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Chem-127 – Impact of Chemistry – H. D. Roth Chapter 10: Drugs, Manipulating Molecules Everyday drugs – are we dependent? Prescrip0on drugs – are we dependent? How harmful are illicit drugs? Are “natural” herbal remedies safer than synthe0c ones? How are effec0ve drugs designed? We begin with some everyday stimulants and drugs HDR-F-2012 Azo dyes were the first commercially produced chemicals. They effectively dyed wool fibers (animal protein). Over 10,000 dyes were screened in vitro in antibacterial tests, but none showed any antibiotic activity. Scientists then turned to in vivo studies with mice that had been infected with a bacterial culture. Several dyes were found to counteract gram-positive bacterial infections. NH2 O H2 N N N S O Prontosil NH2 Gerhard Domagk was a research scientist at Gerhard Domagk was a research scientist at I. G. Farbenindustrie, a German I. G. Farbenindustrie, a German manufacturer of dyes and other chemicals. manufacturer of dyes other chemicals. manufacturer dyes and and chemicals. He carried outofstudies thatother showed Prontosil He carried out studies that showed Prontosil He out studies that showed wascarried an effective antibacterial agent.Prontosil was an effective antibacterial agent. was an effective antibacterial agent. His daughter, who was dying of a streptococcal His daughter, who was dying of a streptococcal infection as a result of cutting her streptococcal finger, was the His daughter, who was dying of infection as a result of cutting hera finger, was the first patient to receive the drug and be cured by infection as to a result ofthe cutting wasby the first patient receive drugher andfinger, be cured it (1935). (1935). Prontosil received wider fame when patientProntosil to receive the drug and fame be cured byitit itfirst received wider when used to to save save the the life life of of Franklin Franklin D. D. was used itwas (1935). Prontosil received wider fame when it Roosevelt, Jr., son of the US president. Roosevelt, sonthe oflife the of USFranklin president. was used toJr., save D. Roosevelt, son of thethat USProntosil president.was Later it wasJr., discovered Later it was discovered that Prontosil was converted to to sulfanilamide sulfanilamide in in living living organisms organisms converted Later it was thatactive Prontosil was and that that thisdiscovered was the the actual actual active compound. and this was compound. Sulfanilamide inhibits the the synthesis synthesis of folic folic acid, acid, converted to sulfanilamide in living of organisms Sulfanilamide inhibits an essential essential chemical compound for bacterial and that thischemical was the actual activefor compound. an compound bacterial growth. Sulfanilamide inhibits the synthesis of folic acid, growth. were found to counteract gram-positive bacterial infections. NH2 O H2 N N N S O Prontosil NH2 first used for war casualties in Sicily and Tunsia. H N R O S N CH3 CH3 O Penicillin O O Penicillins act act by by modifying modifying an an enzyme enzyme involved involved Penicillins in the the synthesis synthesis of of aa bacterium’s bacterium’s cell cell wall. wall. in Actively growing growing bacteria bacteria die die because because they they are are Actively unable to to produce produce aa functional functional cell cell wall. wall. unable Penicillins have have no no effect effect on on mammalian mammalian cells cells Penicillins because they they are are not not enclosed enclosed by by cell cell walls. walls. because The first first penicillin penicillin was was isolated isolated in in 1938 1938 and and The found to to cure cure bacterial bacterial infections infections in in mice. mice. ItIt was was found used successfully successfully in in nine nine cases cases of of human human used bacterial infections infections in in 1941. 1941. By By 1943, 1943, penicillin penicillin bacterial was being being produced produced for for the the military military and and was was was first used used for for war war casualties casualties in in Sicily Sicily and and Tunsia. Tunsia. first Hormones are chemical messengers – organic compounds synthesized in glands and delivered by the bloodstream to target 8ssues in order to s8mulate or inhibit some biochemical process. Many hormones are steroids. Remember: All steroids contain a tetracyclic ring system. The most abundant member of the steroid family in animals is cholesterol, the precursor of all other steroids. HDR-F-2012 Cortison Cor8sone, used extensively in the treatment of rheumatoid inflamma8ons, is one of the adrenocor8cal hormones produced in the outer part of the adrenal gland. These hormones par8cipate in regula8ng the electrolyte and water balance in the body, as well as in protein and carbohydrate metabolism. HDR-F-2012 Steroids CH3 R H H CH3 H C H H C H R H Steroids perform many functions in the body: Function Regulation of secondary sexual characteristics Reproduction and control of the reproductive cycle Regulation of metabolism Examples Estradiol (an estrogen); testosterone (an androgen) Progesterone and the gestagens Digestion of fat Cell membrane component Cholic acid; bile salts Cholesterol C A B Cortisol; cortisone derivatives D This is the basic carbon skeleton for all steroids. 10.7 The sex hormones are divided into three groups: (1) the male sex hormones, or androgens; (2) the female sex hormones, or estrogens; and (3) the pregnancy hormones, or progestins. Testosterone is the principal male sex hormone and is responsible for the development of the male secondary sex characteristics. Synthetic testosterone analogs (anabolic steroids) are used in medicine to promote muscle and tissue growth, for example, in patients with muscular atrophy. Unfortunately, such steroids are also abused and consumed illegally, most commonly by “body builders” and athletes, even though the health risks are numerous, including liver cancer, coronary hear disease, and sterility. Estradiol is the principal female sex hormone. It is responsible for the development of the female secondary sex characteristics and participates in the control of the menstrual cycle. An example of a progestin is progesterone, responsible for preparing the uterus for the implantation of a fertilized egg. Synthetic analogs of estradiol and progesterone are the active agents in the birth control pill, allowing for control of the menstrual cycle and ovulation. It is estimated that 50 to 60 million women worldwide use the pill as the primary form of contraception. RU-486, The Abortion Pill RU-486 acts as an antagonist – a drug that fits into a receptor site, but does not have the customary effect as does another drug; in this case the other drug is progesterone. Antagonist – a drug that binds to a receptor site, but does not– have thethat biological of thesite, binds toeffect a receptor Antagonist a drug Methotrexate is biological a prescription drug used in natural substrate but does not have the effect of the the treatment natural substrate of breast cancer. It can be used to block the action of folic acid, which is Methotrexate is a prescription drug used in required for normal cell division and growth theMethotrexate treatment ofisbreast cancer. Itdrug can used be used a prescription in of an embryo. Like RU-486, itisbe can be used to to block the action of folic acid, which the treatment of breast cancer. It can used induce the firstwhich seven required for cell division and growth to block abortion the normal action ofin folic acid, is weeks of of an embryo. Like RU-486, it can be used to by the required for normal cell division growth pregnancy. Once a drug isand approved of an embryo. it can be used induce abortionLike in theRU-486, first seven weeks of to FDA, a physician can prescribe itof for pregnancy. Onceina the drug is approved by the induce abortion first seven weeks purposes not originally intended by the drug pregnancy. Once a drug is approved FDA, a physician can prescribe it for by the FDA, a physician can prescribe purposes not originally intended it byfor the drug manufacturer. purposes not originally intended by the drug manufacturer. manufacturer. Should such “off-label” prescriptions Should such “off-label” prescriptions be Should such “off-label” prescriptions be allowed? allowed? allowed? be Medicines Prescription, Generic, andand Over-the-Counter Generic, APrescription, generic drug is chemically equivalent to Over-the-Counter the pioneer drug, but cannot be marketed until the patent protection on the pioneer drug has run out after 20 Medicines Medicines years. A generic drug drug is chemically equivalent to the drug, butbut cannot bebe A generic is chemically equivalent to pioneer the pioneer drug, cannot The lower drug commonly marketed under drug its generic name, in this20 marketed untilpriced the patent protection on the hashas run outout after marketed until the patent protection on pioneer the pioneer drug run after 20 case alprazolam instead of Xanax. years. years. The lower drug commonly marketed under its generic name, this The lower pricedpriced drug commonly marketed under its generic name, in in this case alprazolam instead of Xanax. case alprazolam instead of Xanax. Prescription, Generic, and Over-the-Counter Medicines A generic drug is chemically equivalent to the pioneer drug, but cannot be marketed until the patent protection on the pioneer drug has run out after 20 years. 10.10 The lower priced drug commonly marketed under its generic name, in this case alprazolam instead of Xanax. 10.1 Herbal Remedies 10.11 Ephedra – used safely for thousands of years as herbal remedy known as Ma Huang. In 2003, several deaths related to the ingredients led the FDA (in 2004) to ban ephedra products. At this time, there are ongoing discussions to make the product available again. Ephedra The herb contains the amphetamine-like alkaloids – ephedrine and the less active pseudoephedrine. Pseudoephedrene is used as a decongestant Ephedrine is a bronchodilator (opens the airways), and a stimulant Ephedra The herb contains the amphetamine-like alkaloids – ephedrine and the less active pseudoephedrine. Pseudoephedrene is used as a decongestant Ephedrine is a bronchodilator (opens the airways), and a stimulant Ephreda was responsible for the deaths of over 80 people. An ephreda manufacturer challenged the FDA ban in court, claiming that the FDA had failed to prove that ephreda was not safe at low doses. In 2006, the US Court of Appeals for the Tenth Circuit upheld the FDA’s ban on ephreda. Drugs of Abuse Drugs of Abuse OxyContin contains oxycodone Oxycodone has been used safely for many years. But this formulation includes a time-released mechanism for long-lasting treatment of chronic pain. Drug abusers quickly determined how to get around the time-release and were able to rapidly ingest large amounts of oxycodone. The effects were said to be similar to heroin. Over-prescribed in the Appalachian areas in late 1990s and early 2000s. Many became addicted. 10.12 Marijuana – Cannabis sativa THC, or delta-9-tetrahydrocannabinol is the active drug in marijuana. Medical uses continue to be argued, the Federal Government is opposed. MDMA – Ecstacy MDMA or Ecstasy CH3 CH3 3,4-methylenedioxy-n-methylamphetamine Schedule I drug, yet clinical therapists are continuing to argue its potential benefits as a therapeutic agent.