Transcript Aspirin

Chapter 6
Antipyretic Analgesics
&
Nonsteroidal Anti-inflammatory
Agents
Pei YU
Rm. 623, College of Pharmacy
1
Key Word:
Antipyretic Analgesics(解热止痛剂)
 Nonsteroidal (非类固醇类的，非甾体类)
 Anti-inflammatory（抗炎的）

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Background informations
Antipyretic action
Can induce a drop in temperature in feverish conditions.
Analgesic action
Some antipyretics were noted to be excellent analgesics for
the relieve of minor aches and pains, and even survived to
the present time on the basis of the analgetic, rather than
the antipyretic.
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Background informations
Anti-inflammatory
Fever is an outward symptom of inflammation.
These drugs also used extensively in the
symptomatic treatment (对症治疗) of rheumatic
fever (风湿热), rheumatoid arthritis (类风湿性关节炎
RA), and osteoarthritis (骨关节炎 OA).
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Two comparisons

Analgesic effect in comparison with the
morphine-type compounds
Two principal
features:

Low activity for a given dose
Lack of addiction potential
Anti-inflammatory effect in comparison with
the corticosteroids(皮质激素)
Long-term therapy with the corticosteroids often
accompanied by various side effects.
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Section 1
Antipyretic Analgesics
6
Request and Purpose
To master Aspirin and Paracetamol:





structure
chemical name
physico-chemical property
metablism in vivo
clinical application
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Mechanism of action
 Inhitbit the biosynthesis of prostaglandine(前列腺素)in
several tissues such as hypothalamus(下丘脑).
In vitro, all inhibit
the prostaglandine
epoxidase
The effects of relieving fever and
pain parallel their relative
potency to inhibit the epoxidase
 The search for specific inhibitors of cyclooxygenase
(环氧合酶) has opened a new area of research in this
field.
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COX-1 and COX-2
Non-steroidal antiinflammatory drugs
(NSAIDs 非甾体抗炎药) act by inhibiting the
biosynthesis of prostaglandins(PGs) from
arachidonic acid (AA 花生四烯酸).
Two enzymes catalyze the first step in
biosynthesis of PGs, cyclooxygenase 1
and 2 (COX-1 and COX-2).
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COX-1 and COX-2
Although COX-1 and COX-2 catalyze the same biochemical
reaction, they are distinctly in terms of amino acid content,
tissue distribution, and physiological function.
COX-1 is a constitutive enzyme and plays a role in the
production of essential prostaglandins.
COX-2 level is normal lower, it is induced in response to the
release of several proinflammatory mediators. It become
elevated at sites of inflammation.
Leading to the inflammatory response and pain
The selective COX-2 inhibitor emerged from this effort.
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Classification
HO
O
O
Chemical
structure
O
Salicylic acids
O
HO
Anilines
N
H
More toxic
O
Pyrazolones
N
O
N
OH
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Development
B.C. 5 century, chewing willow bark can relieve pain.
In 1838, Salicylic Acid firstly isolated.
In 1860, Kolbe firstly synthesize Salicylic Acid.
In 1875, sodium salicylate clinically used as
antipyretic analgesics.
In 1886, phenol salicylate went on the market.
In 1899, aspirin introduced into medicine,
although it’s first prepared in 1853.
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Salicylic acid
O
OH
OH
Salicylic acid
Salicylic acid is no longer used as an oral medicine
since it is very irritating to the stomach and can cause
serious gastrointestinal bleeding.
13
Derivatives of salicylic acid

Type I:
Modifying the carboxyl group (salts, esters, or
amides).
Hydrolysis takes place in the intestine.

Type II:
Substitution on the hydroxyl group.
Absorbed unchanged into the bloodstream.
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Derivatives of salicylic acid
O
O
O
O
¡¤1/2 M g2
OH
Magnesium
salicylate
O
NH 2
OH
N
OH
OH
Choline Salicylate
O
Salicyamide
O
O
OH
NH 2
O
OH
OH
OH
O
O
Ethoxy
Benzamide
F
Salsalate
F
Diflunisal
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Aspirin
Aspirin—Acetylsalicylic acid
It is more potent, less irritating.
Aspirin is named by taking “a” from acetyl
and adding it to “spirin”. An old name for
salicylic or spiric acid, derived from its
natural source of spirea plants(绣线菊类).
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Development of Aspirin




Widely used during the flu epidemic in Europe in
1917-1918 because it effectively lowers dangerously
high fevers.
By the 1950s aspirin became by far the most widely
used painkiller globally.
Subsequent research indicated that aspirin inhibits
blood clotting at low dosages (80-90mg per day)
Annual production of aspirin is in excess of 40,000
tons worldwide now.
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Physico-chemical property
of Aspirin
HO
Nomenclature:
Acetylsalicylic acid;
2-Acetoxy benzoic acid;
(Aspro, Empirin)
O
O
O
White crystal or white crystalline power
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Physico-chemical property
of Aspirin
Slightly soluble in water (1:300).
 Soluble in alcohol, chloroform and
ether.
 In the presence of moisture air, it is
easy to decompositon and oxidation.

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Physico-chemical property
of Aspirin
 Its solution boiled and showed a violet color on the
addition of ferric chloride solution.
Hydrolyzed to form salicylic acid
 When an aqueous solution of aspirin and sodium
hydroxide is boiling, salicylic acid (white) will be
crystallized out after being acidified.
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Physico-chemical property
of Aspirin
O
O
OH
O
HO
O
OH
O
O
O
O
OH
+
OH
O
OH
O
OH
O
OH
OH
O
O
O
HO
HO
OH
or
O
O
OH
Aspirin hydrolyzes into salicylic acid.
yellow
O
HO
HO
O
O
OH
Blue or brown-black
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Metabolic Pathway of Aspirin



OH
OH
OH
N
H
Glycin
O
O
OH
OH
Salicylglycine
Salicylic acid
Aspirin
O



HO
OH
OGluc
Glucuronide
OGluc
OH
OH
OH
Glucuronide
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Pharmacologic action
 Irreversible inhibition of cyclooxygenase, and used as
an antipyretic, analgesic, and antirheumatic
In clinic widely used for common cold, headache, neuralgia(神经痛),
arthralgia(关节痛), acute and chronic rheumatalgia(风湿痛), etc.
 Inhibit the synthesis of thromboxane A2(血栓素
TXA2), and used as prophylaxis(预防)of heart attack
and thrombotic(血栓)strokes in a low-dosage form.
 Also prophylaxis of colon carcinoma(结肠癌).
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Side effects of Aspirin
Gastric mucosa (胃粘膜) injury, even gastric
and duodenal hemorrhage (十二指肠出血).
The free carboxyl acid.
To make its salt and derivatives.
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Aspirin Derivates
O
O
O
O
O
¡¤ A lOH2+
O
O
2
O
O
O
H3N
NH 3
Aspirin-Lysine
O
O
O
¡¤2Ca2 ¡¤H2N
2
Carbasalate Calcium
N
H
O
NH3
NH2
O
O
O
Benorilate
H
N
O
OH
F
O
Aspirin-Arginine
O
O
O
NH
O
O
Aluminium Acetyl salicylate
O
O
H3N
O
O
O
Flufenisal
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Initiation of
supersensitivity
Impurity test
O
O
O
OH
O
O
O
＜0.003%
+
O
O
O
O

O
O
+
O
O
O
O
O
O
O
O
O
Precipitate
from
Na2CO3
+
OH
O
O
O
O
O

OH
O
O
O
O
+
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Aspirin
 Dry dosage form such as
tablets, capsules, or powders
should be used, since aspirin is
somewhat unstable in aqueous
media.
 All salts of aspirin, except those of aluminum
and calcium, are unstable for pharmaceutical use.
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Synthesis of Aspirin
Decompose
HO
 pKa for acetylsalicylic
acid is 3.5 at 25ºC.
O
OH
+
CH3COOH
Vinegar smell
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Paracetamol
O
HO
N
H
(对乙酰氨基酚)
 N -(4-Hydroxyphenyl)
acetamide;
 Acetaminophen;
 N-Acetal-p-aminophenol;
 4-Hydroxyacetanilide;
 APAP
It is Aniline and p-Aminophenol derivative.
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Synthesis of Paracetamol
Method 1
O
HO
NO2
Fe,HCl
HO
NH2
AcOH
HO
NH
It is stable in the air.
When pH6, it is most stable. T1/2=21.8 year (25ºC)
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Synthesis of Paracetamol
Method 2
Paracetamol
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Development
NH
Antifebrin(Acetanilide)
O
Ferrihemoglobin(高铁血红蛋白)and jaundice(黄疸)
O
NH
Hydroxyl etherification, get Phenacetin
O
APC Renal toxicity(肾毒性), gastric cancer(胃癌)and retina(视网膜)toxicity
O
In 1893, Paracetamol launch
HO
N
H
Found: It is the metabolite of
Phenacetin and Acetanilide after 50 years.
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Physico-chemical property
of Paracetamol





White, odorless, slightly bitter crystalline powder.
Slightly soluble in water, and ether; soluble in
boiling water, acetone, alcohol and sodium
hydroxide.
Formation of a violet color on the addition of
ferric chloride solution.
Mix its diluted HCl solution with sodium nitrite,
then react with -naphthol, present red color.
Hydrolyzed to form primary amine.
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Metabolic Pathway
of Paracetamol
Glu
O
HO
O
S
O
O
O O
N
H
N
H
adults
O
HO
N
H
O
O
O
N
H
Acetanilide
N
H
Paracetamol
HO
childre
n
O
N
OH
Ferrihemoglobin and hepatotoxicity
Phenacetin
O
NH2
Ferrihemoglobin
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HO
O
N
OH
Ferrihemoglobin and hepatotoxicity
O
O
Toxicity metabolite
N
N-Acetylethylenimine quinone
acetylcysteine
HO
O
HO
S
NH
O
GSH
orgatein
O
N
O
SG
HO
O
O
N
N
kidney
Hepatonecrosis,
renal failure
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Metabolism
Paracetamol is metabolised primarily in the liver, into nontoxic products. Three metabolic pathways :

Glucuronidation is believed to account for 40% to 2/3 of the
metabolism.

Sulfation may account for 20–40%.

N-hydroxylation and rearrangement, then GSH
conjugation, accounts for less than 15%.

All three pathways yield final products that are inactive, nontoxic, and eventually excreted by the kidneys.

In the third pathway, the intermediate product NAPQI is toxic.
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Usage of Paracetamol :






Has analgesic and antipyretic activities(releving
fever and pain).
It isn’t anti-inflammatory, different with Aspirin.
Exerts its effects by inhibiting the cyclooxygenase
enzyme centrally but has very little effect
peripherally.
It is considered safer.
Not to exceed the recommended dosages.
Risk of liver toxicity in chronic alcoholics.
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Paracetamol in Clinic



Chinese: 扑热息痛
Is available in several nonprescription
forms (that is OTC).
Is marketed in combination with aspirin
and caffeine. (APC)
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Paracetamol in Clinic




Paracetamol is available in a tablet, capsule, liquid
suspension, suppository（栓剂）, intravenous, and
intramuscular form.
The common adult dose is 500 mg to 1000 mg.
The recommended maximum daily dose, for
adults, is 4 grams.
In recommended doses, paracetamol generally is
safe for children and infants, as well as for adults.
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Summary
HO
O
HO
OH
O
O
O
H
N
O
HO
Salicylic acid
Aspirin
Paracetamol
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