non steroidal anti / orthodontic courses by indian dental academy

ANTI-INFLAMMATORY DRUGS ( NSAIDs)

NON STEROIDAL

INDIAN DENTAL ACADEMY

Leader in continuing dental education www.indiandentalacademy.com

www.indiandentalacademy.com

“Pain is perfect misery, the worst of

evils, and excessive, overturns all

patience”.

John Milton (1608- 1674) Paradise Lost.


One of the greatest services doctors can do their patients is to acquire skill in the management of pain.Pain management in dental patients is individualized according to the quality of the pain, its severity, cause and chronicity. Pain arises when there is a noxious stimulus to the tissues as the result of destruction or injury. Such trauma can occur by means of a disease process, formation of an abscess, or through surgical intervention or extraction of a tooth. www.indiandentalacademy.com

Dental pain is best managed by selecting a pharmacologic agent from one of the three widely used groups.

Local anesthetic

Peripherally acting analgesics

Narcotic and opiates


Bark of willow tree was used in folk medicine for years for mild pain and fever. Salicylic acid was obtained by hydrolysis of the bitter glycoside obtained from this plant. The active ingredient of willow bark was salicin which on hydrolysis yields salicylic acid which was later found in other natural sources.

Acetylsalicylic acid was synthesized in 1853

1875 sodium salicylate was used in fever and pain.

1899 it was found to be effective in arthritis and was well tolerated.www.indiandentalacademy.com

NSAIDs are weak analgesics. They are also called as non narcotic / non opoid analgesics or aspirin type or antipyretic analgesics. They have anti-inflammatory, antipyretic (reduce the elevated body temperature). They have uricosuric properties antiplatelet activity to varying degrees. They do not depress the CNS, do not produce physical dependence and have no abuse liability. These drugs are chemically diverse, but most are organic acids.


PROSTAGLANDINSProstaglandins are naturally occurring substances composed of fatty acids found throughout body tissues. Prostaglandins and Leukotrienes are biologically active derivatives of 20 carbon atom, poly unsaturated essential fatty acids that are released from cell membrane phospholipids.

Prostanoic acidwww.indiandentalacademy.com

IN 1930’S human semen was found to

contract isolated uterine and other smooth

muscle strips and to cause fall in blood

pressure in animals. The active principle was

termed prostaglandin thinking it was derived

from prostrate.


BIOSYNTHESIS OF PROSTAGLANDINS


BENEFICIAL ACTION DUE TO PROSTAGLANDIN SYNTHESIS INHIBITION.

Analgesia : prevention of pain nerve ending sensitization

Antipyresis: reduces the elevated body temperature

Anti-inflammatory

Anti-thrombotic

Closure of ductus arteriosus.www.indiandentalacademy.com

SHARED TOXICITIES DUE TO PROSTAGLANDIN SYNTHESIS INHIBITION

Gastric mucosal damage

Bleeding : inhibition of platelet function

Limitation of renal blood flow : Na + and water retention.

Delay / prolongation of labor

Asthma and anaphylactoid reaction in susceptible individualswww.indiandentalacademy.com

PAIN – is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.

Pain is mainly a protective mechanism for the body ; it occurs whenever any tissue are being damaged , and it causes the individual to react to remove the pain stimulus.


Pain has been classified into two major types:

fast pain and slow pain. Fast pain is felt

within about 0.1 second after a pain stimulus

is applied, whereas slow pain begins only

after 1 second or more and then increases

slowly over many second and sometimes

even minutes. The pain receptors in the skin

and other tissues are all free nerve endings. www.indiandentalacademy.com

They are widespread in the superficial layers of the skin as well as in certain internal tissues, such as the periosteum, the arterial walls, the joint surfaces, and the falx and tentorium of the cranial vault. Most other deep tissues are sparsely supplied; still summate to cause the slow-chronic aching type of pain in these areas are elicited by multiple types of stimuli. They are classified as mechanical, thermal, and chemical pain stimuli. Fast pain is elicited by the mechanical and thermal types of stimuli, whereas slow pain can be elicited by all three types .www.indiandentalacademy.com

The fast-sharp pain signals they are transmitted in the penpheral nerves to the spinal cord by small type A fibers at velocities between 6 and 30 m/sec. On the other hand, the slow: chronic type of pain is specially elicited by the chemical type of pain stimuli but also at times by persisting mechanical or thermal stimuli; this slow-chronic pain is transmitted by C fibers at velocities of between 0.5 and 2m/sec.


Because of this double system of pain innervations, a sudden onset of painful stimulus often gives a double pain sensation a fast-sharp pain that is transmitted to the brain by the A fiber pathway followed a second or so later by a slow pain that is transmitted by the C fiber pathway.


On entering the spinal cord from the dorsal spinal roots, the pain fibers terminate on neurons in the dorsal horns. On entering the spinal cord the pain signals take two pathways to the brain. Through the neospinothalamic tract and through the paleospinothalamic tract.


The fast type A pain fibers transmit mainly mechanical and acute thermal pain. They terminate mainly in lamina I (laimina marginalis) of the dorsal horn, and there excite the second order neurons of the neospinothalamic tract these give rise to long fibers that cross immediately to the opposite side of the cord through the anterior commissure and then pass upward to the brain in the anterolateral columns.


Few fibers of the neospinothalamic tract terminate in the reticular areas of the brain stem, but most pass all the way to the thalamus, terminating in the ventrobasal complex. A few also terminate in the posterior nuclear group of the thalamus. From these areas the signals are transmitted to other basal areas of the brain and to the somatic sensory cortex.


The paleospinothalamic pathway transmits pain mainly carried in the peripheral slow-chronic type C pain fibers; although it does transmit some signals from type- A fibers as well. In this pathway, the peripheral fibers terminate almost entirely in laminas II and III of the dorsal horn which together are called substantia gelatinosa .Most of the signals then pass through one or more additional short fiber neurons within the dorsal horns themselves before entering laminas V through VIII, also in the dorsal horn.


Here the last neuron in the series gives rise to

long axons that mostly join the fibers from the fast

pathway, passing first through the anterior

commissure to the opposite side of the cord and

then upward to the brain in the same anterolateral

pathway. The slow-chronic paleospinothalamic

pathway terminates widely in the brainstem. Only

one-tenth to one fourth of the fibers passes all the

way to the thalamus. www.indiandentalacademy.com

Instead, they terminate principally in one of three areas: (1) the reticular nuclei of the medulla, pons, and mesencephalon; (2) the tectal area of the mesencephalon deep to the superior and inferior coliculli; or (3) the periaqueductal gray region surrounding the aqueduct of Sylvius


Glutamate, the neurotransmitter of the Type A Fast Pain Fibers.

Type C pain fiber terminals entering the spinal cord might secrete both glutamate transmitter and substance P transmitter. The glutamate transmitter acts instantaneously and lasts for only a few milliseconds. On the other hand, substance P is released much more slowly, building up in con centration over a period of seconds or even minutes


Prostaglandins particularly PGE and PGI produce hyperalgesia associated with inflammation. Prostaglandin alone induces pain only in concentration that is unlikely to occur physiologically. However they enhance the potency of algesia (pain inducing) substances by sensitizing the nerve endings of of unmyelinated C fibers and small diameter A fibers endings to other mediators such as bradykinin and histamine Furthermore bradykinin eliminates formation and release of prostaglandins and a positive feed back of sort. www.indiandentalacademy.com

FEVER which means a body temperature above the usual range of normal can be caused by abnormalities in the brain itself or by toxic substances that affect the temperature regulatory centers.

Body temperature between 99ºF (37.22ºC ) and 105ºF(40.57ºC) and onwards is called PYREXIA.

Rise of body temperature above 107ºF (41.66ºC) is called HYPERPYREXIA.www.indiandentalacademy.com

Regulation of body temperature

require a delicate balance between

production of heat and loss of heat and

the hypothalamus regulates the set

point at which body temperature is

maintained.www.indiandentalacademy.com

FEVER PRODUCTION


Many proteins, breakdown products of proteins and certain other substances esp. lipopolysaccharide toxins released from bacterial cell membrane cause the set point of the hypothalamic thermostat to rise. Substances that cause this effect are called pyrogens. The pyrogens can act directly on the hypothalamic temperature regulating centre to increase its set point. It can act indirectly and may require several hours of latency before causing their effect.


When bacteria or breakdown products of bacteria are present in the tissues or the blood, they are phagocytized by the blood leukocytes, tissue macrophages and large granular killer lymphocytes. All these cells in turn digest the bacterial products and then release into the body fluids the substance interleukin1(cytokines) which induces the formation of prostaglandin in vascular organs in the preoptic hypothalamic area. Prostaglandin (PGE2) produced acts on the hypothalamus to elicit fever reaction.


When the set point of the hypothalamic

temperature regulating centre becomes

increased to a higher level than normal all the

mechanisms for raising the body temperature

are brought into play, including heat

conservation . The temperature is increased to

the new set point (higher level) and the body

temperature also approaches this level.www.indiandentalacademy.com

Anti-pyretic action of NSAIDs is central. In fever the temperature regulating system maintains temperature at a higher level than normal. The stimulus for the shift to a higher level is the action of endogenous pyrogens such as interleukin 1 on neurons of the thermoregulatory system in the preoptic hypothalamus. NSAIDs it reduces the effect of pyrogen. www.indiandentalacademy.com

NSAIDs reduces elevated temperature by increased dissipation of heat caused by vasodilatation of superficial blood vessels. The antipyresis may be accompanied by profuse sweating. NSAIDs block both the pyrogen induced production of prostaglandin and the central nervous system response to interleukin 1 and so may reset the “temperature control” in the hypothalamus thereby facilitating heat dissipation.


Therapeutic doses of aspirin affect neither

normal body temperature nor an elevated

temperature associated with exercise, drugs

or hypothalamic lesions as there is no

pyrogen and no production of interleukin 1.


INFLAMMATION

Inflammation is defined as the local response of living mammalian tissue to injury due to any agent. It is a body defense reaction in order to eliminate or limit the spread of injurious agent. The word inflammation means burning.


Signs of inflammation—Roman writer Celsus in 1st century AD named the famous four cardinal signs of inflammation.Rubor (redness)Tumor (swelling)Calor (heat)Dolor (pain)Fifth sign function laesa (loss of function) was later added by Virchow.www.indiandentalacademy.com

Types of inflammationAcute and Chronic Inflammation.

Changes in acute inflammation—Vascular changes Cellular events1.Haemodynamic changes 1. Exudation of leucocytes2.Vascular Permeability 2. Phagoctosis


Chemical mediators of inflammation also called as permeability factors or endogenous mediators of increased vascular permeability .These are a large and increasing number of endogenous compounds which can enhance vascular permeability. The substance acting as a chemical mediator of inflammation may be released from the cells, the plasma or damaged tissue itself. They are broadly classified into 2 groups.


Mediators released by cells1. Vasoactive amines (histamine, 5-

hydroxytryptamine)2. Arachidonic acid metabolite a. Metabolite via cyclo-oxygenase pathway Prostaglandin, ThromboxaneA2, Prostcyclin b. Metabolite via lipo-oxygenase pathway 5HETE, Leukotrienes c.Metabolite via non-enzymatic pathway Chemotatic lipid 3. Lysosomal components4. Platelet activating factor.5. Cytokines (interleukin I, tumor necrosis factor)Mediators originating from plasmaThe kinin systemThe clotting systemThe fibrinolytic systemThe complement system.


NSAIDs reduce the synthesis of eicosonoid mediators of inflammation; it also interferes with chemical mediators of kallikerin system. As a result inhibits granulocyte adherence to damage vasculature, stabilizes lysosmes and inhibits the migration of ploymorphonuclear leukocytes and macrophages into the site of inflammation.


CLASSIFICATION OF NSAIDsA. Analgesic and anti-inflammatory B. Analgesic but poor anti-inflammatory

1 Paraaminophenol derivative

2 Pyrazolone derivatives

3 Benzoxazocine derivative

1 Salicylates2 Pyrazolone derivative

3 Indole derivatives4 Propionic acid derivatives

5 Anthranilic acid derivative6 Aryl-acetic acid derivatives

7 Oxicam derivatives8 Pyrrolo-pyrrole derivative9 Sulfonanilide derivative10 Alkanones


SALICYLATES --- (Aspirin- protype) (Aspirin, Salicylamide, Benorylate, Diflunisal)

The name aspirin was coined from German word for the compound acetylspirsaure (spirea, the genus of plants from which it was obtained and saure, the German word for acid)www.indiandentalacademy.com

Sodium salicylate Aspirin Methyl salicylate

Apirin is acetylsalicylic acid. It is rapidly converted in the body to salicylic acid which is responsible for most of the actions. It is one of the oldest analgesics – anti-inflammatory drugs and still is widely used.


PHARMACOLOGICAL ACTIONS -Analgesic, antipyretic, anti-inflammatory actions Aspirin is a weaker analgesic than morphine type drugs: aspirin 600 mg ~ codeine 60 mg. It relieves inflammatory, tissue injury related, connective tissue and integumental pain but is relatively ineffective in severe visceral and ischemic pain. The analgesic action is mainly due to obtunding of peripheral pain receptors and prevention of PG mediated sensitization of nerve endings. A central sub cortical action raising threshold to pain perception also contributes, but the morphine like action on psychic processing or reaction component of the pain is missing. No sedation, subjective effects, tolerance or physical dependence is produced.


Aspirin resets the hypothalamic thermostat and rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilatation), but does not decrease heat production.Anti-inflammatory action is exerted at high doses (3-6 g/day or 100 mg/kg/day). Signs of inflammation like pain, tenderness, swelling, and vasodilatation and leukocyte infiltration are suppressed. However, the progression of the underlying disease in rheumatoid arthritis, rheumatic fever and osteoarthritis etc. is not affected.


2. Metabolic effects- These are significant only at anti-inflammatory doses. Cellular metabolism is increased, specially in skeletal muscles, due to uncoupling of oxidative phosphorylation by salicylates leads to conversion of a large part of energy derived from oxidation into heat production. Large doses of salicylates may lead to hyperpyrexia. Increased protein catabolism leading to aminoaciduria and a negative nitrogen balance.


Large doses of salicylates produce hyperglycemia

and gylcosuria in normal individuals this is due to

central sympathetic stimulus- release of adrenaline

and gluccocorticoids.


3. Respiration Salicylates stimulate respiration as a result of direct and indirect action. As a result of their action on the mitochondria, at anti-inflammatory doses of salicylate increase the consumption of oxygen primarily by the skeletal muscles. This results in increased production of CO2. Increased production of CO2 production leads to a direct stimulation of the respiratory centre producing an increase in depth and to some extent in the rate of respiration. With the entry of salicylates into the brain, the medullary respiratory centre is stimulated directly. In addition, it also stimulates the chemoreceptors.


This produces an increase in the rate as well

as the depth of respiration leading to

hyperventilation. Hyperventilation is prominent

in salicylate poisoning. Further rise in

salicylate level causes respiratory depression;

death is due to respiratory failure


4. Acid-base and electrolyte balance The respiratory alkalosis produced by the anti-inflammatory doses is countered by the excretion of alkaline urine containing bicarbonate along with sodium and potassium. This is termed the stage of compensatory respiratory alkalosis. Reduction in the bicarbonate and potassium levels reduces the buffering capacity of the extracellular fluids and a patient on aspirin therapy is prone to develop acid-base imbalance .


Hypokalemia as a result of urinary loss of potassium is accompanied by water loss through lungs due to hyperventilation through the skin via augmented sweating and through urine as a result of alkalosis .This may lead to dehydration and hypernatremia. With acute doses of salicylates hypokalemia is aggravated, the respiratory centre is

depressed. With CO2 retention and excess CO2

production continues leads to respiratory acidosis .


To this are added dissociated salicylic acid as well as metabolic acids (lactic, pyruvic, acetoacetic) which are produced in excess and metabolically derived sulfuric and phosphoric acid which are retained due to depression of renal function. These entire combine to cause uncompensated metabolic acidosis since plasma HCO3- is already low. Dehydration occurs in poisoning due to increased water loss in urine (to accompany Na +, K+ and HC03-) increased sweating and hyperventilation.


6. Gastrointestinal tract the ingestion of salicylates may produce dyspepsia, nausea, vomiting as a result of gastric irritation by the released salicylic acid.


Aspirin (pKa 3.5) remains unionized and diffusible in the acid gastric juice, but on entering the mucosal cell (pH 7.1) it ionizes and becomes indiffusible. This 'ion trapping' in the gastric mucosal cell enhances gastric toxicity. Further local absorption into the mucous cell causes inhibition of prostaglandin synthesis , thus causing a loss of protective effect on the stomach. Salicylates also reduce the motility of the stomach and increases the gastric emptying time. These effects increase the period of contact of salicylates with the gastric mucosa.


To avoid gastric irritation salicylate may be administered - with plenty of water after food - With milk - With an alkali such as sodium bicarbonate - As a soluble buffered aspirin - With a prostaglandin analogueAlkali induces the ionization of salicylates thereby reducing their gastric absorption and local irritant effect. As the ionized salicylate is more water soluble, it tends to pass more quickly into the intestine and does not adhere to the mucous membrane of the stomach.


7. Blood- Aspirin, even in small doses irreversibly inhibits TXA2 synthesis by platelets. Thus it interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value. This effect lasts for about a week (turnover time of platelets). Long term use of large dose decreases synthesis of clotting factors in liver and predisposes to bleeding. www.indiandentalacademy.com

This can be detrimental in patients scheduled for

surgery. Bleeding time can be prolonged for a week.

Thus aspirin should not be used in presurgical dosing

for its analgesic effect. Recent evidence shows that a

dose of one aspirin daily can prevent myocardial

infarction and or cerebrovascular accident due to

clots initiated by the same mechanism.


8. Uricosuric effects- Urate present in the glomerular infiltrate is reabsorbed by the proximal tubules of the kidney and the main excretion of urate in urine occur due to its secretion by the distal tubule. Salicylates exhibit biphasic action on the excretion of urate. In small doses (1-2g per day) salicylate interferes with urate secretion by the distal tubule, thereby elevating the plasma urate level. The high doses of salicylates (over 5g per day) inhibit the reabsorption of urate by proximal tubule which can cause uricosuria.


6. CVS -Aspirin has no deleterious effect in therapeutic doses. Larger doses increase cardiac output to meet increased peripheral O2 demand and cause direct vasodilatation. Toxic doses depress vasomotor centre: BP may fall. Because of increased cardiac work and Na + water retention, CHF may be precipitated in patients with low cardiac reserve. www.indiandentalacademy.com

Pharmacokinetics-Salicylates are absorbed from the stomach and largely from the upper part of the small intestine.


On oral administration of a single therapeutic dose, appreciable plasma concentrations are found within 30 minutes, peak plasma level is achieved within 2 hrs and approximately 50% of the dose is eliminated in urine within 24hrs. The plasma half-life ranges from 2-8 hrs. Factors such as particle size, pH of the GIT, solubility of the salicylate preparation, presence of food in the stomach modify the absorption.


Both salicylate and salicylic acid are absorbed from intact skin, esp. when applied with alcohol, petrolatum, lard or lanolin base and systemic poisoning in children has been reported following such local application. Aspirin is rapidly deacetylated in the gut wall, liver plasma and other tissues to release salicylic acid which is a major circulating and active form.


After absorption, approx. 80% of the

salicylate is bound to plasma proteins

mainly albumin. It is rapidly distributed

through most of the tissues and

achieves a significant concentration in

the saliva, milk, spinal, sensorial and

peritoneal fluids and in the

erythrocytes. www.indiandentalacademy.com

Salicylates are mainly metabolized in the liver

and excreted in the urine in the form of

conjugate with glycine and glucuronic acid. A

small portion is oxidized to gentisic acid and

excreted in the urine. High salicylate

concentrations are observed in the liver, heart

and muscle while brain contains relatively

smaller amounts.www.indiandentalacademy.com

Adverse Effects—

Side effects that occur at analgesic dose (0.3-1.5 g/day) are nausea, vomiting, epigastric distress, increased occult blood loss in stools. The most important adverse effect of aspirin is gastric mucosal damage and peptic ulceration.


Hypersensitivity and idiosyncrasy though infrequent, these can be serious. Reactions include rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema, asthma and anaphylactoid reaction. Salicylates induced angioedema and anaphylaxis like reaction respond to adrenaline .Aspirin can induce idiosyncratic mild haemolysis in individuals with glucose 6 phosphate dehydorgenase deficiency (G6PD).


GIT – the commonest side effects of salicylates and other NSAIDs are dyspepsia, nausea, vomiting and heartburn. Therapeutic doses of aspirin may irritate gastric mucosa and increases the blood loss in majority of persons without obvious symptoms. A nonacetylated salicylate may be less irritating, should be avoided in patients with a history of ulcers and should not be used with alcohol or other agents that promote ulcer formation. Risk is greater in elderly and debilitated patients, esophageal injury may also occur.


Haemopoietic system -salicylates in large doses reduce the plasma prothrombin level by interfering with the action of vitamin k in the liver.Kidney- in normal people, aspirin has little effect on the kidney. However if there is an underlying circulatory problem such as congestive heart failure, aspirin decreases renal blood flow. This can precipitate acute renal failure. Aspirin also enhances sodium and water retention which can increase edema formation in some patients.www.indiandentalacademy.com

Reyes syndrome- This serious and often fatal

complication occur a few days after viral infection,

especially influenza and varicella, in children

below12 years. There occur anicteric liver

dysfunction due to hepatic mitochondrial injury

and a consequent metabolic encephalopathy.

Therefore aspirin should be avoided in children

under the age of 12 years.www.indiandentalacademy.com

Pregnancy and infants- When taken during term, aspirin by inhibiting prostaglandin synthesis in the uterus may delay the onset of labor and may cause greater blood loss at delivery. They cause premature closure of the ductus arteriosus with resultant serious pulmonary hypertension in the newborn. Salicylate readily crosses the placental barrier and may prove toxic to the newborn as the ability of the newborn to detoxify and excrete salicylate is poor.


Anti-inflammatory doses (3-6 g/day)

produce the syndrome called salicylism

diziness, tinnitus, vertigo, reversible

impairment of hearing and vision, excitement

and mental confusion, hyperventilation and

electrolyte imbalance.www.indiandentalacademy.com

Salicylism- prolonged administration of salicylates may produce a condition of mild salicylate intoxication termed salicylism. The syndrome usually develops when the plasma salicylate level exceed 25mg% and characterized by headache, dizziness, vertigo, tinnitus, difficulty in hearing, and dizziness of vision, drowsiness ,lethargy, mental confusion, nausea and vomiting. The signs and symptoms of salicylism are reversible on cessation of therapy.www.indiandentalacademy.com

Acute salicylate poisoning – may be due to

overzealous therapy in infants or an accidental

ingestion by children and adults. A serum salicylate

level of 50 mg% indicates mild toxicity, level above

75mg%, are potentially fatal.


Manifestations are- Vomiting, dehydration electrolyte imbalance, acidotic breathing, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory failure cardiovascular collapse.Treatment is symptomatic and supportive. Most important is external cooling and iv fluid with Na+, K+, HCO3-] and glucose: according to need determined by repeated monitoring, Gastric lavage to remove unabsorbed drug; forced alkaline diuresis or haemodialysis to remove absorbed drug is indicated in severe cases. Blood transfusion and vit K should be given if bleeding occurs.


Precaution and contraindication--Aspirin is contraindicated in patients who are sensitive to it and in peptic ulcer, bleeding tendencies, in children suffering from chicken pox or influenza. Due to risk of Reye’s syndrome pediatric formulations of aspirin are prohibited.- In chronic liver disease: cases of hepatic necrosis.- It should be avoided in diabetics, in those with low cardiac reserve or frank CHF and in juvenile rheumatoid arthritis.www.indiandentalacademy.com

-Aspirin should be stopped 1 week before elective surgery.- Given during pregnancy it may be responsible for low birth weight babies. Delayed or prolonged labor, greater postpartum blood loss and premature closure of ductus arteriosus are possible if aspirin is taken at or near term.-It should be avoided by breast feeding mothers.-Avoid high doses in G-6-PD deficient individuals-haemolysis can occur.


Uses--As analgesic-As antipyretic-Acute rheumatic fever-Rheumatoid arthritis-Osteoarthritis-Postmyocardial infarction and post stroke patients


PYRAZOLONES –These are-

-Aminopyrine and antipyrine

-Phenylbutazone and Oxyphenbutazone

-Other drugs like Phenyldimethyl pyrazolone

(analgin)


Antipyrine (phenazone) and amidopyrine (aminopyrine) were introduced in 1884 as antipyretics and analgesics. Their use was associated with high incidence of agranulocytosis: are banned in many countries. Phenylbutazone was introduced in 1949 and soon its active metabolite oxyphenbutazone was also marketed. These two are potent anti-inflammatory drugs. Two other pyrazolones available in India - metamizol and propiphenazone are primarily used as analgesic and antipyretic.


Phenylbutazone It inhibits COX and is more potent anti-inflammatory than the usually tolerated doses of aspirin; somewhat comparable to corticosteroids. The analgesic and antipyretic action is poorer and slower in onset. It is uricosuric by virtue of a metabolite which inhibits renal tubular reabsorption of uric acid. Phenylbutazone causes definite retention of Na + and water by direct action on renal tubules, edema, and expansion of plasma volume occur after 1-2 weeks of use: CHF may be precipitated.


Pharmacokinetics Phenylbutazone is completely absorbed orally. Absorption from i.m. sites is slower and it causes local tissue damage: this route is not recommended. It is 98% bound to plasma: proteins: completely metabolized in liver by hydroxylation and glucuronidation. The plasma t1/2 is 60 hours; even then divided daily doses are given to minimize gastric irritation.


Adverse effects- More toxic than aspirin. Nausea, vomiting, epigastric distress and peptic ulceration are common. Diarrhea and a variety of CNS side effects are reported. Edema is the major limitation of use for more than 1-2 weeks.Hypersensitivity: rashes, serum sickness, hepatitis and stomatits. .Bone marrow depression, agranulocytosis and Stevens-Johnson syndrome are serious dangers. Goiter and hypothyroidism have occurred on long term use.


Uses -Because of risk of fatal agranulocytosis and other serious reactions, phenyl butazone and oxyphenbutazone have-been banned in some countries. With the availability of safer NSAIDs, these drugs should be used only in severe cases not responding to other drugs. Rheumatoid arthritis and ankylosing spondylitis: for short period (1-2 weeks) during an acute exacerbation.Rheumatic fever: cases not responding to aspirin.Acute gout: to suppress the attack. It is nearly as effective as colchicines and better tolerated.Though uricosuric, it is not recommended for long term therapy of chronic gout.


INDOLE DERIVATIVES (Indomethacin, Sulindac )

Indomethacin it is a potent anti-inflammatory drug, comparable to phenylbutazone. In addition, it is a potent and promptly acting antipyretic. Analgesic action is better than phenylbutazone, but it relieves only inflammatory or tissue injury related pain. It is a highly potent inhibitor of PG synthesis and suppresses neutrophil motility. In toxic doses it uncouples oxidative phosphorylation (like aspirin). www.indiandentalacademy.com

Pharmacokinetics Indomethacin is well

absorbed orally; rectal absorption is slow but

dependable. It is 90% bound to plasma

proteins partly metabolized in liver to inactive

products and excreted by kidney. Plasma t1/2

is 2-5 hours.


Adverse effects - A high incidence (upto, 50%) of gastrointestinal and CNS side effects are produced. Marked gastric irritation, nausea, anorexia, gastric bleeding and diarrhea.Frontal headache (very common), dizziness, ataxia, mental confusion, hallucination. Depression and psychosis.Leukopenia, rashes and other hypersensitivity reactions are also reported.Increased risk of bleeding due to decreased platelet agreeability.It is contraindicated in machinery operators, drivers, psychiatric patients, epileptics, kidney disease. pregnant women and in children.www.indiandentalacademy.com

Uses - it is indicated in rheumatoid arthritis not controlled by aspirin. It is particularly efficacious in ankylosing spondylitis, acute exacerbations of destructive arthropathies and psoriatic arthritis. It acts rapidly in acute gout. Malignancy associated fever refractory to other antipyretics may respond to indomethacin. It has been the most common drug used for medical closure of patent ductus arteriosus three 12 hourly doses of 0.1-0.2 mg/kg achieves closure in majority of cases. www.indiandentalacademy.com

PROPIONIC ACID DERIVATIVES ( Ibuprofen, Naproxen, Ketoprofen, Fenoprofen, Flurbiprofen )Ibuprofen was the first member of this class to be introduced in 1969 as a better tolerated alternative to aspirin. The analgesic, antipyretic and anti-inflammatory efficacy is rated somewhat lower than high dose of aspirin. All inhibit PG synthesis, naproxen being most potent; but their in vitro potency for this action does not closely parallel in vivo anti-inflammatory potency. They inhibit platelet aggregation and prolong bleeding time.


Pharmacokinetics - All are well absorbed orally, highly bound to plasma proteins (90-99%), but displacement interactions are not clinically significant dose of oral anticoagulants and oral hypoglycemic need not be altered. Because they inhibit platelet function, use with anticoagulants should, nevertheless, be avoided. All propionic acid derivatives enter brain, synovial fluid and cross placenta. They are largely metabolized in liver by hydroxylation and glucuronide conjugation and excreted in urine as well as bile.www.indiandentalacademy.com

Adverse effects- Ibuprofen and all its congeners are better tolerated than aspirin. Side effects are milder and their incidence is lower.Gastric discomfort, nausea and vomiting, though less than aspirin or indomethacin, are still the most common side effects. However, even some peptic ulcer patients are able to tolerate these drugs. Gastric erosion and occult blood loss are rare.


CNS side effects include headache, dizziness, blurring of vision, tinnitus and depression. Rashes, itching and other hypersensitivity phenomena are infrequent. However, these drugs also precipitate aspirin induced asthma.Fluid retention is less marked than that with phenylbutazone.They are not to be prescribed to pregnant women and should be avoided in peptic ulcer patient.


UsesIbuprofen is used as a simple analgesic and antipyretic in the same way as low dose of aspirin. It is particularly effective in dysmenorrhoea in which the action is clearly due to PG synthesis inhibition. Ibuprofen and its congeners are widely used in rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders, specially where pain is more prominent than inflammation.They are indicated in soft tissue injuries, fractures, vasectomy, tooth extraction, postpartum and postoperatively: suppress swelling and inflammation. www.indiandentalacademy.com

ANTHRANILIC ACID DERIVATIVE

(Mephenamic acid)

Mephenamic acid an analgesic, antipyretic and

anti-inflammatory drug, known from 1950s, but

has not gained popularity because of lower

efficacy. It inhibits PG synthesis and

antagonizes certain actions of PGs as well.

Mephenamic acid exerts peripheral as well as

central analgesic action.www.indiandentalacademy.com

Pharmacokinetics- Oral absorption is

slow but almost complete. It is highly bound

to plasma proteins displacement

interactions can occur; partly metabolized

and excreted in urine as well as bile. Plasma

tl/2 is 2-4 hours.


Adverse effects- Diarrhea is the most

important dose related side effect. Epigastric

distress is complained, but gut bleeding is

not significant.

Skin rashes, dizziness and other CNS

manifestations have occurred. Hemolytic

anemia is rare but serious complication.www.indiandentalacademy.com

Uses Mephenamic acid is indicated primarily

as analgesic in muscle, joint and soft tissue

pain where strong anti-inflammatory action is

not needed. It is quite effective in

dysmenorrhoea. It may be useful in some cases

of rheumatoid and osteoarthritis but has no

distinct advantage www.indiandentalacademy.com

ARYL-ACETIC ACID DERIVATIVES (DiclofenacE, Tolmetin )

Diclofenac sodium a newer analgesic-

antipyretic-anti-inflammatory drug, similar in

efficacy to naproxen. It inhibits PG synthesis

and has short lasting anti platelet action;

Neutrophil chemotaxis and superoxide

production at the inflammatory site are

reduced. www.indiandentalacademy.com

Pharmacokinetics

It is well absorbed orally, 99% protein bound,

metabolized and excreted both in urine and

bile. The plasma t1/2 is 2 hours. However, it

has good tissue penetrability and

concentration in synovial fluid is maintained

for 3 times longer period than in plasma,

exerting extended therapeutic action in joints.www.indiandentalacademy.com

Adverse effects - are generally mild: epigastric

pain, nausea, headache, dizziness, and rashes.

Gastric ulceration and bleeding are less

common. Reversible elevation of serum amino-

transferases can occur; kidney damage is rare.


Uses - Its indications are similar to those of

ibuprofen - rheumatoid and osteoarthritis,

bursitis, ankylosing spondylitis,

dysmenorrhoea, post-traumatic and

postoperative inflammatory conditions -

affords quick relief of pain and wound edema.


OXICAM DERIVATIVES (Piroxicam, Tenoxicam, Meloxicam )Piroxicam It is a novel long acting potent NSAID with anti-inflammatory potency similar to indomethacin and good analgesic-antipyretic action. It is a reversible inhibitor of cyclooxygenase; lowers PG, concentration in synovial fluid and inhibits platelet aggregation-prolonging bleeding time. In addition, it decreases the production of IgM rheumatoid factor. Chemotaxis of leukocytes and ratio of T-helper to T-suppressor lymphocytes are reduced. Thus, it can inhibit inflammation in diverse ways. www.indiandentalacademy.com

Pharmacokinetics it is rapidly and

completely absorbed: 99% plasma protein

bound; largely metabolized in liver by

hydroxylation and glucuronide conjugation;

excreted in urine and bile; enterohepatic

cycling occurs. Plasma t1/2 is long-nearly 2

days. Steady state concentrations are achieved

in a week. Single daily administration is

sufficient.www.indiandentalacademy.com

Adverse effects Common side effects are

heart burn, nausea and anorexia, but it is better

tolerated and less ulcerogenic than

indomethacin or phenylbutazone; causes less

faecal blood loss than aspirin. Rashes and

pruritus are seen in < 1% patients. Edema and

reversible azotemia have been observed.www.indiandentalacademy.com

Uses It is suitable for use as short term

analgesic as well as long term anti-

inflammatory drug - rheumatoid and osteo-

arthritis, ankylosing spondylitis, acute gout,

musculoskeletal injuries, dentistry,

episiotomy, dysmenorrhoea etc. Its efficacy is

comparable to high dose aspirin or

indomethacin.www.indiandentalacademy.com

PYRROLO-PYRROLE DERIVATIVE (Ketorolac)

Ketorolac A novel NSAID with potent analgesic and modest anti-inflammatory activity. In postoperative pain it has equaled the efficacy of morphine, but does not interact with opioid receptors and is free of respiratory depressant, dependence producing, hypotensive and constipating side effects. It inhibits PG synthesis and is believed to relieve pain by a peripheral mechanism. In short lasting pain, it has compared favorably with aspirin. Platelet aggregation is inhibited for short periods.


Pharmacokinetics -

Ketorolac is rapidly absorbed after oral and

i.m. administration. It is highly plasma

protein bound and 60% excreted unchanged

in urine. Major metabolic pathway is

glucuronidation; plasma t1/2 is 5-7 hours.www.indiandentalacademy.com

Adverse effects Nausea, abdominal pain, dyspepsia, ulceration, loose stools, drowsiness, headache, dizziness, nervousness, pruritus, pain at injection site, rise in serumtransaminase and fluid retention have been noted. .No significant drug interactions have been reported and it has been used concurrently with morphine. However, it should not be given to patients on anticoagulants.Its safety in ulcer patients, in cardiac, renal and hepatic disease, children, elderly and pregnant women has not been established.www.indiandentalacademy.com

Uses Ketorolac is frequently used in postoperative and acute musculoskeletal pain: 15-30 mg i.m. every 4-6 hours (max. 120 mg/day). It may also be used for renal colic, migraine and pain due to bony metastasis.Orally it is used in a dose of 10-20 mg 6 hourly for short term management of moderate pain. Continuous use for more than 5 days is not at present recommended. It should not be used for preanaesthetic medication or for obstetric analgesia www.indiandentalacademy.com

SULFONANILIDE DERIVATIVE (Nimesulide )

Nimesulide-Nimesulide- this newer NSAID is a relatively

weak inhibitor of PG synthesis (may be somewhat

selective for COX-2); appears to exert its effects by

other mechanisms like reduced generation of

superoxide by neutrophils, inhibition of PAF

synthesis and TNF release, free radical

scavanging, inhibition of metalloproteinase activity

in cartilage. www.indiandentalacademy.com

The analgesic, antipyretic and anti-inflammatory activity of nimesulide has been rated comparable to other NSAIDs. It has been used primarily for short lasting painful inflammatory conditions like sports injuries, sinusitis and other ear-nose-throat disorders, dental surgery, bursitis, low backache, dysmenorrhoea; postoperative pain and osteoarthritis.


Pharmacokinetics -

Nimesulide is almost completely absorbed

orally, 99% plasma protein bound,

extensively metabolized and excreted mainly

in urine with a t1/2 of 2-5 hours.


Adverse effects of nimesulide are gastrointestinal (epigastralgia, heart burn, nausea, loose motions), dermatological (rash, pruritus) and central (dizziness). Claims of better gastric tolerability than other NSAIDs have not been substantiated. There is also no proof that renal complications associated with NSAID use are missing with nimesulide. However, most asthmatics and those who develop bronchospasm or intolerance to aspirin and other NSAIDs do not cross react with nimesulide. Its specific usefulness appears to be only in such patients. www.indiandentalacademy.com

PARA-AMINO PHENOL DERIVATIVES (Paracetamol )

Phenacetin was introduced in 1887. It was extensively used but is now banned in many countries, including India, because it was implicated in analgesic abuse nephropathy.

Paracetamol (acetaminophen) the deethylated active metabolite of phenacetin, was also introduced in the last century but has come into common use only since 1950.

The central analgesic action of paracetamol is like aspirin, i.e. it raises pain threshold, but has weak peripheral www.indiandentalacademy.com

Anti-inflammatory component. Analgesic action of aspirin and paracetamol is additive. Paracetamol is a good and promptly acting antipyretic.Paracetamol has negligible anti-inflammatory action. It is a poor inhibitor of PG synthesis in peripheral tissues, but more active on COX in brain. One explanation offered for the discrepancy between its analgesic-antipyretic and anti-inflammatory actions is its poor ability to inhibit COX in the presence of peroxides which are generated at sites of inflammation.www.indiandentalacademy.com

Subjective effects: Phenacetin probably produces a sense of relaxation and well being in some people. In the early part of present century it was widely abused by factory workers in the industrializing Europe. It was claimed to reduce tension, fatigue and to increase work capacity: was considered habit forming, but not producing physical dependence though discontinuation did produce mild symptoms. Paracetamol has not shown such a pattern of abuse.www.indiandentalacademy.com

In contrast to aspirin, paracetamol does not

stimulate respiration or affect acid-base, nor

increase cellular metabolism. It has no effect

on CVS. Gastric irritation is insignificant -

mucosal erosion and bleeding occur rarely

only in overdose. It. does not affect function

or clotting factors and is not uricosuric.www.indiandentalacademy.com

Pharmacokinetics Paracetamol is well

absorbed orally, only about 1/3 is protein

bound in plasma and uniformly distributed in

the body. It is conjugated with glucuronic acid

and is excreted rapidly in urine. Plasma tl/2 is

2-3 hours. Effects after an oral dose last 3-

5hrs.www.indiandentalacademy.com

Adverse effects in isolated antipyretic doses paracetamol are safe and well tolerated. Nausea and rashes occur occasionally.Analgesic nephropathy occurs after years of heavy ingestion of analgesics; such individuals have some personality defect. It manifests as papillary necrosis, tubular atrophy followed by renal fibrosis. Urine concentrating ability is lost and the kidneys shrink. Because phenacetin was commonly abused, it was primarily implicated and has gone into disrepute, though other analgesics are also liable to produce similar effects.www.indiandentalacademy.com

Paracetamol poisoning it occurs specially in small children who have low glucuronide conjugating ability. If a large dose (> 150 mg/kg or> 10 g in an adult) is taken serious toxicity can occur. Fatality is common with> 250 mg/kg.Early manifestations are just nausea, vomiting, abdominal pain and liver tenderness impairment of consciousness. After 12-18 hours centrilobular hepatic necrosis occurs which may be accompanied by renal tubular necrosis and hypoglycemia that may progress to coma. Jaundice starts after 2 days. Further course depends on the dose taken. www.indiandentalacademy.com

Fulminating hepatic failure and death are

likely if the plasma levels are above the line

joining 200 g/ml at 4 hours and 30 g/ml at

15 hours. If the levels are lower-recovery with

supportive treatment is the rule.


Mechanism of toxicity N-acetyl-benzoquinone-imine is a highly reactive arylating minor metabolite of paracetamol which is detoxified by conjugation with glutathione. When a very large dose of paracetamol is taken, glucuronidation capacity is saturated, more of minor metabolite is formed- hepatic glutathione is depleted and this metabolite binds to proteins in liver cells (and renal tubules) causing necrosis. Toxicity thus shows a threshold effect manifesting only when glutathione is depleted to a critical point. In chronic alcoholics even 5-6 g/day taken for a few days can result in hepatotoxicity.


Paracetamol is not recommended in premature

infants (2 kg) for fear of hepatotoxicity.

Treatment-If the patient is brought early,

vomiting should be induced or gastric lavage

done. Activated charcoal is given orally or

through the tube to prevent further absorption.

Other supportive measures, as needed, should

be taken. www.indiandentalacademy.com

N-acetylcysteine 150 mg/kg should be infused i.v. over 15 min, followed by the same dose i.v. over the next 20 hours. Alternatively, 75 mg/kg may be given orally every 4-6 hours for 2-3 days. It replenishes the glutathione stores of liver and prevents binding of the toxic metabolite to other cellular constituents.Ingestion-treatment interval is critical; earlier the better. It is practically ineffective if started 16 hours or more after paracetamol ingestion.


Uses Paracetamol is one of the most commonly used over the counter' analgesic for headache, musculoskeletal pain, dysmenorrhoea etc. where anti-inflammatory action is not required. It is one of the best drugs to be used as antipyretic.Dose to dose it is equally efficacious as aspirin for noninflammatory conditions, It is much safer than aspirin in terms of gastric irritation, ulceration and bleeding (can be given to ulcer patients), does not prolong bleeding time. Hypersensitivity reactions are rare; no metabolic effects or acid-base disturbances; can be used in patients in whom aspirin is contraindicated. It does not have significant drug interactions. Thus, it may be preferred over aspirin for most minor conditions.www.indiandentalacademy.com

BENZOXAZOCINE DERIVATIVE (Nefopam)Nefopam It is a recently introduced nonopioid analgesic which does, not inhibit PG synthesis. In traumatic and postoperative pain, it acts rapidly with an efficacy approaching morphine, yet has no opioid actions. Favorable results have been obtained in short lasting musculoskeletal pain not responding to other nonopioid analgesics.Nefopam produces anticholinergic (dry mouth, urinary retention, blurred vision and sympathomimetic (tachycardia, nervousness) side effects, and nausea is often doseLimiting. It is contraindicated in epileptics www.indiandentalacademy.com

Celecoxib

This selective COX-2 inhibitor has become available in India in 2000. It exerts potent anti-inflammatory, analgesic and antipyretic actions with low ulcerogenic potential. Comparative trials in rheumatoid arthritis have found it to be as effective as naproxen or diclofenac, without affecting COX-I activity in gastroduodenal mucosa even at maximal therapeutic dose. Platelet aggregation in response to collagen exposure remained intact in celecoxib recipients. www.indiandentalacademy.com

Though tolerability of celecoxib is better than

older NSAIDs, still abdominal pain, dyspepsia

and mild diarrhea are the most common side

effects.

Celecoxib is slowly absorbed, 97% plasma

protein bound and metabolized primarily by

CYP 2C9 with mean t1/2 of 11 hrs. It is

approved for use in osteo- and rheumatoid

arthritis in a dose of 100-200 mg B D.www.indiandentalacademy.com

Rofecoxib

It is a COX-2 selective inhibitor. Rofecoxib has been found to be as effective as other NSAIDs in osteoarthritis, rheumatoid arthritis as well as in dysmenorrhoea, dental, postoperative and acute musculoskeletal pain at a dose of 12.5-25 mg once daily. Occurrence of peptic ulcer is rare and incidence of ulcer bleeds over 1 year of use has been found to be significantly lower than with other NSAIDs .Rofecoxib has no effect on TXA2 production by platelets. Side effects are mild g.i. complaints, headache and dizziness. www.indiandentalacademy.com

Pedal edema and rise in BP occurs occasionally. Rofecoxib is well absorbed orally, 87% plasma protein bound, extensively metabolized and has an average t1/2 of 17 hours. It should be avoided in presence of severe hepatic/renal disease and in those receiving rifampin, warfarin, methotrexate.


Valdecoxib

Recently marketed selective COX-2 inhibitor having similar efficacy and tolerability profile as Rofecoxib. The plasma t1/2 is 8-11 hours. In osteoarthritis and rheumatoid arthritis it is recommended in a dose of 10 mg once daily, while for primary dysmenorrhoea or post-operative pain upto 20 mg twIce daily may be used.


Name Available as Dose / Frequency

Salicylates(Aspirin)

300, 350 mg tab 300-350 mg t.i.d

Ibuprofen (Brufen) 200, 400mg tab 400-600mg t.i.d

Naproxen (Naprosyn)

250mg tab 250-500mg b.i.d

Diclofenac (voveran)

50mg tab 50mg b.i.d

Piroxicam (pirox) 10-20mg capsules 10-20mg o.d

Paracetamol (Crocin)

300, 500mg 300-500mg t.i.d

Indomethacin (Indocid)

25mg 25-50mg t.id


Choice of Nonsteroidal anti-inflammatory

drug

NSAIDs have their own spectrum of adverse

effects. They differ quantitatively among

themselves in producing different side effects and

there are large inter-individual differences. At

present NSAIDs is a bewildering array of strongly

promoted drugs. No single drug is superior to all

others for every patient. Choice of drug is

inescapably empirical. .www.indiandentalacademy.com

The nature of problem (acute/chronic; pain: inflammation ratio, severity) along with consideration of risk factors in an individual patient directs the initial selection.1. Mild to moderate pain with little inflammation - paracetamol or low dose ibuprofen. 2. Acute musculoskeletal, osteoarthritis, injury associated inflammation - a propionicacid derivative, diclofenac or piroxicam.3. Postoperative or other acute but short lasting painful conditions with minimal inflammation - ketorolac, nefopam.www.indiandentalacademy.com

4. Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheu matic fever - high dose aspirin, indomethacin, naproxen, piroxicam.5. Patients with history of asthma or anaphylactoid reactions to aspirin/other NSAIDs-nimesulide.6. Combination of two or more NSAIDs is not superior to single agents. If at all used, combination therapy should be limited to short periods. www.indiandentalacademy.com

The Propionic acid derivatives and other newer drugs - diclofenac, piroxicam are, in general, better tolerated. Due to risk of Reye's syndrome, aspirin should not be used in children without medical advice. During pregnancy lower dose of aspirin is probably the safest but it should be discontinued near term. The possibility of drug interactions should be considered in patients receiving prolonged therapy with other drugs (e.g. hypertensives, diabetics, ischemic heart disease patients etc.


References –

1.Manual of dental therapeutics Raymond F. Zambite ,James J Sciubber (1993)

2.Medical Pharmacology Clark, Barter, John (1992)

3.Essentials of medical pharmacology K D Tripathi (1999)

4.Concise medical pharmacology Chaudhuri

5.Medical physiologyGuyton Hall www.indiandentalacademy.com

6. Essential pathology for dental studentsHarsh Mohan

7.Pharmacology and pharmacotherapeuticsR. S. Satoskar

8. Textbook of dental pharmacology and therapeutics John G Walton, John W. Thompson


non steroidal anti / orthodontic courses by indian dental academy

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