HORMON TUYEN THNG THAN VA CAC CORTICOID

-1855: Thomas Addition: mo ta benh lien quan en vo

thng than
- 1927: Dch chiet tuyen thng than tiem IV co kha nang
lam cho cho cat bo tuyen thng than song sot.
- 1935-1950: Kendall, Wintersteiner, Reichstein ly trch
c 46 chat ket tinh, 9 chat duy tr c s song, trong
o co desoxycorticosteron va cortison.
-1949: phat hien tac ong viem khp cua cortison
(Henche).
- 1950: tng hp hydrocortison c tc ng tt hn cortison.
Reichstein, Kendall, Henche: NOBEL y hoc va sinh ly 1950
HORMON TUYEN THNG THAN VA CAC CORTICOID
-1953: Simpson va cong s; Reichstein va cong s ly trch
c aldosteron.
-1955 tr i: hn 400 glucocorticoid BTH mi ra i.
- 1969: hng nghien cu nham thay oi tnh chat ly hoa.
HORMON TUYEN THNG THAN VA CAC CORTICOID
S lc ve tuyen thng than
- Tuy : tiet adrenalin
- Vo : tiet hormon steroid
* vo ngoai : tiet mineralocorticoid
* vo gia : tiet glucocorticoid
* vo trong : tiet androgen, mot t estron va progesteron
CORTICOSTEROID = MINERALOCORTICOID + GLUCOCORTICOID
(CORTICOID)
Corticoid
- Cau truc
A B
C
D
CH
3
CH
2
O
HO
C
CH
2
OH
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
perhydro cyclopentan phenantren
= steran = gonan
pregnan
corticoid
C3, C10, C13, C17
Nhom the , nhom the
A/B trans hoac cis
B/C ; C/D: trans
Carbon bt i ?
Can cho hoat tnh
CH
3
CH
3
R
H
A
B
C
D
10
11 13
17
Corticoid
- Phan loai
* Theo chc nang
Mineralocorticoid : desoxycorticosteron
Glucocorticoid : cortison, hydrocortison
* Theo cau truc hoa hoc
desoxycorticosteron corticosteron
cortisol =
hydrocortison
O
C
HOH
2
C
O
11
17
O
C
HOH
2
C
O
HO
O
C
HOH
2
C
O
HO
OH
Desoxy-11 steroid
Oxy-11 steroid Dioxy-11, 17 steroid
Corticoid
- Sinh tong hp
HO
O
pregnenolon
HO
O
O
OH
O
progesteron
17-hydroxypregnenolon
O
OH
O
17-hydroxyprogesteron
O
O
HO
21-hydroxyprogesteron
O
OH
O
HO
11-desoxycortisol
O
OH
O
HO
HO
cortisol
O
O
HO
HO
corticosteron
O
O
HO
OH
OHC
b
c, d
c,d
e
e
f
f
g
b :17 hydroxylase
c: 5-en-3 hydroxysteroid dehydrogenase
d:3-oxosteroid-4,5-isomerase
e: 21-hydroxylase
f: 11 hydroxylase
g: 18 hydroxylase
HO
cholesterol
aldosteron
Corticoid
- Nguon t nhien
T 500kg tuyen thng than bo, co lap c:
- 400 mg corticosteron
- 400 mg dehydrocorticosteron
- 100 mg cortisol
- 100 mg cortison
- 15 mg desoxy-11 corticosteron
- 30 mg aldosteron
cortisol
HOH
2
C
O
O
OH
HO
Corticoid
- Tong hp va ban tong hp
OH
HO
acid desoxycholic
COOH
CO
O
O
11
CH
2
OH
OH
cortison
26 giai oa n
HO
O
O
diosgenin
HO
stigmasterol
O
progesteron
5 giai oan
4 giai oan
O
8 giai oan
HO
O
O
O
hecogenin
19 giai oa n
HO
sitosterol
C
2
H
5
Corticoid- Ban tong hp
1948; Kendall thu c
1kg cortison/630kg acid
desoxycholic
HO
ergosterol
17 G
1000kg men bia
thu c
3-4kg ergosterol
Corticoid
- Ban tong hp desoxycorticosteron
COOH
HO
acid hydroxy-3-etiocholenic
Stigmasterol
HO
HOH
2
C
O
COOH
SOCl
2
COCl
CH
2
N
2
O N
N
O CH
2
OCOCH
3
CH
3
COOH
O
CH
2
OH
H
2
O
Corticoid
- Ban tong hp desoxycorticosteron
phan ng oxy hoa Oppenauer.
1937 (Reichstein,
Kendall, Hench)
CH
2
OH
O
HO
O
CH
2
OH
O
desoxycorticosteron
( t - BuO)
3
Al
Aceton, Benzen, t
o
Corticoid
- Ban tong hp hydrocortison acetat
cortison acetate
O
O OH
O
COOCH
3
11
hydrocortison acetate
O
OH
O
COOCH
3
11
HO
ba o ve carbonyl
v tr 3 va 20 O OH
AcOH
2
C
O
O
11
O
O
(dag cetal vo ng)
NaBH
4
OH
AcOH
2
C
O
O
11
O
O
HO
pho ng thch carbonyl
v tr 3 va 20
Ban tong hp cortisol t progesteron
Corticoid
BTH davao vi sinh vat
O
C
H
3
C
O
progesteron
O
C
HOH
2
C
O
HO
cortisol
OH
Ophiobolus
herpoticus
O
C
HOH
2
C
O
desoxycorticosteron
O
C
HOH
2
C
O
HO
corticosteron
Curvularia
lanata
Trichothecium
roseum
Corticoid
BTH davao vi sinh vat
- Ban tong hp prednisolon
CH
2
OH
O
HO
OH
O
H
H
H
hydrocortison
CH
2
OH
O
HO
OH
O
H
H
H
prednisolon
Corynebacterium simplex
Corticoid
BTH da vao vi sinh vat
HO
sitosterol
C
2
H
5
Khung 17C
HO
Mycobacteriym
Anthrobacter
Brevibacterium
Nocardia
(gia ng hoa)
Corticoid - Tnh chat
Vng A
O
Nhm enone ph uv 239-244 nm
O
Nhm dienone ph uv 238 nm
HO
O
OH
O
CH
2
OH
A
B
C D
Corticoid - Tnh chat
* Phan ng do nhom C=O C
3
: phan ng vi hydrazid
cho hydrazon c mu
O
+
N
C
O
HN NH
2
N HN
C
O
N
(^ max 380 nm)
O
+
N
C
O
HN NH
2
N HN
C
O
N
(^ max 405 nm)
( Phn ng Umberger)
Vng A
HO
O
OH
O
CH
2
OH
A
B
C D
Corticoid - Tnh chat
Vng B
HO
O
OH
O
CH
2
OH
9
6
F
F
F
Ox
(acid chromosulphuric)
F
Corticoid - Tnh chat
Vng C
HO
O
OH
O
CH
2
OH
C
* Phan ng vi acid sulfuric am ac (halochromie hoac halofluorie)
Corticoid - Tnh chat
* Phan ng do nhom alcol bac nhat C21
C O
CH
2
OH
RCOOH
CH
2
OCOR
O C
C O
CH
2
OH
HOOCCH
2
CH
2
COOH
CH
2
OCOCH
2
CH
2
COOH
O C
Vng D
C
CH
2
OH
+ H
3
PO
4
O
O C
CH
2
O
P
ONa
ONa
NaOH
O
Corticoid - Tnh chat
* Phan ng do nhom alcol bac nhat C21
* Chc ancol t do: cho van uc vi thuoc th periodo-bac.
Ancol c ester ha :
ester
hydroxylamin
acid hydroxamic
Fe
3+
/ H
+
phuc mau
Vng D
Corticoid - Tnh chat
* Day -cetol C17 cho tnh kh manh
- Vi AgNO
3
/amonac cho tua xam Ag
- Vi dung dch Fehling un nong cho tua Cu
2
O o gach
- Vi muoi tetrazolium trong moi trng kiem cho mau o
C
N
N
N
N
+
Cl
-
[H]
[O]
C
N
N
N
N
H
tetrazolium formazan
C
O
HOH
2
C
[O]
C
O
HO
Vng D
C
H
O
H
2
C
OH
H
OH
HC
OH
N
N N
N
C
6
H
5
Cl
hv
N
N N
N
C
6
H
5
Cl
NH
N
C
6
H
5
N
N
^ max = 485 nm
H
O
C
O
H
OH
H
C
O
O
OH

Corticoid - Tnh chat
* Phan ng Porter-Silber : cho mau vang am (^max 410 - 420 nm)
Vng D
C
O
H
2
C
OH
H
C
HC
O
H
OH
H
C
OHC
OH
H
H
C
OHC
H
H
O
- H
2
O
+ H
2
N-NH
C
O
HC
N NH
H
C
O
HC
N NH C
6
H
5
H
C
N N C
6
H
5
H
OH
Corticoid - Tnh chat
* Nhom OH-17
Hat tnh ti ch gia tng
O
HOH
2
C
O
HO
F
CH
3
betamethason valerat
O
C
2
H
5
OCOH
2
C
O
HO
F
CH
3
betamethason dipropionat
OCO(CH
2
)
3
CH
3
OCOC
2
H
5
Vng D
HO
O
OH
O
CH
2
OH
A
B
C D
2- Corticoid
- Kiem nghiem
nh tnh
- Pho IR
- Phan ng vi H
2
SO
4
am ac
- Cac phan ng mau khac
- Sac ky lp mong
Kiem tinh khiet
- Nang suat quay cc
- Tap lien quan
nh lng
- Phng phap quang pho UV
O
HOH
2
C
O
HO
F H
OH
H
9 - fluoro hydrocortison
9
O
HOH
2
C
O
H
OH
1
2
HO
CH
3
F
dexamethason
Dexamethasone
Action and use
Corticosteroid.
Preparations
Dexamethasone and Neomycin Ear Spray
Dexamethasone Tablets
Dexamethasone
A. Dissolve 10.0 mg in ethanol R and dilute to 100.0 ml with the
same solvent. Place 2.0 ml of the solution in a stoppered test
tube, add 10.0 ml of phenylhydrazine-sulphuric acid solution R,
mix and heat in a water-bath at 60 C for 20 min. Cool
immediately. The absorbance (2.2.25) of the solution at the
maximum at 419 nm is not less than 0.4.
B. Examine by infrared absorption spectrophotometry
(2.2.24), comparing with the spectrum obtained with
dexamethasone CRS.
C. Examine by thin-layer chromatography (2.2.27),
D. Add about 2 mg to 2 ml of sulphuric acid R and shake to dissolve. Within 5
min, a faint reddish-brown colour develops. Add the solution to 10 ml of water R
and mix. The colour is discharged.
TESTS
Specific optical rotation (2.2.7)
Dissolve 0.250 g in dioxan R and dilute to 25.0 ml with the same solvent. The
specific optical rotation is + 75 to + 80, calculated with reference to the dried
substance.
Related substances
Examine by liquid chromatography (2.2.29).
ASSAY
Dissolve 0.100 g in alcohol R and dilute to 100.0 ml with the same solvent.
Dilute 2.0 ml of the solution to 100.0 ml with alcohol R. Measure the
absorbance (2.2.25) at the maximum at 238.5 nm.
Calculate the content of C
22
H
29
FO
5
taking the specific absorbance to be 394.
Mineralocorticoid
O
HO
CHO
CO
CH
2
OH
CH
OH
CO
CH
2
OH
O
O
Aldosteron
- tac ong mineralocorticoid 25 lan manh hn
desoxycorticosteron acetat
- IM, IV dang natri succinat
Cau truc:
-vi H
2
SO
4
: xanh lam am
vi huynh quang o.
- s dung dang acetat (IM)
- dang pivalat dung trong thu y
HOH
2
C
O
O
desoxycorticosteron
Angiotensinogen
Angiotensin I
Angiotensin II
Renin
men chuyen
VO THNG THAN
TO CHC CAN
CAU THAN
Aldosteron (gi muoi va nc)
Tang the tch
dch ngoai bao
Tang ap suat
ong mach than
_
Mineralocorticoid
S ieu hoa bai tiet
Mineralocorticoid
* Tac dung cua cac mineralocorticoid
- gi Na
+
, bai tiet K
+
- gi nc
* /tr suy thng than (benh Addition) nguyen phat
hoac th phat.
corticosteron
aldosteron
O
HO
CO
CH
2
OH
O
HO
CO
CH
2
OH
OHC
[O]
Glucocorticoid
Glucocorticoid thien nhien:
Cortison 21 acetat: tiem (tac dung keo dai)
Cortisol 21-(3-cyclopentyl propionat)
Hydrocortison natri succinat
HOH
2
C
O
O
desoxycorticosteron
cortisol (1951)
HOH
2
C
O
O
OH
HO
HOH
2
C
O
O
OH
O
cortison (1948)
Corticoid
- C che kiem soat s tiet corticoid
Di oi
CRF (Corticotropin releasing factor)
Tuyen yen
ACTH
Thng than
CORTICOID
_
_
+
+
Receptor noi bao_ glucocorticoid
Thanh lap cac enzym
Thay oi hoat ong te bao
Corticoid
- C che tac dung
Receptor noi bao_ glucocorticoid
Lipocortin
c che phospholipase A2
Ngng thanh lap prostaglandin, leukotrien...
Khang viem
Corticoid
- C che tac dung
Glucocorticoid
Glucocorticoid thien nhien
- Tac ong sinh ly cua hydrocortison
* ieu hoa chuyen hoa carbohydrat
* Tren chuyen hoa protein: tang d hoa protein
* Tren chuyen hoa chat beo: phan bo lai m trong c the
* Tren chuyen hoa nc va chat ien giai: tang gi nc va Na
+
;
tang thai tr Ca
++
* Tren than kinh: gay kch thch
* Tren mau va he lympho: tang hong cau, bach cau, tieu cau
* c che s tao nguyen bao si va thanh collagen vet thng
* Tren he tieu hoa: lam tang tiet dch v va pepsin
* c che tong hp prostaglandin: tac ong khang viem.
* Khang d ng, c che mien dch
Glucocorticoid ban tong hp
Ch nh
* Thieu nang thng than tien phat hoac th phat (benh Addition).
* Benh ve khp: viem khp do thap khp
* Benh than: viem cau than. Hoi chng than nhiem m.
* Roi loan collagen: viem da, ong mach ket hon.
* Benh d ng: me ay, viem mui d ng, cac dang ban da.
* Benh ve ho hap: hen phe quan, viem phoi
* Benh ve da: benh vay nen.
* Benh ng tieu hoa: viem loet ruot ket, viem hoi trang cuoi.
* Benh ung th: u lympho bao, non do chieu xa khi ieu tr ung th
* Benh gan: viem gan man tien trien, viem gan do ru.
* Cac benh khac: soc do nhiem khuan, tang calci mau, ghep c quan.
Glucocorticoid ban tong hp
Tac dung phu
* Xop xng
* Nhiem khuan
* Loet da day
* Hien tng c che truc: di oi-tuyen yen-thng than
* S tha corticoid va benh Cushing
Cac tai bien thng gap khi s dung corticoid tai cho
vi thi gian dai:
* Teo, x cng b
* Da san sui, bien oi mau da tai cho
* Boi nhiem nam, vi khuan
* Cham lien seo
* Glaucome, uc thuy tinh the
Glucocorticoid
Glucocorticoid ban tong hp
HO
O
OH
O
CH
2
OH
9
6
16
21
17
1 - 2
2 - 3
CORTISOL
Glucocorticoid
Glucocorticoid ban tong hp
HO
O
OH
O
CH
2
OH
CORTISOL
ester
CH
2
Cl
CH
2
SH
ester
loai OH
OH-

CH
3
-

acetonid
cyclopentonid
butanonid
F-

Cl-
F-

CH
3
-

pyrazol
oxazol
Glucocorticoid
Glucocorticoid BTH- Non-Delta 1-glucocorticoid
-fludrocortison (fluoro- 9 cortisol)
* GC: 10x/cortisol
* MC: 125x/cortisol
- Fludrocortison (vien)
- Fludrocortion acetat (vien)
- dung tai cho (da, mat, tai)
-9 F, 9 Cl, 9 Br tang s gi Na+ va nc vi hoat tnh F >Cl >Br (t le nghch
vi kch thc halogen)
O
HOH
2
C
O
HO
F H
OH
H
9 - fluoro hydrocortison
9
Glucocorticoid
Glucocorticoid BTH- Delta 1-glucocorticoid
Prednison = delta cortison; Prednisolon = delta hydrocortison
(GC 4-5 x / cortisol)
Prednison:
Vien nen: 1, 5, 20mg
Prednisolon (vien nen 5mg)
acetat (hon dch tiem 25-125mg)
metasulfo-benzoat natri (vien nen 5-20mg, dung
dch uong 1mg)
Prednisolon phosphat dinatri (nho mat 0,25%, nho mui 0,25%)
-17 OH giam tac ong mineralocorticoid tng ng
vi noi oi v tr 1-2.
O
HOH
2
C
O
H H
OH
1
2
O
prednison
O
HOH
2
C
O
HO
H H
OH
1
2
prednisolon
Glucocorticoid
Glucocorticoid BTH- Delta 1-glucocorticoid
-Methyl-6 prednisolon: methyl prednisolon (1956)
(GC: 4-5 x / cortisol)
- Methyl prednisolon: vien nen 4-16mg
- acetat: hon dch tiem 40mg
- hemisuccinat: bot pha tiem 20-40-125-500mg
s 6-methyl hoa se lam cham
s chuyen hoa cua vong A
O
HOH
2
C
O
H
OH
1
2
HO
methyl prednisolon
CH
3
Glucocorticoid
Glucocorticoid BTH- Delta 1-glucocorticoid
- Fluoro-9-hydroxy-16-prednisolon: triamcinolon (GC: 5-10 x /cortisol)
-triamcinolon (vien nen 1 mg, 2 mg, 4 mg, 8 mg)
-triamcinolon acetonid-16,17 (hon dch tiem 40-80mg)
-triamcinolon acetat (bnh xt mieng 100 mcg/1lan xt)
-triamcinolon diacetat 16,17 (hon dch tiem 50mg)
-triamcinolon acetonid 16,17-21-terbutyl acetat (hon dch tiem 40mg)
- triamcinolon 16,17-cyclopentanon acetal, 21-acetat (kem, pomade 0,1%).
- Gay ao thai natri
(dung cho nhng ngi
cao H.A).
-T/ manh hn
prednisolon (#20%),
tng t methylpred.
- Gay chan an, yeu c,
buon non, ngay ngat.
O
HOH
2
C
O
H
OH
1
2
HO
OH
F
triamcinolon
O
HOH
2
C
O
H
O
1
2
HO
O
F
triamcinolon acetonid
- Fluoro-9 -methyl-16- prednisolon: dexamethason (25-30 x/cortisol)
-dexamethason (vien nen 0,5mg)
-dexamethason acetat (vien nen 0,5mg; hon dch tiem 5-15 mg)
-dexamethason isonicotinat (aerosol 0,125mg/lieu)
- dexamethason phosphat natri (dung dch tiem 4-20mg).
Cac nha NC hy vong, nhom 16-
ben hoa chuoi -ketol trong
qua trnh chuyen hoa in vivo
O
HOH
2
C
O
H
OH
1
2
HO
CH
3
F
dexamethason
Glucocorticoid
Glucocorticoid BTH- Delta 1-glucocorticoid
Glucocorticoid
Glucocorticoid BTH- Delta 1-glucocorticoid
- Fluoro-9-methyl-16 prednisolon: bethamethason (25-30 x/cortisol)
- betamethason (vien nen 0,5-1mg; dung dch uong 0,05%).
- betamethason phosphat dinatri (vien nen 0,5mg; ong tiem 4mg;
- betamethason 17-valerat (kem, pomade, lotion 0,05%).
- betamethason 17,21-dipropionat (kem, pomade, lotion 0,1%).
O
HOH
2
C
O
H
OH
1
2
HO
F
CH
3
betamethason
- Fluoro- 6- methyl -16 prednisolon: paramethason (5-10 x/cortisol)
Paramethason acetat
(hon dch tiem 40mg)
- paramethason gay mat nhe natri vi t hoac khong mat kali
Glucocorticoid
Glucocorticoid BTH- Delta 1-glucocorticoid
O
HOH
2
C
O
H
OH
1
2
HO
CH
3
F
paramethason
O
HOH
2
C
O
H
OH
1
2
HO
CH
3
F
dexamethason
Glucocorticoid
Glucocorticoid BTH- Delta 1-glucocorticoid
- Cloro-9-methyl-16 prednisolon: beclomethason
Beclomethason 17, 21-dipropionat (hon dch bm hong 50-250g)
Khong tac dung toan than lieu ieu tr.
Co tac dung tai cho tren phoi (dung e tr hen suyen).
O
HOH
2
C
O
H
OH
1
2
HO
F
CH
3
betamethason
O
O
HO
Cl
CH
3
OH
HO
beclomethason
O
C
2
H
5
OCOH
2
C
O
HO
Cl
CH
3
beclomethason dipropionat
OCOC
2
H
5
Glucocorticoid
Glucocorticoid BTH- Delta 1-glucocorticoid
- Difluoro-6,9-hyfroxy-16-prednisolon: fluocinolon
- Fluocinolon acetonid-16,17: kem, pomade, dung dch dung tai cho
- Fluocinolon acetonid-16,17, acetat-21: pomade, lotion
HO
CH
2
OH
O
F
F
O
OH
OH
fluocinolon
HO
CH
2
OH
O
F
F
O
fluocinolon acetonid
O
O
O
HOH
2
C
O
H
OH
1
2
HO
OH
F
triamcinolon
Glucocorticoid
Glucocorticoid BTH- Delta 1-glucocorticoid
- Fluoro-9-methyl-16-clobetasol-cloro-21-prednisolon: clobetasol
Clobetasol-17-propionat: kem, gel 0.05%
Tac dung khang viem cua clobetasol manh, c s dung tai cho.
O
O
H
OH
1
2
HO
F
CH
3
Cl
clobetasol
O
HOH
2
C
O
H
OH
1
2
HO
CH
3
F
paramethason
Glucocorticoid
Glucocorticoid BTH cu trc c bit
Cortivasol (tc ng 60 x/cortisol)
Cortivasol-21-acetat: hon dch tiem 3,75mg
(khp hoac quanh khp)
O
H
OH HO
OAc
CH
3
CH
3
N
N
(11,16)-21-(Acetyloxy)-11,17-dihydroxy-
6,16-dimethyl-2'-phenyl-2'H-pregna-2,4,6-
trieno[3,2-c]pyrazol-20-one
Glucocorticoid
Glucocorticoid BTH cu trc c bit
Deflazacort
Deflazacort acetat (vien)
Tac ong khang viem (tng ng prednisolon) va c che mien dch.
Dung dang uong e tr hen suyen.
O
H
HO
OAc
O
O
N
deflazacort
(11,16)-21-(acetyloxy)-11-
hydroxy-2-methyl-5H-pregna-1,4-
dieno[17,16-d]oxazole-3,20-dione
HO
O
OH
O
CH
2
OH
C=O CH-OH
activity
OH-
CH
3
-
CH
3
-
MC
9F hay F
GC
MC
GC
MC
GC
MC
Glucocorticoid
Glucocorticoid BTH Quan h cu trc Hat tnh
Hien tng c che truc di oi tuyen yen- thng than
Glucocorticoid ban tong hp
Tng tac thuoc
- Barbituric, rifampicin, phenytoin lam tang chuyen hoa
glucocorticoid
- Tac ong corticosteroid gia tang ngi ang s dung estrogen
hay thuoc nga thai.
- Glucocorticoid tang ng huyet.
- Dung chung vi digoxin co the gay loan nhp.
- Khong dung chung corticoid vi vi vaccin v tac dung c che mien
dch.