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By: William A. Weiss, MD, PhD
- Professor, Neurology UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA
Three anatomic groupings are deﬁned for descriptive purposes: the hindfoot buy mg combipres with visa hypertension before pregnancy, the midfoot discount mg combipres overnight delivery arrhythmia causes, and the forefoot (see Figure 13-3) buy combipres mg without a prescription blood pressure vs blood sugar. Answer: c Ligaments of the ankle syndesmosis include the anterior tibioﬁbular discount mg combipres amex blood pressure of 150/90, pos- terior tibioﬁbular, and inerosseous ligaments. Answer: e the tibial and common peroneal nerves are terminal branches of the sciatic nerve, which arises from the lumbosacral plexus. The common peroneal nerve from L5 branches into the superﬁcial peroneal nerve and deep peroneal nerve, which terminally supply sensation to the dorsal foot and ﬁrst web space, respectively. The tibial nerve, a branch of S1, travels through the popliteal fossa into the deep posterior compartment. The sural 524 Answers to Questions nerve is a sensory branch of the tibial nerve and provides sensation to the posterolateral hindfoot and lateral border of the foot. Answer: e Radiographic studies of the foot and ankle require weight-bearing X-rays when possible. Answer: c Pilon fractures involve the intraarticular fractures of the tibial metaphysis, which extend to the weight-bearing portion of the tibia; a is a Lisfranc fracture-dislocation, and e is also known as a Jones fracture. Answer: b Because the insole of a sneaker can be colonized with the Pseudomonas organism, care should be taken to treat the patient with an infection from a puncture wound for this organism. Answer: c Overuse of the posterior tibial tendon causes conditions that range from mild tendonitis to complete rupture and asymmetrical ﬂatfoot deformity. As the tendon continues to deteriorate and becomes incompetent, a pro- gressive asymmetrical ﬂatfoot deformity develops with lateral hindfoot impingement. She notes that it is signiﬁcantly easier walking in a grocery store pushing a cart than it is to walk in a mall. Past medical history, family history, and social history are otherwise unremarkable. She tends to stand in a forward ﬂexed position, and she has limited extension of the lumbar spine, with pain on extension. Each injection led to good relief of her symptoms but that relief lasted only 2 to 3 weeks. Having failed nonopera- tive treatment, she elected surgery and underwent a decompressive lami- nectomy at L4–L5 with posterolateral fusion, utilizing pedicle screw instrumentation and iliac crest autograft. Lateral radiograph demonstrates a grade 1 degenerative spondylolisthe- sis at L4–L5. Discussion Degenerative spondylolisthesis is common and increases in prevalence with increasing age. It is more common in women than in men, in blacks than in whites, and is found with increased frequency in patients with dia- betes. Degeneration of the disk and facet joints, most commonly at L4–L5, leads to anterior slippage of the cephalad vertebrae (L4 in this case) on the level below (L5). It is common to see spinal stenosis in association with degenerative spondylolisthesis, and this patient’s symptoms, including back pain and stiffness with aching pain into the buttocks, thighs, and legs, are common. A common complaint is pain with walking that is often relieved by stopping and sitting down. Patients frequently note that they can walk farther in a grocery store pushing a cart than they can in a mall. In spinal stenosis, positions of ﬂexion, such as pushing a grocery cart or sitting down, are more comfortable than extension, and the most common Degenerative Spondylolisthesis 529 A B Figure 2. The sagit- tal view demonstrates the spondylolisthesis, as well as the signiﬁcant thecal sac narrowing at L4–L5. The axial view demonstrates enlargement and arthritic change in the facet joints bilaterally, thickening of the ligament ﬂavum, and severe central and lateral recess stenosis. Decompressive laminectomy at L4–L5 with posterolateral fusion, utiliz- ing pedicle screw instrumentation and iliac crest autograft. Treatment options include nonoperative measures such as a daily back exercise regimen, ﬂexion exercises, physical therapy modalities, nonsteroidal antiinﬂammatory medications, or epidural steroid injections. When nonoperative measures fail, surgery is often indicated, usually with good results. The primary goal of the surgical treatment of spinal stenosis is decompression of the affected nerve roots and/or thecal sac. In cases of degenerative spondylolisthesis, because of the risks of further slippage, concomitant fusion is routinely employed. Sauer History A 52-year-old woman presents with worsening bilateral forefoot pain over the last three years. The pain she feels is worse with shoe wear and walking and is relieved by wearing sandals. She also reports having to wear multiple layers of socks to keep her shoes from rubbing on the medial aspects of her forefeet. She describes no pain with arising, no swelling, no loss of sensation, no joint stiffness, and no ﬂatfoot. Her past medical history is signiﬁcant for breast cancer, for which she has had a mastectomy. Physical Examination this is a well-developed, well-nourished female in no apparent distress. Her station shows bilateral hallux valgus with normal-appearing arches and heels in slight valgus positioning. Examination of her right foot and ankle shows a moderate hallux valgus formation with a medial protuberance noted. There is no pain plantarly over the medial or lateral sesamoid, no lesser toe pain, and no medial midfoot or hindfoot pain. Ankle range of motion is 5 degrees of dorsiﬂexion, 40 degrees of plantar ﬂexion, 10 degrees of inversion, and 531 532 S.
Weight-bearing X-rays may show uncovering of the talar head by the navicular as the fore- foot and midfoot abduct combipres mg on line hypertension journal impact factor. Stage I buy cheap combipres mg on-line blood pressure quizzes, which is very mild tendon weakness without ﬂatfoot deformity purchase combipres mg blood pressure negative feedback loop, can be addressed with orthotics buy mg combipres otc can blood pressure medication cause jaw pain, antiinﬂammatory medicines, and physical therapy. There are other surgical options available, and the decision is based on the clinical presentation of the patient. Typically, a triple arthrodesis, or a fusion of the subtalar joint, talonavicular joint, and calcaneocuboid joints, is preferred. Heel Pain Plantar heel pain is one of the most common and most disabling conditions of the foot. There are many causes including tumors, infection, stress frac- tures, inﬂammatory arthropathies, and neuropathies. The most common cause of plantar heel pain is associated with chronic injury of the plantar fascial origin. This heel pain syndrome is also known as heel spur syn- drome and plantar fascitis. Classic pain and stiffness occurs when arising from bed and taking the ﬁrst step on the ﬂoor in the morning. High-heeled shoes typically alleviate symptoms, whereas barefoot walking and wearing ﬂat shoes may increase symptoms. Often there is a tight Achilles tendon complex with limited ankle dorsiﬂexion; occasion- ally, fat pad or heel pad atrophy is present. The normal plantar spur (open arrow) has smooth margins, no sclerosis or erosion, and no adjacent soft tissue swelling. Very small spurs are present at the insertions of the long plantar ligament (arrow) and the Achilles tendon. Treatment is almost always conservative, consisting of rest, antiinﬂamma- tory medication, orthotic devices, and aggressive stretching. Isolated stretching of the gastrocnemius–soleus complex and plantar fascia is impor- tant. Surgery, typically reserved for chronic conditions that have lasted more than 6 six months to a year, involves partial release of the plantar fascial origin. Arthritic Conditions of the Foot and Ankle Causes of ankle joint degeneration include primary osteoarthritis, post- traumatic arthritis, avascular necrosis, osteochondritis dissecans, synovial chondromatosis, and other rheumatologic conditions. Conservative man- agement includes antiinﬂammatory medications, bracing, and intraarticu- lar cortisone injections. The Foot and Ankle 495 arthroscopic versus open, ankle arthrodesis (fusion), or a total ankle replacement. It is important to note that in extensive arthritis of the ankle the standard surgical treatment is arthrodesis (fusion). Total ankle replace- ment, although available and helpful in patients with a low-demand life- style, has not proven effective in long-term management of the osteoarthritic ankle. Rheumatoid Arthritis Rheumatoid arthritis is a systemic disease that commonly involves the foot because there are many joints lined with synovium (Fig. It affects both the synovial lining of the joint and the tendons of the foot and ankle. Plantar (A) and dorsal (B) views of the foot of a patient with rheu- matoid arthritis with characteristic dislocation of all toes, which tend to drift off into marked hallux valgus with dorsal displacement of the phalanges onto the metacarpals. The metacarpal heads become very prominent in the sole of the foot, and large, painful callosities are common. Cooper Physical examination shows an antalgic gait, generalized swelling, and decreased motion in the joints of the foot. Weight-bearing radiographs of the foot and ankle are essential for showing deformity and often show a valgus angulation of either the ankle or subtalar joint. Treatment options include conservative management, such as patient education, activity modi- ﬁcation, intermittent steroid injections, optimizing medical management, shoe modiﬁcations, and the use of an ankle-foot orthosis. Surgical options include simple synovectomy, arthrodesis, and total ankle arthroplasty. Infections Both the bones and joints of the foot can be involved in musculoskeletal septic processes such as osteomyelitis and septic arthritis. Puncture Wounds Puncture wounds in the foot can be caused by many things, including glass, nail, and plant and animal parts. Typically, the puncture occurs through the sole of the shoe or sneaker and enters the foot (Fig. Because the insole of a sneaker can be colonized with the Pseudomonas organism, care should be taken to treat the patient with an infection from a puncture wound for this organism. Puncture injury sites: 1, metatarsophalangeal joint; 2, cartilage of metatarsal head; 3, plantar fascia. The toenail of the right big toe was practically completely separated from its bed and was avulsed. The operation, which was performed under a local anesthetic, consisted of bilateral resection of all onychogenic tissue in the longitudinal grooves. When bone or joint involvement is extensive, aggres- sive surgical debridement is mandatory for satisfactory resolution. Paronychia A paronychia is an infection of the medial or lateral nail fold, often seen in the great toe (Fig.
Each of these steps is a potential site for phar- the vesicles are intimately involved in the release of macological intervention in the normal transmission the transmitter into the synaptic or neuroeffector cleft in process: response to an action potential buy combipres mg on-line heart attack kiss. Following release order combipres mg without a prescription blood pressure medication that helps with acne, the transmitter must diffuse to the effector cells best mg combipres blood pressure chart for child, where it in- teracts with receptors on these cells to produce a re- 1 effective combipres mg blood pressure medication spironolactone side effects. Storage of the transmitter effector cells varies considerably from tissue to tissue. Release of the transmitter by a nerve action poten- Smooth muscle, cardiac muscle, and exocrine gland cells tial do not contain morphologically specialized regions 4. Interaction of the released transmitter with recep- comparable to the end plate of skeletal muscle. Rapid removal of the transmitter from the vicinity of into close contact primarily with the dendrites of the the receptors ganglionic cells and make synaptic connection with 6. Also shown are the release of acetylcholine (exocytosis) and the location of acetylcholinesterase, which inactivates acetylcholine. Synthesis, Storage, Release, and Modiﬁcation of extracellular calcium concentration or Removal of Acetylcholine of calcium entry therefore can markedly affect neuro- the processes involved in neurochemical transmission transmission. The ini- the interactions between transmitters and their tial substrates for the synthesis of acetylcholine are glu- receptors are readily reversible, and the number of cose and choline. Glucose enters the neuron by means transmitter–receptor complexes formed is a direct func- of facilitated transport. The to whether choline enters cells by active or facilitated length of time that intact molecules of acetylcholine re- transport. Pyruvate derived from glucose is transported main in the biophase is short because acetylcholinesterase, into mitochondria and converted to acetylcoenzyme A an enzyme that rapidly hydrolyzes acetylcholine, is highly (acetyl-CoA). The acetyl-CoA is transported back into concentrated on the outer surfaces of both the prejunc- the cytosol. With the aid of the enzyme choline acetyl- tional (neuronal) and postjunctional (effector cell) mem- transferase, acetylcholine is synthesized from acetyl- branes. The acetylcholine is then transported results in a lowering of the concentration of free trans- into and stored within the storage vesicles by as yet un- mitter and a rapid dissociation of the transmitter from its known mechanisms. Any acetylcholine that does reach the circulation is minal branches of an axon causes depolarization of the immediately inactivated by plasma esterases. As a conse- extracellular space (biophase), acetylcholine interacts quence of rapid removal, the magnitude and duration of with cholinoreceptors. This same transport system is essential for the by which the transmitter is removed from the biophase storage of norepinephrine. Noradrenergic transmission is epinephrine to leak from the vesicles into the cytosol. In the neuronal that leaks out of the vesicle is rapidly returned to the cytosol, tyrosine is converted by the enzyme tyrosine hy- storage vesicles by the same transport system that car- droxylase to dihydroxyphenylalanine (dopa), which is ries dopamine into the storage vesicles. It is important converted to dopamine by the enzyme aromatic for a proper understanding of drug action to remember L–amino acid decarboxylase, sometimes termed dopa- that this single transport system, called vesicular trans- decarboxylase. The dopamine is actively transported port, is an essential element of both synthesis and storage into storage vesicles, where it is converted to norepi- of norepinephrine. In the adrenal medulla, the synthesis is carried into the biophase (synaptic or junctional region). The human adrenal medulla contains ap- mitter in the biophase and is readily reversible. In this proximately four times as much epinephrine as norepi- instance, the receptors are adrenoceptors. The absence of this enzyme in noradrenergic Three processes contribute to the removal of nor- neurons accounts for the absence of signiﬁcant amounts epinephrine from the biophase: of epinephrine in noradrenergic neurons. Diffusion from the synapse into the circulation and Tyrosine hydroxylase ultimate enzymatic destruction in the liver and renal H H excretion. This reaction reduces ronal cytosol across the membrane of the vesicle and the biological activity of norepinephrine or epinephrine into the vesicle. The ing norepinephrine from the synapse is the escape of list of its substrates is very large, including endogenous neuronally released norepinephrine into the general substances (norepinephrine, epinephrine, dopamine, circulation and its metabolism in the liver. The liver has tyramine, 5-hydroxy-tryptamine) and many drugs that two enzymes that perform this function: catechol-O- are amines. The respective receptors are the more rapidly acting enzyme, and therefore more called the muscarinic and nicotinic cholinoreceptors or molecules are O-methylated and then deaminated than the muscarinic and nicotinic receptors of acetylcholine. Some norepinephrine and epinephrine ap- the action of acetylcholine at the skeletal muscle pear unchanged in the urine. Based on antagonist selectivity, however, Measurements of norepinephrine, epinephrine, and the autonomic and somatic nicotinic receptors are not their metabolites in the urine constitute valuable diag- pharmacologically identical (see Chapter 14). The combined processes of cause it allows the development of therapeutic agents extraneuronal uptake and O-methylation are believed that can selectively mimic or antagonize actions of to be a minor but functionally signiﬁcant, site of irre- acetylcholine. The receptors for acetylcholine and related drugs However, the responses produced by the drugs in dif- (cholinoreceptors) and for norepinephrine and related ferent autonomic structures differ quantitatively or drugs (adrenoceptors) are different. These were designated tive agonists but also for their respective antagonist as - and -adrenoceptors. Subsequently, it has become drugs; that is, drugs that antagonize or block acetyl- necessary to classify the adrenoceptors further into choline at cholinoreceptors will not antagonize norepi- 1-, 2-, 1-, and 2-receptor subtypes. The 1-adrenoceptors are located at postjunctional Cholinoceptors (postsynaptic) sites on tissues innervated by adrenergic the action of administered acetylcholine on effector neurons. The 1-adrenoceptors are found chieﬂy in the actions of both acetylcholine and muscarine on the vis- heart and adipose tissue, while 2-adrenoceptors are lo- ceral effectors are similar to those produced by cated in a number of sites, including bronchial smooth parasympathetic nerve stimulation. Furthermore, the muscle and skeletal muscle blood vessels, and are asso- effects of acetylcholine, muscarine, and parasympa- ciated with smooth muscle relaxation. Activation of 1-adrenoceptors bacco plant, on autonomic ganglia and the adrenal on cardiac tissue produces an increase in the heart rate medulla. In the human heart, the ratio of 1 to 2 is about 3:2 in atria and 4:1 in ventricles.
The elimination half-life is 1 to 2 hours buy mg combipres with mastercard heart attack 70 blockage, and general may interfere with the absorption of a number more than 90% of an oral dose is excreted in the urine mg combipres fast delivery blood pressure medication omeprazole. Famotidine has an onset of effect within 1 hour after oral administration combipres mg fast delivery hypertension handout, and inhibition of gastric secretion is present for the next 10 to 12 hours buy combipres mg line arrhythmia while sleeping. Elimination is by renal (65–70%) and he- the histamine receptor antagonists (H2 blockers) mar- patic (30–35%) routes. Ranitidine, famotidine, and niza- keted in the United States are cimetidine (Tagamet), tidine do not alter the microsomal cytochrome P450 ranitidine (Zantac), famotidine (Pepcid), and nizatidine metabolism of other drugs, nor do they cause gyneco- (Axid). A reduction in dosage of any of the H2-blockers cell membranes of parietal cells and prevent histamine- is recommended in the presence of renal insufﬁciency. After pro- longed use, down-regulation of receptor production oc- Proton Pump Inhibitors curs, resulting in tolerance to these agents. H2-blockers are approved for the treatment of gastroesophageal re- the proton pump inhibitors available in the United States ﬂux disease, acute ulcer healing, and post–ulcer healing are omeprazole (Prilosec), lansoprazole (Prevacid), pan- maintenance therapy. Although there are substantial toprazole (Protonix), rabeprazole (Aciphex), and es- differences in their relative potency, 70 to 85% of duo- omeprazole (Nexium). These are substituted benzimida- denal ulcers are healed during 4 to 6 weeks of therapy zole prodrugs, which accumulate on the luminal side with any of these agents. These drugs markedly inhibit particularly important in healing, nighttime-only dosing gastric acid secretion. Most are available in low-dose over-the- ously formed, and thus no tolerance develops. The proton pump inhibitors are also used to sorbed following oral administration, with peak blood treat patients with Zollinger-Ellison syndrome, which is levels 45 to 90 minutes after drug ingestion. Blood lev- the result of a gastrin-hypersecreting neuroendocrine els remain within therapeutic concentrations for ap- tumor. Following oral the prodrugs are unstable in the presence of acid administration, 50 to 75% of the parent compound is and therefore must be administered as an enteric-coated excreted unchanged in the urine; the rest appears pri- preparation or as a buffered suspension. The most Cimetidine may infrequently cause diarrhea, nau- commonly reported side effects are diarrhea and sea, vomiting, or mental confusion. Hypergastrinemia has been noted as a reac- with granulocytopenia, thrombocytopenia, and pancy- tion to the marked reduction in acid secretion. Gynecomastia has been carcinoid tumors have developed in rats but not in mice demonstrated in patients receiving either high-dose or or in human volunteers, even after long-term use. The sulfapyridine is absorbed, acetylated, Inﬂammatory bowel disease mainly refers to ulcerative hydroxylated, and conjugated to glucuronic acid in the colitis and Crohn’s disease. The major portion of the sulfapyridine molecule terized by a relapsing inﬂammatory condition involving and its metabolites are excreted in the urine. When involvement is limited to the rectum, it is termed In Crohn’s disease, sulfasalazine acts primarily on in- ulcerative proctitis. Crohn’s disease may involve the gut volved colonic mucosa, although remission of ileal dis- from esophagus to anus; however, the small bowel or ease also has been reported. If the colon is predomi- in the treatment of colonic disease, while corticosteroids nantly involved, the symptoms and presentation are were judged better in the treatment of small bowel dis- quite similar to those of ulcerative colitis. Since sulfasalazine does not prevent relapse of involvement may result in large-volume bloodless diar- Crohn’s disease once remission is achieved, mainte- rhea or obstruction. Fistulas, strictures, Nausea, vomiting, and headaches, the most common and abscess formation are fairly common in Crohn’s side effects, are related to the blood level of sulfapyri- disease. If the dose is reduced, symptoms frequently im- the present primary mode of therapy for these dis- prove. These occur less commonly and are not dose re- including corticosteroids, to help induce remission and lated. Sulfasalazine should not be used in patients various immune modulators, such as azathioprine, 6- with hypersensitivity agranulocytosis or aplastic mercaptopurine or methotrexate, to maintain remis- anemia. Cholestyramine reduces the metabolism of immunosuppressive drugs, and corticosteroids is dis- sulfasalazine. Sulfasalazine causes a reversible decrease cussed in Chapters 43, 57, and 60, respectively. Sulfapyridine istered as a suppository (Canasa) or enema (Rowasa) has no effect on the inﬂammatory bowel disease, and in- for distal colonic disease. Balsalazide 40 Drugs Used in Gastrointestinal Disorders 481 disodium is delivered intact to the colon, where it is hydroxybudesonide) are formed via the cytochrome cleaved by bacterial azoreduction to release equimolar P450 3A enzyme. In vitro studies on the binding of the quantities of mesalamine, the therapeutically active two primary metabolites to the corticosteroid receptor portion of the molecule, and 4-aminobenzoyl- -alanine; indicate that their afﬁnity for the receptor is less than the latter compound is only minimally absorbed and is 1% of that of the parent compound. They include misoprostol, sucralfate, and oc- a mouse–human chimeric monoclonal neutralizing anti- treotide. Speciﬁc indications are for the reduction of signs and symptoms in patients with moderately to severely Misoprostol active Crohn’s disease who have had an inadequate re- Prostaglandins of the A, E, and I type inhibit gastric sponse to conventional therapies (single infusion) and acid secretion. The prostaglandins also stimulate in- for reduction of the number of draining enterocuta- creased mucus and bicarbonate secretion by gastric mu- neous ﬁstulas in patients with ﬁstulizing Crohn’s disease cosa. Responses occur within 2 prostaglandin E, has been approved for use in the pre- 1 weeks of an infusion, and signiﬁcant clinical responses vention of nonsteroidal antiinﬂammatory drug–induced were reported in 50 to 80% of patients in initial trials ulceration. Misoprostol is ab- tenance therapy for Crohn’s disease and to determine sorbed rapidly after oral administration and is hy- the best induction regimen to achieve remission. It is metabolized by the most common side effects, which are related to the liver and excreted mainly in the urine. Adverse ef- the intravenous infusion itself, include rash, low blood fects include crampy abdominal pain, dose-related diar- pressure, chills, and chest pain. The last-named effect generally temporary and often respond to a decrease in has led to its use in the control of postpartum bleeding infusion rate.
De- more on drug classes rather than on individual drugs combipres mg cheap hypertension signs, signed to be used during a single semester generic combipres mg with visa heart attack 40, the book fo- eliminate unnecessary detail such as chemical struc- cuses on the clinical application of drugs within a con- tures cheap combipres mg fast delivery blood pressure standards, and maintain emphasis on structure–activity rela- text of the major principles of pharmacology buy combipres mg fast delivery pulse pressure 66. With these revisions, we hope we have provided a this edition includes a number of new or updated fea- book that is readable, up-to-date, comprehensive but tures that further enhance the appeal of the text. States Medical Licensing Examination guidelines) with detailed answers to help students test their knowledge Charles R. Stitzel Case Studies: Appearing at the end of each chapter, case studies present students with real-life examples of Table of Contents I. Contemporary Bioethical Issues in Pharmacology and Pharmacology 281 Pharmaceutical Research 73 Charles R. Synthetic Organic Antimicrobials: Sulfonamides, Adrenal Cortex 686 Trimethoprim, Nitrofurans, Quinolones, Ronald P. Parathyroid Hormone, Calcitonin, Vitamin D, and Other Vijaya Somaraju Compounds Related to Mineral Metabolism 754 50. Those who became the ancient Chinese wrote extensively on medical most proﬁcient in the use of drugs to treat disease were subjects. The Pen Tsao, for instance, was written about the “mediators” between this world and the spirit 2700 B. The Chinese doctrine the community was derived from the cures that they of signatures (like used to treat like) enables us to un- could effect with drugs. It was believed that the sick derstand why medicines of animal origin were of such were possessed by demons and that health could be re- great importance in the Chinese pharmacopoeia. The largest and perhaps the most impor- Originally, religion dominated its partnership with tant of these, the Ebers papyrus (1550 B. However, the use of drugs to effect today in that they have one or more active substances as cures led to a profound change in both religious thought well as vehicles (animal fat for ointments; and water, and structure. As more became known about the effects milk, wine, beer, or honey for liquids) for suspending or of drugs, the importance of divine intervention began to dissolving the active drug. These prescriptions also com- recede, and the treatment of patients effectively became monly offer a brief statement of how the preparation is a province of the priest rather than the gods whom the to be prepared (mixed, pounded, boiled, strained, left priest served. This process lead to a growing under- overnight in the dew) and how it is to be used (swal- standing of the curative powers of natural products and lowed, inhaled, gargled, applied externally, given as an a decreasing reliance on supernatural intervention and enema). Cathartics and purgatives were particularly in forever altered the relationship between humanity and vogue, since both patient and physician could tell al- its gods. Furthermore, when the priests began to apply most immediately whether a result had been achieved. The level of drug usage achieved by the Egyptians this was the cornerstone for the formation of a science- undoubtedly had a great inﬂuence on Greek medicine based practice of medicine. Battle wounds frequently were cov- cian and protopharmacologist alike that there was ered with powdered plant leaves or bark; their astrin- much variation to be found from one biological extract gent and pain-reducing actions were derived from the to another, even when these were prepared by the same tannins they contained. It was reasoned that to fashion a rational and root (containing atropinelike substances that induce a reproducible system of therapeutics and to study phar- twilight sleep) that protected Ulysses from Circe. The macological activity one had to obtain standardized and oriental hellebore, which contains the cardiotoxic uniform medicinal agents. Veratrum alkaloids, was smeared on arrow tips to in- At the turn of the nineteenth century, methods be- crease their killing power. The fascination of the Greeks came available for the isolation of active principles from with the toxic effects of various plant extracts led to an crude drugs. The development of chemistry made it pos- increasing body of knowledge concerned primarily with sible to isolate and synthesize chemically pure com- the poisonous aspects of drugs (the science of toxicol- pounds that would give reproducible biological results. Plato’s description of the death of Socrates is an In 1806, Serturner (1783–1841) isolated the ﬁrst pure ac- accurate description of the toxicological properties of tive principle when he puriﬁed morphine from the the juice of the hemlock fruit. Many other chemically pure active com- paralysis of sensory and motor nerves, followed eventu- pounds were soon obtained from crude drug prepara- ally by central nervous system depression and respira- tions, including emetine by Pelletier (1788–1844) from tory paralysis, precisely matches the known actions of ipecacuanha root; quinine by Carentou (1795–1877) the potent hemlock alkaloid, coniine. The use of drugs played an inti- an analysis of what was to become one of the basic con- mate part in the rites, religions, history, and knowledge of cerns of pharmacology, that is, the quantitative study of the South American Indians. It was soon realized that drug action is pro- was closely tied to religious thought, and Indian cultures duced along a continuum of effects, with low doses pro- treated their patients with a blend of religious rituals and ducing a less but essentially similar effect on organs and herbal remedies. It also was noted that the appear- various deities were as important as the appropriate ap- ance of toxic effects of drugs was frequently a function plication of poultices, decoctions, and infusions. Early drug practitioners, both in Europe and South Until the nineteenth century, the rapid development America, gathered herbs, plants, animals, and minerals of pharmacology as a distinct discipline was hindered by and often blended them into a variety of foul-smelling the lack of sophisticated chemical methodology and by and ill-ﬂavored concoctions. The preparations were so distasteful led to an attempt to signiﬁcant advances made through laboratory studies of improve on the “cosmetic” properties of these mixtures animal physiology accomplished by early investigators to ensure that patients would actually use them. Estonia, in the late 1840s by Rudolph Bucheim (1820– There has long been a tendency of some physicians 1879) (Fig. The laboratory, built in Bucheim’s to prescribe large numbers of drugs where one or two home, was devoted to studying the actions of agents would be sufﬁcient. We can trace the history of this such as cathartics, alcohol, chloroform, anthelmintics, polypharmaceutical approach to Galen (A. Bucheim believed that “the investi- who was considered the greatest European physician gation of drugs. Galen believed that drugs had cer- for a chemist or pharmacist, who until now have been tain essential properties, such as warmth, coldness, dry- expected to do this. Unfortunately, he often formulated more was required to raise this discipline to the same general rules and laws before sufﬁcient factual informa- prominent position occupied by other basic sciences; this tion was available to justify their formulations. They not only created new laboratories devoted to the laboratory investigation of drugs but also ﬁrmly established the new discipline through the training of future faculty, the writing of textbooks, and the founding of scientiﬁc journals and societies. The latter task was accomplished largely by Bucheim’s Pharmacology, as a separate and vital discipline, has pupil and successor at Dorpat, Oswald Schmiedeberg interests that distinguish it from the other basic sciences (1838–1921), undoubtedly the most prominent pharma- and pharmacy.
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