Part 13 Antipyretic-Analgesic Drugs. A. General Pharmacological properties §1. Inhibition of...

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