antpyretic-analgesic and antinlammatory drugs

8/3/2019 Antpyretic-Analgesic and Antinlammatory Drugs

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ANTIPYRETIC-ANALGESIC AND

ANTIINFLAMMATORY DRUGSPHARMACOLOGY DEPARTMENT

DR AYAM R KALINGONJI(MMED 1)FACILITATOR DR RIMOY


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Non-steroidal ant-inflammatory

drugs(NSAIDs)NSAIDs have three major actions,all of which

are due mainly to the inhibition arachnoic acid

cyclo-oxygenase in inflammatory cells(the

COX-2 isoenzyme),and the resultant decreasein prostanoid synthesis.


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drugs(NSAIDs) Ant-inframatory action

1.The decrease in vasodilator

prostaglandins(PGE2,PGI2)means less

vasodilatation and,indirectly,less oedema.

2.The inhibition of activity of adhesion

molequle.

3.Accumulation of inflammatory cells is alsoreduced.


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drugs(NSAIDs) COX:

COX-1:constitutive enzyme;is involved in

tissue homeostasis.

COX-2:inducible enzyme is responsible for the

production of prostanoid mediators ofinflammation.


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drugs(NSAIDs) ANALGESIC EFFECT:

-Decreased prostaglandin generation means less

sensation of nociceptive nerve endings to

inflammatory mediators such as bradykinin

and 5-hydroxytryptamine.

-Relief of headache is probably due to decreased

prostaglandin-mediated vasodilatation.


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drugs(NSAIDs) ANT-PYRETIC EFFECT:

-This is partly due to a decreased in the

mediator prostaglandin that is responsible for

elevating the hypothalamic set-point for

temperature control in fever.

-Endogenous pyogen(IL-1,TNF,IFN,IL-6)

BBBCNS(PEG.Na+/Ca+.cAMP.CRH)fever


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CLASSIFICATION Selection:Non-selective COX inhibitor

:selective COX inhibitor

Chemical constitution;salicylates

;acetaminophen

;indomethacin


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drugs(NSAIDs) Some important examples are

asprin,ibuprofen,naprexifen,indomethacin,par

acetamol.(the lastagent has analgesic and

antipyretic effects but little ant-inflammatoryaction).


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The salicylates:Asprin Asprin(acetylsalicylic acid) was first isolated in

1829 by Leroux from willow bark.

It can cause irrevesible inactivation of cyclo-oxygenase,acting on both COX-1 and COX-2


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ASPRIN Salicylates are given orally and are rapidly

absorbed:75% metabolized in the liver.

Excretion:85% in alkaline urine

5% in acidic urine


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Pharmacologic effect 1.Ant-pyretic action

It is rapidly effective in febrile patients,yet haslittle effect on normal body temperature.


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Pharmacologic effect Ant-inflammatory effects.

The primary clinical application is in the

treatment of musculoskeletal disorders, such

as rheumatoid arthritis, osteoarthritis andankylosing spondylitis.


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Pharmacologic effects3.Analgesic effect

(a)Is usually effective for low to moderate

intensity pain.integumental pain is relieved

better than the pain from the hollow visceral

areas.


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Pharmacologic effects(b)Relief of pain occur through both peripheral and

central mechanisms.

---peripherally, it inhibits the synthesis of PGs in

inflamed tissues. Thus prevent the sensitization of

pain receptors to both chemical and mechanicalstimuli.

---centrally the analgesic site exists in close proximity to

the antipyretic region in the hypothalamus. Its

analgesia action is not associated with mental

alterations such as hypnosis or changes in sensation

other than pain.


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Pharmacologic effects4.Respiratory effects

(a)High dose result in medullary stimulation, leading to

hyperventilation and respiratory

alkalosis.compesation rapidly occurs because thekidney is able to increase the excretion of

bicarbonate, producing compensated respiratory

alkalosis.

(b)Toxic doses or very prolonged administration can

depress the medullary resulting in an compensatedrespiratory acidosis.


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Pharmacologic effects5.Cardiovascular effects

(a)Therapeutic doses have no significant of

cardiovascular effect. however prophylactic

use of aspirin to reduce thromboembolic

event in coronary and cerebral circulation has

increased. studies have demonstrated that

such use result in long-term survival andreduced frequency of second myocardialinfarctions.


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Pharmacologic effects 5.Cardiovascular effects

(b)High doses my cause peripheral

vasodilatation by exerting a direct effect on

smooth muscle.

(c)Toxic doses depress circulatory directly and by

central vasomotor paralysis.non carcinogenic

pulmonary edema my occur in order patients

on long term Salicylates therapy.


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Pharmacologic effects6.Gastrointestinal effects

(a)It can cause epigastric distress, nausea and vomiting

by irritating the gastric mucosal lining and

stimulating the chemoreceptor trigger zone in the

CNS.(b)It may cause a dose related gastric ulceration,

bleeding and erosive gastritis because of inhibiting

the formation of PGE2,which inhibit gastric acid

secretion and has a cytoprotective effect.salicylate

induced gastric bleeding is painless and may lead toiron deficiency anemia.


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Pharmacologic effects7.Hepatic effects.

(a)Dose-dependent hepatic damage usually

asymptomatic, elevated plasma transaminase

levels are the key indicator of hepatic insult.

(b)More severe and associated with

encephalopathy seen in Reye's syndrome.

Use of Salicylates in children with chicken pox orinfluenza is contraindicated.


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Pharmacologic effects8.Hematologic effects

(a)It inhibits the platelet aggregation by

decreasing production of TXA2.

(b)In doses greater than 6g/dl, aspirin my reduceplasma prothrombin levels.


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Pharmacologic effects9.Renal effects;

It can result in salt and water retention because

of decreasing renal blood flow.

10.Metabolic effects;It can produce hyperglycemia and glycosuria in

larger doses.

11.Endocrine effect;In very larger doses, it can stimulate steroid

secretion by the adrenal cortex.


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Therapeutic uses1.Asprinis used for the restricted situation for the

symptomatic relief of fever. Because of an increased

incidence of Reye's syndrome in children who

previously were given aspirin for the relief of viralfevers, It is now recommended that a child with any

fever be given paracetamol instead,ifmedication is

required.

2.It is useful as analgesics for certain categories ofpain,such as headache, arthritis and dysmenorrhea.


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Therapeutic uses3.It remains the standard, first line drug in the

therapy of rheumatoid arthritis, and can

provide relief in the acute rheumatic fever.

4.Some clinicians recommend small daily doses

of aspirin for prophylaxis of

thromboembolism,stroke,or myocardial

infarction because of its antplatelet activity.


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Adverse effects1.salicylism;usually occurs with repeated

administration with larger doses. Characteristic

findings include.

---headache, mental confusion, lassitude and

drowsiness.---tinnitus and difficult in hearing.

---hyperthermia,sweating,thirst,hyperventilation,

vomiting and diarrhea.2.Bronchspasmin aspirin-sensitive asthmatics.


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Adverse effects3.Gastrointestinal disturbances.

4.Prolongation of bleeding time or reduce

prothrombin level.

5.Other skin eruption, hepatic effects, Reyessyndrome.


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Treatment of aspirin poisoning1.Inducing emesis or administering gastric

lavage.

2.Appropriate infusion measures to correct

abnormal electrolyte balance and

dehydration.

3.Alkalization of urine.

4.dialysis as required


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PARACETAMOLPharmacologic effects

Paracetamol has analgesic and antipyretic actions but

only weak antinflamatory effects.

It appears to be an inhibitor of PG synthesis in the

brain, thus accounting for its analgesic andantipyretic activity.

It is much less effective than aspirin as an inhibitor of

peripherally located PG biosynthesis enzyme system

that plays such an important role in inflammation.

It exerts little or no pharmacologic effect on the

cardiovascular,respiratory,or gastrointestinal systems

on acid base regulation, or on platelet function


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Therapeutic uses Paracetamol provides an effective alternative

when aspirin is contraindicated(e.g., in patient

with peptic ulcer or hemophilia)and when the

antinflamatory action of aspirin is notrequired.


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Adverse effects At therapeutic doses paracetamol is well

tolerated;however,adverse effects includes.

---skin rash and drug fever

---rare incidence of blood dyscrasias

---renal tubular necrosis and renal failure

---hypoglycemic coma At overdose, it result in severe Hepatotoxicity,

and resulting in centrilobular hepatic necrosis.


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INDOMETHACIN Pharmacological effects;

1.Inhibit COX non selectively.

2.Inhibit phospholipase A and C3.Reduce PMN migration

4.Decrease B cell ant T cell proliferation

(10-40 time more potent ant-inflamatory thanaspirin)


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INDOMETHACIN Therapeutic uses;

Because of its toxicity and side effects, it is not

routinely used for analgesia antipyretics.

The major use of indomethacin are in the

treatment of rheumatoid arthritis, ankylosingspondlytis,osteoarthritis and acute gout.


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INDOMETHACIN Adverse effects;

1.Gastrointestinal complaints

2.CNS effects; 25%-50%

3.Hematologic reaction

4.Hypersensitivity reactions;asthma(asprin-

sensitive patient may exhibit cross-reactionsto indomethacin)


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Naproxen and ibuprofen They have prominent anti-inflammatory

action.

Therapeutic uses; rheumatoid arthritis,

ankylosing spondlytis,acute tendinitis,

dysmenorrhea.

Adverse affect;gastrointerstinal effects,

dermatologic problems, thrombocytopenia.

*apply to long term treatment because they arebetter tolerated.


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Selective COX -2 inhibitorCelecoxib,meloxicam and Rofenxib

More selective for COX-2 than COX-1.

Adverse effects are slighter than other NSADs

Long term studies of the incidence of clinically

significant gastrointestinal ulcers and bleedingare not yet compared.


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Clinical use of NSAIDs# For analgesia in painfull

conditions(e.g.headache,dysmenorrhe,backake,boe

metastasis of cancers,postoperative of pain)

The drug of choice for short term analgesia areasipinin,paracetamol,ibuprofen,more potent longer

drugs(diflunisal,naproxem,piroxicam)

The requirement for narcotic analgesics can be

markedly reduses by NSAIDs in some patients withbone metastases of post operative pain.


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Clinical use of NSAIDs# For antinflamatory effects in chronic or acute

inflammatory conditions(e.g rheumatoid arthritis

and renal connective tissue disorders, gout and soft

tissue disease.)

With many NSAIDs the dose required for chronicinflammatory disorders is greater than for simple

analgesia and treatment may need to be continued

for long periods; treatment could be initiated by an

agent known to have low incidence of side effects. ifthis proves unsatisfactory, more potent agent should

be used.


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Clinical use of NSAIDs To lower temperature;paracetomol is

preferred because it lacks gastrointestinal side

effectsand,unlike aspirin, has not been

associated with Reyes syndrome in children.

There is substantial individual variation in

clinical response to NSAIDs and considerable

unpredictable patient preference for one drugrather than other.


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antpyretic-analgesic and antinlammatory drugs

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