PHARMACOGNOSY IIPHAR306

6th Semester 7th Lecture

Prof. Dr. Müberra KoşarAss. Prof. Dr. Aybike Yektaoğlu

Eastern Mediterranean UniversityFaculty of Pharmacy

Department of Pharmacognosy

CLASSIFICATION• According to their botanical and biosynthetic origin, chemical

structure and pharmacological activity of alkaloids can bedivided under various groups

• Alkaloids are classified according to their N atoms whether itis in the ring or outside the ring;

non-heterocyclic or a typical alkaloids (protoalkaloids,biogenic amines) heterocyclic or typical alkaloids aregathered under 14 groups

I. Non-heterocyclic alkaloids

hordenine or N-methyltriamineHordeum distochon, in barleysprouts

mescaline (triptamin) Lophophora williamsii (Cactaceae)

ephedrine Ephedra spp. (Ephedraceae)

colchicin (tropolone core thatcontains N in the side chain)

Colchicum spp. or in the closegenus (Liliaceae)

erythromycin (antibiotic)Streptomyces erythreus(Bacteriophyta, Actinomycetales)

jurubin (3-amino steroid) Solanum paniculatum(Solanaceae)

pachysandrine A (in the side chain next to C17 N-containing steroid)

Pachysandra terminalis(Buxaceae)

taxol(diterpene pseudoalkaloidderivative)

Taxus brevifolia (Taxaceae)

II. Heterocyclic alkaloids1. Pyrrole and pyrrolidinehygrines Coca spp. (Erythroxylaceae)

stachydrineStachys tuberifera (Labiatae), in soybean andother Leguminosae

2. Pyrrolizidinesymphitine, echimidine Symphytum spp.Senesionin, senesifillin, vb. Senecio spp.3. Pyridine and piperidine

trigonellineTrigonella foenum-graecum (Leguminosae), Strophanthus (Apocynaceae), Coffea sp. (Rubiaceae)

coniine Conium maculatum (Umbelliferae)arecoline Areca catechu (Palmae)lobeline Lobelia spp. (Lobeliaceae)pelletierine Punica granatum (Punicaceae)nicotine (pyridine + pyrrolidine)

Nicotiana tabacum and other species(Solanaceae)

piperine Piper spp. (Piperaceae)ricinine Ricinus communis (Euphorbiaceae)

5. Chinolinequinine, quinidine, cinchonine, cinchonidine

Cinchona spp. (Rubiaceae), Remijia spp. (Rubiaceae)

cusparineAngostura or cusparia bark, Galipea officinalis (Rutaceae)

6. Isoquinolinepapaverine, narceine, narcotine

Papaver somniferum (Papaveraceae)

corydaline Corydalis and Dicentra spp. (Fumariaceae)

hydrastine, berberineMost of the Berberidaceae, Ranunculaceae andPapaveraceae species

emetine, sefaline Cephaelis spp. (Rubiaceae)tubocurarine Curare derived from Menispermaceae plantsmorphine, codeine Papaver somniferum (Papaveraceae)erytraline Erythrina spp. (Leguminosae)galantamine Leucojum aestivum (Amaryllidaceae)

4. Tropane (piperidine/ N-methylpyrolidine)hyoscyamine, atropine, hyoscine, meteloidine, etc.

Atropa, Datura, Hyoscyamus, Duboisia, Mandragora and Scopolia species (Solanaceae)

calystegines Convolvulus spp., Ipomoea polpha (Convolvulaceae), some Solanaceae species, Morus spp. (Moraceae)

cocaine Coca spp. (Erythroxylaceae)pseudo-pelletierine Punica granatum (Punicaceae)

7. Aporfine (reducedisoquinoline/naphthalene)boldine Peumus boldus (Monimiaceae)8. Quinolizidinesparteine, cytisine, lupanine, laburnine (lupine alkaloids)

Especially in Leguminosae, Papilionaceae subfamily(Cytisus scoparius, Genista tinctoria, Laburnum ve Lupinus spp.)

9. Indole or Benzopyrroleergometrine, ergotamine Claviceps spp. (Hypocreaceae)lysergic acid amide, clavine alkaloids

Rivea corymbosa, Ipomoea violacea(Convolvulaceae)

physostigmine Physostigma venenosum (Leguminosae)ajmaline, serpentine, reserpine

Rauwolfia spp. (Apocynaceae)

yohimbine, aspidospermine Aspidosperma spp. (Apocynaceae)vinblastine, vincristin Catharanthus roseus (Apocynaceae)calabash curare alkaloids Strychnos spp. (Loganiaceae)strychnine, brucine Strychnos spp. (Loganiaceae)

10. Indolizidine

castanospermineCastanospermum australe (Leguminosae), Alexaspp. (Leguminosae)

swainsonine Swainsona spp. (Leguminosae)11. Imidazole or glicosalinepilocarpine Pilocarpus spp. (Rutaceae)12. Purine(pyrimidine/imidazole)

caffeineTea (Ternstroemiaceae), coffee (Rubiaceae), maté(Aquifoliaceae), guarana (Sapindaceae), cola nuts(Sterculiaceae)

theobromine Cocoa (Sterculiaceae)13. Steroidal (some asglycoside derivatives)solanidine (glycoside=solanine) Potate shoots (Solanaceae)Veratrum alkamine esters andtheir glycosides

Veratrum spp. ve Schoenocaulon spp. (Liliaceae)

conessine Holarrhena antidysenterica (Apocynaceae)funtumine Funtumia elastica (Apocynaceae)14. Terpenoidaconitine, atisine, lyctonine, etc.

Aconitum and Delphinium spp. (Ranunculaceae)

TROPANE ALKALOIDS• pyrrolidine + piperidine

• they are the esters that are formed through the addition of –OH groups tonortropan or tropane skeleton forming alcohols (tropanols andnortropanol) and as a result reacting with various acids

BIOSYNTHESIS of TROPANE ALKALOIDS

DETERMINATION REACTIONS

• give reactions with general alkaloid reagents

• ammonium reineckate (qualitative / quantitative)

• Vitali-Morin reactions tropanol derivatives

• Rathenasinkam reaction pseudotropanol derivatives

• chromatographic methods

paper electrophoresis

TLC

• biological methods (by dropping in cat's eyes pupillary mydriasis /anesthesia formation on tongue) convolvine

EFFECTS• relaxes smooth muscles (stomach, intestine)

• dilates the pupil of the eye

• reduces secretion (saliva, GIS)

• creates dilation of blood vessels

• causes an increase in heart rate and body temperature

• reduces pain and induces sleep

• CNS stimulation then depression

• some of them induces hallucinations

APPLICATION• are used to expand the pupil for eye examinations

• prevents the blockage of digital glycosides (antidote)

• preoperatively due to reducing secretion effect to prepare foranesthesia

• used against motion/sea sicknesses

• can be used in asthma attacks

• antidote in morphine and lead poisoning

• pseudotropanol esters (cocaine) local anesthetic

APPLICATION• hyoscyamine and atropine; for the mydriatic effect, due to this effect used

in ophthalmology (eye drops, ointments and in such forms)

• used to enlarge the pupil in eye surgery

• also used in the acute treatment of arrhythmias

• scopolamine is being used widely preoperatively for the drying ofsecretions produced with anesthetics

• prevents nausea over Nervus vagus, used for motion sickness

APPLICATION• they possess spasmolytic effects. Used to treat spastic colitis, enteritis,

and peptic ulcers

• their sedative and antispasmodic effects reduce the intensity of thetremors and severity in Parkinson's disease, shows positive effects on theimprovement of speaking and acting

• bronchodilator in the treatment of asthma

• subsequent to cardiac arrest as cardiac stimulant

• in several poisining (lead) and overdose (morphine) used as an antidote

ATROPINUM-ATROPINE• an alkaloid obtained from Atropa belladonna

• atropine sulfate ampules can be used SC, IM and IV

• anticholinergic and spasmolytic effect

• due to increased vagal activity in bradyarrhythmias

• for relieving vagal effects such as bradycardia, hypotension andarrhythmias occuring during surgery

• in cardiopulmonary resuscitation

• to reduce and avoid respiratory system secretions during anesthesia

ATROPINUM-ATROPINE• in pylorus, small intestine and colon spasms (irritable bowel syndrome)

• in the urethra and biliary colics

• used as cholinesterase inhibitors (such as neostigmine, pyridostigmine,pilocarpine), muscarine (Inocybe and Cliocybe type mushroom poisoning)or for treating organophosphate toxicity of pesticides

HYOSCYINI HYDROBROMIDUMSCOPOLAMINE BROMOHYDRATE

• obtained from the leaves of Duboisia myoporoides or Datura metel herbs

• raw material is wetted with Na2CO3 and the alkaloids are basidified.Extracted with ether. The ether phase is consumed with diluted acetic acidis taken. Alkaloids diffused into acidic aqueous phase are basidified againwith Na2CO3. Consumed again with the organic solvent and isolated ashydrobromide salt

HYOSCYINI HYDROBROMIDUMSCOPOLAMINE BROMOHYDRATE

• in the prevention of postoperative nausea and vomiting

• in the prevention of nausea and vomiting through sea and motionsicknesses

• against warfare gases as an antagonist in the nerve shocks

PREPARATIONSATROPINE CONTAINING PREPARATIONS

• atropine ampule

• atropine sulphate ampule

• atrosol drop

• lomotil tablets, liquid

SCOPOLAMINE CONTAINING PREPARATIONS

• buscopane ampule, dragees, liquid, plus film-coated tablets

• butopane ampule, dragees

• molitor ampule, plus dragees

• spazmol ampule, plus dragees

• spazmotek ampule,

• tranko-buskas dragees

SOLANACEAE RAW MATERIAL

ATROPA BELLADONNA• homeland South Europe,

Anatolia and Iran

• grows in forests in moist perennial,herbaceous plant with 1-1.5 m inheight

• the leaves are ovate-stemmed, full-edged, acute apex, soft hairspresent on the veins in the lowerface

• flowers have one seat on leaves,bell-shaped (campanulate) anddirty purplish in colour

ATROPA BELLADONNA

ATROPA BELLADONNA

• cherry-sized fruit, very seedy, black, brightly coloured

• 5-lobed star-shaped calyx located at the base of the

ATROPA BELLADONNA• Atropos ancient Greek mythology, "goddess of fate and destiny", the

task of putting an end to human life

• "Bella-Donna" is derived from Italian and means "beautiful woman“. Thejuice of the fruit of the plant have been used by the women to enlarge thepupil (16th century)

ATROPA BELLADONNA• Belladonna folium

microscopic investigation

• glandular hairs;

multicellular &

sequential

• glandular hairs short-stalked multi-cell or longshank, head portion aresingle-celled (Solanaceaetype of glandular hairs)

• crystalline sands inmesophyll cells

• the epidermis haswrinkles on the cuticle

BELLADONNA FOLIUM (Eur.Ph.)

• time of flowering/blooming the leaves are collected from the fruit-bearingplants and these are than dried

Belladonna folium (PHE) - Belladonna leaves

(dried leaves, dried leaves and flowers, sometimes fruit-bearingflowers)

• calculated over hyoscyamine, should not contain less than a total alkaloid of0.30% (Eur. Ph.)

• are cultured in Europe and USA

• A. belladonna var. lutea contains 1% alkaloids

• Atropa acuminata (Indian belladonna) 0.35%

are cultured in India (USP added)

ATROPA BELLADONNA• the raw material contains 0.3-0.6% total alkaloids

• the major alkaloid is hyoscyamine alkaloid (90%)

• 2% atropine, scopolamine, apoatropine, belladonine

• a small amount of volatile bases such as pyridine and N-methylpyrrole

• leaves scopoletine (b-methylesculetine)

not found in Hyocyamus and Datura sp.

in an alkaline medium under UV blue-green fluorescence

BELLADONNA RADIX• the roots contain about 0.4-0.8% alkaloid calculated over the rate of

hyoscyamine

• 82-97% hyoscyamine

• 2.5-15% atropine

• 0.1-2.6% scopolamine, in few amounts belladonine, scopoletine, hygrine,hygroline and cuscohygrine

• 1 year old roots are not suitable because of high alkaloid content. Intrading the three year old roots from fall are preferred

• roots are dug out, washed, sliced and dried

ADULTERATION• in the trade the leaves can be found as pure or adulterated:

Phytolacca decandra (Phytolaccaceae)

Ailanthus glandulosa (Simaroubaceae)

• roots

with the roots of Phytolacca decandra (Phytolaccaceae) it can beadulterated

ATROPA BELLADONNA• is a poisonous plant. Poisoning by this plant the grown pupils draws the

attention

• poisoning as a result of intake of the drug dose more than told that is usedfor the therapeutic treatment or accidental ingestion of fruits and youngstems

HYOSCYAMUS NIGER• a plant has one (var. annua) and two (var.

biennis) year varieties

• an annual variety with 30-50 cm heightpossesses more viscous and hairy leaves

• two year old varieties are higher. They reachup to 80 cm. These varieties have moreleaves. Therefore, this variety is cultivated

• cultivated mainly in the UK, also in USA andEurope

HYOSCYAMUS NIGER• the plant's flowers are pale yellow and

purple veined, base is completely purple

• pharmaceutically acceptable leaves: sessile,15-20, or even up to 25 cm in length with 5-7 cm in width

• gray-green colored leaves are deeply andpointed lobed and lobes are not equal

• there are plenty of hairs on both surfaces.Due to these hairs sticky

HYOSCYAMUS NIGER• fruit 2-eyed, very seedy,

pisidium capsules

• calyx of fruit narrowed inthe middle, bulging in thelower half

HYOSCYAMUS NIGER• in every region of Turkey this plant can be

found at the outer edges of the road and inthe interior of the fields

• Alkaloid-rich species that grow in Turkey:

• H. niger

• H. albus

• H. reticulatus (0.44% total alkaloid)

• H. aureus

• H. pusillus

• H. leptocalyx

HYOSCYAMUS NIGER• Hyoscyami folium

microscopic investigation

• glandular hairs;

multicellular &

sequential

• the stem and the headportion of glandular hairsare multicellular

• mesophyll contains

simple and twin crystals

HYOSCYAMI FOLIUM (BP)

• raw material consists of dried leaves or leaves dried together with flowers ofHyoscyamus niger

• when calculated over hyoscyamine should not contain/carry less than0.05% total alkaloid

• raw material contains 0.045-0.14% total alkaloid

• major alkaloids hyoscyamine (3/4) and scopolamine (1/4)

APPLICATION• dried leaves and flowers of H. muticus is also used as raw material

• grows in North Africa-Egypt, Iran, Pakistan

• cultivated in Southern California

• leaves 1.7%

• stem 0.5%

• flowers 2%

• the main alkaloid is hyoscyamine

• the plant is used to obtain hyoscyamine (as atropine)

DATURA STRAMONIUM• it is a perennial plant. Multi-

branched, 5-7 lobed latge leaves

• leaves are stalked, 15-25 cm inlength, less indented or lobededges; lobes pointed, ends aredeeply toothed. In particular,the lower face is hairy, upperface is almost bare. Green incolour.

• calyx is a long tube, falling. Butthe base remains permanentand its fruit forms a curvedannular at the base

• long corolla, white, 5-lobed atthe bottom and funnel-like

DATURA STRAMONIUM• grows widely in Europe

• Datura is widely available as a wild plant in wild in all the world's warm andmoderate regions

• their soil requirement is not selective they grow on the road edges, ruinsand in the fields as weeds

• it is also called angels trumpets

DATURA STRAMONIUM• blooming vertical fruit, ovoid, spiny

surface capsule and 4 slotted septicidal

• seeds are plenty, flat kidney-like shapesand black in colour

STRAMONII FOLIUM• Stramonii folium

microscopic investigation

• short-stalked and thehead part of amulticellular glandularhairs in the epidermis,which are the types ofSolanaceae

• grainy cuticle, articulatedgranular hairs

• drusen are found inmesophyll

STRAMONII FOLIUM (Eur. Ph.)

• raw material of Datura stramonium and its varieties (Solanaceae) consist ofdry leaves or dry leaves together with flowers

• raw material when calculated in terms of hyoscyamine it should carryover 0.25% total alkaloid

• 0-20-0.45% total alkaloid amount

• hyoscyamine (2/3) and scopolamine (hyoscine) (1/3) makes the majority ofthe total alkaloids of this plant

• total alkaloids contain a small amount of atropine formed through theracemization of hyoscyamine

STRAMONII FOLIUM (Eur. Ph.)

• Datura is cultivated in America and in some European countries

• especially in recent years (with developed seedbeds) the alkaloid amountcould be increased from 0.3% up to 2%

• commercial "datura leaves" consist of dried leaves and flowers of Daturainnoxia and Datura metel that are mainly cultivated in India

• the leaves of these species carries 0.5% alkaloid

APPLICATION• antispasmodic, analgesic and narcotic features. These characteristic features

are caused by hyoscyamine. Shows similar effects to belladonna leaves, inthe same way it enlarges the pupil. Has a sedative effect on the centralnervous system and this effect is stronger than of belladonna

• small and large doses overall physiological and therapeutic activities andtoxicities are practically similar. It can be used with the same doses ofbelladonna and it can be also used interchangeably

• in spasmodic asthma it is used as a cigarrette. Stramonium cigarettesparalyzes the terminal ends of the bronchial tubes so that bronchial spasmsare relieved

DUBOISIA LEAVES

• three types of Duboisia are grown in Australia

• D. myoporoides and D. leichhardtii are the main sources of tropane alkaloids,mainly scopolamine (hyoscine), more than 50 years

• D. hopwoodii contains nicotine and similar alkaloids. Aboriginals of Australiauses this plant to prepare a mixture with leaves where these are mixed withalkaline ashes producing "Pituri " kept in the cheek

Duboisia myoporoides

DUBOISIA LEAVES• D. myoporoides and D. leichhardtii leaves are used to obtain hyoscyamine

and scopolamine

• carries 1-3% of total alkaloid. Leaves are easily collected and is harvestedtwice a year

• from the leaves of Duboisia through tissue culture obtaining ofhyoscyamine and scopolamine studies are carrying and it is intended togain patent in this field

MANDRAGORAE RADIX• Mandragora officinarum var. vernalis (green-white flowers)

• M. officinarum var. autumnalis (pale purple flowers)

• mediterranean region plant

• the fruit is oval, yellow-orange in colour and size similar to theloquat/Japanese medlar (new world fruit). Therefore, there are the cases ofpoisoning

MANDRAGORAE RADIX• roots fleshy gray-yellow in

colour, is divided into two, thenbranched out again. Because theseroots resemble a human being,they are called mandrake root

• roots; 0.4% alkaloid (atropine,scopolamine, hyoscyamine,cuscohygrine)

• raw material shows sedative,narcotic and analgesic effects

• the roots were collected withreligious ceremony

WITHANIA SOMNIFERA• known as Ashwagandha (Withania somnifera), Indian ginseng

• roots carries 4% tropanol and kind of its alcohols

• anaferine, anahygrine, cuscohygrine, pseudotropanol, somniferinin,somniferien, tropanol, withanine, withananine

• there are no acids to form tropane alkaloids in the plant

• ayurvedic is known for providing a healthy and long life, possessingadaptogen effects herb in medicine

• brings physiological functions to normal

• there are positive effects on anxiety and depression. Cardiovascularprotection

• they possess immunostimulatory effects

PSEUDOTROPANOL DERIVATIVES

ERYTHROXYLUM COCA (ERYTHOXYLACEAE)

• in bush or shrub form. Approximately2 m length is reached

• is a native plant of South America

• 500 -2000 m in height cultured(Peru, Bolivia)

• 3 times a year (March, June andNovember) the leaves arecollected

• "Erythroxylum" is red-tree

ERYTHROXYLUM COCAcultivated for centuries

ERYTHROXYLUM COCACultivated Species

• Erythroxylum coca (coca leaf Huanco or Bolivia)

• E. novagranatense var. novagranatense (Colombia coca leaf)

• E. novagranatense var. truxillens (Peru/Truksillo coca leaf)

ERYTHROXYLUM COCA• coca in spanish it is the name given to the tree

• Trujillo is a port city in Peru

• pharmaceutical industry in Peru and Bolivia coca leaves are producedlegally in international treaties

• yet these two countries are illegal coca leaf and cocaine producing countries

• in the highlands of Peru and Bolivia 500-2000 m plants are also cultivated

• 25% of the cultivated leaves are used by the indigenous people, 2% are forthe pharmaceutical industry. The remaining amount is used illegally

ERYTHROXYLUM COCA• Bolivian coca leaf: short-stalked, oval, 2.5-

7.5 cm long; 1.5-4 cm wide; leatheryleaves, greenish-brown to brown incolour, the edges are exact

• Peru / Trujillo coca leaf: pale green incolour, compared to the Bolivian cocaleaves these leaves are thinner and can beeasily broken, lamina 1.6-5 cm in length

COCAE FOLIUM • microscopic investigations:

• simple crystals near the vessels of mesophyll

• sponge parenchyma carries a large vacuoles

• in the lower epidermis stomata and papillary

• stoma with two neighboring cells, the common walls of adjacent cells cannot be observed. Stoma is like in the middle of two cells

COCAE FOLIUM • leaves carries about 0.7-1.5% of total alkaloids

• the coca leaf alkaloids are of 3 types

ecgonine derivatives (cocaine, cinnamyl cocaine, a- and b-truxilline)

tropine derivatives (tropacocaine and valerine)

hygrine derivatives (hygroline and cuscohygrine)

• cocaine (30-50%), cinnamyl cocaine and α-truxilline are the mostimportant alkaloids

• there is also an essential oil in the leaves. Major volatile compound ismethyl salicylate (13.6%)

ERYTHROXYLUM COCA

cocaine

COCAE FOLIUM • before obtaining the cocaine from the leaves

• Coca Paste "Cocaine Paste" is obtained

• mostly done in Colombia. Approximately for 1kg coca paste 100-200 kg ofdry coca leaf is used

• from 2.5 kg of paste 1 kg of cocaine is obtained

• leaves are collected in spring, after June and than in the fall (harvest isdone 3 times a year)

COCAE FOLIUM powdered leaves

water and calcium carbonate

aqueous-alkaline wetted leaves

petroleum ether

stirring

filtration

residue filtrate

aqueous acidic phase organic phase

EXTRACTION

COCAE FOLIUM aqueous acidic phase

alkaline

precipitated alkaloids are filtrated (paste formation)

Coca paste that is smoken in the form of cigarettes is a problem that showsan addiction / of addiction (Peru, Bolivia, Colombia and Ecuador)

EXTRACTION

COCAE FOLIUM • Coca plant is known as the Holy plant of the Incas

• Cocaine was isolated in 1860. Until 1884 it was used only for the purposeas tea and drink

• coca leaves in South America are used to chew by the native people toresolve hunger and thirst. Because it provides an anesthetic effect on thegastric mucosa and corrects the muscle operation and masks the hungerand fatigue

COCAINE • is obtained/derived from the Erythroxylum coca leaf varieties

• or derived from ecgonine derivatives obtained from the plant by semi-synthesis

• cocaine is the methyl ester of ecgonine

• when hydrolyzed ecgonine + benzoic acid and methyl alcohol areproduced

• cinnamyl cocaine formed by ecgonine + cinnamic acid and methylalcohol

• a- and b- truxilline ecgonine + a- and b-truxillic acid and methylalcohol

COCAINE • mixture of alkaloids are hydrolyzed by boiling with diluted HCl

• ecgonine hydrochloride is formed, benzoic acid anhydride benzoylated(benzoyl ecgonine) methylated (by using methyl iodide and sodiummethoxide in methanol) cocaine

COCAINE • Cocaine is obtained by massively different varieties of patented methods

of Erythroxylum coca leaf

• sometimes if ecgonine derivatives are high enough in a plant first esteralkaloids are hydrolized to ecgonine cocaine is obtained by treatmentof the upcoming reaction steps with benzoic acid and methanol

• cocaine psychomotor stimulant and has the potential for stronghabitations. Such behavior reduces eating and sleeping

COCAINE • cocaine is a CNS stimulant due to this property it is used to resolve

sedation and respiratory depressions caused by the narcotic analgesics

• analgesic effect is potentiated. Therefore, used with morpine ormethadone to resolve severe pain of cancer patients

• cocaine; has created a model for synthetic local anesthetics. Used as alocal anesthetic in surgery:

1-4% solutions as local anesthetic

in the form of a 10% solution (used in ear, nose and throatoperations)

COCAINE • cocaine and amphetamine-type addictions are similar to each other in

many ways

• with its psychostimulant effects it causes euphoria (extreme joy).Increases durability to fatigue, exertion, cold, hunger and sleeplessness

• the use of cocaine by this way enters the body in a limited way doesnot lead to social and personal harm. Person in question uses the cocainein the form of cigarette

COCAINE • the euphoric effects of other psychoactive drugs (including heroin) is

stronger. When pure cocaine is taken by pulling to the nose in the form ofsnuff short-term euphoria (extreme joy) state form bears thecharacteristics of local anesthetics. Distribution of nerve fibers and blocksthe transmission of the impulses. Vitality, anxiety, physical and mentalstrength enhancer, has the effect of reducing the feeling of fatigue

• cocaine addiction also shows symptoms like amphetamine addiction inthe nature of psychotic symptoms such as paranoid, aggressive (hostile,aggressive) and antisocial behavior are available. Makes a strongpsychological dependence. Tolerance and physical dependence is notobserved. Withdrawal syndrome is not the case. Makes stroke in highdoses

COCAINE • 1-2 g lethal effect in people with addiction

• acute (sudden) symptoms of poisoning occur in a very short time. Deathcan occur within 2-3 minutes. Restlessness, irritability, excessivetalkativeness, depression, confusion (confusion), dry throat, dizziness,hallucinations are the main symptoms. Excessive reflexes, rapture, rise inblood pressure, irregular breathing occurs after the depression phase. CNS(Central Nervous System) depression, muscle paralysis, respiratory andcirculatory failure and leads to loss of consciousness