Analgesics and NSAIDS, Definition-classification, SAR,Synthesis,Uses,Adverse effects.

1. PRESENTED BY
SURYADEVARA SIREESHA B.PHARM
.
VIGNAN PHARMACY COLLEGE.
Approved by PCI,AICTE, New Delhi. Affiliated to JNTU,Kakinada.
Vadlamudi -522213, Guntur, A.P.

2. CONTENTS:
 Introduction of Pain.
 Pain management.
 Treatment.
 Opium.
 Chemistry of morphine.
 SAR.
 Synthesis.
 Uses.
 Adverse effects.
 NSAIDs.
 New approach.
 Conclusion.
 References.
2

3. CENTRAL ANALGESICS
Agents that decreases acute and some type of chronic pain
are referred as analgesics or analgetics.
PAIN:
Pain is defined as an unpleasant, sensory and emotional
experience associated with actual or potential tissue damage.
Pain is apart of our body’s defense system, it produces a
reflexive, retraction from the painful stimulus and to protect
the affected body part while it heals.
3

4. ACUTE CHRONIC
It is normally
predicted
physiological
response.
E.g.: sprains &
broken bones
etc…,
It is unrelenting,
not-self limiting and
persist from months
to years.
E.g.: osteoporosis,
cancer etc..,
4

5. MECHANISM OF PAIN 5

6. PAIN MANAGEMENT
MILD
If pain
persist
SEVERE
Step:3 potent opioid +/-non
opioid or analgesic adjuvant.
MODERATE
If pain
persist
Step:2 less potent opioid + non opioid
+/- analgesic adjuvant.
Step:1 non opioid +/- analgesic
adjuvant.
6

7. TREATMENT:
 The pharmacological management of pain is the foundation of
pain therapy.
 Analgesics can be classified as :
1. Opioids.
2. Non-opioids.
3. Adjuvant or co-analgesics.
 Opioids are used for effective treatment of pain.
 Non-opioids are effective analgesics for mild to moderate pain.
 Adjuvant to some extent they give relief from pain , but are not
majorly used as analgesics. 7

8. OPIUM
Opium is the latex obtained from incisions
of unripe capsules of “papaver somniferum,” belongs
to family papaveraceae.
• Opium was well known to the ancients about 77 AD .
• It contains 30 alkaloids, the first group is morphine.
• Morphine consists of alkaloids which have a phenanthrene nucleus,
Whereas papaverine group have a benzylisoquinoline structure.
8

9. Phenanthrene
series
Morphine
Codeine
Thebaine
9 to 14
0.5 to 2
0.2 to 1
Benzyl
isoquinoline
series
Papaverine
Noscapine
Narcine
0.8 to 1
3 to 10
0.2 to 0.4
CLASS NAME OF
DRUG
% OF
OPIUM
PRESENT
9

10. CHEMISTRY OF MORPHINE:
 The morphine contains 5 rings.
 It is ‘T’ shaped molecule.
IUPAC NAME:
(5α, 6α) 7,8-didehydro 4,5-epoxy 17-methyl morphinan
3,6-diol.
10

11. MORPHINE
11
(S)
(R)
(R)
(S)
O N-CH3
HO
HO
H
1
2
3
4
5
6
7
14
9
10
11
16
17
12
13
8
A
D
C
E
B

12. STEREOCHEMISTRY:
 Natural morphine molecule exists as a single isomer.
 Naturally occurring levorotatory (-) morphine has 5R,
6S, 9R, 13S, 14R configuration.
 It undergoes epimerization at 14-position, but not
beneficial to analgesic activity.
 Carbons at 5,6,9,13,14 positions are chiral centers.
12

13. CHEMICAL FEATURES OF OPIUM:
POSITION MODIFICATION EFFECTS
Phenolic -OH
-OH to -OCH3
-OH to -OC2H5
Less analgesic, Cough
suppression.
Alcoholic -OH
-OH to -OCH3
-OH to -OC2H5
5 × morphine.
2.4 × morphine.
Allylic unsaturated
linkage
-CH=CH- to –CH2CH2- 1.2 × morphine.
Tertiary nitrogen N-CH3 to NH
N-CH3 to NCH2CH3Ph
< active than
morphine
14 × morphine.
13

14.  Morphine analogues were developed to combat the
problems due to usage of morphine.
1.VARIATION OF SUBSTITUENTS:
 Alkylation of phenolic –OH and N-demethylation lead to
the loss of analgesic activity.
MORPHINE ANALOGUES AS CENTRAL
ANALGESICS:
14

15. 2.DRUG DESECTION:
 Introduction of OH group at C-14 increases activity.
O
O
N-CH3
HO
OH
OXYMORPHINE
15
14

16.  Introduction of allyl cyclo propyl methylene group have
antagonist effect on NITROGEN atom.
 E.g: Naltrexone, Naloxone.
O
O
HO
N
NALTREXONE 16
allyl cyclo propyl methylene

17.  Phenyl ethyl group increases activity by 14 folds.
O
HO
HO
N
17
Phenyl ethyl

18. 3.SIMPLIFICATION :
A. Removing of ring E :-
 Complete loss of activity.
O
HO
HO
NO ACTIVITY. 18

19. B.Removing of ring D:-
Removal of epoxy Bridge produces morphinan with
analgesic activity indicating oxygen is not essential for
activity.
HO
NH
LEVORPHANOL LEVALLORPHAN
N
19
HO

20. C.Removing of ring C and D :-
Produces group of benzomorphous, which retain analgesic
activity.
N
CH3
CH3
PHENAZOCIN
H
N
CH3
CH3
METAZOCINE
OH
CH3
20

21. D.Removing of ring B,C and D :-
 It produces series of compounds known as 4-
phenyl piperidines.
 The activity increases by 6 times by introducing the
phenolic group.
N
N
C2H5OOC
FENTANYL
21

22. CLASSIFICATION OF ANALGESICS & SAR:
Central analgesics are majorily classified into four types:-
1.Morphine &its analogues .
2.Phenyl piperidines.
3.Diphenyl heptanones .
4.Benzazocin derivatives.
SAR OF MORPHINE & ITS ANALOGUES:
O
N
R1
R2
R3
22

23. DRUG R1 R2 R3
OTHER
CHANGES
Morphine -OH -OH -CH3 _
Heroin -OCOCH3 -OCOCH3 -CH3 _
Oxymorphine -OH =O -CH3 1,2
Levorphanol -OH -H -CH3 1,3
Codeine -OCH3 -OH -CH3 _
Oxycodone -OCH3 =O -CH3 1,2
1.Single bond instead of double bond between C-7 & C-8.
2. OH added to C-14.
3.No oxygen between C-5 & C-4.
23

24. SAR OF PHENYL PIPERIDERINES:
N
R3
R2
R1
NAME R1 R2 R3 ANALGESIC
ACTIVITY
Meperidine -CH3 -C6H5 -COOC2H5 1.0
Properidone -CH3 -C6H5 -COOCH(CH3)2 15.0
Ketobemidone -CH3 -C6H4OH -OCOC2H5 6.2
α-Prodine -CH3 -C6H5 -OCOC2H5 5.0
24

25. SAR OF DIPHENYL HEPTANONES:
R2
R1
DRUG R1 R2
ANALGESIC
ACTIVITY
Methadone -COC2H5 -CH2CH(CH3)N
(CH3)2
1
Isomethadone -COC2H5 -CH(CH3)CH2N
(CH3)2
0.65
Phenadoxone
-COC2H5
1.4
Dextromoramide 13
NC
H
O
N
CH3
CH3
N
O
25

26. SAR OF BENZAZOCIN DERIVATIVES:
N R1
C
CH3
CH3
R2
DRUG R1 R2
Pentazocine -CH2CH=C(CH3)2 H
Phenazocin -CH2CH2C6H5 H
Cyclozocin H
Ketazocin =O
C
C 26

27. SYNTHESIS OF METHADONE:
27
2-dimethyl aminopropyl
chloride
METHADONE
Diphenyl aceto
nitrile

28. SYNTHESIS OF MPERIDINE:
CN
+
Cl
NH2
N
CN
N
COOC2H5
MEPERIDINE
Phenyl acetonitrile
spiroalkylation
EtOH/HCL
H2O with NAOH
28
N-(2-chloroethyl)propan-1-amine

29. MECHANISM OF ACTION:
Opioid receptors.
Acts on G-Protein coupled receptors.
Inhibits Adenyl cyclase.
Promotes opening of K+ channels & inhibits opening of Ca+2 channels.
Reduces neuronal excitability & increases K+ conductance.
Causes hyper polarization & shows inhibitory pathway & relieves pain.
29

30. RECEPTORS
Opioid receptors are of 3 types. They are µ , k , δ.
COMPOUND µ k δ
PURE AGONIST:
Morphine
Methadone
Codeine
+ + +
+ + +
+
+
0
+
+
0
0
PARTIAL ANTAGONIST:
Bupreorphine
Butraphanol
Propiram
+ + +
+ +
+ +
_
+ + +
0
0
0
0
30

31. USES:
Opium and morphine are widely used as
analgesics to relieve pain.
 Used as hypnotic.
 Used to treat painful myocardial ischemia with pulmonary oedem.
 Used to treat cough.
 Euphoria, sedation.
 Pupillary constriction.
31

32. ADVERSE EFFECTS:
 Respiratory depression.
 Hypotension.
 Constipation.
 Urinary retention.
 CNS problems:
Mental clouding
Nausea.
Vomiting.
Headache.
Fatigue.
 Tolerance.
 Drug dependence.
32

33. MANIFESTATION OF OPIATE WITHDRAWL:
TIME MANIFESTATION
6-12hrs Intense carving for the drug, lethargy,
weakness.
12hrs Yawning, lacrimation, tremors &
anorexia.
48hrs Peak of withdrawal syndrome.
Fever, increase in B.P & heart rate.
7-10 days Symptoms clear up but restless, insomnia,
weakness & pain for several weaks. 33

34. OPIOID POISONING:
 Numerous reasons contribute to poisoning due to opioids.
 It may occur due to clinical over dosage & many times when
drug is ingested in large amounts with suicidal intentions.
SYMPTOMS OF TOXICITY:
1. Coma, decreased respiration, pulmonary oedema.
2. Cyanosis, hypothermia, hypotension.
3. G.I spasm.
34

35. Toxic & Lethal Dose:
Toxic dose-60mg.
Lethal dose-250mg.
TREATMENT:
1.Re-establishment of vital function such as respiration and blood
circulation by the use of ABCD intervention.
2. Gastric lavage, which is done using KMnO4 solution,
followed by stomach wash with sodium sulphate.
3. If opioids are ingested through oral route, then emetics and
cathartics are used.
4.Respiratory depression can be reversed by the use of specific
antidotes like naloxone. 35

36. DOSAGES:
 Dose for diagnosis of poisoning is 0.2-0.4mg
intravenously.
 Dose should be repeated twice or thrice every 2-3
minutes.
 In neonates, respiratory depression which results
from administration of morphine to mother during
delivery, is treated using 10µg/Kg naloxone given
through intravenous/intramuscular/subcutaneous
route.
36

37.  These are typically used to combat
inflammation.
 The clinical features of inflammation have been
recognized since ancient times as swelling,
redness, pain & heat.
 Inflammation can also cause disease due to
damage of healthy tissue.
37

38. CLASSIFICATION:
1.Salicylic acid derivatives: Aspirin, Salsalate, Diflunisol.
2.P-amino Phenol derivatives: Paracetmol, Phenacetin.
3.Pyrazoline dione derivatives : Phenyl butazone, Oxyphenbutazone.
4.Anthranilic acid derivatives : Mefenamic acid, Flufenamic acid.
5.Arylalkanolic acid derivatives:
(a)Indole acetic acid: Indomethacin.
(b)Indene acetic acid: Sulindac.
(c)Pyrrole acetic acid: Tolmetin.
38

39. 6.Oxicams: Pyroxicam, Meloxicam.
7.Miscellaneous: Nambumetone, Nimesulide, Analgin.
8.Selective COX-2inhibitors: Celecoxid, Rofecoxid.
MECHANISM OF ACTION:
 NSAIDs are reversible, competitive
inhibitors of co-activity.
 Drug inhibit irreversibly by acetylating
Co-enzymes.
 Inhibits prostaglandins synthesis.
39

40. DIFFERENT DERIVATIVES:
1. Salicylates.
2. P-amino phenol derivatives.
3. 3,5-pyrazolinediones.
4. Pyrazoline derivatives.
5. Anthranilic acid derivatives.
40

41. SALICYLATES:
DRUG R1 R2
Salicylic acid H H
Methyl salicylate CH3 H
sodium salicylate Na H
Phenyl salicylate C6H5 H
COOR1
OR2
41

42. P-AMINO PHENOL DERIVATIVES:
NHCOCH3
ACETANILIDE
NHCOCH3
0C2H5
PHENACITIN
NHCOCH3
OH
PARACETAMOL
42

43. 3,5-PYRAZOLINEDIONES:
DRUG R R4
Phenyl butazone H -C4H9
Oxyphenbutazone OH -C4H9
Sulphinpyrazone H -(CH2)2SOC6H5
N
N
H
O
O
R4
R
43

44. PYRAZOLONE DERIVATIVES:
DRUG R2 R4
Antipyrine CH3 H
Aminopyrine
CH3
N(CH3)2
Dipyrone CH3 CH3-N-CH2SO3Na
N
N
O
R4
CH3
R2
44

45. ANTHRANILIC ACID DERIVATIVES:
DRUG R1 R2 R3
Mefinamic acid CH3 CH3 H
Flufinamic acid H CF3 H
Meclofinamic acid Cl CH3 Cl
COOH
NH
R1
R2
R3
45

46. SYNTHESIS OF ASPIRIN:
SALICYLIC ACID ASPIRIN
46

47. SYNTHESIS OF PARACETAMOL:
P-AMINO PHENOL P-ACETAMINO PHENOL
47

48. SYNTHESIS OF NIMESULIDE:
48

49. SYNTHESIS OF MELOXICAM:
49

50. SYNTHESIS OF IBUPROFEN:
50
Benzyl isobutyl. Acetyl chloride
IBUPROFEN

51. USES:
 Anti-inflammatory.
 Analgesic.
 Anti-pyretic.
 Inhibition of platelet aggregation.
 Rheumatoid arthritis.
 Oseto arthritis.
 Gout.
 Myocardial infraction.
51

52. 52
NSAIDs GROUP SPECIFIC ADVERSE EFFECTS.

53. ADJUVANT ANALGESICS IN THE TREATMENT OF
PAIN:
CLASS DRUGS
Antidepressants. Amitriptyline, Imipramine,
venlafaxine.
Antiepileptic. Gabapentin, Carbamazepine,
Phenytoin.
Antiarrhythmics. Mexiletine.
Topical. Ketorolac, lidocaine
Steroids. Prednisone.
Muscle Relaxation. Cyclobenzaprine, Baclofen.
53

54. NEW APPROACHES
 Enkephalinase Inhibitors, Such as the
experimental drug RB120 Produce analgesia, together
with other Morphine – like effect, without causing
dependence.
 Agonists at nicotinic Ach receptors based on Epibatidine
(an alkaloid from frog skin), which is a potent nicotinic
agonist & unexpectedly a potent analgesic.
54

55. CONCLUSION
 Pain management is a challenging task, as it adversely affects the
patient life style and there cannot be a permanent relief from the pain
due to terminal illness like cancer.
 Use of medication depends on the symptom associated with disease
of the patient.
 Now a days a variety of drugs are available in the market to combat
the consequences of pain.
 They are useful for the treatment of the pain to improve the quality of
life of patient.
55

56. REFERENCES:
 Foye’s principals of medicinal chemistry-7th edition(Pg:658-695).
 Wilson & Gisvolds textbook of organic , medical & pharmacentical analysis –
12th edition(Pg:776-805).
 Remingtions – The science & practice of pharmacy vol-II-22th
edition(P.g:2679&2682).
 Basic & Clinical pharmacology by katzung – 11th edition(Pg:692-720).
 Rang & Dale’s pharmacology-6th edition.
 Trease & Evans pharmacognosy(Pg:357-363).
 Pharmacology & Pharmacotherapeutics -R.S.Satoskar – 12th edition.
56

57. 57