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The drug is approved for rheumatoid arthritis generic finasteride 5 mg mastercard hair loss cure etf, osteoarthritis buy finasteride with a visa hair loss cure genetic, tendinitis purchase finasteride 5mg visa hair loss in men 14k, bursitis, and acute gouty arthritis. Principal adverse effects are abdominal distress, dyspepsia, nausea, vomiting, and diarrhea. The drug has analgesic and antipyretic properties but is not employed to relieve fever or pain unrelated to inflammation. Adverse effects occur in 25% to 40% of patients, causing between 5% and 10% to discontinue treatment. Nonetheless, caution should be exercised in patients with a history of peptic ulcer disease. Gastrointestinal effects (abdominal pain, constipation, diarrhea, dyspepsia, flatulence, nausea, and vomiting) occur in 20% to 25% of patients. The drug has a long half-life (15–20 hours) and undergoes elimination in the urine (50%) and feces (50%). The recommended dose for initial and maintenance therapy of osteoarthritis and rheumatoid arthritis is 7. Meloxicam is now available in a “Solumatrix” form using “fine particle technology” sold as Vivlodex. Capsules (5 and 10 mg) of Vivlodex contain particles of meloxicam that are 10 times smaller than traditional tablets. However, even with coxibs, patients can develop clinically significant gastroduodenal ulceration and bleeding. The drug is indicated for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, acute pain, and dysmenorrhea. In addition, celecoxib is used off-label for a rare genetic disorder known as familial adenomatous polyposis, which predisposes to development of colorectal cancer. Owing to concerns about cardiovascular safety, celecoxib is considered a last-choice drug for long-term management of pain (see later under “American Heart Association Statement on Cyclooxygenase Inhibitors in Chronic Pain”). Celecoxib does not decrease platelet aggregation and hence does not promote bleeding. To minimize risk, celecoxib should be used in the lowest effective dosage for the shortest time needed. Other measures to reduce risk are discussed later under “American Heart Association Statement on Cyclooxygenase Inhibitors in Chronic Pain. These two factors —unimpeded platelet aggregation and increased vasoconstriction—increase the likelihood of vessel blockage after the process of thrombosis has begun. Sulfonamide Allergy Celecoxib contains a sulfur molecule and hence can precipitate an allergic reaction in patients allergic to sulfonamides. Accordingly, these drugs are contraindicated during the third trimester of pregnancy. Drug Interactions Warfarin Celecoxib may increase the anticoagulant effects of warfarin and may thereby increase the risk for bleeding. Celecoxib itself does not inhibit platelet aggregation and does not promote bleeding. However, the drug may enhance the anticoagulant effects of warfarin (perhaps by increasing warfarin levels). Celecoxib may be combined with warfarin, but effects of warfarin should be monitored closely, especially during the first few days of treatment. Other Interactions Information on the interactions of celecoxib with other drugs is limited. Conversely, celecoxib may increase levels of lithium (a drug for bipolar disorder). Preparations, Dosage, and Administration Celecoxib [Celebrex] is available in capsules (50, 100, 200, and 400 mg). To minimize cardiovascular risk, the drug should be used in the lowest effective dosage for the shortest time needed. Approved dosages are as follows: • Osteoarthritis—100 mg twice daily or 200 mg once daily • Rheumatoid arthritis—100 or 200 mg twice daily • Acute pain—On day 1, 400 mg initially plus another 200 mg if needed; on all subsequent days, 200 mg twice daily as needed • Primary dysmenorrhea—Same as for acute pain Acetaminophen Acetaminophen [Tylenol, Ofirmev, many others] is like aspirin in some respects but different in others. Acetaminophen has analgesic and antipyretic properties equivalent to those of aspirin. In addition, acetaminophen does not suppress platelet aggregation, does not cause gastric ulceration, and does not decrease renal blood flow or cause renal impairment. Mechanism of Action Differences between the effects of acetaminophen and aspirin are thought to result from selective inhibition of cyclooxygenase, the enzyme needed to make prostaglandins and related compounds. Pharmacokinetics Acetaminophen is readily absorbed after oral dosing and undergoes wide distribution. Most of each dose is metabolized by the liver, and the metabolites are excreted in the urine. Acetaminophen can be metabolized by two pathways; one is major, and the other is minor (Fig. In the major pathway, acetaminophen undergoes conjugation with glucuronic acid and other compounds to form nontoxic metabolites. In the minor pathway, acetaminophen is oxidized by a cytochrome P450–containing enzyme into a highly reactive toxic metabolite: N-acetyl-p- benzoquinone imine. At therapeutic doses, practically all of the drug is converted to nontoxic metabolites through the major pathway. Only a small fraction is converted into the toxic metabolite through the minor pathway. Furthermore, under normal conditions, the toxic metabolite undergoes rapid conversion to a nontoxic form; glutathione is required for the conversion. In the event of acetaminophen overdose, a larger than normal amount is processed through the minor pathway, and hence a large quantity of the toxic metabolite is produced. As the liver attempts to clear the metabolite, glutathione is rapidly depleted, and further detoxification stops. As a result, the toxic metabolite accumulates, causing damage to the liver (see later). Acetaminophen does not cause gastric ulceration or renal impairment and does not inhibit platelet aggregation. Individuals who are hypersensitive to aspirin only rarely experience cross-hypersensitivity with acetaminophen. Additional studies that examined a possible relationship between acetaminophen and hypertension in both men and women found conflicting results. Until more data become available, it would be prudent to monitor blood pressure in patients who take acetaminophen daily. Studies have shown an association between acetaminophen and development of asthma. That is, people may be taking acetaminophen because they have respiratory symptoms, rather than having respiratory symptoms because they took acetaminophen. Rarely, patients experience anaphylaxis, a severe hypersensitivity reaction characterized by breathing difficulty associated with swelling of the face, mouth, and throat. These reactions can occur at any time, even if the patient has taken acetaminophen previously. If rash appears while taking acetaminophen, the drug should be stopped and the patient should seek medical attention.

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The nostrils are round and hori- Academy of Facial Plastic and Reconstructive Surgery discount finasteride 1mg free shipping hair loss lexapro, 83% of zontally oriented with an overall wider base cheap finasteride master card hair loss 21 year old male. The alae are often facial plastic surgeons in this country believe that facial plastic thick quality finasteride 5mg hair loss zomig, hooded, and flaring. Overall, the central portion of the surgery will continue to grow in ethnic populations, which they face tends to protrude more relative to the lower third, and ret- attribute to a greater awareness of cosmetic procedures, access rognathism has been shown to be a normal variant in the His- to ethnic specialists whom they regard as more attuned to their panic-American population. Rhinoplasty protrusion correlates with a nasolabial angle that tends to be is the most popular facial plastic surgical procedure requested neutral to acute giving the impression of underrotation. Interestingly, despite originating from areas of dras- tically dissimilar climates, studies do not consistently suggest a 77. This can be traced back to the racial het- erogeneity of what is termed the Mestizo population, which in itself represents a diverse mix of the Native American tribes and 77. Beauty The historical pattern of immigration and migration resulted in regional differences within Latin America in the phenotypical A major complexity in dealing with the Hispanic-American expression of various racial components. In an anthropometric nose is understanding and accepting cultural differences in the analysis of female Latin American noses, Milgrim et al found concept of beauty. Classic ideas about aesthetic ideals are three main anatomic prototypes with corresponding geographic derived from artists of the Renaissance period, who developed regions: the Caribbean, Central America, and South America. In another absolute sense, for Caucasian patients; however, these have analysis, Daniel grouped patients based on nasal characteristics proved to be less effective in ethnic populations. In our experience, we ever, there are features of beauty that appear to be more subjec- too have seen Hispanic Americans to be a heterogeneous popu- tive, especially across cultures. Racial and ethnic distinctions become especially blurred average, or prototypical, facial features of a given ethnic popula- in border states and cities where interracial mixing has become tion likely reflect the most adaptive design produced for their even more commonplace. All in all, this makes generalizations particular environment based on the laws of natural selection. It follows that attraction and mating with the “average” is advantageous because offspring will gain the benefits of such adaptations. Despite this, a certain Anatomy degree of harmony and balance between facial components is Although diversity in anatomy does exist within the Mestizo required to be perceived as beautiful, no matter the race, cul- population, features of what is anthropologically termed the ture, or ethnicity. These incisions are extended along finer, thinner noses with a slightly more concave dorsum than a the alar cartilage margins from laterally to medially down along high-profile nose with a very prominent tip. Males, on the the length of the columella without disrupting the lateral other hand, prefer a “macho” nose with a higher, somewhat attachments to the alar tissues. In fact, some will specifically request preserva- then connected using a low inverted-V transcolumellar incision. When in doubt, we find that a larger Using a combination of sharp and blunt dissection, the skin nose is preferable to a smaller one. All too often, we have seen envelope should be dissected as close to the underlying lower results from older methods that created a scooped out, lateral and upper lateral cartilages as possible to minimize upturned nose with all the telltale signs of an outdated rhino- bleeding. Because some surgeons have been reluctant to update dorsum in a subperiosteal plane with limited elevation of the their techniques, we have seen a backlash in the Latin commun- soft tissue envelope along the nasal sidewalls. These expecta- Goals for the upper nose are to narrow the nasal bones and tions may vary not only with the patient but also with family improve the dorsal height. Failure to under- encountered, this consists either of a dorsal hump reduction stand these differences in the individual, social, and ethnic per- with the possibility of augmentation to the radix or complete ception of beauty may lead to postoperative angst and dissatis- augmentation of the nasal dorsum. Unfortunately, the rise in ethnic rhinoplasty has been influence tend to have a bony dorsal hump, which is reduced accompanied with a rise in “ethnic restoration” rhinoplasty. Compli- a scalpel and may include portions of the cartilaginous septum, cating this is other-race face perception, or the idea that an upper lateral cartilages, or both. Computer imaging can often be effec- deformity may require the placement of spreader grafts. Narrowing of the nasal bones requires lateral osteotomies in a high-low-high fashion and possibly medial osteotomies as well. If the patient’s nose begins below the upper eyelid lash line Once the plan has been well established, planning and execut- or the radix is deep, which is often present in the Castilian nose, ing surgical maneuvers can be facilitated by compartmentaliz- we may place a radix graft composed of crushed cartilage ing the problems and potential solutions. For augmentation of the entire dorsum, some pre- tional rhinoplasty, we may approach the various regions of the fer alloplastic grafts,16,17 whereas others prefer bone grafts. With the particular anatomic We prefer irradiated rib cartilage homografts, which can be features present in the mesorrhine nose, augmentation, and not carved into the desired shape and, in our hands, have resulted reduction, is of greatest importance. Some surgeons favor an in low rates of warping, resorption, infection, or extrusion. We may also notch the inferior end of the graft, to ing the greatest exposure, the external approach ensures accu- which we secure a columellar strut (i. This provides rate and secure placement of a large number of grafts, symmet- further stability to our graft. Placing an augmentation graft not ric tip work of higher sophistication, and safer debulking of the only raises the dorsal height but also gives the illusion of nar- skin envelope. A meticulous, multilayer, tension-free dosure is critically important especially after increasing tip projection. If the patient Presurgical markings are made prior to placement of intra- presents with thick supratip skin, we remove soft tissue from nasal 4% cocaine pledgets and infiltration of 1% lidocaine with the skin envelope in the region of the tip and supratip. After an adequate time for deconges- open technique is used and the nasal tip skin is elevated, tion has passed, opening the nose begins with bilateral alar the skin envelope is retracted superiorly while a finger is 614 Rhinoplasty for the Hispanic Nose Fig. A significant dorsal reduction, lateral crural steal maneuver, and columellar strut improve the profile and three-quarter view while also contributing to tip support. We position a small scissor parallel to the der- the domes at a greater height pulls up on the ala, thus reducing mis while debulking to prevent inadvertent injury to the sub- alar flare and producing a more triangular base. Early authors employed aggressive trimming of increase in projection also helps to refine the tip by thinning lower lateral cartilages, at times extending their cephalic trims the skin envelope. The vestibular mucosa is dissected from continuity of the dome cartilages, there is no weakening of the the underside of the dome cartilage in the regions where the tip. However, care must be taken to not overrotate the nose and sutures are to be placed. It is Because the Hispanic-American nose is often underprojected important to remember that relatively common bimaxillary and underrotated, an ideal procedure is the lateral crural protrusion can make the nasolabial angle less accurate than the steal. Placement of a radix graft (green) reduced the amount of required dorsal reduction. A lateral crural steal maneuver (double blue arrows) improved the rotation and projection of the nasal tip. A tongue-in-groove maneuver (single blue arrow) addressed excess anterior columella. Widely divergent medial crura may require resection of Alar base modifications generally follow dosure of the marginal intervening soft tissue followed by binding of the medial and transcolumellar incisions. Usually a columellar strut is interposed between the ure is critically important especially after increasing tip projec- medial crura in a pocket dissected between the membranous tion.

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Although a noncompetitive antagonist illustrate the relationship among drug dose 5mg finasteride visa new hair loss cure close to market, receptor occu- also shifts the agonist’s dose-response curve to the right best buy finasteride hair loss in men enhancement, it pancy order finasteride 5mg on-line what causes hair loss in mens legs, and the magnitude of the resulting physiologic effect. The amount of reduction is in all of the receptors are occupied, and the half-maximal proportion to the dose of the antagonist. The effects of a response is produced when 50% of the receptors are occu- noncompetitive antagonist cannot be overcome or sur- pied. In some cases, fewer than 50% of total receptors will mounted with greater doses of an agonist. This is because only a fraction of the total receptors are needed to Quantal Dose-Response Relationship produce the maximal response. The remaining unbound In quantal dose-response relationships, the response eli- receptors are considered to be spare receptors. An example of an all-or-none effect is sleep or dose that produces 50% of the maximal response. The law of mass action explains the relationship between a more realistic estimate of drug safety (see Fig. Because the dose that will kill 1% (E) graded and quantal dose-response curves of animals is twice the dose that is required to produce the 4. In a log dose-response plot, drug effcacy is determined therapeutic effect in 99% of animals, the drug has a good by the maximal height of the measured response on the margin of safety. Agonists have both affnity (E) blocks the effect of the antagonist and effcacy, whereas antagonists only have receptor affnity. The answer is B: the concentration of drug and the association or dissociation of drug-receptor complex. The description of molecular events initiated with the the equilibrium dissociation constant, comes from the ligand binding and ending with a physiologic effect is kinetic rate (k2) of drug-receptor dissociation divided by called the rate (k1) of drug-receptor association. The answer is D: position of the curve along the log- (B) signal transduction pathway dose axis. Potency and effcacy can be determined from (C) ligand-receptor binding a graph of the log dose-response curve by visual inspec- (D) law of mass action tion. The height of the curve along the effect or y-axis is (E) intrinsic activity or effcacy a measure of effcacy. G protein–coupled receptors that activate an inhibitory the log-dose axis or x-axis determines potency such that Gα subunit alter the activity of adenylyl cyclase to curves to the left represent more potent drugs than curves (A) increase the coupling of receptor to G protein to the right. It is possible to have an receptor, but rather blocks the receptor so that agonists agent that is highly potent but does not have great cannot bind and produce an effect. The answer is D: cannot produce the full effect, even at pathway, but not to the maximal degree. An agonist acts at its receptor to activate the degree to which a ligand activates its receptor is called signal transduction pathway and produce an effect. An effcacy, it is clear that partial agonists do not have full antagonist binds to its receptor, producing no effect at the effcacy. The overwhelming success in modern associated with administering the drug to healthy human pharmacotherapy in treating disease states attests to the subjects and patients. However, drugs based on the proven correlation between drug toxicity in can also be poisons causing unwanted adverse effects, and animals and humans. This chapter begins with a description of drug involve short-term and long-term administration of the development and the processes for evaluating drug safety drug and are designed to determine the risk of acute, sub- and effcacy and then discusses the various types of adverse acute, and chronic toxicity, as well as the risk of terato­ effects and interactions that are caused by drugs. After animals erations for specifc populations, such as the neonate and the are treated with the new drug, their behavior is assessed and elderly, are highlighted, and the laws relating to drug use their blood samples are analyzed for indications of tissue and abuse are briefy reviewed. Offspring are also studied for adverse Drug development in most countries has many features in effects. However, because studies of Discovery and Characterization chronic toxicity of new drugs in animals may require years New drug compounds are synthesized de novo or are iso- for completion, it is usually possible to begin human studies lated from a natural product, or a combination of the two while animal studies are being completed if the acute and as in semisynthetic compounds. Synthetic drugs may be subacute toxicity studies have not revealed any abnormalities patterned after other drugs with known pharmacologic in animals. This led to and methods of the proposed clinical studies and the quali- the subsequent development of clonidine for treating fcations of the investigators. The subjects harmful or benefcial effects on vital organ function, includ- typically undergo a complete history and physical examina- ing cardiovascular, renal, and respiratory function; (2) eluci- tion, diagnostic imaging studies, and chemical and pharma- date the drug’s mechanisms and therapeutic effects on target cokinetic analyses of samples of blood and other bodily organs; and (3) determine the drug’s pharmacokinetic pro- fuids. The pharmacokinetic analyses provide a basis for esti- perties, thereby providing some indication of how the drug mating doses to be employed in the next phase of trials, and would be handled by the human body. Although a few the other examinations seek to determine if the drug is safe people object to using animals, there are even fewer willing for use in humans. These studies use a small number of patients to Discovery and • Isolate or synthesize a new drug. Placebo-control design includes a group receiving an identi- • Propose clinical studies (sites, cal formulation but with no active ingredients. With some investigators, protocols, and diseases, it is unethical to administer a placebo because of methods of data analysis). In such cases the new drug is compared with the standard drug for treat- Clinical studies • Phase 1: Gather data on drug safety and pharmacokinetics in ment of that disease. Steps in the process of drug development in the United clinical indications for the drug. Subacute toxicity Administer the drug for 90 days in two species via a Behavioral and physiologic changes, blood chemistry levels, route intended for humans. Chronic toxicity Administer the drug for 6-24 months, depending on the Behavioral and physiologic changes, blood chemistry levels, type of drug. Teratogenesis Administer the drug to pregnant rats and rabbits during Anatomic defects and behavioral changes in offspring. Examine cultured Evidence of chromosome breaks, gene mutations, mammalian cells for chromosomal defects. Carcinogenesis Administer the drug to rats and mice for their entire Higher than normal rate of malignant neoplasms. Some drugs is composed of representatives of medical and pharmacy are found to have other clinical uses after the drug has been colleges and societies from each state. These indications are known as information on the chemical analysis of drugs and indicates unlabeled or “off-label” uses. In some cases, manufacturers will 110% of the labeled amount of acetylsalicylic acid (aspirin). This was done for tion and many other aspects of drug product composition the antidepressant bupropion, the exact same drug mar- and analysis. Postmarketing surveillance is particularly Amendments to the Food, Drug, and Cosmetic Act. One type concerns drug safety and effcacy determined to be unsafe for use without the supervision of and regulates the processes by which drugs are evaluated, a designated health care professional. The other type focuses on the pre­ been marketed for a period of time or if it is found to be vention of drug abuse. The Act was passed in response to the The Kefauver­Harris Amendments were passed in 1962, sale of patent medicines, often by so-called “snake-oil sales- largely in response to reports of severe malformations in men,” which contained toxic or habit-forming ingredients.

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Disul- Fomepizole fram inhibits aldehyde dehydrogenase and leads to the accumula- tion of acetaldehyde during ethanol ingestion buy generic finasteride line hair loss control. Fomepizole inhibits Methanol Formaldehyde Formate alcohol dehydrogenase and is used in methanol or ethylene glycol poisoning order finasteride line hair loss underactive thyroid. Hence 1 mg finasteride free shipping hair loss cure tips, ethanol metabolism alone, the cost of health care, lost work hours, criminal activ- exhibits zero-order kinetics, except when serum concentra- ity, and other problems related to alcohol use is roughly $90 tions of ethanol are very low. An adult The alcohols and glycols most commonly ingested are weighing 70 kg usually metabolizes only about 10 mL of ethanol, methanol, and ethylene glycol. A standard drink is life-threatening toxicity, even when ingested in relatively a 12-ounce serving of beer, a 5-ounce glass of wine, or 1. However, long-term ethanol use or ethanol with- to enable rapid and almost complete absorption from the drawal may lower the seizure threshold and thereby cause gut. Predictably, ethanol potentiates the effects of from the stomach, and food slows its absorption by slowing benzodiazepines and barbiturates, so the combination of the rate of gastric emptying. In many individuals, reinforce- for further oxidation to carbon dioxide and water. The oxi- ment leads to the continued consumption of alcoholic bever- dation of ethanol uses signifcant quantities of nicotinamide ages and to ethanol intoxication. This diuretic effect is augmented by the consumption of About 2% of ethanol is excreted unchanged by the kidneys large volumes of alcoholic beverages, such as a six-pack and lungs. Hence, alcohol consumption can Because ethanol can markedly impair the psychomotor skills contribute to hypothermia during cold weather. Consumption of large amounts of Barbiturates and Benzodiazepines ethanol on a long-term basis can eventually lead to alcoholic The pharmacologic properties of barbiturates and benzodi- cardiomyopathy and cardiac arrhythmias. These drugs are In alcoholic patients, thiamine defciency secondary to a sedative-hypnotic agents that are prescribed for the treat- poor diet is commonly observed, which leads to nerve demy- ment of anxiety disorders, insomnia, and other conditions. This, in turn, causes peripheral neuropathies, They are used recreationally for their euphoric and anxiolytic characterized by paresthesias and reduced sensory acuity. The administration of thiamine among the most widely abused sedative-hypnotic drugs. Although this drug is not approved for Alcoholic patients can also develop several metabolic dis- use in the United States, it is used throughout much of the orders. In the United States metabolites and lactate to accumulate and eventually con- it is widely available from street dealers and is sometimes tributes to liver degeneration (cirrhosis) and impaired gly- referred to as roofes, derived from its trade name, Rohyp- cogenolysis. A dietary defciency of folate club drug, and a drug that contributes to date rape. It is an can lead to megaloblastic anemia, whereas a defciency of extremely potent benzodiazepine that is tasteless when dis- other vitamins and antioxidants contributes to the overall solved in a beverage. Hence, The consumption of signifcant quantities of ethanol victims do not recall events that happen while under the during pregnancy is responsible for the occurrence of the infuence of the drug. Formate is primarily responsible and from synergistic effects when mixed with alcohol. It is for optic nerve damage, which can result in visual feld also listed by the Drug Enforcement Administration as a impairment or permanent blindness. Opioids Hemodialysis is also used to reduce methanol levels in severe The most commonly abused illicit opioid drug is heroin. Fomepizole, an inhibitor of alcohol dehydro- This drug is prepared from morphine by the addition of genase, can also be administered; this prevents the formation acetyl groups, so structurally it is known as diacetylmor- of toxic metabolites in cases of methanol and ethylene glycol phine. Isopropyl alcohol is considerable drug tolerance and physical dependence, and converted to acetone, a substance that can be smelled on they undergo a wide variety of withdrawal symptoms (see the breath. The treatment of intoxication is largely Table 25-3) if they abruptly discontinue their use of the drug supportive. Ethylene glycol is contained in automobile antifreeze and Other opioids produce effects similar to those of heroin, deicing fuids, and its ingestion can cause anion gap meta- but usually to a lesser degree. Owing to its sweet taste and appealing color, children with the route of administration. Opioids administered often die from ethylene glycol poisoning from automobile orally tend to produce less euphoria and dependence than antifreeze left accessible in the garage. Treatment consists of supporting vital functions, giving for heroin as well as the opioid withdrawal reaction without ethanol or fomepizole, managing acidosis, and performing causing signifcant reinforcement or exacerbating drug hemodialysis. The An 18-year-old man is brought to the emergency room in an unresponsive state with depressed respiration, pinpoint euphoria and other reinforcing effects are caused by increased pupils, and cold, clammy skin. His pulse rate is 40 beats/ dopamine levels in the nucleus accumbens, whereas the min. The needle tracks and the triad of apnea or depressed res- piration, miosis (pinpoint pupils), and a comatose state indi- cate that the patient arrived at the hospital in an opioid Methamphetamine overdose condition. Needle tracks in his arms suggest heroin Amphetamine and methamphetamine are closely related use, although prescription opioids are also increasingly sympathomimetic amines, and both are drugs of abuse. Nal- the two, methamphetamine is often preferred by abusers oxone is a pure opioid receptor antagonist and can quickly because it causes less norepinephrine to be released and can reverse the near-death condition of an opioid overdose, a be more easily pyrolyzed (burned) and smoked. When phenomenon sometimes called the Lazarus effect, from the methamphetamine free base is extracted by ether, pyrolyzed, biblical story. As the elimination half-life of naloxone is and smoked, it is called ice or crystal meth. The euphoria sometimes shorter than that of the opioid that caused the produced by smoking “ice” is much greater than that pro- overdose, patients may be given multiple doses of naloxone duced by taking methamphetamine orally, presumably and monitored so that a relapse does not occur. It is recom- mended that patients who receive naloxone be continuously because of the faster rate at which dopamine levels are observed for a minimum of 2 hours after the last dose. The inexpensive cost and not uncommon that the overdosed individual will be angry relative ease of making methamphetamine from precursor at the hospital staff for reversing the opioid effect, and drugs found in nonprescription cold medicines enabled an naloxone may precipitate an opioid withdrawal syndrome. Other Amphetamine Derivatives Several other amphetamine derivatives have been clandes- marketed as OxyContin, gained notoriety among street tinely synthesized and sold as designer drugs on the users because a dose intended for 24-hour pain relief in street. This has led to an increase both psychostimulant and psychotomimetic effects by in the number of deaths caused by opioid overdose. Amphetamine also facilitates the reverse transport of the catecholamines inside the terminal out through the Other Stimulants reuptake transporter into the synapse. At high concentra- Cocaine tions, amphetamine, but not all derivatives, can also inhibit Cocaine produces both psychostimulant and local anes- monoamine oxidase and by this second mechanism can thetic activity and has limited clinical use as a local anes- increase the levels of catecholamines. Cocaine binds to the neu- Nicotine, the principal alkaloid of plants of the genus Nico- rotransmitter transport proteins and causes them to undergo tiana, is widely available in the form of various tobacco a conformational change that reduces their capacity to products that can be chewed or smoked. By this absorbed into the circulation from the mouth or the respira- mechanism, cocaine increases the synaptic concentration of tory tract and is then quickly distributed to the brain. When has a half-life of about 30 minutes, it is metabolized to the native South Americans chew the leaves to relieve fatigue, active metabolite, cotinine, which has a half-life of about 2 relatively few adverse effects are seen. The induction of cytochrome P450 enzymes by tars forms of cocaine, however, is associated with signifcant drug contained in cigarette smoke accelerates the metabolism dependence, as well as cardiovascular, pulmonary, and neural of nicotine, and this leads to the development of pharma- toxicity. Because the use of In the past, many cocaine users took powdered cocaine cigarettes accelerates the metabolism of β-adrenoceptor hydrochloride by insuffation (snorting). Cocaine taken in antagonists, benzodiazepines, opioids, and theophylline, this manner is absorbed across the nasal mucosa and into cigarette smokers may require higher doses of these drugs to the circulation. In addition to activating nicotinic recep- serum levels that are comparable to those obtained by tors, nicotine inhibits monoamine oxidase. For this reason, ability to inhibit this enzyme partly explains its ability to crack cocaine produces a euphoric effect that is more activate dopaminergic neurotransmission and its depen- intense than that obtained by snorting cocaine.