Non- analgesics The most common non-opioid analgesics are derivatives of:

 aniline: : acetylsalicylic acid  propionic acid:  pirazolone: , ,

These drugs also act antipyretically and some of them have anti- inflammatory action (acetylsalicylic acid, ibuprofen).

New non-opioid analgesics include , flupirtin and . The chemical structure and action of non-opioid analgesics

Paracetamol, R = H O N-(4-Hydroksyphenyl)acetamid ACETAMINOPHEN, APAP, CODIPAR, PANADOL, HN CH3 PARACETAMOL

Propacetamol, R = -CO-CH2-N(CH3)2 PRO-DEFALGIN OR Paracetamol is known to have , and only slight anti- inflammatory action. 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. COOH Acetylsalicylic acid, O CH3 Acidum acetylsalicylicum O , 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 TXA2 from . 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 in the endothelium and 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.

- O O O O OH O O- CH + 3 O CH3 - H O CH3 O + O H+ O

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). - O O CH3 OH + HO O

H O (hydrolysis) 2 O - O - O O O O O CH HO NH HN 3 CH O CH3 3 OH (Interaction) +

O CH3 XH (mechanism of action) O - O O O OH CH3 + X 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. O Ibuprofen, IBUPROFEN, ZUPAR H3C OH -Methyl-4-(2-methylpropyl)benzenacetate acid 2-(p-isobutylphenyl)propionic acid

CH3 S(+)-Ibuprofen, SERACTIL CH3 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.

O

H C Ar 3 OH Ar CH -2 hydroxylation -1 hydroxylation 3 CH3 OH _ CH3 CH OH CH3 2 oxydation CH3

IBUPROFEN Ar

3 hydroxylation CH3

Ar COOH

CH3 -oxydation HO CH 3 Ar COOH Conjugation _ _ H2C O R(-)-Ibu _ _ I phase CoA-SH HC O R(-)-Ibu metabolites _ _ H2C O Ac R(-)-Ibu R(-)-Ibu-S-CoA Conjugation H C _ OH ( +- )-Ibu 2 _ + HC OH CoA-SH _ _ H2C O Ac Conjugation S(+)-Ibu S(+)-Ibu-S-CoA I phase _ _ metabolites H2C O S(+)-Ibu CoA-SH HC_ O _ S(+)-Ibu Conjugation _ _ H2C O Ac 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. Phenazone, R = H 2,3-Dimethyl-1-phenyl-3-pirazolin-5-on

CH3 N R = CH Propyphenazone, O N 3 CH3 CH3 Metamizol, PYRALGINUM R = N R 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. COOH

N

O

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. H2N H N O N CH3 Flupirtin O N H F

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. Nefopam

H C 3 N O 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 and other by broadening he antinociceptive action of the opioid and possibly other mechanisms, generally lowering the dose requirements of both when they are used concomitantly.

17 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.

18 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. Afferent fibers: C, A Substance P Aff e r ent fibers CGRP A  Glutamate Enkephalin Somatostatin

NA > Glutamate Posterior horn A f ferent fibers of the spinal cord Brain stem A > GABA 5-HT

Glycine

Descending system stimulation inhibition The analgesic action of non-opioid analgesics

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. The analgesic action of non-opioid analgesics

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. The analgesic action of non-opioid analgesics 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. The analgesic action of non-opioid analgesics

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 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. COX-dependent mechanisms COX-independent mechanisms

Apoptosis Phospholipids

Sphingomyelin Ceramide

Arachidonic acid PPAR

Non-selective inhibitors NF-B Apoptosis COX-1 (ASA, )

Selective inhibitors Target COX-2 (Celecoxibe, Rofecoxibe) places COX-independent Angiogenesis Prostaglandins

stimulation Apoptosis inhibition The chemopreventive action of ASA

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 ) with DNA. TNF active macrophages

R

N CYLD IKK Genes transcription

NFB N NFB NFB non-active active The chemopreventive action of ASA

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 together with NSAIDs or glycocorticoides. Adverse effects determined by the mechanism of action

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. Adverse effects determined by the mechanism of action

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. Adverse effects determined by the mechanism of action

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. Adverse effects determined by the mechanism of action

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. Adverse effects determined by the mechanism of action

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. Adverse effects determined by the mechanism of action

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. O O O HN CH H N CH 3 3 H N CH3 PAPS UDPGA

~30% ~65% OH OSO3H Glucuronate Paracetamol sulfate PARACETAMOL Paracetamol glucuronate

~4% Cytochrome P-450

O O O HN CH HN 3 CH3 HN CH3 Toxic doses Therapeutic doses

Glutathione Protein Liver cells proteins Glutathione Glutathione S-transferase OH O OH N-Acetyl- Death of cell Mercapturic acid p-benzochinonimine (non-toxic) (toxic) The specific adverse effects non-opioid analgesics

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 specific adverse effects non-opioid analgesics

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 specific adverse effects non-opioid analgesics

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 specific adverse effects non-opioid analgesics

The derivatives of , 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 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. The specific adverse effects non-opioid analgesics

In an acidic environment, 4- 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. The application of non-analgesics in certain kinds of pain

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 application of non-analgesics in certain kinds of pain

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 .

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

The pain-inhibitory action of benzodiazepins, baclofene and (agonist of -adrenoreceptors) is also observed in the spinal cord.