analgesics...unlike other non-opioid analgesics, ibuprofen has a chiral center. in therapy racemate...

Analgesics

Non-opioid analgesics

The most common non-opioid analgesics are derivatives of:

aniline: paracetamol

salicylic acid: acetylsalicylic acid

propionic acid: ibuprofen

pirazolone: phenazone, propyphenazone, metamizole

These drugs also act antipyretically and some of them have anti-

inflammatory action (acetylsalicylic acid, ibuprofen).

New non-opioid analgesics include ketorolac, flupirtin and

nefopam.

HN

OR

CH3

O

Paracetamol, R = H

N-(4-Hydroksyphenyl)acetamid

ACETAMINOPHEN, APAP, CODIPAR, PANADOL,

PARACETAMOL

Propacetamol, R = -CO-CH2-N(CH3)2PRO-DEFALGIN

Paracetamol is known to have analgesic, antipyretic and only slight anti-

inflammatory action.

Propacetamol is also used intravenously in patients who can not take

paracetamol orally as an analgesic, for example after surgical procedures, or to

relieve fever in infections and neoplastic diseases.

The chemical structure and action of non-opioid analgesics

O

COOH

O CH3

Acetylsalicylic acid,

Acidum acetylsalicylicum

ASPIRIN, POLOPIRYNA

Acetylsalicylic acid (ASA) demonstrates the following kinds of

action:

analgesic (at low doses, two 300 mg tablets 4 times daily)

antipyretic (at the above doses)

anti-inflammatory/antirheumatic (at high doses only)

prevention of platelet aggregation (at low doses, 160 mg daily)

initiation of apoptosis and inhibition of angiogenesis.

When administered orally, ASA reaches the small intestine through

the stomach and after resorption it is directed to the liver through

the portal vein. In intestinal mucus, in the potral vein and in the

liver, ASA is partially deacetylated by non-specific esterases. The

first metabolite of ASA is salicylic acid.

The half-time of ASA in the stomach or in the intestinal fluid is 16-

17 hours, similarly to its half-time in a physiological buffer.

In the pre-systemic circulation ASA inhibits the action of cyclo-

oxygenase in the platelets by irreversible acetylation of serine 530

in the active center of COX-1. It prevents the formation of TXA2from arachidonic acid.

Only 45%-50% of unchanged ASA reaches the systemic

circulation.

In this system ASA inhibits COX-2 (induced by the blood flow) in

the endothelium and inductive COX-2 in tissues by acetylation of

serine 516 in COX-2. These reactions prevent synthesis of

prostacyclin in the endothelium and prostaglandins in tissues.

In plasma, further acetylation of ASA is caused by non-specific

esterases.

The half-time of ASA in plasma or in the whole blood is only 15-

20 min.

ASA behaves like active acetic acid.

OH

CH3

O

O

O

+ H+

- H+

O -

CH3

O

O

O

O O

O

O-

CH3

Its acetyl rest is transmitted to other functional groups, such as

water (hydrolysis),

other drugs (interactions),

foods or

enzymes (e.g. cyclo-oxygenase (mechanism of action).

H2O (hydrolysis)

O

O

OO -

CH3

O

OH

O-

HO NH

O

CH3

(Interaction)

(mechanism of action)

CH3

O

HO+

O

OH

O-

XH

O

OH

O-

+ X

O

CH3

N

O

CH3

CH3

O

O

H

+

ASA is excreted with urine as salicylic acid (70-80%) and as its

glucuronide and glycinate.

This metabolism depends on pH and is partially limited by

enzymatic capacity, which is responsible for the elongation of the

half-time of salicylic acid from 2 to 3 and even 10 hours at higher

doses (over 4 g).

Salicylic acid also inhibits the activity of COX by blocking it

competitively.

CH3

CH3

O

OHH3C

Ibuprofen, IBUPROFEN, ZUPAR

-Methyl-4-(2-methylpropyl)benzenacetate acid

2-(p-isobutylphenyl)propionic acid

S(+)-Ibuprofen, SERACTIL

Ibuprofen has strong analgesic, antipyretic and anti-

inflammatory/ antirheumatic action.

Unlike other non-opioid analgesics, ibuprofen has a chiral center.

In therapy racemate and S(+)-ibuprofen are used.

Only isomer S(+)is active and it also shows antiaggregative

action.

Ibuprofen is metabolized as a result of , and -oxidation and

the conjugation of ibuprofen and its metabolites. The action of

those metabolites is unknown.

H3C

IBUPROFEN

Ar COOH

Ar

CH3

COOH

CH3

CH3

Ar

HO

CH3

Ar

_CH2 OH

O

OH

CH3

CH3

hydroxylation hydroxylation

hydroxylation

oxydation

-oxydation

-1

3

-2

Ar

CH3

CH3

OH

Conjugation

+

I phase

metabolites

CoA-SH

CoA-SH

_H2C OH

_HC OH

_ _H2C O Ac

S(+)-Ibu-S-CoAS(+)-Ibu

R(-)-Ibu R(-)-Ibu-S-CoAH2C O Ac

_ _HC O R(-)-Ibu

_ _

H2C O R(-)-Ibu_ _

CoA-SH

-+( )-Ibu

Conjugation

Conjugation

H2C O S(+)-Ibu_ _

HC O S(+)-Ibu_ _

H2C O Ac_ _Conjugation

I phase

metabolites

In the body, non-active R(-)-isomer is partially inverted to S(+)-

isomer, but R(-)-isomer is not considered a pro-drug.

The accumulation of non-active R(-)-isomer in the fatty tissue is

significantly higher than the accumulation of S(+)-isomer.

The above inversion of ibuprofen is catalysed by acetyl-CoA.

The product of the reaction of ibuprofen with acetyl Co-A (R(-)-

IBU-S-CoA) is converted to S(+)-IBU-S-CoA.

The CoA-tioesters of R(-) and S(+)-IBU react with the OH groups of

acylglycerol.

The resulting ‘hybride-esters’ have very long half-time of

elimination (approx. 150 hours) compared to ibuprofen (t1/2=2 hours)

and increase the permeability of cell membranes.

N

NCH3

CH3

O

R

Phenazone, R = H

2,3-Dimethyl-1-phenyl-3-pirazolin-5-on

Propyphenazone,

Metamizol, PYRALGINUM

CH3

CH3

R =

R = N

CH3

_CH2 SO3 Na

Phenazone, propyphenazone and metamizol (the strongest non-

opioid analgesic) act analgesically and antipyretically.

At therapeutic doses they do not exhibit anti-inflammatory action.

Recently the use of pirazolones has decreased because of their

adverse effects.

Ketorolac is an analgesic that acts longer and more strongly than

metamizol. It is used to relieve short-term pain.

Ketorolac is contraindicated because of the many adverse effects it

produces.

It is not recommended in pregnancy or lactation and to treat pain in

children and older patients.

Caution should also be exercised when ketorolac is used in patients

with liver and/or kidney dysfunction, heart failure and arterial

hypertension, and also in patients receiving diuretics and/or

NSAIDs.

N

O

COOH

In the treatment of pain caused by elevated muscle tone, analgesics

together with drugs that relax muscles are used.

In these cases flupirtin may be an alternative drug.

Its action is centrally analgesic and spasmolitic.

Flupirtin causes antinociception by stimulating the descending

noradrenergic rout of modulating pain.

It also increases the binding of GABA with GABAA- receptors.

CH3

FH

NN O

N

H

O

H2N

Flupirtin

17

Nefopam

ONH3C

5-Metylo-1-fenylo-1,3,4,6-tetrahydro-2,5-

benzoksazocyna

Nefopam (Acupan, Silentan, Nefadol and Ajan) is a centrally-acting non-opioid analgesic

drug of the benzoxazocine derivative. It is used for the relief of moderate to severe pain as an

alternative to opioid analgesic drugs. Animal studies have shown that nefopam has a potentiating

(analgesic-sparing) effect on morphine and other opioids by broadening he antinociceptive action

of the opioid and possibly other mechanisms, generally lowering the dose requirements of both

when they are used concomitantly.

18

Side effects

Nausea, nervousness, dry mouth, light-headedness and urinary retention; Less common side

effects include vomiting, blurred vision, drowsiness, sweating, insomnia, headache, confusion,

hallucinations, tachycardia, aggravation of angina and rarely a temporary and benign pink

discolouration of the skin or erythema multiforme.

Contraindications

In people with convulsive disorders, those that have received treatment with irreversible MAO

inhibitors within the past 30 days and those with myocardial infraction pain, mostly due to a lack

of safety data in these conditions.

Interactions

It has additive anticholinergic and sympathomimetic effects with other agents with these

properties. Its use should be avoided in people receiving some types of antidepressants (tricyclic

antidepressants or MAO inhibitors) as there is the potential for serotonim syndrome or

hypertensive crises to result.

The mechanism of action

The analgesic action of non-opioid analgesics

It is thought that the analgesic action of non-opioid analgesics

involves the inhibition of transmission of pain stimuli in the spinal

cord.

Interneurons and glial cells are involved in the modulation of pain

in the spinal cord, where the pro-analgesic transmitters of pain are

glutamate, substance P and prostaglandins, while the transmitters

inhibiting pain are enkephalins, GABA and glycine.

The antinociceptive transmitters in the descending routes are 5-HT

and NA.

Posterior horn

of the spinal cord

Glutamate

Substance P

CGRP

Glutamate

Afferent fibers: C, A

Glycine

GABA

Enkephalin

Somatostatin

Brain stem

>

>

NA

5-HT

stimulation

inhibition

Descending system

A

A

Afferent fibers

Afferent fibers


It is believed that the mechanism of action of non-opioid

analgesics is determined by selective inhibition of COX-3, which

is present in the heart and the aorta. Isoenzyme COX-3 is fully

inhibited by paracetamol and, probably, by other non-opioid

analgesics.

Other mechanisms of action may include reduction of the

permeability of nerve cell membranes and the blocking of

transmission in peripheral afferent nerve fibers.


ASA also affects serotoninergic transmission. Research has shown a

correlation between analgesia induced by ASA and the turnover of

serotonine in the brain and between the influence of ASA on the

synthesis of serotonine by removing tryptophane (precursor of

serotonine) from its binding with the proteins of plasma.

PGE2 sensitizes nerve ends to the action of bradykinin, histamin and

other chemical mediators released locally in inflammation.

Non-opioid analgesics inhibit the feeling of pain of low to moderate

intensity. Compared to opioids, NSAIDs (ASA, ibuprofen) are more

effective in the treatment of pain caused by inflammation.


A pain stimulus increases the activity of peripheral receptors of pain.

This nociceptive information is then transmitted to the spinal cord,

where it is changed into the kinetic and sympathetic reflexes.

The stimulus of pain, after transformation in the spinal cord, is

transmitted by the anterolatered fascicule to the CNS.

The transformation of the pain stimulus in the spinal cord mainly

leads to pain relief and a decrease in the nociceptive activity of this

stimulus.


In the case of persisting pain stimuli a reverse reaction may occur,

resulting in easier transmission of information.

The pain becomes chronic and more acute. This symptom is called

wind-up.

It is difficult to predict this kind of change in the sensitivity of the

nociceptive system. It is essential to begin the therapy of persisting

pain at a proper time. It is especially important in surgical procedures

in order to avoid the wind-up symptom before anesthesia is stopped.

The antipyretic action of non-opioid analgesics

Fever appears when the function of the thermoregulatory center in the

hypothalamus is disturbed. This center consists of anterior and posterior parts.

The stimulation of the anterior part causes loss of the heat of the body because

of the dilation of blood vessels and increases sweating.

When this center is deactivated the body does not react to an increase in the

ambient temperature.

When the posterior part is stimulated, the heat of the body is retained as blood

vessels constrict and the production of sweat stops. A disturbance of the

function of this center reduces the reaction of the body to a decrease in the

ambient temperature.

The antipyretic action of non-opioid analgesics

An increase in the body temperature during illness is mainly a result of the release of

pyrogenes by microorganisms. Pyrogenes are usually liposaccharides.

When these bacterial pyrogenes are collected from blood by the cells of the

reticuloendothelial system, cytokins are released from polimorphic leucocytes and

monocytes, which stimulate the synthesis of PGE2 in the hypothalamus.

PGE2 disturbs the function of the thermoregulatory center, which results in an

increased production of heat and its inhibited elimination. In spite of the elevated

temperature of the body, the patient can shiver and feel cold because of the

constriction of the blood micro-vessels.

Non-opioid analgesics cool the body by inhibiting the synthesis and release of PGE2.

The anti-inflammatory action of ASA and other NSAIDs

The anti-inflammatory action of ASA and other NSAIDs is determined

by the inhibition of induced COX-2 in tissues with inflammatory

changes.

ASA inhibits COX-1 160 times more strongly than COX-2, so the

anti-inflammatory action of ASA is observed at significantly greater

doses than anti-aggregative, anti-analgesic and antipyretic action.

For ibuprofen, this ratio is 15.

It is thought that the anti-inflammatory action of salicylates can also be

caused by the reuptake of free radicals.

The anti-aggregative action of ASA and other NSAIDs

When the metabolism of arachidonic acid and the action of metabolites

were understood ASA became an important anti-aggregative drug, used

mainly in secondary prevention of myocardial infarction and ischemic

apoplexy. Its beneficial preventive action is caused by the following:

• ASA shows long-term anti-aggregative action because it acetylates

irreversibly the serine 530 of COX-1 in platelets. As a nuclear platelets

cannot synthesize new molecules of the enzyme, new platelets containing

COX-1 must be created to produce TXA2, which takes several days. The

life time of platelets is 3-7 days.

Other NSAIDs, for example ibuprofen, also inhibit the aggregation of

platelets but their action is shorter, because they inhibit COX

competitively.

The anti-aggregative action of ASA and other NSAIDs

• Only 45 to 50 per cent of unchanged ASA enters the circulatory

system.

In plasma ASA is deacetylated by non-specific esterases. The half-time

of ASA in plasma or in the whole blood is only 15-20 min. ASA very

weakly inhibits the constitutive COX-2 (induced by the blood flow) that

is produced by the endothelium of the blood vessels.

Additionally, the cells of the endothelium, which have nuclei, can

produce a new enzyme that replaces the one that is irreversibly inhibited.

For that reason, ASA inhibits only slightly the synthesis of PGE2 by the

endothelium. That is very important because PGE2 prevents the adhesion

of platelets to the endothelium and the production of atheromatous

plaque.

The chemopreventive action of ASA

In 1998, it was discovered that ASA may become an important drug for the

chemoprevention of certain tumors, especially the tumors of the large intestine

and the colon.

The effectiveness of ASA in the treatment of certain skin tumors is also being

investigated.

In the neoplastic cells of the epithelium of the large intestine an elevated level of

PG and an increased expression of the COX-2 gene are observed.

Examinations of various populations have shown that patients receiving ASA in

cardiac protection develop less frequently intestinal tumors.

The risk of neoplastic changes in the colon was found to be 30-50% lower in

patients taking ASA than in the control group.

Various mechanisms of this action are possible, including COX-dependent and

COX-independent mechanisms.

PPAR

NF-B

Target

places

COX-independent

Apoptosis

Phospholipids

Arachidonic acid

Prostaglandins

COX-1

COX-2

Sphingomyelin Ceramide

COX-independent mechanismsCOX-dependent mechanisms

Apoptosis

Apoptosis

Angiogenesis

(Celecoxibe, Rofecoxibe)Selective inhibitors

(ASA, Sulindac)Non-selective inhibitors

stimulation

inhibition


Apoptosis induced by I-COX involves COX-dependent and COX-independent

mechanisms.

The inhibition of COX-2 causes an increase in the amount of arachidonic

acid, which stimulates the conversion of sphingomieline to ceramide, the

mediator of apoptosis.

The inhibition of COX-2 can also cause apoptosis by changing the

production of PGs and decreasing the level of the angiogenic factor.

ASA, sulindac and other types of I-COX-2 can also influence apoptosis

through:

- the inhibition of the activation of the nucleus factor (NF-) or

- an influence on the binding of PPAR (peroxime-proliferator-

activated receptor ) with DNA.

activenon-active

IKKCYLD

active macrophagesTNF

R

N

N

NFB NFB NFB

Genes transcription


The NF- binding with a carrier is inactive. The kinase I- is activated by

cytokin- (tumor necrosis factor), which is responsible for the phosphorylation of

NF-.

The phosphorylation of the inactive molecule NF- causes the separation of the

inhibitory unit I-, which leads to the activation of NF- and its transport to

cellular nuclei and affects the transcription of certain genes by NF-.

The activity of the kinase I- is controlled by the protein CYLD.

When a deficit of this protein occurs, an excessive amount of NF- moves to cell

nuclei and causes transcription of certain genes, which makes the apoptosis of cells

imposible.

Salicylates block the activation of genes by NF-, which restores the equilibrium

of cells.

The adverse effects of non-opioid analgesics

The adverse effects non-opioid analgesics may result from:

the inhibition of COX

idiosyncratic or unpredictable action.

Adverse effects determined by the mechanism of action

The inhibition of the synthesis of PGs stops the cytoprotective action

of PGE2 on the mucosa of the stomach.

The decreased release of mucus can cause bleeding and peptic ulcers

in the stomach. This risk is greater in patients who previously

reported adverse gastric symptoms, in older people and in patients

receiving glycocorticoides.

It is thought that high-risk individuals should receive misoprostol

together with NSAIDs or glycocorticoides.


As the level of PGE2 decreases, gastrointestinal disorders may

appear, which results from elevated intestinal motor activity and the

decreased elimination of Na+ ions and water by the kidneys. The

malfunctioning of the kidneys is not very strong, does not have

clinical importance and disappears when the drug is withdrawn but

sometimes acute renal failure may occur.

The deficit of PGE2 creates the danger of the closure of Botall’s duct.

For that reason NSAIDs should not be administered to women in the

first trimester of pregnancy. At present, synthetic PGE1 (Alprostadil,

MINPROG) is administrated palliatively to neonates in order to dilate

the arterial duct (Botall’s duct) until a surgical operation is

performed.


One of the adverse effects of non-opioid analgesics, such as the

inhibition of the aggregation of platelets, is used in therapy.

ASA is applied in low doses as anticoagulant but long-term

administration of ASA creates the danger of brain bleeding.

Because of that the use of ASA is not recommended in primary

prevention in healthy people, while it is recommended in secondary

prevention in patients after myocardial infarction.


Pseudoallergic hypersensitivity to salicylates

Clinical symptoms of ASA intolerance are similar to the type 1 allergic reaction,

and range from an immediate response (nettle rash, rhinitis, asthma, angioneurotic

oedema) to anaphylactic shock.

The release of histamine is stimulated but the level of plasmic IgE does not change,

which is called a pseudoallergic reaction.

Hypersensitivity to salicylates is caused not only by ASA but especially by its

impurities and metabolites. The most important impurities are acetylsalicylacid

anhydride and acetylsalicylsalicylic acid.

These compounds are very reactive chemically and can bind with the albumins of

plasma. The action of these complexes is highly immunogenic and produces

salicyl-specific reactions of hypersensitivity.


The acetyl group of a spontaneous ASA metabolite also acts

allergenogenically.

There are various hypotheses explaining another intolerance

symptom called aspirin asthma.

It is believed that it can be caused by a genetic defect in the

metabolism of arachidonic acid.

Because this phenomen is also typical of other weak analgesics, it is

called analgesic intolerance.


According to another hypothesis, the mechanism of action of all

weak analgesics involves the inhibition of COXs.

As weak analgesics do not inhibit lipooxygenases, leukotriens

constricting blood vessels predominate among the metabolites of

arachidonic acid.

Leukotrienes C-E are thought to be the slow-reacting-substance in

anaphylaxis (SRS-A). This pathomechanism is considered possible

but has not been proved.

Another hypothesis, presented by Schlumgerer, holds that as a result

of viral infection the spectrum of ASA metabolites is changed.


Caution is recommended when using ASA in children because of a

relationship between the administration of salicylates and Reye’s

syndrome in patients under 18.

This syndrome is viral encephalopathy accompanied by the fatty

degeneration of internal organs.

The specific adverse effects non-opioid analgesics

The hepatotoxic and nefrotoxic action of paracetamol at large doses

is caused by the reactive metabolite of this drug.

Paracetamol is mainly eliminated as glucuronate (approx. 65%) and

sulphate (approx. 30%), but approx. 4% of a dose is oxidized to

reactive N-acetyl-p-benzochinonoimine by microsomal enzymes.

In the presence of a sufficient amount of glutathione this metabolite

is transformed to non-toxic mercaptane.

H HCH3 CH3

Cytochrome P-450~4%

Glucuronate

~65%

UDPGA

O

N

O

OH

N

PARACETAMOL

PAPS

~30%

Paracetamol glucuronate Paracetamol sulfate

H CH3

O

N

OSO3H

H CH3

Death of cell

Liver cells proteins

Toxic doses

Therapeutic doses

N-Acetyl-

p-benzochinonimine

(toxic)

O

O

N

Glutathione

Glutathione S-transferase

H CH3

Protein

N

OH

O

H CH3

Glutathione

Mercapturic acid

(non-toxic)

N

OH

O


When a dose of paracetamol is too large or when other drugs reacting

with glutathione are administrated at the same time the capacity of

glutathione S-transferase can be exceeded.

Then the reactive metabolite may create a covalent union with the

nucleophile groups of proteines, for example DNA, which causes the

necrosis of cells.

The hepatotoxic action of paracetamol is usually observed at daily

doses greater than 10 g.

However, significant differences between individuals are observed.

In the case of liver disorders hepatotoxic action is possible even at a

daily dose greater than 4 g.

When paracetamol has been overdosed, for example as a result of a

suicide attempt, sulfhydryl compounds are used as an antidote, for

example acetylcysteine.

At present a protective use of acetylcysteine together with

paracetamol is being investigated.


The deficit of glutathione can also result from a genetic defect

involving the deficit of glucose-6-phosphate dehydrogenase.

Even at therapeutic doses paracetamol can increase this deficit and

cause hemolytic anemia.

Although genetic enzymopathy is rare in middle Europe, it is more

common among the Mediterranean population and negroic people.

This problem affects one per cent of the world population.


The derivatives of pyrazolone, may cause allergic symptoms

(pruritius, nettle rash) and even shock, especially after intravenous

administration.

It is thought that these drugs have properties typical of haptens.

The use of pyrazolones can lead to changes in the hematopoietic

system (agranulocytosis). These symptoms are rarely observed, but

as they are life-threatening their significance must not be ignored.


In an acidic environment, 4-aminophenazone derivatives react with

nitrites, creating nitrozoamines, which have carcinogenic properties.

Although in clinical research the carcinogenic action of pyrazolones

has not been proved, they are being withdrawn from therapy because

of the possibility of such action and especially due to the risk of

agranulocytosis.


Glycosteroids

The application of glycosteroids in the treatment of pain involves not

only the inhibition of the biosynthesis of PGs and leukotriens, but

also cytokins.

Cytokins, like other pain mediators such as protons, bradykinin,

serotonine and PGs, increase the sensitivity of nociceptors.

Glycosteroids even at low doses inhibit the production of IL-1, IL-6,

the tumor necrosis factor and gamma interferone and because of that

they remove the feeling of pain.

The application of non-analgesics in certain kinds of pain

The blocking of the sympathic system

In some illnesses, for example in Sudeck’s disease or in the

dystrophia of soft tissues and bones, pain is removed by the blocking

of the sympathic system.

To achieve that local-anesthetic drugs administered intraspinally,

-adrenolytic drugs and reserpine are used.


The inhibition of pain in the spinal cord

Glutamate, an important stimulating neurotransmitter in the spinal cord, controls

the influx of Ca2+ and Na+ ions to cells.

In the treatment of pain it can be effective to block the ion channels dependent on

NMDA by using the antagonists of NMDA channels, such as phencyclidine or

ketamine.

Because of its strong adverse effects, ketamine is only used to treat the most

difficult cases.

The pain-inhibitory action of benzodiazepins, baclofene and clonidine (agonist of

-adrenoreceptors) is also observed in the spinal cord.


analgesics...unlike other non-opioid analgesics, ibuprofen has a chiral center. in therapy racemate...

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