Analgesics - antipyretics
= „weak“ analgesics = non-opioid analgesics
Most of them also ••non-steroidal anti-inflamatory drugs (NSAIDs) antirheumatics
Oldřich Farsa 2011
Metabolism of eicosanoids
O
Oarachidonic
acid
O
H2
=
- C O
- R1
OH
OH
R2
- R2
- O
CH3
C O P O
H2
O
N+ CH3
CH3 glucocorticoids
inhibitors of
phspholipase A2
prostaglandins sythesis = = "weak"
COOH
analgesics +
lipoxygenase inhibitors
+ NSAIDs
arachidonic acid
cyclooxygenases (COX1 + COX2)
lipoxygenase
OOH
COOH
O
O
COOH
5-hydroperoxy-6-trans-8,11,14-cis-eikosatetraenoic acid
PG G2
OOH
(5-HPETE)
cyklooxygenases
prostacyklin synthase
PG I2 = prostacyklin
endothelium cells
tromboxan synthase
PG H2
TX A2
LT A4 isomerases
trombocytes
PG D2
PG E2
LT C4
LT B4
PG F2
α
all the cells
LT D4 LT E4
Effects of prostaglandins
Prostaglandin E, F2α : ache, fewer, inflammation, sekretion of HCl↓, stomach mucosa capilaries dilatation, contraction of uterus, kidneys: excretion of Na+ and H2O ↑
Prostacyclin (prostaglandin I ): vasodilatation, platelets aggregation inhibition
2
Tromboxan: vasokonstriction, platelets aggregation activation Leukotriens: alergic reactions (e.g. asthma bronchiale)
Cyklooxygenases (= prostaglandin G/H synthases)
COX1
Constitutive: in all the tissues Functions: •••protection of stomach mucosa (vasodilatation) diuresis platelets aggregation (TXA)
COX2
Philipp Needlemann inventor of COX isoenzymes
Constitutive: kidneys, brain (co-localized with cyclins D1 and E) Inducible: macrophages, neutrophfils, fibroblasts, endothelium cells Functions:
(1989)
vasodilatation (PG I )
•••
2
porod (děložní stahy) childbirth (uterus contractions) inflammation processes COX3 ?? (= COX1b; brain ?)
Classification of COX inhibitors
(antipyretics, NSAIDs)
Non-selective (COX1 + COX2)
••••Anilides Salicylates Phenamates Aryl- and heteroaryl alkanoic acids
•Aryl- and heteroaryl acetic acids
- •
- Aryl- and heteroaryl propionic acids
•••Oxicames 1,2-Dihydropyrazolidine-3-ones 2,5-Pyrazolidinediones
Selective (COX1<COX2): nimesulide Specific (COX2)
•
Coxibes
Anilides
- HN
- O
- HN
- O
- HN
- O
O
OH
paracetamol acetaminophen
4-(acetylamino)phenol
phenacetin
N-(4-ethoxyphenyl)acetamide
acetanilide
- (
- )
N-phenylacetamide
nephrotoxicity
Dinyl® - analg.
1886: Antifebrin®
para-(acetylamino)phenol p-(acetylamino)phenol
Paralen , Panadol …. mixture with caffeine, aminophenazone and barbiturates
Paracetamol
•
inhibits COX only in CNS (COX3 ?) not in periphery ⇒
•effects: analgesic, antipyretic (not antiinflamatory,
antirheumatic)
Použití ve směsích s(e) Usage in mixtures with •codeine, caffeine ⇒ effect enhancement (Korylan tbl.®,
- HN
- O
Panadol tbl.®, Efferalgan codein tbl. eff.®) •••expectorants (guajfenesin, terpin) antitussives (dextromethorphan) H -antihistaminines (pheniramine, chlorphenamine,
OH
1
dimenhydrinate, promethazin, doxylamin) together with α-sympatomimetics (phenylefrine, pseudoephedrine)
•••spasmolytics (pitophenon) myorelaxants (chlorzoxan, carisoprodol) NSAID (acetylsalicylic acid, propyphenazon – Valetol®)
Metabolism of paracetamol
Ourine
O
O
O
2% urine
S
HO
HO
O
OH
O
- O
- 42 %
- 52 %
urine conjugation conjugation
- HO
- OH
- N
- O
- N
- O
N
O
CH3
paracetamol sulfate
CH3
CH3
paracetamol glucuronide
4 % cytochrome
P-450
RS
R-SH
(glutahione,
N-acetylcysteine)
OH N
ON
R-SH = glutathion ⇒
⇒ merkapturic acid
- O
- O
- CH3
- CH3
- N-acetyl-p-benzoquinoneimine
- urine
N-(4-oxocyclohexa-2,5-diene-1-ylidene)acetamide
NAPQI
HEPATOTOXIC
Thiols detoxicating N-acetyl-p-benzoquinoneimine
γ − Glu-Cys-Gly
HS
O
H
O
O
- HO
- N
H
O
- N
- N
- H
- H
- OH
glutathione
SH O
OH
- H3C
- N
H
O
N-acetyl-L-cysteine
mucolytic
ACC®, Mucobene®
Synthesis of paracetamol
OH
OH
Sn
CH3COOH
Morse, Chem. Ber. 11, 232 (1878)
- HN
- O
NO2
CH3
OH
O
NO2
H3C
2-nitrophenol
OH
OH
O
OH
OH
H3C
- HNO3
- O
Fe, HCl
- HN
- O
NO2
NH2
CH3
4-(acetylamino)phenol phenol
4-nitrophenol
4-aminophenol
Propacetamol – paracetamol prodrug
•for intravenous application
O
Cl
+ H
N
O
- HN
- O
CH3
4-(acetylamino)phenyl-N,N-diethylglycinate hydrochloride
2-[4-(acetylamino)phenoxy]-N,N-diethyl-2-oxoethaneaminium chloride
propacetamol hydrochloreid
Pro-Dafalgan® (UPSA Laboratoires)
O
N
O
H
O
Oesterase
H2O
N
+
HO
- HN
- O
- HN
- O
CH3
CH3
Salicylates
OOO
H3C H3C
HO HO
- O
- OH
- O
- OH
HO
O
hydrolýza oxidace
- O
- CH3
O
OH
O
- HO
- OH
salicylic acid
2-hydroxybenzoová kys. salicin
acetylosalicylic acid
2-acetoxybenzoic acid
(2-hydroxymethylphenyl)-
β
-D-glucopyranoside
1838 Piria: the first synthesis since 1878 used as antipyretic and antirheumatic
1827 Leroux: isolation from willow
1897 Felix Hoffmann - industrial synthesis
1899 – Aspirin® (Bayer)
- Felix Hoffmann
- Sir John R. Vane
Effects of acetylosalicylic acid
„Wanted“:
- O
- OH
•••••antipyretic
- O
- CH3
analgesic
O
anti-inflamatory antirheumatic
®
antithrombotic (↓ platelets aggregation) – Anopyrin
„Unwanted“:
- •
- ulcerogenic
•Rey syndrom in childern after viral infection
(hepatopathy, encefalopathy) ⇒ contra-indication in childern
•bleeding (e.g. from nose - ↓ platelets aggregation) Intoxication = „salicylism“ – infliction of CNS (psychical malfunctios, buzz in ears, dizzines, deafness), methabolic acidosis
Mechanis of action of acetylosalicylic acid (ASA)
•irreversible inhibition od cyclooxygenases by acetylation of serine rest
Ser
- HO
- O
O
- O
- CH3
- H3C
- O
+
OH
COX
+
- O
- O
COX
NH2
O
NH2
- HO
- O
OH
+
- O
- OH
O
- O
- CH3
Metabolism of ASA
proceeds in liver
HO HO
O
OH
O
O
••
O
ASA
all metabolits are excreted
t1/2= 15 min.
- HO
- OH
by urine
O1-salicyoylglucuronic acid
5 %
- O
- OH
OH
- glucuronation
- CH3COOH
+
O
OH
O
HO
HO salicylic acid.
10 %
Oconjugation with Gly
O
O
OH
O
NH
HO
OH
OH hydroxylation
O1-(2-carboxyphenyl)glucuronic acid
10 % salicyluric acid
(N-salicyoylglycine)
- 75 %
- O
- OH
OH
HO gentisic acid
< 1 %
Syntheses of ASA
- O
- OH
OH
- O
- OH
O
Gerhardt, Justus Liebigs Ann. Chem. 87, 164 (1853) Gilm, Justus Liebigs Ann. Chem. 112, 181 (1859) Kraut, Justus Liebigs Ann. Chem. 150, 10 (1869)
- O
- O
- H3C
Cl
CH3
O
H3C
H3C
- O
- OH
OH
OO
- O
- OH
- O
- O
Felix Hoffmann
CH3
Other salicylates
CH3
CH3
CH3
O
O
- O
- O
O
O
F
O
- O
- O
- O
- O
- O
- O
- Al
- Al
- Al
OH
O
O
- O
- O
- O
- O
F
OH
- O
- O
- O
O
CH3
CH3
2',4'-difluoro-4-hydroxy-1,1'-biphenyl-3-carboxylic acid pentakis(acetylosalicyoyloxy)trialuminium dioxide
- aloxiprin
- diflunisal
- Superpyrin®
- Unisal® tbl.
Anthranilic acid derivatives – phenamates
= substition derivatives of 2-phenylaminobenzooic acid derived from salicylates by substitution of hydroxy group with
•
(phenyl)amino moiety
OH
O
R3
HN
R1
R2
••••aromatic amino acids substituted on the aniline ring only inhibit both COX1 and COX2 (selectivity?; COX3?) analgesics, antipyretics, antimigrenics, anti-inflammatory
Phenamates
OH
O
R3
HN
R1
R2
- R1
- R2
- R3 Chemica name
- INN / preparation
2-(2,3-dimethylphenylamino)- benzoic acid
-CH3 -CH3 -H
mephenamic acid
2-(2,6-dichloro-3- methylphenylamino)benzoic acid
-Cl -CH3 -Cl -CH3 -Cl -H
meclophenamic acid
2-(3-chloro-2- methylphenylamino)benzoic acid
tolphenamic acid
Migea rapid®
2-(3-trifluoromethylphenylamino)benzoic acid
- -H
- -CF3 -H
fluphenamic acid
Tolphenamic acid
Synthesis
K+
OH
N
O
- O
- O
NH2
H
N
CH3 Cl
Br
O
+
1.(CH3COO)2Cu, DMF 2. H+
H3C
Cl
Kaltenbronn J.S. et al., Arzneim. Forsch 33, 621-627 (1983)
Selectivity against COXs
IC (COX1)
50
IC (COX 2) =
10
50
Grossmann C. J. et al., Inflammation Res. 44, 253-257 (1995)
Niflumic acid and its esters
F
F
- F
- F
F
F
H
N
HN
C
N
O
O
OH
OH
2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid
fluphenamic acid
niflumic acid
•isosteric substitution benzene ⇒ pyridine, or –CH= ⇒
-N=
••inhibit both COX1 and COX2 anti-inflamatory, antirheumatics; usually topically administered
Niflumic acid and its esters
•
esters are prodrugs which can better penetrate through the skin
R
2-{ [(3-trifluormethyl)phenyl]amino}nicotinic acid
H
niflumic acid
Niflugel®, Nifluril®
F
F
F
-||- 2-(morpholine-4-yl)ethylester
HN
N
morniflumate
N
O
O
O R
-||- 1-oxo-2-(3H)-benzofurane-3-ylester
talniflumate
OO
Aryl- and heteroarylalkanoic acids
Structure-activity relationships (SAR)
•the aliphatic part of the molecule is more specific for the effect
than the aromatic one
O
ARY >
O
- ARY
- O
- O
- ARY
O
=
=
>
OH
ARY
OH
ARY
OH
- H3C
- OH
OH
ARY = aryl, heteroaryl
Aryl- and heteroarylacetic acids and their functional
derivatives
O
H2C
R
Y
R = aryl or heteroaryl
Y = OH, NHOH, NHR, OCH2COOH, or other
•••antirheumatics, anti-inflamatory, analgesics, antipyretics inhibition of both COX1 and COX2 adverse effects (AE) like in salicylates Aryl- and heteroarylacetic acids and their functional derivatives
O
(fenacs)
H3C
O
O R
O
- Cl
- Cl
NH
Cl
N
CH3
- O
- O
R
R = H
R = H
{2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid
[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid
diclofenac indomethacin
••
•
- used since 1975
- used since 1963
- now mainly topically
- Voltaren®, Veral®, Myogit®,
Dicloreum®
Indobene® cps, Bonidon® gel,
Elmetacin® spr
R= OCH2COOH
{2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid carboxymethylester
R = OCH2COOH
[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid caboxymethylester
aceclofenac acemetacin
Heteroarylacetic acids and their derivatives
O O
HN O
N
O
- O
- O
- N
- N
- CH3
- O
H3C N
O
- H3C
- CH3
Cl
proglumetacin
Cl
Cl
N
N
N
S
OH
OH
O
O
[3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-yl]acetic acid [4-(4-chlorophenyl)-2-phenyl-1,3-thiazole-5-yl]acetic acid
- fentiazac
- lonazolac
•
isosteres
Aryl- a heteroarylacetic acids
CH3 N
CH3
O
O
