Analgesics

Non-Steroidal Anti-Inflammatories (NSAIDS)

Since the introduction of acetylsalicylic acid (aspirin) as the first non steroidal anti-inflammatory (NSAID) in 1897, NSAIDs have been widely used in the management of pain, fever and inflammation.

NSAIDS exert their actions by inhibition of the cyclooxygenase (COX) pathway which converts arachidonic acid to prostaglandin H2 (PGH2). PGH2 is converted by other enzymes to several other prostaglandins, thromboxane A2 (TXA2) and prostacyclin (PGI2) respectively.

There are two forms of prostaglandin cyclooxygenases: COX-1 and COX-2.  COX-1 is the enzyme involved in the formation of prostaglandins for housekeeping functions which protect normal physiological functioning. COX-1 is located in endothelial cells, platelets, kidney, GI tract and many other locations, is expressed at fairly constant levels and may provide protective action on gastric mucosa, on endothelium and in the kidney. The COX-2 enzyme is normally absent but is highly inducible by numerous factors associated with inflammation. 

PGE2 and PGI2 are the most important prostaglandins involved in pain. Inhibition of their synthesis is a primary mechanism of NSAID-mediated analgesia.  The anti-pyretic effect is believed to be due to the inhibition of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus and the resetting of the thermoregulatory system, leading to vasodilatation and increased heat loss.

GI effects are the most common adverse effects of NSAIDS due to a decrease in the production and cytoprotective activity of prostaglandins. The rationale behind the development of COX-2 inhibitors was that inhibition of COX-2 would reduce the inflammatory response and pain but not inhibit the cytoprotective action of prostaglandins in the stomach, which is largely mediated by COX-1.

 

Aspirin (acetylsalicylic acid):  The first NSAID; rapidly absorbed from the intestine as well as from the stomach. It irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue. This is in contrast to other NSAIDs which are reversible inhibitors. Low dose long term aspirin use blocks the formation of thromboxane A2 in platelets producing an inhibitory effect on platelet aggregation. This effect is useful in preventing or reducing the risk of myocardial infarction in patients with a history of heart disease or peripheral vascular disease. Aspirin is extensively hydrolyzed to salicylic acid during absorption after oral administration. This hydrolysis is completed systemically. Salicylic acid is eliminated by renal excretion and by metabolic conversion to conjugates with glycine and glucuronic acid respectively, and to gentisic acid. The serum half-life of salicylic acid is dose-dependent.

Chemical Formula: C9H8O4

Molecular Weight: 180.16

Dosage: Aspirin tablets 325mg, 4 times daily; low dose 75 -81 mg/day

Half -Life: 300 -650mg dose: 3.1 -3.2 hours

                 1g dose: 5 hours

                 2g dose: 9 hours

Volume of distribution: 0.1 – 0.2 L/Kg

Metabolized in the liver through glucuronide formation (to produce salicyl acyl glucuronide and salicyl phenolic glucuronide), conjugation with glycine (to produce salicyluric acid), and oxidation to gentisic acid. Excretion by the kidney.

 

PMID: 3888490. Needs CJ, Brooks PM. Clinical pharmacokinetics of the salicylates.

Clin Pharmacokinetics  10: 164 – 177, 1985

 

Ibuprofen

Chemical Formula: C13H18O2

Molecular weight: 206.28

Dosage: 6mg/kg

Half Life: 1.7 +/- 0.4 hours (n = 8)

Steady State Volume of Distribution: 12.2 +/- 2.8 L (n = 8)

Clearance: 73.7 +/- 19.4 ml/min

 

PMID: 9515184.  Davies NM. Clinical pharmacokinetics of ibuprofen. The first 30 years.

Clin Pharmacokinetics 34: 101 – 154, 1998.

 

PMID: 8562298. Knights KM, McLean CF, Tonkin AL, Miners JO. Lack of effect of gender and oral contraceptive steroids on the pharmacokinetics of (R)-ibuprofen in humans.

Br J Clin Pharmacol 40: 153 – 156, 1995.

 

Naproxen

Chemical formula: C14H14O3

Molecular weight: 230.26

Dosage: 500mg orally

Half Life: 24.7 +/- 6.4 h (range 7 to 36 h); n = 10

 

PMID: 8212758. Vree TB, Biggelaar-Martea M, Verwey-Van Wissen CP, Vree ML, Guelen PJ. The pharmacokinetics of naproxen, its metabolite O-desmethylnaproxen, and their acyl gluronides in humans. Effect of cimetidine. Br J Clin Pharmacol 35: 467- 472, 1993.

 

COX-2 Selective Agents

As mentioned above COX-2 inhibitors were developed to minimize the gastrointestinal side effects commonly associated with earlier NSAIDs. Concern has arisen however due to a doubling in the incidence of heart attack and stroke in patients taking rofecoxib (Vioxx) and valdecoxib (Bextra) and so these two drugs have been removed from the market. One possible explanation is that inhibition of COX-2 mediated production of the vasodilator PGI2 by endothelial  cells, while not affecting the prothromboc actions of COX-1 in platelets, increases the chance of blood clots.  Celecoxib (Celebrex) remains on the market and is approved for the treatment of osteoarthritis and rheumatoid arthritis.

 

Celecoxib (Celebrex):

Chemical Formula: C17H14F3N3O2S1

Molecular weight: 381.38

Dosage: Capsules come in 4 strengths: 50, 100, 200 and 400mg respectively.

200mg once daily or 100mg twice daily.

Half Life; 11.2 hours (range 11-16)

Clearance: 500mL/min

Volume of distribution (steady state): 429L

Celebrex is eliminated by hepatic metabolism involving mainly CYP2CP. Following a single oral dose of radio labeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted in the urine.

 

PMID: 16968831 McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase:

a systematic review of the observational studies of selective and nonselective inhibitors of

cyclooxygenase 2.  JAMA 296: 1633 – 1644, 2006

 

Shi S, Klotz U. Clinical use and pharmacological properties of selective COX-2 inhibitors. Eur J Clin Pharmacol 64: 233 – 252, 2008.

 

Acetaminophen (Paracetamol /Tylenol):  Acetaminophen has both analgesic and antipyretic effects. The exact mechanism of action is still unclear but is thought to result from a tissue-dependent inhibition of both central and peripheral cyclooxygenase enzymes and hence prostaglandin synthesis. It is not generally classified as a NSAID, however, because of its weak anti-inflammatory action.  Paracetamol is metabolized primarily in the liver by glucuronidation and sulfate conjugation.

 

Chemical Structure: C8H9NO2

Molecular Weight: 151.17

Dosage: 15mg/Kg orally every 6 hours.

Volume of distribution: 75.8 +/- 9.3 L (n = 12)

Half Life: 2.8 +/- 0.3 hours (n = 12)

Clearance: 19.0 +/-  1.2 L/hour (n = 12)

 

PMID: 20207720. Mannery YO, Zieglar TR, Park Y, Jones DP. Acetaminophen elimination half-life in humans is unaffected by short-term consumption of sulfur amino acid-free diet. J Pharmacol Exp Ther 333: 948 – 953, 2010.

 

PMID: 16413237. Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharm & Ther 79: 9 – 19, 2006.

 

PMID: 22039164. Hinz B, Brune K. Paracetamol and cyclooxygenase inhibition: is there a cause for concern? Ann Rheum Dis 71: 20 – 25, 2012.

 

Opioid Analgesics

An opiate describes any of the narcotic opioid alkaloids found as natural products in the opium plant. Opioids describe all drugs with opium pharmacological action. Opioids mediate their actions by binding and activating opioid receptors both in the peripheral nervous system and those that are found in inhibitory pain circuits that descend from the midbrain to the spinal cord dorsal horn.  The most commonly known opioids are morphine, codeine, oxycodone, hydrocodone and heroin. Morphine consists of a benzene ring with a phenolic hydroxyl group at position 3 and an alcohol hydroxyl group at position 6 and at the nitrogen atom. Codeine is basically morphine that is O-methylated at position 3, while heroin is morphine O-methylated at position 3 and 6.

Most opioids are metabolized by glucuronidation or by the P450CYP system. The CYP450 enzymes are a super-family of heme-containing, microsomal drug-metabolizing enzymes that are important in the biosynthesis and degradation of endogenous compounds, chemicals, toxins and medications. More than 2,700 individual members of the CYP450 super-family have been identified, and 57 cytochrome P450 enzymes are recognized in humans

 

Morphine

Chemical Formula: C17H19NO3

Molecular Weight: 285.34

Half-Life: 2 – 3.5 hours

Metabolized primarily in the liver

 

Codeine:

Chemical Formula: C18H21NO3

Molecular Weight: 299.37

Half Life: 3 Hours

 

Codeine analgesia depends on the formation of the opioid metabolites morphine and morphine-6-glucuronide. About 10% of an oral dose of codeine is converted into morphine by the enzyme cytochrome P4502D6.

 

PMID: 9010701. Poulson L, Brosen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 51: 289 – 295, 1996.

 

PMID: 21995512. Lorenzi KI, Daali Y, Dayer P, Desmeules J. Pharmacokinetic-pharmacodynamic modeling of opioids in healthy human volunteers. A minireview.

Basic & Clinical Pharmacology & Toxicology 110: 219 – 226, 2012.

 

PMID: 18443637 Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology.

Pain Physician 11 (2 Suppl): S133 – S153, 2008.

 

Oxycodone

Chemical Formula: C18H21NO4

Molecular Weight: 315.37

Half-Life: 2-3 hours

PMID: 1389934. Poyhia R, Seppala T, Olkkola KT, Kalso E. The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects.

Br J Clin Pharmacol 33: 617 – 621, 1992.

PMID: 1958450.  Poyhia R, Olkkola KT, Seppala T, Kalso E.  The pharmacokinetics of oxycodone after intravenous injection in adults. Br J Clin Pharmacol 32: 516 – 518, 1991.

Feedback and Knowledge Base