Meaning of DRUG CULT in English

group using drugs to achieve religious or spiritual revelation and for ritualistic purposes. Though the idea may be strange to most modern worshippers, drugs have played an important role in the history of religions. The ceremonial use of wine and incense in contemporary ritual is probably a relic of a time when the psychological effects of these substances were designed to bring the worshipper into closer touch with supernatural forces. Modern studies of the hallucinogenic drugs have indicated that such drugs, in certain persons under certain conditions, release or bring about what those persons claim to be profound mystical and transcendental experiences, involving an immediate, subjective experience of ultimate reality, or the divine, resulting from the stirring of deeply buried unconscious and largely nonrational reactions. Modern students of pharmacological cults who have participated in cultic drug ceremonies and used the drugs themselves have been astonished at the depth of such experiences. R. Gordon Wasson has suggested that the religious impulse itself may have had its origin in the amazement felt by primitives on accidentally finding and ingesting plants with hallucinogenic properties while foraging for food; this view is not held by most scholars of religion. Whatever the psychological origins of such reactions, they are viewed as religious in nature and have been structured and channelled through cultic forms. Through cultic leaderssuch as shamans, witch doctors, and medicine menas well as through tradition, pharmacological cults have specified not only how the cultic drugs should be assimilated but also how they should be gathered and prepared; generally also there are specifications for participants' behaviour outside the ceremonies, in the practical affairs of living. Western observers of primitive cultures, such as missionaries, colonial administrators, and travellers, have often regarded such practices as demonstrating superstition and folly. Anthropologists and other scientific observers who have attempted to participate sympathetically in tribal rituals, however, not only have reported the useful aspects of such practices in primitive society but also have collected information that is of use to science, medicine, religion, and social theory. Drugs usually encountered in cultic ceremonies are generally classifiable as narcotic. Few of these are true narcotics, however, in the sense of being numbing or producing sleep. They are called hallucinogens when they produce changes in perception. A hallucinogenic drug may lead to experiences that resemble psychoses, in which case it is called psychotomimetic; under other circumstances it may cause a quasi-mystical, or psychedelic, experience. Most psychedelic drugs tend to stimulate rather than numb the mind, whereas some true narcotics, such as alcohol and opium, in turn stimulate and stupefy the mind at different stages of their physical effect. Most cultic drugs come from plants, though Western cults more recently formed have made use of the active principles of natural drugs in synthetic form and of synthetic analogs of naturally occurring compounds. Additional reading General works dealing with drug cults include R.C. Zaehner, Mysticism, Sacred and Profane (1957, reissued 1980), mainly a criticism of the views of Aldous Huxley on drugs, and Drugs, Mysticism, and Make-Believe (1972; also published as Zen, Drugs, and Mysticism, 1973); W.T. Stace, Mysticism and Philosophy (1960, reprinted 1987), a very clear account of mysticism that alludes to drugs; Daniel H. Efron, Bo Holmstedt, and Nathan S. Kline (eds.), Ethnopharmacologic Search for Psychoactive Drugs (1967, reissued 1979), a review by international experts, including material on cults; Peter T. Furst (ed.), Flesh of the Gods: The Ritual Use of Hallucinogens (1972, reissued with changes, 1990), based on a 1970 lecture series; and Paul H. Ballard (ed.), Psychedelic Religion? (1972), a collection of papers from a colloquium. Valentina Pavlovna Wasson and R. Gordon Wasson, Mushrooms, Russia, and History, 2 vol. (1957); and R. Gordon Wasson, Soma: Divine Mushroom of Immortality (1968), are required readings for those who wish to be thoroughly informed on mushroom cults. References on peyote include J.S. Slotkin, The Peyote Religion (1956, reprinted 1975), a detailed and thorough reference; Weston La Barre, The Peyote Cult, 5th ed., enlarged (1989); Guy Mount, The Peyote Book: A Study of Native Medicine, 3rd ed. (1993); and Fernando Bentez, In the Magic Land of Peyote (1975; originally published in Spanish, 1968), and Los hongos alucinantes, 6th ed. (1985), by an authority on the use of hallucinogens among the Indians of Mexico. Walter Houston Clark The Editors of the Encyclopdia Britannica Types of drugs Autonomic nervous system pharmacology The nervous system of vertebrates comprises two main divisions: the central nervous system, which includes the brain and spinal cord; and the peripheral nervous system, which can be further divided into the somatic nervous system, whose main function is to innervate body structures (e.g., most skeletal muscles) under conscious, voluntary control, and the autonomic nervous system, which is concerned with the involuntary processes of the body's glands, large internal organs, cardiac muscle, and blood vessels. The autonomic nervous system consists of the sympathetic and the parasympathetic systems, which are distinct both functionally and anatomically. The sympathetic system initiates a series of reactions, called fight-or-flight reactions, that prepare the body for activity. The heart rate increases, blood pressure rises, and breathing quickens. The amount of glucose in the blood rises, providing a reservoir of quick energy. The flow of blood to the skin and body organs decreases, allowing more blood to flow to the heart and muscles. The parasympathetic system generally functions in an opposite way, initiating responses associated with rest and energy conservation; its activation causes breathing to slow, salivation to increase, and the body to prepare for digestion. This picture is, however, a considerable oversimplification. The autonomic nervous system as a whole exerts a continuous, local control over the function of many organs (such as the eye, lung, urinary bladder, and genitalia), regardless of whether the body is preparing to react or to rest. The main physiological actions produced by the autonomic nervous system are shown in Table 1. The autonomic nervous system exerts its control through a network of nerve fibres that originate from the cells in the spinal cord. Each of these neurons ends by forming a junction with a second neuron, often called a ganglion cell because in some cases these second neurons are grouped together in swellings called ganglia. The first neuron is therefore called preganglionic and the second, postganglionic. The junction between the preganglionic and postganglionic neurons is called a synapse. As the electrical nerve impulse reaches the end of the preganglionic neuron, it causes the release of a chemical substance called a neurotransmitter. There is no direct contact between the two neurons. The neurotransmitter diffuses across the gap between them and acts on the postganglionic neuron by initiating in it a further electrical impulse. Postganglionic neurons innervate the target organs and elicit responses in them once again by inducing a neurotransmitter. Mechanism of action The discovery of chemical transmitters (neurotransmitters) was an important event in pharmacological history. While a student at Cambridge in 1904, T.R. Elliott found that the effects of stimulating sympathetic nerves closely resembled the effects of injecting chemical substances obtained from the adrenal gland. He suggested that the sympathetic nerves produced their effects by releasing a substance mimicking the action of epinephrine (adrenaline). The work of Henry Dale, a British physiologist working in London in 1914, suggested that acetylcholine was the neurotransmitter at the synapse between preganglionic and postganglionic sympathetic neurons and also at the ends of postganglionic parasympathetic nerves. He showed that acetylcholine could produce many of the same effects as direct stimulation of parasympathetic nerves. Firm evidence that acetylcholine was in fact the neurotransmitter came in 1921, when the German physiologist Otto Loewi discovered that stimulation of the autonomic nerves to the heart of a frog caused the release of a substance, later identified to be acetylcholine, which slowed the beat of a second heart perfused with fluid from the first. Similar direct evidence of the release of a sympathetic neurotransmitter, later shown to be norepinephrine (noradrenaline), was obtained by Walter Cannon at Harvard also in 1921. Figure 2: Organization of the autonomic nervous system. In the autonomic nervous system, nerve fibres are classified on the basis of the neurotransmitter released at the synapse. Nerve fibres that release the neurotransmitter acetylcholine are termed cholinergic fibres; nerve fibres that release the neurotransmitter norepinephrine are termed adrenergic fibres. Cholinergic fibres comprise the axons of the preganglionic sympathetic and both the preganglionic and the postganglionic parasympathetic neurons. The axons of the postganglionic sympathetic neurons are generally autonomic adrenergic fibres. The scheme in Figure 2 is complicated by the fact that these neurotransmitters are now known to have a negative feedback effect in inhibiting their own further release. They do this by combining with presynaptic receptors on the nerve terminals as well as with the postsynaptic receptors on the target organs. Both acetylcholine and norepinephrine act on more than one type of receptor. Dale found that two foreign substances, nicotine and muscarine, could each mimic some, but not all, of the parasympathetic effects of acetylcholine. Nicotine stimulates skeletal muscle and sympathetic ganglia cells. Muscarine, however, stimulates receptor sites located only at the junction between postganglionic parasympathetic neurons and the target organ. Muscarine slows the heart, increases the secretion of body fluids, and prepares the body for digestion. Dale therefore classified the many actions of acetylcholine into nicotinic effects and muscarinic effects. It has subsequently become clear that there are two distinct types of acetylcholine receptors affected by either muscarine or nicotine. A similar analysis of the sympathetic effects of norepinephrine, epinephrine, and related drugs was carried out by an American pharmacologist, Raymond Ahlquist, who suggested that these agents acted on two principal receptors. A receptor that is activated by the neurotransmitter released by an adrenergic neuron is said to be adrenoceptive or to be an adrenoceptor. Ahlquist termed the two kinds of adrenoceptor alpha (a) and beta (b). This theory was confirmed when Joseph Black developed a new type of drug that was selective for the b-adrenoceptor. Both a-adrenoceptors and b-adrenoceptors are divided into subclasses: a1 and a2; b1 and b2 (Table 1). These receptor subtypes were recognized by their responses to specific agonists and antagonists. Once recognized, they provide important leads in developing new drugs with high activity of a certain kind. For example, salbutamol was discovered as a specific b2-adrenoceptor agonist. It is used to treat asthma and is a great improvement over its predecessor, isoproterenol; because the activity of isoproterenol is not specific, it acts on b1-adrenoceptors as well as b2-adrenoceptors, resulting in cardiac effects that are unwanted and sometimes dangerous. A complex relationship exists between function and receptor type for a-adrenoceptors and b-adrenoceptors. Alpha1-adrenoceptors usually mediate smooth muscle contraction, particularly the constriction of the blood vessels (vasoconstriction) that results from a buildup of calcium ions within the cell. Alpha2-adrenoceptors are located primarily on nerve terminals, where they act to inhibit the release of the neurotransmitter. Beta1-adrenoceptors are found in the heart and increase the force and rate of the heart's action: b2-adrenoceptors are primarily found in smooth muscle and produce relaxation. Beta-adrenoceptors of both types are involved in the metabolic effects of epinephrine and norepinephrine on liver, fat, and muscle cells, which convert energy stores to freely usable metabolic fuels. The receptor specificity of various agonists and antagonists is summarized in Table 2. It is now known that acetylcholine and norepinephrine are not the only neurotransmitters. There is strong evidence that adenosine triphosphate (ATP), a substance of special importance as a metabolic energy source within cells, also functions as a neurotransmitter in postganglionic autonomic nerves, and it probably mediates some responses (e.g., bladder contraction and vasoconstriction) previously ascribed to acetylcholine and norepinephrine. Dopamine, known to be a metabolic precursor of norepinephrine, is also thought to mediate vasodilator responses in some organs, especially the kidney. A wide variety of peptides, such as substance P, vasoactive intestinal polypeptide, and cholecystokinin, all of which exert powerful effects on target organs, have been detected in autonomic neurons, and it is likely that these also function as neurotransmitters. Types of drugs Cardiovascular system pharmacology Drugs that affect the function of the heart and blood vessels are among the most widely used in medicine. Although these drugs may exert their primary effect either on the blood vessels or on the heart itself, the cardiovascular system functions as an integral unit. Thus, drugs that affect blood vessels are often useful in treating conditions in which the primary disorder lies in the heart itself, or vice versa. Examples of disorders in which such drugs may be useful include hypertension (high blood pressure), angina pectoris (pain resulting from inadequate blood flow through the coronary vessels to the muscular wall of the heart), heart failure (inadequacy of the output of the heart in relation to the needs of the rest of the body), and arrhythmias (disturbances of cardiac rhythm). Drugs affect the function of the heart in three main ways. They can affect the force of contraction of the heart muscle (inotropic effects); they can affect the frequency of the heartbeat, or heart rate (chronotropic effects); or they can affect the regularity of the heart beat (rhythmic effects). Drugs affect blood vessels by altering the state of contraction of the smooth muscle in the vessel wall, altering its calibre, or diameter, thereby regulating the volume of blood flow. Such drugs are classified as vasoconstrictors if they cause the smooth muscle lining to contract, and vasodilators if they cause it to relax. Drugs may act directly on the smooth muscle cells, or they may act indirectly, for example by altering the activity of nerves of the autonomic nervous system that regulate vasoconstriction or vasodilation (see above Autonomic nervous system pharmacology). Another type of indirect mechanism is the action of vasodilator substances that work by releasing a smooth muscle relaxant substance from the cells lining the interior of the vessel. Some drugs mainly affect arteries, which control the resistance to blood flow in the vascular system, an important determinant of the arterial blood pressure; others mainly affect the veins, which control the pressure of blood flowing back to the heart, and hence the cardiac output (i.e., the volume of blood pumped out by the heart per minute). Inotropic agents Inotropic agents are drugs that influence the force of contraction of cardiac muscle, thereby tending to affect the cardiac output. Drugs have a positive inotropic effect if they increase the force of contraction of the heart. The most important group of inotropic agents is the cardiac glycosides, substances that occur in the leaves of the foxglove (Digitalis purpurea) and other plants. Although they have been used for many purposes throughout the centuries the effectiveness of cardiac glycosides in heart disease was established in 1785 by an English physician, William Withering, who successfully used an extract of foxglove leaves to treat heart failure. Many closely related glycosides with similar pharmacological actions are found in various plants, but they differ in ease of absorption from the gastrointestinal tract and in duration of action. The two compounds most often used therapeutically are digoxin and digitoxin. The most useful effect of cardiac glycosides is their ability to increase the force of contraction of cardiac muscle. They have, however, several additional effects, most of which are disadvantageous. These include a tendency to block conduction of the electrical impulse that causes contraction as it passes from the atria to the ventricles of the heart (heart block). Cardiac glycosides also have a tendency to produce an abnormal cardiac rhythm by causing electrical impulses to be generated at points in the heart other than the normal pacemaker region, the cells that rhythmically maintain the heartbeat. These irregular impulses result in ectopic heartbeats that are out of sequence with the normal cardiac rhythm. Occasional ectopic beats are harmless, but if this process continues to a complete disorganization of the cardiac rhythm (ventricular fibrillation), the pumping action of the heart is stopped, causing death within minutes unless resuscitation is carried out. Because the margin of safety between the therapeutic and the toxic doses of glycosides is relatively narrow, they must be used carefully. Cardiac glycosides are believed to increase the force of cardiac muscle contraction by binding to and inhibiting the action of a membrane enzyme that extrudes sodium ions from the cell interior. Inhibiting the free flow of sodium ions from the interior of the cell across the membrane to the exterior of the cell causes the intracellular sodium concentration to rise. The interior of the cell then becomes depolarized, or electrically less negative than normal with respect to the exterior of the cell. Because the cell is able to exchange sodium ions within the cell for calcium ions outside it, there is a secondary rise in intracellular calcium. This subsequently increases the force of contraction, since intracellular calcium ions are responsible for initiating the shortening of muscle cells. The disturbances of rhythm that may be caused by cardiac glycosides result partly from the depolarization and partly from the increase in intracellular calcium. Because these rhythm disturbances are caused by the same underlying mechanism that causes the beneficial effect, there is no likelihood of finding a cardiac glycoside with a significantly better margin of safety. Apart from their cardiac actions, these glycosides tend to cause nausea and loss of appetite. Because digoxin and digitoxin have long plasma half-lives (two and seven days, respectively), they are liable to accumulate in the body. Treatment with either of these drugs must involve careful monitoring to avoid the adverse effects that may result from their slow buildup in the body. The second type of inotropic agent that increases the force of cardiac muscle contraction includes epinephrine and norepinephrine. In addition to affecting the force of contraction, however, they also increase the heart rate. This, and the fact that they are quickly metabolized by the body and act only for a few minutes, means that they are not useful inotropic agents. The third type of inotropic agent that acts as a cardiac stimulant is the caffeine-related series of drugs represented by theophylline. Its action, like that of epinephrine, depends on an increase in the intracellular concentration of cyclic adenosine 3,5-monophosphate, which indirectly increases the influx of calcium ions into the cells, thereby increasing the force of contraction of cardiac muscle. Types of drugs Drugs affecting blood When a small blood vessel is cut, a repair mechanism (hemostasis) is activated that eventually seals the cut and prevents further blood loss. What is in fact a lifesaving mechanism that protects the wounded body from hemorrhage becomes life threatening when clots (thrombi) form within functional blood vessels (thrombosis). Thrombosis tends to occur in blood vessels damaged by artherosclerosis or in vessels with a sluggish blood flow. In veins, portions of the thrombi (emboli) may break off and pass along the bloodstream to become lodged in the arteries of the heart. The drugs described in this section either inhibit hemostasis or they act to enhance the mechanisms that lyse, or dissolve, thrombi. The clotting process essentially involves the conversion of a soluble plasma protein, fibrinogen, into strands of the insoluble protein fibrin, which forms a mesh that traps platelets. The trigger for hemostasis is an injury to the endothelium, the cells lining the blood vessels, so that the underlying layer of collagen is exposed. The series of events leading to clot formation in a cut blood vessel are (1) constriction of the blood vessel by serotonin, epinephrine, and the thromboxane A2, which diminishes blood loss; (2) formation of a plug of platelets (the platelet phase) by ADP and thromboxane A2, also released by platelets, which act in a positive feedback process that makes more platelets adhere to the collagen and to each other; and (3) the conversion of the plug into a clot of fibrin (the coagulation phase). The formation of fibrin entails the sequential interaction of more than a dozen clotting factors, which are protease enzymes (i.e., they accelerate the breakdown of proteins). Each of these clotting factors activates the next in a coagulation cascade of proteolytic reactions that break down protein molecules. The penultimate reaction is the conversion of the soluble fibrinogen to soluble fibrin under the influence of the enzyme thrombin (factor IIa). Soluble fibrin is converted to insoluble fibrin strands by activated factor XIII (fibrin-stabilizing factor), and covalent cross-linkages form between the fibrin strands to give a strong and rigid network. Several of the clotting factors (II, VII, IX, X) require the presence of vitamin K for their activation. Consequently, inhibition of vitamin K blocks the propagation of coagulation pathways. Under normal conditions the adhesion of platelets to vessel walls is prevented by the vascular endothelial cells, at least in part by their ability to release prostaglandins called prostacyclin or prostaglandin I2, which reduce platelet stickiness and cause dilation of the blood vessels. A fibrinolytic system exists in the body that restricts thrombus propagation beyond the site of injury and is also involved in the lysis of clots as wounds heal. The fibrinolytic system degrades fibrin and fibrinogen to products that act to inhibit the enzyme thrombin. The active enzyme involved in the fibrinolytic process is plasmin, which is formed from its precursor, plasminogen, under the influence of an activating factor released from endothelial cells. If formed in the circulating blood, plasmin is normally inhibited by a circulating plasmin inhibitor. Anticoagulant drugs Anticoagulant drugs prevent the formation of thrombi by inhibiting the coagulation phase. They are used to prevent the formation and spread of venous and arterial thrombi; however, they are ineffective against existing thrombi. Anticoagulant therapy is used to treat deep-vein thrombosis and pulmonary embolism arising after immobilization or surgery; systemic or coronary arterial embolism caused by heart diseases or replacement of the prosthetic valve; and disseminated intravascular coagulation, which is a systemic activation of the coagulation system that leads to consumption of coagulation factors and hemorrhage. Heparin, used primarily in hospitalized patients, is a mixture of negatively charged mucopolysaccharides. An endogenous substance whose physiological role is not understood, heparin blocks the coagulation cascade by promoting the interaction of a circulating inhibitor of thrombin (antithrombin III) with activated clotting factors. Because it is not well absorbed whentakenorally, heparin is given intravenously to inhibit coagulation immediately; the onset of the drug's effect is delayed after subcutaneous administration. Heparin is not bound to plasma proteins, it is not secreted into breast milk, and it does not cross the placenta. The drug's action is terminated by metabolism in the liver and excretion by the kidney. The major side effect associated with heparin is hemorrhage; thrombocytopenia (reduced number of circulating platelets) and hypersensitivity reactions also occur. Oral anticoagulants and heparin have additional anticoagulant effects. Heparin-induced hemorrhage may be reversed with the antagonist protamine, a positively charged protein that has a high affinity for heparin's negatively charged molecules, thus neutralizing the drug's anticoagulant effect. When given in combination with heparin, dihydroergotamine, which constricts veins and increases blood flow, increases heparin's antithrombotic effect. Oral anticoagulants are derivatives of 4-hydroxycoumarin (coumarin) or indan-1,3-dione (indandione). Structurally the coumarin derivatives resemble vitamin K, an important element in the synthesis of a number of clotting factors. Interference in the metabolism of vitamin K in the liver by coumarin derivatives gives rise to clotting factors that are defective and incapable of binding calcium ions (another important element in the activation of coagulation factors at several steps in the coagulation cascade). When anticoagulants are taken orally, several hours are required for the onset of the anticoagulant effect because time is required both for their absorption from the gastrointestinal tract and for the clearance of biologically active clotting factors from the blood. Warfarin, the most commonly used oral anticoagulant, is rapidly and almost completely absorbed; the absorption of dicumarol and other anticoagulant agents, however, is slower and less consistent. Oral anticoagulants bind extensively to plasma proteins, have relatively long plasma half-lives, and are metabolized by the liver and excreted in the urine and feces. They may cross the placenta to cause fetal abnormalities or hemorrhages in neonates; their appearance in breast milk apparently has no adverse effect on nursing infants. Hemorrhage is the principal toxic effect during oral anticoagulant therapy, but each of the coumarin derivatives causes its own idiosyncratic side effects. Vitamin K, when given intravenously to promote the synthesis of functional clotting factors, stops bleeding after several hours. Plasma that contains normal clotting factors is given to control serious bleeding. Oral anticoagulants may interact adversely with other drugs that bind to plasma proteins or are metabolized by the liver. Types of drugs Drugs affecting muscle Smooth muscle Smooth muscle is found primarily in the internal body organs and performs many functions, including control of the diameter, or calibre, of blood vessels, control of the propulsive activity of the gastrointestinal tract, contraction of the urinary bladder, contraction of the uterus, control of ocular focusing and pupil diameter, and control of the calibre of the respiratory airways. Whereas striated, or skeletal, muscle is controlled from the central nervous system by way of somatic motor nerves, smooth muscle is controlled by the autonomic nervous system and by hormones. In many situations, smooth muscle undergoes spontaneous, often rhythmic, contractions that are not dependent on outside nerve impulses. Smooth muscle contracts much more slowly than striated muscle and in general shows a much broader sensitivity to drugs. Smooth muscle contraction is initiated by depolarization (the sharp influx of positively charged ions) of the cell membrane. This causes calcium-selective ion channels in the membrane to open, allowing calcium to flow into the cell. The contractile mechanism of smooth muscle cells, like that of striated muscle, involves the sliding action of overlapping protein filaments composed of actin and myosin molecules. The free calcium ions diffuse to the myosin and activate its enzymatic activity, which begins the process of contraction. Most of the drugs that stimulate or inhibit smooth muscle contraction do so by regulating the concentration of intracellular calcium, but other intracellular messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are also involved (see above General principles). The main classes of drugs with important effects on smooth muscle are shown in Table 3. Adrenoceptor agonists, muscarinic agonists, nitrates, and calcium antagonists are considered in other sections and are not discussed here. Several local hormones that are released from cells or formed in tissue act on target cells in close proximity to each other. Because they are destroyed rapidly in the bloodstream they do not function as true blood-borne hormones. Local hormones are usually formed in response to tissue injury, and they are partly responsible for inflammatory and allergic reactions. Smooth muscle responses (e.g., constriction, vasodilation, and edema), particularly in blood vessels and bronchi, are an important component of such reactions. Apart from histamine (see above Drugs affecting blood) the main agents known to function as local hormones are kinins and prostanoids. The kinins are peptides that are formed by the enzymatic cleavage of a plasma protein. This cleavage occurs when an enzyme, also present in plasma, is activated in the presence of damaged tissue. Bradykinin, a peptide consisting of a chain of nine animo acids, is an extremely potent vasodilator. Elsewhere in the body, however, bradykinin contracts smooth muscle, particularly in the bronchi and gastrointestinal tract. It also causes the secretion of fluid from the walls of these structures. Constriction of smooth muscle in the bronchi and increased fluid secretion contribute to the airway obstruction that occurs in an asthmatic attack. Bradykinin is probably the causative agent of asthma as well as diarrhea, since similar mechanisms of action occur in the intestine. Bradykinin has no therapeutic uses, but if developed, a selective antagonist of bradykinin might be a useful drug to block its inflammatory and allergic reactions. Prostanoids (prostaglandins) and leukotrienes (a related group of lipids) are derived by enzymatic synthesis from one of three 20-carbon fatty acids, with the most important in humans being arachidonic acid, a constituent of cell membranes. When a membrane enzyme, phospholipase C, is activated, arachidonic acid is released and converted by intracellular enzymes to unstable intermediates, which are further metabolized, depending on the group of enzymes involved, to prostanoids or leukotrienes. The synthesis and release of prostanoids and leukotrienes occurs when cells are damaged, even mildly. They are important in producing tissue responses to injury as well as in other physiological reactions. Derivatives of prostanoids have as their basic structure a five-carbon ring with two side chains, and they differ from each other in the substitutions on the ring structure. The derivatives are distinguished by the letters A through I. In relation to smooth muscle, the most important prostanoids are prostaglandins E1, E2, and F2 (the subscript numbers denoting the 20-carbon precursor and the number of double bonds in the molecule) and leukotrienes C4 and D4; the most important sites of action are bronchial and uterine smooth muscle (see Table 3). Leukotrienes are powerful bronchoconstrictors, and they are believed to be synthesized and released during asthmatic attacks. Prostaglandins in minute amounts produce a broad range of physiological effects in almost every system of the human body. Prostaglandins E1 and E2 are dilators, and prostaglandins of the F series are bronchoconstrictors. Prostaglandin E1 also dilates blood vessels, and it is sometimes administered by intravenous infusion to treat peripheral vascular disease. Most prostaglandins cause uterine contraction, and they are sometimes administered to initiate labour (see below Reproductive system pharmacology). Ergot alkaloids (see above Cardiovascular system pharmacology) are produced by a parasitic fungus that grows on cereal crops. Among the many biologically active constituents of ergot, ergotamine and ergometrine are the most important. The main effect of ergotamine is to constrict blood vessels, which can be so intense as to cause gangrene of fingers and toes, giving rise to the name St. Anthony's Fire for the syndrome produced by ergot poisoning. Dihydroergotamine, a derivative, is used in treating migraine (see above Cardiovascular pharmacology). Ergometrine has much less effect on blood vessels but a stronger effect on the uterus. It can induce abortion, though not reliably. Its main use is to promote a strong uterine contraction immediately after parturition, thus reducing the likelihood of bleeding. Both ergotamine and ergometrine cause smooth muscle to contract. Morphine, an opioid widely used for its painkilling properties, causes smooth muscle contraction in certain situations, which gives rise to some of its side effects. It contracts bronchial smooth muscle (probably by releasing histamine) and may precipitate an attack of asthma. It also causes spasm of the sphincters of the gastrointestinal tract, giving rise to constipation, and spasm of the biliary and urinary tracts. It is therefore not generally suitable for treating pain associated with renal or biliary stones. Skeletal muscle Skeletal muscle contracts in response to electrical impulses that are conducted along motor nerve fibres originating in the brain or spinal cord. The motor nerve fibres reach the muscle fibres at sites called motor end plates, located roughly in the middle of each muscle fibre. The motor end plate stores vesicles of the neurotransmitter acetylcholine. An impulse arriving at the motor end plate causes many acetylcholine-containing vesicles to be discharged into the narrow synaptic cleft between the end plate and the membranes of the muscle fibre. Acetylcholine binds to nicotinic receptors on the muscle fibre membrane, causing ion channels to open and allowing a local influx of positively charged ions into the muscle fibre. The muscle fibre is thus depolarized (i.e., its internal potential becomes less negative), and if this local depolarization is large enough a propagated electrical impulse is set up that activates the contractile machinery along the whole length of the fibre. The process occurs within one to two milliseconds (msecs). The released acetylcholine is inactivated within one msec by the action of the enzyme acetylcholinesterase, which is located in the synaptic cleft. The process normally has a large margin of safety because the amount of acetylcholine released is more than enough to activate the muscle fibre. Because the contractile mechanism of skeletal muscles is relatively insensitive to drug action, the most important group of drugs that affect the neuromuscular junction act on (1) acetylcholine synthesis, (2) acetylcholine release, (3) acetylcholine receptors, or (4) acetylcholinesterase. Hemicholinium and botulinum toxin each cause neuromuscular paralysis by blocking acetylcholine synthesis and acetylcholine release, respectively (see above Autonomic nervous system pharmacology). There are a few drugs that facilitate acetylcholine release, including tetraethylammonium and 4-aminopyridine. They work by blocking potassium-selective channels in the nerve membrane, thereby prolonging the electrical impulse in the nerve terminal and increasing the amount of acetylcholine released. This can effectively restore transmission under certain conditions, but these drugs are not selective enough for their actions to be of much use therapeutically. Neuromuscular blocking drugs act on acetylcholine receptors and fall into two distinct groups: nondepolarizing (competitive) and depolarizing blocking agents. Competitive neuromuscular blocking drugs act as antagonists at acetylcholine receptors, reducing the effectiveness of acetylcholine in generating an end-plate potential. When the amplitude of the end-plate potential falls below a critical level, it fails to initiate an impulse in the muscle fibre, and transmission is blocked. The most important competitive blocking drug is tubocurarine, which is the active constituent of curare, a drug with a long and romantic history and one of the first drugs whose action was analyzed in physiological terms. Claude Bernard, a 19th-century French physiologist, showed by experiment that curare causes paralysis by blocking transmission between nerve and muscle, without affecting nerve conduction or muscle contraction directly. Curare is a product of plants (mainly Chondodendron species) that grow primarily in South America and has been used there for centuries as an arrow poison. Tubocurarine is a complex molecule containing two basic groups that are thought to bind to the receptor in the same way that acetylcholine does. Tubocurarine is used in anesthesia to produce the necessary level of muscle relaxation. It is given intravenously, and the paralysis lasts for about 20 minutes, although some muscle weakness remains for a few hours. After it has been given, artificial ventilation is necessary because breathing is paralyzed. Tubocurarine tends to lower blood pressure by blocking transmission at sympathetic ganglia, and, because it can release histamine in tissues, it also may cause constriction of the bronchi. Synthetic drugs are available that have fewer unwanted effectsfor example, gallamine and pancuronium. The action of competitive neuromuscular blocking drugs can be reversed by anticholinesterases, which protect acetylcholine against rapid hydrolysis and can increase the amplitude of the end-plate potential enough to restore effective transmission. This is a useful way to restore muscle function at the end of a surgical operation. Anticholinesterase drugs (see above Autonomic nervous system pharmacology) inhibit the rapid destruction of acetylcholine at the neuromuscular junction and thus enhance its action on the muscle fibre. Normally this has little effect, but in the presence of a competitive neuromuscular blocking agent, transmission can be restored. This provides a useful way to terminate paralysis produced by tubocurarine or similar drugs at the end of surgical operations. Neostigmine often is used for this purpose, and atropine is given simultaneously to prevent the parasympathetic effects that are enhanced when acetylcholine acts on muscarinic receptors. Anticholinesterase drugs also are useful in treating myasthenia gravis, in which progressive neuromuscular paralysis occurs as a result of the formation of antibodies against the acetylcholine receptor protein. The number of functional receptors at the neuromuscular junction becomes reduced to the point where transmission fails. Anticholinesterase drugs are effective in this condition because they enhance the action of acetylcholine and enable transmission to occur in spite of the loss of receptors; they do not affect the underlying disease process. Neostigmine and pyridostigmine are the drugs most often used because they appear to have a greater effect on neuromuscular transmission than on other cholinergic synapses, and this produces fewer unwanted side effects. The immune mechanism responsible for the inappropriate production of antibodies against the acetylcholine receptor is not well understood, but the process can be partly controlled by treatment with steroids or immunosuppressant drugs such as azathioprine. Depolarizing neuromuscular blocking drugs, of which succinylcholine is the only important example, act in a more complicated way than nondepolarizing, or competitive, agents. Succinylcholine has an action on the end plate similar to that of acetylcholine. When given systemically, it causes a sustained end-plate depolarization, which first stimulates muscle fibres throughout the body, causing generalized muscle twitching. Within a few seconds, however, the maintained depolarization causes the muscle fibres to become inexcitable, so that they fail to respond to nerve stimulation. The paralysis lasts for only a fe

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