ANALGESIC DRUGS V. Gerl According to: H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore: Pharmacology, 5th e

1
ANALGESIC DRUGS
V.
GerlAccording to - H.P.Rang, M.M.Dale,
J.M.Ritter, P.K.Moore Pharmacology, 5th ed.-
R.A.Howland, M.J.Mycek Lippincotts Illustrated
Reviews Pharmacology, 3rd ed.
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ANALGESIC DRUGS /1/ MORPHINE - LIKE DRUGS
(OPIOID, NARCOTIC ANALGESICS) /2/
ANALGESIC-ANTIPYRETICS AND ANTIINFLAMMATORY
DRUGS MECHANISM OF PAIN AND NOCICEPTION Nocicept
ion mechanism whereby noxious peripheral stimuli
are transmitted to CNS. Polymodal nociceptors
(PMN) peripheral sense organs that respond to
noxious stimuli, mostly nonmyelinated C-fibres
whose endings respond to thermal, mechanical and
chemical stimuli.
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Chemical mediators - chemical stimuli acting on
PMN to cause pain - bradykinin, 5-HT,
capsaicin (from pepper) - neurotransmitters
released locally in inflammation - 5-HT,
histamine, acetylcholine - prostaglandins -
sensitization of PMN Transmitters of PMN
neurons fast transmitters (glutamate, ATP) and
peptides (substance P, Calcitonin-gene-related-pe
ptide, i.e. CGRP) modulatory transmitters met-
enkephalin, endorphin, 5-HT, noradrenaline Nocice
ptive fibres terminate in the dorsal horn (1st
neurone), forming synaptic connection with
transmission neurones running to thalamus (2nd
neurone) then to cortex (3rd neurone).
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OPIOIDS (MORPHINE-LIKE) ANALGESICS AND
ANTAGONISTS Opioids - natural or synthetic
produce morphine-like effects. They act by
binding to specific opioid receptors in the CNS
effects mimic the action of endogenous
peptide neurotransmitters (e.g., leu- and
met-enkephalins). They relieve severe pain -
essential in treatment of major diseases, trauma,
and surgery. Danger of the drug abuse.
Although the opioids have a broad range of
effects, their primary use is to relieve intense
pain and the anxiety that accompanies
it. Antagonists they can reverse actions of
opioids, important clinically treatment of
overdose.
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OPIOID ANALGESICS AND ANTAGONISTS
STRONG AGONISTS
Alfentanil Fentanyl
Heroin
Meperidine
Methadone
Morphine
Remifentanil
Sufentanil
MODERATE/LOW AGONISTS
Codeine
Oxycodone
Propoxyphene
MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS
Buprenorphine
Butorphanol
Nalbuphine
Pentazocine
ANTAGONISTS
Naloxone Naltrexone
(according to Lippincotts Pharmacology, 2006
OTHER ANALGESICS
Tramadol
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• morphine analogues closely related in structure
  to morphine often synthesized from it they may
  be agonists (e.g. morphine, diamorphine (heroin)
  and codeine), partial agonists (e.g. nalorphine
  and levallorphan) or antagonists (e.g. naloxone)
• synthetic derivatives with structures unrelated
  to morphine
• ? phenylpiperidine series, e.g. pethidine,
  fentanyl
• ? methadone series, e.g. methadone,
  dextropropoxyphene
• ? benzomorphan series, e.g. pentazocine,
  cyclazocine
• ? semisynthetic thebaine derivatives, e.g.
  etorphine,
• buprenorphine.
• Loperamide - an opiate but it does not enter
  the CNS - it lacks analgesic activity. However,
  like other opiates it inhibits peristalsis - used
  to control diarrhea.

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Division (in relation to the activity) 1. Strong
agonists (e.g. morphine, meperidinepethidine,
methadone, fentanyl, sufentanil, alfentanil,
remifentanil) 2. Moderate agonists (e.g.
propoxyphene, codein, oxycodone) 3. Mixed
agonist-antagonists (e.g. pentazocine,
buprenorphine, nalbuphine, butorphanol) 4. Other
analgesics ( tramadol) 5. Antagonists (naloxone,
naltrexone)
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OPIOID RECEPTORS Specific protein receptors on
the membranes of certain cells mostly in the CNS
and the GIT. All are coupled to inhibitory G
proteins, and inhibit adenylyl cyclase. They may
be also associated with ion channels to
increase K efflux (hyperpolarisation) or reduce
Ca influx (impeding neuronal firing and
transmitter release). The major effect of the
opioids are mediated by three families of
receptors - each exhibits a different specifity
for the drug(s) it binds. ? /mu/ - analgesic
activity, euphoria, sedation, depression,
dependence ? /delta/ - peripheral action,
interaction with enkephalins ? /kappa/ -
analgesia at the spinal level
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Distribution of receptors The highest density
in 5 general areas of the brain involved in
integrating information about pain. 1. Brainstem
mediate respiration, cough, nausea and vomiting,
maintenance of blood pressure, pupillary
diameter, control of stomach secretion. 2. Medial
thalamus mediate deep pain that is poorly
localized and emotionally influenced. 3. Spinal
cord In the substantia gelatinosa - receipt and
integration of incoming sensory information,
leading to the attenuation of painful afferent
stimuli. 4. Hypothalamus affect neuroendocrine
secretion. 5. Limbic system The greatest
concentration in the amygdala. Receptors probably
may influence emotional behaviour. 6. Periphery
binding to peripheral sensory nerve fibers and
terminals (inhibition of the Ca-dependent release
of pro-inflammatory substances /Substance P/ from
endings) contribution to anti-inflammatory
effects of opioids? 7. Immune cells the role has
not been determined
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Mechanism of action of m-opioid receptor
agonists in the spinal cord.
Activation of the opioid receptor decreases Ca2
influx in response to incoming action
potential. This decreases release of excitatory
neurotransmitters, such as glutamate.
PRESYNAPTIC NEURON
Opioid receptor
Synaptic vesicle
Ca2
Ca2
Glutamate
K
K
Excitatory response
Opioid receptor
Activation of the opioid receptor increases K
efflux and decreases the response of
the post-synaptic neuron to excitatory
neuro- transmitters.
(according to Lippincotts Pharmacology, 2006
POSTSYNAPTIC NEURON
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STRONG AGONISTS MORPHINE The major analgesic
drug contained in crude opium the prototype
agonist (codeine is present in lower
concentrations and is less potent). The opioid
agonists all have similar actions, high affinity
for ? receptors, varying affinities for ? and ?
receptors. Mechanism of action
Major effect - by interacting with opioid
receptors. Opioids cause
hyperpolarization of nerve cells, inhibition of
nerve firing, and presynaptic inhibition of
transmitter release.
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Morphine acts at k receptors in the substantia
gelatinosa of the spinal cord it decreases the
release of substance P (which modulates pain
perception in the spinal cord). It also appears
to inhibit the release of many excitatory
transmitters from nerve terminals carrying
nociceptive (painful) stimuli.
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Actions /1/ CNS a. analgesia - relief
of pain without the loss of consciousness.
(both by enhancing the pain threshold at the
spinal cord level, and more importantly, by
altering the brains interpretation of pain).
Patients are aware of the presence of pain, but
the sensation is not unpleasant. b.
Euphoria powerful sense of contentment and
well-being (may be caused by stimulation of
the ventral tegmentum). c. Respiratory
depression by reduction of the sensitivity of
respiratory center neurons to carbon dioxide.
Respiratory depression - the most common
cause of death in acute opioid overdose.
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d. Depression of cough reflex Morphine and
codeine have antitussive properties. The
cough suppression does not correlate
closely with analgesic and other effects
(probably different receptors are involved in
the antitussive action than in analgesia). e.
Miosis (pupillary constriction) The pinpoint
pupil - characteristic of morphine use -
results from stimulation of ? and ? receptors.
Excitation of the Edinger-Westphal nucleus of
the oculomotor nerve enhanced
parasympathetic stimulation to the eye. Little
tolerance to the effect (all addicts -
except those on meperidine demonstrate
pin-point pupils) - important diagnostically
(most other causes of coma and respiratory
depression produce dilation of the pupil) ! f.
Nausea and emesis stimulation of the
chemoreceptor trigger zone in the area
postrema vomiting. However, the emesis does
not produce unpleasant sensations.
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/2/ GIT It relieves diarrhea and dysentery. It
decreases motility and increases tone of smooth
muscle! Morphine increases pressure in the
biliary tract. !! Morphine also increases the
tone of the anal sphincter and ureteric spasm
harmful in biliary colic due to gallstones,
retention of urine (catheterization in
intoxication with M.) !! Morphine produces
constipation, with little tolerance developing.
/3/ Inhibition of cilia motility
Important in bronchi (disturbances with
expectoration) and in ovary tube (sterility).
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/4/ Cardiovascular system M. has no
major effects on the blood pressure or heart rate
(high doses hypotension and bradycardia -
action on the medulla). Because of respiratory
depression and carbon dioxide retention, cerebral
vessels dilate and increase the cerebrospinal
fluid pressure usually contraindicated in
severe brain injury. /5/ Histamine
release Morphine releases histamine from mast
cells bronchoconstriction, hypotension,
urticaria, itching, sweating. Asthmatics should
not receive the drug. /6/ Hormonal
actions Inhibition of the release of
gonadotropin-releasing h. and
corticotropin-releasing h., decrease in
the concentration of luteinizing h.,
follicle-stimulating h., ACTH, and ß-endorphin.
Testosterone and cortisol levels decrease. It
increases prolactin and growth h. release by
diminishing dopaminergic inhibition.
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It increases antidiuretic hormone -
urinary retention. Note It also can inhibit
the urinary bladder voiding reflex
catheterization may be required. /7/
Increased polysynaptic spinal cord
activity Increased disposition to convulsions
/Straub tail reaction in mice - raising and
stiffening of the tail due to the spasm of a
muscle at the base of the tail/. /8/
Immunosuppressant activity Increased
susceptibility to infections after long-term
abuse.
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• Therapeutic use
• Analgesia Only few other drugs that are as
  effective in treatment of
• pain. Opioids induce sleep - in situations when
  pain is present and sleep
• is necessary, they may be used to supplement the
  properties hypnotics.
• Note The hypnotic drugs are not usually
  analgesic, and may
• have diminished sedative effect in the presence
  of pain.
• b. Treatment of diarrhea Morphine decreases the
  motility of smooth
• muscle and increase tone (through the
  intramuscular nerve plexus).
• c. Relief of cough Suppression of the cough
  reflex (codeine
• or dextromethorphan are more widely used).
• d. Treatment of acute pulmonary edema i.v.
  morphine relieves dyspnea
• caused by pulmonary edema in left ventricular
  failure - possibly by its
• vasodilatory effect.

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Pharmacokinetics a. Administration Absorption
from GIT is slow and erratic, and the drug is
usually not given orally (but new slow-release
tablets exist). Codeine - well absorbed after
oral administration. Significant first-pass
metabolism in the liver - therefore,
intramuscular, subcutaneous, or i.v. injections
produce the most reliable responses. Note In
cases of chronic pain associated with neoplastic
disease frequent use of the new slow-release
tablets orally or pumps that allow the patient to
control the pain through self-administration. Opia
tes - for nonmedical purposes taken by inhaling
powders or smoke from burning crude opium (rapid
onset of the action).
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b. Distribution M. rapidly enters all body
tissues, incl. fetuses of pregnant women, and
should not be used for analgesia during labor.
Infants born of addicted mothers show physical
dependence on opiates and exhibit withdrawal
symptoms if opioids are not administered. Only a
small part of morphine crosses the blood-brain
barrier, because morphine is the least lipophilic
of the common opioids. (More lipid-soluble
opioids - fentanyl, methadone, heroin, - readily
penetrate into CNS).
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c. Fate M. is conjugated in the liver to
glucuronic acid. Morphine-6-glucuronide - potent
analgesic the conjugate at the 3-position is
much less active. Conjugates - excreted
primarily in the urine (small quantities in the
bile). The duration of action of morphine is 4 -
6hours when administered systemically longer
action when injected epidurally (its low
lipophilicity prevents redistribution from the
epidural space. Note A patient's age can
influence the response to morphine. Elderly
patients are more sensitive to the analgesic
effects (decreased metabolism, decreased lean
body mass, renal function, etc.) They should be
treated with lower doses. Neonates should not
receive morphine because of their low conjugating
capacity.
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• Adverse effects
• - Severe respiratory depression occurs, coma.
• - Constipation.
• - Vomiting, dysphoria.
• - Allergy-enhanced bronchoconstriction,
  hypotensive effects, itching,
• low blood volume.
• - The elevation of intracranial pressure,
  particularly in head injury,
• can be serious. It enhances cerebral and spinal
  ischemia.
• - In prostatic hypertrophy, morphine may cause
  acute urinary retention.
• - A serious action - the stoppage of respiratory
  exchange in emphysema
• or cor pulmonale patients. Respiration must be
  carefully watched.
• In adrenal insufficiency or myxedema there may
  be extended and
• increased effects.
• Use with caution in patients with bronchial
  asthma or liver failure.

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Tolerance and physical dependence Repeated use
produces tolerance to the respiratory depressant,
analgesic, euphoric, and sedative effects of M.
Tolerance usually does not develop to the miosis
and constipatiion. Physical and psychological
dependence readily occur. Withdrawal symptoms -
series of autonomic, motor, and psychological
responses that incapacitate the individual and
cause serious-almost unbearable-symptoms.
However, it is very rare that the effects are so
profound as to cause death. Note Detoxification
of heroin- or morphine-dependent individuals -
usually methadone or clonidine.
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TOLERANCE AND DEPENDENCE Tolerance to opioids
(i.e. an increase in the dose needed to produce
the effect) develops rapidly. Dependence -
involves two separate components - physical and
psychological dependence. Physical dependence -
associated with a physiological withdrawal
syndrome (or abstinence syndrome). Morphine also
produces strong psychological dependence,
expressed as craving for the drug.
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Tolerance It can be detected within 12-24 hours
of M. administration. Tolerance - to most of the
effects (analgesia, emesis, euphoria,
respiratory depression) none or little effects
on the constipating and pupil-constricting
actions. Thus, addicts may take 50x the normal
analgesic dose with relatively little respiratory
depression, but marked constipation and pupillary
constriction. The mechanisms of tolerance some
mechanisms can be excluded (e.g., increased
biotransformation, reduced affinity for
receptors, down-regulation of receptors,
inhibition of the release of endogenous opioids).
Tolerance - a general phenomenon of opioids -
irrespective of which type of receptor they act.
Cross-tolerance occurs between drugs acting at
the same receptor, but not between opioids that
act on different receptors.
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Physical dependence - characterised by a
clear-cut abstinence syndrome. Abstinence
syndrome - somewhat resembling severe influenza,
yawning, mydriasis, fever, sweating,
piloerection, nausea, diarrhoea, insomnia.
Extreme restlessness and distress - accompanied
by a strong craving for the drug. Maximum - after
2-3 days mostly disappear in 8-10 days some
residual symptoms and physiological abnormalities
persist for several weeks. Re-administration of
M. rapidly abolishes the abstinence syndrome.
Changes related to the abstinence syndrome
e.g., spinal reflex hyperexcitability in
morphine-dependent animals, and it can be
produced by chronic intrathecal as well as
systemic administration of morphine. The
noradrenergic pathways emanating from the locus
ceruleus may also play an important role in
causing the abstinence syndrome - a2- agonist
clonidine is sometimes used. The rate of firing
of locus ceruleus neurons is reduced by opioids,
and increased during the abstinence syndrome.
Similar changes affect dopaminergic neurons in
the ventral tegmental area that project to the
nucleus accumbens.
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Interactions The depressant actions of
morphine - enhanced by phenothiazines, MAO
inhibitors, tricyclic antidepressants. Low doses
of amphetamine strangely enhance analgesia, as
does hydroxyzine.
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MEPERIDINE (pethidine) A synthetic opioid
structurally unrelated to morphine. Used for
acute pain. 1. Mechanism of action binding
particularly to m receptors. It also binds to k
receptors. 2. Actions Depression of
respiration, no significant cardiovascular action
when given orally. i.v. - a decrease in
peripheral resistance and an increase in
peripheral blood flow, and increase in cardiac
rate. It dilates cerebral vessels, increases CSF
pressure, and contracts smooth muscle (the latter
to a lesser extent than morphine). Meperidine
does not cause pinpoint pupils but causes the
pupils to dilate - because of an atropine-like
action.
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3. Therapeutic uses Analgesia for any type of
severe pain. It is not useful in the treatment of
diarrhea or cough. Commonly employed in
obstetrics. 4. Pharmacokinetics Well absorbed
from GIT, useful when administered orally.
Mostly administered i.m. Duration of action of
2 - 4 hours. It is N-demethylated to
normeperidine in the liver excreted in the
urine. Because of its shorter action and
different route of metabolism, meperidine is
preferred over morphine for analgesia during
labor.
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5. Adverse effects Large or repetitive doses -
anxiety, tremors, muscle twitches, convulsions
(rarely) due to the accumulation of
normeperidine. Large doses - it dilates the
pupil and causes hyperactive reflexes
difference from opioids. Severe hypotension can
occur if administered postoperatively. Due to
its antimuscarinic action - dry mouth and blurred
vision. When used with major neuroleptics,
depression is greatly enhanced. Administration to
patients taking monoamine oxidase inhibitors can
provoke severe reactions, such as convulsions and
hyperthermia. Meperidine can cause dependence.
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Differences against morphine - shorter duration
of the action (particularly marked in neonate)
preferred during labour - not biotransformed
by conjugation (which is deficient in newborns) -
N-demethylated in the liver to norpethidine
(hallucinogenic and convulsant effects - after
large oral dose) - rather restlessness than
sedation - no miosis - lower antitussive effect -
antimuscarinic (i.e., parasympatholytic) activity
lower spasm of smooth muscle, dry mouth,
blurring of vision
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METHADONE A synthetic, orally effective
opioid, cca equal in potency to morphine but
induces less euphoria and has a somewhat longer
duration of action. 1. Mechanism of action by
the µ receptors. 2. Actions The analgesic
activity is equivalent to morphine.
Well-absorbed orally, in contrast to morphine.
The miotic and respiratory-depressant actions
have average half-lives of 24 hours. It also
increases biliary pressure and is also
constipating. 3. Therapeutic uses Used in the
controlled withdrawal of dependent abusers from
heroin and morphine.
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It causes a withdrawal syndrome that is milder
but more protracted (days to weeks) than with
other opioids 4. Pharmacokinetics Readily
absorbed after oral administration. It
accumulates in tissues, where it remains bound to
protein, from which it is slowly released.
Biotransformed in the liver excreted in the
urine, mainly as inactive metabolites. I.e., it
has longer duration of action (bound in
extravascular compartment) less acute
physical abstinence syndrome (psychological
dependence similar) used widely in treating
morphine and heroine addiction (in presence of
methadone, morphine does not cause the normal
euphoria) 5. Adverse effects It can produce
physical dependence like morphine.
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FENTANYL related to meperidine, it has
100-fold analgesic potency of morphine, used in
anesthesia. A rapid onset and short duration of
action (15 - 30 minutes), usually injected i.v.,
epidurally, or intrathecally. Epidural use for
analgesia postoperatively and during labor. An
oral transmucosal preparation and a transdermal
patch are also available. The transmucosal
preparation - used in the treatment of cancer
patients. The transdermal patch - use with
caution, because death resulting from
hypoventilation has been known to occur. The
transdermal patch creates a reservoir of the drug
in the skin. Hence, the onset is delayed 12
hours, and the offset is prolonged.
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Metabolized to inactive metabolites by the
CYP4503A4 system, and drugs that inhibit this
isozyme can potentiate the effect of fentanyl.
Most of the drug and metabolites are eliminated
through the urine. Adverse effects - similar to
those of other µ receptor agonists. Because of
life-threatening hypoventilation, the fentanyl
patch is contraindicated in the management of
acute and postoperative pain or pain that can be
ameliorated with other analgesics. Unlike
meperidine, it causes pupillary constriction.
It is used in neuroleptanalgesia (with
droperidol) !!
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SUFENTANIL, ALFENTANIL, REMIFENTANIL related to
fentanyl - they differ in their potency and
metabolic disposition. Sufentanil is even more
potent than fentanyl, whereas the other two are
less potent but much shorter-acting. ETORPHINE
- about 1000 times more potent than morphine,
used to immobilise wild animals. HEROIN
(diamorphine) - does not occur naturally.
Produced by di- acetylation of morphine, it leads
to a 3-fold increase in its potency. Its greater
lipid solubility - it crosses the blood-brain
barrier more rapidly than morphine (a more
exaggerated euphoria when taken by injection).
Pharmacologically similar to morphine. Great
lipid solubility rapidly crosses the HEB and
gives greater "rush", shorter duration of action
(2 hrs), very strong dependence.Converted to
morphine in the body, but its effects last about
half as long. In most countries it has no
accepted medical use.
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Time to peak effect and duration of action of
several opioids administered intravenously.
Time to peak effect
Key
Duration of action
20 minutes
Morphine
4 hours
15 minutes
Meperidine
2 4 hours
5 minutes
Fentanyl
15 30 minutes
(according to Lippincotts Pharmacology, 2006
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MODERATE AGONISTS CODEINE (methylmorphine) a
much less potent analgesic than morphine, but a
higher oral effectiveness. It shows good
antitussive activity at doses that do not cause
analgesia. It has a lower potential for abuse
than morphine, and rarely produces dependence.
Lower euphoria than morphine. In most cough
preparations it has been replaced by, e.g.
dextromethorphan. Less polar better
absorption after p.o. administration. About 20
of the analgesic potency of morphine mild
types of pain. Frequently combined in
analgesic-antipyretic preparations with
salicylates or acetaminophen. . Also respiratory
depression, practically of low importance. Antitus
ssive activity, constipation.
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OXYCODONE - a semisynthetic derivative of
morphine. Orally active sometimes formulated
with aspirin or acetaminophen. Used to treat
moderate to severe pain. Metabolized to products
with lower analgesic activity. Excretion is via
the kidney. Abuse of the sustained-release
preparation - many deaths. The higher-dosage
forms of the latter preparation should be used
only by patients who are tolerant to opioids.
40
PROPOXYPHENE - a derivative of methadone. The
dextro isomer - an analgesic to relieve mild to
moderate pain. The levo isomer is not analgesic
- it has antitussive action. A weaker analgesic
action than codeine. Often used in combination
with aspirin or acetaminophen for an analgesia.
Well absorbed orally, metabolized in the liver.
It can produce nausea, anorexia, and
constipation. Toxic doses - respiratory
depression, convulsions, hallucinations, and
confusion. A very serious problem can arise in
some individuals, with resultant cardiotoxicity
and pulmonary edema. Note When used with
alcohol and sedatives, a severe CNS depression is
produced, and death by respiratory depression and
cardiotoxicity can result. The respiratory
depression and sedation can be antagonized by
naloxone, but the cardiotoxicity cannot.
41
MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS
Drugs that stimulate one receptor but block
another mixed agonist-antagonists. The effects
depend on previous exposure to opioids. In
individuals who have not recently received
opioids, mixed agonist-antagonists show agonist
activity and are used to relieve pain. In the
patient with opioid dependence, the
agonist-antagonist drugs may show primarily
blocking effects-that is, produce withdrawal
symptoms.
42
PENTAZOCINE - agonist on k receptors, a weak
antagonist at m and d. It promotes analgesia by
activating receptors in the spinal cord - used to
relieve moderate pain. Administered orally or
parenterally less euphoria. Higher doses -
respiratory depression and decreases the activity
of the GIT. High doses increase blood pressure
and can cause hallucinations, nightmares,
tachycardia, and dizziness ---- its decreased
use. In angina, it increases the mean aortic
pressure and pulmonary arterial pressure and the
work of the heart. It decreases renal plasma
flow. Despite its antagonist action, pentazocine
does not antagonize the respiratory depression of
morphine, but it can precipitate a withdrawal
syndrome in a morphine abuser. Tolerance and
dependence develop.
43
BUPRENORPHINE - a partial agonist at the m
receptor. It acts like morphine in naive
patients, but it can also precipitate withdrawal
in morphine users. A major use - in opiate
detoxication (it has a less severe and shorter
duration of withdrawal symptoms compared to
methadone). It causes little sedation,
respiratory depression, and hypotension, even at
high doses. In contrast to methadone (available
only at specialized clinics) - buprenorphine is
approved for office-based detoxification or
maintenance. Administered sublingually or
parenterally a long duration of action (tight
binding to the receptor). Metabolized by the
liver excreted in the bile and urine. Adverse
effects respiratory depression (cannot be
reversed by naloxone), decrease in blood
pressure, nausea, dizziness.
44
NALBUPHINE, BUTORPHANOL only a limited role in
the treatment of chronic pain. Neither is
available for oral use. Their propensity to
cause psychotomimetic effects is less than that
of pentazocine. Nalbuphine does not affect the
heart or increase blood pressure, in contrast to
pentazocine and butorphanol. A benefit of all
three medications - they exhibit a ceiling effect
for respiratory depression.
45
MEPTAZINOL and DEZOCINE - recently introduced
unusual chemical structure. Meptazinol can be
given orally or by injection it has a short
plasma half-life. It seems to be relatively free
of morphine-like side-effects, causing neither
euphoria nor dysphoria, nor severe respiratory
depression. But, it produces nausea, sedation
and dizziness, and has atropine-like
side-effects. Because of its short duration of
action and lack of respiratory depression -
advantages for obstetric analgesia. Dezocine -
a partial agonist at µ-receptors - analgesic
activity similar to morphine but with
respiratory depressant activity that reaches a
'ceiling' at high doses.
46
OTHER ANALGESICS TRAMADOL - a centrally acting
analgesic that binds to the m-receptor. In
addition, it weakly inhibits re-uptake of
norepinephrine and serotonin. Used in moderate
to moderately severe pain. Its
respiratory-depressant activity is less than that
of morphine. Naloxone can only partially reverse
the analgesia produced by tramadol. The drug
undergoes extensive metabolism, and one
metabolite is active. Concurrent use with
carbamazepine results in increased imetabolism,
presumably by induction of the cytochrome P450
system 2D6. Quinidine (inhibits this isoenzyme),
increases levels of tramadol.Anaphylactoid
reactions were reported. Important the
seizures - especially in patients taking
selective serotonin re-uptake inhibitors or
tricyclic antidepressants. Tramadol should also
be avoided in patients taking MAO inhibitors.
47
ANTAGONISTS They bind with high affinity to
opioid receptors, but fail to activate the
receptor-mediated response. Administration of
opioid antagonists produces no profound effects
in normal individuals. However, in patients
dependent on opioids, antagonists rapidly reverse
the effect of agonists and precipitate the
symptoms of opiate withdrawal.
48
NALOXONE - used to reverse the coma and
respiratory depression of opioid overdose. It
rapidly displaces receptor- bound opioids - it is
able to reverse the effects. Within 30 seconds
of i.v. administration, the respiratory
depression and coma are reversed. A half-life of
60 to 100 minutes. Because of its relatively
short duration of action, a depressed patient who
has been treated and recovered may lapse back
into respiratory depression. It is a competitive
antagonist at m, k and d, receptors, with a
ten-fold higher affinity for m receptors than for
k (explanation of the fact that it reverses
respiratory depression with only minimal reversal
of the analgesia that results from agonist
stimulation of k receptors in the spinal cord).
Naloxone produces no pharmacologic effects in
normal individuals, but it precipitates
withdrawal symptoms in opioid abusers.
49
NALTREXONE Actions similar to those of naloxone.
Longer duration of action - a single oral dose
blocks the effect of injected heroin for up to 48
hours. Naltrexone in combination with clonidine
- and, sometimes, with bruprenorphine - is
employed for rapid opioid detoxification. It
may also be beneficial in treating chronic
alcoholism by an unknown mechanism, but
benzodiazopines and clonidine are preferred.
Adverse effect hepatotoxicity. ( NALORPHINE -
partial agonist of morphine, used previously as
an antidote in acute morphine and heroine
overdosage it can not antagonize effects of
pentazocine and other partial agonists, none or
few clinical use)
50
Clinical uses of analgesic drugs

• Used to treat and prevent pain, e.g.
• ? pre- and postoperatively
• ? common painful conditions including
  headache, dysmenorrhoea, labour, trauma, burns
• ? many medical and surgical emergencies
  (e.g. myocardial
• infarction, renal colic)
• ? terminal disease (especially metatastic
  cancer).
• Opioid analgesics - used also in some non-painful
  conditions, e.g. acute heart failure (because of
  their haemodynamic effects) and terminal chronic
  heart failure (to relieve distress).

51

• A progressive approach is often used, starting
  with NSAIDs, supplemented first by weak opioids
  and then by strong opioids.
• Generally - severe acute pain - treated with
  strong opioids given by injection. Mild
  inflammatory pain (e.g. sprains, mild arthralgia)
  - treated with NSAIDs (e.g. ibuprofen) or by
  paracetamol supplemented by weak opioids (e.g.
  codeine, dextropropoxyphene). Severe pain (e.g.
  cancer pain) - treated with strong opioid.
  Patient - controlled infusion systems are useful
  postoperatively.
• Chronic neuropathic pain - often unresponsive to
  opioids and treated with tricyclic
  antidepressants (e.g. amitrityline) or
  anticonvulsants (e.g. carbamazepine, gabapentin).

52
Anti-inflammatory Drugs Inflammation a
normal, protective response to tissue injury
caused by physical trauma, chemicals,
microbiologic agents i.e., iIt is the body's
effort to inactivate or destroy invading
organisms or irritants, and set the stage for
tissue repair. Sometimes inappropriately
triggered by an innocuous agent (pollen, an
autoimmune response e.g. in asthma, rheumatoid
arthritis) - then the defense reactions
themselves may cause progressive tissue
injury. Anti-inflammatory or immuno-suppressive
drugs may be required to modulate the
inflammatory process. Inflammation is triggered
by the release of chemical mediators from injured
tissues and migrating cells. Chemical mediators
- amines (histamine and 5-hydroxytryptamine) -
lipids (prostaglandins) - small peptides
(bradykinin), - larger peptides,
(inter-leukin-1). Anti-inflammatory drug may
interfere with the action of a particular
mediator important in one type of inflammation
but be without effect in inflammatory processes
not involving the drug's target mediator.
53
Summary of anti-inflammatory drugs
ANTI-INFLAMMATORY DRUGS
NSAIDS
Aspirin Diflunisal Diclofenac Etodolac Fenamates F
enoprofen Flurbiprofen Ibuprofen Indomethacin Keto
profen Meloxicam Methylsalicylate Nabumetone Napro
xin Nimesulide Oxaprazin Piroxicam Sulindac Tolmet
in
COX-2 INHIBITORS
Celecoxib
OTHER ANALGESIC
(according to Lippincotts Pharmacology, 2006
Acetaminophen
54
ANTI-INFLAMMATORY DRUGS (continued)
DRUGS FOR ARTHRITIS
Adalimumab Anakinra Chloroquine Etanercept Gold
salts Infliximab Leflunomide Methotrexate D-Penici
llamine
DRUGS FOR GOUT
Allopurinol Colchicine Probenecid Sulfinpyrazone
(according to Lippincotts Pharmacology, 2006
55
PROSTAGLANDINS All of the nonsteroidal
anti-inflammatory drugs (NSAIDs) act by
inhibiting the synthesis of prostaglandins (PGS).
A. Role of PGS as local mediators Produced by
virtually all tissues act locally on the tissues
where are synthesized rapidly metabolized. PGS
do not circulate in the blood in significant
concentrations. Thromboxanes, leukotrienes, and
the hydroperoxyeicosatetraenoic and
hydroxyeicosatetraenoic acids (HPETEs and HETEs,
respectively) are related lipids.
56
B. Synthesis of PGS Arachidonic acid - the
precursor - a component of the phospholipids of
cell membranes. Free arachidonic acid is
released from tissue phospholipids by
phospholipase A2 and other acyl hydrolases. Two
major pathways in the synthesis of the
eicosanoids from arachidonic acid. 1.
Cyclooxygenase pathway PGS, thromboxanes,
prostacyclins are synthesized via the COX
pathway. Two related isoforms of the
cyclooxygenase Cyclooxygenase-1 (COX-1) -
responsible for the physiologic production of
prostanoids. Cyclooxygenase-2 (COX-2) causes the
elevated production of prostanoids that occurs in
sites of disease and inflammation.
57
COX-1 - a "house- keeping enzyme" - regulates
normal cellular processes (e.g. gastric
cytoprotection, vascular homeostasis, platelet
aggregation, and kidney function). COX-2 is
constitutively expressed in some tissues (brain,
kidney, bone). Its expression at other sites is
increased during states of inflammation. The
conformation for the substrate binding sites and
catalytic regions are slightly different. (e.g.,
COX-2 has a large space at the site where
inhibitors bind). The structural differences
between COX-1 and COX-2 permitted the development
of COX-2-selective inhibitors. COX-2 expression
is inhibited by glucocorticoids this effect may
contribute to their anti-inflammatory effects.
58
2. Lipoxygenase pathway Lipoxygenases can act
on arachidonic acid to form 5-HPETE, 12-HPETE,
and 15-HPETE, that are converted to their
hydroxylated derivatives (HETES) or to
leukotrienes or lipoxins, depending on the
tissue. Antileukotriene drugs, e.g., zileuton,
zafirlukast, and montelukast, are useful for the
treatment of moderate to severe allergic asthma.
C. Actions of PGS Many of the actions of PGS -
by their binding to cell membrane receptors that
operate via G proteins, which subsequently
activate or inhibit adenylyl cyclase or stimulate
phospholipase C. This causes an enhanced
formation of diacylglycerol and IP3. PGF2a,
leukotrienes and thromboxane A2 - mediate actions
by activating phosphatidylinositol metabolism and
causing an increase of intracellular Ca2.
59
D. Functions in the body PGS act as local
signals. Their functions vary widely depending
on the tissue e.g., the release of TXA2 from
platelets triggers the recruitment of new
platelets for aggregation (the first step in clot
formation). However, in other tissues, elevated
levels of TXA2 - e.g., smooth muscle contraction.
Further effects - gastric cytoprotection,
vascular homeostasis, platelet aggregation,
kidney function. PGS - also mediators that are
released in allergic and inflammatory processes.
60
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS NSAIDs -
chemically dissimilar agents that differ in their
antipyretic, analgesic, and anti-inflammatory
activities. They act primarily by inhibiting the
COX enzymes - this leads to decreased PGS
synthesis with both beneficial and unwanted
effects. Long-term treatment with COX-2-specific
inhibitors have been shown to increase the risks
of myocardial infarctions and strokes several of
these drugs was withdrawn. Recommendation to
take the lowest dose that is effective for as
short a period as possible.
61
NSAIDs (non-steroidal antipyretic and
antiinflammatory drugs) Most drugs have three
major effects - antipyretic (lowering a raised,
not normal temperature) - due to a decrease in
PGE2, which is generated in response to
inflammatory proteins and is responsible for
elevating the hypothalamic set-point for
temperature control - analgesic (reduction of
certain sorts of pain) - decrease PGs
generation, relief of headache due to decreased
PGs-mediated vasodilatation - anti-inflammatory
(modification of the inflammatory reaction) -
decrease in PGE2 and PGI2 less
vasodilatation, less oedema Not all NSAIDs are
equally potent in each of these actions.
62

• A. ASPIRIN and other salicylates - the prototype
  of traditional NSAIDs.
• It is the most commonly used the drug to which
  all other anti-inflammatory agents are compared.
• About 15 of patients show an intolerance to
  aspirin.
• aspirin (acetylsalicylic acid)- sodium
  salicylate- methylsalicylate (topically used)-
  diflunisal
• (Note Some newer NSAIDs are superior to aspirin
  in certain patients - they have greater
  anti-inflammatory activity, - and/or cause less
  gastric irritation, - they can be taken less
  frequently. However, they are frequently more
  expensive, and may be more toxic in other ways).

63
1. Mechanism of action Aspirin - unique among
the NSAIDs it irreversibly acetylates (and thus
inactivates) COX. Other NSAIDs, incl.
salicylate, are all reversible inhibitors of COX.
Aspirin - rapidly deacetylated by esterases,
producing salicylate, which has
anti-inflammatory, antipyretic, and analgesic
effects. The antipyretic and anti-inflammatory
effects are due primarily to the blockade of PGS
synthesis at the thermoregulatory centers in the
hypothalamus and at peripheral target sites.
Furthermore - by decreasing PGS synthesis - they
also prevent the sensitization of pain receptors
to stimuli. Aspirin may also depress pain stimuli
at subcortical sites (i.e., the thalamus and
hypothalamus).
64
Metabolism of aspirin and acetylation of
cyclooxygenase by aspirin
Acetyl group that is transferred to
cyclooxygenase
COOH
C
O
CH3
O
Aspirin (Acetylsalicylic acid)
H2O
Cyclooxygenase (active)
Normal deacetylation by esterase
Acetylated cyclooxygenase (inactive)
Acetate
C
CH3
O
COOH
OH
(according to Lippincotts Pharmacology, 2006
Salicylic acid (Salicylate)
65
2. Actions Salicylates reduce inflammation
(anti-inflammation), pain (analgesia), and fever
(antipyrexia). (Not all NSAIDs are equally
potent in each of these actions). a.
Anti-inflammatory actions inhibition of COX
activity decrease in the formation of PGS it
modulates those aspects of inflammation in which
PGS act as mediators. Note Acetaminophen - a
useful analgesic and antipyretic, but it has weak
anti-inflammatory activity (not useful in the
treatment of inflammation).
66
b. Analgesic action PGE2 it sensitizes nerve
endings to bradykinin, histamine, and other
mediators released by the inflammatory process.
Thus, by decreasing PGE2 synthesis, aspirin and
other NSAIDs repress the sensation of pain.
Salicylates - used mainly for the management of
pain of low to moderate intensity. NSAIDs are
superior to opioids for the management of pain in
which inflammation is involved. Combinations of
opioids and NSAIDs - effective in pain caused by
a malignancy.
67
c. Antipyretic action Fever occurs when the
set-point of the anterior hypothalamic
thermoregulatory center is elevated. This can be
caused by PGE2 synthesis, stimulated when an
endogenous fever-producing agent (pyrogen), such
as a cytokine, is released from white cells that
are activated by infection, hypersensitivity,
malignancy, or inflammation. The salicylates
lower body temperature in patients with fever by
impeding PGE2 synthesis and release. Aspirin
resets the "thermostat" toward normal, and it
rapidly lowers the body temperature of febrile
patients by increasing heat dissipation as a
result of peripheral vasodilation and sweating.
Aspirin has no effect on normal body
temperature.
68
d. Respiratory actions At therapeutic doses
increase in alveolar ventilation. Note
Salicylates uncouple oxidative phosphorylation ?
elevated CO2 and increased respiration. Higher
doses direct action on the respiratory center
in the medulla ? hyperventilation and respiratory
alkalosis (usually compensated by the kidney). At
toxic levels, central respiratory paralysis
occurs, and respiratory acidosis ensues due to
continued production of CO2. e. GIT effects
PGI2 inhibits gastric acid secretion, PGE2 and
PGF2a stimulate synthesis of protective mucus in
both the stomach and small intestine. In the
presence of aspirin, they are not formed ?
increased gastric acid secretion and diminished
mucus protection ? epigastric distress,
ulceration, hemorrhage. At ordinary aspirin doses
- as much as 3 to 8 ml of blood may be lost in
the feces per day. Note The PGE1 derivative
misoprostol, the proton pump inhibitor omeprazol,
and H2-antihistamines reduce the risk of gastric
ulcer, and are used in the treatment of gastric
damage induced by NSAIDs.
69
f. Effect on platelets (TXA2 enhances
aggregation, PGI2 decreases it). Low doses
(60-80 mg daily) of aspirin can irreversibly
inhibit thromboxane production in platelets
without markedly affecting TXA2 production in the
endothelial cells of the blood vessel. Note The
acetylation of COX is irreversible. Because
platelets lack nuclei, they cannot synthesize new
enzyme, and the lack of thromboxane persists for
the lifetime of the platelet (3 to 7 days). This
contrasts with the endothelial cells (with
nuclei) therefore they can produce new COX.
Because of the decrease in TXA2, platelet
aggregation (the first step in thrombus
formation) is reduced ? anticoagulant effect with
a prolonged bleeding time. g. Actions on the
kidney COX inhibitors prevent the synthesis of
PGE2 and PGl2 (they are responsible for
maintaining renal blood flow). Decreased
synthesis of PGS - retention of sodium and water
and edema and hyperkalemia may occur.
Interstitial nephritis can also occur with all
NSAIDs except aspirin.
70

• 3. Therapeutic uses
• a. Antipyretics and analgesics
• Aspirin, sodium salicylate, choline salicylate,
  choline magnesium salicylate - used as
  antipyretics and analgesics
• headache, arthralgia, myalgia,
• in the treatment of gout, rheumatic fever, and
  rheumatoid arthritis.
• Note Salicylates are the drugs of choice in the
  treatment of rheumatoid arthritis.
• b. External applications Salicylic acid is used
  topically to treat corns, calluses, and
  epidermophytosis. Methyl salicylate ("oil of
  wintergreen") is used externally as a cutaneous
  counterirritant in liniments.
• c. Diflunisal, a diflurofenyl derivate of
  salicylic acid, is not metabolized to salicylate
  - it cannot cause salicylism. Diflunisal is 3-4
  times more potent than aspirin as an analgesic
  and an anti-inflammatory agent, but it does not
  have antipyretic properties. Note Diflunisal
  does not enter the central nervous system (CNS)
  and therefore cannot relieve fever.

71
c. Cardiovascular applications inhibition of
platelet aggregation. Low doses of aspirin are
used prophylactically to decrease the incidence
of transient ischemic attack and unstable angina
in men as well as that of coronary artery
thrombosis. Aspirin also facilitates closure of
the patent ductus arteriosus (PGE2 is responsible
for keeping the ductus arteriosus open). d.
Colon cancer Chronic use of aspirin may reduce
the incidence of colorectal cancer.
72
4. Pharmacokinetics a. Administration and
distribution After oral administration, the
unionized salicylates are passively absorbed from
the stomach and the small intestine. Rectal
absorption of the salicylates is slow and
unreliable, but it is a useful route for
administration to vomiting children.
Salicylates (except for diflunisal) cross HEB
and the placenta. Salicylates, especially
methyl salicylate, are absorbed through intact
skin.
73
b. Dosage Analgesic activity at low doses only
at higher doses anti-inflammatory activity. E.g.,
about 600 mg of aspirin 4 times a day produces
analgesia, about 4 6 g per day produce both
analgesic and anti-inflammatory activity. Low
dosages of aspirin (160 mg every other day)
reduces the incidence of recurrent IM, reduces
the mortality in post-myocardial infarction
patients. Aspirin in a dose of 160 to 325 mg/day
- beneficial in the prevention of the first IM
(at least in men over the age of 50 years).
Prophylactic aspirin therapy is advocated in
patients with clinical manifestations of coronary
disease if no contraindications are present.
74
Dose-dependent effects of salicylate
Vasomotor collapse Coma Dehydration
Lethal Severe Mild
150
Intoxication
100
50
Tinnitus Cental hyperventilation
Plasma concetration of salicylate (mg/dL)
Anti-inflammatory
10
Analgesic Antipyretic Antiplatelet
0
Gastric bleeding Impaired blood
clotting Hypersensitivity reactions
(according to Lippincotts Pharmacology, 2006
75
c. Fate Normal low dosages (analgesic and
antipyretic) - aspirin is hydrolyzed to
salicylate and acetic acid by esterases in
tissues and blood. Salicylate is converted by the
liver to water-soluble conjugates that are
rapidly excreted by the kidney - elimination with
first-order kinetics and a serum half-life of 3.5
hours. Anti-inflammatory dosages (4 g/day), the
hepatic enzymes saturated - zero-order kinetics
observed - a half-life of 15 hours or more.
Saturation of the hepatic enzymes requires
treatment for several days to one week.
Salicylate (organic acid) is secreted into the
urine and can affect uric acid excretion. At low
doses of aspirin, uric acid secretion is
decreased, whereas at high doses, uric acid
secretion is increased.
76
Effect of dose on the half-life of aspirin
Aspirin Aspirin (low
dose) (high dose)
12
12
11
11
1
1
10
10
2
2
9
9
3
3
4
8
4
8
7
5
7
5
6
t1/2 3 hours
t1/2 15 hours
(according to Lippincotts Pharmacology, 2006
77
5. Adverse effects a. GIT The most common
epigastric distress, nausea, and vomiting.
Microscopic GI bleeding - almost universal in
patients treated with salicylates. Note Aspirin
is an acid. At stomach pH, aspirin is uncharged-
i.e., it crosses into mucosal cells, where it
ionizes and becomes trapped, thus potentially
causing direct damage to the cells. Aspirin
should be taken with food and large volumes of
fluids to diminish GI disturbances. b. Blood
The irreversible acetylation of platelet COX ?
reduction of platelet TXA2 ? inhibition of
platelet aggregation, prolonged bleeding time.
Thus, aspirin should not be taken for at least
one week prior to surgery. When salicylates are
administered, anticoagulants may have to be given
in reduced dosage.
78
c. Respiration In toxic doses - respiratory
depression and a combination of uncompensated
respiratory and metabolic acidosis. d. Metabolic
processes Large doses of salicylates uncouple
oxidative phosphorylation. The energy normally
used for the production of ATP is dissipated as
heat ? the hyperthermia caused by salicylates
when taken in toxic quantities. e.
Hypersensitivity About 15 of patients -
hypersensitivity reactions. Symptoms urticaria,
bronchoconstriction, angioneurotic edema. Fatal
anaphylactic shock is rare. f. Reye syndrome
Aspirin given during viral infections has been
associated with an increased incidence of Reye
syndrome, which is an often fatal, fulminating
hepatitis with cerebral edema. This is especially
encountered in children (who therefore should be
given acetaminophen). g. Drug interactions
Concomitant administration of salicylates with
many drugs may produce undesirable side effects.
79
Drugs interacting with salicylates
Decreased urate excretion (contraindicated
patients with gout)
Probenecid Sulfinpyrazone
Hemorrhage
Probenecid Sulfinpyrazone
Heparin or oral anticoagulants
Reduced rate of aspirin absorption
Antacids
SALICYLATES
Bilirubin Phenytoin Naproxen Sulfinpyrazone Thiope
ntal Thyroxine Triiodothyronine
(according to Lippincotts Pharmacology, 2006
Increased plasma concentration leading to
prolonged half-lives, therapeutic effects, and
toxicity
80
6. Toxicity Salicylate intoxication may be mild
or severe. The mild form - called salicylism
nausea, vomiting, hyperventilation, headache,
mental confusion, dizziness, and tinnitus. Large
doses of salicylate - severe intoxication may
result. The symptoms as above plus restlessness,
delirium, hallucinations, convulsions, coma,
respiratory and metabolic acidosis, and death
from respiratory failure. Children are
particularly prone to salicylate intoxication.
Ingestion of cca 10 g of aspirin ? it can cause
death in children. Treatment of salicylism
measurement of serum concentrations and of pH.
Mild cases - symptomatic treatment. Increasing
the urinary pH enhances the elimination of
salicylate. Serious cases - i.v. fluid,
hemodialysis or peritoneal dialysis, correction
of acid-base and electrolyte balances. Note
Diflunisal does not cause salicylism.
81
B. Propionic acid derivatives IBUPROFEN and
related drugs(naproxen, fenoprofen, ketoprofen,
flurbiprofen, oxaprozin) are reversible
inhibitors of COX. All possess
anti-inflammatory, analgesic, and antipyretic
activity. Especially for the chronic treatment
of rheumatoid arthritis and osteoarthritis (lower
frequency of GIT adverse affects). Well absorbed
orally, they are almost totally bound to serum
albumin. Note Oxaprozin has the longest
half-life, and is administered once daily.
Hepatic metabolism, excreted by the kidney.
The most common adverse effects are GI
(dyspepsia, bleeding). CNS side effects
(headache, tinnitus, dizziness) also were
reported.
82
C. Acetic acid derivatives INDOMETHACIN,
SULINDAC, ETODOLACAll have anti-inflammatory,
analgesic, and antipyretic activity. Reversible
inhibition of COX. Generally not used to lower
fever. Very potent. But, the toxicity of
indomethacin limits its use (for the treatment of
acute gouty arthritis, ankylosing spondylitis,
osteoarthritis of the hip). Also beneficial in
the pain in uveitis and postoperative ophthalmic
pain. Useful as an antipyretic for Hodgkins
disease when the fever is refractory to other
agents. Sulindac (a prodrug, related to
indomethacin). Useful in rheumatoid arthritis,
ankylosing spondylitis, osteoarthritis, and acute
gout. The adverse reactions are less severe than
in indomethacin. Etodolac - effects similar to
other NSAIDs. GIT problems may be less common.
83
Adverse effectsIn up to 50 patients treated
with indomethacin. In cca 20 they lead to the
discontinuation in the use. Most adverse effects
are dose related.a. GIT nausea, vomiting,
anorexia, diarrhea, abdominal pain. Ulceration of
the upper GIT.b. CNS The most severe - frontal
headache (25-50 patients who chronically use
indomethacin). Other dizziness, vertigo,
light-headedness, mental confusion.c. Acute
pancreatitis is known to occur. Hepatic effects
are rare (though some fatal cases of hepatitis
and jaundice were reported).d. Hematopoietic
reactions neutropenia, thrombocytopenia,
aplastic anemia (rarely).e. Hypersensitivity
reactions rashes, urticaria, itching, acute
attack of asthma, and 100 cross-reactivity with
aspirin.InteractionsAdministration of
indomethacin may decrease antihypertensive effect
of furosemide, thiazide diuretics, beta-blockers,
ACE-inhibitors.
84
D. Oxicam derivatives PIROXICAM and MELOXICAM -
used to treat rheumatoid arthritis, ankylosing
spondylitis, and osteoarthritis. They have long
half-lives (which permit administration once a
day). GIT disturbances in approx. 20 treated
with piroxicam. Meloxicam is relatively COX-2
selective and at low to moderate doses shows less
GI irritation than piroxicam. However, at high
doses, meloxicam is a nonselective NSAID
(inhibition COX-1 and COX-2). Excreted in the
urine, interference with the excretion of
lithium. E. Fenamates MEFENAMIC ACID,
MECLOFENAMATE - no advantages over other NSAIDs.
Side effects e.g., diarrhea (even severe with
inflammation of the bowel), hemolytic anemia.
85
F. Other agents 1. DICLOFENAC - long-term use in
the treatment of rheumatoid arthritis,
osteoarthritis, and ankylosing spondylitis. It
is more potent than indomethacin or naproxen. An
ophthalmic preparation is also available.
Diclofenac accumulates in synovial fluid. The
urine is the primary route of excretion for the
drug and its metabolites. Its toxicities are
similar to those of the other NSAIDs. GIT
problems are common, elevation of hepatic
enzymes. 2. KETOROLAC - can be administered i.m.
in the treatment of postoperative pain and
topically for allergic conjunctivitis. It
undergoes hepatic metabolism the drug and
metabolites are eliminated via the urine. The
same side effects as the other NSAIDs.
86
3. TOLMETIN, NABUMETONE, NIMESULID as potent as
aspirin (in treating rheumatoid arthritis or
osteoarthritis), they act preferentially
selectivity to COX 2), lower adverse effects. 4.
DIFLUNISAL (see salicylates) a derivative of
salicylic acid, it is not metabolized to
salicylate ? it cannot cause salicylate
intoxication. 3 4 fold more potent than
aspirin as an analgesic and anti-inflammatory
agent, but it has no antipyretic properties.
Diflunisal does not enter the CNS ? it cannot
relieve fever.
87
5. PHENYLBUTAZONE (and others oxyphenbutazone,
azapropazone, kebuzone, klofezone,
propyphenazone, aminophenazon (amidopyrine not
used), noramidopyrine, metamizole Powerful
anti-inflammatory effects, weak analgesic and
antipyretic activities. Only in short-term
therapy of acute gout and in acute rheumatoid
arthritis when other NSAIDs agents have failed.
The usefulness of phenylbutazone is limited by
its toxicity. They are rapidly and completely
absorbed after oral or rectal administration.
88
Adverse effects Phenylbutazone - adverse effect
occur in nearly 50 of those treated. The drug
should be given for short periods of time-up to 1
week only. Patients should be observed, and
frequent blood tests should be taken. - The most
common - nausea, vomiting, skin rashes, and
epigastric discomfort. - Other - fluid and
electrolyte retention (with edema and decreased
urine volume). - Diarrhea, vertigo, insomnia,
blurred vision, euphoria, nervousness, hematuria.
- Phenylbutazone reduces the uptake of iodine by
the thyroid glands, sometimes resulting in
goiter and myxedema. - The most serious adverse
effects are agranulocytosis and aplastic anemia.
89
IV. COX-2-SELECTIVE NSAIDs The structural
difference between COX-1 and COX-2 allowed the
development of COX-2-selective agents, such as
celecoxib and valdecoxib. They differ from
traditional NSAIDs, which inhibit both COX-1 and
COX-2. However, some traditional NSAIDs
(etodolac, meloxicam, and nimesulide) display
some level of COX-2 selectivity. COX-2
inhibitors - an advantage - a lower risk for the
development of GI bleeding. They also have no
significant effects on platelets. However, the
COX-2 drugs (like the traditional NSAIDs) may
cause renal insufficiency and increase the risk
of hypertension. For patients who require
chronic use of NSAIDs and are at high risk for
NSAID-related GIT toxicity, primary therapy with
a COX-2-selective inhibitor is a reasonable
option. !!!! But long-term treatment with COX-2
inhibitors - was shown to increase the risks of
myocardial infarctions and strokes several of
the drugs was withdrawn (e.g., Rofecoxib) !!!!!
90
A. CELECOXIB More selective inhibition of COX-2
than of COX-1. At concentrations achieved in
vivo, celecoxib does not block COX-1. The
inhibition of COX-2 is time-dependent and
reversible. Approved for treatment of
osteoarthritis and rheumatoid arthritis. Unlike
aspirin, coxib does not inhibit platelet
aggregation and does not increase bleeding
tielecme. 1. Pharmacokinetics readily absorbed
(a peak concentration in 3 hrs), extensively
metabolized in the liver by CYP2C9 and excreted
in the feces and urine. Half-life cca 11 hours -
usually taken once a day.
91

• 2. Adverse effects
• GIT abdominal pain, diarrhea, dyspepsia
  however the incidence of ulcers is lower
  comparing with nonselectiv