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198 Antipyretic Analgesics

Antipyretic Analgesics

The large and important family of drugs for the treatment of pain, inflammation, and fever has to be subdivided into two groups that differ in their mechanism of action and spectrum of activity, namely,

1.Antipyretic analgesics

2.Nonsteroidal anti-inflammatory drugs

(NSAIDs)

all of which have the chemical character of acids.

Antipyretic analgesics represent p-ami- nophenol or pyrazolone derivatives with clinically useful analgesic and antipyretic efficacy. Their mechanism of action is not completely understood but thought to be mediated via inhibition of prostanoid formation by variants of COX enzymes. Acetaminophen (paracetamol), phenazone, and dipyrone belong in this group.

Acetaminophen has good analgesic ef - cacy in commonplace pain, such as toothache and headaches, but is of less use in inflammatory and visceral pain. It exerts a strong antipyretic effect. The adult dosage is 0.5–1.0 g up to 4 times daily; the elimination half-life is about 2 hours. Acetaminophen is eliminated renally after conjugation to sulfuric or glucuronic acid. A small portion of the dose is converted by hepatic CYP450 to a reactive metabolite that requires detoxification by coupling to glutathione. In suicidal or accidental poisoning with acetaminophen (10 g), the depleted store of thiol groups must be replaced by administration of acetylcysteine. This measure can be life-saving. Long-term therapy with pure acetaminophen preparations does not cause renal damage, reported earlier after use of stimulant combination preparations. Fixed combinations with codeine may be used with hardly any reservation.

Dipyrone (metamizole) is a pyrazolone derivative. It producesstrong analgesia,even in pain of colic, and has an additional spasmolytic effect. The antipyretic effect is marked. The usual dosage is about 500 mg

orally. Higher doses (up to 2.5 g) are needed for biliary colic. The effect of a standard dose lasts ~ 6 hours.

Use of dipyrone is compromised by a very rare but serious adverse reaction, viz., bone marrow depression. The incidence of agranulocytosis remains controversial; probably, one case occurs in > 100 000 treatments. Hypotension may occur after intravenous injection. Dipyrone is not for routine use; however, short-term administration is recommended for appropriate individual cases.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

This term subsumes drugs other than COX-2 inhibitors that (a) are characterized chemically by an acidic moiety linked to an aromatic residue; and that (b) by virtue of inhibiting cyclooxygenases, are effective in suppressing inflammation, alleviating pain, and lowering fever. Cyclooxygenases (COX) localized to the endoplasmic reticulum are responsible for the formation from arachidonic acid of a group of local hormonescomprising the prostaglandins, prostacyclin, and thromboxanes. NSAIDs (except ASA) are reversible inhibitors of COX enzymes. These enzymes possess an elongated pore into which the substrate arachidonic acid is inserted and converted to an active product. NSAIDs penetrate into this pore and thus prevent access for arachidonic acid, leading to reversible blockade of the enzyme.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Antipyretic Analgesics vs. NSAIDs

199

A. Comparison of antipyretic analgesics with a nonsteroidal anti-inflammatory drug

Tooth-

 

Head-

Fever

 

 

 

 

 

ache

 

ache

 

 

 

 

 

Inflammatory

Effective

 

 

 

 

 

 

 

 

 

 

 

pain

 

 

Less effective

 

 

 

 

 

 

 

 

 

 

 

Pain of colic

 

 

 

 

 

 

Acetaminophen

Acetylsalicylic acid

Dipyrone

 

 

 

COOH

 

 

O

 

 

OH

 

 

H2C

S

OH

 

 

 

 

 

 

 

 

 

O

C CH3

H3C

N

O

CH3

 

 

 

 

 

 

O

 

O

 

 

N

 

HN

C

 

O

 

 

 

 

N

CH3

 

 

 

 

 

CH3

 

 

 

 

 

 

 

only

 

 

 

 

 

 

Acute

with

 

 

 

 

 

 

 

Chronic

 

 

very

 

 

 

massive

 

 

 

 

 

 

 

abuse

 

 

rarely

 

 

 

over-

 

 

 

 

 

 

 

 

 

 

 

 

 

 

dose

 

 

 

 

 

 

 

 

>10g

 

 

 

 

 

 

 

 

 

 

 

 

Irritation

 

 

 

 

 

 

 

Broncho-

of

 

 

 

 

 

 

 

constriction

gastro-

 

 

 

Risk of

 

 

 

 

intestinal

 

 

 

ana-

 

 

 

 

mucosa

 

 

phylactoid

 

 

 

Impaired

 

 

 

 

shock

 

 

 

 

 

 

 

 

Hepato-

 

Nephro-

hemostasis with

Agranulo-

 

 

toxicity

 

toxicity

risk of bleeding

 

cytosis

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

200 Nonsteroidal Anti-inflammatory Drugs

Cyclooxygenase (COX) Inhibitors

Two principal types of COX can be distinguished:

COX-1 is constitutive, that is, always present and active; it contributes to the physiological function of organs. Inhibition inevitably produces unwanted effects, such as mucosal injury, renal damage, hemodynamic changes, and disturbances of uterine function.

COX-2 is induced by inflammatory processes and produces prostaglandins that sensitize nociceptors, evoke fever, and promote inflammation by causing vasodilation and an increase in vascular permeability. However, in some organs, COX-2 is also expressed constitutively (kidney, vascular endothelium, uterus, and CNS).

Nonselective COX inhibitors derive from salicylic acid. The majority are carbonic acids, such as ibuprofen, naproxene, diclofenac, indometacin, and many more; or enolic acids, such as azapropazone and meloxicam. All these drugs inhibit both COX enzymes.

The molecules of COX-1 and COX-2 reveal a pharmacologically important difference: the enzymatic pore width of COX-2 exceeds that of COX-1. The nonselective COX inhibitors can also enter the narrower pores and thus inhibit both cyclooxygenases.

Efforts have succeeded to develop inhibitors that readily enter the slightly wider pores of COX-2 but not the COX-1 pores, giving rise to the specific COX-2 inhibitors

(denoted coxibs). These drugs consist of a hetero-aromatic ring bearing two phenyl ring substituents, one of which contains a SO2 group (see formulas in A). The advantage of coxibs lies in their lesser propensity to cause mucosal injury. This effect has been reported in large clinical trials (but subsequently queried). However, a number of adverse reactions are now known that are consistent with COX-2 also serving constitutive functions. Furthermore, one needs to consider that COX-1 functions may be more or less

affected at suf ciently large dosages. Selectivity factors (COX-1/COX-2 ratio) determined biochemically in vitro range from 30 to 400.

Coxibs available at present include: celecoxib (daily dosage 200–400 mg), valdecoxib (10–20 mg) (no longer available in the US) and its prodrug parecoxib (40 mg i.v.!).

Coxibs are not drugs for routine use and should only be employed in a targeted manner, in particular when antiarthritis treatment with nonselective NSAIDs has led to gastrointestinal mucosal damage (bleeding, gastritis, ulcerations). Contraindications must be heeded, in particular, advanced congestive heart failure, hepatic and renal diseases, inflammatory bowel diseases, and asthma. Concern over an increased risk of stroke and myocardial infarction in vulnerable patient populations has led to withdrawal of rofecoxib (Sept. 2004), raising strong suspicion that this represents a coxib class effect.

Acetylsalicylic acid (ASA) merits a separate comment. Acetylation of salicylic acid significantlyreducesitsabilitytoinduce mucosal injury. After absorption of ASA, the acetyl moiety is cleaved with a t½ of 15–20 minutes, salicylic acid then being present in vivo. For anti-inflammatory therapy, the required dosage of ASA lies above 3 g daily. For

treatment

of

ordinary pain, a dose of

~ 500 mg

is

needed. At low dosage

(100–200 mg

daily), following absorption

into the portal circulation, ASA causes a long-lasting blockade of COX-1-mediated thromboxane synthesis in platelets because of an irreversible acetylation of the enzyme. Since platelets represent anuclear cell fragments, they are unable to synthesize new COX molecules.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Nonsteroidal Anti-inflammatory Drugs

201

A. Nonsteroidal anti-inflammatory drugs (NSAIDs)

0.3 – 6.0 g

Nonselective COX inhibitors

 

 

COO

 

 

COO

 

 

0.05 – 0.15 g

200 – 400 mg

 

 

 

 

CH2

 

 

 

 

OH

 

H

 

 

 

 

 

 

 

 

 

 

 

Acetyl-

Salicylic acid

Cl

N

Cl

 

 

 

salicylic

COO

 

 

 

 

 

acid

 

 

 

 

 

 

 

O

O

C

CH3

Diclofenac

 

CH3

 

 

H2N

 

 

 

 

 

S

 

O

 

 

 

 

CH

COOH

O

 

 

 

CH3

 

N

 

 

 

 

 

 

 

N

CF3

 

 

 

 

 

 

 

Celecoxib

 

 

H3C

CH CH2

 

 

 

H3C

 

 

 

 

 

Ibuprofen

 

 

 

 

 

 

 

 

 

 

 

O

Rofecoxib*

Naproxen

CH3

 

 

 

 

 

 

H3C

 

 

 

 

 

CH

COO

 

S

 

 

 

 

 

 

 

 

 

O

 

 

 

H3C

O

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

0.6 – 2.4 g

 

 

 

 

 

 

 

 

 

12.5 – 25 mg

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

COX-2 inhibitors

 

 

 

 

 

0.5 – 1.0 g

daily doses

 

B. Adverse effects of nonsteroidal anti-inflammatory drugs

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Arachidonic acid

 

 

 

 

 

Cyclooxygenases

 

 

 

 

 

 

 

 

 

 

Lipoxygenases

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nonselective

 

 

COX -2

 

 

 

 

 

 

 

COX inhibitors

 

 

inhibitors

 

 

 

 

 

 

 

Prostaglandins decreased

Leukotrienes increased

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gastric mucosal

 

 

Lower

 

 

 

(depending on

 

 

damage with

 

 

incidence of

 

 

 

supply of arachidonic

 

 

ulcer formation,

 

 

gastropathy

 

 

 

acid)

 

 

bleeding, and

 

 

 

 

 

 

 

 

 

 

 

 

perforation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nephropathy, decreased excretion of NaCl and

 

 

Bronchoconstriction,

 

 

H2O, edemas, increased blood pressure, impaired

 

 

bronchial asthma,

 

 

wound healing, diarrhea, disturbed uterine motility

 

 

proinflammatory effect

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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