A presentation on Analgesics which includes basic terminologies, mechanisms and pathway for pain, pharmacology of pain receptors and synthesis of related medicinal compounds.
2. Nociception and Pain
Nociception is the mechanism whereby noxious peripheral stimuli are
transmitted to the central nervous system.
Pain is a subjective experience and difficult to quantify, is very
important protective phenomenon that accompanies many
pathological conditions and is not always associated with
nociception (or) an unpleasant sensory and emotional experience
with actual or potential tissue damage.
Superficial:
- Stimulation of skin & mucous membranes
- Fast response
Deep:
- Arises from muscles, joints, tendons, heart ..etc.
- Slow response
Analgesia – absence of pain
3. Pain receptors in our bodies are nerves that transmit pain.
These are free nerve endings located in various body
tissues that respond to thermal, mechanical and chemical
stimuli.
When stimulated, these pain receptors generate an
impulse. The pain results of various impulses arriving at
the spinal cord and the brain.
When tissues become injured, they release chemicals
called prostaglandins and leukotrienes that make the
pain receptors more sensitive and thus causing pain.
4. Acute Vs chronic
Acute pain Chronic pain
Sudden onset
Temporary (disappears
once stimulus is removed)
can be somatic, visceral,
referred
Associated anxiety
Physiological responses to
acute pain include increased
RR, HR, BP and reduction in
gastric motility – sympathetic
response)
Persistent – usually lasting
more than six months
Cause unknown – may be
due to neural stimulation or a
decrease in endorphins
Physiological responses are
less obvious especially with
adaptation.
Psychological responses
may include depression
5. Nociceptive Vs Neuropathic
Nociceptive pains result from activation of
nociceptors (Pain receptors)
Neuropathic pains result from direct injury to nerves
in the peripheral nervous system
6. Somatic Vs Visceral
Somatic pain
Superficial: stimulation of receptors in skin
Deep: stimulation of receptors in muscles, joints and
tendons
Visceral pain
Stimulation of receptors in internal organs, abdomen and
skeleton
Often poorly localised as fewer receptors located in viscera
Visceral pain can be referred.
7. Referred pain
Pain experienced at a point distant to its point of origin
Area of referred pain is supplied by same spinal segment as
actual site of pain
Brain misinterprets signals as coming from somatic regions
Knowledge of different types of referred pain is important in
clinical diagnosis because in many visceral ailments the only
clinical signs is referred pain.
8. Somatogenic Vs Psychogenic
Somatogenic pain is a pain originating from an actual
physical cause e.g. trauma, ischaemia etc
Psychogenic pain is pain for which there is no physical
cause. It is not however imaginary pain and can be as
intense as somatic pain.
9. Pain pathway
There are four processes in the pain pathway
Transduction
Noxious stimuli translated into electrical activity at sensory
nerve endings
Transmission
Propagation of impulses along spinothalamic pathway.
Modulation
Transmission is modified
Perception
Affective / motivational aspect
Each of these processes present a potential target for analgesic
therapy
10. Cell Membrane Phospholipids
Arachidonic Acid
Endoperoxides
Thromboxane
Prostaglandins Prostacyclin
Toxic Oxygen Radicals
Cyclo-oxygenase
C
O
X
Phospholipase
Tissue Trauma
11. Action of cyclo-oxygenase
COX – 1 enzyme
Constitutive pathway
(stable conc)
phospholipid
Arachidonic acid
Prostaglandins associated with
normal body functions
e.g. prostaglandin E2 (for
kidney function), prostaglandin
I2 (for stomach protection)
COX-2 enzyme
Induced
pathway
phospholipid
Arachidonic acid
Inflammatory
prostaglandins
12. NSAIDS: Mode of action
NSAIDS block both COX-1 and COX-2
This accounts for most of the side effects of NSAIDS
Different types of NSAIDS have different specificities
for COX-1 and COX-2
This contributes to differences in side effects between
the NSAIDS.
14. Analgesics / Pain killers are common pain relievers acting centrally
to elevate pain threshold without disturbing consciousness or
altering other sensory modalities.
Many analgesics also have antipyretic properties as well. They can
be used to reduce fever
Some analgesics are also anti-inflammatory and anti-clotting drugs
as well
Classification:
(i) Opioid analgesics / Narcotic analgesics / Morphine like substances
– predominantly acts on CNS
(ii) Non-opioid analgesics / NSAID – predominantly acts on
peripheral nerves
16. Mild analgesics
They work by blocking the enzyme-controlled
synthesis of prostaglandins.
The main effects of prostaglandins are:
The constriction of blood vessels, which helps
increase the body temperature.
Direct effect on the body’s heat regulating centre,
hypothalamus, which produces fever.
Increase of the permeability of capillaries which
allows water to pass to the tissue and cause pain
and swelling.
17. Natural Painkillers
They are produced naturally in the body.
Endorphins and Enkephalins are the natural
opiates found in the part of the brain and the
spinal cord that transmit pain impulses.
They are able to bind to neuro-receptors in the
brain and produce relief from pain.
The temporary loss of pain immediately after an
injury is associated with the production of
these chemicals.
18. Strong analgesics
They temporarily bind to the opiate receptor sites in the brain
preventing the transition of pain impulses
-The opium alkaloids:
Opiate: it is a natural or synthetic drug that exerts actions on the body
similar to those induced by morphine.
Narcotic: is a term generally used for drugs that have both a narcotic
and analgesic
Narcotic analgesics mainly acts by opioid receptor (GPCR),
(i) Mu – responsible for most of the analgesic effects of opioids, and
for some major unwanted effects like respiratory depression,
euphoria, sedation and dependence
(ii) Kappa – Contribute to analgesia at the spinal level, and may elicit
sedation and dysphoria, but produce relatively few unwanted effects,
and do not contribute to dependence
(iii) Delta- important in the periphery, but may also contribute to
analgesia
19. (iv) σ-receptors - not true opioid receptors, but are the site of action
of certain psychotomimetic drugs, with which some opioids interact
Note:
All opioid receptors are linked through G-proteins to inhibition of
adenylate cyclase.
They also facilitate opening of K+ channels (causing
hyperpolarisation), and inhibit opening of Ca2+ channels (inhibiting
transmitter release).
These membrane effects are linked to the decrease in cAMP
formation.
24. (i) Synthesis of Salicylates
a) Synthesis of Aspirin
b) Synthesis of Salsalate
25. c) Synthesis of Sulphasalazine
(ii) Synthesis of P-amino phenol derivatives
a) Synthesis of Phenacetin
b) Synthesis of paracetamol
26. (iii) Synthesis of 3,5-pyrazolidine diones
a) Synthesis of phenylbutazone
(iv) Synthesis of Anthranilicacid derivatives
a) Synthesis of Flufenamic acid
b) Synthesis of Mefenamic acid
Ullman condensation is type of
Aromatic amination reaction
between aryl halogen acids and
aryl amines
27. (v) Synthesis of Indole acetic acid derivatives
a) Synthesis of Indomethacin
28. (vi) Synthesis of Indene acetic acid derivatives
a) Synthesis of Sulindac
Reformatski is an organic reaction, which condenses aldehydes or ketones with
α-halo esters using a metallic zinc to form β-hydroxy-esters.
29. Vii) Synthesis of Pyrrole acetic acid Derivatives
a) Synthesis of Tolmetin Sodium
b) Synthesis of Zomepirac
30. Viii) Synthesis of Aryl acetic acid derivatives
a) Synthesis of Ibufenac
b) Synthesis of Diclofenac
Wolf-kishner reduction is a chemical rxn that fully reduces a ketone or aldehyde
to an alkane. It involved heating the hydrazine with Na-ethoxide in a sealed vessel
at about 180 °C. Diethylene glycol (DEG) is usually used as solvent.
Willgerodt oxidation is is an organic rxn converting an aryl alkyl ketone to the
corresponding amide and carboxylic acid as side rxn product by reaction with Sulphur,
Con. NH4OH and pyridine.
31. ix) Synthesis of Aryl propionic acid derivatives
a) Synthesis of Ibuprofen
b) Synthesis of Fenoprofen
32. X) Synthesis of Heteroaryl acetic / propionic acid derivatives
a) Synthesis of Caprofen
Xi) Synthesis of Oxicams
a) Synthesis of Piroxicam
33. Xii) Synthesis of COX-2 inhibitors
a) Synthesis of Celecoxib
Xiii) Synthesis of Miscellaneous agents
a) Synthesis of Nimesulide
34. SAR of Salicylates
-a) Subst. on either the –COOH or –OH grp may affect the potency and toxicity.
-b) Reducing the acidity of –COOH grp retains the analgesic action but is devoid of
-Anti-inflammatory property. E.g. Salicylamide
-c) Placing the –OH grp meta / para to –COOH grp totally abolishes the analgesic activity.
d) Subst. with halogens on the aromatic ring will increases the potency as well as
-toxicity.
e) Subst. of aromatic ring at the 5th posn of salicylic acid increases the anti-
inflammatory activity. E.g. Diflunisal
SAR of p-amino phenol derivatives
a) Esterification of the phenolic grp with methyl or propyl grps produces derivatives with
greater side effects than ethyl derivatives.
b) Subst. on the N2 atom which reduces the basicity, and also reduce activity unless the
subst. is metabolically labile. e.g. acetyl
c) Amides derived from –COOH are less active or inactive. e.g. N-phenyl benzamides.
35. SAR of 3,5-pyrazolidinediones
a) Pharmacological activity is related to the acidic H at 4th posn. Thus, presence of
dicarbonyl grp at 3rd & 5th posn increases the acidity of H atom at the 4th posn.
b) Decreasing or eliminating the acidity by removing the acidic H at the 4th posn may
completely abolishes anti-inflammatory activity. e.g. 4,4-dialkyl derivatives.
c) If acidity is increased too much, anti-inflammatory & Na retaining activity decreases,
while other property such as the uricosuric effect increases.
d) A single alkyl grp at the 4th posn increases the anti-inflammatory activity. Although
n-butyl group increases the activity more.
e) Presence of keto group in the γ-posn of the butyl side chain produces the active
compound with better anti-inflammatory activity.
f) Presence of γ-OH-n-butyl derivative possesses pronounced uricosuric activity but gives
lesser anti-inflammatory activity.
g) Subst. of 2-phenyl thio ethyl group at the 4th posn produces anti-gout activity
e.g. Sulphin pyrazone.
i) Presence of both phenyl group is essential for both anti-inflammatory & analgesic activity.
g) m-Subst. in one of the aryl rings gives inactive compounds, but p-Subst. with –CH3, -Cl,
NO2 or OH in one of the phenyl rings retains the activity.
h) Replacement of one of the N2 atom with an O2 atom yields Isoxazole analogs which are as
active as pyrazolidinediones.
36. SAR of Anthranilic acid derivatives
•a) The position of the –COOH group is more important for the activity whereas
the m & p-amino benzoic acid analogs are not active.
b) Replacement of –COOH group with the Isosteric tetrazole results in the retention of
anti-inflammatory activity.
c) Subst. on the anthranilic acid ring generally decreases the activity.
d) Subst. on the N-aryl ring can leads to conflicting results. (i.e.) In the UV erythema
assay for anti-inflammatory, the order of activity was, 3’> 2’> 4’ for monosubst.
With CF3 grp (Flufenamic acid) being particularly potent.
e) The opposite order of activity was observed in Rat Paw oedema assay, that is 2’-Cl
> 3’-Cl analogs.
37. f) In disubst. derivatives, the nature of two subst. is the same, 2’,3’-disubst. appears to
be the most effective. E.g. Mefenemic acid
g) The –NH group of anthranilic acid is essential for the activity, since replacement of
–NH group with O, CH2, S, SO2, N-CH3 or NCOCH3 functionality significantly
reduces the activity.
SAR of Aryl alkanoic acid derivatives
a) All the agents posses a centre of acidity, which can be represented by –COOH,
an enol, hydroxamic acid, sulphonamide or tetrazole.
b) The centre of acidity is generally located one carbon atom adjacent to a flat
surface represented by an aromatic / heteroaromatic ring.
c) The distance between these centres is critical because increasing this distance to
2 or 3 carbons generally decreases the activity.
d) Susbt. of –CH3 group on the carbon atom separating the aromatic ring tends to
increase the anti-inflammatory activity.
38. SAR of Indole acetic acid derivatives
a) Replacement of the –COOH group at 3rd posn with other acidic functionalities
decreases the activity. Amide analogs are inactive.
b) Subst. at R1, useful for increasing anti-inflammatory activity are ranked as
C6H4CH2 > CH3 > H
c) Acylation of the Indole Nitrogen with aryl / alkyl carboxylic acids results in the
decreasing of activity.
d) The N-benzoyl derivatives subst. in the Para position with F, Cl, CF3 & S-CH3
groups are the most active.
e) At the 5th position, X-subst. activity are ranked as OCH3 > F > N(CH3)2 > CH3 >
COCH3 > H than the unsubstituted analogs.
f) Presence of Indole ring nitrogen is not essential for activity because the
corresponding 1-benzylidenylindene analogs (i.e. Sulindac) is also active.
g) CH3 group at 2nd position are more active than aryl subst. analogs.
h) Subst. of CH3 group at the α-position of the acetic acid side chain leads to equally
active analogs.
i) Anti-inflammatory activity is displayed only by the dextrorotatory enantiomer (25
times more active than phenylbutazone)
39. SAR of Pyrrole aceticacid derivatives
a) Replacement of p-Tolyl group with p-chloro benzoyl group produces little effect on
activity.
b) Introduction of –CH3 group in the 4th position and p-chloro benzoyl analog (i.e.
Zomepirac) was 4 times as potent as Tolmetin.
SAR of Oxicams
a) Most active analogs have subst. –CH3 group on the N2 and electron withdrawing subst.
like Cl, CF3 on the anilide phenyl group.
b) Introduction of heterocyclic ring in the amide chain significantly increases the anti-
inflammatory activity. (e.g.) Sudoxicam (2-thiazolyl ring) is potent than Indomethacin.
c) Interchanging of benzene ring with Thiophene gives biologically active compounds.
(e.g.) Tenoxicam.
40. SAR of COX-2 Inhibitors
- Diaryl heterocycle with Cis-Stilbene moiety and changes in the Para position of one of the
aryl rings play an important role in the COX-2 selectivity.
(e.g) Celecoxib – SO2NH2 grp
Parecoxib – SO2NHCOCH3 grp (Prodrug for Valdecoxib)
Rofecoxib and Etoricoxib – SO2CH3 grp
- The oxidation state on the sulphur is important for selectivity.
- Sulfones and Sulfonamides are selective for COX-2 but Sulfoxides and Sulfides are not.
41. Narcotic Analgesics / Opioid analgesics
These are naturally occurring, semi-synthetic and synthetic drugs, which have morphine like
action (i. e) relief from pain and depression of CNS associated with drug dependence (Mental
and Physical) and withdrawal side effects.
Therapeutic Uses
- Management of pain (Acute / Chronic / Severe)
- Cough Suppression
- Treatment of Diaarhoea.
- Management of acute pulmonary oedema & acute MI
- Pre-operative medication & Intra-operative adjunctive agents in anaesthesia
Side effects
- Respiratory depression
- Physical dependency & addiction
- Nausea, Vomiting & Constipation
Classification
I) Morphine analogs
R’RName
HHMorphine
HC2H5Ethyl
morphine
HCH3Codeine
COCH3COCH3Heroine
51. Bischler-Napaieralski reaction is an intramolecular electrophilic
aromatic substitution reaction that allows for the cyclization of β-
arylethylamides or β-Arylethylcarbamates. The reaction is most
notably used in the synthesis of isoquinolines in presence of
POCl3.
Birch reduction is the organic reduction of aromatic rings in liquid
ammonia with sodium, lithium or potassium and an alcohol, such
as ethanol and tert-butanol. This reaction is quite unlike catalytic
hydrogenation, which usually reduces the aromatic ring all the way
to a cyclohexane. It converts aromatic compounds having a
benzenoid ring into a product, 1,4-cyclohexadienes, in which two
hydrogen atoms have been attached on opposite ends of the
molecule.
53. Knoevenagel condensation is a nucleophilic addition of an active
hydrogen compound to a carbonyl group (aldehyde or ketone)
followed by a dehydration reaction in which a molecule of water is
eliminated (hence condensation). The product is often an alpha,
beta conjugated enone. The catalyst is usually a weakly basic
amine
54. Synthesis of Meperidines / Phenyl(ethyl)Piperidines
Synthesis of Meperidine / Pethidine
Synthesis of Ketobemidone
63. SAR of Morphine
(i) Modification on alicyclic ring:
-The alcoholic OH group at C-6 when methylated, esterified, oxidized, removed or
replaced by halogen means analgesic activity and toxicity increases.
-Saturation of the double bond at C-7 results in more potent compound. (e.g).
Dihydromorphine, Dihydro codeine
-The 14-β-OH group generally increases μ-agonistic property and decreases the antitussive
activity.
-Bridging of rings through ethylene linkage gives potent derivatives. (e.g) Buprenorphine,
Etorphine (1000 times more potent than morphine as μ-agonist)
(ii) Modification on phenyl ring:
-Aromatic phenyl ring is essential for activity.
-Modification on phenolic –OH group decreases the activity.
-Any other substitution on phenyl ring decreases the activity.
64. (iii) Modification of 30 Nitrogen atom:
-Presence of 30 Nitrogen atom is necessary for good opioid activity.
-The size of the N-substitution only determines the compounds potency, it’s agonistic and it’s antagonistic
property. (e.g) N-CH3 leads to good agonistic property.
Increased the size of substitution by 3-5 carbon atoms lead to antagonistic property.
Still larger substitution on N-atom lead to agonistic property.
N-allyl and N-cyclo alkyl group lead to antagonistic property
(iv) Modification of Epoxide / Ether bridge:
-Removal of 4,5-epoxide bridge in morphine results in morphinans.
-Only levo isomer of morphinan possess opioid activity (e.g) levorphanol – more potent than morphine.
Dextro isomer possess anti-tussive activity.
.
65. SAR of Phenyl (ethyl)piperidines / Meperidine analogs:
-Replacement of C-4 phenyl group of meperidine by H, alkyl, aryl, aralkyl and heterocyclic
group decreases the analgesic activity.
-Introduction of m-OH group on the phenyl ring increases the activity.
-Presence of phenyl and ester group at 4th position of 1-methyl piperidine results in optimum
activity.
-Replacement of the carbethoxy group in Mepiridine by acyloxy group gave better analgesic
as well as spasmolytic.
-Replacement of phenyl group by phenylethyl derivative is seems to be 3-times as active as
Mepiridine. The amino congener is 4 times more active (Anileridine)
Enlargement of piperidine ring to 7-membered hexahydro azepine is less active but has low
incidence of side effects. (e.g) Proheptazine
-Contraction of piperidine ring to pyrrolidine gives more active compound but causes abuse
liability (e.g) Alphaprodine and Procilidine.
-In fentanyl, the phenyl and acyl groups are separated by Nitrogen. It is 50 times stronger than
morphine with minimal side effects. It’s short duration of action makes it well suited for use
in anaesthesia.
-The C-3 methyl analog with an ester group at C-4 like lofentanil is 8400 times more potent
than Meperidine as an analgesic. P-Chloro analog loperamide cannot penetrate BBB
sufficiently to produce analgesia.
-Diphenoxylate, a structural hybrid of Meperidine and Methadone is devoid of analgesic
activity. It is effective in the treatment of diarrhoea.
66. SAR of Diphenyl Heptanone / Methadone analogs:
-The levo Isomer of Methadone and Isomethadone are twice as effective as their racemic
mixture.
-Removal of any one of the phenyl group sharply decreases the activity.
-Placement of m-OH group in any of the phenyl ring decreases the analgesic activity.
-Replacement of terminal dimethylamino group at R4 by piperidine group decreases the
activity.
Replacement of propionyl group at R4 by H, OH or acetyloxy group leads to decreased
activity, where as amide, pyrrolidinoyl, morpholino group increased the activity by
several times (e.g) Dextromoramide
SAR of Benzomorphan / Benzazocine analogs:
-Trimethyl compound (R1=R2= CH3) is more active than dimethyl (R1=H, R2= CH3)
compound.
-Placement of N-phenyl ethyl results in more activity than N-Methyl compound.
-Placement of –OH group at C-9, decreases the activity.
-N-allyl or N-cyclo propyl methyl group confers antagonistic activity (e.g) Levorphanol,
Naloxone and Naltrexone.
