Anesthetics

The easiest pain to bear is someone else’s. In the preanesthesia era, the prospect of surgery was so terrifying that it was not uncommon for a tough-hearted man to commit suicide rather than go through that unbearable, excruciating agony. It is hard to believe t hat t here was a time when nothing was effective to a lleviate surgical pain. The patients were simply strapped down and that was it. As a consequence, speed was the most important attribute of a surgeon in those days. A great English surgeon, Robert Liston at the University College Hospital, once boasted that he had amputated a leg in 29 seconds, along with a testicle of his patient and a finger of his assistant. The operation rooms were often strategically located at the tops of towers in the hospitals to keep fearful screams from being heard. During wartime, surgeries were even worse than battlefield injuries, because during the fight soldiers were temporarily “hypnotized” and became oblivious to pain. Before anesthesia, surgeons resorted to whatever means were available to deaden the pain oft heir patients during operations. The three most popular methods were alcohol, ice, and narcotics. Legend has it that a surgeon first conceived the idea of operating during a patient’s alcoholic coma when he noticed that a drunkard had had parts of his face chewed away by a hog but was not aware of it during a drunken stupor. Chinese surgeon Bian Què (401–310 B.C.) was reported to have operated on a patient’s brain using herbal extracts to render him unconscious more than 2,000 years ago. Hua Tuo (115–205 A.D.) made his patients take an effervescing powder (possibly cannabis) in wine that produced numbness and insensibility before surgical operations. Cold deadens pain by slowing the rate impulse conduction by nerve fiber. Some surgeons used ice to numb limbs before amputations. This method was invented by Baron Dominique Jean Larrey (1766–1842), surgeon of Napoleon’s Grande Armée.

Drugs to Kill Germs

Surgical standards before antiseptics starkly contrasted to the surgical art today. Conditions were especially atrocious for amputations and for compound fractures in which the bones penetrated the skin and were exposed to the air. Patients who did not die from the surgery often died of postsurgical infections and subsequent blood poisoning. James Young Simpson, a Scottish surgeon and obstetrician who was the first to use chloroform as an anesthetic (see chapter 7), once said of surgical operations: “A man laid on the operating table in one of our surgical hospitals is exposed to more chance of death than the English soldier on the battlefield of Waterloo.” The mortality rate in hospitals after surgeries was 40–60%. During the American Civil War, the surgical fatalities were just as horrific as those from combat. A commonly used antiseptic in the battlefield was exceedingly corrosive nitric acid (HNO3— ouch!). However, in 1867, Joseph Lister’s use of carbolic acid, whose chemical name is phenol, as an antiseptic changed the prospect of surgery. In Greek, septic means “rotten.” Antiseptics, in turn, are substances used to treat a person to prevent the occurrence of infection. They are also known as germicides. Joseph Lister (1827–1912) was born to a Quaker family in southern England. His father, Joseph Jackson Lister, was a wine merchant and a wellknown microscopist. In his youth, Joseph Lister practiced surgery under the tutelage of James Syme in Edinburgh and married Agnes, his mentor’s daughter. He had to give up his religion because Quakers at that time did not allow marriages outside the faith. That turned out to be a worthwhile sacrifice, because his marriage brought him lifelong joy. Lister became a surgeon at Glasgow Royal Infirmary in 1860. He was acutely conscious of the appalling conditions in the infirmaries and determined to do something about postsurgical infections. In 1865, Lister was introduced to Louis Pasteur’s exploits with germs by Thomas Anderson, chair of the chemistry department at Glasgow. Afterward, he personally repeated all the experiments that Pasteur published. However, simple and direct applications of the Pasteurization process would not be ideal during surgery—after all, boiling patients would not be acceptable.

Anti-Inflammatory Drugs

Inflammation and immunity, like all other normal reactions of the body, are meant to preserve or restore health. They can nonetheless cause a range of uncomfortable symptoms. Inflammation is such a complicated process that one would have a hard time reaching a consensus on its definition. Historically, inflammation was one of the earliest recognized and defined diseases. Two thousand years ago, Roman physician and encyclopedist Aulus Cornelius Celsus (25 B.C.–50 A.D., not to be confused with Celsius, the unit for temperature) described the four cardinal signs of inflammation: calor (warmth), dolor (pain), tumor (swelling), and rubor (redness). The fifth element of inflammation, functio laesi (loss of function or movement), was noted later. Classic inflammatory diseases include rheumatoid arthritis and Crohn’s disease, an inflammatory bowel disease. However, evidence is mounting that inflammation is implicated in many diseases that are not normally considered inflammatory. For instance, when arterial plaques become inflamed they can burst open, prompting a myriad of heart diseases. Inflammatory bowel conditions greatly increase the risk of colon tumors. Even diabetes has been associated with a number of inflammatory compounds. It was hard to define what inflammation was, but finding a remedy was even more challenging. Aspirin, available in 1880, represented possibly the first really effective treatment for inflammation, whereas cortisone and other corticosteroids were not available for the treatment of rheumatoid arthritis until the early 1950s. Louis Pasteur stated, “Dans les champs de l’observation, le hazard ne favorise que les esprit préparés” [In the field of experimentation, chance favors the prepared mind]. Like numerous cases in drug discovery, Philip S. Hench’s discovery of cortisone for the treatment of rheumatoid arthritis illustrates Pasteur’s point. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by pain, swelling, and subsequent destruction of joints. Until the late 1940s, there was no viable treatment, and, understandably, pessimism prevailed in medical society about its prognosis. Even William Osler, one of the greatest physicians, said “When an arthritic patient walks in the front door, I want to run out the back door!” The situation did not change much until Hench discovered a “miracle drug” in 1949.

Drugs of the Mind

Alcohol produces a range of central-nervous-system-related biological effects, including anxiety reduction, euphoria, sedation, disinhibition, aggression, blackouts, tolerance, addiction, and withdrawal. The Chinese have used alcoholic drinks since 5000 B.C. Presumably, man ventured to drink the liquid from fermented grain, liked the intoxicating effect, and started to make it on purpose. Alcohol has been used as an anesthetic for millennia (see chapter 7). Alcohol is indispensable in medicine as a solvent. Laudanum, a staple of the medicine chest in the nineteenth century, was simply an alcoholic solution of opium. NyQuil, a cough syrup, and Listerine, an oral antiseptic, all contain copious amounts of ethanol. Alcohol has beneficial effects when consumed in moderate amounts. Research strongly suggests that moderate consumption of alcohol, especially red wine and dark beer, seems to have protective effects on the heart. The hallmarks of the Mediterranean diet are olive oil and red wine, and people from such countries have fewer cardiovascular events. Flavonoids, the active principle in red wine, are thought to exert beneficial cardiovascular effects. According to the Bible (Genesis 9:20–21), Noah was the first man who discovered wine: “Noah, a man of the soil, was the first to plant a vineyard. When he drank some of its wine, he became drunk and lay uncovered inside his tent.” The New Testament gives an account of Jesus performing his first miracle—turning water into wine. Despite the beneficial effects of moderate alcohol consumption, excessive use of alcohol damages the brain, heart, and liver. Even mild drunkenness can cause temporary loss of memory. The liver metabolizes alcohol with an enzyme called alcohol dehydrogenase, which turns alcohol into acetaldehyde. Because acetaldehyde is acutely toxic, people—including many Asians—who lack alcohol dehydrogenase cannot tolerate much alcohol. This is the reason that their faces become flush when they drink alcohol and that there are fewer incidents of alcoholism in Asians. Alcoholism is known to cause psychosis and alcoholic dementia. To fight the “demon rum,” on January 16, 1919, the U.S. Congress passed the Eighteenth Amendment, prohibiting “the manufacture, sale, or transportation of intoxicating liquors.” It was repealed 14 years later, the only amendment to the U.S. Constitution that has been repealed.

Sex and Drugs

The word aphrodisiac comes from the name of Aphrodite, the Greek goddess of sexual love, fertility, and beauty. An aphrodisiac is any drug that arouses the sexual instinct. Throughout recorded history, humans have gone to great lengths in pursuing enhancement of sexual activity and desire. In Shakespeare’s Midsummer Night’s Dream (II, i), Oberon begged for the love potion:… Fetch me that flower; the herb I show’d thee once: The juice of it on sleeping eyelid laid Will make a man or woman madly dote Upon the next live creature that it sees… Perhaps the best-known aphrodisiac is alcohol, which was recognized thousands of years ago for its possible aphrodisiac properties. Shakespeare described the effect of liquor through the porter in Macbeth (II, iii):… Lechery, Sir, it provokes, and unprovokes; It provokes the desire, But it takes away the performance. Therefore much drink may be said to be an equivocator with lechery; It makes him, and it mars him; It sets him on, and it takes him off; It persuades him, and disheartens him; Makes him stand to, and not stand to; In conclusion, equivocates him in a sleep, and, Giving him the lie, leaves him…. Aphrodisiacs are not a mere recreational curiosity in medicine; they may genuinely help some patients on antidepressants who suffer decreased libido as a side effect. According to the mechanisms of action, libido lifters can be divided into seven categories:… 1. Serotonin antagonists: cyproheptadine and granisetron 2. Adrenergic antagonists: yohimbine and trazodone 3. Cholinergic agonists: bethanechol chloride 4. Dopamine-enhancing drugs: bupropion, amantadine, and bromocriptine 5. Autoreceptor agonists: buspirone and pindolol 6. Stimulants: amphetamine, methylphenidate, and ephedrine 7. Herbals: ginkgo biloba and L-arginine… Aphrodisiacs can be obtained from plants and animals or made through chemical synthesis. Although many aphrodisiacs have not been rigorously proven effective in clinical trials, in reality, a psychological boost is likely enough to help, because many sexual problems are “in the mind” anyway.

Cancer Drugs: From Nitrogen Mustards to Gleevec

Whereas infectious diseases are the scourge of developing countries, cancer is the most significant affliction in developed countries. At the beginning of 2005, the American Cancer Society announced that, for the first time, cancer had surpassed heart disease as the number one killer of Americans. Cancer, which is the uncontrollable multiplication of cells, has been in existence as long as animals have; evidence of cancers has been found in dinosaur bones. Cancers have also been found on mummies dating back 2,500 years. An operation to remove cancer was documented in the Ebers papyrus found in Egypt. In ancient times cancer was a relatively rare disease, because infectious diseases often made the life span so short that cancer had little chance to proliferate. Hippocrates (460–370 B.C.) coined the word cancer, which means “crab” in Greek. There are over 110 types of cancer, which can be divided into four categories depending on the tissue involved: carcinoma, lymphoma, leukemia, and sarcoma. Carcinomas are the most common, with 85–90% of all cancers falling into this category. Carcinomas are tumors that originate in epithelial tissue such as skin, breast, lung, prostate, stomach, colon, ovary, and so forth. Lymphomas are cancers of the lymphatic system. Leukemia is the cancer of the blood, bone marrow, and liver. Sarcomas, the rarest of all four types, are tumors arising from cells in connective tissue, bone, or muscle. It seems inconceivable that we had almost no clue about the origin of cancers up until the mid-1970s, despite the existence of cancer that predates human life. The debate raged on as to what caused cancer, with one camp believing that carcinogens (cancer-causing agents such as chemicals, X-ray, and ultraviolet light) were to blame, whereas the other thought that viruses were the culprits. The carcinogen theory took root first. As early as 1775, British doctor Percival Pott made the astute epidemiological observation that young English boys employed as chimney sweeps were more prone to develop scrotal skin cancers than their French counterparts. Further scrutiny revealed that the continental sweeps bathed more frequently after work, which prompted Pott to speculate that long exposure to coal tar caused skin cancer. In 1915, 140 years later, Katsusaburo Yamagiwa and Koichi Ichikawa confirmed Pott’s theory in an animal model.

Diabetes Drugs

Diabetes mellitus is a multisystem disease associated with the loss of control of physiological glucose concentrations in the blood. The disease is broadly broken down into two types based on factors that include age, acuteness of onset, underlying glucose-handling deficit, and therapy. Type 1 diabetes usually manifests acutely in the young, secondary to some underlying insult (possibly infectious) to the islet cells of the pancreas, resulting in an absolute lack of insulin. Type 2 diabetes is more frequently associated with maturity, obesity, and gradually increasing blood glucose concentrations; it may be asymptomatic for some time and discovered on routine glucose screening. In fact, as weight increases among the general population of the developed world, type 2 diabetes is becoming an epidemic. Type 1 diabetes always requires insulin replacement therapy, whereas type 2 can frequently be controlled with diet, weight loss, and oral medications that enhance residual pancreatic function. Diabetes has been known since antiquity. In fact, the term diabetes mellitus comes from the Greek meaning “siphon and honey” due to the excess excretion (siphon or faucet) of hyperglycemic (sweetened, or honeyed) urine. In ancient times, most cases of diabetes were of type 1, with acute onset in the young, which was often fatal. Type 2 diabetes was extremely rare when sources of nutrition were scarce and obesity was not prevalent. Diabetes was also known as “wasting” because diabetics were not able to metabolize the sugar content of food and eventually died from wasting away. Because of the effect of excess blood glucose, the blood of the diabetic is hyperosmolar (concentrated), and this triggers compensatory thirst (in an attempt to dilute the hyperglycemia and return the blood to a normal concentration). This excess thirst results in the common diabetic symptom of polydipsia (excessive drinking secondary to thirst, resulting in the urge to drink frequently) and polyuria (excess urination). Even before many modern diagnosis tools became available, savvy doctors could diagnose diabetic men just by looking at their shoes for the telltale white spots from urine with high sugar content. In fact, tasting urine samples of diabetics was a routine diagnostic tool for diabetes. Even the breath of a severe diabetic was sweet—a sickly smell as a result of acidosis. In addition, it has been mentioned that ants would track to the urine of diabetics.

Cardiovascular Drugs: From Nitroglycerin to Lipitor

Cardiovascular diseases are the leading cause of death worldwide and are projected to remain in the lead through 2025. Heart-related diseases include angina, arrhythmia, atrial fibrillation, congestive heart failure, hypertension, atherosclerosis, myocardial infarction (heart attack), and sudden cardiac death. More than 300,000 Americans suffer sudden heart attacks each year. In addition, one of the more important recently identified drug-induced cardiac events, which has occasionally resulted in drugs being withdrawn, is drug-induced torsade des pointes. This is a rare, fatal arrhythmia that has been associated with some drugs that prolong the QT interval of the electrocardiogram (ECG). Hypertension is America’s number one chronic disease. Fifty million Americans, one in six, suffer from high blood pressure. Similarly, high blood pressure affects about one-sixth of the world’s population (1 billion people) worldwide—mostly in the developed world. If uncontrolled, it can lead to heart attack, heart failure, stroke, and other potentially fatal events. Great strides have been made during the past 50 years in conquering cardiovascular diseases. Cardiopulmonary resuscitation (CPR) was developed by a group of researchers at the Johns Hopkins University in 1961. The 1960s also saw the emergence of beta-blockers. Calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and statins appeared in the 1980s and the 1990s. Angiotensin II receptor blockers (ARBs) also emerged in the 1990s. The heart, about the size of a person’s fist, beats about 2.8 billion times in a lifetime, pumping blood and oxygen through the body. Although its function was shrouded in mystery for centuries, mankind has come a long way in understanding how the heart works anatomically and physiologically, although we haven’t made much progress in understanding its “emotional” nature. Greek philosopher and anatomist Aristotle (384–322 B.C.) was the founder of biology. He was very interested in human and animal anatomy, especially the cardiovascular systems in higher animals. In his books he described, for the first time, the human blood system with an emphasis on the deeper-lying vessels. He incorrectly believed that the heart was the organ in which emotions were generated, whereas the function of the brain was to cool the blood. More than 500 years later, the German-born Roman physician Galen (130–200 A.D.) made two revolutionary discoveries about the cardiovascular system.

Reflections

In this book, I have chronicled eight categories of medicines. As a testament to the changing times, the old European master-apprentice relationship between drug discoverers is a thing of the past. This truth is exemplified by the feud between Selman Waksman and Albert Schatz (see chapter 2). I have no doubt that Waksman sincerely believed that he was the one responsible for the discovery of streptomycin. After all, streptomycin was the fruit of decades of his endeavor with soil microbiology in general and actinomycetes in particular. Schatz happened to be at the right place at the right time. Waksman’s conviction would have been completely acceptable if it had taken place just a century ago. Since the new millennium, vilifying the pharmaceutical industry has become fashionable. One of the crimes that the pharmaceutical industry is accused of committing involves the so-called me-too drugs. Even Merck’s former head of research Ed Scolnick once declared: “We at Merck do not do me-toos, if it is not innovative, we are not interested.” But history is replete with examples in which incremental improvements of a prototype yielded much better drugs. The first ACE inhibitor was teprotide, a peptide with nine amino acids, inspired by a Brazilian snake venom extract. Peptides did not survive in the stomach juice, which broke them down into amino acids. Therefore, the prototype teprotide could be used only by IV injection. With brilliant insight, David Cushman and Miguel Ondetti at Squibb Pharmaceuticals designed and synthesized captopril. Captopril was the first oral ACE inhibitor, which contributed tremendously to the management of hypertension. In theory, captopril is indeed a “me-too” drug to teprotide, but most patients would certainly prefer to take an oral drug than to have injections for the same purpose. Because captopril has a short duration of action, it has to be taken more than once a day. It possessed a trio of shortcomings: bone marrow suppression (due to a decrease in circulating white blood cells), skin rash, and a loss of taste.