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Transcript
Amino Alkaloids *phenylalkylamine= aromatic ring +alkyl chain +( N) amide. alkyl chain : 1 carbon :benzyl amine derivative 2 carbon: phenylethylamine derivative 3 carbon : B-amino-phenyl-propane. *Adrenaline and nor adrenaline catecholamine to get benefit of this cmp given parentrally because they are inactive in GIT. so you need step of isolation(extraction) to these cmp , therefore they are not occuring naturally active , so there is no difference between lab preparation and naturally modified. Capsaicinoides *Capsa=box ;empty from inside. *warmer climate more pungent taste. *Fruit also contain Vit. C -capsaicine="amide " grp. capsaicine most pungent taste. Benzylamine = acid moeity + Amine moiety. SAP (phenylalanine) desaminationcinnamic acid methoxylationferulic acid beta-oxidation vanillic acid reduced vanilline transamination vanillyamine. 10 C :1 decenoic acid " must be straight FA" isodecenoic acid not straight 8-methyl-6-nonanefatty acid =Isodecenoic acid. 1 In the last lecture, we started to discuss Derivatives of aromatic amino acids ; Phenylalanine & Tyrosine. And we classified these alkaloids as Alkaloidal amines (Amino Alkaloids),because :1) The nitrogen is not a part of the heterocyclic ring. 2) The nitrogen is originating from a Trans-amination reaction. The Phenylalkylamines They are subclassified depending on the number of carbons of the side chain. Either we'll have Capsaicinoids ,or Benzylamine derivatives, or Phenylethylamine derivatives, or β-amino-phenylpropane derivatives. Phenylethylamine derivatives Already it's a very indicating name : There's an aromatic ring and the side chain ; an ethyl amine (with 2 carbons & amino group ) and here we are talking again about the precursors Phenylalanine & Tyrosine. In fact, both amino acids proceed into two important reactions :1) Decarboxylation : to obtain corresponding amines. 2) Modification : What are the modifications?! a) Hydroxylation (oxidation ) on the aromatic ring . b) Hydroxylation( oxidation ) of side chain. c) Methylation . These are basically important reactions to obtain different closely related phenylethylamine derivatives . The amino acid Tyrosine para-hydroxyphenylalanine, it can be easily decarboxylated to its biogenic amine : Tyramine. It's in fact with this chapter ,we are entering a very important chapter of the pharmacology ( the chapter of Catecholamines ) 2 Catecholamines They are important neurotransmitters of the mammalian organisms ,and they are derivatives of this group of amino acids ( Amino acid derivatives ). Obtained by the simple reactions mentioned above : a) Hydroxylation (oxidation ) on the aromatic ring . b) Hydroxylation( oxidation ) of side chain. c) Methylation And these Catecholamines are : Adrenaline (Epinephrine), Noradrenaline (Norepinephrine) ,& Dopamine. There are many plants containing Adrenaline , Noradrenaline,& Dopamine ,but as plant constituents of less importance because of their instability in GIT of humans. Catecholamines should be administered parenterally (injection ) in order to observe their activity. And when we talk about plant constituents ,our primary objective is to use these plants as such after drying in form of infusion or in form of a Tea . Isolation from the plant ; when we are using the pure isolated compounds then there's no difference from the synthetic compounds. it follows the single entity regulations ,like the cardiac glycoside Digoxin . but as plant constituents ,if we them in form of simple preparations ,then we are talking about Herpal Remedies. Therefore, because of their instability in GIT ,none of these catecholamines are of plant constituents of interest, unless we use these plants as a source of more economical production of these compounds. so we cannot use them to benefit as a Tea of Epinephrine or such. But, there are other drug constituents structurally closely related to these substances ,and stable in the GIT ; a Phenylethylamine derivative : Mescaline . Mescalin A phenyethylamine derivative; 3,4,5-trimethoxyphenethylamine ( as a representative of GI stable derivative ). It's the active principal obtained from the cactus Lophophora williamsii ( Cactaceae ) . 3 These cacti are growing mainly in Southern America and Northern Mexico. And they became famous because the American Indians or the old inhabitants of Mexico were using these plants in a dry form or in form of a tea as a means of inducing hallucinations during religious ceremonies. The crude drug is called " Mescal Buttons "; Flattened-shaped button-like outgrowths on the stem of the cactus ,so they were taking either these mescal buttons or they were making slices (transversal cuts) then they were drying them and taking them in the mouth ( ingestion ) ,or in the form of a tea . As a result of this ,they were experiencing certain hallucinations ,and they were aiming to have these hallucinations in order to get a better connection with their Gods (to become nearer to their Gods) when they were mentally ,somehow , exciting from the normal performance and entering in an outside world; a transient world ; or an imaginary world . Hallucinations were accompanied primarily by visual symptoms; observing flashing lights ,bright colors (colored hallucinations) , distortion of the shapes ( or objects of their surroundings taking different shapes ), and they were hearing non-existing music & sounds. Mescaline is classified as one of the three important psychedelic agents ,these are :1) Mescaline ( Natural ) 2) Psilocybin ( Natural ) 3) LSD ( Semi-synthetic ) - Lysergic acid Diethylamide : The most famous & the most potent among the three. The first two are not used commonly ,even in the experimental psychiatry ,because LSD has superseded them. What is the Mescaline structurally ? It's as we have seen in Adrenaline , Noradrenaline , & dopamine with a difference; that there's a third hydroxylation in the aromatic part , and none of the hydroxyl groups are occurring in the free form ; they are possessing methyl groups. Mescaline can be synthesized from tyrosine or a hydroxylated phenylalanine,which is decarboxylated to tyramine then followed by oxidation ( Hydroxylation) to dopamine. Dopamine converts into mescaline in a biosynthetic pathway involving m-O-methylation and aromatic hydroxylation. 4 so, it's a very structurally simple compound with buzzard effect on the mood of human-beings (Hallucinations). But, again, it's not a wide spread misused drug ( it's not used worldwide ). β-amino-phenylpropane derivatives Indicating the β position of the amino carbon on the side chain Most important derivative of this this group : Ephedrine Ephedrine A β-amino-phenylpropane derivative; 2-(methylamino)-1-phenylpropan-1-ol , which has adrenaline-like activities ( sympatho-mimetic ), but ephedrine is orally-active ,and with longer duration of action than adrenaline. It's obtained from Ephedra sinica ( Ephedraceae) and other related species. It's one of the eldest medicinally reported plants. E.sinica comes from China, has been used in traditional Chinese medicine for thousands of years under the name " ma huang " It was primarily used in the treatment of common cold ,but it's now claimed for its vasoconstriction activity and possibilities to be used as a vasoconstrictor in the treatment of rhinitis , and for its bronchodilator activity in the treatment of allergic asthma. Ephedrine and ephedrine based compounds are banned by FDA, In response to accumulating evidence of adverse effects and deaths related to ephedra. It's accompanied in the plant with its stereoisomer Pseudoephedrine , and pseudoephedrine is used for its vasoconstriction activity ( α-adrenergic activity ) in the treatment of rhinitis . And all products based on ephedrine and pseudoephedrine are banned from the Sport activities ,classified as a Doping agent (The use of performance-enhancing drugs in human sport is commonly referred to by the term doping ) In fact, until the late 70's ,ephedra preparations were widely used in weightreducing tablets;due to their activity on the fat consumption ,but nowadays it's not permitted to use either ephedrine or pseudoephedrine in the weightreducing preparations ,because they get the user a mild high ,these plant products are classified as "Uppers" ,so they are considered as "Ecstacy" ( entactogenic /psychoactive) ; because they have amphetamine-like activity. 5 Structure & Correlation of Ephedra alkaloids Alkaloids do not occur in a single form . In the plant, we always have major alkaloids & minor alkaloids ( (1)Major + (n) Minor ) , so mainly the major alkaloid is accompanied with a number of minor alkaloids ,therefore, when we say ephedrine and pseudoephedrine, then we'll expect there are other closelyrelated alkaloids that are occurring in the ephedra species ,and they have correlations with one another. Epherda alkaloids are derivatives of the amino acids ; phenylalanine ( mainly) & tyrosine ,but the amino acid is not donating the nitrogen . The nitrogen is intorduced by a Trans-amination reaction. Different intermediates are converted into the Diketone ; the occurrence of the diketone is an essential intermediate in the biosynthetic pathway ,otherwise,we cannot continue with the trans-amination reaction. And as as a result of the transamination ,we obtain a basic intermaediate termed the Cathinone, that still possesses one of the carbonyl groups as a keto group, and the other keto group has already changed versus the amino group. Now, the next reaction is the Reduction ,the carbonyl group can be reduced ,then we obtain two isomeric compounds : Norephedrine & Norpseudoephedrine. * The prefix "nor-" indicates that there must be a closely-related compound with an additional methyl (it indicates either a nor-methyl or a nor-methoxy) So, when we say : norephedrine & norpseudoephedrine, then there must be methylated derivatives ,and these methylated derivatives are : Ephedrine & Pseudoephedrine. Further methylation of this amino group ( there's still a hydrogen that can be replaced with another methyl group ) will obtain :From ephedrine : N-methylephedrine. & From pseudoephedrine : N-methylpseudoephedrine. These substances ( Ephedrine & Pseudoephedrine ) have similar activities to that of Amphetamine . Also basic similarities to the structure of Amphetamine but the absence of hydroxyl group . There's also methamphetamine ; one of the hydrogens is methylated . Important Note 6 Norpseudoephedrine is also termed as "Cathine" , Structurally the same. ( Different researchers were working on Ephedra species and others on Catha edulis ( Khat Tea ). Those working on Catha edulis isolated compound which they termed as " Cathine " and those working on Ephedra species isolated the same compound and termed it as "Norpseudoephedrine". So, two different reserchers isolated the same compound ,named differently ). Therefore, when we say "Khat leaves " ,we don't say it contains Norpseudoephedrine , we say it contains Cathine . But ,in fact, Cathine is structurally nothing else than Norpseudoephedrine. Khat or Abyssinian Tea Alkaloids found in the Khat are very closely-related to Ephedra alkaloids ,and there are other secondary metabolites. It's the leaf of Catha edulis ( Celastraceae ); a small tree which is cultivated in Yemen, Somalia , and Ethiopia . It's the primary plant for misused leaves of this tea. The active principals are found in the leaves. The major active compound is Cathinone ( not Cathine ). It's preferred to use the cut leaves when they are young leaves ( why ?! ) Because during their development, the cathinone is reduced to cathine and norehedrine. So, in the young leaves ,the major constituent is Cathinone , and this ketone is the major active principal and has the major biological activity of the cut leaves ( when we use older leaves ,we isolate cathine ). *In general, It's rich in alkaloids. * It contains complex alkaloids called Cathedulins. *There are also flavonoids , tannins , volatile oils ...etc. ( rich in secondary metabolites ). * The effect of Cathinone is similar to that of Amphetamine. Khat is classified in some countries of the Arabic world as a Social drug like in Yemen. It's forbidden in Saudi Arabia . Black-listed in Soudan and Somalia . It's not internationally used widely. 7 The misuse is restricted to Arabic World ; this is easily explained because the activity is best observed in young fresh leaves ,which means if they want to transfer the leaves from Yemen ( for example ) to the States or Europe, then there will be complicated procedures, while the majority of other hallucinogenic preparations like marihuana are already used as dried material. So, it's not wide spread throughout the world like other addicted drugs. * When young leaves are kept in banana leaves ,they keep their freshness for 24 hours. * Usually , the leaves should be used within the first 24 hours of preparation. * It's classified in Yemen as a Social drug ; because it increase the selfconfidence ,talkativeness, and alertness of the users . But main activity is suppression the feeling of hunger , therefore , Anorexia is one of the adverse effects seen in individuals who are using these leaves for long term. Inflammation of the oral cavity is common. The plant also contains tannins constipation is a common observation as a side effect . * By chewing the leaves , the user will have a Constant mild high * Long-term use is associated with impotency & female infertility . Colchicine Another class of derivatives of Penylalanine & Tyrosine . Obtained from Colchicum autumnale ( Liliaceae ). This is a small class of secondary metabolites and observed only primarily in two families : Amaryllidaceae & Liliaceae . Colchicine is representing the family Liliaceae as a derivative of the different alkaloids which are originating from Phenylalanine & Tyrosine. Colchicine is pharmacologically an important drug., available in the market ( Colchicine tablets are available in the Jordanian market ) ,and it's used primarily for the control of Acute attacks of Gout. Note : Ingredient of Colchicine table is natural ,not synthetic. Colchicine isolated as a pure compound either from the seeds or from the tuber-like underground parts of the plant Colchicum autumnale , so seeds and corms are collected ,submitted to extraction , and then Colchicine is obtained . It's not only Colchicine in the plant , there's also Demecolcine and other related alkaloids . 8 Biosynthesis of Colchicine Biosynthesis of Colchicine is one the most complex biosynthetic pathways , because it includes both amino acids together ( both Phenylalanine & Tyrosine ), but each amino acid has a different pathway * Phenylalanine proceeds in Shikimic acid pathway, it will be dis-aminated ( lose the amino group ) and then formation of the shikimic acid ( Cinnamic acid ; C6-C3 derivatives ) * While Tyrosine will be decarboxylated and converted to its biogenic amine : Tyramine , and the nitrogen of Tyramine is incorporated in the structure of colchicine ( The nitrogen atom in Colchicine is Tyrosine-derived ). So, in the biosynthesis of Colchicine ,there's no trans-amination reaction. Structure of Colchicine It has an aromatic ring ( ring A ) , a 7-membered ring ( ring B ) , a tropolone ring ( ring C ) ; whis is a pseudo-aromatic 7-membered ring ). Biosynthetically , ring A is derived from Phenylalanine ,which also contributes carbon atoms 5,6,and 7 of ring B , while the rest is originating from the amino acid Tyrosine. Colchicine is not a true alkaloid because nitrogen is not part of the heterocyclic ring, it's on the side chain . There's an amide group ( nitrogen is part of the amide function ) , and its presence indicates that Colchicine is non-basic neutral alkaloid. *Colchicine has a potent anti-inflammatory activity . * It's a cytotoxic agent ( Anti-tumor agent ) : But until now ,neither colchicine nor any semi-synthetic derivative of colchicine is utilized pharmacologically as anti-tumor agent, it's nit used because of its toxicity ; the cytotoxicity is affecting the cancerous cells and the normal cells ( non-selective toxicity ) , so it's not used despite its very potent anti-mitotic activity . * Colchicine is highly poisonous , it's used in Europe primarily as a suicidal agent. ------------------------------------------------------------------------------------ Pyridine and piperidine alkaloids Alkaloids which are possessing either a pyridine or piperidine in their structure 9 are called pyridine-piperidine alkaloid,s allthough the origin of the pyridine and piperdine can be of different amino acids. The first type we’ll talk about is Coniine: Coniine is an exceptional case where no amino acids are involved in providing the N but the transamination rxn; the nature has no limits as you can see, as we are used on the N not to be a part of a heterocyclic ring structure! , but coniine is an exceptional case, its N is a result of transamination rxn and it’s included in a heterocyclic ring. You can always be surprised with the nature providing us with different toxic and biologically active substances. Coniine is the toxic principle of Conium maculatum plant which belong to the Apiaceae family , its fruit is similar to anise fruits the same size and appearance . It exist in jordan in wadi shoaib , you can see the Conium maculatum next to the anise plants they grow in the same climate conditions but the Conium is the toxic plant in the family Apiacea . As mentioned before ( hahahah 3a asas fe 7ad b7dar wela 3aref :p) a nonoxygenated substances are oily as in the case of Coniine .it’s an oily liquid as it doesn’t have an oxygen in its structure ,it cause paralysis of the diaphragm ( interrupt respiration then death) Again the N should be originated from an amino acid but this is an exceptional case it comes from transamination and here the acetic pathway is involved in the biosynthesis We have 4 acetate units ---- polyketomethylene ----- transamination -- cyclisation. 10 Arecoline and Areca catechu Arecoline Arecaidine Arecoline it’s from the family Arecaceae it’s called betel nut, the seeds contain the active principle , it can occur as a single compound or with other closely related alkaloids like its derivative Arecaidine . It’s use is only important from the pharmacological point in the veterinary medicine ( ) الطب البيطريit is used widly as a vermifuge ( )مضاد للديدان The precursor in its synthesis is the nicotinc acid which is formed by the rxn of L-aspartic acid + 3-phosphoglycerylaldehyde and several intermediate compounds are formed until nicotinc acid is formed then it is converted to arecoline . L-aspartic acid+ 3-phosphoglycerylaldehyde--- --- --- nicotinic acid-- - arecoline In fact arecoline seeds are of importance for the veterinary medicine in south Asia where the plant is growing in countries like India and Serilanka, but also in these countries they chew the betel “betel chewing”, but they have to make preparation of it to form chewing gum of it Leaves of the betel+lime (as the alkaline media) + tannin + betel nut (which contain Arecoline) -- they chew it through the day to achieve a refreshment and relaxation but hallucinations do not occur . This relaxation effect result from the ( ARECAIDINE ) msh ARECOLINE Demethylation of arecoline results in Arecaidine formation and that happens in alkaline media (that’s why the lime used for) by the addition of lime when the person chew the betel gum, arecaidine is formed and the accumulation of it is responsible for the relaxation effect . 11 Adverse effect : can cause inflammation ,yellow teeth caused by the tannin , and over years with continuous use it can cause cancer! The betel leaves and tannine-- for aroma. The betel nut- responsible for the relaxation effect due to the arecaidine formed from the arecoline. Nicotine and Nicotina tabacum When we talk about the pyridine-piperidine derivatives, the most important representative is the Nicotina tabacum ( people smoke it), it is the oldest one of the eldest attitudes of human being and the most officially acceptable social behavior ( smoking cigarette) Nicotina tabacum is the representative of the family Solanaceae ,so far around 100 species have been identified ,some of them are wild others are widely culturated to cover the need of the cigarette industry We have many alkaloids in this plant ,some of them are liquid but the most important alkaloids found in Nicotina tabacum are: The diffrences between them that both the nicotine and nornicotine are based on pyridine-pyrrolidine whereas the anabasine is based on the pyridinepiperidine . NORnicotine : nor- here means that its missing a methyl group (CH3). The damages and health effect are well known, starts with the nicotine which is used as insecticide and it’s more stable in its sulphate form and can be used out door ,it’s used in the agriculture . As we mentioned in previous lectures the pyridien itself is used as indoor insecticide because it gets degraded fast “not stable” . 12 In closed places like greenhouses, you can use the nicotine , just leave an open bottle of nicotine and it will be enough to kill insects, but in open places you should use its sulphate form as it’s more stable. The lethal dose is ≈ 100 mg you can obtain that from smoking 5 cigarrates but because the smoker exhales it he doesn’t get the whole amount so it won’t kill IMMEDIATELY (but it will kill you eventually!!) Tobacco has more than 3000 compounds in it, depending on the sensitivity of the GCLS device used to indicate them , divided into 2 groups : Particulate & gaseous (volatile) The 3000 compounds are components of the tar! Which is the polycyclic aromatic hydrocarbon , the most cancerous one! Biosynthetic origins of tobacco alkaloids : Heterocyclic structure found in the Nicotina tabacum alkaloids : Pyridine Piperidine Pyrrolidine Now the pyridine is formed from the nicotinic acid which is formed by the aspartic acid the pyridine can be converted easily into piperidine but that’s not what happens in nature it’s more complicated to form the piperidine and use it to form the anabasine . Instead of L-aspartic acid--nicotinic acid-- pyridine and conver it it to piperidine ,what happens is that the plant uses another amino acid which is Llysine . The pyrrolidine originate from L-ornithine . 13 L-lysine L-ornithine L-aspatic acid - 5 important amino acids are involved in the synthesis of alkaloids : tyrosine ,alanine,lysine,orthnithine,aspartic acid 3 of them are alphatic and 2 are aromatic And then the condensation between the pyridine and pyrrolidine to form nicotine and nornicotine and condensation of pyridine with piperidine to form anabasine . Tropane alkaloids : Are also a very important as antispasmodic and anesthetic they are distributed in few families : 1-Solanaceae: Atropa bellladona , Datura stramonim, Hyoscyamus niger, H.muticus , Withania somnifera . 2-Erythroxylaceae: Erythroxylum coca. Again different isoisermism of tropane alkaloids their structure are not very complex because the nucleus of its alkaloid tropane is composed of 2 rings structure :piperidine+pyrrolidine and what is important that two carbons and N are common to the rings of the piperidine and pyrrolidine ; you can write the structure in different ways : 14 All tropane alkaloids have a methyl group unless they are NOR-tropanes The biosynthesis , nothing new in this case for the formation of piperidine ring. But here we are using acetoacetate (small carbons) in order to complete the carbons of the tropane ring and all the carbons of the 4 acetylacetate is used for the formation of the Coca alkaloids and all the carbons of the 3 acetylacetate fused for the formation of the Solanaceae alkaloids . The Coca and Solanaceae alkaloids are ester alkaloids and to form an ester alkaloid we need an alchohol moiety and an acid moiety .in fact these heterocyclic structures which are occurring in 2 stereoisomers has a hydroxyl group which is always attached to the carbon no.3 of the tropane nucleus ,this alcoholic hydroxyl group occur as an α or β ,the compound that has an α is called α-tropine and the one that has the β is called pseudotropine ( β-tropine). Example is the tropanol : The α configuration attached to C no.3 is α-tropanol which occurs primaly in the Solanaceae alkaloids and the β form is pseudotropanol . * Acid moieties in natural and semisynthetic alkaloids : In the case of Solanaceae, the acid moiety is tropic acid which possess an asymmetric carbon so we’ll except to have an L- and D- configuration of the tropic acid, and keep in mind they occur as a racemic mixture. The biologically active tropic acid is the L-tropic acid this is why we keep saying L-hyoscyamin and so on to indicate the precursor of it which is the L-tropic 15 acid, hyoscyamin is racemized to atropine ( atropine as racemate of D and L isomer) , when we use atropine, we have to use the double dose of hyoscyamin to achieve the same effect . Atropine acid and apoatropine , (the prefix apo- is based on the prefix asometimes), and here it means losing an h2O molecule so (atropine – h2O = apo-atropine). The synthetic available marketed products are based on Mandelic acid (homatropine). Tropane alkaloids/ester formation : These alkaloids as mentioned before are occurring in their ester form ( because of the esterification of -OH group on carbon number 3 in case of tropanol with the carboxyl group in case of the tropic acid There are some other alcoholic moieties isolated such as alcoholic hyoscyamine = scopolamine; it has an epoxy group between carbon no.6 and no.7, in its biosynthesis an O is introduced to carbon no.6 ,with the presence of the necessary enzymes,6-hydroxy tropanol will be converted to 6,7-epoxytropine which is termed as Scopine and with the addition of tropic acid it will be converted to Scopolamine . The important plants of tropane alkaloids have been mentioned before : Atropa belladonna ….. . Atropine :pharmacological properties/uses: - Plz refere to ur sheet to memorize them Alkaloids of atropine and related substances have been isolated as an important anticholinergic substances , the difference between atropine and scopolamine is that later is classified as an CNS depressant while atropine and hyoscyamine are stimulants but other than that ,they posse the same activities. They are used to counter act the insecticides poisoning and nerve paralyzing gases. Coca alkaloids : In case of tropane alkaloid ,we said that’s it’s either produced using 3 acetyl acetate or 4 acetate to give Ecgonine ( a tropane alkaloid) , the latter is 16 different, it has an additional carboxylic acid attached to carbon no.2 of the tropane. ( the dr said carbon no.3 but I checked the internet, its carbon no 2 ) tropane + -COOH ---- In the case of Coca alkaloids ,we have 2 ester group; why? Because we have ecgonine alkaloid which has a free –OH group which will be converted to ester by an alcohol moiety an a free –COOH group which will be converted to ester by an acid moiety . The alcohol moiety is methanol to provide the –CH3 to the –COOH and convert it to ester. And the acid moiety is usually Benzoic acid. Ecgonine + -CH3 (from the methanol) --- ( carbomethoxy-ψ-tropine) + benzoic acid-- L-cocain . 17 Benzoic acid can be replaced by other acids such as : 1- cinnamic acid and the formed alkaloid is cinnamyl cocain. 2- Truxillic acid(dimmeric cinnamic acidsto have α and β-truxillins . cinnamic acid . truxillinic acid. Cocain : It’s a major alkaloid in Erythroxylum coca . In the group of secondary metabolite of the tropane alkaloid ,two important ones are mentioned : 1- The one used as anticholinergic . 2- the local anesthetic (Cocain), it’s advantage that until now it is not overcome by any synthetic local anesthetic because the cocain form a vasoconstriction effect when used topically (in ophthalmic preparation for example) while synthetic doesn’t! , so when we use a synthetic local anesthetic we have to add a vasoconstrictive agent . we need the vasconstriction effect to eliminate the sweating from the surrounding tissue . until 1910 cocain was legal in the coca-cola ! but then they started to use different species of the coca that doesn’t contain cocain . 18