PHARMACOGNOSY II PHAR306 6th Semester 7th Lecture

Prof. Dr. Müberra Koşar Ass. Prof. Dr. Aybike Yektaoğlu Eastern Mediterranean University Faculty of Pharmacy Department of Pharmacognosy CLASSIFICATION

• According to their botanical and biosynthetic origin, chemical structure and pharmacological activity of can be divided under various groups

• Alkaloids are classified according to their N atoms whether it is in the ring or outside the ring; non-heterocyclic or a typical alkaloids (protoalkaloids, biogenic amines) heterocyclic or typical alkaloids  are gathered under 14 groups I. Non-heterocyclic alkaloids Hordeum distochon, in barley hordenine or N-methyltriamine sprouts mescaline (triptamin) Lophophora williamsii (Cactaceae) ephedrine Ephedra spp. (Ephedraceae) colchicin (tropolone core that Colchicum spp. or in the close contains N in the side chain) genus (Liliaceae) Streptomyces erythreus erythromycin (antibiotic) (Bacteriophyta, Actinomycetales) Solanum paniculatum jurubin (3-amino steroid) (Solanaceae) pachysandrine A (in the side Pachysandra terminalis chain next to C17 N-containing (Buxaceae) steroid) taxol (diterpene pseudoalkaloid Taxus brevifolia (Taxaceae) derivative) II. Heterocyclic alkaloids 1. Pyrrole and pyrrolidine hygrines spp. (Erythroxylaceae) Stachys tuberifera (Labiatae), in soybean and stachydrine other Leguminosae 2. Pyrrolizidine symphitine, echimidine Symphytum spp. Senesionin, senesifillin, vb. Senecio spp. 3. and Trigonella foenum-graecum (Leguminosae), trigonelline Strophanthus (Apocynaceae), Coffea sp. (Rubiaceae) coniine (Umbelliferae) arecoline Areca catechu (Palmae) lobeline Lobelia spp. (Lobeliaceae) pelletierine Punica granatum (Punicaceae) (pyridine + Nicotiana tabacum and other species pyrrolidine) (Solanaceae) piperine Piper spp. (Piperaceae) ricinine Ricinus communis (Euphorbiaceae) 4. Tropane (piperidine/ N- methylpyrolidine) , , Atropa, Datura, Hyoscyamus, Duboisia, Mandragora hyoscine, meteloidine, etc. and Scopolia species (Solanaceae) Convolvulus spp., Ipomoea polpha (Convolvulaceae), calystegines some Solanaceae species, Morus spp. (Moraceae) Coca spp. (Erythroxylaceae) pseudo-pelletierine Punica granatum (Punicaceae) 5. Chinoline quinine, quinidine, cinchonine, Cinchona spp. (Rubiaceae), Remijia spp. (Rubiaceae) cinchonidine Angostura or cusparia bark, Galipea officinalis cusparine (Rutaceae) 6. Isoquinoline papaverine, narceine, Papaver somniferum (Papaveraceae) narcotine corydaline Corydalis and Dicentra spp. (Fumariaceae) Most of the Berberidaceae, Ranunculaceae and hydrastine, berberine Papaveraceae species emetine, sefaline Cephaelis spp. (Rubiaceae) tubocurarine Curare derived from Menispermaceae plants , codeine Papaver somniferum (Papaveraceae) erytraline Erythrina spp. (Leguminosae) galantamine Leucojum aestivum (Amaryllidaceae) 7. Aporfine (reduced isoquinoline/naphthalene) boldine Peumus boldus (Monimiaceae) 8. Quinolizidine sparteine, cytisine, Especially in Leguminosae, Papilionaceae lupanine, laburnine (lupine subfamily(Cytisus scoparius, Genista alkaloids) tinctoria, Laburnum ve Lupinus spp.) 9. Indole or Benzopyrrole ergometrine, ergotamine Claviceps spp. (Hypocreaceae) lysergic acid amide, clavine Rivea corymbosa, Ipomoea violacea alkaloids (Convolvulaceae) physostigmine Physostigma venenosum (Leguminosae) ajmaline, serpentine, Rauwolfia spp. (Apocynaceae) reserpine yohimbine, aspidospermine Aspidosperma spp. (Apocynaceae) vinblastine, vincristin Catharanthus roseus (Apocynaceae) calabash curare alkaloids Strychnos spp. (Loganiaceae) strychnine, brucine Strychnos spp. (Loganiaceae) 10. Indolizidine Castanospermum australe (Leguminosae), Alexa castanospermine spp. (Leguminosae) swainsonine Swainsona spp. (Leguminosae) 11. Imidazole or glicosaline pilocarpine Pilocarpus spp. (Rutaceae) 12. Purine (pyrimidine/imidazole) Tea (Ternstroemiaceae), coffee (Rubiaceae), maté caffeine (Aquifoliaceae), guarana (Sapindaceae), cola nuts (Sterculiaceae) theobromine Cocoa (Sterculiaceae) 13. Steroidal (some as glycoside derivatives) solanidine (glycoside=solanine) Potate shoots (Solanaceae) Veratrum alkamine esters and Veratrum spp. ve Schoenocaulon spp. (Liliaceae) their glycosides conessine Holarrhena antidysenterica (Apocynaceae) funtumine Funtumia elastica (Apocynaceae) 14. Terpenoid , atisine, lyctonine, and Delphinium spp. (Ranunculaceae) etc.

TROPANE ALKALOIDS

• pyrrolidine + piperidine

• they are the esters that are formed through the addition of –OH groups to nortropan or tropane skeleton forming (tropanols and nortropanol) and as a result reacting with various acids of TROPANE ALKALOIDS DETERMINATION REACTIONS

• give reactions with general 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 / 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 for anesthesia • 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 • is being used widely preoperatively for the drying of secretions 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 the tremors and severity in Parkinson's disease, shows positive effects on the improvement 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 • 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 and arrhythmias 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 of pesticides HYOSCYINI HYDROBROMIDUM SCOPOLAMINE BROMOHYDRATE • obtained from the leaves of Duboisia myoporoides or herbs

• raw material is wetted with Na2CO3 and the alkaloids are basidified. Extracted with ether. The ether phase is consumed with diluted acetic acid is taken. Alkaloids diffused into acidic aqueous phase are basidified again

with Na2CO3. Consumed again with the organic solvent and isolated as hydrobromide salt HYOSCYINI HYDROBROMIDUM SCOPOLAMINE BROMOHYDRATE

• in the prevention of postoperative nausea and vomiting

• in the prevention of nausea and vomiting through sea and motion sicknesses

• against warfare gases as an antagonist in the nerve shocks PREPARATIONS

ATROPINE 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 in height

• the leaves are ovate-stemmed, full- edged, acute apex, soft hairs present on the veins in the lower face

• flowers have one seat on leaves, bell-shaped (campanulate) and dirty 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“. The juice of the fruit of the plant have been used by the women to enlarge the pupil (16th century) ATROPA BELLADONNA

• Belladonna folium  microscopic investigation • glandular hairs; multicellular & sequential • glandular hairs short- stalked multi-cell or long shank, head portion are single-celled (Solanaceae type of glandular hairs) • crystalline sands in mesophyll cells • the epidermis has wrinkles on the cuticle BELLADONNA FOLIUM (Eur.Ph.)

• time of flowering/blooming the leaves are collected from the fruit-bearing plants and these are than dried Belladonna folium (PHE) - Belladonna leaves (dried leaves, dried leaves and flowers, sometimes fruit-bearing flowers) • calculated over hyoscyamine, should not contain less than a total alkaloid of 0.30% (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. In trading 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 be adulterated 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 used for the therapeutic treatment or accidental ingestion of fruits and young stems

• a plant has one (var. annua) and two (var. biennis) year varieties

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

• two year old varieties are higher. They reach up to 80 cm. These varieties have more leaves. Therefore, this variety is cultivated

• cultivated mainly in the UK, also in USA and Europe 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 and pointed 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 in the middle, bulging in the lower half HYOSCYAMUS NIGER

• in every region of Turkey this plant can be found at the outer edges of the road and in the 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 head portion of glandular hairs are multicellular

• mesophyll contains simple and twin crystals HYOSCYAMI FOLIUM (BP)

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

• when calculated over hyoscyamine  should not contain/carry less than 0.05% 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 in length, less indented or lobed edges; lobes pointed, ends are deeply toothed. In particular, the lower face is hairy, upper face is almost bare. Green in colour. • calyx is a long tube, falling. But the base remains permanent and its fruit forms a curved annular at the base • long corolla, white, 5-lobed at the 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 and moderate regions

• their soil requirement is not selective  they grow on the road edges, ruins and 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 shapes and black in colour STRAMONII FOLIUM

• Stramonii folium  microscopic investigation • short-stalked and the head part of a multicellular glandular hairs in the epidermis, which are the types of Solanaceae • grainy cuticle, articulated granular hairs • drusen are found in mesophyll STRAMONII FOLIUM (Eur. Ph.)

• raw material of Datura stramonium and its varieties (Solanaceae) consist of dry leaves or dry leaves together with flowers • raw material  when calculated in terms of hyoscyamine it should carry over 0.25% total alkaloid • 0-20-0.45% total alkaloid amount • hyoscyamine (2/3) and scopolamine (hyoscine) (1/3) makes the majority of the total alkaloids of this plant • total alkaloids contain a small amount of atropine formed through the racemization 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 amount could be increased from 0.3% up to 2% • commercial "datura leaves" consist of dried leaves and flowers of 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, in the same way it enlarges the pupil. Has a sedative effect on the central nervous system and this effect is stronger than of belladonna

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

• in spasmodic asthma it is used as a cigarrette. Stramonium cigarettes paralyzes the terminal ends of the bronchial tubes so that bronchial spasms are 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 Australia uses this plant to prepare a mixture with leaves where these are mixed with alkaline 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 harvested twice a year • from the leaves of Duboisia through tissue culture  obtaining of hyoscyamine and scopolamine  studies are carrying and it is intended to gain patent in this field MANDRAGORAE RADIX

• 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 the loquat/Japanese medlar (new world fruit). Therefore, there are the cases of poisoning MANDRAGORAE RADIX

• roots  fleshy gray-yellow in colour, is divided into two, then branched out again. Because these roots 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 with religious 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, possessing adaptogen effects  herb in medicine • brings physiological functions to normal • there are positive effects on anxiety and depression. Cardiovascular protection • they possess immunostimulatory effects PSEUDOTROPANOL DERIVATIVES ERYTHROXYLUM COCA (ERYTHOXYLACEAE) • in bush or shrub form. Approximately 2 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 and November)  the leaves are collected • "Erythroxylum" is red-tree ERYTHROXYLUM COCA cultivated for centuries ERYTHROXYLUM COCA

Cultivated 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 produced legally 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 for the 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; leathery leaves, greenish-brown to brown in colour, the edges are exact

• Peru / Trujillo coca leaf: pale green in colour, compared to the Bolivian coca leaves these leaves are thinner and can be easily 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 can not 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 most important alkaloids

• there is also an essential oil in the leaves. Major volatile compound is methyl 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 of dry 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 is done 3 times a year) COCAE FOLIUM powdered leaves water and calcium carbonate aqueous-alkaline wetted leaves petroleum ether stirring EXTRACTION filtration

residue filtrate

aqueous acidic phase organic phase COCAE FOLIUM aqueous acidic phase alkaline EXTRACTION precipitated alkaloids are filtrated (paste formation)

Coca paste that is smoken in the form of cigarettes is a problem that shows an addiction / of addiction (Peru, Bolivia, Colombia and Ecuador) 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 purpose as tea and drink

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

• cinnamyl cocaine formed by  ecgonine + cinnamic acid and methyl alcohol

• a- and b- truxilline  ecgonine + a- and b-truxillic acid and methyl alcohol 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 methoxide 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 ester alkaloids are hydrolized to ecgonine  cocaine is obtained by treatment of the upcoming reaction steps with benzoic acid and methanol

• cocaine  psychomotor stimulant and has the potential for strong habitations. 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 or methadone to resolve severe pain of cancer patients

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

1-4% solutions as local anesthetic in the form of a 10% solution (used in ear, nose and throat operations) 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  does not lead to social and personal harm. Person in question uses the cocaine in 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 of snuff  short-term euphoria (extreme joy) state form  bears the characteristics of local anesthetics. Distribution of nerve fibers and blocks the transmission of the impulses. Vitality, anxiety, physical and mental strength enhancer, has the effect of reducing the feeling of fatigue

• cocaine addiction also shows symptoms like amphetamine addiction  in the nature of psychotic symptoms such as paranoid, aggressive (hostile, aggressive) and antisocial behavior are available. Makes a strong psychological dependence. Tolerance and physical dependence is not observed. Withdrawal syndrome is not the case. Makes stroke in high doses COCAINE

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

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