HOA DC

MUC TIEUTrnh bay c Phng hng va trien vong phat trien HD Cau truc hoa hoc, lien quan CT va TD cac thuoc ieu che, kiem nghiem cac thuoc thong thng Tnh chat ly hoa, s dung cac thuoc tr benhieu che va nghien cu cac chat lam thuoc Kiem nghiem va tieu chuan hoa thuoc mi Hng dan s dung thuoc Nhiem vu

CHNG TRNH HOA DC I (LY THUYET)Chng 1. HOA DC AI CNGChng 2. KHANG SINHChng 3. THUOC KHANG KY SINH TRUNGChng 4. THUOC SAT KHUANChng 5. THUOC GIAI OCChng 6. DC PHAM PHONG XAChng 7. THUOC KHANG UNG THChng 8. THUOC CAN QUANG

CHNG TRNH HOA DC II (LY THUYET)Chng 9. THUOC TAC ONG TREN HE TIM MACH Chng 10. THUOC T LEN MAU VA HE TAO MAU Chng 11. VITAMIN VA KHOANG CHATChng 12. THUOC TAC ONG TREN HE TIEU HOA Chng 13. THUOC TAC ONG TREN HE TKTWChng 14. THUOC T LEN QUA TRNH DAN TRUYEN TKChng 15. THUOC TAC ONG TREN HE MIEN DCHChng 16. THUOC TAC ONG TREN HE HO HAP Chng 17. HORMON VA THUOC CHNH RL HORMON

CHNG TRNH HOA DC III (THC HANH)ieu che mot so thuoc thong thngKiem nghiem cac thuoc /C c theo DKiem nghiem mot so hoa dc khac theo D

HOC PHAN BO SUNGChuyen e t chon cho lp D5 On tap cac hoc phan LT I va II Hoa my pham : cac chat s dung /cosmeticsKhoa luan tot nghiep cho D5 va CT4

HOA DC & CAC MON HOC KHACLa mon hoc nghiep vu DcCac mon c s cua HDHoa ly, Hoa phan tch, Hoa VC, Hoa HCVi sinh, Ky sinh, Sinh hoa, Benh hocLa mon cot loi (theo phan loai cua Bo GDTLa mon c s cua

Bao cheKiem nghiem

LCH S PHAT TRIEN HOA DC THE GII Thi trung co : la cac nha hoa hoc The ky VII-XII : cac nha luyen an (Alchimist) : muoi Hg, As TK XV-XVI : Paraxels xdng hoc thuyet Y Hoa hoc TK XVII XVIII : Hoa hoc phat trien kha manh TK IXX : thong thng ong Tay, chiet xuat, xac nh CT cac hp chat, NC lien quan CT-TD, TH cac chat thay the.

Cac alkaloid TH cac chat giam au, gay ngu va gay te

CAC PHAT MINH HOA DC BAN AU TK IXX

Ten alcaloidNam phat minhTen ngi phat minhNam xac nh cau trucNamtong hpLoai thuoc tm ra t mau alcaloid thien nhienMorphin 1803-1804Ch.Derosne va Seguin19251952Thuoc giam au gay nguQuinin1820 Pelletier& Caventou19071945Thuoc chong sot ret -ha sotCafein 1820 Runge Robique. Pelletier & Caventou18831895Thuoc kch thch than kinh trung ngCocain 1862 Whler18981923Thuoc gay tePilocarpin1875 Gerard Hardy19031933Thuoc cng oi giao cam

PHAT TRIEN HOA DC TOC O NHANHThuoc : nhu cau cua i songNguyen lieu phong phu : hoa dau, than, dc lieuTien bo nhanh trong TH hoa hocCong nghe len men nhieu tien boCong nghe sinh hoc phan tTrang thiet b nhieu oi mi va thanh tuLi nhuan cao DC : NGANH KINHTE-KY THUAT

NGUON NGUYEN LIEU HOA DC Khoang san Nc ot : cac muoi vo c, iod Rong bien Cat Quang moong vat Phu tang : pancreatin, insulin, thyroxin, heparin, mat Sinh vat bien : prostaglandin, toxin

NGUON NGUYEN LIEU HOA DC Thc vatNguon dc lieu phong phu Alcaloid : morphin, cafein, papaverin, atropin Camphor, tinh dau. Terpen khac : artemisininHoa chat Than Go Kh ot Cracking dau mo.

HOA DC VIET NAMTrc 1945 : nhap t Phap1945-1954 : san xuat cac thuoc thiet yeu cho chien tranhSau 1954 : sx them cac muoi vo cHien nay : sx n gian, 1 so NL t dc lieu Cha c au t San xuat nho, lo. Trung Quoc, An o ??? Chnh phu a chu trong (2007) Chng trnh Hoa Dc

PHNG HNGVA TRIEN VONG NC THUOC CHA BENH- Ly thuyet va thc nghiem.- Moi lien quan gia cau truc va cac ac tnh ly hoa.- Moi lien quan gia CT-hoat tnh dc.QSARs : thap nien 80

KHAO SAT SAN PHAM

DC ONG HOC1- Hap thung uong, chch, tai cho, di li, qua da, hau monKS khong hap thu : ch TD tai cho (nystatin, strepto...)2- Phan boMuc ch : en ung o benh- Lincomycin : xng, khp (# tetracyclin)- Roxithromycin : tuyen tien liet (# quinolone)

3- Chuyen hoaa phan gan : lien hp, red-ox- Mot so ch TD sau chuyen hoa : ftalazol, ester erythro- Mot so chat manh hn : OH-nalidixic > 16 lan Cac chat chuyen hoa : TD cua thuoc Chloramphenicol : tang chuyen hoa rifampicin Ketoconazole : tang chuyen hoa thuoc nga thai

Cac chat chuyen hoa : TD cua thuoc Macrolid va nam ca ga Imipenem va cilastatin

4- ao thaing ao thai : ng dung tr lieu va oc tnh- ng tieu : cac quinolon, mot so cephalosporin cac aminoside. Chu y cac KS oc tnh vi than- ng gan mat : rifampicin, lincomycin, macrolid Chu y oc tnh va cac thuoc co chu trnh RUOT-GAN- Tai mui hong : rovamycinepH nc tieu :Acid se de tai hap thu KS acid va thai KS kiemKiem se de tai hap thu KS kiem va thai KS acid

CAC THONG SO DC ONG HOC C BAN1- The tch phan bo (VD, L/kg) Thuoc tan / m nhieu : VD nho (cac azole khang nam) Thuoc tan / nc nhieu : VD ln (cac KS chch)Tr so VD thng c cho san vi moi thuocc khao sat tren ngi bnh thng, khoe manhVD =Tong lng thuoc a vao c the[C] thuoc / huyet tngDose = [C] x VD

2- He so thanh thai (Cl, ml/min) La o thanh loc, bieu th kha nang cua mot c quan (gan hay than) loc thuoc ra khoi huyet tng Tren thc te ngi ta quan tam en ClCr cua BN

Phai giam lieu (=1/2 tren BN suy than) Chon thuoc thai qua gan cho BN suy than Chon thuoc thai qua than cho BN suy gan Ngi BT : ClCr # 60- 120ml/min/1,72m2 BN suy than : ClCr < 30ml/min

3- Dien tch di ng cong (AUC, mg.h.ml-1, g.h.ml-1)La lng thuoc trong mau con hoat tnh sau 1 TGTnh AUC :Thc nghiem : nh lng theo tng thi gian ve ng cong va tnh toan da vao phan mem co san

Cong thc : F : tr so sinh kha dung cua thuoc F = 1 trong trng hp IV Thong thng F < 1

SINH KHA DUNG (BIOAVAILABILITY)SKD tuyet oi : la t le gia SKD ng uong va IV V du : amoxicillin co SKD tuyet oi = 85%SKD tng oi : la t le gia SKD ng uong cac thuoc V du : paracetamol do VN sx so vi Panadol(R)anh gia SKD : Th nghiem giai phong hoat chat (dissolution test) Th nghiem in vivo

4- Thi gian ban huy (T1/2) Co lien quan en so lan lap lai dung thuoc trong ngay CS-S # 5 x T1/2 (bai xuat = phan bo) Thi gian bai xuat hoan toan # 7 x T1/2 BN benh ly : Cl giam --> keo dai T1/2 Cac thuoc the he sau thng co T1/2 dai Can s dung lieu cao hn e at CS-S nhanh

Thi gian tren MIC (%) (Time over MIC)Thi gian ton tai cua thuoc ma nong o con ln hn MICY ngha : so lan dung thuoc trong ngayV du : Augmentine bidAp dung bid khi thuoc co TOMIC > 40%

TNG TAC THUOC - THUOC, THUOC - THC AN, UONGCo nhieu tng tac : vat ly, hoa hoc, dc ly...Cac tng tac co the : tang TD, giam TD, tang oc tnh...Cac antacid : thng lam giam hap thu thuocCac vitamin co kim loai : thng hay tao phcSa thng cha Ca lng lnNc rau, hoa qua co cha tanin va cac chat khac Uong thuoc nhieu nc loc Chu y cac thuoc b thc an can tr hap thu

CAU TRUC HOAT TNHPhan t co TD sinh hoc : khung PT va nhom chc (quyet nh kieu TD sinh hoc)Nhom chc : nhom tac dung (quyet nh TD) va nhom anh hng (TC ly hoa DH thay oi) nh hng cho cac nha nghien cu

NHOM MANG HOAT TNHN = 2 hay 3X = O, N, OH, OCO, ether oxyd, goc cha noNhieu HC co TD co chung nhom chc tren

StrychninAtropin

CocainQuininAdrenalinHistamina ng dung TH cac thuoc SR, te, tam than, antiH1

Ban chat cac goc co mang nhom hoat tnhHoat tnh sinh hoc phu thuoc vao goc co gan nhom HTCo TD tng ho nhau TD tong the cua phan tArtemisinin (Sot ret)Ascaridol (Tr giun)

Co mach Dan machThay oi goc gan co TD ao ngcTram camHng phan

KCH THC CUA PHAN TCinchocainTD gay te max khi la goc C4H9R = -CH2CH2N(CH3)2 : khang H1R = -CH2CH2N(C2H5)2 : anti-parkinsonR = -(CH2)2CH2N(CH3)2 : an thanNhan phenothiazin

KHOANG CACH GIA CAC NHOM HOAT ONG14,5 CURARISANT Khoang cach gia cac nhom tao k cho tng tac vi thu the tot hn am bao s mem deo hay cng nhacCac thuoc te, thuoc khang histamin, khang tiet cholin

V TR CAC NHOM HOAT ONGong phan v tr cung anh hng en TD sinh hocCh nhom OH orto co TD khang laoAcid Nicotinic (vit. PP)Acid isonicotinic INH(khang lao)Khong khang lao

HNH THE PHAN T (CAU TRUC LAP THE) Cac chat oi quang (Enantiomers) : co Carbon bat oi C*ong phan quang hoc (Optical isomers) Co cung tnh chat ly hoa (TOnc, TO soi, d, ch so khuc xa Quay phai hay quay trai mat phang anh sang phan cc TD sinh hoc khac nhauCac ong phan (-) thng co hoat tnh cao hn (+)VD : (-) Hyoscyamin > 40 lan (+) hyoscyamin (+) Chloramphenicol khong co TD khang sinh Cac acid amin, levothyroxinNgoai le : 1 so chat (-) va (+) co TD nh nhau : camphor

X> 17 lanLipidAnionLipidAnionR(-) Epinephrin : 3 iem ganS (+) : 2 iem gan

HNH THE PHAN T (CAU TRUC LAP THE) Cac chat ko oi quang : ()Co cac ac tnh ly hoa nh nhauCau hnh dang S hay R toc o phan ng khac nhau1R,2S Ephedrinc che thu the va 1R,2R - EphedrinCh c che thu the

HNH THE PHAN T (CAU TRUC LAP THE)ong phan hnh hoc (Geometrical Isomers = P cis-trans)Co cung CTPT, dang cis (Z) va trans (E) co TD SH khac nhauDang trans ben hn dang cis

Trans (E)Cis (Z)Terpin

HNH THE PHAN T (CAU TRUC LAP THE)ong phan cau dangCis (e,e)Betaprodin Trans (a,e)Alphaprodin

NHOM THE VA CAC NHOM CHCCac hp chat hydrocarbon cha no Co hoat tnh manh hn, phan ng hoa hoc tot hn HC no VD : cac acid beo cha noCac hp chat gan them halogen Tang hoat tnh, cng o, oc tnh Cai thien TC Dc ong hoc TD sinh hoc thay oiCac hp chat co cha Oxygen OH alcol lam tang hoat tnh (gay ngu bac I < II < III) NHieu nhom OH v ngot OH phenol tang hoat tnh

NHOM THE VA CAC NHOM CHCAldehyd, ceton, carboxyl Aldehyd co kha nang phan ng cao Carboxyl lam tang tnh tan, thay oi pH anh hng en TC dc ong cua thuoc co nhom acidNitrogen Anh hng en tnh Red-Ox Thng co trong cac thuoc than kinh, diet KST, amib Ester nitr va nitric : gian mach (trinitroglycerin)

NHOM THE VA CAC NHOM CHCNhom aminoTang oc tnh cua phan tAmin I : kch thch he TKTWAmin II : hoat tnh cao hn amin IIIAmin IV : chuyen sang TD phong be hach than kinh.Goc alkylGan vao HC oc (cyanid, arsenic) lam oc tnhNhom C2H5 TD tot hn nhom CH3 tren he TKTWAlkyl hoa cac nhom chc thay oi tnh chat ly-hoaSo C trong alkyl anh hng en TC vat ly ah hap thuTD tang dan en 6 C.

NHOM THE VA CAC NHOM CHCNhom thiol SHDe lien ket va phan ng hoa hoc (Red-Ox, lien hp)ng dung lam thuoc giai oc, khang khoi uBALThioguanin5- FU

NHOM THE VA CAC NHOM CHCThay oi cac nhom gan vao nhan benzenThem alkyl vao benzol : tang oc tnh, alkyl cang dai oc tnh2 goc alkyl oc tnh, TD manh v tr orto va para Halogen lam tang oc tnhAldehyd thm va ceton thm oc tnh cao hn benzolCarboxyl lam giam oc tnh benzolAmin gan vao tang oc tnh nhng co TD ha nhiet, giam au

TNH CHAT LY HOA VA HOAT TNH SINH HOCo hoa tan Carboxyl Hydroxyl Aldehyd Ceton Amin Amid Imid (cac goc a nc) va Methyl Methylen Ethyl Propyl Alkyl Phenyl (cac goc k nc).pH moi trng anh hng en tnh chat dc ong cua thuocAnh hng en khuech tan, phan phoi, tham thauo hoa tan giam dan theo cac nhom sau :Tnh acid-kiemAnh hng en s hap thu, thai tr cua thuoc

TNH CHAT LY HOA VA HOAT TNH SINH HOCKhoi lng phan tHydrocarbon khi tang M th giam oc tnhCac polymer tuy thuoc M ma TC ly-hoa thay oi

Sc cang be matAnh hng en o bam dnh cua cac phan tCac thuoc sat trung (savon , amoni IV)

PHNG PHAP NGHIEN CU MOI LIEN QUAN NH LNG GIA CAU TRUC-TAC DUNG Cau truc-tnh chat (Structure-Property Relationships = SPR)Tnh chat-tac dung (Property-Activity Relationships = PAR)Cau truc-tac dung (Structure-Activity Relationships = SAR)Tong cac moi lien quan tren : QSARs

MUC CH NGHIEN CU Tang cng hieu lc cua thuoc : cac KS, cac thuoc NSAIDs Giam thieu TD phu : drotaverin la cai tien cua papaverin Bien TD phu thanh TD chnh : morphin, loperamid Tm cac chat oi khang, giai oc : nalorphin, naloxon vs morphin Thay oi tnh chat ly-hoa cua thuoc n gian hoa cau truc e de dang tong hp : cocain cac T. te

CAC HNG NC BIEN OI CAU TRUCTH cac chat co cau truc tng t

Cau truc chung cua cac barbituric X = O: Cac barbituric X = S: Cac thiobarbituricDCI (Biet dc)R1R2R3XTac dungBarbital(Veronal)-C2H5-C2H5HOChat mau tac dung an than, gay nguPhenobarbital(Gardenal)-C2H5HOThem tac dung chong co giatMephobarbital(Prominal)-C2H5-CH3OTac dung chong co giat manh hnButobarbital(Soneryl)-C2H5-C4H9HOAn than, gay ngu, giam auPentobarbital(Nembutal)-C2H5HOAn than, gay ngu, tien meThiopental(Penthotal)-C2H5HS30 60phGay me ngan (TM)

Cau truc chung cua cac penicilin

DCIRBien oi tac dungNguyen mauPenicilin-GC6H5-CH2 -Pho khang khuan hepB dch v pha huy, B S.A.* e khangPeniclin-VBen vi aciduong cChat bien oiMethicilinNhay cam vi S.A.*(Staphylococcus aureus = Tu cau) a e khang penicilinAmpicilinHoat pho rong, uong c, hap thu tot qua ng tieu hoa

CAC HNG NC BIEN OI CAU TRUCTH cac chat co cau truc thu gon hay m rong

Chat mau AtropinCac thuoc co cau truc c thu gon hoac m rong

Ester tropinic cua acid tropic8-Isopropylnor-atropin methobromid (Them mot nhom isopropyl)Ester tropinic cua acid mandelic (Bt mot nhom CH2 -)Giam co that c trnGiam tiet cua cac tuyen Dan ong t keo daiGiam co that c trn, tac dung chon loc tren kh phe quanDan ong t ngan hn atropine

CAC HNG NC BIEN OI CAU TRUCThe cac nhom ong the tch ien (Isoteres)The cac nhom ong the tch ien sinh hoc (Bioisoteres)

Thay the cac nhom ong ang hoa hocTong hp cac tien hoat chat

Xem chng thiet ke thuocPhenacetin paracetamolCarbimazol MethimazolTerfenadin Fexofenadin6-APA va 7-ACA

CAC HNG NC BIEN OI CAU TRUCDa tren cac thu the sinh hoc (receptor)R cholinergic: muscarinic va nicotinicR adrenergic: -adrenergic (1 va 2) va -adrenergic (1 va 2)R histaminic: H1 va H2.R serotoninergic: S1 va S2.R morphin (thu the )R dopaminR prostaglandinR GABA (gamma-aminobutyric acid)

CAC HNG NC BIEN OI CAU TRUCDa tren cac chat c che enzymThuoc Chat chuyen hoa mat tac dungEnzymCyt.P450c che enzym Keo dai TD cua thuoc Angiotensin converting enzym (ACE) : cac thuoc ha huyet ap c che beta-lactamase : tang TD cac KS betalactamin c che cholinesterase (prostigmin) : acetylcholin ben la thuoc tr tang nhan ap, nhc c, teo c Allopurinol c che xanthin oxydase : purin ko uric (Goutte)

CAC HNG NC BIEN OI CAU TRUCS dung cac phng trnh va mo hnh toan hocLog 1/C = - K12 + K2 +K3 + K4Es + K5Phng trnh Hansch

Mo hnh toan hoc Free-WilsonRB = Log 1/C = aij xi + Co nhieu ng dung trong thc tea TH nhieu phan t thuoc co TD sinh hoc

QUA TRNH NGHIEN CU TAO THUOC MIThc nghiem co nh hng

Morphin nhan morphinan xng song TD thuoc Quinin cac thuoc tr sot ret nhan quinolin Cocain cac thuoc teTong hp sang loc ket luanMat thi gian, ton kem (10.000 chat c 1 chat) THIET KE THUOC

QUA TRNH NGHIEN CU TAO THUOC MIThiet ke thuocDa tren nghien cu QSARsHo tr bang may tnhRut ngan thi gian nghien cu hn

CAC GIAI OAN NC A THUOC RA TH TRNG1- Tien lam sangNC tong hp hoa hocSang loc dc ly

Lap ho s xin th lam sangTnh an toan trc mat va lau daiTD dc ly chnh va phu : in vitro, in vivo, in situ, ngiDc ong hoc

Cac ho s ky thuat (giai oan tren)D kien chng trnh nghien cu tren ngi

CAC GIAI OAN NC A THUOC RA TH TRNG2- Lam sangGiai oan 1 : 20-50 volunteersGiai oan 2 : 50-100 benh nhanGiai oan 3 : so ong benh nhanGiai oan 4 : theo doi ADR sau khi thuoc a ra th trngTrc giai oan 4XD tieu chuan chat lng, NC o on nh, tap phan huySX th, xay dng qui trnh ky thuatNop n xin phep san xuat va lu hanh (NDA)ieu tra nhu cau th trng, pub, marketing

NOI DUNG KHAO SAT MOT SAN PHAMnh ngha : co cau truc xac nh, a tinh khiet dc dung1- Ten khoa hoc : IUPAC2- Ten thong dung (goc) : ten rieng VN, ten theo DCI 3- Ten thng mai (ten biet dc) : nhan hieu hang hoa , kieu dang

TEN CHUNG CHUANLOAI THUOCV DU THUOC-bamatThuoc an than nhom carbamatMeprobamat-cillinKhang sinh nhom A.6APAmpicillin-cyclinKhang sinh nhom tetracyclinDoxycyclin-quinD/c quinoleinCloroquinSulfa-Cac sulfamid khang khuanSulfadoxinCeph- hay Cef-Khang sinh nhom cephalosporinCephalexin

NOI DUNG KHAO SAT MOT SAN PHAMCong thc CT cau tao phang (thang, vong) CT khong gian (lap the) CT phan t (CT tho)PP ieu cheTnh chat ly-hoaKiem nghiem nh tnh Th tinh khiet nh lng

NOI DUNG KHAO SAT MOT SAN PHAMCong dung Cach dungTac dung (dc ly)Thong so DHCh nhTD phuoc tnh, tai bienChong ch nhTng tac thuocLieu lngDang bao cheBao quano on nh Tuoi tho - Han dung