PRESENTED BY

SURYADEVARA SIREESHA B.PHARM

.

VIGNAN PHARMACY COLLEGE.

Approved by PCI,AICTE, New Delhi. Affiliated to JNTU,Kakinada.
Vadlamudi -522213, Guntur, A.P.
CONTENTS:
 Introduction of Pain.
 Pain management.
 Treatment.
 Opium.
 Chemistry of morphine.
 SAR.
 Synthesis.
 Uses.
 Adverse effects.
 NSAIDs.
 New approach.
 Conclusion.
2
 References.
 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
 ACUTE CHRONIC
It is normally It is unrelenting,
predicted not-self limiting and
physiological persist from months
response. to years.
E.g.: sprains & E.g.: osteoporosis,
broken bones cancer etc..,
etc…,

4
MECHANISM OF PAIN 5
 PAIN MANAGEMENT

Step:3 potent opioid +/-non

SEVERE
opioid or analgesic adjuvant.

If pain
persist

MODERATE Step:2 less potent opioid + non opioid

+/- analgesic adjuvant.
If pain
persist

Step:1 non opioid +/- analgesic 6

MILD
adjuvant.
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
7
majorly used as analgesics.
 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
 NAME OF % OF
CLASS OPIUM
DRUG
PRESENT

Morphine 9 to 14
Phenanthrene Codeine
series 0.5 to 2
Thebaine 0.2 to 1

Benzyl Papaverine 0.8 to 1

isoquinoline Noscapine 3 to 10
series
Narcine 0.2 to 0.4

9
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
 MORPHINE

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

11
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
CHEMICAL FEATURES OF OPIUM:

POSITION MODIFICATION EFFECTS

-OH to -OCH3 Less analgesic, Cough

Phenolic -OH -OH to -OC2H5 suppression.

-OH to -OCH3 5 × morphine.

Alcoholic -OH -OH to -OC2H5 2.4 × morphine.

Allylic unsaturated -CH=CH- to –CH2CH2- 1.2 × morphine.

linkage

Tertiary nitrogen N-CH3 to NH < active than

morphine
N-CH3 to NCH2CH3Ph 13

14 × morphine.
 MORPHINE ANALOGUES AS CENTRAL
ANALGESICS:

 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.

14
2.DRUG DESECTION:
 Introduction of OH group at C-14 increases activity.

HO

O
N-CH3
14
OH

OXYMORPHINE
15
 Introduction of allyl cyclo propyl methylene group have
antagonist effect on NITROGEN atom.

 E.g: Naltrexone, Naloxone.

HO
allyl cyclo propyl methylene

O
N

NALTREXONE 16
 Phenyl ethyl group increases activity by 14 folds.

HO

O
N

Phenyl ethyl
HO

17
3.SIMPLIFICATION :
A. Removing of ring E :-

 Complete loss of activity.

HO

HO

NO ACTIVITY. 18
B.Removing of ring D:-
Removal of epoxy Bridge produces morphinan with
analgesic activity indicating oxygen is not essential for
activity.
HO HO

N
NH

LEVORPHANOL LEVALLORPHAN

19
C.Removing of ring C and D :-
Produces group of benzomorphous, which retain analgesic
activity.

OH

H N
N CH3
CH3
CH3
CH3
CH3

PHENAZOCIN
METAZOCINE

20
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
C2H5OOC
N

FENTANYL

21
 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:

R1

O
N R3

22

R2
 R1 R2 R3 OTHER
DRUG CHANGES
-OH -OH -CH3 _
Morphine
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. 23

3.No oxygen between C-5 & C-4.

 SAR OF PHENYL PIPERIDERINES:
R3
N R1
R2

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
 SAR OF DIPHENYL HEPTANONES:

R2

R1

DRUG R1 R2 ANALGESIC
ACTIVITY
Methadone -COC2H5 -CH2CH(CH3)N 1
(CH3)2

Isomethadone -COC2H5 -CH(CH3)CH2N 0.65

(CH3)2

Phenadoxone CH3 1.4

N
-COC2H5 CH3

25
O
Dextromoramide N
13
O C N
H
SAR OF BENZAZOCIN DERIVATIVES:

C
CH3 N R 1
R2

CH3

DRUG R1 R2

Pentazocine -CH2CH=C(CH3)2 H

Phenazocin -CH2CH2C6H5 H

Cyclozocin C
H

Ketazocin C
=O 26
 SYNTHESIS OF METHADONE:

Diphenyl aceto 2-dimethyl aminopropyl

nitrile chloride

METHADONE 27
SYNTHESIS OF MPERIDINE:

CN Cl
spiroalkylation N
+ NH 2

Phenyl acetonitrile N-(2-chloroethyl)propan-1-amine CN

EtOH/HCL
H2O with NAOH

COOC2H5

MEPERIDINE

28
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
 RECEPTORS
Opioid receptors are of 3 types. They are µ , k , δ.

COMPOUND µ k δ

PURE AGONIST:

Morphine +++ + +
+++ 0 0
Methadone
+ + 0
Codeine
PARTIAL ANTAGONIST:

Bupreorphine +++ _ 0
++ +++ 0
Butraphanol
++ 0 0
Propiram 30
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
ADVERSE EFFECTS:
 Respiratory depression.
 Hypotension.
 Constipation.
 Urinary retention.
 CNS problems:
Mental clouding
Nausea.
Vomiting.
Headache.
Fatigue.
 Tolerance.
 Drug dependence.
32
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
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
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
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
 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
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
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
DIFFERENT DERIVATIVES:

1. Salicylates.

2. P-amino phenol derivatives.

3. 3,5-pyrazolinediones.

4. Pyrazoline derivatives.

5. Anthranilic acid derivatives.

40
SALICYLATES: COOR 1

OR2

DRUG R1 R2

Salicylic acid H H

Methyl salicylate CH3 H

sodium salicylate Na H

Phenyl salicylate C6H5 H 41

P-AMINO PHENOL DERIVATIVES:

NHCOCH 3 NHCOCH3

0C 2H5
PHENACITIN
ACETANILIDE
NHCOCH3

OH

PARACETAMOL

42
3,5-PYRAZOLINEDIONES:
H O
R4
N
O
N

DRUG R R4

Phenyl butazone H -C4H9

Oxyphenbutazone OH -C4H9
43
Sulphinpyrazone H -(CH2)2SOC6H5
 PYRAZOLONE DERIVATIVES:
CH 3
R4

O
N R2
N

DRUG R2 R4
Antipyrine CH3 H

Aminopyrine N(CH3)2
CH3

Dipyrone CH3 CH3-N-CH2SO3Na 44

ANTHRANILIC ACID DERIVATIVES:
COOH

R1
R2

NH

R3

DRUG R1 R2 R3
Mefinamic acid CH3 CH3 H

Flufinamic acid H CF3 H

Meclofinamic acid Cl CH3 Cl 45

SYNTHESIS OF ASPIRIN:

SALICYLIC ACID ASPIRIN

46
SYNTHESIS OF PARACETAMOL:

P-AMINO PHENOL P-ACETAMINO PHENOL

47
SYNTHESIS OF NIMESULIDE:

48
SYNTHESIS OF MELOXICAM:

49
SYNTHESIS OF IBUPROFEN:

Benzyl isobutyl. Acetyl chloride

IBUPROFEN

50
 USES:

 Anti-inflammatory.

 Analgesic.

 Anti-pyretic.

 Inhibition of platelet aggregation.

 Rheumatoid arthritis.

 Oseto arthritis.

 Gout.

 Myocardial infraction.
51
 52
NSAIDs GROUP SPECIFIC ADVERSE EFFECTS.
ADJUVANT ANALGESICS IN THE TREATMENT OF
PAIN:

CLASS DRUGS

Antidepressants. Amitriptyline, Imipramine,

venlafaxine.

Antiepileptic. Gabapentin, Carbamazepine,

Phenytoin.

Antiarrhythmics. Mexiletine.

Topical. Ketorolac, lidocaine

Steroids. Prednisone. 53

Muscle Relaxation. Cyclobenzaprine, Baclofen.

 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
 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
 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).

56
 Pharmacology & Pharmacotherapeutics -R.S.Satoskar – 12th edition.
57