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62 Pharmaceutical Chemistry
Fig. 3.1: Algorithm for pain management based on the WHO three-step analgesic ladder
(Source: http://www.who.int/cancer/palliative/painladder/en/)
The prototype ligand for the receptor in morphine was isolated from opium (Papaver
somniferum) in 1806 by a German pharmacist, Seturner. He named the compound
“morphine” after the Greek god of dreams “Morpheus” and different derivatives have
been synthesized worldwide (Fig. 3.2).
Me
N
R R
Morphine, R = R1= OH
Codeine, R = OMe, R
Heroin, R = R1 = OAc
O
1
= OH
1
Me
N
HO O
Hydromorphone, R = OH
Hydrocodone, R = OMe
Fig. 3.2: Morphinans
O
Morphinan
R O
Oxymorphone, R = OH
Oxycodone, R = OMe
Me
N
OH
O
3.5 ANTI-INFLAMMATORY DRUGS
There is no international consensus upon the classification of analgesics/antipyretics. In
textbooks, it is mostly classified in two groups depending on their efficacy; non-narcotic
analgesics (for the mild to moderate pain, some of which may also have antipyretic
actions), and narcotic opioid analgesics (which are principally used in the relief of severe
Analgesics, Antipyretic and Anti-Inflammatory Agents 63
pain, and may produce dependence). Analgesics are drugs used to relieve pain or known
as “pain killers”. Many analgesics also have marked anti-inflammatory actions and
therefore are used for the treatment of arthritis and other inflammatory conditions. Most
anti-inflammatory drugs exhibit their effects by the inhibition of prostaglandin synthesis.
At the primary health-care level, non-narcotic analgesics are of major concern because of
their wide use.
Antipyretics are the drugs used in lowering the temperature, and are considered to
involve the hypothalamus. Normal body temperature varies according to the individual’s
age, sex, level of physical and emotional stress, the environmental temperature, time of the
day, and the anatomical site at which the temperature is measured. Paracetamol, aspirin,
and ibuprofen have similar antipyretic activity.
Anti-inflammatory agents are drugs that alleviate symptoms of inflammation, but do
not necessarily deal with the cause. NSAIDs have been shown to be effective as aspirin
(ASA), but not superior. Cross-sensitivity between aspirin and NSAIDs is high (can be up
to 97% with ibuprofen). Ibuprofen, Ibufenac, and Diclofenac, etc., are examples of this
class.
Almost three decades ago, steroid drugs (viz., Dexamethasone, E-Methasone,
Triamcinoline, Prednisolone, and Hydrocortisone) were considered to be the drugs of
choice as anti-inflammatory agents. Due to several adverse effects of these steroids,
scientists replaced these drugs by much safer and well tolerated non-steroidal antiinflammatory drugs (NSAIDs).
3.5.1 Non-Steroidal Anti-Inflammatory Analgesics (NSAIDs)
Most of the NSAIDs are known to be inhibiting the prostaglandin synthesis by almost
completely blocking the activity of the precursor enzyme, cyclooxigenase (COX). Since
platelets have no DNA, they are unable to synthesise new COX once aspirin irreversibly
inhibits the enzyme. Other NSAIDs COX inhibitors such as ibuprofen, Diclofenac, and
Indomethacin act similarly as aspirin in that they bind to COX but they do not covalently
modify the enzyme and thus do not irreversibly inhibit the platelet function. Ibuprofen
was the first of these compounds to be marketed and it was followed by a number of other
compounds such as Naproxen and Ketoprofen, which are more potent than ibuprofen.
Chronic use of NSAIDs, as in rheumatoid arthritis, is likely to cause adverse effects
which include: gastric and duodenum ulceration, impaired renal function with sodium
and water retention, bone marrow depression, allergic skin rash and bronchial asthma and
hence the search continues for more selective agents.
Newer NSAIDs are called COX-2 selective inhibitors. However, several new COX-2
selective inhibitors have been withdrawn, recently, after evidence emerged that COX-2
inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the
microvasculature in the body express COX-2, and by selectively inhibiting COX-2,
64 Pharmaceutical Chemistry
prostaglandins, specifically PGI2 prostacyclins, are downregulated with respect to
thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anticoagulative
effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attack and
other circulatory problems. Due to these foreseen risks, COX-2 inhibitors are being
withdrawn from the market. The current status of these agents is shown in Table 3.1,
Fig. 3.3.
Table 3.1: Chemical classes of NSAIDs
Chemical classes of NSAIDs
Phenylpropionic acid class Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen,
Oxicam class Meloxicam, Piroxicam
Acetic acid class Diclofenac, Indomethacin, Ketorolac, Nabumetone,
Anthranilic acid (fenamate) class Meclofenamate, Mefenamic acid
Naproxen, Oxaprozin
Sulindac, Tolmetin
Me COOH
Cl Cl
Me
Ibuprofen
Me
OH
O
S
N
Me
S
O O
Meloxicam
Fig. 3.3: Structure: Chemical classes of NSAIDs
COOH
NH
Diclofenec
MeO
O
Indomethacin
COOH
NH
Me
Me
Mefenamic acid
COOH
Me
N
Cl
3.6 OPIOID RECEPTOR DISCOVERY
Opioid peptides are short sequences of amino acids that bind to opioid receptors in the
brain; opiates and opioids mimic the effect of these peptides. Opioid receptors are a class
of G protein–coupled receptors that are characterized by seven transmembrane domains.
Opioid peptides may be produced by the body itself, for example, endorphins. High
densities of opioid receptors are located in all areas of the CNS known to be involved in
integrating information about pain (in brainstem, the medial thalamus, the spinal cord, the
hypothalamus, and the limbic system). Brain opioid peptide systems are known to play an
important role in motivation, emotion, attachment behaviour, the response to stress and
pain, and the control of food intake.
Analgesics, Antipyretic and Anti-Inflammatory Agents 65
Opioid compounds and their receptors exist throughout the central and peripheral
nervous systems and in other tissues. Opioid systems are involved in a diverse array of
homeostatic functions and movement control as well as the processing of noxious sensory
inputs. The antinociceptive system, involved in pain modulation, is itself exceedingly
complex. Information about this system is an useful background for understanding the
effects of opioid analgesics. There was no direct evidence for the existence of specific
opioid receptors until the 1970s when Goldstein et al. found that radiolabelled Levorphanol
bound stereospecifically to certain mouse brain fractions. They hypothesized that this
compound is bound to an “opiate receptor”. This prediction gained attention and credit in
1973 when additional studies showed that opioid agonists and opioid antagonists compete
for the same binding site. Hughes in 1975 also confirmed the existence of an opioid receptor
and intensified the SAR studies of the analgesic opioids.
The first endogenous peptide was termed enkephalin, which was found to be a mixture
of the two pentapeptides (methionine-enkephalin (Met-enkephalin) and leucine-enkephalin
(Leu-enkephalin)) that only differ in their terminal amino acid. Much synthetic work has
been done in an attempt to increase the duration of action of the opioid peptides and
maintain their analgesic effect. The naturally occurring and synthetic analgesics are
facilitated greatly by dividing them into two categories:
(a) Morphine and related compounds
(b) The antipyretics and anti-inflammatory analgesics and other related drugs of
analgesic properties are used as analgesic adjuvant.
Recently, the P (P
and P2), N, and G receptors have been cloned and their cDNAs have
1
been sequenced, yielding invaluable information about the receptor structure and function.
Drugs that bind to opioid receptors are classified as agonists, partial agonists, mixed
agonist-antagonists, and antagonists. Receptor activation by an agonist initiates
pharmacologic actions (Table 3.2), whereas an antagonist occupies the receptor without
their effects. If a drug has a sufficiently low intrinsic activity, high receptor occupancy still
produces less than a maximal response, these drugs are called partial agonists. Partial
agonists may also have antagonistic properties, because they compete with pure agonists
for occupying of opioid receptor sites, for example, morphine is considered the prototypical
P-agonist.
Table 3.2: Receptor activation by an agonist initiates pharmacologic actions
Opioid receptors, their location, and responses mediated by them
Receptor CNS location Response on activation
Brain (laminae III and IV and the cortex,
P
thalamus, periaqueductal gray), spinal cord
(substantia gelatinosa)
Brain (hypothalamus, periaqueductal gray,
N
claustrum), spinal cord (substantia gelatinosa)
Brain (pontine nucleus, amygdale, olfactory
G
bulbs, deep cortex)
P
: supraspinal analgesia, physical dependence; P2:
1
respiratory depression, meiosis, euphoria, reduce
gastrointestinal motility, physical dependence
Spinal analgesia, sedation, meiosis, inhibition of
antidiuretic hormone release
Analgesia, euphoria, physical dependence
66 Pharmaceutical Chemistry
3.6.1 Mechanisms of Opioid Analgesia
Pain transmission in the spinal cord is regulated by a balance of facilitatory and inhibitory
influences operating on the neural circuits of the somatosensory system. Noxious stimuli
activate high-threshold primary sensory neurons in the periphery. This activity is
conducted to their central terminals, which synapse on second-order nociceptive neurons
in the spinal cord. Although opioid compounds are active in the periphery as well, they
produce analgesia primarily by inhibiting nociceptive transmission in the CNS. Opioid
receptors located presynaptically and postsynaptically at the first central synapse in the
spinal cord have been most extensively studied. Those located on the presynaptic nerve
terminal decrease the release of excitatory neurotransmitters from nociceptive neurons,
specifically the neurons that send small C-fibres and A-Dž fibres into the periphery and
respond to a variety of noxious stimuli. This presynaptic inhibition is caused by the effects
of opioid receptor activation on ion channels. Specifically, opioid activation leads to
hyperpolarization of the membrane through the opening of potassium channels or closing
of calcium channels. These hyperpolarized neurons are less likely to have spontaneous
discharge or evoked responses. Opioid receptors located postsynaptically have similar
effects on the second-order neuron. Hyperpolarization caused by changes in ion fluxes
leads to a reduced response of this neuron as it receives excitatory input from the firstorder nociceptive neurons. Signal transduction from opioid receptors occurs through
binding to inhibitory G proteins. One opioid receptor can regulate several G proteins and
multiple receptors can activate a single G protein. Likewise, a single G protein can regulate
several effectors, and a single effector can be activated by several G proteins. Through
these mechanisms, a cascade of complex processes can be initiated involving the activation
of protein kinases, stimulation of genes, and generation of other neuromodulators. These
processes, in turn, alter the response characteristics of the neuron and lead to synthetic
processes that can change various receptors or other structures. The interactions and
outcomes remain poorly understood and are undergoing intensive investigation.
3.6.2 Peripheral Opioid Mechanisms
Recently, opioid receptors that are capable of mediating analgesia in humans have been
discovered on peripheral sensory nerve terminals. The prevailing peptides found in the
periphery are the endorphins and enkephalins. Pharmacologic experiments indicate that the
characteristics of receptors located in the periphery are very similar to those of receptors
in the brain. This peripheral opioid system interacts with immune functions. During
inflammation, opioid peptides secreted by immune cells can activate opioid receptors on
sensory nerve terminals to inhibit nociception. In addition, humans have been shown to
possess a peptide called enkelytin (proenkephalin A), which has a potent antibacterial
action. It has been suggested that immune or neural signalling leads to enhanced
proenkephalin proteolytic cleaving, thereby causing the release of both opioid peptides
and enkelytin simultaneously. These findings constitute a new concept of intrinsic pain
Analgesics, Antipyretic and Anti-Inflammatory Agents 67
control that involves mechanisms traditionally used by the immune system for mounting
a host response to fight pathogens. Existence of peripheral opioid mechanisms has
suggested the potential utility of peripherally administered opioid medications. For
example, some placebo-controlled studies have demonstrated that relatively low doses of
morphine, when administered into a site of peripheral injury (such as a joint space after
surgery), can produce analgesia. Other studies suggest a similar outcome from morphine
applied topically to painful wounds, a result that is independent of systemic drug uptake.
Further studies are needed to clarify the efficacy of peripherally administered opioid
medications and to explain why there is such interindividual variance in responses.
Me
N
6-glucuronidation
N
NH
HO OH
O
Active
MeO OH
N-
CYP
m
CYP2C8 (minor)
ethylation
3
A4 (major)
HO OH
Fig. 3.4: Metabolism of codeine and morphine
O
Codeine
O-demethylation
Me
N
O
Morphine
CYP2D6
MeO OMeConj
Conj = Glucuronide or sulfate
3-glucuronidation or
6-glucuronidation
O OMeConjConj
O
N
O
Inactive or active
Morphine is extensively metabolized via phase II conjugation to morphine-3-glucuronide
(60%), morphine-6-glucuronide (9%), and to a lesser extent the N-demethylated metabolite
(3%). Much controversy exists on the contribution of the metabolites of both codeine6-glucuronide and morphine-6-glucuronide to their analgesic effect. In some studies, the
6-glucuronide metabolite of both drugs contributes significantly to their potency. In other
studies, the 6-glucuronide metabolites of morphine and codeine produce very little
analgesic effect (Fig. 3.4).
Codeine is available in several combination products with aspirin, ibuprofen or
acetaminophen for the treatment of moderate pain. Heroin is an alternative analgesic to
morphine. Heroin can pass through the blood-brain barrier quicker than morphine and
lead to the euphoric “rush” that becomes so addictive to addicts. Morphinans (Levorphanol)
are approximately 7.5 times more potent than morphine orally.
68 Pharmaceutical Chemistry
3.7 ASPIRIN
Analgesic, anti-inflammatory, and antipyretic property of aspirin was
unknown till the mid-twentieth century. Heinrich Dreser reported that the
aspirin directly acts on the CNS and gets pain relieved. Later, a biochemist
named Harry Collier (in 1958) from Parke Davis started work to understand
the relationship between kinins and the effects of aspirin. Later, Dreser
COOH
O Me
O
Aspirin
introduced aspirin (Aspro, Empirin) as a medicine.
He found some evidences that aspirin worked directly pain and inflammation rather
than on the CNS while experimenting on guinea pigs by giving them aspirin which
inhibited the bronchoconstriction effects of bradykinin. Later, Collier collaborated with
pharmacologist John Vane at the Royal College of Surgeons, England and they found that
aspirin inhibited the release of an unidentified chemical generated by guinea pig lungs, a
chemical that caused rabbit tissue to contract. In 1971, Vane identified the chemical (which
they called “rabbit-aorta contracting substance” or RCS) as a prostaglandin where they
suggested that aspirin and similar drugs (the non-steroidal anti-inflammatory drugs or
NSAIDs) worked by blocking prostaglandin syntheses. Later research showed that NSAIDs
such as aspirin worked by inhibiting COX, the enzyme responsible for converting
arachidonic acid into a prostaglandin.
It is a non-steroidal anti-inflammatory drug (NSAID) with a wide range of physiological
effects. It can be used to treat and prevent heart attacks and blood clots at very low doses.
It can also be used as an analgesic to reduce pain and as an antipyretic to reduce fever at
high doses. Moreover, it is an effective anti-inflammatory agent used to treat rheumatic
fever, gout and rheumatoid arthritis. It is also an anticoagulant as it dissolves corns and
calluses and provokes loss of uric acid (a toxin) but promotes retention of fluids in the
kidneys. It kills bacteria and induces peptic ulcers. The exact mechanisms of its
pharmacological actions are still under study. It is not advisable to keep aspirin products
in the kitchen or bathroom cabinets because aspirin is slowly decomposed into acetic and
salicylic acids in the presence of heat and moisture.
3.7.1 Specification
Name : 2-(Acetoxy) benzoic acid
Molecular formula : C
9H8O4
Molecular Weight : 180.157 g/mol
Melting Point : 135°C
Physical state : Odourless; colourless to white crystalline powder
Solubility : Soluble and aqueous and organic media
3.7.2 Synthesis of Aspirin
The reaction between salicylic acid and acetic anhydride, in the presence of a catalytic
amount of an acid (sulphuric acid and occasionally phosphoric acid) leads to an ester
called aspirin and so the process is also known as esterification.
COOH
Reaction mechanism
OH
Me
Analgesics, Antipyretic and Anti-Inflammatory Agents 69
O
O
Me
O
+
H
COOH
Me
O
CH3COOH
O
+
H
O
OOMe
O
Me
O
H
O
-CH3COOH
Me
OH
+
Me
COOH
A
O
H
COOHCOOH
O
HO
COOH
H
Me
O
O Me
A
O
Me
-AH
O
A
H
COOH
O
HO
AH
COOH
O
Me
O
O Me
O
Me
3.7.3 Mode of Action of Aspirin
Intake of aspirin results in several different effects in the host body such as prevention of
clotting, reduction of inflammation, relief of pain (analgesia) and the reduction of fever. It
is believed that aspirin causes low production of prostaglandins and Thromboxane A2
(TXA2) in the body due to its irreversible inactivation of the COX enzyme which was
discovered by British pharmacologist, John Robert Vane in 1971 (Fig. 3.5). The COX enzyme
is required for the synthesis of prostaglandin and thromboxane. Active site of COX enzyme
contains serine residue which can covalently attach to the aspirin. Aspirin acts as an
acylating agent for the serine residue. At least two different types of COX occur: COX-1
and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of
COX-2. COX-2 normally produces prostanoids, most of which are proinflammatory.
aspirin-modified PTGS2 produces lipoxins, most of which are anti-inflammatory. Newer
NSAID drugs, COX-2 inhibitors (coxibs), have been developed to inhibit only PTGS2, with
the intent to reduce the incidence of gastrointestinal side effects. This makes aspirin
different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible
inhibitors. However, other effects of aspirin, such as uncoupling oxidative phosphorylation
in mitochondria (by diffusing from the inner membrane space as a proton carrier back into
the mitochondrial matrix) where it ionizes once again to release protons. In short, aspirin
buffers and transports the protons (acting as a competitor to ATP synthase) and the
modulation of signalling through NF-NjB (Nuclear Factor Kappa-light-chain-enhancer of
activated B cells, which is a protein complex that controls transcription of DNA), are also
being investigated.
70 Pharmaceutical Chemistry
The high doses of aspirin may actually cause fever due to the heat released from the
electron transport channel, however, an antipyretic action of aspirin has been seen with
lower doses. Recent data also suggests that salicylic acid and its derivatives modulate
signalling through NF-NjB. NF-NjB is a transcription factor complex that plays a central role
in many biological processes, including inflammation.
O
COOH
O
O
OH
Thromboxane A2
Fig. 3.5: Structure of Thromboxane-A2 and I2-Prostacylin
Me
HO
I
-Prostacyclin
2
HO
COOH
Me
3.7.4 Aspirin Metabolism
Aspirin undergoes ester hydrolysis in the gut and subsequently in the blood. Salicylic acid
is a weak acid and very little of it is ionised in the stomach after oral administration.
Aspirin is poorly soluble in the acidic conditions and therefore poorly absorbed in the
stomach. Aspirin irritates the gastric mucosa due to a direct acid effect and also inhibits
the synthesis of cytoprotective prostaglandins (viz., PGE2) which can lead to
bronchoconstriction (aspirin asthma).
In the small intestine, more of the salicylate is dissolved at elevated pH and is rapidly
absorbed due to the increased surface area in that region of the gut. The effects of aspirin
outlast its presence in plasma where t
inhibited due to covalent binding of the acetyl residue to serine-530 in the enzyme. Then
the duration of the effect depends on the rate of resynthesis of the enzyme. Aspirin is more
selective for COX-1 in its inhibitory action. Furthermore, the concentration of free salicylate
in the plasma may contribute to the effect. About 50–80% of salicylate in the blood is
protein bound. Saturation of binding sites leads to more free salicylate and increased
toxicity. Aspirin inhibits platelet aggregation and thus prolongs bleeding time; thus it
should not be used in patients with impaired blood coagulation. As much as 80% of the
therapeutic dose of salicylic acid is metabolised in the liver. Salicylate conjugates with
glycine to produce salicyluric acid, while with glucuronic acid, salicyl acyl and phenolic
glucuronide are generated. Small amounts of salicylic acid are also hydroxylated to gentisic
acid. With large salicylate doses, the kinetics switch from the first order to zero order, as
metabolic pathways become saturated and renal excretion becomes increasingly important.
Salicylate is excreted by the kidneys in the form of salicyluric acid (75%), free salicylic acid
(10%), salicylic phenol (10%), acyl (5%) glucuronides, and gentisic acid (< 1%) (Fig. 3.6).
is approximately 20 min since COX are irreversibly
1/2
Analgesics, Antipyretic and Anti-Inflammatory Agents 71
Aspirin
O
OH
O
MeO
Fig. 3.6: Metabolism of aspirin
O
Me OH
Acetic acid
O
N
H
OH
Salicyluric acid Gentisic acid
+
Conjugation
with glycine
OH
O
O
OH
Salicylate
O
Oxidation
HO
O
OH
OH
3.7.5 Side Effects
An allergic reaction to aspirin may lead to difficulty in breathing, hives, swelling in face,
lips, tongue, or throat, ringing in your ears, confusion, hallucinations, rapid breathing,
seizures (convulsions), severe nausea, vomiting, or stomach pain, bloody or tarry stools,
coughing up blood or vomit that looks like coffee grounds, fever lasting longer time, upset
stomach, heartburn, drowsiness, and mild headache.
3.7.6 Avoidance of Aspirin
Individuals having bleeding disorder such as haemophilia.
Individuals allergic to an NSAIDs (non-steroidal anti-inflammatory drugs) such as
Advil, Motrin, Aleve, Orudis, Indocin, Lodine, Voltaren, Toradol, Mobic, Relafen,
Feldene, etc.
Avoid medication to a child or teenager with a fever, flu symptoms, or chicken pox.
Salicylates can cause Reye’s syndrome, a serious and sometimes fatal condition in
children.
Women pregnant or planning to become pregnant and breast feeding.
Individuals drinking alcohol (alcohol may increase your risk of stomach bleeding).
3.8 IBUPROFEN
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). It
works by reducing hormones that cause inflammation and pain in
the body. Ibuprofen is used to reduce fever and treat pain or
inflammation caused by many conditions such as headache,
toothache, back pain, arthritis, menstrual cramps, or minor injury.
Ibuprofen
Me
COOH