Bai 06 - Thuoc Tac Dung Tren He Adrenergic [Bacsihoasung.wordpress.com]

dc l hc 2007 - i hc Y H ni(sch dng cho sinh vin h bc s a khoa)

Bi 6: Thuc tc dng trn h adrenergic

Mc tiu hc tp: Sau khi hc xong bi ny, sinh vin c kh nng:1. Trnh by c chu trnh chuyn ha ca catecholamin ti ngn dy thn kinh giao

cm2. Phn bit c tc dng ca adrenalin, noradrenalin v DA3. Phn bit c tc dng ca thuc cng 1 v 2: Isoproterenol, dobutamin v

salbutamol4. Phn tch c c ch tc dng ca cc thuc hu giao cm5. Trnh by c tc dng v p dng iu tr ca thuc hy giao cm6. Phn bit c c ch tc dng v p dng iu tr ca thuc hy 1

H adrenergic l h hu hch giao cm, gii phng cht trung gian ha hc gi chung lcatecholamin v u mang nhn catechol (vng benzen c hai nhm -OH v tr ortho v mt gcamin chui bn. Cc catecholamin gm c adrenalin (c sn xut ch yu tu thn g thn)noradrenalin ( u tn cng cc si giao cm) v dopamin ( mt s vng trn thn kinh trungng).


Hnh 6.1. Sinh tng hp catecholamin1. Chuyn ha ca catecholaminCatecholamin c sinh tng hp t tyrosin di tc dng ca mt s enzym trong t bo acrm tu thng thn, cc nron hu hch giao cm v mt s nron ca thn kinh trung ngtheo s trn (hnh 6.2)


Hnh 6.2. Chuyn vn ca catecholamin ti tn cng dy giao cmTyrosin c vn chuyn vo u tn cng dy giao cm nh c ht vn chuyn ph thuc Na +(A). Tyrosin c chuyn ha thnh dopamin (DA) ri c cht vn chuyn (B) a vo cc tid tr (cc ht). Cht vn chuyn ny cng vn chuyn c noradrenalin (NA) v vi amin khc.Trong ti d tr, DA c chuyn ha thn h NA. in th hot ng lm m knh calci, Ca 2+vo t bo, gii phng NA t ti d tr.


Sau khi c tng hp, mt phn catecholamin s kt hp vi ATP hoc vi mt dng protein hatan l chromogranin tr thnh dng khng c hot tnh, khng b cc e nzym ph hu, lu litrong cc kho d tr l nhng ht c bit nm bo tng (khong 60%), cn mt phn khc(khong 40%) vn dng t do trong bo tng, d di ng, nm ngoi ht. Gia hai dng nylun c s thng bng ng, khi dng t do gim i th li c b sung ngay t cc kho d tr.Lng noradrenalin trong bo tng iu chnh hot tnh ca tyrosin hydroxylase theo c chiu ha ngc chiu: khi noradrenalin tng th hot tnh ca enzym gim, v ngc li. Mtkhc, cc cht cng receptor 2 lm gim gii phng noradrenalin ra khe xinap v do trlng ca noradrenalin trong bo tng s tng ln.Theo gi thit ca Burn v Rand (1959 - 1962) di nh hng ca xung tc thn kinh, ngn dygiao cm lc u tit ra acetylcholin, l m thay i tnh thm ca mng t bo, do Ca ++ tngoi t bo thm nhp c vo trong t bo, ng vai tr nh mt enzym lm v lin kt ATP -catecholamin, gii phng catecholamin ra dng t do.Sau khi c gii phng, mt phn noradrenalin s tc n g ln cc receptor (sau v trc xinap),mt phn chuyn vo mu tun hon tc dng xa hn ri b ging ha, cn phn ln (trn80%) s c thu hi li, phn nh khc b mt hot tnh ngay trong bo tng.

Hnh 6.3. S phn ca noradrenalin khi c gii phng1. Tc dng trn receptor sau (1a) v trc (1b) xinap2. Thu hi3. Vo tun hon v b chuyn ha bi COMT4. Chuyn ha trong bo tng bi MAO

Catecholamin b mt hot tnh bi qu trnh oxy ha kh amin do hai enzym MAO (mono - amin oxydase) v COMT (catechol - oxy- transferase) cui cng thnh acid 3 - methoxy- 4hydroxy mandelic (hay vanyl mandelic acid - VMA) thi tr qua nc tiu.MAO c nhiu trong ti th (mitochondria), v vy n ng vai tr ging ha catecholamin trongt bo hn l tun hon. Phong to MAO th lm tngcatecholamin trong m nhng khng nh hng n tc dng ca catecholamin ngoi lai.


COMT l enzym ging ha catecholamin ngoi t bo, c mng xinap v nhiu ni nhngm cao hn c l gan v thn. Phong to COMT th ko di c thi gian tc dng cacatecholamin ngoi lai.Receptor: Adrenalin v noradrenalin sau khi c gii phng ra s tc dng ln cc receptor cah adrenergic. Ahlquist (1948) chia cc receptor thnh hai loi v do chng c tc dngkhc nhau trn cc c quan (bng sau).Ta thy rng tc dng cng c tnh cht kch thch, lm co tht cc c trn, ch c c trnthnh rut l gin. Ngc li, tc dng cng c tnh cht c ch, lm gin c, tr c tim lilm p nhanh v p mnh.Land, Arnold v Mc Auliff (1966) cn chia cc receptor thnh hai nhm 1 (tc dng trn timv chuyn ha m) v nhm 2 (lm gin mch, gin kh o v chuyn ha ng). 2 trcxinap kch thch lm tng gii phng NA, c vai tr iu ha ngc vi 2.Theo xut ca Langer (1974), cc receptor c chia thnh hai loi: loi 1 l receptor sauxinap, lm co mch tng huyt p, loi 2 l receptor trc xinap, c tc dng iu ha, khi kchthch s lm gim gii phng norad renalin ra khe xinap, ng thi lm gim tit renin, gy hhuyt p. Cc receptor 2 c nhiu h giao cm trung ng. Hin cng thy c receptor 2 sau xinap ca mch mu v t bo c trn (lm co), m m v cc t bo biu m xut tit (rut,thn, tuyn ni tit)Dopamin ch yu tc dng thn kinh trung ng, thn v cc tng, trn cc receptor c hiui vi n gi l cc receptor dopaminergic (receptor delta - )

Bng 6.1: Cc receptor adrenergicReceptor

Cht chvn

Chtikhng

M p ng C ch phn t

1 Adr NA>>IsoPhenylephrin

Prazosin - C trnthnh mch- C trnsinh dctit niu- Gan- C trnrut- Tim

Co thtCo thtHu glycogenTn to ngu cc ha vginTng co bp, lonnhp

Kch thchphospholipase C to IP3 vDAG; tng Ca++cytosol- Hot ha knhK+ ph thuc voCa++- c ch dng K+

2 AdrNA >>IsoClonidin

Yohimbin

- T bo ca ty- Tiu cu- Tn cngsi TK- C trnthnh mch

Gim tit insulinNgng ktGim tit NACo

- c ch adenylcyclase(Gi) - Hot haknh K+- c ch knh Ca++-Tng lung Ca,tng Ca++ trongcytosol

1 Iso>Adr =NADobutaminMetoprolol

- Tim Tng tn s, bin v tc dn

Hot haadenylcyclase v


- T bogn cuthn

truyn A-VTng tit renin

knh Ca

2 Iso>Adr >>NATerbutalin

ICI118551

- C trn(mch khqun,rut...)- C vn- Gan

- Gin- Hu glycogengn K+- Hy glycogen- Tn to ng

Hot haadenylcyclase

3 Iso=NA>AdrBRL 37344ICI118551CGP20712A

Hu lipid Hot haadenylcyclase

Iso*: Isoproterenol Adr: adrenalin NA: noradrenalinGhi ch ca bng 3:

- Mi receptor u kch thch adenylcyclase thng qua protein G S v lm tng AMPv, ngoi racn lm knh calci cm ng vi in th ca c vn v c tim.- Receptor 2, tri li, c ch adenylcyclase thng qua protein G i, ng thi hot ha knh kali,c ch knh calci.- Receptor 1 kch thch lm tng calci ni bo thng qua 2 cht trung gian Diacylglycerol(DAG) v Inositol triphosphat (IP 3).2. Thuc cng h adrenergicL nhng thuc c tc dng ging adrenalin v noradrenalin , kch thch hu hch giao cm nncn gi l thuc cng giao cm. Theo c ch tc dng c th chia cc thuc ny lm hai loi:- Loi tc dng trc tip trn cc receptor adrenergic sau xinap nh adrenalin, noradrenalin,isoproterenol, phenylephrin- Loi tc dng gin tip do kch thch cc receptor trc xinap, lm gii phng catecholamin nisinh nh tyramin (khng dng trong iu tr), ephedrin, amphetamin v phenyl - ethyl- amin. Khidng reserpin lm cn d tr catecholamin th tc dng ca cc thuc s gim i. Trong nhmny, mt s thuc c tc dng kch thch thn kinh trung ng theo c ch cha hon ton bit r(nh ephedrin, amphetamin), reserpin khng nh hng n tc dng ny; ho c c ch mono-amin- oxydase (MAOI), lm vng bn catecholamin.2.1.Thuc cng receptor alpha v beta2.1.1.Adrenalinc, bng AL hormon ca tu thng thn, ly ng vt hoc tng hp. Cht t nhin l ng phn ttuyn c tc dng mnh nht.2.1.1.1.Tc dng


Adrenalin tc dng c trn v receptor.- Trn tim mch:Adrenalin lm tim p nhanh, mnh (tc dng ) nn lm tng huyt p ti a, tng p lc tngt cung ng mch ch v xoang ng mch cnh, t pht sinh cc phn x gim p quady thn kinh Cyon v Hering lm cng trung tm dy X, v vy lm tim p chm dn v huytp gim. Trn ng vt th nghim, nu ct dy X hoc tim atropin (hoc methylatropin) trc ct phn x ny th adrenalin ch lm tim p nhanh mnh v hu yt p tng rt r.Mt khc, adrenalin gy co mch mt s vng (mch da, mch tng - receptor ) nhng li gygin mch mt s vng khc (mch c vn, mch phi - receptor ...) do huyt p ti thiukhng thay i hoc c khi gim nh, huyt p tru ng bnh khng tng hoc ch tng nh trongthi gian ngn. V l adrenalin khng c dng lm thuc tng huyt p.Tc dng lm gin v tng lu lng mch vnh ca adrenalin cng khng c dng trong iutr co tht mch vnh v tc dng ny li km theo lm tng cng nng v chuyn ha ca c tim.Di tc dng ca adrenalin, mch mu mt s vng co li s y mu ra nhng khu vc t chunh hng hn, gy gin mch th ng nhng ni (nh mch no, mch phi) do d gycc bin chng t mch no, hoc ph phi cp.- Trn ph qun:t tc dng trn ngi bnh thng. Trn ngi b co tht ph qun do hen th adrenalin lm ginrt mnh, km theo l co mch nim mc ph qun, lm gim ph cho nn nh hng rt tt titnh trng bnh. Song adrenalin b mt tc dng rt nhanh vi nhng ln dng sau, v vy khngnn dng ct cn hen.- Trn chuyn ha:Adrenalin lm tng hu glycogen gan, lm tng glucose mu, lm tng acid bo t do trong mu,tng chuyn ha c bn, tng s dng oxy c a m.Cc c ch tc dng ca adrenalin hay catecholamin ni chung l lm tng tng hp adenosin 3' -5'- monophosphat (AMP- vng) t ATP do hot ha adenylcyclase (xem s )

S tc ng ca catecholamin ln chuyn ha ng v mCatecholamin Cafein

Diazoxid (-)

Adenylcyclase PhosphodiesteraseATP 3', 5'- AMP AMP

(AMP vng)

Triglycerid Triglycerid lipase


Glycogen (-)Glycogen

Phospho- Glucose- 1- phosphat synthetase Diglycerid Acid borylase

Glucose- 6- phosphat Monoglycerid Acid bo

Glucose mu Nng lngAcid lactic Glycerol Acid bo

2.1.1.2. p dng iu tr:- Chng chy mu bn ngoi (p ti ch dung dch adrenalin hydroclorid 1% lm co mch).- Tng thi gian gy t ca thuc t v adrenalin lm co mch ti ch nn lm chm hp thu thuct.- Khi tim b ngng t ngt, tim adrenalin trc tip vo tim hoc truyn mu c adrenalin vong mch hi tnh.- Sc ngt: dng adrenalin tng huyt p tm thi bng cch tim tnh mch theo phng phptrng bm tim.Liu trung bnh: tim di da 0,1- 0,5 mL dung dch 0,1% adrenalin hydroclorid.Liu ti a: mi ln 1 mL; 24 gi : 5 mLng 1 mL = 0,001g adrenalin hydroclorid2.1.2. Noradrenalin (arterenol)c, bng AL cht dn truyn thn kinh ca cc si hu hch giao cm. Tc dng mn h trn cc receptor ,rt yu trn , cho nn:- Rt t nh hng n nhp tim, v vy khng gy phn x cng dy ph v.- Lm co mch mnh nn lm tng huyt p ti thiu v huyt p trung bnh (mnh hn adrenalin1,5 ln)- Tc dng trn ph qun rt yu, v c trn ph qun c nhiu receptor 2.- Tc dng trn dinh dng v chuyn ho u km adrenalin. Trn nhiu c quan, tc dng caNA trn receptor km hn adrenalin mt cht. Nhng do t l cng tc dng gia v khc nhau nn tc dng chung khc nhau r rt.Trn thn kinh trung ng, noradrenalin c nhiu vng di i. Vai tr sinh l cha hon tonbit r. Cc cht lm gim d tr catecholamin no nh reserpin, methyldopa u


gy tc dng an thn. Tri li, nhng thuc c ch MAO, lm tng catecholamin th u c tcdng kch thn.iu ha thn nhit ph thuc vo s cn bng gia NA, serotonin v acetylcholin phn trcca vng di i.C th cn tham gia vo c ch gim au: thuc lm gim lng catechola min tim vo no thtc ch c tc dng gim au ca morphin.Ch nh: nng huyt p trong mt s tnh trng sc: sc nhim c, nhim khun, sc do dng...Ch truyn nh git tnh mch t 1 - 4 mg pha long trong 250- 500 mL dung dch glucose ngtrng. Khng c tim bp hoc di da v lm co mch ko di, d gy hoi t ti ni tim.ng 1 mL = 0,001g2.1.3. DopaminDopamin l cht tin thn ca noradrenalin v l cht trung gian ha hc ca h dopaminergic.C rt t ngn dy giao cm. Trong no, tp trung cc nhn xm trung ng v b en vn.Trn h tim mch, tc dng ph thuc vo liu:- Liu thp 1- 2 g/ kg/ pht c gi l "liu thn", tc dng ch yu trn receptor dopaminergicD1, lm gin mch thn, mch tng v mch vnh. Ch nh tt trong sc do suy tim hoc do gimth tch mu (cn phc hi th tch mu km theo).- Ti thn, "liu thn" ca dopamin lm tng nc tiu, tng thi Na +, K+, Cl-, Ca++, tng sn xutprostaglandin E2 nn lm gin mch thn gip thn chu ng c thiu oxy.- Liu trung bnh > 2- 10 g/ kg/ pht, tc dng trn receptor 1, lm tng bin v tn s tim.Sc cn ngoi bin ni chung khng thay i.- Liu cao trn 10g/ kg/ pht tc dng trn receptor 1, gy co mch tng huyt p.Trong lm sng, tu thuc vo tng loi sc m chn liu.Dopamin khng qua c hng ro mu noCh nh: cc loi sc, km theo v niung 200 mg trong 5 mL. Truyn chm tnh mch 2 - 5 g/ kg/ pht. Tng gim s git theo hiuqu mong mun.Chng ch nh: cc bnh mch vnh2.2. Thuc cng receptor 2.2.1. Metaraminol (Aramin)Tc dng u tin trn receptor 1. Lm co mch mnh v lu hn adrenalin, c th cn do kchthch gii phng noradrenalin, khng gy gin mch th pht. Lm tng lc co bp ca c tim, tlm thay i nhp tim. Khng kch thch thn kinh trung ng, khng nh hng n chuyn ha.V mt gc phenol trn vng benzen nn vng bn hn adrenalin.Dng nng huyt p trong cc trng hp h huyt p t ngt (chn thng, nhim khun, sc).


Tim tnh mch 0,5- 5,0 mg trong trng hp cp cu. Truyn chm tnh mch dung dch 10 mgtrong 1 mL. C th tim di da hoc tim bp. ng 1 mL= 0,01g metaraminol bitartrat.2.2.2. Phenylephrin (neosynephrin)Tc dng u tin trn receptor 1. Tc dng co mch tng huyt p ko di, nhng khng mnhbng NA. Khng nh hng n nhp tim, khng kch thch thn kinh trung ng, khng lmtng glucose huyt.Ch nh: nh noradrenalinTim bp 5- 10 mgTruyn chm vo tnh mch 10 - 15 mg trong 1000 mL dung dch glucose ng trngCn dng chng xung huyt v gin ng t trong mt s ch phm chuyn khoa.2.2.3. Clonidin (Catapressan)Clonidin (dicloro- 2, 6 phenyl- amino- imidazolin) c tc dng cng receptor 2 trc xinap trung ng v thuc qua c h ng ro mu- no. Tc dng cng 2 sau xinap ngoi bin chthong qua nn gy tng huyt p ngn. Sau , do tc dng cng 2 trung ng chim u th,clonidin lm gim gii phng NA t cc nron giao cm hnh no, gy gim nhp tim, gimtrng lc giao cm, gim lu lng mu no, tng, thn v mch vnh, a n h huyt p.Clonidin lm cn bi tit nc bt, dch v, m hi, lm gim hot tnh ca renin huyt tng,gim li niu. ng thi c tc dng an thn, gim au v gy mt mi. Mt s t c gi cho rngclonidin gn vo receptor imidazolin thn kinh trung ng, l loi receptor mi ang cnghin cu.Tc dng khng mong mun: ng g, kh mingCh nh: tng huyt p th va v nng (xin xem bi "Thuc cha tng huyt p")Chng ch nh: trng thi trm cm.Khng dng cng vi guanetidin hoc thuc lit hch v c th gy cn tng huyt p.Liu lng: vin 0,15 mg. Ung liu tng dn ti 6 vin mt ngy, tc dng xut hin chm.Dng cng vi thuc li niu, tc dng h huyt p s t ng.2.3. Thuc cng receptor C 4 tc dng dc l chnh- Tc dng gin ph qun, dng cha hen: loi cng 2.- Tc dng gin mch: loi cng 2- Tc dng kch thch 1 lm tng tn s, tng lc co bp ca c tim, tng tc dn truyn trongc tim, tng ti mu cho c tim.- Trn t cung c cha, thuc cng 2 lm gim co bp c dng chng da xy thai.2.3.1. Isoproterenol (Isoprenalin, Isuprel, Aleudrin, Novodrin, Isopropyl noradrenalin)


Tc dng u tin trn receptor (1 v 2). Lm tng nhp tim, tng sc co bp ca c tim vcung lng tim, gy gin mch, h huyt p, lm gin kh qun nhanh v mnh (gp 10 lnadrenalin), ng thi lm gim tit dch nim mc nn ct cn hen rt tt.Dng trong cc trng hp nhp tim chm thng xuyn , nghn nh tht hon ton, lon nhp donhi mu c tim: truyn tnh mch 0,5mg trong 250 - 500 ml dung dch glucose 5%. Tc dngtng ng huyt km adrenalin v cn trc tip kch thch t bo ty tit insulin.Trong hen ph qun v trn kh ph mc mn tnh, t di li vin 10 mg, 2 - 3 ln/ ngy.Khng ung v b chuyn ha nhanh.ng Novodrin 1 mL= 0,5 mg isoprenalin clohydratVin 10- 20 mg isoprenalin sulfatPhun dch 1 phn nghn2.3.2. Dobutamin (Dobutrex)Cng thc gn ging dopamin: tc dng u tin trn 1 receptor. Tc dng phc tp dodobutamin raxemic c 2 ng phn; ng phn ( -) dobutamin c tc dng cng 1 mnh, gytng huyt p; trong khi ng phn (+) dobutamin li c tc dng i lp hy 1. C hai ngphn u c tc dng cng , nhng ng phn (+) 10 ln mnh hn ng phn ( -). Tc dngca dobutamin raxemic l tng hp ca c hai ng phn.Trn tim, do dobutamin lm tng co bp mnh v t lm tng nhp , v vy khng lm tng nhucu s dng oxy ca c tim. Tc dng km isopr oterenol. t tc dng trn mch nhng lm ginmch vnh. Tc dng li niu ch yu l do tng lu lng tim.Ch nh: suy tim cp sau m tim, nhi mu c timV thi gian bn thi ch khong 2 pht nn ch dng bng ng truyn chm tnh mch.Ch phm: Dobutamin hydroclorid (Dobutrex) l 20 mL cha 250 mg dobutamin. Khi dng, halong trong 50 mL dung dch dextrose 5%, truyn tnh mch vi liu 2,5 - 10 g/ kg/ pht. Nunhp tim tng nhanh, gim tc truyn.2.3.3. Thuc cng u tin (chn lc) rece ptor 2L thuc thng c dng iu tr ct cn hen. Tuy nhin, liu cao cng vn kch thch c 1,lm tng nhp tim. V vy hng nghin cu ti vn l tm cch thay i cu trc c cc thuctc dng ngy cng chn lc trn 1 hn v c sinh kh dng cao hn. ng thi dng thuc didng kh dung trnh hp thu nhiu thuc vo ng ton thn, d gy tc dng ph (tim pnhanh, run tay)Cc thuc cng 2 dng di dng kh dung, ngoi tc dng lm gin ph qun cn c th cch gii phng leucotrien v histamin khi dng bo phi (xem thm bi "Thuc iu chnhri lon h hp")Chng ch nh: bnh mch vnh, lon nhp tim, cao huyt p nng, i tho ng, cng gip.Dng ko di lin tc, tc dng c th gim dn do s lng recept or 2 mng t bo sau xinapgim ("down regulation")2.3.3.1. Terbutalin


Do c vng resorcinol trong cu trc nn khng b COMT metyl ha. Sau kh dung, tc dng kodi c 3- 6 gi.2.3.3.2. Albuterol (Salbutamol - Ventolin)Tnh cht dc l v ch nh iu tr nh terbutalin. Dng ng ung hoc kh dung. Sau khdung, tc dng ti a vo pht th 15 v duy tr c 3 - 4 gi.- Vin gii phng chm (Volmax): 4 - 8 mg 2 ln/ ngy- Kh dung nh liu (Ventolin): 100 g/ nht bp 2 nht/ ln 3- 4ln/ ngy cch nhau 4ting.2.3.2.3. RitodrinDng lm gin t cung, chng non (xem bi " Thuc tc dng trn t cung"). Hp thu nhanhqua ng ung nhng sinh kh dng ch c 30%. Thi tr qua nc tiu 90% di dng linhp. Tim tnh mch, 50% thi tr di dng nguyn cht.2.4. Thuc cng giao cm gin tip2.4.1. Ephedrin (ephedrinum)c, bng BEphedrin l alcaloid ca cy ma hong (Ephedra equisetina v Ephedra vulgaris). Hin nay tng hp c. Trong y hc, dng loi t tuyn v raxemic.L thuc va c tc dng gin tip lm gii phng catecholamin ra khi ni d tr, va c tcdng trc tip trn receptor.Trn tim mch, so vi noradrenalin, tc dng chm v yu hn 100 ln, nhng ko di hn ti 10ln. Lm tng huyt p do co mch v kch th ch trc tip trn tim. Dng nhiu ln lin nhau, tcdng tng p s gim dn (hin tng quen thuc nhanh: tAChyphylaxis)Thng dng chng h huyt p v kch thch h hp trong khi gy t tu sng, trong nhimc ru, morphin, barbiturat.Kch thch trung tm h hp hnh no v lm gin ph qun nn dng ct cn hen, tc dngtt trn tr em.Trn thn kinh trung ng, vi liu cao, kch thch lm mt ng, bn chn, run, tng h hp.Ephedrin d dng hp thu theo mi ng. Vng bn vi MAO. C huyn ha gan, khong 40%thi tr nguyn cht qua nc tiu.

Dng di th mui clohydrat hoc sulfat d ha tan.Ung 10- 60 mg / ngy. Liu ti a 24h l 150 mgTim di da, bp tht hoc tnh mch 10 - 20 mg/ ngyNh nim mc (mt, mi) dung dch 0, 5- 3%ng 1 mL= 0,01g ephedrin clohydratVin 0,01g ephedrin clohydrat


Pseudoephedrin l ng phn lp th ca ephedrin, t gy tim nhanh, tng huyt p v kch thchthn kinh trung ng hn ephedrin. Thng c dng trong cc ch phm nh mi chng xun ghuyt nim mc.2.4.2. AmphetaminL thuc tng hp phenylisopropanolamin. Tc dng dc l theo kiu ephedrin, gin tip lmgii phng noradrenalin (v c th cn c dopamin v serotonin) ra khi ni d tr. Khcephedrin l thm vo thn kinh trung ng nhan h, tc dng kch thch mnh tm trng v snhanh nhn do tc ng ln v no v h lin vng hot ha (v vy, c xp vo loi doping,cm dng trong thi u th thao). Cn c tc dng gy chn n, dng chng bo ph.Mt s dn xut ca amphetamin (methamphetamin, dimethoxyamphetamin...) kch thch thntrung ng rt mnh, gy lon thn, u xp vo cht ma tu.2.4.3. Phenylpropanolamint tc dng trung ng hn. ngoi bin, tc dng co mch thng c dng chng ngtmi, l thuc phi hp trong v in thuc chng cm cm (Atussin, Decolgen). Tuy nhin, gn ythy nhiu tc dng ph trn tim mch nn c xu hng khng dng na.3. Thuc hu h adrenergicL nhng thuc lm mt tc dng ca adrenalin v noradrenalin. Cc thuc ny thng cdng iu tr chng tng huyt p, bnh Raynaud, lon nhp tim, hi chng cng tuyn gip(tim nhp nhanh, li mt, gin ng t, tng h hp; chnh l nhng du hiu cng giao cm).Cc thuc c chia thnh hai nhm:- Thuc hy giao cm (sympatholytic): l nhng thuc phong to nron adrenergic trc xinap,lm gim gii phng catecholamin, khng c tc dng trn receptor sau xinap, khi ct cc dyhu hch giao cm th thuc mt tc dng. Do thiu cht dn truyn thn kinh ni sinh, tnh cmth ca cc receptor sau xinap vi catecholamin ngoi lai s tng ln.- Thuc hu adrenalin (adrenolytic) l nhng thuc phong to ngay chnh cc receptor adrenergicsau xinap, cho nn khi ct t cc si hu hch giao cm, tc dng ca thuc khng thay i.Catecholamin c ni sinh ngoi lai u b mt tc dng.1.1. Thuc hu giao cmCc thuc c th c tc dng nhng khu sau:1.1.1. c ch tng hp catecholaminThuc hay c dng l methyl dopa (Aldomet) phong ta dopa decarboxylase, lm dopakhng chuyn thnh dopamin v 5 - hydroxytryptophan khng chuyn thnh 5 -hydroxytryptamin (5 HT- serotonin). Do s lng catecholamin v serotonin c ngoi binv thn kinh trung ng u gim. Mt khc cn ngn cn kh nng gn catecholamin vo ccht lu tr.Ngoi ra, trong c th methyldopa cn c th chuyn thnh methyl noradrenalin, tc dngnh mt cht trung gian ha hc gi chim ch ca noradrenalin (xem bi "Thuc cha tnghuyt p")Tc dng ph: m mng, c ch tm thn, chng mt, nhc u, kh ming, ph.


Khng dng khi c ri lon tun hon no v mch vnh, cc trng thi trm cm, ri lon gan,thn.Liu lng: ung vin 250 mg. C th dng ti 8 vin/ ngy.Ch phm: Dopegyt vin 0,25 g methyl dopa.Carbidopa v bemerazid, c ch dopa decarboxylase ngo i bin. c dng phi hp vi l -dopa iu tr bnh Parkinson.1.1.2. Lm gim d tr catecholamin trong cc ht* Reserpin:Lm gii phng t t catecholamin t cc ht lu tr ra ngoi bo tng MAO ph hu, do lng catecholamin gim c trn thn kinh trung ng (gy an thn), c ngoi bin (lm hhuyt p). Reserpin cn cn tr qu trnh gn catecholamin (c ni sinh ln ngoi sinh) vo ccht lu tr.* Guanetidin (Ismelin)Chim ch noradrenalin trong cc ht lu tr v tr thnh cht trung gian ha hc gi. Khcreserpin l lc u guanetidin gy tng nh huyt p do lm gii phng nhanh noradrenalin radng t do, mt khc guanetidin khng thm c vo thn kinh trung ng nn khng c tcdng an thn.Tc dng ti a xut hin sau 2 - 3 ngy v mt i 6- 10 ngy sau khi ngng thuc.Khng dng cho ngi bnh c lot d dy, suy mch vnh, suy thn. Khng dng cng viclonidin.Liu lng: lc u ung 10 mg/ ngy, sau tng dn ti 50 - 75mg/ ngyCh phm: vin 10 v 20 mg1.1.3. Ngn cn gii phng catecholaminBretylium (Darentin)C ch cha tht r. c ch gii phng catecholamin, nhng khng nh hng n tc dng caadrenalin v noradrenalin ngoi lai. C th l bretylium lm cho mng cc ht lu tr gimtnh thm vi ion Ca++ m lm cho catecholamin khng c gii phng ra.C tc dng gy t ti ch.V c nhiu tc dng ph (nh xung huyt nim mc mi, kh th, a lng, h huyt p, nhcc) cho nn cn t c s dng lm sng.1.1.4. Thay th catecholamin bng cc cht trung gian ho hc giMt s cht khng c tc dng dc l, nhng chim ch ca catecholamin v cng c giiphng ra di xc tc kch thch dy giao cm nh mt cht trung gian ha hc, c gi l chttrung gian ha hc gi:- methyldopa to thnh methyl noradrenalin- Thuc c ch MAO: tyramin chuyn thnh octopamin- Guanetidin


1.2. Thuc hu adrenalinCc thuc phong ta tc dng trn receptor tng i c hiu hn thuc kch thch, ngha lnhiu thuc kch thch c tc dng c trn hai loi receptor v , cn thuc phong to thngch tc dng trn mt loi receptor m thi. Do thuc loi ny c chia thnh hai nhm:thuc hu v thuc hu adrenergic.1.2.1. Thuc hu - adrenergicV phong to cc receptor nn lm gim tc dng tng huyt p ca nor adrenalin, lm ongc tc dng tng p ca adrenalin. Khng c ch tc dng gin mch v tng nhp tim ca ccthuc cng giao cm v u l tc dng trn cc receptor . Hin tng o ngc tc dng tngp ca adrenalin c gii thch l cc mao m ch c c hai loi receptor v , adrenalin tcdng trn c hai loi receptor , nhng bnh thng, tc dng chim u th nn adrenalin lmtng huyt p. Khi dng thuc phong to , adrenalin ch cn gy c tc dng kch thch trncc receptor nn lm gin mch, h huyt p.Nhm thuc ny c ch nh trong cc cn tng huyt p, chn on u tu thng thn, iu trbnh Raynaud. Hin ang nghin cu thuc hu 1A iu tr ph i lnh tnh tuyn tin lit.Nhc im chung l d gy h huy t p khi ng, nhp tim nhanh, xung huyt nim mc mi,co ng t, bun nn, nn v tiu chy do tng nhu ng d dy - rut.Cc thuc ch khc nhau v cng tiu chy v thi gian tc dng.1.2.1.1. Nhm haloalkylamin:C phenoxybenzamin (dibenzylin) v diben amin.V ha hc, c cng thc gn ging nh m tc nit (nitrogen mustard). Khi vo c th, aminbc 3 c chuyn thnh etylen amoni, cht ny gn cht vo cc receptor theo lin kt cngha tr (ch yu l receptor 1), gy c ch rt mnh v ko d i (ti 24 gi cho mt ln dngthuc) theo kiu c ch mt chiu.Liu lng: phenoxybenzamin, vin nang 10 mg, ung 2 - 10 vin/ ngy1.2.1.2. Dn xut imidazolinC tolazolin (Priscol, Divascon) v phentolamin (Regitin)c ch tranh chp vi noradrenalin recepto r 1 v 2 nn tc dng yu v ngn hnphenoxybenzamin nhiu.Liu lng: Priscol ung hoc tim bp 25 - 50 mg/ ngy. Regitin ung 20 - 40 mg/ ngyCn dng chn on u tu thng thn: nghim php c coi l dng tnh nu ngi bnhngh ngi, hon ton yn tnh, tim bp hoc tim tnh mch 5 mg phentolamin, sau vi pht lmhuyt p ti a v ti thiu h khong 4 - 5 cmHg, duy tr c 7 pht ri tr li huyt p ban utrong 10- 15 pht.3.2.1.3. Prazosin (Minipress): cht in hnh phong to 1. Dng iu tr tng huyt p, ung 1 -20 mg mt ngy. (xin xem bi "Thuc cha tng huyt p")3.2.1.4. Alcaloid nhn indol:


Cc alcaloid ca nm ca g (ergot de seigle; Secale cornutum; Claviceps purpurea), c chiathnh hai nhm: loi hu giao cm v lm co bp t cung (gm ergotamin, ergotoxin) v loi lmco bp t cung n thun (ergometrin).Vi liu thp, ergotamin c tc dng cng giao cm nh v ngn cn thu hi noradrenalin ngn dy giao cm. Liu cao, tri li c tc dng phong to recepto r . Ngoi ra cn c tc dngtrc tip lm co c trn, nn c th lm co mch tng huyt p, hoc hoi t u chi v vch mitrong trng hp nhim c mn tnh do n la mch m mc, lm co tht rut, ph qun v tcung.Ch nh: ct cn migren, ri l on thi k mn kinh, chy mu t cung sau s rauDn xut hydro ha ca cc ergot (nh dihydroergotamin, hydroergotoxin) c tc dng phong to tng ln trong khi tc dng co c trn gim xung. Ngoi tc dng phong to receptor , tcdng h huyt p ca ergotamin cn c gii thch l lm gim trng lc trung tm vn mchv kch thch trung tm ph giao cm. Do c dng lm thuc gin mch, h huyt p: ung4- 6 mg/ ngy, hoc tim di da 0,1 - 0,5 mg/ ngy.Chng ch nh: c thai, ri lon m ch vnh- Yohimbin: l alcaloid ca Corynantheyo himbe c nhiu Chu Phi. Cu trc ha hc gnging reserpin, tranh chp vi NA ti receptor 2. D vo thn kinh trung ng. Tc dng yu vngn, nn t c dng trong iu tr.Trong lm sng cn dng lm thuc cng dng, v ngoi tc dng gin mch cn kch thchphn x tu.Liu lng: Yohimbin clorhydrat 5 - 15 mg/ ngy1.2.2. Thuc hu adrenergicCn gi l thuc "phong to " (" blocking agent") c tc dng c ch tranh chp viisoproterenol cc receptor. Cht u tin c tm ra l dicloisoproterenol (Powell v Slater,1958). c dng nhiu trong lm sng.1.2.2.1. Tc dng dc l: c 4 tc dng dc l chnh vi mc khc nhau gia cc thuc:* Kh nng hu giao cm : l tnh cht chung duy nht ca tt c cc thuc hu :- Trn tim: lm gim nhp tim (20 - 30%), gim lc co bp ca c tim, gim lu lng tim, gimcng nng v gim s dng oxy ca c tim, gim tc dn truyn ca t chc nt. Ch yu ldo hu 1.- Trn kh qun: lm co, d gy hen. Ch yu l do hu 2, gy tc dng khng mong mun.- Trn thn: lm gim tit renin, h huyt p trn ngi c HA cao- Trn chuyn ha: c ch hu glycogen v hu lipid+Tc dng lm n nh mng: ging quinidin, lm gim tnh thm ca mng t bo v i s traoi ion nn c tc dng chng lon nhp tim.+ C hot tnh ni ti kch thch receptor : mt s thuc phong to khi gn vo cc receptor li c tc dng kch thch mt phn. Hiu qu thc t t quan trng, nhng c th hn ch tcdng lm gim nhp tim, gim co bp c tim, gim co kh qun ca chnh n.


+ Tnh chn lc: nhiu thuc phong to i lp vi tt c cc tc dng cng giao cm ca (1: tim v 2: mch, kh qun). Nhng mt s thuc li ch phong to c mt trong hai loireceptor (1hoc 2), v th phn bit thnh cc loi phong to chn lc trn giao cm :- Loi tc dng chn lc trn 1 hay loi chn lc trn tim ("cardioselectifs"), nh practolol,acebutalol, atenolol. Thng dng metoprolol (Lopressor) v atenolol (T enormin)Li ch ca loi thuc ny l:- Do rt km tc dng trn 2 ca kh qun nn hn ch c tai bin co tht kh qun.- Km tc dng trn 2 ca thnh mch s c li cho iu tr cao huyt p (gim co mch ngoibin)- Do rt km tc dng trn 2 ca thnh mch vnh nn khng bc l tc dng cng -adrenergic (tc dng co mch vnh ca CA tun hon trong mu). Bnh thng, do c tc dng th tc dng ca b lu m. Khi b phong to th tc dng ca s c bc l ra.- Do khng nh hng n cc receptor trong hu glycogen nn khng lm nng thm tnh trngh ng huyt.- Loi c tc dng chn lc trn 2, ng u l Butoxamin, t c ngha trong lm sng.1.2.2.2. Ch nh chnh- Cn au tht ngc, ch yu do lm gim s dng oxy ca c tim . Trong nhi mu c tim, timtnh mch ngay t gi u s lm gim lan rng nhi mu v ci thin c tin lng bnh.- Lon nhp tim: nhp nhanh xoang, nhp nhanh trn tht, tim cng gip, cung ng nh donhim c digital.- Tng huyt p: do lm gim lu lng tim, gim sc cn ngoi bin, gim tit renin v gimgii phng noradrenalin (xin xem thm bi "Thuc cha tng huyt p")- Mt s ch nh khc; cng gip, migren, glocom gc m (do lm gim sn xut thu dch),run tay khng r nguyn nhn.1.2.2.3. Chng ch nh:- Suy tim l chng ch nh chnh v n c ch c ch b tr ca tim.- Bloc nh- tht v thuc c tc dng lm gim dn truyn ni ti trong c tim.- Hen ph qun. Loi c tc dng chn lc trn receptor 1 dng cho ngi hen t nguy him hn,nhng vi liu cao, trong iu tr tng huyt p th cng b mt tnh chn lc.- Khng dng cng vi insulin v cc sulfamid h ng huyt v c th gy h ng huyt tngt.- C thai: khng chng ch nh tuyt i, nhng gp tr mi b chm nhp tim, h nghuyt, suy h hp, thai chm pht trin.1.2.2.4. Cc tc dng khng mong munc chia lm hai loi:* Loi tai bin l hu qu ca s phong to receptor


- Tim: suy tim do lm yu co bp ca c tim, chm nhp tim, nh tht phn ly .- Mch: hi chng Raynaud, tm lnh u chi, i khp khing, (thng gp vi propranolol, do b phong to th s cng). Cc thuc chn lc trn 1 v c hot tnh kch thch ni ti th t taibin ny hn- Phi: cc thuc c tc dng hu 2 > 1 s gy co kh qun, kh th. Khng dng cho ngihen.- Thn kinh trung ng: mt mi, mt ng, hay ng m, o nh, trm cm, thng gp hn vicc thuc d tan trong m v d thm vo t bo thn kinh (propranolol, metoprolol), loi t tantrong m (atenolol, nadolol) t tai bin hn.- Chuyn ho: lm h ng huyt (cn thn trng vi ngi b i tho ng), tng triglyceridtrong mu.* Loi tai bin khng lin quan n tc dng phong to - Hi chng mt- da- tai: xut hin ring hoc phi hp vi cc tn thng ca mt (vim gicmc, vim cng mc), da (sn nga lng bn tay, bn chn, dy da), tai (ic v vim tai nng). gp vi practolol, iu tr trong 1 - 2 nm- Vim phc mc x cng: au cng bng phc mc c nhng mng dy do t chc x . Sau khingng thuc hoc iu tr bng corticoid s khi. Gp sau khi iu tr ko di trn 30 thng.- Trn thc nghim, gp ung th tuyn c, ung th v, lymphosarcom. Do cn theo di trnngi khi dng liu cao ko di.1.2.2.5. Tng tc thuc- Cc thuc gy cm ng cc enzym chuyn ha gan nh phenytoin, rifampin, phenobarbital,ht thuc l, s lm tng chuyn ha, gim tc dng ca thuc hu .- Cc mui nhm, cholestyramin lm gim hp thu- Cc thuc hu c tc dng hip ng vi thuc chn knh calci, cc thuc h huyt p- Indomethacin v cc thuc chng vim phi steroid lm gim tc dng h huyt p ca cc thuchu .1.2.2.6. Phn loi

Khng c tc dng "chn lctrn tim"

C tc dng "chn lc trn tim"

n nh mng Khng nnh mng

n nh mng Khng n nhmng

Khng cngni ti

Propranolol SotalolTimolol

EsmololAtenolol

C cng niti

AlprenololOxprenolol

Pindolol AcebutololMetoprololPractolol


S phn loi ny gip cho chn thuc trong iu tr. Th d bnh nhn c r i lon co tht phqun th nn dng loi c tc dng "chn lc trn tim"; bnh nhn c nhp tim chm th dng loi"c cng ni ti "1.2.2.7. Mt s thuc chnh* Propranolol (Inderal, Avlocardyl) L isopropyl aminonaphtyl oxypropranolol. C tc dng phong t o nh nhau trn c 1 v 2,khng c hot tnh ni ti kch thch. Tc dng:- Trn tim:lm gim tn s, gim lc co bp, gim lu lng tim ti 30%. c ch tim l do tcdng ring ca propranolol ngn cn calci nhp vo t bo c tim, gim nng cal ci trong tili ni bo.- Trn mch vnh: lm gim lu lng 10 - 30% do c ch gin mch. Lm gim tiu th oxy cac tim.- Trn huyt p: lm h huyt p r sau 48 gi dng thuc. Huyt p ti thiu gim nhiu.- Ngoi ra cn c tc dng chng lon n hp tim, gy t (do tc dng n nh mng) v an thn Ch nh:- Tng huyt p, lon nhp tim, nhp nhanh xoang, cung ng nh, nhp nhanh trn tht, bnhcng gip, suy mch vnh. Ung liu hng ngy 120- 160 mgVin 40 v 160 mg- Dng trong cp cu lon nhp tim do nhim c digital hay do thng tim, do t ng ni khqun.Tim tnh mch 5- 10 mg. ng 5 mgChng ch nh: ngoi chng ch nh chung, propranolol khng c dng cho ngi c thaihoc lot d dy ang tin trin.Thuc c d dng hp thu qua ng tiu ha do tan nhiu trong m. Gn vo protein huyttng ti 90- 95%, m ti a trong mu t c sau khi ung t 1 - 2 gi. Chuyn ha thnhhydroxy- 4- propranolol v acid naphtoxyl acetic rt nhanh ti gan nn ch khong 25% liu ungvo c vng tun hon, t/2: 3 - 5 gi.Vin 40 mg. Ung trung bnh 2 - 4 vin / ngy, chia lm nhiu lnng 1 mL= 1 mg. Dng cp cu, tim tnh mch rt chm, t 1 - 5 mg/ ngy* Pindolol (Visken);C tc dng cng ni ti v khng nh hng n vn chuyn ca ion Ca++ nn lm tng lcco bp v tn s ca tim. Thng dng trong cc trng hp c lon nhp chm vi liu ung 5 -30 mg/ ngy. Tan va trong m, sinh kh dng 75% v t/2 = 3 - 4 gi.* Oxprenolol (Trasicor):


Dng iu tr cao huyt p, cn au tht ngc, lon nhp tim. Ung 160 - 240 mg/ ngy.* Atenolol (Tenormin): Tc dng chn lc trn 1- rt tan trong nc nn t thm vo thn kinhtrung ng, sinh kh dng 50%, t/2 = 5 - 8 gi. Ung 50- 100 mg/ ngy.* Metoprolol (Lopressor). C tc dng chn lc trn tim (1) nn gy cn hen ph qun (2).Ung 50- 150 mg/ ngy. Hp thu nhanh qua ng ung, sinh kh dng 40% v t/2 = 3 - 4 gi.

cu hi t lng gi

1. Trnh by sinh chuyn ha ca catecholamin ti ngn dy giao cm.2. Trnh by s phn loi cc receptor ca h giao cm: v tr, p ng v cht ch vn.3. Phn tch, so snh tc dng v p dng iu tr ca adrenalin, noradrenalin v

dopamin.4. Phn bit tc dng ca thuc cng 1 v 2 giao cm.5. Trnh by c ch tc dng, tc dng v p dng lm sng ca isoproterenol,

dobutamin v albuterol (Salbutamol, Ventolin).6. Phn tch c ch ca cc thuc hu giao cm.7. Trnh by c im tc dng v p dng iu tr ca thuc hu giao cm, nu 2

thuc th d.8. Trnh by tc dng dc l v p dng lm sng ca thuc hu .

Trnh by cc tc dng khng mong mun ca thuc hu .

Bai 06 - Thuoc Tac Dung Tren He Adrenergic [Bacsihoasung.wordpress.com]

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