1. Alkaloids

2. Phytochemistry and Plant Metabolism Intermediary Metabolism: enzyme-mediated and carefully regulated chemical reactions (Metabolic Pathways) Primary Metabolism: Biochemistry Processes resulting in primary metabolites (carbohydrate, amino acid,..) Secondary Metabolism: Natural Products chemistry resulting in secondary metabolites ( Flavonoids, alkalaoids,…). Building clocks for 2ry metabolites are derived from 1ry metabolites, namely, acetate, mevalonate and shikimate.

3. Alkaloids are: Secondary Metabolites Alkali-Like compounds…Difficult to be defined…But, Generally known as “All Organic Nitrogenous Compounds With a Limited Distribution in Nature”… “have Physiological Activity” Not homogenous group of compounds! Found in plants, microorganisms. Extracted from seeds, fruits, leave, roots and barks

4. Non-peptidic, non-nucleosidic nitrogen containing cpds usually derived from an amino acid. Found in plants, insects, amphibians, fungi, sponges etc.  Bitter tasting, generally white solids (exception - nicotine is a brown liquid).  Alkaloids are “secondary metabolites”, they are not involved in primary metabolism. Most studied group of natural products Many have heterocyclic rings as a part of their structure Many are basic (“alkaline”, due to an unshared pair on N)

5. Discovery: Narcotine first alkaloid discovery Coniine first alkaloid to have its structure established and synthesized Paclitaxel revolution in alkaloid Naming: (ends with ine) From plant generic name (Atropine) From specific plant yielding it (Cocaine) From physiological activity (emetine) From discoverer

6. Chemistry: Alkaloids may contain one or more nitrogen atoms, as 1 o, 2 o, 3 o & 4 o. Most of them contain oxygen Found as free or nitrogen oxides Degree of basicity depends on the structure Converted to their salts when treated with H+, while when treated with OH, they give up their free amine.

7. Properties: Sparingly soluble in water… salts are freely soluble in water. Free alkaloids are soluble in ether, chloroform and non-polar solvent…important for isolation and purification Crystalline to amorphous or liquid when lack Oxygen Have bitter taste Form double salts with heavy metals reagents (I, Hg), Wagners, Mayer, and Dragendroff reactions

8. Functions: Provide Nonspecific Basic compounds (N) Source for their associated acids End products Part of some metabolic sequences Defense N.B. Plants which accumulate alkaloids develop even when deprived the alkaloid Plants which do not produce alkaloid survive when administered alkaloid

9. Tests: Alkaloids are precipitated when treated with neutral - slightly acidic solution of Dragendroff, Mayer, Wagner reagents. Precipitates are amorphous to crystalline Proteins can give false positive rxn Caffeine gives false negative rxn, and can be detected by potssium chlorate and HCl solution and exposing the dried residue to NH 3.

10. They give a precipitate with heavy metal iodides. –Most alkaloids are precipitated from neutral or slightly acidic solution by Mayer's reagent (potassiomercuric iodide solution). Cream coloured precipitate. –Dragendorff's reagent (solution of potassium bismuth iodide) gives orange coloured precipitate with alkaloids. –Caffeine, a purine derivative, does not precipitate like most alkaloids.

11. Extraction: Powder is moistened and treated with lime, extracted with organic solvent and back extracted with aqueous acid OR Powder is extracted with water or acidified aq. alcohol, organic acids remove the organic material and free alkaloids are precipitated by adding Na-bicarbonate or NH 3

12. Isolation of Alkaloids Process remained unchanged >1,000 years Plant Material Acid solution EtOAc: neutral/weakly basic alkaloids 1) Methanol 2) Concentrate 3) Partition EtOAc/2% acid Petroleum ether extracts non-polar fats and waxes Residue: polar material Wash with petroleum ether Basic aqueous solution of quaternary alkaloids 1) Ammonia 2) Partition with EtOAc EtOAc: basic alkaloids

13. Purification of Alkaloids Gradient pH as alkaloids are basic Volatile alkaloids: distillation Crystallisation Fractional or acid/base pair Chromatography HPLC, GC, TLC and CC

14. MORPHINE - A TYPICAL ALKALOID.. contains nitrogen basic due to the unshared pair heterocyclic ring Found only in the Opium Poppy - papaver somniferum Plant source. Most alkaloids are found in plants. ….. not ubiquitous.

15. There are three main types of alkaloids: Terpenoids or purines colchicine

16. HOW ARE ALKALOIDS CLASSIFIED ? Common classification schemes use either: The heterocyclic ring systems found as a part of the compound’s structure. - in terms of their BIOLOGICAL activity, - BIOSYNTHETIC pathway (the way they are produced in the plant). The plant or plant family where they originate* * The majority of alkaloids (>90%) are found in plants - therefore, we will speak mostly about plants and their biochemistry.

17. HETEROCYCLIC RING SYSTEMS

18. (cont)

20. Some Examples of Classification BY RING TYPE

22. Amino Acid Precursors

23. Some Examples of Classification BY PLANT FAMILY : These alkaloids are found in Amaryllidaceae daffodils narcissus lillies etc belladine lycorine tazettine galanthamine The other three are biochemically derived from belladine. “ Amaryllis ” Alkaloids

24. THE PURPOSE OF ALKALOIDS IN PLANTS (?) The spectacular pharmacological properties of many of the alkaloids keeps asking about their purpose in plants. Many ideas have been advanced: What seems most likely is that there are many reasons why plants elaborate alkaloids, and in many cases the purpose of the alkaloid may be unique to a given plant. Defense Mechanisms Insect Repellants Herbivore Attractants Nitrogen StorageGrowth Regulation Vestiges of Old Metabolic Experiments Metal ion transport (chelates)Competitive Herbicides Anti-fungals Insect Attractants

25. Alkaloids derived from lysine and ornithine (arginine)

26. Alkaloids derived from ornithine: Biosynthesis of Cocaine

27. Biosynthesis of Cocaine

28. Alkaloids derived from tyrosine. Morphine Biosynthesis

31. Alkaloids derived from tryptophan. Physostigmine biosynthesis

32. COOH CO 2 R-CHNH 2 R-CH 2 NH 2 -H 2 O RN=CHR’ RNH-CH-R’ CH 2 R’’ Schiff Base Alkaloid COOH Transamination R’-CHO R’-CHNH2 -CO2 Alkaloid Biosynthesis Mannich Condensation + H-C-H R” carbonion Amino AcidsSchiff BaseAlkaloid

33. Classification: (BioSynthetic Origin) 1.Ornithine Derived Alkaloids 2.Lysine Derived Alkaloids 3.Nicotinic Acid Derived Alkaloids 4.Tyrosine Derived Alkaloids 5.Tryptophan Derived Alkaloids 6.Anthranilic Acid Derived Alkaloids 7.Histidine Derived Alkaloids 8.Amination Reacrion Derived Alkaloids 9.Purine Alkaloids Based on Amino Acid from which they were derived

34. 1-Ornithine Derived Alkaloids 1.Pyrrolidine and Tropane Alkaloids (Hyoscymine, Hyoscine, Atropine) 2.Pyrrolizidine Alkaloids 2-Lysine Derived Alkaloids 1.Piperidine Alkaloids (Lobelia) 2.Quinolizidine Alkaloids 3.Indolizidine Alkaloids 3-Nicotinic Acid Derived Alkaloids 1.Pyridine Alkaloids (Nicotinic Acid)

35. 4-Tyrosine Derived Alkaloids 1.Phenylethylamin and simple tetrahydroisoquinoline Alkaloids (curarine) 2.Modified Benzyltetrahydroisoquinoline Alkaloids (Opium Alkaloids) 3.Phenethylisoquinoline Alkaloids (Colchicine) 4.Terpenoid Tetrahydroisoquinoline Alkaloids ( Emetine) 5-Tryptophan Derived Alkaloids 1.Simple Indole Alkaloids (Psilocybin) 2.Simple Carboline Alkaloids 3.Terpenoid Indole Alkaloids (Reserpine, Deserpine, Vincristine, Vinblastine, Strychnine) 4.Quinoline Alkaloids (Quinidine, Quinine) 5.Pyrroloindoline Akaloids (Physostigmine) 6.Ergot Alkaloids (Ergotamine)

36. 6-Anthranilic Acid Derived Alkaloids 1.Quinazoline Alkaloids 2.Quinoline and Acridine Alkaloids 7-Histidine Derived Alkaloids 1.Imidazole Alkaloids (Pilocarpine) 8-Amination Reaction Derived Alkaloids 1.Acetate Derived Alkaloids 2.Phenylalanine derived alkaloids (Ephedrine) 3.Terpenoid Alkaloids 4.Steroid Alkaloids 9-Purine Derived Alkaloids Caffeine, theobromine, theophylline

37. 1-Ornithine Derived Alkaloids Tropane alkaloid There are two important types of tropane alkaloids:

38. Tropane Alkaloids 1-Ornithine Derived Alkaloids

39. What do these groups have in common? They all possess the tropane nucleus. Bicyclic system made up of a 5-membered ring (1, N, 5, 6, and 7) and a 6-membered ring (1, 2, 3, 4, 5, N). N is common to both. The nucleus always carries an oxygen in position 3.

40. Tropane Alkaloids Are esters of hydroxytropanes and various acids (tropic, tiglic) -Tropane moiety is formed from ornithine -Acid moiety from Phenylalanine. Plant family contains tropane alkaloids are Solanaceae Alkaloids found in roots and leaves mainly. Vary with age, length and light intensity. Belladonna and Scopolia contains hyoscyamine and Datura Stronium as dominant alkaloid Hyoscine is found in other spp of Datura as dominant alkaloid Atropine mainly is found in Atropa Belladona Cocaine is found Erythroxylum Coca

41. Tropane Alkaloids They are ester alkaloids resulted from the coupling of organic acids with amino alcohol (Base). The parent base is the “Tropane” base. Tropane Alkaloids are classified into: 1- Solanaceous Tropane Alkaloids. 2- Erythroxylon (Coca) Alkaloids.

42. 1.A. Solanaceous alkaloids Solanaceous alkaloids come from the solanaceae (tomato and potato). Some of the alkaloids they produce are: Atropine Hyoscyamine Hyoscine Hyoscyamine is the pure optical isomer; (+)Hyoscyamine, (-)Hyoscyamine. Atropine is the racemic of hyoscyamine. Atropine = (±)Hyoscyamine. The 3-hydroxy derivative of tropane is known as TROPINE.

43. Esterification of tropine with tropic acid yields hyoscyamine (tropine tropate).

44. Atropine & Hypscyamine Hyoscyamine is the major natural alkaloid with negative optical rotation (l- form). During extraction hyoscyamine racemizes to the optically inactive dl Atropine. Both alkaloids composed of tropine base and tropic acid.

45. Hyoscine (Scopolamine) Hyoscine is an ester of l-tropic acid with scopoline base. Hyoscine is a syrupy liquid.

46. Separation of the Alkaloidal mixtures:

47.  Chemical tests: Vitali-Morin’s test: Solid alkaloid + fuming HNO 3 → Evaporate to dryness, dissolve residue in acetone, add methanolic solution of KOH → Violet colour. P-dimethylaminobenzaldehyde: Alkaloid + reagent in porcelain dish and heat on boiling water path → Intense Red Colour → Cherry Red after cooling. Gerrard’s test: Alkaloid + 2% HgCl 2 in 50% Ethanol → Red colour Atropine Red after warming Hyoscyamine White ppt Hyoscine

48. Structure Activity Relationship Cationic Head: Positively charged Quaternary ammonium compounds Cyclic substitution: at least one cyclic substituent, aromatic the most used Esteratic Group: Necessary for effective binding Hydroxyl Group: enhances the activity Position of OH to Nitrogen in receptive area 2-3 o A Stereochemistry is of small contribution for antagonistic activity A, B = Bulky Groups C = H,OH -C - Chain A B C N

49. Atropine or  Hyoscyamine Scopolamine or Hyoscine Anticholinergics Inhibit the neurological signals transmitted by the endogenous neurotransmitter, acetylcholine. Symptoms of poisoning include mouth dryness, dilated pupils, ataxia, urinary retention, hallucinations, convulsions, coma, and death Atropine has a stimulant effect on the CNS and heart, whereas scopolamine has a sedative effect. Hyoscyamine and Hyoscine

50. Pharmacological Activity These alkaloids compete with acetylcholine for the muscarinic site of the parasympathetic nervous system thus preventing the passage of nerve impulses, and are classified as anticholinergics.

51. Acetylcholine binds to two types of receptor site, described as muscarinic or nicotinic, from the specific triggering of a response by the Amanita muscaria alkaloid muscarine or the tobacco alkaloid nicotine respectively.

53. The structural similarity between acetylcholine and muscarine can readily be appreciated, and hyoscyamine is able to occupy the same receptor site by virtue of the spatial relationship between the nitrogen atom and the ester linkage. The side-chain also plays a role in the binding, explaining the difference in activities between the two enantiomeric forms.

54. The agonist properties of hyoscyamine and hyoscine give rise to a number of useful effects, Including: antispasmodic action on the gastrointestinal tract, antisecretory effect controlling salivary secretions during surgical operations, and as mydriatics to dilate the pupil of the eye. Hyoscine has a depressant action on the central nervous system and finds particular use as a sedative to control motion sickness.

55. One of the side-effects from oral administration of tropane alkaloids is dry mouth (the antisecretory effect) but this can be much reduced by transdermal administration. In motion sickness treatment, hyoscine can be supplied via an impregnated patch worn behind the ear.

56. Hyoscine under its synonym scopolamine is also well known, especially in fiction, as a ‘truth drug’. This combination of sedation, lack of will, and amnesia was first employed in child-birth, giving what was termed ‘twilight sleep’, and may be compared with the mediaeval use of stramonium.

57. The mydriatic use also has a very long history. Indeed, the specific name belladonna for deadly nightshade means ‘beautiful lady’ and refers to the practice of ladies at court who applied the juice of the fruit to the eyes, giving widely dilated pupils and a striking appearance, though at the expense of blurred vision through an inability to focus.

58. Atropine also has useful antidote action in cases of poisoning caused by cholinesterase inhibitors, e.g. physostigmine and neostigmine and organophosphate insecticides.

59. It is valuable to reiterate here that the tropane alkaloid-producing plants are all regarded as very toxic, and that since the alkaloids are rapidly absorbed into the blood stream, even via the skin, first aid must be very prompt. Initial toxicity symptoms include skin flushing with raised body temperature, mouth dryness, dilated pupils, and blurred vision.

60. Semisynthetic Derivatives 1. Homatropine is a semi-synthetic ester of tropine with racemic mandelic (2-hydroxyphenylacetic) acid and is used as a mydriatic, as are tropicamide and cyclopentolate 2. Tropicamide is an amide of tropic acid, though a pyridine nitrogen is used to mimic that of the tropane. 3. Cyclopentolate is an ester of a tropic acid-like system, but uses a non-quaternized amino alcohol resembling choline. 4. Glycopyrronium has a quaternized nitrogen in a pyrrolidine ring, with an acid moiety similar to that of cyclopentolate. This drug is an antimuscarinic used as a pre medicant to dry bronchial and salivary secretions.

62. 5. Hyoscine butylbromide is a gastro- intestinal antispasmodic synthesized from (−)-hyoscine by quaternization of the amine function with butyl bromide. The quaternization of tropane alkaloids by N-alkylation proceeds such that the incoming alkyl group always approaches from the equatorial position.

63. 6. ipratropium bromide 7. oxitropium bromide The potent bronchodilator ipratropium bromide is thus synthesized from noratropine by successive isopropyl and methyl alkylations whilst oxitropium bromide is produced from norhyoscine by N- ethylation and then N-methylation. Both drugs are used in inhalers for the treatment of chronic bronchitis.

64. 8. Benzatropine (benztropine) is an ether of tropine used as an antimuscarinic drug in the treatment of Parkinson’s disease. It is able to inhibit dopamine reuptake, helping to correct the deficiency which is characteristic of Parkinsonism.

65. Atropa Belladona

66. Belladonna The deadly nightshade Atropa belladonna (Solanaceae) has a long history as a highlypoisonous plant. The generic name is derived from Atropos, in Greek mythology the Fatewho cut the thread of life. The berries are particularly dangerous, but all parts of the plant contain toxic alkaloids, and even handling of the plant can lead to toxic effects since the alkaloids are readily absorbed through the skin. Although humans are sensitive to the toxins,some animals, including sheep, pigs, goats, and rabbits, are less susceptible. Cases are known where the consumption of rabbits or birds that have ingested belladonna has led to human poisoning.

67. Belladonna herb typically contains 0.3–0.6% of alkaloids, mainly (−)-hyoscyamine Belladonna root has only slightly higher alkaloid content at 0.4–0.8%, again mainly (−)-hyoscyamine. Minor alkaloids including (−)-hyoscine and cuscohygrine are also found in the root, though these are not usually significant in the leaf. The mixed alkaloid extract from belladonna herb is still used as a gastrointestinal sedative, usually in combination with antacids. Root preparations can be used for external pain relief, e.g. in belladonna plasters.

68. Datura Stramonium

69. Datura stramonium is commonly referred to as thornapple on account of its spikey fruit. It is a tall bushy annual plant widely distributed in Europe and North America, and because of its alkaloid content is potentially very toxic. Indeed, a further common name, Jimson or Jamestown weed, originates from the poisoning of early settlers near Jamestown,Virginia. At subtoxic levels, the alkaloids can provide mild sedative action and a feeling of well-being. In the Middle Ages, stramonium was employed to drug victims prior to robbing them. During this event, the victim appeared normal and was cooperative, though afterwards could usually not remember what had happened. For drug use, the plant is cultivated in Europe and South America. The leaves and tops are harvested when the plant is in flower. Stramonium leaf usually contains 0.2–0.45% of alkaloids, principally (−)-hyosycamine and (−)-hyoscine in a ratio of about 2:1. In young plants, (−)-hyoscine can predominate

70. Hyoscyamus Niger

71. Hyoscyamus Hyoscyamus niger (Solanaceae), or henbane, is a European native with a long history as a medicinal plant. Its inclusion in mediaeval concoctions and its power to induce hallucinations with visions of flight may well have contributed to our imaginary view of witches on broomsticks. The plant has both annual and biennial forms, and is cultivated in Europe and North America for drug use, the tops being collected when the plant is in flower, and then dried rapidly. The alkaloid content of hyoscyamus is relatively low at 0.045–0.14%, but this can be composed of similar proportions of (−)-hyoscine and (−)-hyosycamine. Egyptian henbane, Hyosycamus muticus, has a much higher alkaloid content than H. niger, and although it has mainly been collected from the wild, especially from Egypt, it functions as a major commercial source for alkaloid production. Some commercial cultivation occurs in California. The alkaloid content of the leaf is from 0.35% to 1.4%, of which about 90% is (−)-hyoscyamine.

72. Duboisia Hopwoodii

73. Mandragora Officinarum

74. Scopolia Carniolica

75. Anisodus tanguticus var. viridulus (C. Y. Wu & C. Chen). Solanaceae Herbs perennial, 40-80(- 100) cm tall. Roots stout. Stems glabrous or pubescent. Petiole 1-3.5 cm; leaf blade lanceolate, oblong, or ovate.

76. Anisodamine Anisodamine is an anticholindergic alkaloid that had been recently been isolated from Anisodus tanguticus, an herb found primarily in the Tibetan region. This compound was introduced into clinical use in China as a synthetic drug in 1965, initially for the treatment of epidemic meningitis. Later, anisodamine was shown to produce favorable results in treatment of numerous serious ailments, including shock, glomerular nephritis, rheumatoid arthritis, hemorrhagic necrotic enteritis, eclampsia, and lung edema. The mechanism of its actions were sought and traced to a vasodilating action that affected the microcirculation. In China it is believed that anisodamine possesses good and reliable effects in the treatment of septic shock and morphine addiction. However, this drug is not without its side effects.

77. Anisodamine

78. Cocaine Aneasthetic Effect Better local aneasthetic were discovered CNS Stimulant: Brompton’s cocktail Drug of Abuse The free base is used for inhalation 1.B. Cocaine

80. 2- Erythroxylon (Coca) Alkaloids Occurrence: Coca leaves contain about 2% total alkaloids. Main Alkaloids are: 1- Cocaine. 2- Cinnamylcocaine. 3.  - truxilline. The base for Coca Alakloid is called “Ecogonine”

81. It is the major Alkaloid in Coca leaves. Cocaine is diester Alkaloid. Heating at 160 0 C in conc. HCl leads to hydrolyses of cacaine to MeOH, Benzoic acid and Ecogonine base. Cocaine

82. Production of Cocaine commercially: The total Alkaloids are hydrolysed to obtain the free base. The base is then Methylated with HCl in MeOH. The Methylated base is then esterified with Benzoly chloride. Cinnamylcocaine

83. Uses: Cocaine was used as local anesthetic. Cocaine has a CNS stimulant activity so is one of the widely abused drugs.

84. Structure Activity Relationship Aryl group connected to carboxylic acid ester Lipophilic hydrocarbon chain Basic amino group -C- O - Chain O║O║ ArylN

85. Erythroxylum Coca

87. Cocaine Addiction

88. Cocaine Coca leaves

89. The coca paste is dissolved in hydrochloric or sulphuric acid. Potassium permanganate mixed with water is added to the paste and acid solution.

90. How is cocaine used? The principal routes of cocaine administration are oral, intranasal, intravenous, and inhalation. The slang terms for these routes are, respectively, "chewing," "snorting," "mainlining," "injecting," and "smoking" (including freebase and crack cocaine). Snorting is the process of inhaling cocaine powder through the nostrils, where it is absorbed into the bloodstream through the nasal tissues.

91. Injecting releases the drug directly into the bloodstream, and heightens the intensity of its effects. Smoking involves the inhalation of cocaine vapor or smoke into the lungs, where absorption into the bloodstream is as rapid as by injection. The drug can also be rubbed onto mucous tissues. Some users combine cocaine powder or crack with heroin in a "speedball."

92. Cocaine use ranges from occasional use to repeated or compulsive use, with a variety of patterns between these extremes. There is no safe way to use cocaine. Any route of administration can lead to absorption of toxic amounts of cocaine, leading to acute cardiovascular or cerebrovascular emergencies that could result in sudden death. Repeated cocaine use by any route of administration can produce addiction and other adverse health consequences.

93. How does cocaine produce its effects? A great amount of research has been devoted to understanding the way cocaine produces its pleasurable effects, and the reasons it is so addictive. One mechanism is through its effects on structures deep in the brain. Scientists have discovered regions within the brain that, when stimulated, produce feelings of pleasure. One neural system that appears to be most affected by cocaine originates in a region, located deep within the brain, called the ventral tegmental area (VTA).

94. Nerve cells originating in the VTA extend to the region of the brain known as the nucleus accumbens, one of the brain's key pleasure centers. In studies using animals, for example, all types of pleasurable stimuli, such as food, water, sex, and many drugs of abuse, cause increased activity in the nucleus accumbens.

96. Researchers have discovered that, when a pleasurable event is occurring, it is accompanied by a large increase in the amounts of dopamine released in the nucleus accumbens by neurons originating in the VTA. In the normal communication process, dopamine is released by a neuron into the synapse (the small gap between two neurons), where it binds with specialized proteins (called dopamine receptors) on the neighboring neuron, thereby sending a signal to that neuron. Drugs of abuse are able to interfere with this normal communication process.

97. For example, scientists have discovered that cocaine blocks the removal of dopamine from the synapse, resulting in an accumulation of dopamine. This buildup of dopamine causes continuous stimulation of receiving neurons, probably resulting in the euphoria commonly reported by cocaine abusers.

98. As cocaine abuse continues, tolerance often develops. This means that higher doses and more frequent use of cocaine are required for the brain to register the same level of pleasure experienced during initial use.

99. Recent studies have shown that, during periods of abstinence from cocaine use, the memory of the euphoria associated with cocaine use, or mere exposure to cues associated with drug use, can trigger tremendous craving and relapse to drug use, even after long periods of abstinence.

100. What are the short-term effects of cocaine use? Cocaine's effects appear almost immediately after a single dose, and disappear within a few minutes or hours. Taken in small amounts (up to 100 mg), cocaine usually makes the user feel euphoric, energetic, talkative, and mentally alert, especially to the sensations of sight, sound, and touch.

101. It can also temporarily decrease the need for food and sleep. Weight loss Some users find that the drug helps them to perform simple physical and intellectual tasks more quickly, while others can experience the opposite effect.

102. The duration of cocaine's immediate euphoric effects depends upon the route of administration. The faster the absorption, the more intense the high. Also, the faster the absorption, the shorter the duration of action. The high from snorting is relatively slow in onset, and may last 15 to 30 minutes, while that from smoking may last 5 to 10 minutes. The short-term physiological effects of cocaine include constricted blood vessels; dilated pupils; and increased temperature, heart rate, and blood pressure

103. Large amounts (several hundred milligrams or more) intensify the user's high, but may also lead to bizarre, erratic, and violent behavior. These users may experience tremors, vertigo, muscle twitches, paranoia, or, with repeated doses, a toxic reaction closely resembling amphetamine poisoning.

104. Some users of cocaine report feelings of restlessness, irritability, and anxiety. In rare instances, sudden death can occur on the first use of cocaine or unexpectedly thereafter. Cocaine-related deaths are often a result of cardiac arrest or seizures followed by respiratory arrest.

105. What are the long-term effects of cocaine use? Auditory hallucinations Cocaine is a powerfully addictive drug. Once having tried cocaine, an individual may have difficulty predicting or controlling the extent to which he or she will continue to use the drug. Cocaine's stimulant and addictive effects are thought to be primarily a result of its ability to inhibit the reabsorption of dopamine by nerve cells. Dopamine is released as part of the brain's reward system, and is either directly or indirectly involved in the addictive properties of every major drug of abuse.

106. An appreciable tolerance to cocaine's high may develop, with many addicts reporting that they seek but fail to achieve as much pleasure as they did from their first experience. Some users will frequently increase their doses to intensify and prolong the euphoric effects. While tolerance to the high can occur, users can also become more sensitive (sensitization) to cocaine's anesthetic and convulsant effects, without increasing the dose taken.

107. This increased sensitivity may explain some deaths occurring after apparently low doses of cocaine. Use of cocaine in a binge, during which the drug is taken repeatedly and at increasingly high doses, leads to a state of increasing irritability, restlessness, and paranoia. This may result in a full-blown paranoid psychosis, in which the individual loses touch with reality and experiences auditory hallucinations.

108. What are the medical complications of cocaine Gastrointestinal complications There are enormous medical complications associated with cocaine use. Some of the most frequent complications are cardiovascular effects, including disturbances in heart rhythm and heart attacks; such respiratory effects as chest pain and respiratory failure; neurological effects, including strokes, seizure, and headaches; and gastrointestinal complications, including abdominal pain and nausea.

109. Cocaine use has been linked to many types of heart disease. Cocaine has been found to trigger chaotic heart rhythms, called ventricular fibrillation; accelerate heartbeat and breathing; and increase blood pressure and body temperature. Physical symptoms may include chest pain, nausea, blurred vision, fever, muscle spasms, convulsions and coma.

110. Different routes of cocaine administration can produce different adverse effects. Regularly snorting cocaine, for example, can lead to loss of sense of smell, nosebleeds, problems with swallowing, hoarseness, and an overall irritation of the nasal septum, which can lead to a chronically inflamed, runny nose. Ingested cocaine can cause severe bowel gangrene, due to reduced blood flow.

111. And, persons who inject cocaine have puncture marks and "tracks," most commonly in their forearms. Intravenous cocaine users may also experience an allergic reaction, either to the drug, or to some additive in street cocaine, which can result, in severe cases, in death. Because cocaine has a tendency to decrease food intake, many chronic cocaine users lose their appetites and can experience significant weight loss and malnourishment.

112. Research has revealed a potentially dangerous interaction between cocaine and alcohol. Taken in combination, the two drugs are converted by the body to cocaethylene. Cocaethylene has a longer duration of action in the brain and is more toxic than either drug alone. While more research needs to be done, it is noteworthy that the mixture of cocaine and alcohol is the most common two-drug combination that results in drug-related death.

113. Medicinal use Medicinally, cocaine is of value as a local anaesthetic for topical application. It is rapidly absorbed by mucous membranes and paralyses peripheral ends of sensory nerves. This is achieved by blocking ion channels in neural membranes. It was widely used in dentistry, but has been replaced by safer drugs, though it still has applications in ophthalmic and ear, nose, and throat surgery. As a constituent of Brompton’s cocktail (cocaine and heroin in sweetened alcohol) it is available to control pain in terminal cancer patients. It increases the overall analgesic effect, and its additional CNS stimulant properties counteract the sedation normally associated with heroin

114. SAR The essential functionalities of cocaine required for activity were eventually assessed to be the aromatic carboxylic acid ester and the basic amino group, separated by a lipophilic hydrocarbon chain. Synthetic drugs developed from the cocaine structure have been introduced to provide safer, less toxic local anaesthetics

115. Synthetic and semi synthetic derivatives Benzocaine is used topically, but has a short duration of action Procaine, though little used now, was the first major analogue employed

116. Tetracaine (amethocaine), oxybuprocaine, and proxymetacaine are valuable local anaesthetics employed principally in ophthalmic work. The ester function can be replaced by an amide, and this gives better stability toward hydrolysis in aqueous solution or by esterases.

117. Lidocaine Lidocaine (lignocaine) is an example of an amino amide analogue and is perhaps the most widely used local anaesthetic, having rapid action, effective absorption, good stability, and may be used by injection or topically.

118. Lidocaine, although introduced as a local anaesthetic, was subsequently found to be a potent antiarrhythmic agent, and it now finds further use as an antiarrhythmic drug, for treatment of ventricular arrhythmias especially after myocardial infarction. Other cocaine related structures also find application in the same way, including tocainide, procainamide, and flecainide. Tocainide is a primary amine analogue of lidocaine, whilst procainamide is an amide analogue of procaine. In mexiletene, a congener of lidocaine, the amide group has been replaced by a simple ether linkage.

120. Pyrrolizidine Alkaloids Two molecules of ornithine are utilized in formation of the bicyclic pyrrolizidine skeleton, the pathway proceeding via the intermediate putrescine. Because plants synthesizing pyrrolizidine alkaloids appear to lack the decarboxylase enzyme transforming ornithine into putrescine, ornithine is actually incorporated by way of arginine

122. Many pyrrolizidine alkaloids are known to produce pronounced hepatic toxicity and there are many recorded cases of livestock poisoning. Potentially toxic structures have 1,2-unsaturation in the pyrrolizidine ring and an ester function on the side-chain. Although themselves non-toxic, these alkaloids are transformed by mammalian liver oxidases into reactive pyrrole structures, which are potent alkylating agents and react with suitable cell nucleophiles, e.g. nucleic acids and proteins The tobacco alkaloids, especially nicotine, are derived from nicotinic acid but also contain a pyrrolidine ring system derived from ornithine as a portion of their structure.