You are on page 1of 11

Pharmacological Properties of the Poppy by : Crystal M.

Cunningham The opium poppy is cultivated in many countries such as Iran, Turkey, Canada, and Asia. It has white, pink, red, or purple leaves and its seeds range in color from white to blue. The plant is believed to have evolved from a wild strain which grows in coastal areas of the Mediterranean Sea (1). A milky exudate is collected by making incisions into the seed pods(2). This exudate is then dried. Opium is extracted from the dried juice of the unripe seedpods, figure 1. The term opium alkaloids refers to the compounds which are Figure 1Opium Poppy extracted from the poppys exudate. The chief constituents of opium are the alkaloids codeine, papaverine, morphine, and thebaine. All of these molecules except thebaine are used for their analgesic, antitussive, and antidiarrheal properties. Thebaine does not have an analgesic affect but is still used pharmaceutically to produce morphine analogs (1). Poppy alkaloids have been used to treat pain associated with toothaches and coughs since antiquity. Morphine and codeine are the two major analgesics, little is said about papaverine
OMe

though it is capable of relaxing smooth muscles and acts


OMe as a cerebral vasodilator, figure 2.

The use of opium for therapeutic value can be


MeO MeO N

traced to c.460 B.C. The Father of Medicine Hippocrates, acknowledged the usefulness of opiums narcotic effect in treating internal diseases, diseases of

Figure 2: Papaverine

women, and epidemics (3). When the reformation was at its height, Stones of Immortality

were made of opium thebaicum, citrus juice and quintessence of gold. These magic stones were prescribed as painkillers. Almost as early as these medicinal uses for opium became apparent, its potential for addiction became obvious leading to controlled production of its substituents in many countries. Opium addiction reached such epidemic proportions in China that it was used as a form of money (4). In 1729 the Chinese emperor issued an edict prohibiting the smoking of opium in its domestic sale and regulating it for medicinal purposes only. The Western World also saw the adverse affects of opium. The United States Congress banned opium in 1905 as a consequence of the alarming rate of heroin (a morphine derivitive) addiction in 1903 (3). It soon became apparent that prolonged use of opium for pain treatment would result in addiction. The Birth of Opium Research The inevitable result of addiction, when prescribed for chronic pain, led to extensive research on opium to obtain a potent but nonaddictive painkiller. The fastest advancements of this task were occurring in Germany. A group of chemists were attempting to make the addictive properties of opium lessen, while at the same time preserving its antitussive and analgesic effects. The addictive component of opium is morphine named after the Greek God of dreams, Morpheus (5). Morphine was first isolated in 1803 by Friedrich Sertuerner of Paderborn Germany. Sertuerner dissolved opium in acid and then neutralized it with ammonia (3). This resulted in the precipitation of morphine. This is similar to the method currently used for morphine extraction. The extraction process involves dissolving the opium in hot water and then adding calcium hydroxide (lime). The addition of the calcium hydroxide precipitates the non-morphine

alkaloids and the addition of ammonium chloride precipitates the morphine from solution. The resulting precipitates are formed via a manipulation of pH which causes one substance to be soluble while the other is not and vice versa. After morphines isolation in 1803, the search for a nonaddictive analgesic continued. In 1898 the producers of aspirin, Bayer Pharmaceutical company of Germany, were the first to announce they had produced the new nonaddictive opiate derivitive (6). The new drug, 3,6diacetylmorphine, or simply diacetyl morphine, was trademarked under the name Heroin. The structures of both morphine and heroin are shown below in figures 3 and 4. The structural differences between these two molecules is the addition of an acetyl group. Unfortunately this addition had the opposite of the desired affect. Heroin is three times more potent than morphine and even more addicting (6). The addition of the acetyl groups causes an increase in the lipophilic properties of the drug. This increase in lipid solubility provides accelerated penetration into the central nervous system (CNS) yielding an almost instant euphoric effect. The addition of the acetyl groups also decreases the polarity of the molecule making the passage across the fatty tissues of the blood brain barrier (BBB) easier.

Figure 4: Morphine

Figure 3: Heroin :3,6-diacetylmorphine

One of the acetyl groups is removed before entering the brain. Thus the mono acetyl product, 6acetylmorphine is even more potent than heroin because it penetrates into the brain even faster (1). The rate at which the drug reaches the CNS is further enhanced if the drug is injected intravenously or smoked.

Heroin was not the first semi-synthetic morphine derivative to be introduced as having Figure 5:Codeine. Diethylmorphine substitutes the methyl and hydroxyl for the ethyl group. therapeutic value. Ethylmorphine was the first derivative introduced into the clinical setting.

This drug was synthesized to relieve coughs. Codeine, figure 5, another opium alkaloid, had proven ineffective for tuberculosis cough and it was hoped that ethylmorphine would be able to suppress the dreadful cough of tuberculosis. Ethylmorphiness cough suppressing effect was hoped to be increased by the introduction of the alkyl groups into the morphine molecule (6). The Bayer company claimed that the alkyl groups increased cough suppression while lessening its narcotic effect. The British Pharmaceutical Codex of 1907 anticipated that the new heroin would have properties of ethylmorphine and thus be more like codeine. Receptor System It is a bit trifling that the opiate receptors of humans, which are very stereospecific, should even occur in nature. Then again, maybe nature is not so fortuitous, these receptors are also found in rats and in lower invertebrates such as the slug (7). Precursors to the metabolically active morphine molecule have been isolated from human metabolic pathways. These same precursors are found in the poppy plant as precursors of natural opiates (8).

The chemical structure of opiates is very similar to that of naturally occurring compounds called endorphinsand enkephalins. The similarities between these two structures allows the opiate to bind to the endorphins nerve receptor sites in the brains pleasure centers. This is the opiates mechanism for causing analgesic effects (9). Endorphins are released in the response to discomfort and pain. Opiates, because of their structure, are disguised as high levels of endorphins giving a euphoric effect. The pleasure areas of the brain are not the only location of opiate receptors in the body. Another location for the opiate receptor is in the respiratory center of the brain (9). This causes depression of the respiratory system and slows breathing. The opioid receptors in the G.I. tract are responsible for adverse effects of the drug such as nausea and vomiting. This same receptor site gives the opiate alkaloids antidiarrheal properties (9). Repeated use of opiates causes these receptor systems to become tolerant and lose sensitivity to the drug. An increased dosage of the drug is required to achieve the pain inhibiting effects. Long-term use of opioids can deplete the bodys natural supply of endorphins and dopamine. This results in long-term or chronic depression (10). The treatment for opioid addiction is time consuming and often unsuccessful but, recovery is possible. There is an estimate of 400,000 deaths per year due to alkaloid addiction in the United States alone (9). Opioid addiction therapy includes successful detoxification, rehabilitation, and sometimes methadone maintenance. Physical, mental, and emotional pain usually accompany an individual trying to obtain abstinence from potent opiates such as morphine. Research has shown that when addicted animals go off drugs, levels of dopamine become extremely low very quickly (11). This is accompanied by withdrawal symptoms such as shaking, sweating, and vomiting.

An individual with a history of substance abuse should be prescribed opiates with caution. If possible a physician should even take the time to get to know the patient. The extra time spent in properly evaluating an individual before dispensing an addictive drug is priceless. The amount of energy and dollars spent in the detoxification process of an addicted individual is enormous, not only financially but physically and psychologically. Although there is a potential for abuse and addiction, the therapeutic value of the morphine drug is unquestionable. Morphine is currently the benchmark against which all other analgesics are judged (5). It has held this position since its identification over 200 years ago. Morphine and other opioid derivatives are used to treat individuals with severe and/or chronic pain. Opiods are used for pain associated with AIDS, cancer, and multiple sclerosis. Structure-Activity Relationships Previously described were the opiates mechanism of action, the binding of the pleasure centers of the brain. This is accomplished via its passing through the BBB and its high affinity for the central nervous system. Studies have shown that the N-oxide and N-methyl quaternary salts of morphine are inactive (1). These salt forms are capable of having the same effect as morphine if they are directly injected into the brain, thus bypassing the BBB. The injection directly into the brain resulting in analgesic effects shows that inactivity of the salts is due to their difficulty passing the BBB when charged. It also indicates that the nitrogen is ionized when bound to the receptor (1). The importance of the substituents on the ring also varies. The methyl substituent is not essential for activity but the Nitrogen is. The ether bridge is also not necessary for analgesic activity but the aromatic ring is (1). Morphine also has several chiral carbons which have specific stereospecificity resulting in the stereoisomer being inactive. The natural form of

morphine is a single enantiomer (1). Drug simplification studies have also been done on the morphine molecule. Drug simplification studies help to determine what functional groups are necessary for proper activity.
O Me Ph CO2Et N Me2

These studies involve changing basic components of the molecule and studying the effects. These types of studies have led to several other subgroups of the opiates: morphinians resulting from the removal of the oxygen bridge are more potent than morphine, and benzophorans sythesized by removal of the

Figure 6: Methadone

5-membered and the 6-membered hydroxylated hexane. The benzophorans have a similar analgesic effect but without the side-effects of addiction. The compound methadone is formed by removal of all rings except the phenol. This is also comparable to morphine but has lesser side effects and withdrawal symptoms. Methadone is often given
MeO

to drug addicts to substitute for morphine or heroin, figure 6.


O NCH3

It was mentioned earlier that the poppy alkaloid thebaine has no analgesic activities. Chemists have used some very

MeO

Figure 7: Thebaine

classic reactions to make this molecule even more powerful than

morphine. By reacting the thebaine, figure 7, molecule with methyl vinyl ketone via a DielsAlder reaction and then adding groups by a Grignard reaction, analgesics rated as 10 000 times more powerful than morphine are produced. The side-effects of this compound are severe and it is not in use (1). Metabolism of Morphine: Differences Between Adults and Children Morphine is the most common drug prescribed for acute or chronic pain. The metabolism of the drug occurs in the liver. Morphine is metabolized into morphine-3-

glucuronide and morphine-6-glucuronide (12). These glucuronides are very soluble and eliminated through the urinary system. The glucuronides also have ironic characteristics. Morphine-6-glucuronide is 40 times as potent as its parent compound. Morphine-3-glucuronide has an opposite effect acting as an antagonist to morphine-6-glucuronide and morphine. The ratio of morphine-3-glucuronide to morphine-6-glucuronide is crucial for the exertion of proper analgesic activity, metabolism, and reduced side-effects. High levels of this ratio are responsible for two phenomenons: hyperalgesia an allodynia. Hyperalgesia occurs when a painful stimulus is perceived as more painful than usual. Allodynia occurs when a normally painless stimulus is perceived as painful (12). Studies have shown that the morphine-3-glucuronide ratio is dependent on age. This ratio in children is approximately half that in adults . Allodynia and Hyperalgesia have been frequently seen in adults and it is rarely seen in children. In premature neonates this ratio was even threefold to fivefold times lower that in older children (12). The metabolic products of morphine is dependent on age showing differences in the ratio of metabolic products and kinetics in children versus adults. Young children lack some of the morphine metabolizing enzymes necessary to produce hyperalgesia or allodynia, although it sometimes does occur. Based on the structural similarities between morphine and codeine, one could think it is a possibility for morphine to be oxidized to codeine. This possibility has been ruled out through the use of GC/MS assay testing (13). Morphine In the year 2000 Morphine has brought about many moral and ethical questions. It has gone through phases of being outlawed and reinstated for therapeutical use several times. The potent morphine derivative, Heroin, is currently banned in the United States but it is used for medical treatment in

other countries. The prescribing of morphine, as recommended by the World Health Organization, is based on an individuals personal pain threshold (6). The current research on opiates is focused on the binding between the drug and the human receptors. Scientists are trying to find new ways of synthesis to provide analgesic effects without the side-effects
O H O H

and problem of addiction. Current research is also making


O N

an attempt to combat drug addiction and ease withdrawal symptoms. The rapid advancement of technology is making the synthesis of these drugs and their mechanisms for

Figure 8: Naltrexone delivery possible.

Devices are currently being developed that will be triggered by morphine to release naltrexone, a morphine antagonist, figure 8 (14). Cellulose acetatephthalate microspheres are coated with trilaurin which then disperse the naltrexone. Naltrexone is also dispersed in an noctyl half ester of methyl vinyl ether and maleic anhydride copolymer and fabricated into a disk. This disk releases naltrexone over a two week period while the microspheres release it rapidly. The disk and microspheres are placed in a semi-permeable membrane that is activated by morphine. Morphine activates the devices causing the release of naltrexone. The naltrexone then binds to the morphine receptor instead of morphine. This technique seems to be useful in the treatment of heroin addiction (14). Igenious ideas like these are what will provide some answers to the ethical and moral questions that morphine has caused. Scientific manipulation did cause the spree of heroin addiction to begin, but at the time it was one of the only available potent analgesics to prevent dreadful and unperceivable human pain and suffering. Today scientists are able to use state of

the art technology, such as molecular modeling software, to make predictions about newly synthesized drugs. By having an understanding of structure, metabolism, and receptor-substrate binding, nonaddictive analgesics with little side effects could be developed. Eventually, the poppy could be used for its simple aesthetic value. References 1. Opium-Poppy, Cultivation, Morphine, and Heroin Manufacture ( Jan. 2000). Available: http://rhodium.lycaeum.org/chemistry/opium/html. 2. The Opium Poppy (Jan. 2000). Available:http://www.heroin.org/poppy.html. 3. A Brief History of Opium (Jan. 2000). Available: http://opiods.com/timeline/index.html. 4. The Opium War (Jan. 2000). Available: http://www.dimensional.com/~randl/opie.htm. 5. Starr, Cynthia. (1998) Opioid Analgesia: An essential tool in chronic pain. Patient Care.,32(12):47-62. 6. Sneader, Walter. (1998) The Discovery of Heroin. The Lancet., 352:1697-2002. 7. Wise, R.A. (1987) The Role of Reward Pathways in the Development of Drug Dependence. Pharmacological Ther., 35:227-63 8. Chemical Services Inc. (1988) Internal Drug Factories in Mammals. Science News., 133(2):24 9. Peterson, Andrew. (1997) Analgesics., RN 60(4):45-51. 10. Beebe, Diane., Walley, Elizabeth. (1991) Substance Abuse: The Designer Drugs. American Family Physician., 43(5):1689-1699. 11. Adler, Tina. (1994) Source of Withdrawal Pangs Found in the Brain. Science News., 146(11):166-168.

12. Heger, Seben., Maier, Christoph., Otter, Karin., Helwig, Ulf., Suttorp, Meinolf., (1999) Morphine Induced Allodynia in a Child With a Brain Tumour. British Medical Journal., 319:627631. 13. Mitchell JM., Paul, BD., Welch, P., Cone, EJ., (1991). Forensic Drug Testing for Opiates. II. Metabolism and Excretion Rate of Morphine In Humans After Morphine Administration. J. Anal. Toxicology., 15(2):49-53. 14. Roskos, KV., Tefft, JA., Heller, J (1993) A Morphine-triggered Delivery System Useful in the Treatment of Heroin Addiction., Clin Mater., 13(1-4):109-119.