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.

Generic Drugs, Brand Names, and Tier I Drugs

Most people think that generic drugs always work, that all Tier I drugs of an HMO are pharmacologically equivalent,and that generic drugs are cheaper. Only the last statement is true, and the pharmacies also love generics because they have higher profit margins. (Brand name $80, charge to you $100, profit$20; generic $20, price to you $50, profit $30.) However, the generics do not always work as well as brand names, because there can be different "inert" compounds added to the parent drug to make the tablet. The FDA requires that the blood levels of the generic be the same as the brand name (+/- 10%), but only the brand name drug has been tested for clinical efficiency. There is no way of comparing tissue levels of the brand name drug to the generic, and this is especially important with drugs that act on the central nervous system (tranquilizers, sleeping pills, pain pills) after crossing the blood-brain barrier. Again, no generic is tested for clinical efficiency against the brand name drug.

The blood-brain barrier is nature's way of protecting the brain from noxious compounds that are dissolved in your blood. A drug has to cross the blood-brain barrier (through capillary walls) to reach the brain and achieve its effect. Whether a particular drug can do this is usually only determined by trial and error. For instance, penicillin readily crosses the blood-brain barrier, and is therefore extremely active in treating meningitis. Keflex, a cephalosporin, cannot cross the blood-brain barrier, and is therefore useless in treating meningitis, although it generally can treat any soft tissue infection or lung infection that penicillin does.
Within a particular class of drugs (e.g. beta-blockers) if a drug is lipophilic, this affects the ability of the brain to absorb the drug once it gets there. Marijuana is extremely lipophilic, so it is released very slowly from fatty tissue in the brain, and your urine can test positive for at least two weeks after inhaling it. There can also be subtle differences within a class of drugs: Coreg is the only beta-blocker shown to reduce microalbinuria in diabetic patients.

When it comes to other groups of drugs, there is wide human variation in responsiveness, since we are all biochemically different. Claritin and Zyrtec are over-the-counter (OTC) anti-histamines, and sometimes one will work on a patient's allergies, and sometimes the other, since they are chemically very different. Allegra is a prescription antihistamine, which works better in many patients, but unlike Medicare Part D, most HMO's ask me to certify that both OTC drugs did not work before they will pay for Allegra. The same problem arises is proton-pump inhibitors (PPI's) for acid reflux. The HMO's want me to try the patient on OTC Prilosec before paying for Prevacid, Aciphex or Nexium. Furthermore, if I want to prescribe Nexium at a double dose to suppress acid symptoms, which some patients need, I generally have to send them to a GI doctor to have the payment okayed. Remember, if you are forced to buy an OTC drug, your co-pay is 100%, and the cost to your HMO is $0.

The worst scenario is in CNS-acting drugs. In my experience, generic Ativan works less than 10% of the time, so if a patient does not respond to generic Ativan, I am not sure of the cause. I also have found that generic Prozac works less than 50% of the time, and there are treatment problems with generic Wellbutrin. If a patient responds well to the anti-depressant Lexapro, the HMO generally asks me to switch the patient to a generic form of Celexa, even though they are chemically totally different drugs. I have also found that the beta-blocker Nadolol is excellent prophylaxis against migraines, as is Inderal LA, but since only Inderal (which requires dosing 4 x a day) is available in a generic form, the LA Rx. is generally not paid for.

In your own case, I am certain that aspirin, Advil, and Alleve all work differently in you, even though they all are NSAID's (anti-inflammatories).

Viagra, Levitra, and Cialis all work to treat erectile dysfunction, but sometimes one drug will work, and sometimes another.

The main point is that drugs with the same physiological endpoint in the human body have different chemical structures, and they cannot all work equally well.