Analgesics

.
 Analgesic
The major classes
1. Paracetamol and NSAIDs
2. COX-2 inhibitors
3. Opiates and morphinomimetics
4. Specific agents
Analgesics
analgesics (also known as a painkillers) are
a group of drugs used to relieve pain (achieve
analgesia). Analgesic drugs act in various ways
on the peripheral and central nervous systems;
they include paracetamol (acetaminophen), the
non-steroidal anti-inflammatory drugs (NSAIDs)
,narcotic drugs such as morphine, synthetic
drugs with narcotic properties such as
tramadol, and various others.
Mode of action
Most NSAIDs act as non-selective inhibitors of
the enzyme cyclooxygenase, inhibiting both
the cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2) isoenzymes.
Cyclooxygenase catalyzes the formation of
prostaglandins and thromboxane from
arachidonic acid (itself derived from the cellular
phospholipid bilayer by phospholipase A2).
Prostaglandins act as messenger molecules in
the process of inflammation.
 PGs
of lipid compounds that are derived
enzymatically from fatty acids and have
important functions in the body.

Prostaglandins are found in most tissues and

organs. They are produced by all nucleated
cells except lymphocytes.
They are lipid mediators that act upon platelets,
endothelium, uterine and mast cells.
 Biosynthesis of PGs
phospholipid (in cell wall lipid)
↓ ←-------(phospholipase A )
2

arachidonic acid
PGsynthase↓cox1
&2 ↓
Prostaglandins ↓
leukotrines

↓ ↓
prostacyclin thromboxane
 Classes of NSAIDs
Ø Salicylates Ø Arylanthranilic acids (
 Acetylsalicylic acid (Aspirin) fenamic acids)
 Methyl salicylate  Mefenamic acid
 Magnesium salicylate  Meclofenamic acid
 
Ø Arylalkanoic acids Ø Pyrazolidine derivatives
 Diclofenac  Phenylbutazone
 Bromfenac  Phenazone
 Indomethacin  Sulfinpyrazone
 Sulindac Ø Oxicams
 Tolmetin  Piroxicam
Ø Arylpropionic acids  Meloxicam
(profens)
 Ibuprofen
 Fenoprofen
Ø COX-2 inhibitors
 Celecoxib
 Ketoprofen
 Pharmacokinetics
Most NSAIDs are weak acids, They are
absorbed well from the stomach and intestinal
mucosa. They are highly protein-bound in
plasma (typically >95%), usually to albumin.
Most NSAIDs are metabolized in the liver to
inactive metabolites which are typically
excreted in the urine .
Ibuprofen and diclofenac have short half-lives
(2-3 hours). Some NSAIDs (typically oxicams)
have very long half-lives (e.g. 20-60 hours).
 Adverse effects of
NSAIDs
The two main adverse drug reactions
associated with NSAIDs relate to
gastrointestinal (GI) effects and renal effects of
the agents.
These effects are dose-dependent, and in
many cases severe enough to pose the risk of
ulcer perforation, upper gastrointestinal
bleeding, and death, limiting the use of NSAID
therapy.
 Adverse effects …CONT

1. Dyspepsia, nausea and vomiting. Gastric damage

may occur in chronic users, with risk of haemorrhage.
The cause is suppression of gastroprotective
prostaglandins in the gastric mucosa.
2. Skin reactions.
3. Reversible renal insufficiency. Seen mainly in
individuals with compromised renal function when the
compensatory prostaglandin E2-mediated
vasodilatation is inhibited.
4. Analgesic-associated nephropathy . This can
occur following long-continued high doses of NSAIDs
and is often irreversible.
5. Liver disorders, bone marrow depression.
Relatively uncommon.
6. Bronchospasm. Seen in 'aspirin-sensitive'
 opioid analgesic
An opioidis a morphine - acting analgesic, used
for pain relief. These agents work by binding to
opioid receptors, which are found principally in
the CNS and the GIT. The receptors in these
two organ systems mediate both the beneficial
effects, and the undesirable side effects.
There are three principal classes of opioid
receptors , μ , κ , δ (mu, kappa, and delta).
 classes of opioids
There are a number of broad classes of opioids:
2. natural opiates, including morphine, & codeine
3. semi-synthetic opiates, created from the
natural opioids, such as hydromorphone,
desomorphine, diacetylmorphine (Heroin ).
4. fully synthetic opioids, such as fentanyl,
pethidine, methadone, tramadol .

NOTE: endogenous opioid peptides, produced

naturally in the body, such as endorphins,
enkephalins, dynorphins, and endomorphins.
indications for opioids
The sole clinical indications for opioids in the United
States, are:
2. Analgesia i.e. to combat pain of various types and
induction and the continuance of anesthesia as well
as allaying patient apprehension right before the
procedure. Fentanyl, oxymorphone, hydromorphone,
and morphine are most commonly used for this
purpose, in conjunction with other drugs such as
scopolamine, short and intermediate-acting
barbiturates, and benzodiazepines, especially
midazolam which has a rapid onset of action and
lasts shorter than diazepam or similar drugs.
3. Cough (codeine, dihydrocodeine )
 Indications for
opioids….cont.
3.Diarrhea (generally loperamide,
diphenoxylate) but , morphine may be
used in some cases of severe diarrheal
diseases)
Diarrhea of Irritable Bowel Syndrome
(Codeine, diphenoxylate, loperamide)
4.Anxiety due to shortness of breath
(oxymorphone and dihydrocodeine only)
 Adverse effects

 nausea and vomiting, drowsiness, itching, dry

mouth, miosis, and constipation. Fortunately,
most of these are not a problem .
 Infrequent adverse reactions in patient
taking opioids for pain relief: These
include:
 dose-related respiratory depression (see below),
confusion, hallucinations, hypothermia,
bradycardia/tachycardia, orthostatic hypotension,
dizziness, headache, urinary retention, ureteric or
biliary spasm, muscle rigidity, myoclonus (with
high doses), and flushing.
 Adverse effects…CONT.
 Opioid-induced hyperalgesia has been
observed in some patients, whereby
individuals using opioids to relieve pain may
paradoxically experience more pain as a
result of their medication. This phenomenon,
although uncommon, is seen in some
patients,when dose is escalated rapidly.
 Both therapeutic and chronic use of opioids
can compromise the function of the immune
system. Opioids decrease the proliferation of
macrophages and lymphocytes, and affect
cell differentiation .
 Tolerance
Tolerance is the process whereby
neuroadaptation occurs (through receptor
desensitization) resulting in reduced drug
effects. Tolerance is more pronounced for some
effects than for others - tolerance occurs
quickly to the effects on mood, itching, urinary
retention, and respiratory depression, but
occurs more slowly to the analgesia and other
physical side effects.
 Tolerance..CONT.
Tolerance to opioids is attenuated by a number
of substances, including :
calcium channel blockers.
intrathecal magnesium and zinc .
NMDA* antagonists such as ketamine.
All can be used to reduce tolerance to opioid
drugs.

*NMDA receptor antagonists are a class of anesthetics that work to

antagonize, or inhibit the action of, the N-methyl d-aspartate
receptor (NMDAR).
Dependence
Dependence is characterised by extremely
unpleasant withdrawal symptoms that occur if
opioid use is abruptly discontinued after
tolerance has developed.
Addiction is the process whereby physical
and/or psychological dependence develops to a
drug - including opioids. The withdrawal
symptoms can reinforce the addiction, driving
the user to continue taking the drug.
 Treating opioid adverse
effects
Nausea& Vomiting: haloperidol,ondansetron
are very effective
Drowsiness: oxycodone
Itching: fexofenadine
Constipation :stool-softeners
Respiratory depression: respiratory stimulant
currently approved for this purpose is
doxapram. tolerance to respiratory depression
occurs rapidly, so that it is not a clinical
problem
 Contraindications for
opioids
Some opioids are relatively contraindicated in
renal failure because of the accumulation of
the parent drug or their active metabolites
(e.g. morphine and oxycodone). Age (young or
old) is not a contraindication to strong opioids.
Some synthetic opioids such as pethidine have
metabolites which are actually neurotoxic and
should therefore be used only in acute
situations.