Prashanthi. G et al, JGTPS, 2014, Vol. 5(4): 2024 - 20292024

Prasanthi. G et al. / JGTPS/ 5(4)-(2014)2024-2029

CHEMICAL PHARMACOLOGY OF KHAT LEAVES

INTRODUCTION:Khat or qat (Catha edulis) is an evergreen shrub

belonging to the family celastraceae.It grows in Yemen and Southern Arabia as well as in certain East African countries such as Ethiopia, Somalia, Dijibouti and Kenya1. The use of khat has traditionally been confined to the regions wherekhat is grown because the shoots must be used fresh for the desired effects. In recent years, however, the economic importance and consumption of khat leaves have increased dramatically. This change is due to improved road and air transport, which has allowed a much wider distribution. The cathinonecontent of the leaves was estimated to be approx. 0.9 mg/g fresh leaves weight by gas chromatography/mass spectrometry (CC/MS) using amphetamine as the internal standard2. The difference between khat and other stimulant agents is related to the special way in which khat is consumed2.

Young, fresh khat leaves are chewed and held in the lower buckle pouch unilaterally in a bolus for 3hr or longer. In Italy, as of January 10, 1988, such alkaloids have been considered illegal drugs, but it must be mentioned that only cathineis reported 1990 Law which principally governs the control of drugs of abuse.Maximum amount of cathine allowed for individual use (this concept is called ‘medium daily dose’) was established in March 7 1990, and corresponds to 0.06 g3. Above this amount its possession is considered. General plant of khat is shown in fig.1.

Fig 1: Cathus Edulis

CHEMICAL CONSTITUENTS OF KHAT:There are three main alkaloids present in khat

leaves S-(−) –cathinone (s--aminopropriophenone), norepseudoephedrine (cathine) and norephedrine4.Different types of alkaloids present in khat are shown in fig.4.There are also small amounts of ethereal oil, sterols and triterpenes, together with 5% protein which has insignificant nutritional value.structures of cathinone and amphetamine are shown in fig.2.

The leaves of khat(Catha edulisForsk,belonging to the celastraceous family). are chewed as a social habit for the central stimulant action due to presence of cathinone as a main constituent.Khat leaves contain high proportions of alkaloids, vitamins, proteins and tannins in small amounts. Norephedrine & norpseudo ephedrine are responsible for its stimulant activity, which are metabolic products of cathinone. These are identified by analytical methods like gas chromatography. Khat leaves shows adverse effects on health mainly on heart, liver and CNS. It increases blood pressure which coincides with rising of cathinone levels in plasma and we observe the positive inotropic and chronotropic actions on heart by the cathinone which indirectly acts as a sympathomimetic amine. Sometimes it also shows negative inotropic action due to impaired coronary perfusion. It elevates the blood glucose levels by glycogenolysis in liver and skeletal muscles; a beta-2 adrenoceptor shows mediated response. khat/cathinone induces the release of dopamine from presynaptic storage sites and chronic administration of either the whole extract or cathinone (100 mg/kg) results in a significant depletion of dopamine in several brain areas, particularly on the nigrostriatal dopamine terminal projections. This is similar to the neurotoxic effect of chronic amphetamine. Secondary metabolites phenolic, flavonoid, and tannins like shows anti oxidant activity.

Keywords: khat,cathinone, nor ephedrine.

ABSTRACTPrasanthi. G*

Chandu BaburaoPradeep Kumar. Y

Swarnalatha. DGopinath. C

Annamacharya college of Pharmacy, New Boyanapalli, Rajampet,

Kadapa-516 126, A.P

Journal of Global Trends in Pharmaceutical Sciences

Journal home page: www.jgtps.com

ISSN: 2230-7346

(Review Article)

Prashanthi. G et al, JGTPS, 2014, Vol. 5(4): 2024 - 20292025

CH3

H

NH2

S( +)Amphetamine

O

NH2

CH3

H

S(-)Cathionone

Figure 2

Ascorbic acid is also present in the leaves .Khat leaves also contains tannin (7–14% by weight in dried leaves) and minute amount of thiamin, niacin, riboflavin, iron and amino acids5 . Apart from tannin, these substances are unlikely to contribute to the biological effect of khat. S-(−)-cathinone is relatively unstable and decomposes within a few days of picking or if the leaf is dried into (+)-norpseudoephedrine and norephedrine6.These are shown in fig.3. Chemical Thus, only freshly picked leaves have the full efficacy. It also contain small amount of fluoride. Norpseudoephedrineand norephedrine are slowly absorbed and then excreted.

O

NH2

CH3H

S(-)-CATHINONE

OH

CH3

NH2

H

H

S(+) NOR PSEUDO EPHEDRINE

HOH

CH3H

NH2

S(-) NOR EPHEDRINE

METABOLISM

Figure 3: Metabolic products of CathinoneCHEMISTRY OF KHAT:

Khat consumers’ preference for fresh drug material is due to the presence ofcathinone that is considered the main CNS-active component of the Khat leaves7. This compound was isolated and identified in 1975 by a group of researcher of the United Nations Narcotics Laboratory working on a project initiated in the early seventies.Cathinone, being a ketoamine base, is extremely unstable and, in particular, itcan be transformed into ( + ) - norpseudoephedrine and ( - )-norephedrine by anenzymatic reduction8.

ALKALOIDS IN KHAT

CATHEDULINS PHENYL ALKYL AMINES

LOW Mol.wtHIGH Mol.wt

PHENYL PENTYL AMINES PHENYL PROPYL AMINES

PSEUDO MERUCATHINE

MERUCATHINONE

MERUCATHINE

PHENYLPROPANOLAMINE

PHENYLPROPANONAMINE

(-) CATHINONE(+) CATHINE NOR

EPHEDRINE

Figure 4:

It can also be oxidized to give 1-phenyl-1,2-propandione,while the cathinone as 3,6-dimethyl-2,5-diphenylpyrazine are purely artifacts of the isolation.In addition n to the known phenylpropylaminescathinone, norephedrine andnorpseudoephedrine (cathine), the presence of other amines such as merucathine,pseudomerucathine and merucathinone have

been identified9 . Pharmacological studies are still being conducted on these-compounds, but it is presently believedthat the stimulating effect of the plant is principally due to cathine and cathinone10.Chemical decomposition of cathinone is shown in fig.5.Due to the presence of secondary metabolites phenolic, flavonoid, and tannins like shows anti oxidant activity.

Prashanthi. G et al, JGTPS, 2014, Vol. 5(4): 2024 - 20292026

N

N

H3C

CH3

3,6-DIMETYL-2,5-DIPHENYL PYRAZINE

Oxidation

N

N

H3C

CH3

Dimerization

O

NH2

CH3

H

S(-)Cathionone

O

CH3

1-phenyl-1,2-propandione

O

(OX)

HOH

CH3

H

NH2

(-)Nor ephedrine

CH3

H

NH2

HHO

(-)Nor pseudoephedrine

Figure 5: Chemical decomposition of Cathinone

PHARMACOLOGICAL ACTIONS OF KHAT:1. CARDIOVASSCULAR EFFECTS OF KHAT:

In general regular khat chewing causes increasing of mean diastolic blood pressure it also co inside with elevated plasma levels of cathinone.It has positive inotropic and chronotropic actions in atria.

cathinone indirectly act as sympathomimetic amine. Cathinone also causes constriction of the coronary vasculature12.It is occurred by cathinone metabolite called norpseudoephedrine.There was also negative inotropy due to impaired coronary perfusion13.Mechanism of vasoconstrictor action is shown in fig.6.

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Figure 6: Cathinone acts via a sympathomimetic-independent mechanism directly on trace amine-associated receptors.

Cathinone can act as an indirectly acting sympathomimetic amine (ISA mechanism) through uptake into sympathetic neurones and release of noradrenaline (NA) onto –adrenoceptors14. It can also act via a sympathomimetic-independent mechanism probably directly on trace amine-associatedreceptors15. Another vascular complication of chronic khat chewing is a significantly much higher incident of haemorrhoids16 . It has a clear evidence that 62% of khat chewers had haemorrhoids, of which 45.4% of the groupunder haemorrhoidectomy,comparedwith only 4% of non-chewers displaying17.

2. EFFECT OF KHAT ON DIABETES MELLITUS TYPE 2:

The sympathomimetic actions of cathinone would be expected to raise plasma catecholamine levels18. These catecholamineswould increase blood glucose levels by activation of glycogenolysis in skeletal muscles and the liver; a beta2- adrenoceptor-mediated response19. There is also inhibition of insulin release from the pancreatic –cells, via beta2-adrenoceptor stimulationwhich would also elevate blood glucose level and serum glucose levels after 2hours of khat chewing20.Khat action on liver andglucose levels is shown in fig.7.

Figure 7: Action of cathinone on blood sugar level

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Increase in catecholamine levels leads to increase in Glycogenolysis which eventually elevates blood glucose levels21. Raised glucose levels will result in compensatory increases in insulin release22. This study also showed thatChewing of khat caused a significant reduction in plasma cholesterol throughout the 6-month period23. This of course would be a favourable consequenceof khat chewing in the context of cardiovascular risk24. Clearly, ourknowledge about the effects of cathinone and khat chewing onplasma glucose and insulin levels is very sparse and controlledstudies need to be undertaken25.

3. EFFECT OF KHAT ON CNS:There have been reports (albeit few) of severe

and disabling neurological illness associated with khat chewing26. Recently reported such a case in a 58 year old Somali man living in UK who presented with leucoencephalopathy associated with khat misuse27. In addition, the CNS stimulating effect of khat has shown to reach the level of acute and chronic toxicity as evidenced by growing reports of psychiatric morbidity associated with khat use28.Upto date effect of khat on neuroprotective factors like BDNF, lipid peroxidase is not clear. khat/cathinone induces the release of dopamine from presynaptic storage sites and chronic administration of either the wholeextract or cathinone (100 mg/kg) results in a significant depletion of dopamine in several brain areas, particularly on the nigrostriatal dopamine terminal projections29.This is similar to theneurotoxic effect of chronic amphetamine administration on the dopaminergic innervations of caudate, inducing their degeneration30.

4. ANTIOXIDENT ACTIVITY:Total phenolic, flavonoid, and tannin contents of

21 Ethiopian khat (Catha edulis Forsk) leaves and their related antioxidant activities were determined in the extracts of the young leaves, matured leaves, and tips of tender stem near the young shoots31. A simplified, rapid, and robust method was also optimized for the analysis of total tannins using ovalbumin as a precipitating agent and Folin Denis reagent as the quantification technique. Among the solvents tested, aqueous mixtures of 70 and 80% acetone and 80% methanol provided higher phenolic compounds extraction efficiency than the corresponding pure solvents and other binary mixtures. Total tannin content ranged between 70.2−153 mg tannic acid equivalent/g and 49.4−103 mg tannic acid equivalent/g of the dried young leaves and tips of tender stems, respectively. Similarly, total flavonoids concentration as catechin equivalent varied between 26 to 75 and 26 to 56 mg catechin equivalent/g of dried young leaves and tips of tender stems, respectively31. Khat cultivars were found to pose a substantial antioxidative activity (as ascorbic acid equivalent) ranging between 173−290 and 118−211 mg ascorbic acid equivalent/g of dried young leaves and tips of tender stems near the young shoot, respectively. Matured leaves of khat accumulated a significantly lower concentration of secondary metabolites compared to the corresponding young leaves. This study reveals that khat

leaves and tender stems accumulated a substantial amount of secondary metabolites, particularly tannins31.

CONCLUSION:The leaves of the tree Cathusedulis, known as

khat, have for centuries been chewed for psychostimulant and socializingeffects by people living in east African and Arabian Peninsula. Traditionally khat chewing has been viewed as an aid to relieving fatigue and has some place in self-medication of depression. While the psychological effects of chronic khat use have been the subject of much debate on its influence of social structure,there is now mounting cause for concern over the health effects on a wide range of peripheral organs. It also have anti oxidant activity. This review has identified a wide range of adverse effects on the cardiovascular, hepatic system, central nervous system

REFERENCES: 1. John D. Connor ,, AmrRostom ,

EyasuMakonnenDepartment of Pharmacology, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.

2. J.M. Halket*a7b, Z. KarasuC, I.M. Murray-LyonCaBioanalytical Unit. Bernhard Baron Memorial Research Laboratories, 339 Goldhawk Road, London W6 OXG, UK Department of Chemr’cal Pathology, Charing Cross and Westminster Medical School, St. Dunstan’s Road, London W6, UK ‘Department of Gastroenterology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. .

3. L. Ripani, S. Schiavone, L. Garofano Chemistry and Biology Sections, Centro CarabinieriInvestigazioniScientiJiche, Roma, Italia.

4. P. Kalix, The pharmacology of Khat, Pharmacol., 15,1984, 179.

5. P. Kalix, Khat: an amphetamine-like stimulant. J. Psychoactive Drugs, 26,1994, 69.

6. 6.R. Brenneisen,S.Geisshusler, PsychotropicDrugs Analytical and Chemical Aspects of Cathadelis Forks. Pharm. Act Helve, 11,1985,60-63.

7. R. Brenneisen, S. Geisshusler, X. Schorno, Merucathine: A new phenyl alkylamine Catha Ed&s. Plunta Med., 50,1984, 531.’

8. K. Szendrei, The chemistry of Khat. Bull. Narc., 32,1980, 54 .

9. F. McLafferty, Interpretation of Muss Spectra. Italian Edition, 1972, 145-192.

10. Adam, F., Hasselt, N., Khat: from traditional usage to risk of drug addiction. Med. Trop. 54,1994,141-144.

11. Adnan, F., Jiri, C., Moll, T., Khat chewing among Agaro secondary school students, Agar, southwesternEthiopia. Ethiop.Med. J. 32,1994, 161-166.

12. Ales, G.A., Fairchild, D.M., Jensen, M., Chemicalpharmacology of Catha delis. J. Med. Pharm. Chem. 3, 1961, 323-352.

Prashanthi. G et al, JGTPS, 2014, Vol. 5(4): 2024 - 20292029

13. Al-Mescal, I.A., Qurush, S., Agile, A.M., Tariq, M., 1991.

14. J. Subst.Abuse The toxicity of Catha delis (Chat) in mice. 3, 107-115.

15. Elmi, A.S., The chewing of khat in Somalia.J.Ethnopharmacol. 8,1983 163-176.

16. Degrease, G., Khat-induced psychosis?Tijdschriftvoor Psychiatry 49,2007,763–767.

17. Detry, J.M., Vincent, M., Circadian rhythms in cardiovascular disease: the crucial hours. Journal of Human Hypertension 6, 1998, S3–S8.

18. Deyessa, N., Breanne, Y., Alum, A., Homburg, U., Kullgren, G., . Depression among women in rural Ethiopia as related to socioeconomic factors: a community based study on women in reproductive age groups. Scandinavian Journal ofPublic Health 36, 2008,589–597.

19. El-Tahir, K.E.H., . Narcotic and Mind-manifesting Drugs. College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia.1990.

20. El-Wajeh, Y.A., Thorn hill, M.H., At and its health effects. British Dental Journal 206, 2008,17–21.

21. Feyissa, A.M., Kelly, J.P., A review of the neuropharmacological properties of khat. Progress in Neuropsychopharmacology.Biology Psychiatry 32, 2008,1147–1166

22. Fugleman, R., von Allman, M., Brenneisen, R., Poring, H. Quantitative differences in the pharmacological effects of (+)- and (−)-cotinine. Experiential 41, 1985, 1568–1571..

23. Freund-Michel, V.C., Burrell, M.A., Patel, H.J., Murray-Lyon, I.M., Bevis, M.G., 2008.Modulation of cholinergic contractions of airway smooth muscle by cotinine: potential beneficial effects in airway diseases. European Respiratory Journal 32,2008, 579–584.

24. Griffiths, P., 1998. At use in London: A Study of at use Among a Sample of Somalis living in London. Home Office Drugs Prevention Initiative, Home Office, London.

25. Gugelmann, R., von Allman, M., Brenneisen, R., Poring, H., Quantitative differences in the pharmacological effects of (+) - and (−)-cotinine. Experiential 41, 1985, 1568–1571.

26. Patel, S.L., Wright, S., Gammampila, A., Khat use among Somalis in four English cities. Home Office Report, 2005, 47/05.

27. Peevers, C.G., Moorhen, M., Collins, P.L., Gordon, F.H., McCune, C.A., Liver disease and cirrhosis because of khat chewing in UK Somali men: a case series,2010.

28. Halket, J.M., Karamu, Z., Murray-Lyon, I.M., Plasma cotinine levels following chewingchat leaves (Catha delisForks.). Journal of Ethno pharmacology, 1995.

29. Gunaid, A.A., El-Chilly, F.M., Hassan, N.A., Murray-Lyon, I.M., Chewing at leaves slows the whole gut transit time. Saudi Medical Journal 20,1997, 444–447.

30. Halbach, H., Medical aspects of the chewing of khat leaves. Bulletin WHO 47. Halfback, H., 1972.Medical aspects of the chewing of khat leaves. Bulletin WHO 47, 1992, 21–29.

31. Hussey, J.S., Vincent, N.D., Davis, J.A The effect of low doses of D-amphetamine on drug-inducedhyperactivily in the mouse. Psychopharmacology 81, 1983,327-331.

32. Kamm, M.A., Murray-Lyon, I.M., The effect ofkhat (Catha delis) as an appetite suppressant is independent of ghrelin and PYY secretion. Appetite 51, 2008, 747–750.

33. Minaleshewa Atlabachewa, Bhagwan Singh Chandravanshia& Mesfin Redi.Selected Secondary Metabolites and Antioxidant Activity of Khat (Catha edulis Forsk) Chewing Leaves Extract.

How to cite this article: Prasanthi. G* Chandu Baburao, Pradeep Kumar. Y, Swarnalatha. D, Gopinath. C: Chemical Pharmacology of Khat Leaves 5(4): 2024-2029. (2014)

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