2. NARCOTIC AND NON-NARCOTIC
ANALGESICS
Analgesics are agents that relieve pain by acting
centrally to elevate pain threshold without
disturbing consciousness or altering other sensory
modalities.
Certain analgesics like Aminopyrine and
Phenylbutazone also possess anti-inflammatory
properties.
Such substances and the gold compounds are
used in the treatment of arthritis.
3. Many drugs that are used to relieve pain are
not analgesics; ie.,
The general anesthetics relieves pain by
producing unconsciousness,
Local anesthetics prevent pain by blocking
peripheral nerve fibers,
Antispasmodics relieve pain by relaxing smooth
muscles and the adrenal corticoids relieve pain
associated with rheumatoid arthritis by anti-
inflammatory action.
4. Analgesics are classified into two major
categories:
1. Opioid analgesics or narcotic analgesics
(centrally acting).
2. Non-opioid analgesics (peripherally
acting).
5. Narcotic analgesics will be classified on the
basis of their structural derivation from
morphine.
They may be classified into following
categories:
1. Natural alkaloids of opium:
Morphine and codeine.
2. Semisynthetic analogs:
Hydromorphone,
Oxymorphone,
Oxycodone.
CLASSIFICATION
7. MORPHINE AND ITS DERIVATIVES
1. A rigid pentacyclic structure consisting of a benzene
ring (A), two partially unsaturated cyclohexane rings (B
and C), a piperidine ring (D) and a dihydrofuran ring
(E).
Rings A, B and C are the phenanthrene ring system.
This ring system has little conformational flexibility.
Ring A and its 3-hydroxyl group is an important
structural feature for analgesic activity.
Removal of the 3- OH group reduces analgesic activity
by 10-fold.
8. 2. Two hydroxyl functional groups, a C3-phenolic OH (pKa
9.9) and a C6- allylic OH.
3. An ether linkage between C4 and C5.
4. Unsaturation between C7 and C8.
5. A basic, 3°-amine function at position 17.
6. 5 Centers of chirality (C5, C6, C9, C13 and C14) with
morphine exhibiting a high degree of stereo-selectivity of
analgesic action. Only (-)-morphine is active
9. SAR of Morphine
SAR of Morphine was studied by
1. Modification of alicyclic ring
2. Modification of aromatic ring
3. Modification of 3 Nitrogen
4. Epoxide bridge.
10. 1. Modification on alicyclic ring
• The alcoholic hydroxyl group at C-6 when
methylated, esterified, oxydized, removed, or
replaced by halogen - analgesic activity as well as
toxicity of the compound increased.
• The reduction of C-6 keto group to C-6 β hydroxyl in
oxymorphone gives Nalbupine, it shows antagonistic
action of μ receptors.
• The saturation of the double bond at C-7 position
gives more potent compound. Examples, Dihydro
morphine and Dihydro codeine.
• The 14 β hydroxyl group generally enhances μ
agonistic properties and decreases antitussive
activity. However, activity varies with the overall
substitution on the structure.
11. • Bridging of C-6 and C-14 through ethylene
linkage gives potent derivatives.
• Reaction of thebaine with dienophile (i.ediel’s
alder reaction) results in 6, 14
endoethenotetrahydrothebaine derivatives,
which are commonly called ‘oripavines’. Some
oripavines are extremely potent μ agonist, for
example, Etorphine and Buprenorphine are the
best known. These derivatives are about
thousand times more potent than morphine as μ
agonist
12. • An aromatic phenyl ring is essential for
activity.
• Modification on phenolic hydroxyl group
decreases the activity.
• Any other substitution on phenyl ring
diminishes activity.
2. Modification on phenyl ring
13. • A tertiary amine is usually necessary for good
opioid activity.
• The size of the N substitution can dictate the
compounds potency and its agonists and its reverse
antagonistic property
• The N-methyl substitution is having good agonistic
property, when increased the size of the substitution
by 3–5 carbons results in antagonistic activity. Still
larger substitutent on N returns agonistic property of
opioids, for example, N-phenyl ethyl substitution is
ten times more potent than N-methyl groups. • N-
allyl and N-cylo alkyl group leads to narcotic
antagonistic property.
3. Modification of 3° nitrogen
14. • Removal of 3,4 epoxide bridge in morphine
structure result in the compound that is refered
to as morphinans.
• The morphinans are prepared synthetically. As
the synthetic procedure yielded compound is a
racemic mixture, only levo isomer possesses
opioid activity while the dextro isomer has useful
antitussive activity, for example, Levorphanol and
Butorphanol.
• Levorphanol is a more potent analgesic than
morphine.
4. Epoxide Bridge
17. PROPERTIES & USES:
It exists as a white or almost white crystalline powder or
colourless, silky needles or cubical masses, efflorescent in a
dry atmosphere.
It is soluble in water, slightly soluble in ethanol, and
insoluble in toluene.
Morphine is conjugated by hepatic enzyme at phenolic (3-
OH) position to from 3-glucuronide metabolite.
Glucuronidation of morphine also leads to Ndemethylation
to normorphine, which has decreased opioid activity and it
undergoes N and O conjucation and excreted.
Compounds with N-alkyl groups larger than methyl get N-
dealkylated as a major route of inactivation. It is used as an
opioid receptor agonist and analgesic.
18. STORAGE:
It should be stored in well-closed airtight containers and
protected from light.
DOSE:
The usual, adult, oral dose is 10 to 30 mg 6 times/day.
DOSAGE FORMS:
Chloroform and Morphine tincture I.P., B.P., Morphine
suppositories I.P., B.P., Morphine sulphate injection I.P.
19. Meperidine (Pethidine) analogues
results in rapid metabolism.
Esterase cleaves the ester bond to
leave the inactive 4-carboxylate
derivatives.
They also undergo N-demethylation
to give Nor meperidine.
MEPERIDINE ANALOG
21. PROPERTIES & USES:
It is a narcotic analgesic, having related chemical
structure to that of pethidine.
Anileridine is more active than merperidine and has
the same uses and limitations.
DOSE:
The usual oral dose is 25 mg every 6 h.
23. PROPERTIES & USES:
It is a white crystalline powder, soluble in water, and freely
soluble in alcohol.
It may be used for the relief of a variety of Pain (moderate
to severe pain), including the pain of labour and
postoperative pain.
Pethidine has atropine-like action on smooth muscle.
It is normally used to induce both sedation and analgesia
simultaneously.
STORAGE:
It should be stored in well-closed airtight containers and
protected from light.
DOSE:
Usual dose is 50 to 100 mg I.M. Occassionally given orally.
DOSAGE FORMS:
PethidineHCl injection I.P. PethidineHCl tablets I.P. Pethidine
injection B.P., Pethidinetablets B.P.
25. USES:
It is a synthetic analogue of pethidinewith some
analgesic activity,
But is mostly used in the treatment of diarrhoea
associated with gastroenteritis, irritable bowel, acute
infections, hypermotility, ulcerative colitis, and
sometimes even in food poisoning.
STORAGE:
It should be stored in well-closed airtight containers and
protected from light
27. PROPERTIES & USES:
It is a white or almost white powder soluble in water,
freely soluble in methanol, and sparingly soluble in
alcohol.
Fentanyl is related to pethidine and also to basic
anilides with analgesic properties, and is characterized by
high potency, rapid onset, and short duration of action.
It is a potent narcotic analgesic employed for the arrest
of pain and it may also be employed as an adjuvant for
all such drugs mostly used for regional and general
anesthesia.
28. STORAGE:
It should be stored in well-closed airtight container and
protected from light.
DOSE:
By I.M. in preoperative medication 0.05 to 0.1 mg, 30 to
60 min before surgical treatment, for rapid analgesic
action, 0.05 to 0.1 mg by IV.
DOSAGE FORMS:
Fentanyl injection B.P.
29. E. Loperamide.
STRUCTURE:
PROPERTIES & USES:
It is a white or almost white powder, slightly soluble in
water, freely soluble in alcohol and methanol.
It is used as a safe and effective opioid derivative with
pheripheral μ opioid and weak anticholinergic property.
STORAGE:
It should be stored in well-closed airtight container and
protected from light.
31. PROPERTIES & USES:
It is a white or almost white crystalline powder, freely
soluble in ethanol and soluble in water.
Even methadone, which looks structurally different from
other opioid agonists, has steric forces that produce a
configuration that closely resembles the opioid agonists.
Methadone metabolizes to form an active α-dinormethadol
and dinor-L-α-acetylmethadol (LAAM), then it undergoes N-
demethylation to form inactive pyrrolidines, an pyrrolines
which are excreted in urine.
Methadone is more active and more toxic than morphine.
It can be used for the relief of many types of pain.
In addition, it is used as narcotic substitute treatment
because it prevents morphine abstinence syndrome.
The toxicity of methadone is three to ten times that of
morphine, but its analgesic effect is twice that of morphine
and ten times that of meperidine
32. STORAGE:
It should be stored in well-closed airtight container and
protected from light.
DOSAGE FORMS:
Methadone HCl injection I.P., Methadone HCl tablets I.P.,
Methadone injection B.P., Methadone Linctus B.P.,
Methadone oral solution (1 mg/ml), B.P., Methadone
tablets B.P.
33. B. Propoxyphene hydrochloride.
STRUCTURE:
PROPERTIES & USES:
It is a white or almost white crystalline powder, very
soluble in water and freely soluble in alcohol.
It has no anti-inflammatory or antipyretic action and has
little antitussive activity despite the fact that its levo isomer is
used for this purpose.
It is used to control mild-to-moderate pain and used along
with other analgesics having anti-inflammatory and
antipyretic properties, such as paracetamol and aspirin.
34. STORAGE:
It should be stored in well-closed airtight containers and
protected from light.
DOSE:
The usual does is 65 mg, 3 or 4 times/day
DOSAGE FORMS:
Co-proxamol tablets B.P.
35. A. Pentazocine
STRUCTURE:
PROPERTIES & USES:
It is a white or almost white powder sparingly soluble in water,
soluble in ethanol, and sparingly soluble in methylene chloride.
A synthetic analgesic agent, when administered orally in a 50 mg
dose, it appears to be equivalent in analgesic effectiveness to 60
mg of codeine.
Pentazocine in a parenteral dose of 30 mg or an oral dose of 50
mg is about as effective as 10 mg of morphine in most patients.
There is some evidence that the analgesic action resides
principally in the (–) isomer, and a dose of 25 mg is approximately
equivalent to 10 mg of morphine sulphate.
MORPHANE ANALOG
36. B. Levorphanol tartarate.
STRUCTURE:
PROPERTIES & USES:
It is a white or almost white powder sparingly soluble
in water, soluble in ethanol, and sparingly soluble in
methylene chloride.
Its an opioid analgsic. It acts on certain centers in the
brain to give you pain relief.
