1. MEDICINAL CHEMISTRY-III
Lecture 2
Saturday 12/ 5/ 1432H
Prof. Dr. Wafaa Zaghary

2. Analgesic Classifications of analgesic: Mild analgesics
The traditional manner of classifying pain relieving drugs has been on the basis of strong and addictive (or narcotic) compounds and the mild analgesics (or non-narcotic).
Mild analgesics
a. Analgesic –antipyretic
b. Anti-inflammatory analgesic analgesics
Strong analgesics
a. Narcotic Analgesic
b. Agonist/antagonist analgesic

3. Antipyretics
Are those drugs which have an effect on body temperature and are usually restricted to cases where the temperature rises and may be dangerous in itself as those diseases which are not responding to chemotherapy e.g. viral diseases. This is mediated through the thermoregulatory centre in the hypothalamus.

4. Analgesic
Drugs that relieve mild to moderate pain such as headache, myalgia…etc.
when an anti-inflammatory effect is not needed.

5. Anti-inflammatory
Anti-inflammatory drugs are those drugs used in connective tissue diseases. Inflammation is a normal protective response to tissue injury caused by noxious chemicals, physical trauma or a microbiological agent.
It is divided into 3 stages:
The initial response to tissue injury:
It is mediated by the release of autocoids like: histamine, serotonin, leukotriene, prostaglainds …etc.
Immune response; immunologically competent cells are activated in response to antigens released during the inflammatory response.
In these cases the reaction is changed to chronic inflammation reaching to the underlying tissues as in rheumatic arthritis (pain and deleterious effect upon cartilage and bone).

6. This damage causes leukocytes to release liposomal enzymes (hydrolytic enzymes proteases…..).
Anti-inflammatory drugs may act by interfering with one or more of these processes:-
-antibody production or antigen-antibody complex.
-interference with the formation and release of chemical mediator of inflammation.
-stabilization of liposomal membranes.

7. Characters of NSAIDs
Carboxylate or enolic H (acidic H) compounds anion attached to a cationic site in the receptor.
Lipophilic group, non coplanar with the with ring bearing the carboxylic acid function.

8. Kiefer et al. Nature 405, (2000)

11. Mild analgesics Analgesic-Antipyretic
Drugs in this category have the ability to alleviate mild and on occasion severe pain. These agents are also effective in reducing fever to normal level.
Examples :-
Acetanilide, acetophenetidine (phenacetin) and acetaminophen (paracetamol).

12. Both acetanilide and phenacetin are metabolized to the active acetaminophen.

13. Non –Steroidal Anti-inflammatory Drugs (NSAIDs)
These agents have analgesic and anti-inflammatory effects and owe their therapeutic and side effects to inhibition of cyclooxygenase enzymes.
There are two forms, of cyclooxygenase.
A constitutive form……..(cyclooxygenase-1)
An inducible form……..(cyclooxygenase-2)

14. Thus, a new hypothesis has been suggested to explain the effects of NSAIDs;
Inhibition ofcyclooxygenase-2 accounts the therapeutic benefits.
Inhibition ofcyclooxygenase-1 accounts the
side effects.

15. Aspirin is considered the prototype of mild analgesic and anti-inflammatory agent.
NSAIDs are still evaluate by comparison
to it. Physician still considered the first agent of choice for the treatment of rheumatic conditions.

16. NSAIDs may be classified on basis of their basic chemical structure as:
Salicylates
Para-aminophenol derivatives
Anthranilates
Aryl acetic acids
Aryl propionic acid
Pyrazolinone derivatives
Acidic Enolic Compounds
Cox-2 inhibitors

17. I- Salicylates Aspirin
Acetyl salicylic acid, aspirin, 2-acetoxy benzoic acid
Acetyl salicylic acid is the prototype of NSAIDs.
Synthesis

18. Inhibition of COX by Aspirin

19. Attempts to modify aspirin chemically to either circumvent its potential gastro-intestinal intolerance:
-its poor aqueous solubility, its poor stability towards hydrolysis, makes liquid dosage forms impossible.
The modification involved
derivatization of the carboxy function (such as ester removal in vivo),
variation of he acyl group (to increase stability) into the benzene ring,
forms a simple alkyl or alkoxy group to fluorinated phenyl such as Diflunisal

20. Diflunisal Uses Anti-inflammatory, analgesic and antipyretic
The main side effects are gastrointestinal disturbances, headache and rash.

21. Metabolism of aspirin

22. Most of salicylates are rapidly absorbed after oral administration
Most of salicylates are rapidly absorbed after oral administration. Because they are weak acids, they are absorbed from stomach.
All esters and salts of salicylic acid are initially hydrolyzed to give the free salicylic acid.
Major metabolite of salicylic acid is its conjugation with ether, glucouronic acid and glycine.
Minor metabolites result from microsomal aromatic hydroxylation

23. Structure Activity Relationships
The active moiety …….. salicylate anion
Benzoic acid itself has weak activity.
OH group at m-, or p- to the OH group abolish activity
4-aminosalicylic acid is inactive…….because
Substitution of halogen on the aromatic ring ……….
Substitution of aromatic ring at position 5 increase anti-inflammatory activity e.g. Diflunisal.