Drugs are chemical compounds that modify the way the body and mind work. Most people think that these biological activities should help or heal sick people or animals.
There is, however, no known drug that is not harmful or even poisonous at high doses, and much of the scientific work on drugs has attempted to widen the gap between effective and toxic doses.
The word drug has acquired bad connotations in recent years because the widespread abuse of a few chemicals that affect the central nervous system has become a serious sociological problem. Nevertheless, drugs act on many other organs in the body, can benefit as well as harm the nervous system, and have made possible a revolution in the way modern doctors treat disease.
Just as there is no health benefit without potential toxicity, there is no absolute goodness about drugs. However, their enormous health benefits outweigh the drawbacks in individual cases. The history, discovery, manufacture, action, acceptance, and rejection of drugs are the themes of this book.
It used to be said that what distinguishes humans from animals is that people take drugs. This old adage is no longer quite true. Rats and monkeys that have been addicted experimentally to some drugs will inject themselves with those drugs to support their addictions. But otherwise the old saying still holds.
The history of drugs is shrouded in the beginnings of the human race. Alcohol was made, drunk, and used to excess as far back as memory and records go. Tobacco (Nicotiana), hemp (Cannabis sativa), opium poppy (Papaver somniferum), and other plants containing drugs have been chewed and smoked almost as long as alcohol, and coffee has been served in the Middle East throughout that area's history.
Tobacco was carried from Virginia to England by Sir Walter Raleigh, whose pipe smoking prompted Elizabeth I to remark, "I don't like this herb." Of course, the queen did not know anything about tar and nicotine, but she became one of the first people to initiate the acrimonious debate about tobacco constituents that we face today. Likewise, the effects of cannabis have given it a bad name.
Coffee was introduced by the Ottomans to the Western world when the Turks made a foray into central Europe in the 16th century. Its active alkaloid, caffeine, is often on the forbidden list for patients suffering from rapid heart beat or angina. Some of the chemicals that flavor coffee, such as esters of caffeic acid, stimulate cardiac hormones and thus add to the danger of disturbing the rhythm of the heartbeat.
Apes and humans are believed to have taken their separate evolutionary ways some 5-10 million years ago. In those times, prehumans, almost humans, and later, nomadic groups of obviously human individuals roamed the landscape in search of food and shelter.
The driving forces behind this foraging behavior were the need to defend themselves against the environment and the need to reproduce their species. The earliest humans were often threatened by malnutrition or even starvation; by predators-both animal and competing or cannibalistic human hunters; and by parasites and degenerative diseases.
The kindling and taming of fire further separated humans from animals. Fire gave primitive nomads some protection from cold and a way to make food more palatable.
The earliest records of their short and deprived years, estimated as no more than a couple of decades, are wall paintings and carvings on rocks that have endured for thousands of years in jungles or deserts.
The pictures give us little insight into any healing arts those forebears may have invented. Probably accidental discovery of the healing powers of roots, barks, leaves, and berries and of nutritional sources of proteins and starch occurred even during those earliest stages.
Only recently, 10,000-20,000 years ago, nomadic tribes began to settle down in some parts of the world and formed small agricultural communities. This development was one of the most profound changes in the history of the human race.
Planting seeds, domesticating animals, and erecting permanent shelters for humans and animals improved nutrition, provided more comfortable, though still primitive, living accommodations, and started the societal bonds that developed into villages, towns, and cities, where the first truly historical times began.
At this stage, when people began to live close together, certain rules were established to bring needed order out of unstructured conglomerated living. Strong individuals emerged as the leaders of tribal or village communities.
Ambitious leaders increased their power by shrouding their personalities and decisions in mystery, elevating them to an exalted reputation.
Thus emerged the concept of superhuman beings, of gods with powers over natural phenomena such as fertility, family bonds, lightning, and the awesome power of storms.
When the demands of multiple deities for sacrifices grew excessive, all these powers and supernatural beliefs and superstitions were united in monotheistic religions, often after catastrophic wars and through a longing for peace.
The deities were represented ritualistically by priests and priestesses, and valuable sacrifices offered by the people further enhanced the splendor and power of these leading personalities.
Part of the influence of these commanding individuals came from the personal help they could give to sick, wounded, and otherwise afflicted members of their groups. The medicine man, witch doctor, or shaman was the first person to turn to in distress.
Sometimes authority lay in an influential woman who functioned as priestess, nurse, and midwife. In most cases, power, enforced by superstition, centered in a dominant male recognized as healer, priest, judge, and leader in peace and war. A knowledge of healing herbs formed part of his power base and prerogative; among his duties was applying such healing products when needed.
Botanical specimens taken from trees, shrubs, and other plants formed the mainstay of most of these early medicines. Sometimes the shaman deepened the mystery of the power of his medication by adding parts of animals, and even human hearts.
Some mind-induced (psychosomatic) illnesses were probably improved by suggestions, just as they are today. Also, some functional disorders responded to the active chemicals in suitably chosen plants. It must have been hard for a medicine man to decide which plant to give a patient. Trial and error was the order of the day.
Even after a healing effect was found in a certain plant, it was probably used for a variety of illnesses, whether identical in symptoms or only vaguely similar. Modern physicians still face complicated choices in diagnosis and drug therapy in spite of help from analytical tests, X-rays, ultrasound, nuclear magnetic resonance visualization, blood cell counts, urinalysis, and other laboratory aids.
We can only imagine the dilemma of an ancient medicine man, who was guided only by vague symptoms such as a generalized pain, nausea, fever, or convulsions.
In such a dilemma, and without any knowledge of anatomy or pathology, some herbal concoction was given in the hope that it would work. The medicine man undoubtedly added prayers or exorcisms to the medication and believed sincerely that his ministrations would aid the afflicted.
Cynical healers also appeared. In Roman times, predictions about world affairs as well as the course of a patient's disease were based on the inspection of the intestines of newly slaughtered chickens. There was a saying that described one of these healer-seers (called a haruspex) encountering another member of the guild: Haruspex, haruspicem videns ridet ("When one haruspex sees another, he laughs").
Fortunately, some medicine men and women were careful observers, who had a patient's recovery uppermost in mind. Especially those who had risen to power and influence and had a scientific bent or deep compassion could be relied upon to search for valid explanations of their findings.
One of the oldest records of such medicinal recommendations is found in the writings of the Chinese scholar-emperor Shen Nung, who lived in 2735 B.C., or 4730 B.P. (before the present). He compiled a book about herbs, a forerunner of the medieval pharmacopoeias that listed all the then-known medications.
The drug consists of the powdered roots of a plant in the breakstone family (Saxifragaceae, now identified as Dichroa febrifuga, Lour.). Almost 4700 years later, a group of Chinese chemists isolated two compounds (the dichroines) from the plants, one of which later proved to control bird malaria.
The leaves of this plant-called Shun Chi or chuine in present-day China-also contain antimalarial chemicals (the febrifugines), one of which is identical with one of the dichroines. These alkaloids (organic bases) were studied and synthesized during World War II in an effort to protect Americans from malaria in the Pacific and other tropical campaigns.
However, chemists could not separate the nausea the drugs produced from their antimalarial effects.
The emperor Shen Nung also observed the stimulating effect of another ancient Chinese medicinal plant, Ma Huang. This one, now called Ephedra sinica, contains a number of alkaloids, chief of which, ephedrine, was isolated by the Japanese chemist Nagai in 1887, more than 4600 years after the effect of the plant had been recorded.
Ephedrine and some closely related compounds are responsible for the ability of the wiry plant to stimulate blood pressure and breathing. The drug also contracts blood vessels. The Chinese book Pen Tsao (Herbal Medicines) of 5000 B.P. recommends castor oil for purging and the opium poppy for sleep.
The 5000-year tradition of natural drugs continues to flourish in China even today. A curious philosophy underlies their reasoning: Diseases are evil occurrences that are counteracted by good influences, they say, and nature is good and therefore healing.
The traditional Chinese physicians overlook the fact that nature is not always kind. Cataclysms such as earthquakes, floods, and hurricanes threaten life.
Medicinal plants are toxic, often deadly poisonous. The widespread toxicity of botanical materials can be seen in the history of assassinations, suicides, and accidental poisoning by swallowing certain plant products, as well as the killing of game and enemies with curare-tipped arrows.
Some Chinese pharmacognosists claim that synthetic compounds with no structural resemblance to harmless natural products are more dangerous than naturally occurring plant constituents, but this claim is unsubstantiated.
Some synthetic compounds are highly toxic, others are not, and the same is true of natural products. In thousands of cases, chemical manipulation of their structure has lessened the toxicity of natural alkaloids, antibiotics, hormones, snake venom's, and other biologically active substances.
Frequently, these semisynthetic chemical cousins or analogues can be used in clinical medicine much more safely than their natural ancestors.
Much knowledge of early drugs has been lost from every civilization. What remains is passed on in sporadically recorded epics and folklore unearthed by archaeologists and linguistic scholars. Tropical and subtropical regions, with their greater variety of plants, have given us most of the descriptions of these medicines.
Although some ancient drugs have survived throughout the ages and are still used in a refined form, they amount to a small percentage of modern medications.
Ancient Hindu records mention eating chaulmoogra fruit to treat leprosy. We now know that the fruit contains several oils not very effective against leprosy bacteria. Treating the disfigured areas with these oils has been replaced entirely by swallowing dapsone, a synthetic drug, or by using other medicines.
A treatment still in use in underdeveloped regions for some intestinal problems is ipecac, the powdered roots of ipecacuanha (Cephaelis species). These plants were already being used by Brazilian Indians before the European conquest.
The Indians treated "bloody flux," a form of amoebic diarrhea, with "igpecaya." Samuel Purchas (ca. 1577-1626) in Purchas his Pilgrims published a description of this material in 1615. As often happens in medicine, the successful recovery of a highly placed person made treatment with a new drug popular.
In the case of ipecacuanha, the dauphin, son of Louis XV, was cured of his amoebic infection by the physician Claude-Adrien Helvetius (1715-1771).
However, amoebiasis was not studied intensively until 1875, and another 35 years passed before extraction of ipecac showed that the alkaloids emetine and cephaline were the active ingredients of the plant.
Ipecac had been used for centuries to make poisoned people vomit; unfortunately, this property has limited the use of emetine for curing amoebiasis.
Mediterranean peoples used to pulverize the dried flower heads of species in the ragweed family, especially Artemesia maritima, to get rid of intestinal worms.
This plant is native to south-central Russia. Its active ingredient, santonin, was synthesized by British and Swiss organic chemists, yet studies have not been able to separate clinically effective doses from toxic ones.
However, santonin is still used for roundworm infections in farm animals.
Another plant used to treat worms is goosefoot (Chenopodium anthelminticum). From its flowers comes a volatile oil that contains the active principle ascaridole. The Romans gave it the name Chenopodium; the Hebrews called it Jerusalem Oak; and others dub it Mexican tea.
Likewise, a thick, dark green oil that helps to expel tapeworms can be pressed from the male fern (Dryopteris filix-mas). This plant's use is ancient. Its active ingredient is also ascaridole. In humans it is effective only at almost toxic doses, and it is prescribed mostly in veterinary medicine.
Early medicine men used it because they needed medications regardless of side effects. Many of these antique natural drugs would be unacceptable to today's regulatory agencies such as the U.S. Food and Drug Administration, as well as to the medical profession.
In the recent past, many of these mushrooms as well as flowers and shrubs have been extracted chemically, and their active ingredients have been identified.
For example, peyote, a small cactus, now named Lophophora williamsii, contains alkaloids, especially mescaline, that cause hallucinations.
The Indians called sacred mushrooms teonacatl (nahuatl means God's flesh). Some of these mushrooms belong to Psilocybe species and contain hallucinogens (psilocine, psilocybin).
These and other plants that produced temporary psychotic reactions were abhorred by the Spanish priests, who saw their use as rites of the devil.
Other South American Indians, especially those in the Peruvian Andes mountains, made several early discoveries of drug-bearing plants. Two of these plants contain alkaloids of worldwide importance that have become modern drugs. They are cocaine and quinine.
Cocaine is extracted from leaves, especially from Erythroxylum coca, a bushy shrub native in South American countries at high altitudes, such as Bolivia, Peru, Ecuador, and Chile. Cocaine is the primary alkaloid in these leaves.
Cocaine's potential for addiction was known and used with sinister intent by South American Indian chiefs hundreds of years ago.
The chiefs maintained a messenger system along the spine of the Andes to control their thinly populated kingdoms, which stretched for thousands of miles along the mountains and were isolated from each other by the rugged terrain. The messengers had to run at high altitudes and needed stimulants for this exhausting task.
Their wealthy employers provided the runners with coca leaves for this purpose and enslaved them further by paying them with more coca leaves, thus maintaining the addiction for which the poor runners were willing to continue their never-ending jobs. When coca leaves reached Europe with the Spanish conquistadores, they led to one of the first European waves of euphoric hallucinogenic drugs.
Quinine was isolated from the bark of the cinchona tree by the French chemists Joseph-Biename Caventou and Pierre-Joseph Pelletier in 1820, 200 years after the bark was introduced into Europe for the treatment of malaria. The Peruvian Indians had recognized for years the value of the quinquina tree for treating feverish patients.
Some historians believe that malaria was imported to South America by the conquistadores and their African slaves. A persistent story exists about Dona Francisca Henriquez de Ribera, wife of Count Chinchon, the Spanish viceroy of Peru. She fell ill with malaria (the "tertians" variety with chills and fever that recur every third day) and was cured by an Indian healer who gave her the bark.
In gratitude for the cure, the countess distributed the bark to other patients in Lima and thus alerted Spanish physicians to its clinical potential. The great Swedish botanist Linnaeus (Carl von Linne, 1707-1778) later called the tree cinchona in honor of Countess Chinchon, misspelling her name in the process.
It is improbable that the countess persuaded Spanish doctors to use the bark because she died in Cartagena, Colombia, in 1641, while returning home. Because the antimalarial value of cinchona became more widely recognized while supplies of the bark fell short of demand, the cost of the powder was often matched by its weight in gold.
The cinchona tree grows wild in the sub-Andean jungles, and a number of European powers tried to transplant it to other tropical places. Peruvian officials realized what a gold mine these trees represented and strictly prohibited their export.
A British attempt to smuggle some trees out of Peru failed, but two Dutch adventurers managed to get a few specimens across the border. The stolen trees were taken to Java and became the ancestors of later improved plantation trees that, before 1940, furnished 97% of the world's supply of quinine.
The inaccessibility of Java-and of Sri Lanka, where a few smaller plantations existed-became a source of worry for European drug factories that were the principal sources of pure quinine. This concern was felt acutely by German manufacturers in World War I, when they were unable to supply European colonies in Africa with the drug.
In World War II, British and American suppliers also were cut off from their Oriental sources of quinine when the Japanese occupied Java and Malay.
In both instances, the drug shortage stimulated intensive research to surmount this handicap, and the resulting new compounds are almost the only effective synthetic antimalarials we have today. Nevertheless, quinine has kept a modest but important and inexpensive place in antimalarial treatment.
As the centuries unrolled and new civilizations appeared, cultural, artistic, and medical developments shifted toward the new centers of power. A reversal of the traditional search for botanical drugs occurred in Greece in the fourth century B.C. (about 2400 B.P.), when Hippocrates (estimated dates, 460-377 B.C.), the "Father of Medicine," became interested in inorganic salts as medications.
The ethics of Hippocrates as incorporated in the physicians' Hippocratic oath have survived better than his preference for inorganic salts.
However, we still use magnesium sulfate (named Epsom salts for the British town of Epsom), both internally and externally; aluminum salt astringents; sodium and potassium chlorides and calcium salts for various deficiencies; barium sulfate as an X-ray contrast agent; and - sodium iodide to prevent thyroid disorders, as well as stannous fluoride to prevent tooth decay.
Gold compounds are experiencing a renaissance in the treatment of arthritis, and silver nitrate was used to protect the eyes of newborn infants from gonorrheal blindness before penicillin took its place.
Lithium salts are used in gout and to smooth out the biphasic phase of manic-depression. Many heavy metals are incorporated as traces in diet supplements because they have been recognized as essential parts of important biological catalysts.
The next great-and reactionary-influence on medicinal thought came from a Greek physician from Pergamum, Claudius Galenus, or Galen (129-ca. 199 A.D.), who taught in Rome. Galenic medicine consisted of preparations of plants by soaking (infusion) or boiling (decoction).
As Oliver Wendell Holmes said, "These Galenists were what we should call herb doctors today." Galen claimed that herbal mixtures could provide all the essentials for health and therefore could be applied to all conceivable health defects. He was also a vegetarian.
We know today that a strict vegetarian diet, without milk, cheese, or eggs cannot contain all the protein-building amino acids needed for normal growth and body maintenance. In Galen's storeroom (apotheke), some metallic substances, such as copper and zinc ores, iron sulfate, and cadmium oxide, were still present, probably as a tribute to Hippocrates' drug inventory.
Galen insisted on carefully identifying the type and age of botanical materials and thus foreshadowed the value of controlling the purity of drugs. Among his favorite and potent drugs were hyoscyamus (which contains atropine), opium (the source of morphine), and squill (which contains heart stimulants, cardiac glycosides similar to digitalis).
Galen's teachings made such a profound impact on medieval society and medicine that they were followed for more than 1000 years. In western Europe, where medical knowledge was encased in Catholic monasteries, Galen's prescriptions were embraced by the conservative monks.
Although some teachings of contemporary Islamic scholars filtered into this environment, many centuries passed before herbal medicine could be replaced by newer treatments.
After the fall of the Roman and Byzantine empires and the rise of Islam in the Middle East, the "civilized world" of Europe was in decline. The migration of Eastern peoples, the constant and cruel wars all over the continent, and the absence of cultural and intellectual life-styles made scholarly studies of drugs impossible.
The herb gardens of monasteries were the chief source of healing plants, but infections, heart disease, cancer, and the innumerable battle wounds and disfigurements from torture could not be treated rationally. Plagues swept across the continent and the British isles, chiefly bubonic plague, viral pandemics, and later syphilis.
The victims were laid to rest in mass graves with no medicines to ease their final agonies. Life was hard and, on the average, short; at 50 or 55 a person was an ancient senior citizen; most died in their 40s or earlier.
Bleeding the patient by opening a vein or with leeches was one of the few medical treatments and was used for various ills. Amputation of wounded or badly infected limbs was carried out without benefit of anesthesia or soap-and-water hygiene; cesarean deliveries meant the cruel and certain death of the mother.
These desperate health conditions applied to kings and serfs alike for almost 1500 years. It is no wonder that a better life could be imagined only in the heavens, which represented a hypothesis that had never been proved.
The little that was known about healing plants, minerals, and tissues was called materia medica, a term still used for drug information at the turn of this century. Latin was used throughout the collective accounts of this subject because it was the professional language of the monks and also because it kept the common people in ignorance.
When pamphlets could no longer hold the accumulating knowledge of materia medica, larger, more formal collections were gathered in national pharmacopoeias. The first of these books appeared in Florence in 1498, six years after Christopher Columbus landed in Dominica, followed by others in Nuremberg (1535), Basel (1561), Augsburg (1564), and London (1618).
Standards of purity and methods of preparing various drug products accompanied the descriptions of botanical and mineralogical specimens. One item tells how to make a sort of candy of red rose petals for pale tired people and of white roses for those with too ruddy complexions.
The late Middle Ages coincided with the upsurge of alchemy, a primitive chemistry dealing mostly with inorganic substances. The renewed interest in inorganic materials pushed botanical sources of medicines into second place temporarily. True, quinine (cinchona) appeared during that century, but the next great botanical drug, digitalis, was not introduced until the end of the 1700s.