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ANALGESICS
Analgesics are the compounds,which relieve pain without producing
unconsciousness.
But this condition is also foundin case of local anesthetics. General anesthetics
produce unconsciousness. So how can we differentiate between analgesics and
local anesthetics?
Non-narcotic analgesics: these compounds change the feeling of pain
(threshold of pain). They reduce perception of pain and integration of pain.
Local anesthetics: these compounds inhibit conduction of nerve impulses.
There is a center in brain where all the impulses are integrated or perceived. In
case of local anesthetics, impulses don’t reach to the brain.
There are 2 types of the compounds:
Centrally acting: they act at hypothalamic region of brain. Example: nonnarcotics and salicylates
Peripherally acting: they act through PGs (prostaglandins). Example:
salicylates.
Salicylates have both actions that is central and peripheral.
The action of centrally acting compounds can be verified by inhibiting the pain
induced by electrical shocks or stimulation in brain, EEG monitors the duration
of electrical current. Compounds, which reduced electrically induced pain, have
centrally acting mechanism and hence they are centrally acting compounds.
Analgesics may be classified as false analgesics and true analgesics.
False analgesics:
There are a number of compounds, which can relieve pain by removing the
cause of pain. These compounds are classified as analgesics because they
relieve pain, but actually they are not relieving pain, so they are called as false
analgesics. For example antibiotics can be used in fever and inflammation. In
this case they are going to effect those organs, resulting in relieve in fever and
inflammation. But the pain due to the fever and inflammation as also reduced.
In this way, theses compounds going to act indirectly by relieving causes of
pain. So they are false analgesics.
True analgesics:
They relieve pain whether the cause is there or not. For example in case of
fracture, cause is there but the pain is suppressed by pain killers. So these
compounds are termed as true analgesics.
Classification on the basis of narcotics or non-narcotics:
Compounds, which produce narcosis and addiction, are centrally acting
compounds. Example: morphine,which has got addiction property, is very good
analgesic but undesirable effectis narcosis or addiction. As it is good analgesic,
there are number of derivatives of morphine to separate the 2 activities that are
narcotic activity and analgesic activity.
SALICYLATES:
Salicylates are the compounds that have got central activity that is through
hypothelemic region of the brain. It is also peripheral acting (through
prostaglandins). It is itself potent analgesic compound and have anti-pyretic,
anti-inflamatory activities that’s why it ahs classified as NSAIDs. It has got
anti-platelet aggregating activity and some what mild anti-hypertensive
activity. Its activity on heart was termed as side effect but now this side effect
is considered as therapeutic effect. The dose, which is used in different
condition, is different.
1. ·When used as analgesic or anti-pyretic, the dose is 300mg/ 3 – 4 times a
day.
2. ·It is anti-rheumatic compound and in this case the dose is in grams and
used for longer period.
3. ·As preventive measure as anti-platelet the dose is 75 –150mg/ day or
may be on alternative days. While different studies suggests that 40 – 8mg is also sufficient for the preventive use or prophylactic agent.
One of the derivatives of the salicylic acid is ortho hydroxy benzoic acid. The
compound itself has got analgesic as well as anti-pyretic activity. But due to the
gastric irritationor ulceration, a number of other derivatives has synthesized.
Salicylic acid has 2 functional groups, COOH and OH.
Substitution on COOH:
Attempts were made to synthesized compound by substitution on COOH
group. From this type of substitution slats are formed by treating with base that
is Na salts, Li salts, Ca salts, Al salts.
Na salts are available in different dosage forms. They are easily soluble in
water and used in different preparations but still all of these compounds have
got side effects.
Colium derivatives are also available which is water-soluble and peak value is
also attained before the aspirin. May be used in combination to avoid gastric
irritation.
Substitution on OH group:
Different substitutions are carried out. One of the most important is acetylation
and by this we have got acetyl salicylic acid that is aspirin. The name aspirin
was first given by DRESSER and the same person introduced it in medicine. It
was first synthesizedby KOLBE and FELIX HOFFMAN determined
pharmacological activity. Compound is still toxic and when used in high dose
for long period, the toxicity increased. Gastric ulceration is one of the toxic
effects. To avoid this toxic effect, number of changes was made. May be the
different substances are added to the preparation for example Na2CO3, Nacitrate, Na- butamate, and got dispirin. Dispirin contain Na- citrate and buffnin
contains Ca- citrate. Butamate is used to make basic pH and we form Ca salt of
butamate. It is less toxic than acetyl salicylic acid.
Substitution on both COOH andOH:
BENORYLATE:
One of the examples is BENORYLATE, which is an ester of acetyl salicylic
acid. It is less gastric irritant but it is nephrotoxic and in some cases, eye
damage or optic toxicity is also observed. Therefore its use has suspended. This
esterification is done to decrease the gastric irritation. Compound may be used
in combination with other analgesic agent that is acid aminophene.
DI-FLUNISYL:
It is another derivative, which is more potent and is termed as DOLOBATE.
[fig. 12]
This compound is more potent buthas not got anti-platelet aggregating activity.
If we consider the SAR:
1. ·The carboxyl group is essential for activity but COOH can be
substituted by iso-stearic group or some other acidic groups. But mainly
we have derivatives, which contain COOH group. So these compounds
are also called as acidic analgesics.
2. ·Halogenated derivatives are also active but may be more toxic.
3. ·OH is substituted and must be present at ortho position.
4. ·Introduction of CH3 group at 3rd position, that is adjacent to OH group.
May have got activity. Due to the introduction of CH3 group, metabolic
rate is decreased and rate of excretion is also decreased.
Salicylatse bound very strongly to the serum albumin. They displace different
other compounds, may be other drugs and may cause toxic effects. For example
WARFARIN, which is ananti-coagulant and when used with salicylates,
salicylates completely displaced it from serum albumin, hence the amount of
WARFARIN increased in serum.
DERIVATIVES
OF
PYRAZOLIDINEOR
PYRAZOLIDINEDIONE:
PYRAZOLONE
OR
[fig.13]
Derivatives of pyrazolone are phenazone, aminopyrien and dipyrone.
If R1 is CH3 then it is phenazone. Also known as anti-pyrine.
When R1 is CH3 and R2 is N (CH3)2, then it is aminopyrine.
In case of dipyrone, R1 is CH3and R2 is N CH3 SO2Na. It is also known as
NOVALGINE.
These compounds are toxic in nature. Main toxicity is agranulocytosis. Antipyrine has got historical importance. It is one of the compounds, which was
initially synthesized and termed as first synthetic compound used as analgesic.
It is still used in different otic preparations.
Phenazone and aminopyrine have anti-pyretic activity. There activity is
comparable with aspirin but more toxic than aspirin.
Dipyrone and aminopyrine are not used now due to toxicity and they are not the
official drugs now.
Derivatives of 3,5pyrazolidinedione
· One of the most important compounds that is phenylbutazone. In it R1 is a
phenyl group that is C6H5 and R2 is butyl group that is C4H9. [fig. 14]
It is potent analgesic and anti-pyretic and completely and readily absorbed from
intestine. The peak plasma level is attained with in 2 hrs. It strongly binds with
plasma protein and displaces number of other drugs. For example: sulfonamide,
tolbutamide, indomethacine, glucocorticoids etc. it compete for same receptor
site. About 400 – 600mg/day is sufficient to occupy all the absorptive sites.
More than this dose will cause side effects. Its all of the metabolites are
active.Oxyphene butazone is its metabolite and is active compound. But now
oxyphenebutazone is synthesized and is available independently. In metabolic
pathway,next metabolite has OH group. The attack is on different position that
is alpha, beta, and gamma. And the metabolite is gamma hydroxy phenyl
butazone.This is also active. In next step OH group is converted to keto group
and we get keto metabolite, which is also active.
After observation it was found that when the acidic character of the molecule is
increased, the anti-inflammatory activity and analgesic activity is decreased but
another activity is introduced and enhanced that is urocosuric activity
(increases the excretion of uric acid).
·
So the next derivative is sulfine pyrazone. The introduction of sulfon
group increases the acidity and now this compound is used as urocosuric agent
instead of analgesic and anti-inflammatory. Compound isused in acute arthritis,
gout and spondilitis.
·
Para-hydroxy derivative is another derivative and is also known
as oxyphenbutazone.
Derivatives of sulfinepyrazone:
Mode of action is similar to aspirin and salicylic acid. It inhibits PGs synthesis.
It also inhibits enzyme histidine decarboxylase and thus induces antiinflammatory effect.
Side effects of phenylbutazone and oxyphenbutazone:
Epigastric discomfort, nausea,vomiting, some cases of peptic ulcer are also
reported, Na and water retention. Due to this reason phenyl butazone is now not
use as anti-rheumatic and anti-inflammatory agent. Generally used in
combination with salicylates.Agranulacytosis and aplastic anemia are
occasionally reported side effects.
N-aryl anthranilic acid andits derivatives:
Also called as FENAMATES. Anthranilic
acid is the derivative of benzoic acid that is ortho amino benzoicacid or 2
amino benzoic acid. It is also the derivative of salicylic acid thatis OH group is
replaced by NH2.
·
2, 3, 6 positions are important for substitution. If 2 methyl groups are
introduced
at
2
nad
3
position,
then
we
will
getMEFENAMICACID (PONSTAN). It is most important and commonly
used derivative of this compound.
·
In mefanimic acid if, Cl is introduced at 2, 6 positionit
is MECLOFENAMIC ACID. It is 25 times more potent than MEFENAMIC
ACID.
·
In N-aryl anthranilic acid, CF3 is introduced at 3position and we
get FLUFENAMIC. It is more active and more toxic
All of theses compounds are usedin rheumatoid arthritis and osteo arthritis.
If we consider SAR
Most important point is the positionof aryl group. Aryl group is introduced at N
of anthranilic acid. It is said that at this ortho postion, the substance will keep
the substitute out of place of parent molecule.
ANILIN AND ITS DERIVATIVES:
Anilin itself is potent analgesic compound. Main toxicity is met
hemoglobinemia. Hemoglobin is converted into methylated hemoglobin. When
derivatization was initiated, OH group was introduced at ortho, para and meta
position and converted into aminophenones. Still the compound is toxic and
among these compounds, active compound is para OH derivative.
Then
acetylation
was
done
in
aminophenones
and
we
get ACETANALIDE {fig. 16}
Aminophenones and acetanilide was then used and use of anilin was inhibited.
From ACETANALIDE, para OH derivative that isACETAMINOPHEN
(paracetamol) or para hydroxy acetanilide is obtained. This is active
compound. This is analgesic, anti-pyretic. The compound has not got antiinflammatory activity. Still the compound is toxic but is used.
Another derivative was synthesized in which H of OH was substituted with
ethyl
group
and
we
got PHENACETIN.
This
compound
hasNEPHROTOXICITY. So now only paracetamol is inuse. Phenacetin is
rarely used and may be used in combination. It is not used alone.[fig. 17]
ARYL ACETIC ACID DERIVATIVES:
These are 5 member or 6 member aromatic
rings, or the combination of 2 or more rings. Aryl acetic acid derivatives are
classified into 2 types:
1.
If we are using INDOL, it may be termed as aryl acetic acid or indol
acetic acid. [fig. 18]
Indomethacin is most important compound of this series. It is used as antirheumatic agent in osteo arthritis, in gouty arthritis, rheumatoid arthritis and
spondilitis. fig. 19]
SAR OF INDOMETHACIN
In indomethacien, COOH is most important for activity. If it is replaced by
another group then activity will be lost.
The substitution can be done at para position of benzyl ring. This may be
substituted by Cl or equivalent groups or CF3 or other halogens or may be by
SCH3.
The 5 position of the indol ring can be substituted by number of compounds
such as methyl amino group, aryl oxygroup and acetyl group. The resulting
compound has got number of side effects such as peptic ulceration or GIT
disturbance or gastric disorders. Headache and vertigo is also reported while in
some cases latent septic condition is also observed in children. It is not used
now but used in combination.
Another derivative, which is synthesized according to the requirement,
is SULINDAC or CLINORIL. In first step H is removed and after that
compound become less toxic. Gastric irritationis reduced. CNS effects are also
reduced but another toxicity that is crystal urea is found. Then number of
modification has carried out anf finally SULINDAC or CLINORIL is obtained
in which Cl group was replaced by SCH3 and methoxy group is replaced by F
group and now this compound is used in medicine as anti-rheumatic and is
more active in gouty arthritis.
2.
Another aryl acetic derivative, in which pyrol ring is present instead of
indol that is aryl acetic acid or pyrol acidic acid derivative [fig. 20]
TOLMETIN is most important compound in this series. Na slat of this
compound is used. This compound is active analgesic agent and as compare to
indomethacin, it has essential structural requirement that is acetic acid or
COOH and the ring, which is attached to COOH. tolmetin is rapidly absorbed,
readily eliminated and peak value is attained in 30 to 60 min. the CH3 group
which is substituted at para position. We have got dicarboxylic derivative.
Instead of COOH halogensare introduced such as Cl so compound have got
analgesic activity and termed as ZOEMPERIC. But compound have got
certain side effects such as sever anaphylactic reactions therefore now it is not
used or recommended by FAD as official drug in USA. While Na salt of this
compound is available in other countries
PHENYL ACETIC ACIDDERIVATIVES:
IBUFENIC ACID is derivative of this series. It is synthesized from aryl acetic
acid. [21]
It is used in rheumatic arthritis. It is less toxic then indomethacin but this is not
used now.
ALPHA METHYL PHENYL ACETIC ACID
Another derivative is synthesized from ibufenic acid, which is more potent and
just by single point modification. We introduced methyl group at alpha position
of acetic acid and termed as ALPHA METHYL PHENYL ACETIC ACID.
This compound is brufen or ibuprofen.[22]
Then from ibuprofen, derivatives are synthesized. Instead of butyl group, some
other groups are substituted. For example, phenol, benzyl but substitution is
done at some other position that is at meta position. When phenol is substituted
at meta position, FENOPROFEN is obtained. When benzyl is substituted at
meta position, KETOPROFEN is obtained.[23]
Phenoprofen is lipid soluble compound and it is rapidly absorbed. Its activity
is equal to Indomethacin. It inhibits the PGs synthesis as well as it inhibits the
rate of collegen synthesis and activate the fibrinolytic system that is it can be
usedas fibrinolytic agent. This is the only compound which has this type of
activity.
If we consider SAR of phenoprofen
Phenol group at meta position is responsible for the activity while the para and
ortho isomers are inactive.
The carbonyl group should be separated from the aromatic ring by the distance
of 1C atom or by one methalene group in the series (that is CH2 __ COOH or
CH2 __ CH2 __COOH). if the separation increased, the activity is decreased.
The substitution at acetic acid such as alpha methyl substitution will increase
the potency.
Ester form and amide form are also active.
Ca salt is available by the name of NALFON
Ketoprofen is insoluble in water. It is soluble in ethanol and CHCL3. it is
rapidly and completely absorbed.
Some derivatives are synthesized by substitution at para position. For example,
thianyl carbonyl is introduced at para position and we getSUPROFEN. It is
alos rapidly and completely absorbed. Peak value is obtained in 1 hour. 200mg
is equivalent to 650mg aspirin. Decreased renal function is the main side effect.
[24]
Another derivative is formed by substitution at ortho position and we
got DICLOFENAC. [25]
DICLOFENAC is most active compound. It is VOLTREN. It is available in
form of Na and K salts and available in different dosage forms
pyroxican or enolin acid derivative:
A ring is present in the structure and is attached with C == O or we can say it as
carboxamide. Charges(as shown in figure) represent the binding site with the
receptor. These compounds are termed as ACID ANALGESIC COMPOUNDS
because they have acidic character (that is COOH, enolic acid or other acidic
groups) and ionizble group should be present in these compounds. [27]
We have got structurally related compounds but in all compounds we have
structural requirements, which are common in all these compounds. By
observing these sites, receptors were developed and given by BACKELL AND
CRAZY and termed as BACKELL RECEPTOR and after some modification
called as BACKELLAND CRAZY RECEPTOR. It is a hypothetical receptor.
[28]
BACKELL AND CRAZY observed the SAR of different compounds having
different structures but all of these structures have same sites, which are
essential for binding. After this observation, they postulate receptor and called
as hypothetical receptor or backell and crazy receptor. Hypothetical receptor
has different surfaces or cavities for docking. The carboxylic group or other
equivalent group will accumulate in site A and other moiety gets fit into site B.
The common structural features/ requirements for non-narcotic analgesic
compounds:
·
COOH group and its equivalent such as enolic must be present in an
active molecule.
·
It should be separated from aromatic ring, by 1methalene group or by 1
C. the separation if increased, the activity will be decreased.
·
Straight chain, aryl acids, butyl acid such as phenyl butazone have got
activity but they are metabolized by mean of beta oxidation and they are
converted into corresponding aryl acetic acid that is they serve as pro-drug and
after the generation of acetic acid they become active.
·
The substitution at acetic acid is possible. The substitution at alpha C will
increase the activity but the small alkyl group can be substituted. By increasing
the size of substitution the activity will be decreased.
OTHER ANALGSIC COMPOUNDS:
We have got number of compounds that don’t
have rapid action that is onset of action is not rapid and even the analgesic
effect can’t be found with in minutes and hours. So those compounds are used
for long period.
·
One of the compounds is AUROTHIOMALIC ACID. We have gotthe
Na salts of aurothiomalic acid. [fig. 30]
· Then we have derivative of glucose that is aurothioglucose.
·
There are some other compounds, but they are not termed as analgesics.
They
are
used
as DMARD (disease
modified
anti-rheumatic
drug). Methotraxate is anti-neoplastic agent. Penicilamide, cyclophosphamide,
hydroxy chloroquine are the few examples, which are used as DMARD.
DERIVATIVES OF ANALGESICSTHAT ARE USED FOR SOME OTHER
ACTIVITIES RATHER THAN ANALGESIC ACTIVITY
There are certain compounds, which are derived from analgesic agents and
then the analgesic activity is reduced while other activities like uricosuric
activity is enhanced. They are termed as uricosuric agents. They increase the
excretion of uric acid. Almost all of the compounds we have discussed have
analgesic activity and anti-inflammatory activity and used in rheumatic
arthritis.
·
Sulfinpyrazone has uricosuric activity. It is used ingouty arthritis. So it is
also used as uricosuric agent.
·
Probencride that is para di propyl sulfanyl benzoic acid is uricosuric
agent. It is used to block the renal excretion of penicilline in resistant subjects.
So penicillin is retained for longer period of time. [31]
· Aluprinol, also termed as inhibitor of urate synthesis. From hypoxanthane,
xanthane is formed which is converted to uric acid in the presence of enzyme
xanthane oxidase. Aluprinol or xyloprin or loprin are the inhibitor of this
enzyme xanthan oxidase.
· DMARD is not classified as analgesics but generally included in NSAIDs
because they are used in gouty arthritis.