Clinical Pharmacology and Therapeutics

156 ANALGESICS AND THE CONTROL OF PAIN
Cell body
Spinal ganglion
(DRG)
Cytokines
Na +
TTX resistant
TTX sensitive K +
Prostaglandins
Bradykinin
Neurotrophins
Histamine
Serotonin
GP130
trk
VDCCs
5-HT
EP
B
Nociceptor
H
ATP Adrenaline ACh
P2X
Adren.
TRPV1
Ca 2+ H + Ca
Na +
2+
Ca 2+
Capsaicin,
K +
Heat,
Mechanical Protons
stimuli
Resiniferatoxin
M
Neuropeptides
NK1
CGRP
SST,etc.
Proteinases
PARs
Figure 25.2: Influence of inflammatory mediators on activity of a C-fibre nociceptor. DRG, dorsal root ganglion, TTX, tetrodotoxin;
GP130, glycoprotein 130; trk, tyrosine kinase; 5-HT, 5-hydroxytryptamine (serotonin) receptor; EP, prostaglandin EP receptor; B,
bradykinin receptor; H, histamine receptor; P2X, purinergic P2X receptor; Adren, adrenoceptor; M, muscarinic receptor; NKT,
neokyotorphine; CGRP, calcitonin gene-related peptide; SST, somatostatin; PARs protease activated receptors; TRPV1, transient receptor
potential vanilloid 1 receptor; VDCCs, voltage-dependent calcium channels.
Key points
Mechanisms of pain and actions of analgesic drugs
• Nociception and pain involve peripheral and central
mechanisms; ‘gating’ mechanisms in the spinal cord and
thalamus are key features.
• Pain differs from nociception because of central
mechanisms, including an emotional component.
• Many mediators are implicated, including prostaglandins,
various peptides that act on μ-receptors (including
endorphins), 5HT, noradrenaline and anandamide.
• Analgesics inhibit, mimic or potentiate natural
mediators (e.g. aspirin inhibits prostaglandin
biosynthesis, morphine acts on μ-receptors, and tricyclic
drugs block neuronal amine uptake).
SITES OF ACTION OF ANALGESICS
Drugs can prevent pain:
• at the site of injury (e.g. NSAIDs);
• by blocking peripheral nerves (local anaesthetics);
• by closing the ‘gates’ in the dorsal horn and thalamus (one
action of opioids and of tricyclic antidepressants that
inhibit axonal re-uptake of 5HT and noradrenaline);
• by altering the central appreciation of pain (another effect
of opioids).
DRUGS USED TO TREAT MILD OR
MODERATE PAIN
PARACETAMOL
Uses
Paracetamol is an antipyretic and mild analgesic with few, if
any, anti-inflammatory properties and no effect on platelet
aggregation. It has no irritant effect on the gastric mucosa and
can be used safely and effectively in most individuals who are
intolerant of aspirin. It is the standard analgesic/antipyretic
in paediatrics since, unlike aspirin, it has not been associated
with Reye’s syndrome and can be formulated as a stable suspension.
The usual adult dose is 0.5–1 g repeated at intervals
of four to six hours if needed.
Mechanism of action
Paracetamol inhibits prostaglandin biosynthesis under some
circumstances (e.g. fever), but not others. The difference from
other NSAIDs is still under investigation.
Adverse effects
The most important toxic effect is hepatic necrosis leading to
liver failure after overdose, but renal failure in the absence of
liver failure has also been reported after overdose. There is no
convincing evidence that paracetamol causes chronic liver
disease when used regularly in therapeutic doses (4 g/24
hours). Paracetamol is structurally closely related to phenacetin
(now withdrawn because of its association with analgesic
nephropathy) raising the question of whether long-term abuse
of paracetamol also causes analgesic nephropathy, an issue
which is as yet unresolved.
Pharmacokinetics, metabolism and interactions
Absorption of paracetamol following oral administration is
increased by metoclopramide, and there is a significant relationship
between gastric emptying and absorption. Paracetamol is
rapidly metabolized in the liver. The major sulphate and glucuronide
conjugates (which account for approximately 95% of a
paracetamol dose) are excreted in the urine. When paracetamol
is taken in overdose (Chapter 54), the capacity of the conjugating
mechanisms is exceeded and a toxic metabolite, N-acetyl benzoquinone
imine (NABQI), is formed via metabolism through the
CYP450 enzymes.