part 13 antipyretic-analgesic drugs. a. general pharmacological properties §1. inhibition of...
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Part 13Part 13
Antipyretic-Analgesic Antipyretic-Analgesic DrugsDrugs
A.A. General Pharmacological properties General Pharmacological properties
1. 1. Inhibition of prostaglandin (PG) synthesisInhibition of prostaglandin (PG) synthesis
inhibitinginhibiting cyclooxygenase cyclooxygenase ((COXCOX ,环氧酶,环氧酶 ),), decreasing the synthesis of PGs and TXAdecreasing the synthesis of PGs and TXA22, ,
resulting antipyretic, analgesic, and anti-inflaresulting antipyretic, analgesic, and anti-inflammatory effectsmmatory effects
non-steroidal anti-inflammatory drugs non-steroidal anti-inflammatory drugs ((NSAIDsNSAIDs, , 非甾体抗炎药非甾体抗炎药))
2. 2. Antipyretic effectsAntipyretic effects
Inhibition of PGEInhibition of PGE22 production in the hypothal production in the hypothal
amus induced by endogenous pyregens after pamus induced by endogenous pyregens after pathological stimulation athological stimulation temperature temperature
notes:notes: symptomatic control only, not be indicated isymptomatic control only, not be indicated in all patients with fever.n all patients with fever.
The effect on body temperature is different from tThe effect on body temperature is different from that of chlorpromazine.hat of chlorpromazine.
A.A. General Pharmacological properties General Pharmacological properties
Comparison of properties of two types of drugsComparison of properties of two types of drugs
3. 3. Analgesic effectsAnalgesic effects
Analgesic effect is resulted from inhibition of PGEAnalgesic effect is resulted from inhibition of PGE2 2
production. production. Effective on the pain of low to moderate intensity reEffective on the pain of low to moderate intensity re
lated to inflammatory responses.lated to inflammatory responses.PGEPGE22:: a pain stimulant and hyperalgesic agent a pain stimulant and hyperalgesic agent
The analgesic effect is different from opioid analgesiThe analgesic effect is different from opioid analgesics.cs.
A.A. General Pharmacological properties General Pharmacological properties
Comparison of properties of two types of drugsComparison of properties of two types of drugs
4. 4. Anti-inflammatory effectsAnti-inflammatory effects
PGs induce inflammatory responses.PGs induce inflammatory responses. Inhibition of PG production can relieve inflamInhibition of PG production can relieve inflam
matory responses, such as congestion, exudatimatory responses, such as congestion, exudation, pain.on, pain.
The effect is different from that of glucocorticThe effect is different from that of glucocorticosteroids.osteroids.
A.A. General Pharmacological properties General Pharmacological properties
Comparison of properties of two types of drugsComparison of properties of two types of drugs
多环节抑制炎症病变
5. 5. COX-1 / COX-2 and selectivity of the drugsCOX-1 / COX-2 and selectivity of the drugs
COX-1:COX-1: constructive;constructive; involved in physiologic regul involved in physiologic regulatory functions in GI tract, kidney, atory functions in GI tract, kidney, etc.etc.; ;
inhibition of COX-1 is related to the adverse effectinhibition of COX-1 is related to the adverse effects.s.
COX-2:COX-2: inducible;inducible; involved in pathological respon involved in pathological responses such as inflammation, and pregnancy; ses such as inflammation, and pregnancy;
inhibition of COX-2 is related to the therapeutic einhibition of COX-2 is related to the therapeutic effects.ffects.
A.A. General Pharmacological properties General Pharmacological properties
(-)(+)
(+)
(-)
B.B. Salicylates Salicylates
Aspirin Aspirin 阿司匹林阿司匹林
Acetylsalicylic acid Acetylsalicylic acid 乙酰水杨酸乙酰水杨酸
CH3
COOH
O C
O
COOH
OH
COONa
OHAspirin Aspirin
阿司匹林阿司匹林
Salicylic acidSalicylic acid
水杨酸水杨酸
Salicylic sodiumSalicylic sodium
水杨酸钠水杨酸钠
Aspirin Aspirin 阿司匹林阿司匹林
1. 1. ADMEADME
transformed to salicylic acid form in the bodytransformed to salicylic acid form in the body hepatic metabolism is primarily conjugation.hepatic metabolism is primarily conjugation. excretion from urine, the excretion of unchanged forexcretion from urine, the excretion of unchanged for
ms of aspirin is increased in the alkalinized urine.ms of aspirin is increased in the alkalinized urine. larger doses ( > 1 g/d):larger doses ( > 1 g/d): non-linear eliminationnon-linear elimination, zero o, zero o
rder kinetic process, easier to accumulation and intorder kinetic process, easier to accumulation and intoxication.xication.
B.B. Salicylates Salicylates
2. 2. Pharmacological effects and clinical usesPharmacological effects and clinical uses
(1) Antipyretic, analgesic and anti-inflammato(1) Antipyretic, analgesic and anti-inflammatory effectsry effects
moderate doses (0.3moderate doses (0.3 ~~ 0.6 g):0.6 g): antipyretic and analgesic effe antipyretic and analgesic effectscts
larger doses (3larger doses (3 ~~ 5 g/d):5 g/d): anti-inflammatory and anti-rheum anti-inflammatory and anti-rheumatic effects; only relieves symptoms. atic effects; only relieves symptoms.
to treat acute rheumatic fever(to treat acute rheumatic fever( 急性风湿热急性风湿热 ), ), to abate pain and symptoms of rheumatic & rheumatoid arto abate pain and symptoms of rheumatic & rheumatoid ar
thritis (thritis ( 风湿性和类风湿性关节炎风湿性和类风湿性关节炎 ).).
B.B. Salicylates Salicylates
(2) Inhibition of platelet aggregation(2) Inhibition of platelet aggregation
small doses (small doses (3030 ~~ 100 mg/d100 mg/d):): inhibiting TXA inhibiting TXA22 synth synth
esis, preventing thrombosis.esis, preventing thrombosis. used to treat ischemic heart disease, reduce the used to treat ischemic heart disease, reduce the
mortality of myocardiac infarction, and prevent ceremortality of myocardiac infarction, and prevent cerebral thrombosis.bral thrombosis.
larger doses:larger doses: inhibiting PGI inhibiting PGI22 synthesis, promoti synthesis, promoti
ng thrombosis.ng thrombosis.
PGIPGI22:: vasodilation and platelet depolymerization ( vasodilation and platelet depolymerization ( 血小板解聚血小板解聚 ).).
B.B. Salicylates Salicylates
The mechanism of The mechanism of aspirin:aspirin:
Target enzymes Target enzymes acetylatedacetylated
The mechanism of aspirin: The mechanism of aspirin: Target enzymes acetylatedTarget enzymes acetylated
3. 3. Adverse effectsAdverse effects
(1) GI reactions(1) GI reactions
stimulating gastric mucosa and CTZ (larger dosestimulating gastric mucosa and CTZ (larger doses);s);
inhibiting PG synthesis in GI tractinhibiting PG synthesis in GI tract
irritant symptoms; gastric bleeding; ulcerous disirritant symptoms; gastric bleeding; ulcerous disordersorders
Contraindications: Contraindications: ulcerous disordersulcerous disorders
B.B. Salicylates Salicylates
(2) Prolongation of bleeding time(2) Prolongation of bleeding time
small doses:small doses: inhibiting platelet aggregation inhibiting platelet aggregation
larger doses:larger doses: inhibiting synthesis of thrombogen inhibiting synthesis of thrombogen
Contraindications: Contraindications: one week prior to surgery; one week prior to surgery; severe hepatic damage; severe hepatic damage; vitamin K deficiency;vitamin K deficiency; prothrombinopenia (prothrombinopenia ( 凝血酶原减少症凝血酶原减少症 ).).
B.B. Salicylates Salicylates
(3) Allergic reactions(3) Allergic reactions
urticaria (urticaria ( 荨麻疹荨麻疹 ), ), angioneurotic edema, angioneurotic edema, aspirin-induced asthma,aspirin-induced asthma, occasionally anaphylactic shock.occasionally anaphylactic shock.
Contraindications:Contraindications: bronchial asthmabronchial asthma
B.B. Salicylates Salicylates
Aspirin-induced asthma:Aspirin-induced asthma:
Phospholipids of cell menbranePhospholipids of cell menbrane AspirinAspirin Phospholipase APhospholipase A2 2 ((PLAPLA22))
(-) (-) Arachidonic acidArachidonic acid
Cyclooxygenase Cyclooxygenase Lipoxygenase Lipoxygenase (( 脂氧酶脂氧酶 )) (( 环氧酶环氧酶 ) ) PGH PGH2 2 5-HPETE 5-HPETE
↓↓Prostaglandins (PGs)Prostaglandins (PGs) ↑Leukotrienes (LTs)↑Leukotrienes (LTs) (( 前列腺素前列腺素 )) (( 白三烯白三烯 ))
(4) Salicylism (4) Salicylism ((水杨酸反应水杨酸反应))
dose > 5 g/d:dose > 5 g/d: CNS symptoms, including mental CNS symptoms, including mental confusion; hyperventilation.confusion; hyperventilation.
i.v.i.v. NaHCO NaHCO33 can promote the excretion of aspiri can promote the excretion of aspirin.n.
(5) Hepatic damage (5) Hepatic damage
Overdose: Overdose: hepatic damage hepatic damage Reye’s syndrome (Reye’s syndrome ( 瑞夷综合征瑞夷综合征 ):): in children, seve in children, seve
re hepatic damage (re hepatic damage ( 严重肝损害严重肝损害 ) and encephalopath) and encephalopathy (y ( 脑病脑病 ))
B.B. Salicylates Salicylates
Dose-response Dose-response relationship of relationship of aspirin:aspirin:
therapeutic effects; therapeutic effects; adverse effectsadverse effects
4. 4. Drug interactionsDrug interactions
B.B. Salicylates Salicylates
C.C. Para-aminophenol derivatives Para-aminophenol derivatives
Acetaminophen Acetaminophen 对乙酰氨基酚对乙酰氨基酚
ParacetamolParacetamol 扑热息痛扑热息痛
NHCOCH3
OH
Acetaminophen Acetaminophen ((对乙酰氨基酚对乙酰氨基酚):):
antipyretic and analgesic effects are mild aantipyretic and analgesic effects are mild and lasting, nd lasting, but almost no anti-inflammatory ebut almost no anti-inflammatory effects, ffects, - not a- not a NSAIDNSAID
higher selectivity to COX in CNS. higher selectivity to COX in CNS.
mainly used in cold, fever, and headache, mainly used in cold, fever, and headache, etetcc..
overdose can damage liver and kidney.overdose can damage liver and kidney.
C.C. Para-aminophenol derivatives Para-aminophenol derivatives
Differences between NDifferences between NSAIDs and AcetaminoSAIDs and Acetamino
phenphen
Toxic metabolites of Toxic metabolites of acetaminophenacetaminophen
D.D. Other anti-inflammatory drugs Other anti-inflammatory drugs
Salicylates:Salicylates: aspirin aspirin
Para-aminophenol derivatives:Para-aminophenol derivatives: acetaminophen acetaminophen
Indole and indene acetic acid derivatives:Indole and indene acetic acid derivatives:
indomethacin, sulindac, etodolacindomethacin, sulindac, etodolac
Propionic acid derivatives:Propionic acid derivatives:
ibuprofen, naproxen, fenopofen, ketoprofenibuprofen, naproxen, fenopofen, ketoprofen
COX-2 selective inhibitors:COX-2 selective inhibitors: meloxicam, celecoxib, rofenxid meloxicam, celecoxib, rofenxid
Others:Others: phenylbutazone, diclofenac phenylbutazone, diclofenac
N
CH2CH3CO
C
O
Cl
CH3
OH
O
CH3
CHCOOH
CH3
CH2CH
CH3
NS
N
CONH
O O
CH3
OH
indomethacinindomethacin吲哚美辛吲哚美辛
piloxicampiloxicam吡罗昔康吡罗昔康
ibuprofenibuprofen布 洛 芬布 洛 芬
D.D. Other anti-inflammatory drugs Other anti-inflammatory drugsindomethacin indomethacin 吲哚美辛吲哚美辛:: stronger efficacy, controlstronger efficacy, control
ling special types of fever; severe adverse effectsling special types of fever; severe adverse effects
ibuprofen ibuprofen 布洛芬布洛芬(芬必得)(芬必得):: stronger antipyretic, astronger antipyretic, a
nalgesic and anti-inflammatorynalgesic and anti-inflammatory effects; weaker GI reeffects; weaker GI reactions; vision damageactions; vision damage
piloxicam piloxicam 吡罗昔康吡罗昔康 :: long-acting anti-inflammatory along-acting anti-inflammatory and analgesic agent; long-term use induces hemorrhand analgesic agent; long-term use induces hemorrhage and ulcers in GI tractge and ulcers in GI tract
COX-2 selective anti-inflammatory drugsCOX-2 selective anti-inflammatory drugs
Meloxicam Meloxicam 美洛昔康美洛昔康
stronger effect on COX-2 than COX-1stronger effect on COX-2 than COX-1
long-acting (tlong-acting (t1/21/2 20 h) 20 h)
weaker GI reactionsweaker GI reactions
CelecoxibCelecoxib 塞来昔布塞来昔布
Selective COX-2 inhibitor Selective COX-2 inhibitor