A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

158 ANALGESICS AND THE CONTROL OF PAIN
Michaelis-Menten
Salicylurate (50%)
Salicylate
First-order
First-order
First-order
Urinary salicylate (15%)
Salicyl acyl glucuronide (10%)
Gentisic acid (5%)
Michaelis-Menten
Salicyl phenolic glucuronide (20%)
Figure 25.5: The main pathways of salicylate
metabolism and excretion.
salicylate has dose-dependent (non-linear) kinetics (Chapter 3)
at high therapeutic doses or after overdose. Urinary elimination
of salicylate is considerably influenced by pH, being more rapid
in alkaline urine, which favours the charged (polar) anionic
form that is not reabsorbed, rather than the free acid (Chapter 6).
This property is utilized in the treatment of salicylate overdose
by urine alkalinization and demonstrates the principle of ion
trapping. (Chapter 54).
Drug interactions
Aspirin increases the risk of bleeding in patients receiving
anticoagulants via effects on platelets, gastrotoxicity and,
in overdose, by a hypoprothrombinaemic effect. Aspirin
should not be given to neonates with hyperbilirubinaemia
because of the risk of kernicterus as a result of displacement
of bilirubin from its binding site on plasma albumin
(Chapter 13).
IBUPROFEN
Ibuprofen has an approximately similar analgesic potency to
paracetamol and, in addition, has useful anti-inflammatory
activity, so it is an alternative to aspirin for painful conditions
with an inflammatory component (e.g. sprains and minor soft
tissue injury). It is also useful in dysmenorrhoea. It is a
reversible cyclo-oxygenase inhibitor, but causes rather less
gastric irritation than aspirin and other NSAIDs at normal
doses, and is available over the counter in the UK and in many
other countries. A suspension is available for use in children.
It can cause other adverse reactions common to the NSAIDs,
including reversible renal impairment in patients who are elderly
or have cirrhosis, nephrotic syndrome or heart failure. It
reduces the efficacy of antihypertensive medication and of
diuretics by blocking formation of vasodilator and natriuretic
prostaglandins in the kidney.
For more detailed discussion of other common NSAIDs,
which are widely used, see Chapter 26.
TOPICAL NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS
Several NSAIDs (including ibuprofen and piroxicam) are
available as topical preparations. Systemic absorption does
occur, but is modest. Their effectiveness in soft tissue injuries
and other localized inflammatory conditions is also modest.
They occasionally cause local irritation of the skin, but adverse
effects are otherwise uncommon.
NEFOPAM
Use
Nefopam is chemically and pharmacologically unrelated to
other analgesics. It is intermediate in potency between aspirin
and morphine. Unlike NSAIDs, it does not injure the gastric
mucosa. It is less of a respiratory depressant than the opioids
and does not cause dependence. It is useful when opioidinduced
respiratory depression is unacceptable. Neither tolerance
nor drug dependence occur.
Mechanism of action
Nefopam is a potent inhibitor of amine uptake and potentiates
descending pathways that operate the gate mechanism
described above.
Adverse effects and contraindications
Nefopam has few severe (life-threatening) effects, although convulsions,
cerebral oedema and fatality can result from massive
overdose. It is contraindicated in patients with epilepsy, and also
in patients receiving monoamine oxidase inhibitors (see below).
It should not be used in acute myocardial infarction, as it
increases myocardial oxygen demand and may be pro-dysrhythmogenic.
Nefopam causes a high incidence of minor adverse
effects, especially after parenteral use. These include sweating,
nausea, headache, dry mouth, insomnia, dizziness and anorexia.
Nefopam is contraindicated in glaucoma, and can cause urinary
retention in men with prostatic hypertrophy.
Pharmacokinetics
Nefopam is rapidly absorbed following oral administration.
It is extensively metabolized by the liver to inactive compounds
excreted in the urine. Presystemic metabolism is
substantial.
Drug interactions
Nefopam can cause potentially fatal hypertension with
monoamine oxidase inhibitors (MAOIs) and potentiates the
dysrhythmogenic effect of halothane.