edited by MARYVIRGINIAORNA,0.S.U College of New Rochelle New Rochelle, NY 10801
Consumer Applications of Chemical Principles: Drugs John W. Hill Susan M. Jones Univerisity of Wisconsin-River Fails River Fails, WI 54022
Drugs are chemical substances. Their action in the human body involves chemical reactions. Surely, then, we can apply some chemical principles to the selection and use-or avoidance-of drugs. Acid-Base Chemistry of Drugs Princioles of acid-base chemistrv can be applied to a range .. of medications from antacids and aspirin to nicotine and &caine. The reactions oi'l'umsm with stomach acid is not unlike that of marble or limestone with hydrochloric acid: CaCOa(s)+ 2HCl(aq)
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CaZ+(aq)+ COdg) + H20+ 2C1-(aq)
Acid-base chemistry of other drugs can he more complex, yet atill understandable to herinning chemistry students. Solubility relationships-can he used to explain why magnesium ions and cellulose act as laxatives and why different forms of cocaine are used for smoking and "snorting." Molecular shape can be used to explain taate, smell, and the artion oi morphine and of the endorphins. The endorphins in turn ran explain the mysterious effects of acupuncture and of placehos. Thi, fit ofadrug molecule with a rereptor on the suriace of a nerve cell can explain the action of atropine as the antidote for poisoning hy organophosphorous compounds. The fit of a substrate molecule on an enzyme can explain how our bodies detoxify ethanol. That these enzymes build up in chronic alcoholics and that they also fit and deactivate the male hormone testosterone explains the well-known syndrome of alcoholic impotence. Space does not permit discussion of all these topics here. Indeed, many other examples are possible. In this paper, we illustrate the use of chemical principles in understanding drugs by examining nicotine, cocaine, some anesthetics, and aspirin. Nicotine
Nicotine is an alkaloid with the molecular formula C I ~ H I ~(Fig. N ~1). I t is quite soluhle in both water and in nonpolar solvents as we might expect from the formula. Each of the nitrogen atoms has an unshared pair of electrons and is capable of accepting a proton. Aqueous solutions of nicotine are basic (KI,~ = 5.4 X 10-l a t 37OC). ClaH14Nz+ Hz0 e C~QH~INZH+ + OHNicotine is rapidly absorbed through the fatty membranes of the cells that line the lungs and is transported to the hrain
Brief descriptions of phenomena, topics, facts, etc. that chemical educators have found to be of interest in their teaching are presented in a "note-type" format throughout Un, JOURNAL.
328
Journal of Chemical Education
Acetylraticylie acid (Aspirin)
Figure 1. Some dnqs (two bases and an acW.
in 7s. Some of it is stored in fatty tissues (mcluding the brain!). In --- acidic -~~~~~solutions. nicotine is readilv converted to its coniugate acid, which is'much less soluble in fat. ~
~
~
CIQHI~N~ + H30Ce CioHi4NzH++ OHNicotine is excreted through the kidneys. The distribution of nicotine hetween aqueous~mediaand fatty tissue depends on the pH. The more acidic the medium, the more nicotine there .-- - is in the ornumated form. The more acidic the urine, the faster nicotine is excreted. As the brain's supply of nicotine is depleted, the smoker begins to desire another cigarette. When does the pH of the urine drop? After a meal. When the person is under stress. When the person is consuming ethanol. When does a smoker nearly always want a cigarette? You guessed it. Cocaine
Cocaine is an alkaloid with the formula C17H210aN (Fig. 1). I t is slightly soluhle in water (1.67 g/L) but quite soluhle in chloroform (1400 g/L) and other solvents of low polarity. Cocaine is a base (Kb = 2.6 X a t 25'0. Even though onlv slightlv soluhle in water, saturated aqueous solutions turn rld lit-mu; to blue. Cocaine reacts with hydrochloric acid to form a salt called cocaine hydrochloride. Cocaine is extracted from leaves of the coca plant. The ground leaves are made basic with 7% aqueous sodium car-
honate and extracted with kerosene. The kerosene layer is drawn off and acidified with dilute hydrochloric acid, precipitating cocaine hydrochloride, the usual street form of the drug. Cocaine hydrochloride is quite soluble in water (2500 g/L). When sniffed up the nose, it is readily absorbed through the mucous membranes. Cocaine is a local anesthetic; i t blocks nerve impulses. Unlike other local anesthetics, it is a powerful stimulant. Cocaine also constricts hlood vessels. Tissue is destroved hv heine-deprived of its hlood sunnlv. . ~ i k most e salts, cocaine hydrochloride is &Aery volatile. Attempts t o smoke it would merelv decom~oseit. For smoking, street "coke" is converted to the "fre'hase." CnHzlOaNCCl- + OH(cocaine hydrochloride)
F?
CI~HIIOIN+ Hz0 + C1(free base)
The free base separates from the solution as a gummy mass. This material can he smoked as is or can be further nurified by extraction with ether. (The noted romedian, ~ i c h a r dI'ryor, was burned in anether fire,allercdlv while iree-hasine in his kitchen.) Free base approaches 100% in purity and 7s thus much more potent than most street coke. I t is also volatile and fat soluhle. The partition coefficient for cocaine (''free base") is:
That for cocaine hydrochloride in the same solvent is:
Free base is smoked, often by adding it to tobacco or marijuana. At the temperature of combustion. the cocaine is readilv volatilized. The fat-soluble free base is also rapidly ahsorheh through the fatty cell memhranes of the lungs. Ingested by smoking, free base is quicker acting and gives a more powerful stimulant effect, hut this effect is followed bv a d e e ~ e der pression than that which follows snorting. ' ' ~ C i nthe ~ hook" is a slang term for using more cocaine to treat that depression. Cocaine is soluble in the fat-like tissue of the brain. I t acts as a stimulant by preventing the re-uptake of the neurotransmitter norepinephrine. The receptor nerve cells are constantly stimulated until the norepinephrine is depleted-in ahout 30 min. This depletion results in depression, anxiety, and the desire for more cocaine. Contrary to the belief of many athletes, cocaine does not improve performance; i t merely masks fatigue. Another chemical aspect of the cocaine scene is quality control. Manv street samples of "cocaine" are fakes. A common suhstituiion is that of amphetamine (a stimulant) plus procaine (a local anesthetic). Even when eenuine. cocaine is kually "cut" 6% to 30%. Diluents include procaine; lidocaine, amphetamines, caffeine, sugar, borax (I), and anything else that the user might think is the real thing. Aspirin
Aspirin is acetylsalicylic acid, C ~ H ~ O Z C O O(Fig. H 1). I t is considerahlv more soluhle in chloroform than in water. Asnirin is a weak acid. CsH70zCOOH + Hz0 e CsH702C00K. = 3.27 X 10 (at 25 OC)
+ H30+
We can do the usual calculations. includine that for the nH of a saturated solution. We can also ralrulaw-the ratio of anion concentration to that of freeacid at various DH values. At nH 5, the ratio is 32, and the aspirin is mainly &I the form of the water-soluble anion. At pH 2 (the approximate pH of the
stomach). the ratio is 0.032. and the aspirin is mainlv in the form of the fat-soluble uncharged molecule. These aspirin molecules readily penetrate the fatty lining of the stomach. In doing so, some of the capillaries that supply the cells of the lining are broken down and bleeding results. General Anesthesia
The important medical area of anesthesia can he used to illustrate important chemical principles such as molecular shapes, solubility rrhionships, ind some aspects of acid-base chemistry. First we will h r ~ kat the old rule that "like dissol\,es like," generally interpreted to mean that polar substances (such as water) dissolve other polar suhstances. Consider methanol (dipole moment = 1.69 D (Dehye units) and chloromethane (dipole moment = 1.87 D). The former is completely miscible with water and the latter is only slightly soluble, The crucial thing is not polarity hut the ability to hydrogen-bond to water-the presence of a F, 0 , or N atom in the molecule. The ootenw of an inhalant anesthetic is oro~ortionalto its lipophiiicity (oil solubility). This potency has deen correlated with the partition of the drug between the gas phase and olive oil. A higher partition coefficient indicates a higher potency. The process is called a hydrophobic interaction; the anesthetic molecules cannot form hydrogen bonds readily. Instead, they interact with the fat-like cell membrane to change its permeability. This interaction is prohahly a nonspecific one with the lipid hilayer, although there could he interaction with hydrophobic sites on receptor proteins. I t is hypothesized that interaction with the lipid matrix causes local disordering so that the phospholipidmolecules are not free to change from the gel to the liquid-crystalline state. lnhihition of the would-be soontmmus flurtuarions of volume causes changes in the structural state of membranebound proteins and their functional properties. The flux of ions determining neuron excitability is then altered. Of the known general anesthetics, nitrous oxide is still used extensively. Diethyl ether and some other popular anesthetics of the past are seldom used because of their flammahilitv. Some i f the more popular new agents that replace them &e enflurane, isoflurane, and halothane. Nitrous Oxide
Nitmus oxide (NzO) is a gas at room temperature and is the only inorganic gas that is practical for clinical anesthesia. I t has no appreciable odor or taste. The oil:gas partition coefficient is low, 1.4 a t 3I0C. Inspired 20% nitrous oxide produces analgesia equivalent to morphine. Some adults lose consciousness with 30% NzO while unconciousness is produced in most individuals at 80%. Unfortunately, a t this &d higher ratios of N20 to air there is the danger of hypoxia. Nitrous oxide is ordinarily used in conjunction with thiopental or neuromuscular blocking agents to augment anakesia. Rapid recoverv is experienced from this . anesthetic. Enflurane
Enflurane (2-chloro-1,1,2-trifluoroethyldifluoromethyl ether) (Fig. 2) can he used in as small a concentration as 4% to achieve anesthesia to depths appropriate to surgery in less than 10 min. Usually, though, a short-acting barbiturate is infused intravenously to render the patient unconscious and enflurane a t 1.&3% is wed to maintain anesthesia. The oi1:gas partition coefficient is 98 a t 3I0C. makine the notencv " hieher u than that of nitrous oxide. Enflurane can cause deep anesthesia involving respiratory and circulatory depression. At high concentrations, i t can cause seizures, especiallv when there are low carbon dioxide levcls. ~ ( l v a n t a g e o u s l y . ~ n f l \ ~ r allows a n e for smooth adjustment of the depth of anesthesia with littlp rhanee - in pulse . or respiratory rate. It is an adequate muscle relaxant for surgery
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Volume 62 Number 4
A ~ r i 1985 l
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2'
H I
C'ocH,cH2-y+-cH.cH,
0 NH,
Halothane
Cnflurane
Isoflurane
Figure 2. Some general anesthetics.
CHICHl
CILidocaine (Xylocaine)
Procaine (Novocaine)
on its own and results in less nostonerative shiverine. arrhythmias, nausea, and vomiting than halothane (to be'discussed later) and methoxvflurane. Orieixiallv it was used as a substitute for halothane to avoid repeatedadministration of the latter, hut studies indicate that the differences between the agents is much less dramatic than first thought. lsoflurane Isoflurane (Fig. 2) is also quite potent with an oi1:gas partition coefficient of 99, making its potency comparable to enflurane. Halothane Halothane (Fig. 2) provides for a smooth and rather rapid loss of conciousness and ptoduces anesthesia with abolition of responses to painful stimulation due to its oi1:gas partition coefflcient of 225. Like enflurane, it provides for a rapid change of depth of anesthesia. I t also has a low incidence of toxic effects, though the margin of safety is quite low, i.e., halothane can cause c~rculatorydepression and a profound decrease of arterial blood flow. Thiopental is usually used for rapidity, pleasantness, and convenience of admmistration for induction of anesthesia. Halothane is then used for maintenance of anesthesia during surgery.
Mepivicaine Figure 3. Some local anesthetics
Thiopental (Pentothal)
Local Anesthetics Local anesthetics are drugs that blwk transmission of nerve sienals when amlied to ncrvr tissue. Thev nct on nll kindsof nerves and on ail parts of the nervous system. Phencyclidine (PCP)
Procaine A tvnical .. local anesthetic is ~ r o c a i n e(Novocaine) (Fia. 3). This and other rnolrcules that have a local anesthetic effect ha5.e both hvdn,uhol~icand hvdronhilic reeions. 'l'hrir rxnct mode of action isnot known, h i t it is thought that they control nermeahilitv of cell membranes. Conduction alona a nerve axon invo~vksa slight depolarization of the membrane. This causes a large transient increase in the Dermeabilitv of the membrane to sodium ions. Local anesthetics decrease (or block completely) this increased permeability. They prohably do so by fitting specific receptor sites within the sodium ion channel. Lidocaine Lidocaine (Fig. 3), another well-known local anesthetic, is also used to treat cardiac arrhythmias. It probably is effective simply by decreasing the excitability of the cardiac cells. Lidocaine and mepivicaine (Fig. 3) are presently the most widely used local anesthetics. Dental use accounts for over 50 million dosages of each of the two drugs annually where they are used mainly for tooth extraction and root canal work. Cocaine Cocaine was the first local anesthetic. It was introduced into medicine by Sigmund Freud and Karl Koller in 1884. Unlike the other local anesthetics, cocaine is a powerful central nervous system stimulant (see above). For that reason, cocaine is seldom used as a local anesthetic today. 330
Journal of Chemical Education
Ketamine
Figure 4. Some inhavenous anesthetics.
Intravenous Anesthetics Thiopental We know a good deal less about intravenous anesthetics. The most common of these is thiopental (Pentothal). This barbiturate is administered as the sodium salt, but is rapidly converted to the un-ionized form in the body and stored in fat. The molecular formula of thiopental is CnH17N202SH (Fig. 4). Thiopental acts on the brain stem and midbrain, probably by depressing synaptic transmission processes. Little detail is known about the action a t the molecular level. Ketamine Hydrochloride Another intravenous anesthetic is ketamine hydrochloride (Ketalar), C11H17ClONT- (Fig. 4). This compound is soluble in water to the extent of about 20 g/100 mL. Ketamine is called a dlssociatlue anesthetic. It induces hallucinations similar to those reported by people who have had near-death experiences. They seem to remember observing their rescuers from a vantage point above it all or moving through a dark tunnel toward a bright light. Unlike thiopental, ketamine seems to affect associative pathways before hitting the brain stem. Little detail is known of the action of ketamine a t the molecular level. If it acts by fitting receptors in the body, then we can assume-by analogy to the presence of morphine recep-
tors and the presence of endorohins in the bodv-that our bodies produce their own chemkals that fit those receptors. These compounds mav be svntbesized or released onlv in extreme cir~~umsrances'surh ;s those near-death experiences. Is it possil~lethat we are on the threshold of'the discoverv of the chemistry of life after death?
