CENTRAL ANALGESICS & NSAIDs PRESENTED BY

SURYADEVARA SIREESHA B.PHARM

.

VIGNAN PHARMACY COLLEGE.Approved by PCI,AICTE, New Delhi. Affiliated to JNTU,Kakinada.

Vadlamudi -522213, Guntur, A.P.

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CONTENTS:

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

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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.

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PAIN

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..,

5MECHANISM OF PAIN

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PAIN MANAGEMENT

MILD

If pain persist

SEVEREStep: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.

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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.

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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.

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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

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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.

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MORPHINE

(S)

(R)

(R)

(S)

O N-CH3

HO

HO

H

1

23

4

5

67

14

9

1011

16

17

12

13

8

A

D

C

EB

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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.

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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.

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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:

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2.DRUG DESECTION:

Introduction of OH group at C-14 increases activity.

O

O

N-CH3

HO

OH

OXYMORPHINE

14

16

Introduction of allyl cyclo propyl methylene group have

antagonist effect on NITROGEN atom.

E.g: Naltrexone, Naloxone.

O

O

HO

N

NALTREXONE

allyl cyclo propyl methylene

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Phenyl ethyl group increases activity by 14 folds.

O

HO

HO

N

Phenyl ethyl

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3.SIMPLIFICATION :

A. Removing of ring E :-

Complete loss of activity.

O

HO

HO

NO ACTIVITY.

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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

HO

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C.Removing of ring C and D :-

Produces group of benzomorphous, which retain analgesic

activity.

N

CH3

CH3

PHENAZOCIN

HN

CH3

CH3

METAZOCINE

OH

CH3

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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

NC2H5OOC

FENTANYL

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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:

ON

R1

R2

R3

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DRUG R1 R2 R3OTHER 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.

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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

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SAR OF DIPHENYL HEPTANONES:

R2

R1

DRUG R1 R2ANALGESIC ACTIVITY

Methadone -COC2H5 -CH2CH(CH3)N (CH3)2

1

Isomethadone -COC2H5 -CH(CH3)CH2N (CH3)2

0.65

Phenadoxone-COC2H5

1.4

Dextromoramide

13NC

HO

N

CH3

CH3

N

O

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SAR OF BENZAZOCIN DERIVATIVES:

N R1C

CH3

CH3

R2

DRUG R1 R2

Pentazocine -CH2CH=C(CH3)2 H

Phenazocin -CH2CH2C6H5 H

Cyclozocin H

Ketazocin =O

C

C

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SYNTHESIS OF METHADONE:

2-dimethyl aminopropyl chloride

METHADONE

Diphenyl aceto nitrile

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SYNTHESIS OF MPERIDINE:

CN

+

Cl

NH2

N

CN

N

COOC2H5

MEPERIDINE

Phenyl acetonitrile

spiroalkylation

EtOH/HCL

H2O with NAOH

N-(2-chloroethyl)propan-1-amine

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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.

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RECEPTORSOpioid 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

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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.

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ADVERSE EFFECTS: Respiratory depression. Hypotension. Constipation. Urinary retention. CNS problems:

Mental clouding

Nausea.

Vomiting.

Headache.

Fatigue. Tolerance. Drug dependence.

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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.

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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.

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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.

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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.

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NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

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.

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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.

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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.

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DIFFERENT DERIVATIVES:

1. Salicylates.

2. P-amino phenol derivatives.

3. 3,5-pyrazolinediones.

4. Pyrazoline derivatives.

5. Anthranilic acid derivatives.

 

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SALICYLATES:

DRUG R1 R2

Salicylic acid H H

Methyl salicylate CH3H

sodium salicylate Na H

Phenyl salicylate C6H5H

COOR1

OR2

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P-AMINO PHENOL DERIVATIVES:

NHCOCH3

ACETANILIDE

NHCOCH3

0C2H5

PHENACITIN

NHCOCH3

OH

PARACETAMOL

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3,5-PYRAZOLINEDIONES:

DRUG R R4

Phenyl butazone H -C4H9

Oxyphenbutazone OH -C4H9

Sulphinpyrazone H -(CH2)2SOC6H5

N

N

H

O

OR4

R

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PYRAZOLONE DERIVATIVES:

DRUG R2 R4

Antipyrine CH3 H

AminopyrineCH3

N(CH3)2

Dipyrone CH3 CH3-N-CH2SO3Na

N

NO

R4

CH3

R2

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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

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SYNTHESIS OF ASPIRIN:

SALICYLIC ACID ASPIRIN

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SYNTHESIS OF PARACETAMOL:

P-AMINO PHENOL P-ACETAMINO PHENOL

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SYNTHESIS OF NIMESULIDE:

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SYNTHESIS OF MELOXICAM:

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SYNTHESIS OF IBUPROFEN:

Benzyl isobutyl. Acetyl chloride

IBUPROFEN

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USES:

Anti-inflammatory.

Analgesic.

Anti-pyretic.

Inhibition of platelet aggregation.

Rheumatoid arthritis.

Oseto arthritis.

Gout.

Myocardial infraction.

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NSAIDs GROUP SPECIFIC ADVERSE EFFECTS.

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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.

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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.

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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.

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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.

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