Drugs, Pharmacology, and Humans, Part I

     Many patients do not fully understand the purpose of medication, and fall into the false belief that the less medicine they take, the less sick they are. While it certainly is  true that the patient who takes no medicine is fundamentally healthier than the patient who takes medicine, in some cases the patient who takes medicine (e.g. statins to lower cholesterol) may end up being healthier (have less chance of a heart attack) than the patient who takes none. The purpose of most medications  is  to try to return the patient to the "normal" state, i.e. one in which a doctor's attention is not needed. I will discuss several classes of medicines in this blog.

     I first want to emphasize the fact that not all side-effects are dose-dependent. Therefore any medicine you take can cause side effects without benefits if the dose is too low. Thus unless you take the full dose of the medicine as prescribed by your doctor, you are exposing yourself to possible side effects without getting the full benefit of the medicine. I have seen patients try to self-taper asthma, diabetes and blood pressure medicines, always without any benefit to them.

     Generics usually work as well as brand-name medicines, with the notable exception of any medicine that acts on the CNS system---i.e. the brain (and the spinal cord). This is because there is a natural blood-brain barrier that prevents many drugs from diffusing from the blood stream across the capillary wall and into the brain cells. Most notably, I have found that generic Prozac, generic Wellbutrin, and especially generic Ativan do not always have the same effect as does the brand name drug.

     Many patients ask "How do I know that we will not find out 20 years down the road that the medicine you are prescribing will not be found to have dangerous side effects?" Of course they never ask this question about the sweetener in diet sodas, the chemicals in herb tea, the various vitamins and pills they buy in a health food store, etc. In fact virtually no food that we ingest has been examined for long-term effects with two notable exceptions: alcohol in any form can reduce your risk of a heart attack, and although reducing the amount of salt in your daily diet can lower your blood pressure, this dietary intervention has  NOT been shown to  reduce your risk of a heart attack or to  increase your life span.

     Blood pressure medicine: Like diabetes, high blood pressure can be a "silent killer". The most destructive result of untreated hypertension is a stroke, which often leads to either death or permanent paralysis of a limb or one side of the body, along with the loss of speech, etc. And we know from clinical trials that treating high blood pressure with drugs can greatly lower your risk of having a stroke. We have no way of predicting which  bodily organ the high blood pressure will affect. If untreated it can cause ministrokes, heart failure, kidney failure, and /or damage to your vision. Just as a low salt diet can lower pressure, a diuretic ("water pill") is and should generally be the first line of treatment for this disease. A diuretic increases the amount of salt excreted in your urine, and thereby lowers the total amount of salt in your body. If it is not the first medicine you are given, it should be the second, as an added treatment, because lowering the amount of salt in your body potentiates the anti-hypertensive effect of all other classes of blood pressure-lowering medicines. The other medicines used to treat hypertension are beta-blockers, calcium channel blockers, ACE inhibitors, ARB's, other vasodilators, and anti-renin drugs.

     The choice of a second anti-hypertensive drug if a diuretic alone does not achieve a low enough blood pressure depends on the type of individual as well as his/her underlying medical conditions and medications that are already being taken. Male, female, black, white, old, young, heart failure, asthma, COPD, GERD, smoker, chronic edema, are all some of the factors that will affect the choice of a second anti-hypertensive. I would also like to state that for reasons that we do not understand, black males are the most likely to suffer a stroke from untreated hypertension, and therefore blood pressure must be treated aggressively and closely monitored in this group.

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!

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.