The drugs dealt with in this section include aspirin and other salicylates, NSAIDs, opioid analgesics, and miscellaneous analgesics, such as nefopam and paracetamol. table 1 below, contains a listing, with a further classification of NSAIDs.
Aspirin and NSAIDs generally undergo few clinically significant pharmacokinetic interactions. The majority are highly protein bound, and have potential to interact with other drugs via this mechanism. However,with a few exceptions, most of these interactions are not clinically important (see Protein-binding interactions, ).
Of newer NSAIDs, celecoxib is metabolised by cytochrome P450 isoenzyme CYP2C9, and inhibits CYP2D6. Rofecoxib,now withdrawn, inhibits CYP1A2, see Tizanidine + CYP1A2 inhibitors interaction. Nevertheless, most of important interactions with NSAIDs and aspirin are pharmacodynamic. Aspirin and all non-selective NSAIDs inhibit platelet aggregation, and so can increase risk of bleeding and interact with other drugs that have this effect. NSAIDs that are highly selective for cyclooxygenase-2 (COX-2) do not inhibit platelet aggregation.
Aspirin and all NSAIDs (including COX-2 selective NSAIDs) affect synthesis of renal prostaglandins, and so can cause salt and water retention. This can increase blood pressure and affect antihypertensive therapy.
Aspirin and non-selective NSAIDs inhibit mechanisms that protect gastrointestinal mucosa and so cause gastrointestinal toxicity
Morphine is metabolised by glucuronidation by UDP-glucuronyltransferases,mainly to one active and one inactive metabolite. The glucuronidation of morphine can be induced or inhibited by various drugs. Morphine is not significantly affected by cytochrome P450 isoenzymes. The semi-synthetic morphine analogues,hydromorphone and oxymorphone, are metabolised similarly.
Codeine,dihydrocodeine, and hydrocodone are thought to be pro-drugs, and require metabolic activation, possibly by CYP2D6 or UGT enzymes. Inhibitors of these enzymes may therefore reduce their efficacy. Oxycodone is also metabolised by CYP2D6 and CYP3A4.
Pethidine is metabolised via several cytochrome P450 isoenzymes. If metabolism of pethidine is increased it can lead to increased production of toxic metabolite, norpethidine, and increased CNS adverse effects.
Methadone is principally metabolised by CYP3A4 and CYP2D6,although CYP2C8 may also play a role. Buprenorphine is metabolised by CYP3A4.
Alfentanil is extensively metabolised by CYP3A4,and has been used as a probe drug for assessing CYP3A4 activity. Fentanyl and sufentanil are also metabolised,but because they are high hepatic-extraction drugs (see Changes in first-pass metabolism, ) they are less affected by inhibitors or inducers of CYP3A4, although in some instances this may still lead to clinically significant effects.
Paracetamol is not absorbed from stomach, and rate of absorption is well correlated with gastric emptying rate. Paracetamol has therefore been used as a marker drug in studies of gastric emptying. Paracetamol is primarily metabolised by liver to a variety of metabolites, principally glucuronide and sulfate conjugates. Hepatotoxicity of paracetamol is thought to be due to a minor metabolite,N-acetyl-p-benzoquinone imine (NAPQI), which is inactivated with glutathione and excreted as mercapturate and cysteine conjugates. When liver stores of glutathione are depleted, and rate of production of NAPQI exceeds rate of production of glutathione, excess NAPQI attaches to liver proteins and causes liver damage. CYP2E1 may be involved in formation of this hepatotoxic metabolite.
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Aloxiprin,Aspirin, Benorilate, Choline salicylate, Diflunisal, Ethenzamide, Lysine aspirin, Magnesium salicylate, Salsalate, Sodium salicylate
Floctafenine,Flufenamic acid, Meclofenamic acid, Mefenamic acid, Tolfenamic acid
Acemetacin,Indometacin, Sulindac
Lornoxicam,Meloxicam, Piroxicam, Tenoxicam
Alclofenac,Diclofenac
Dexketoprofen,Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Oxaprozin, Tiaprofenic acid
Azapropazone,Feprazone, Kebuzone, Metamizole sodium (Dipyrone), Oxyphenbutazone, Phenylbutazone
Celecoxib,Etodolac, Etoricoxib, Meloxicam (see under Oxicams), Nimesulide, Parecoxib, Rofecoxib, Valdecoxib
Benzydamine hydrochloride,Felbinac, Ketorolac, Nabumetone, Phenazone (Antipyrine), Tolmetin
Alfentanil,Fentanyl, Remifentanil, Sufentanil
Codeine,Dextropropoxyphene (Propoxyphene), Dihydrocodeine
Buprenorphine (also used for opioid dependence),Butorphanol, Meptazinol, Nalbuphine, Pentazocine
Dextromoramide,Diamorphine (Heroin), Dipipanone, Hydrocodone, Hydromorphone, Methadone (also used for opioid dependence), Morphine, Oxycodone, Oxymorphone, Papaveretum, Pethidine (Meperidine), Tramadol
Nefopam,Paracetamol (Acetaminophen)
| Table 1 Analgesics and NSAIDs | |
| Group | Drugs |
| Aspirin and oral salicylates | Aloxiprin, Aspirin, Benorilate, Choline salicylate, Diflunisal, Ethenzamide, Lysine aspirin, Magnesium salicylate, Salsalate, Sodium salicylate |
| NSAIDs | |
| Fenamates | Floctafenine, Flufenamic acid, Meclofenamic acid, Mefenamic acid, Tolfenamic acid |
| Indole- and indene-acetic acids | Acemetacin, Indometacin, Sulindac |
| Oxicams | Lornoxicam, Meloxicam, Piroxicam, Tenoxicam |
| Phenylacetic acid derivatives | Alclofenac, Diclofenac |
| Propionic acid derivatives | Dexketoprofen, Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Oxaprozin, Tiaprofenic acid |
| Pyrazolone derivatives | Azapropazone, Feprazone, Kebuzone, Metamizole sodium (Dipyrone), Oxyphenbutazone, Phenylbutazone |
| Selective inhibitors of cyclo-oxygenase-2 (Coxibs) | Celecoxib, Etodolac, Etoricoxib, Meloxicam (see under Oxicams), Nimesulide, Parecoxib, Rofecoxib, Valdecoxib |
| Other | Benzydamine hydrochloride, Felbinac, Ketorolac, Nabumetone, Phenazone (Antipyrine), Tolmetin |
| Opioid and related analgesics | |
| Anaesthetic adjuncts | Alfentanil, Fentanyl, Remifentanil, Sufentanil |
| Mild to moderate pain | Codeine, Dextropropoxyphene (Propoxyphene), Dihydrocodeine |
| Moderate to severe pain: | |
| Partial agonists and agonists/antagonists | Buprenorphine (also used for opioid dependence), Butorphanol, Meptazinol, Nalbuphine, Pentazocine |
| Pure agonists | Dextromoramide, Diamorphine (Heroin), Dipipanone, Hydrocodone, Hydromorphone, Methadone (also used for opioid dependence), Morphine, Oxycodone, Oxymorphone, Papaveretum, Pethidine (Meperidine), Tramadol |
| Miscellaneous | Nefopam, Paracetamol (Acetaminophen) |