect in the PDR, it is difficult for you to sue them if you get the side effect. Sometimes this is overdone, as in the case of steroid creams which have the same steroid warnings as to high-dose oral medicine. Later published studies may show that the theoretically predicted side effect does not occur, but unless the drug company wants to spend the money to submit new studies to the FDA, this result never appears in the PDR.

BTW, over-the-counter drugs have a much less stringent warning requirement, which is usually to call your doctor after several days or doses. Nowhere on any aspirin bottle, for instance, are you warned that if you have nasal polyps and asthma, a single dose of aspirin can kill you by causing severe allergic bronchospasm. Maybe that's why when Bayer first patented aspirin it was available by prescription only.

Now, what happens after the drug is released by the FDA to be available to the public through a doctor's Rx? All doctors are requested to report any unusual occurrences (lab tests, physical side effects, acute medical attacks) that occur to patients on the drug. The problem is that the drug initially was tested on naive patients, i.e. on patients on no other drug. But the typical patient in his/her sixties is usually on five to seven drugs (diabetes, hypertension, high cholesterol, GI reflux, etc.) so the new drug is added to the chemical mix, and now we have the patient undergoing a new drug test (i.e. 6 drugs plus the newbie) that has never been studied before, and there are certainly no published results dealing with this particular combination. So if the doctor reports an effect, it is initially impossible to know if the effect is due to the drug (if indeed i t is) or to the combination of the new drug with one of the other six. And no one, to my knowledge, when they file an incident report with the FDA include any information on any artificial sweeteners the patient may be ingesting, which is, of course, a 7th drug.

More to come in a later blog, but one caveat of which you may not be aware. NO governmental body tests, clears or approves any new surgical technique. So if a doctor can convince you to be the first patient in the world to undergo robotic prostate or heart surgery, so be it. And no one really tests new drugs on children or pregnant women, for obvious reasons. I personally feel that any parent who volunteers his/her child for any new drug test is guilty of child abuse!

Saturday, October 16, 2010

Stress, Part II

All of us, by being civilized by our parents, our schools and society, become stressed and, usually neurotic. Freud in his "Civilization and Its Discontents" showed that in his opinion, the best we can be after being civilized is a well-adapted neurotic. Huck Finn put it more succinctly when he talked about how he would no longer be the same person after being civilized by soap and water and schooling. Karen Horney discussed the problem at greater length in "The Neurotic Personality in our Time".

I am not going to discuss Rousseau's "noble savage" or the French view of the importance of the school system in instructing its citizens how to think, or even McKinley's bloody, misguided attempt to "Christianize" the Philippines after the Spanish-American War. I guess for McKinley the Philippines' being instructed in Catholic catechism and being converted from paganism didn't count, since he was a Protestant. And that's where we learned the virtues of waterboarding in getting prisoners to talk , only to turn around and try judicially and execute those Japanese POW commandants who waterboarded American POW's.I'll only mention in passing Jacqueline Kennedy's deathbed comment that she wished she had "drunk more champagne", and observe that few if any humans on their death beds
said that they wish they worked harder and did more things that they found emotionally distressing, rather than having more fun and more orgasms. (As an aside, I once had a girlfriend who felt that a night without an orgasm was a wasted night, but that is a different story, and from a different country.)(And no, the "wench" as Marlowe called her, is not dead.) At least we were never as brutally civilized towards a greater good for the greater end as were the Kulaks in Stalinist Russia, the Chinese peasants and intellectuals in the "Great Leap Forward", or anyone who wore glasses and might be an intellectual in the horrifying regime of Pol Pot in Cambodia. The Civil Wars in Africa defy anyone's explanation, except for the trite observation that there, God appears to be dead.

Let us note in passing that the rules in elementary school seem to be created by women for girls,, with its emphasis on neatness, minimal direct confrontation, the importance of group behavior, and the superiority of means over ends (might does NOT make right, unless the teacher in bawling you out). On the other hand,in the business world and the army rules are made by men for men, where the ends justify the means, the only people you may not lie to are close friends, and fellow workers (military, medicine), your word (but not your valuation on the stocks you are selling) is your bond, and cheating is forbidden only at the poker table (but not on the golf course, where many unofficial Mulligans are taken). The same is true of all colleges, where internet-driven plagiarism seems to be the norm, but the lines of battle are not as clearly marked out.

In thirty years, I have found that the more you do that is emotionally conflicting, the angrier you get. Since women are not allowed to show anger directly, this gets converted into depression,, or into anxiety or panic attacks when their subconscious is afraid that the anger will erupt in a socially unacceptable way. Men just grab the nearest M-16 or AK-47 and shoot up their workplace, so that if the flags fly at half-mast at the post office, it means they are hiring again.

But above all, this suppressed anger and depression transforms itself into bodily complaints. The pain threshold in every body organ gets lowered. It becomes an effort to get out of bed, you gain weight, stop exercising, drag yourself to work and back to home. Men nick themselves while shaving, women lose their appetite and sex drive, as do men, and both report (to me , when I ask) even a decrease of romantic/sexual dreams and masturbation. I will admit, however, that female masturbation has increased with good orgasmic results ever since the invention and sales of the Sybian.

Women are trained by society to never think of themselves first, and to feel guilty if they do. The majority cannot turn off their cellphones for one hour, in case an "emergency comes", and they must imagine that 911-EMT is not up to the job. If a daughter gets divorced, the father feels bad for the daughter and the mother feels guilty ("what did I do wrong?). It isn't a coincidence that ever since the Greek habit of capturing barbarians to be slaves died out that Hinduism, Orthodox Judaism, Rigid (Calvinist) Protestantism, and all Orthodox Moslem priests believe that a woman should be subservient to man, a fact that carried over into Napoleonic Law, when married women were not allowed to own property on their own.

If you continue to do what you don't want to do emotionally, you will eventually crash as the brain runs out of the psychic energy it needs to control and repress those "socially unacceptable" thoughts of your anger that you have been reduced to emotional slavery, never doing what you really want to do, and always feeling that YOUR feelings, wants, needs and desires don't count and we become abjectly depressed, which we continues until we feel free again.. And then people around you will ask why you changed, because they didn't. And the more "noes" you give, the happier you will be, and the more energy you will have.

I leave you with three thoughts: (1) "No" is a complete sentence not only where sex is concerned, but in all phases and activities of life, whether you are going away for a college reunion or baby-sitting, and needs no explanation. (2) You are always right, so if the play bores you, leave at intermission and read a book; the play rarely gets better.
(3) If you have an increase in psychic pain, or develop a new muscle spasm or headache or eye twitch or GI distress or--- you truly are under pressure, and need to "get out of Dodge" as rapidly as possible. You can always say you have to go to church or synagogue right now---people may think that is odd, but no one will criticize you. Then you can sit in a pew in quiet, recompose your thoughts, and meditate on how important you really are.

'More to come when I see the comments on this blog topic.

Friday, October 15, 2010

Does Calcium Intake Increase Cardiac Risk?

There was a recent article published in the British Medical Journal whose results suggested that calcium supplements increased heart attack risk. This was a meta-analysis combining 12 different studies with different groups of people, etc. The results of a meta-analysis are ALWAYS suspect, since they are a mathematical construct which may or may not represent the true state of affairs. The concept of combining several studies, none of which reached statistical significance, and re-analyzing them as a group, hoping the "law of large numbers", by combining them, would produce a scientific result was first advanced by Peto in several articles in the Lancet over 10 years ago, and I refer my more mathematically inclined readers to his papers. I was never convinced of the validity of his analysis and conclusions, and feel strongly that the results, if any, of a meta-analysis should be treated as a hypothesis to be tested rigorously by a proper, future medical study.

I discussed my mathematical objections at great length in this blog in my issue of May 30, 2009. The essential point is that the writer chooses which studies to include and chooses which of two methods he will use for analysis as to clinical significance: one depends on randomness (and hence the law of large numbers), and the other does not, and the two methods can easily give opposite results. I refer my interested readers back to the issue entitled"Analysis of Meta-Analysis, at

I feel that it is unfortunate that authors of meta-analyses do not mention at the end of their articles the reasons that their particular analysis may be mathematically and statistically suspect.