Anesthetics, diuretics& NSAIDs - Copy.ppt

ppt

1. Abdu Tuha (B.Pharm., MSc in Medicinal
Chemistry.)
General and Local Anesthetics

2. Local anesthetics
2
Localanesthetics
Blockthenervethatcarriesthepainsensation
andautomaticimpulsesinlocalareasofthe
body
Preventconductionandformationofanaction
potentialbyeitherfullorpartialblockageof
sodiumionchannel
Usedindentistry,ophthalmologyandminor
surgicaloperations
6/16/2024

3. Local …
3
Ester and amide type
Cocaine,an alkaloid from the leaves of
Erythroxylon coca, was the first local anesthetic
The development of local anesthetics began after the
discovery of local anesthetic properties of cocaine
Because of its addictiveproperties the search for
non-habit forming local anesthetics beganN
CH
3
H
C
O
O
CO
2CH
3
6/16/2024

4. Local …
4
The carbomethoxygroup is not required for local action as
seen in tropacocainewhich lack this group
The synthesis and testing of -eucaine showed a tropane
ring is not a prerequisite for local anesthetic activity
Based on the above findings many other simple analogs
like procaine and benzocaine were synthesizedN
CH
3
H
C
O
O
H H
3C
H
3C
OC
O
H
H
3C H
2N COOC
2H
5 H
2N COOCH
2CH
2N(C
2H
5)
2
-eucaine
Tropacocaine
Benzocaine Procaine
6/16/2024

5. Local …
5
General structural featuresLipophilic centerEster or Amide Bridge Hydrophilic center N
CH
3
H
C
O
O
CO
2CH
3 ArylCXAminoalkyl
O CH
3
R
1
NHC
O
R
2
Cocaine
Benzoic acid derivatives
Anilides derivatives
6/16/2024

6. Local …
6
SAR of local anesthetics
The lipophilic center is usually either acyclic or
heterocyclic system
The hydrophilic center is normally a secondary or
tertiary amine, which may or may not be cyclic
Tertiary amines are more useful since they are less
irritating to tissue
The hydrophilic center may be attached to ester or
amide by a short hydrocarbon chain
The lipophilic center is responsible for lipid
solubility as it affects cell penetration and their
6/16/2024

7. Local …
7
The hydrophilic center provides water solubility and is
believed to be involved in binding to the receptor
For best action a balance between lipophilic and hydrophilic
center is essential
Ester type require a carbonyl group in conjugationwith an
aromatic ring or related system
When X= CH
2, there is no activity; carbonyl is not
conjugated
When X = , there is activity as the aromatic ring is
conjugated with carbonyl groupH
2N XC
O
OCH
2CH
2N
C
2H
5
C
2H
5 C
H
CH
6/16/2024

8. Local …
Benzoic acid derivatives
Generic name R
1
R
2
Hexylcaine H
Dyclonine
Piperocaine H
8H
2CHN
HC
CH
3 NH
2CH
2C N
H
3C
H
2CH
2CH
2C CH
3CH
2CH
2CH
2O R
1 C
O
OR
2 6/16/2024

9. In the lidocaine (the amino
amide) series the ortho
dimethyl groups are
required for protection from
amide hydrolysis ensuring
desirable duration of action
Generic name R
1
R
2
Etidocaine CH
3
Mepivacaine CH
3
Bupivacaine CH
3
lidocaine CH
3
prilocaine CH
3
9NHCH
2OCHN
CH
2
CH
3
CH
2CH
3
CH
2CH
2CH
3 N
H
3C CH
2CH
2CH
2CH
3 NHCH
2OCH
2N
C
2H
5
C
2H
5 NHCOCHNHCH
2CH
2CH
3
CH
3 CH
3
R
1
NHC
O
R
2 6/16/2024

10. General Anaesthetics
10
Generalanaesthesiaisacontrolledreversible
depressionofthefunctionalactivityoftheCNS
The neurophysiologic state produced by general
anesthetics is characterized by five primary effects:
Unconsciousness,
Amnesia,
Analgesia,
Inhibition of autonomic reflexes, and
Skeletal muscle relaxation.
Early agents were ether, chloroform & nitrous oxide
6/16/2024

11. Nowadays, multiple drug regimes are used
including;
Pre-anaesthesia +skeletal muscle relaxants
+ drugs to control side effects + actual
anaesthetic agent are used in combination
General anaesthetics are given either by
inhalationor i.v.
6/16/202411

12. General…
12
Inhalation anaesthetics (gases and liquids)
Current inhalation drugs include halothane & several
other F&Cl-containing molecules, and nitrous oxide.
Gas inhalation anaestheticsH
2
C
H
2CCH
2
N
2OCF
3CHClBr CHCl
2CF
2OCH
3 CHClFCF
2OCHF
2 CF
3CHClOCHF
2 CHF
2OCHFCF
3
Desflurane
Isoflurane
Enflurane
Methoxyflurane Halothane
Nitrous oxide
Cyclopropane
6/16/2024

13. General …
14
Intravenous anaesthetic
They produce unconsciousnessbut not sufficient depth to
permit surgical procedures
The intravenous anaesthetics is given prior to inhalation
anaesthetics
Classification
Ultrashort acting barbiturates
Benzodiazepines
Ketamine hydrochloride
Propofol
Etomidate
6/16/2024

14. 6/16/202415Cl
NHCH
3 HCl
O
Ketamine
•The presumed mechanism of action of propofolis through potentiationof the
chloride current mediated through the GABA
Areceptor complex.
•Etomidateappears to have GABA-like effects and seems to act primarily
through potentiationof GABA
A-mediated chloride currents,
•Ketamine’smajor effect is probably produced through inhibition of the NMDA
receptor complex.

15. Non-Streoidial Anti-Inflammatory
Drugs (NSAIDs)

16. NSAIDs…
17
These drugs are of different chemical structures and are
used for treatment of inflammatoryand painfulconditions
TheCOXenzymeexistsinatleasttwoisoforms.
COX-1isconstitutiveisoformthatisresponsibleforthe
basalproductionofprostaglandins,prostacyclins,and
thromboxanes.
COX-2isinduciblebycytokinesandotherinflammatory
stimuliandisbelievedtopredominateduringchronicCell injury
Cell membrane
Phospholipase A2
Arachidonic acid
Prostaglandins
Cyclooxygenase
Lipoxygenase
Leukotrienes
NSAIDS
Inhibit Cyclooxygenase
6/16/2024

17. NSAIDs…
18
Prostaglandins contribute to sign and symptoms of
inflammatory processes including painand edemaCOOH COOH
6/16/2024
Prostaglandins
Arachidonic acid

18. 6/16/202419

19. NSAIDs…
20
Non-steroidal ant-inflammatory drugs can be
divided:
1.Saliclyates
2.Para-aminophenol derivatives
3.pyrazolone and pyrazolidinediones derivatives
4.Arylacetic acids
5.Arylpropionic acids
6.Anthranilates
7.Arylsulfonamides
8.COX-2 Selective Inhibitors (diaryl pyrazole
6/16/2024

20. NSAIDs…
21
Salicyates
Are derivatives of salicylic acid and are two types (I and II)
Type I represents those that are formed by modifying the
carboxyl group.
Type II (a and b) represents those that are substitution
on the hydroxylgroup of salicylic acid
The derivatives were introduced to prevent gastric
symptom and undesirable tests of some common
salt of salicylateC
OH
O
OH
1
2
3
4
5
6 C
OH
O
OR C
OR
O
OH C
O
O
OH
CR
O
Type I Type IIa Type IIb
6/16/2024

21. NSAIDs…
22
Structure activity relationship
The active moiety appears to be the salicylate anion
Reduction of the acidity of the carboxylic group of the
salicylate retain analgesic effect eliminating anti-
inflammatory (Salicylamide)
Shift of phenolic OH group to meta or Para to carboxyl
abolish activity
Halogen atom substitution on the aromatic ring enhances
potency & toxicity
Hydrophobic substituent at 5 position of salicylic acid
improved activityC
O
O
OH
CCH
3
O C
OH
O
NH
2 C
OH
O
OH
F
F
Aspirin Salicylamide Diflunisal
6/16/2024

22. NSAIDs…
23
2. Para-aminophenol derivatives
Are para aminophenol derivatives
They possess analgesic and antipyretic but not
anti-inflammatory activity
Paracetamol is a prototype
Based on the discovery that anilineand
acetanilidehave powerful antipyretic property NH
2
OH
6/16/2024

23. NSAIDs…
24
Both are converted to paracetamol and are
more toxic NHCCH
3
O
OH
NHCCH
3
O
OC
2H
5
NHCCH
3
O
Acetanilid Paracetamol Phenacetin
6/16/2024

24. NSAIDs…
25
Structure activity relationship
Amino phenols are less toxic than corresponding aniline
derivatives
Esterificationof phenolicgroup with methyl or propyl
group produce more toxic derivative than ethyl
Nitrogen substituentsthat reduce its basicityreduce
activity unless it is metabolically removed
Paracetamoloverdose causes sever hepatotoxicity
with necrosis and liver failure
Due to the formation of hepatotoxic
metabolite
6/16/2024

25. NSAIDs…
26OH
NHCCH
3
O
Sulfate
Major
Glucuronide
OH
NCOCH
3HO
O
NCH
2OCH
3
O
NCH
2OCH
3
glutathione*
Major
Paracetamol
minor
*N-acetylimidoquinone
"toxic metabolite"
glutathione 6/16/2024

26. NSAIDs…
27
3. 3, 5-pyrazolidinediones
The most important once are phenylbutazoneand
oxyphenylbutazone(its metabolite)
Both of them inhibit prostaglandin synthesis and stabilize
lysosomal membranes
Have analgesic, antipyretic and anti-inflammatoryeffectsN
H
NH
O
O
1
2
34
5 N
N
O
OH
3CH
2CH
2CH
2C N
N
O
OH
3CH
2CH
2CH
2C
OH
Phenylbutazone Oxyphenylbutazone
6/16/2024

27. NSAIDs…
28
Structure activity relationship
Hydrogen atom at C4 is acidic & this is enhanced by the
two-ketone groups
Decreasing /eliminating acidity abolishes activity
If acidity increases too much uricosuric activity increases
while ant inflammatory decreases
Single alkyl substituent at C4 enhances anti-inflammatory
activity n-butyl is the most active
The presence two phenyl groups in the ring nitrogen is not
important for anti-inflammatory & analgesic activity
Pyrrole ( )and isoxazole ( ) analogue of phenylbutazone
retain activity H
N
2
3
4
5
1 O
N
6/16/2024

28. NSAIDs…
29
4. Arylalkanoic acids
Arylalkanoic acid represents the largest numbers
of NSAIDs
Have analgesic, antipyretic and anti-inflammatory
propertyARC
H
H
COH
O ARC
CH
3
C
H
OH
O
Aryl or Hetero-aryl acetic acid analogs
Aryl or Hetero-aryl propionic acid analogs
6/16/2024

29. NSAIDs…
30
Structure activity relationship
All agents have an acidicand aromaticcenter
Derivatives of aryl or heteroaryl acetic/propionic acid
correlates with carboxylic acid and double bond at position
C5 and C8 of arachidonic acid
The activity of ester& amide derivatives carboxylic acid is
due to its metabolic hydrolysis
The center of acidity is located onecarbon atom from the
aromatic ring
This distance is critical
Increase distance to two or three carbons generally
diminishes activity
6/16/2024

30. NSAIDs…
31
Methylsubstitution on the carbon atoms separating the
acid and aromatic group increasesanti-inflammatory
activity
Groups more than methyl decrease anti-
inflammatory activity
A second area of lipophilicitynon-coplanarwith aromatic
ring enhances activity
This lipophilicarea corresponds to the double bond of C11of
arachidionicacid OH
O
N
Cl
11
8
5
14
OH
O
6/16/2024

31. NSAIDs…
32
Aryl and heteroarylacetic acidsN
CH
2
CO
Cl
CH
3
CO
2H
H
3CO CH
S
CH
2CO
2H
CH
3
F
O
CH
3
Indomethacin Sulindac
6/16/2024

32. NSAIDs…
33
Structure activity relationship
N-benzoyl derivatives substituted in the Para-position with
fluoro, chloro, trifluoromethyl, or thiomethyl group are the
most active
The 5 –position of the indole ring is most flexible with regard
to the nature of substituent, which enhances activity.
Substituents such as methoxy, fluoro, dimethylamino,
methyl, allyloxy, and acetyl are more active than un-
substituted indole ring
The presence of an indolenitrogen is not essential for
activity because the corresponding 1-benzylidenyl analogs
6/16/2024

33. NSAIDs…
34
Aryl and heteroarylpropionic acid derivatives
The substitution of an -methyl on the alkanoic acid portion
of acetic acid enhances anti-inflammatory actions and
reduces side effects(H
3C)
2HCH
2C CH
CH
3
CO
2H O CH
CH
3
CO
2H C
O
CH
CH
3
CO
2H H
3CO
CH
CH
3
CO
2H
Ibuprofen
Fenoprofen calcium
Ketoprofen
Naproxen
6/16/2024

34. NSAIDs…
35
5. Arylanthranilic acids
The anthranilic derivatives are nitrogen isosters of
salicylic acid
Are the results of the application of bioisosteric drug
designNH
2
COOH NH
COOH
1
4
2
3
5
6
1'
2'
3'
4'
5'
6'
anthranilic acid
Structure of arylanthilic acids
6/16/2024

35. NSAIDs…
36NH
COOH
CH
3
CH
3 NH
COOH
CF
3 NH
COO
-
Na
+
CH
3
Cl
Mefenamic acid Flufenamic acid
Meclofenamate sodium
6/16/2024

36. NSAIDs…
37
SAR
Substitution on the anthranilic acid ring generally
reducesactivity while substitution of the N-aryl ring
can lead to conflictingresults
The most active once have a small alkyl or halogen
substituent at 2’, 3’and/or 6’position of the N-aryl
moiety
Among disubstituted N-arylfenamates 2’and 3’
derivatives are most active
These Substituents serve to force the N-aryl ring out
of co planarity with anthranilic acid
6/16/2024

37. NSAIDs…
38
NH moiety is essential for activity
Replacement of NH with O, CH
2, S, SO
2, NCH
3
or NCOCH
3significantly reduces activity
The positionrather than the natureof the acidic
function is critical for activity
Replacement of carboxylic acid function with
isosteric tetrazole moiety has little effect on
activity
6/16/2024

38. NSAIDs…
39
6. Arylsulfonamides (Oxicams)
Theoxicamsareagroupofnon-steroidalanti-
inflammatoryagentscontaining2H-1,2-
benzothiazine-3-carboxamide1,1-dioxidemoiety
ascommonstructureentity.S
N
R
1
OHO
N
H
R
OO
6
7
8
6/16/2024

39. NSAIDs…
40
SAR
Within the series of 4-hydroxyl-1, 2-benzothiazine carboxamides
Optimal activity is observed when R1 is methylsubstituent
R (Carboxamides substituent) is generally an Aryl / heteroaryl
substituent because alky substituent are less active
N-hetrocyclic carboxamides are more acidic than the
corresponding aryl carbamate
In the aryl series meta-substituted derivatives are generally
more potent than para-isomers
In the aryl series maximum activity is observed with a meta-Cl
substituent
Eg, Ampiroxicam, Piroxicam, Tenoxicam, Droxicam, Lornoxicam
6/16/2024

40. 6/16/202441
Ampiroxicam
Meloxicam
Tenoxicam

41. 7. COX-2 Selective Inhibitors
AllCOX-2inhibitorsarediaryl-5-membered
heterocycles.
Celecoxibhasacentralpyrazoleringandtwo
adjacentphenylsubstituents,
Rofecoxibhasacentralfuranoneringandtwo
adjacentphenylsubstituents.
Valdecoxibhasacentraloxazolering
TheCOX-2inhibitorshaveanalgesic,
antipyreticandinflammatoryactivity
comparabletootherNSAIDs
6/16/202442

42. 6/16/202443

43. These compounds produce less GI ulceration and
hemorrhage than NSAIDs due to their COX-2
selectivity.
Also they do not inhibit platelet aggregation and
have minimal renal and CV side effects.
6/16/202444

44. DIURETICS

45. DIURETICS
46
Diuretics are drugs that promote the output of urine
excreted by kidney.
Diuretics mainly promotes the excretion of the
sodium ions(Na
+
), chloride ions(Cl
-
) or bicarbonate
ions(HCO
-3
) and water from the body,
The net result being increase in urine flow.
These drugs act by decreasing tubular reabsorption
6/16/2024

46. DIURETICS…
47
Diuretics Are Very Effective
For The Treatment Of Cardiac Edema (CHF)
Nephrotic Syndrome
Diabetes Insipidus
Hypertension
Nutritional Edema
Edema Of Pregnancy
Cirrhosis Of Liver
Lower the Intracellular And Cerebrospinal
Fluid Pressure.
6/16/2024

47. DIURETICS…
48 6/16/2024

48. DIURETICS…
49
CLASSIFICATION
I. Carbonic anhydrase inhibitors (Site-I Diuretics)
Acetazolamide, Methazolamide, Dichlorphenamide,
Disulfamide, Ethoxzolamide.
II. Thiazide and Thiazide like Diuretics (Site-III Diuretics)
Chlorthiazide, Benzthiazide, Hydrochlorothiazide,
Hydroflumethiazide, Bendroflumethiazide,
Trichlormethiazide, Methyclothiazide, Polythiazide,
Cyclothiazide, Mefruside, Clopamide, Xipamide,
Indapamide, Quinethazone, Metolazone,
Clorexolone, Chlortalidone.
6/16/2024

49. DIURETICS…
50
III. High ceiling or Loop Diuretics (Site-II Diuretics)
Organo mercurials –Chlormerodine mercury,
Meralluride, Mercaptomerin, Merethoxylline
procaine, Mersalyl.
5-Sulfamoyl & 3-Amino Benzoic acid derivatives-
Bumetanide, Furosemide,
4-Amino-3-pyridine sulphonyl ureas-Torsemide,
Triflocin.
Phenoxy acetic acids-Ethacrynic acid.
6/16/2024

50. DIURETICS…
51
IV. Potassium sparing Diuretics (Site-IV
Diuretics)
1. Aldosteron inhibitors –Spiranolactone,
Metyrapone
2. 2,4,7-Triamino-6-aryl pteridines –Triamterene
3. Pyrazinoyl Guanidines –Amiloride. HCl.
V. Xanthine Derivatives -
Caffeine, Theophylline, Theobromine.
VI. Miscelleneous -
6/16/2024

51. DIURETICS…
52
I.Carbonic anhydraseinhibitors (Site-I Diuretics)
–Inhibit the enzyme carbonic anhydrasein proximal
tubular epithelium.
–Decrease the exchange of Na
+
for H
+
Acetazolamide
Methazolamide
diclofenamide
Disulfamide
6/16/2024

52. 53 6/16/2024

53. DIURETICS…
54
Structure Activity Relationship for CAI
The free sulfamoylnitrogen is important for
diuretic activity.
Substitution of the methyl group on one of the
ring nitrogen (Methazolamide) retains the activity.
The heterocyclic sulphonamides have highest
lipid/water partition coefficient and lowest pKa
values
have greatest CA inhibitory and diuretic activity.
The benzene meta sulphonamide derivatives
6/16/2024

54. DIURETICS…
55
II. Thiazide and Thiazide like Diuretics (Site-III Diuretics)
chlorthiazide
Hydrochlorthiazide
Benzthiazide
Hydroflumethiazide
Bendroflumethiazide Methylchlothiazide
6/16/2024

55. DIURETICS…
56
Mechanism of action of Thiazides
These drugs blocks the reabsorptionof Na+, Cl-
exchange in the distal convoluted tubuleby
inhibiting the luminal membrane-bound Na+/ Cl-
co transport system.
Structure Activity Relationship for Thiazides
Thiazideshaving benzothiadiazine1,1-dioxide
with weakly acidic character is important for good
activity.
Presence of electron withdrawing group at C-6 is
necessity for good diuretic activity.
Substitution of chlorine at C-6 has good activity.
6/16/2024

56. DIURETICS…
57
Substitution of CF
3group has more lipid soluble
and larger diuretic action than Chlorocompound.
Presence of electron donating groups like methyl
or methoxyat C-6 reduces the diuretic activity
Removal or replacement of sulphonamideat C-7
reduces the diuretic activity.
Saturation of double bond between 3&4 having 10
times more diuretic activity than unsaturated
analogue.
Introduction of lipophilicgroups such as aralkyl,
halo alkyl, thioetherenhances the diuretic activity
and increase the duration of action.
Alkyl substitution at N
2lowers the polarity and
enhances the duration of action.
6/16/2024

57. DIURETICS…
58
III. High ceiling or Loop Diuretics (Site-II Diuretics)
Furosemide
Ethacrynic acid
Bumetanide
6/16/2024

58. DIURETICS…
59
Mechanism of action of Loop Diuretics
The diuretics inhibit the Na+/K+/ Cl-cotransport
system located in the luminal membrane of cells in
the limb of Henle’s loop.
The carboxylate moity is responsible for their
competing with Cl-for the Cl-binding site on
Na+/K+/ Cl-cotransport system.
6/16/2024

59. 6/16/202460

60. DIURETICS…
61
StructureActivityRelationshipforLoopdiuretics
5-sulfomoyland2-aminobenzoicacidgroupisrequired
forgooddiureticactivity.
Substitutionat1stpositionmustbeacidicforgood
diureticactivity.
Theactivatinggroupat4th,canbeClorCF
3group,
increasestheactivity.
Phenoxy,alkoxy,anilino,benzylorbenzoylgroups
substitutedat4thpositiondecreasesdiureticactivity.
Furfuryl,benzylandthienylmethylgroupat2-position
6/16/2024

61. DIURETICS…
62
IV. Potassium sparing Diuretics (Site-IV Diuretics)
Amiloride hydrochloride
Triamterene
Spironolactone (aldactone)
6/16/2024

62. 6/16/202463

63. 6/16/202464
DIURETICS…
Spiranolactone
Inhibitsthereabsorptionof2-3%ofthefilteredloadsodium
atsite-IVbycompetitivelyinhibitingtheactionof
aldosterones.
Directpharmacologicantagonismofmineralocorticoid
receptors
Thealdosteronemineralocorticoidreceptor(MR)complex
bindsontheDNAtospecifichormoneresponseelement,
whichleadstogenespecifictranscription.
Triamterene&Amiloride
InhibitionofNa+influxthroughionchannelsintheluminal
.