Analgegics & Anti Inflammatories in OS-Dr.siddHARTH

7/27/2019 Analgegics & Anti Inflammatories in OS-Dr.siddHARTH

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Dr.Siddharth Dhanaraj,BDS.,MDS.,

Lecturer Dept of Oral & Maxillofacial Surgery

Faculty of Dentistry

MAHSA University


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INTRODUCTION Analgesics are drugs that relieve pain due to

multiple causes. Drugs that relieve pain due to asingle cause, e.g. ergotamine (migraine), glyceryltrinitrate (angina pectoris) are not classified as

analgesics!


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CLASSIFICATION OF ANALGESICS

Analgesics are classified into 2 main groups: Opioid (Narcotic) Analgesics

Are the most powerful analgesics that can relieve anytype of pain except itching.

Act mainly at the level of the cortex. Can produceaddiction.

Example: Morphine and codeine.

Non-opioid Analgesics (analgesics- antipyretics)

Are mild analgesics and effective in mild types of painas headache, toothache ...

Act on the level of the thalamus and hypothalamus. No addiction.

Used to lower the elevated body temperature.

Example: NSAIDs e.g. salicylates, and

Paracetamol


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NSAIDS Non-steroidal anti-inflammatory drugs (NSAIDs) are a group

of drugs that share in common the capacity to induce: analgesic effect.

antipyretic effect.

anti-inflammatory effect.

This group possesses a common mode of action which is toblock prostaglandin biosynthesis by inhibiting cyclo-

oxygenase enzyme.

Inhibition of this enzyme centrally produce the analgesic

antipyretic effect of this group.

While inhibition of this enzyme peripherally produce its

anti-inflammatory effect. Paracetamol inhibit this enzyme

centrally only so it has no anti-inflammatory effect. It has only

analgesic and antipyretic effects. It is not included in NSAIDs.


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1. A suggested treatment algorithm

(American Journal of Medicine 105, 53S-60S, 1998)

Moderate-to-severe pain

Moderate pain

Mild-to-moderate pain Acetaminophen or Ibuprofen

NSAIDs or Tramadol

Opioids or Tramadol


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Classification of NSAIDs

I. Non-selective COX inhibitors: These NSAIDs inhibit theconstitutive COX-1

and the inducible COX-2 so are liable to be associated withgastrointestinal tract upset and renal impairment on longterm use. This group is further classified according tochemical structure into:1) Salicylates e.g. acetyl salicylic acid.

2) OtherNSAIDs:o a) Ibuprofen.o b) piroxicam

o c) Diclofenac .

o d) Indomethacin.

II. Selective COX-2 inhibitors: These NSAIDs selectively inhibitCOX2 and are less liable to be associated with side effects.Example: Celecoxib:

Celecoxib is a selective COX-2 inhibitor that spares COX-1, soit does not inhibit the synthesis of the protectiveprostaglandin in the gut. Hence, its anti-inflammatory effectis

associated with less gastrointestinal adverse effects.


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History - Salicylates Salicylates were first discovered when the observation was made that

chewing willow bark could relieve pain

Hippocrates: Willow bark as a pain killer during childbirth Stone (1700) Extract of willow bark to reduce fever Piria (1838) Isolation of salicin from willow bark Kolbe (1853) Synthesis of salicylate from salicin

Von Gerhardt at Beyer Pharmaceutical Co.

synthesized acetyl SA (ASA) in 1850 Hoffman, at Beyer gave ASA to his rheumatoid father Beyer started sales of Aspirin in1899

Acetylsalicylic acid (aspirin)was introduced as apain reliever in 1899, at that time it was used

in doses of 650 mg every 4 hours


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History - Salicylates


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History In 1899Aspirin acetylsalicylic acid was

named; the "a" --- acetyl grouping and the "spirin" -

-- botanical genus spiraea, from which salicylatescould be extracted.

Now, more than 30 million people consume NSAIDsdaily and of these 40% of the patients are more than

60 years of age.

In 1969 the first association between prostaglandinproduction and the actions of aspirin- like drugs

In 1992 new enzyme was cloned & was calledcyclooxygenase 2 (COX- 2) or PGH 2 synthase 2


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NSAIDsMechanism of action of NSAIDS: Anti-inflammatory effect of NSAIDs due to inhibition of

that produce prostaglandin H synthase (Cyclooxygenase/COX), which convert arachidonic acid to Tx and PG.NSAIDs not have effect on lipoxygenase.


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ASPIRIN

Pharmacological Actions of Salicylates (Sodium salicylate andacetyl salicylic acid):

(1) Analgesic actionSalicylates act on subcortical level to produce their analgesicaction:1. By raising the threshold to painful stimuli relayed from the thalamusto the sensory cortex. 2. Through its anti-inflammatory actionbecause inflammed tissue will stimulate the pain receptors.

(2) Antipyretic action In fever, there is release of PG E1 and E2 in the hypothalamus.

Salicylates lower the elevated body temperature to normal by: Inhibiting prostaglandin synthesis (centrally). Acting on heat regulating center in the hypothalamus promoting

loss of heat by: (a) Vasodilatation of cutaneous blood vessels stimulating radiation. (b) Increasing sweating and encouraging evaporation. (c)

Mobilization of fluids from tissues to blood.


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(3) Anti-inflammatory and anti-rheumatic action

Relieves muscular pain. Relieves joint pain and swelling. This effect is due to decreasing the synthesis ofprostaglandins.


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1. AntipyreticEffects

"normal" temperature: slightly affected

"elevated" temperature: reduced

The higher temperature, the more potent

Mechanisms of Antipyretic Action

Blocks pyrogen-induced prostaglandinproduction in thermoregulatory center (CNS)


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NSAIDs

PyrogenProstaglandins

pGE2

thermoregulatory

center

heat production Heat dissipation

set point

Fever

Antipyretic MechanismBlock prostaglandins

production

Sites of action:

Central Nervous System


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2. Analgesic Effects

Effective to mild to moderate pain

0.5g of aspirin is a weak or mild

analgesic that is effective in short,

intermittent types of pain as

encountered in neuralgia,myalgia , toothache.


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Analgesic Effects

Pain may arise from:

Musculature, dental work , vascular , postpartumconditions, arthritis , bursitis

Sites of action:peripherally -- sites of inflammation

subcortical sites


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NSAIDs

Prostaglandins

pGE2 pGF2

Nerve ending of

pain

Pain

Bradrkininhistamine

factors

+

block prostaglandinsproduction

Sites of action:

peripheral tissue


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3. Anti-inflammatory Effects

NSAIDs only inhibit the symptoms of inflammation

But they neither arrest the progress of the disease nordo they induce remission


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Anti-inflammatory Effects

Reduced synthesis:

--eicosanoid mediators

Interference:

--kallikrein system mediators

--inhibits granulocyte adherence

--stabilizes lysosomes

--inhibits leukocyte migration


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How can NSAIDs inhibit theprostaglandin production?

The Mechanism of NSAIDs


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The principal pharmacological effect of NSAIDs is

due to their ability to inhibit prostaglandin

synthesis by blocking the cyclooxygenase

COX activityof both COX-1 and COX-2.NSAIDs----- acetylation of COX

(reversible or irreversible)

Mechanism of action


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NSAIDs

Prostaglandins

pGE2 pGF2

Symptoms of

inflammation

Red, swelling,

Heating, Pain

Bradrkinin

Histamine

5-HT

Inflammatory

factors

+

block prostaglandinsproduction

Sites of action:

peripheral tissue


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PGE2 vasodilatation, pain sensitization, gastric

cytoprotection [mucous/HCO3 secretion], fever

PGF2 bronchoconstriction, uterine contraction

PGI2 inhibition of platelet aggregation, gastriccytoprotection

TXA2 platelet aggregation

Th i U


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Therapeutic Useso Fever (non-specific).

o Analgesic (headache, toothache, myalgia andarthralgia).

o Common cold (lowers fever and relieves headacheand muscle aches).

o In gout (above 5 gm/day)o Rheumatoid arthritis ( 5-6g/day).

o Acute rheumatic fever (6-12g/day) (to relieve fever,arthritis but not the cardiac

o

complications).o Reducing the risk of myocardial infarction. Aspirin in

low dose (75- 150 mg/ day or

o lower) inhibits platelet aggregation i.e. anti-thrombotic.


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Differences between

NSAIDs and

Acetaminophen


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Side effects of aspirin Gastrointestinal symptoms

CNS toxicity

Allergic reaction (urticaria, angioneurotic edema,

aspirin asthma, occasionally anaphylactic shock) Salicylate reaction (CNS reaction)

Renal damage

Hematologic effects Metabolic acidosisstimulates medullary

respiratory centerrespiratory alkalosis


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Aspirin Toxicity - Salicylism Headache - tinnitus - dizziness

hearing impairment

dim vision Confusion and drowziness Sweating and hyperventilation Nausea, vomiting

Marked acid-base disturbances Hyperpyrexia Dehydration Cardiovascular and respiratory collapse, coma

convulsions and death

Reye's syndrome: In which there is severe hepaticinjury and encephalopathy may occur

following the use of salicylates to control fever in viralinfections in children.

Long term abuse of analgesic mixtures may lead to

nephropathy.


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Aspirin Toxicity - Treatment Gastric lavage.

Correction of hyperthermia by cold waterfomentation.

Correction of dehydration by I.V. fluids.

For hemorrhage: Vitamin K or blood transfusion.

Alkalinization of urine by intravenous injection of NaHCO3 to increase the excretion of

salicylates. Hemodialysis in severe cases.


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Paracetamol It is an analgesic-antipyretic with no anti-

inflammatory action. It effectively inhibits PGsynthesis in the CNS resulting in analgesic andantipyretic effects but it is a weak

PG inhibitor in peripheral tissue thus has no anti-inflammatory effect.

Actions:

Analgesic antipyretic (inhibits COX enzymecentrally).

No anti-inflammatory effect (does not inhibit thisenzyme peripherally).

No uricosuric effect.


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ParacetamolTherapeutic Uses:

Paracetamol is a commonly used analgesicantipyretic instead of aspirin in cases of:

Peptic or gastric ulcers (it causes no GITdisturbances)

Bleeding tendency, (it does not affect platelet

function) Allergy to salicylates.

Viral infections in children (to avoid Reyesyndrome).


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Adverse effects At therapeutic doses, paracetamol is well

tolerated; however, adverse effects include:

-----Skin rash and drug fever.

-----Rare instances of blood dyscrasias.-----Renal tubular necrosis and renal failure.

-----Hypoglycemic coma

At overdose, it can result in severehepatotoxicity, resulting in centrilobular

hepatic necrosis.


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Paracetemolno significant anti-inflammatory effect, but

used for its mild analgesic effect.

Well-absorbed and without GIT irritation.

Serious disadvantage: at high doses, severe hepatotoxicity

results.


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Acute paracetamol poisoning

- small children- having low hepatic glucuronide conjugating ability.- if large doses >250mg/kg

Manifestations- Nausea , vomiting. Abdominal pain Liver impairment- hepatic necrosis Impaired consciousness Renal tubular necrosis

Rx-Gastric lavage, activated charcoalN-acetylcysteine 150mg/kg i.v over 15 mins followed by samedose over 20 hrs.


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Propionic acid derivatives(Ibuprofen)

Inhibit PG synthesis

Adverse effects:

o Ibuprofen and all its congeners are bettertolerated than aspirin. Gastric erosion and occult

blood loss are rare.o Rashes, itching and other hypersensitivity

phenomena are infrequent. However, thesedrugs precipitate aspirin-induced asthma.

Use:o Ibuprofen is used as a simple analgesic and antipyretic in the same wavas low dose of aspirin.

o Dose of ibuprofen is 200- 400 mg, ketoprofen 50-100 mg (also inhibit LOX), flurbiprofen 5 mg.


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Enolic acid derivatives (Piroxicam)

Long acting potent NSAID with similar anti-

inflammatory action of indomethacin.

Reversible inhibitor of COX; decrease theproduction of IgM rheumatoid factor andleucocyte chemotaxis.

PK: Rapidly absorbed, 99% protein bound;metabolized in liver, excreted in urine and bile,plasma t1/2 is 2 days

ADR: similar to ibuprofen

Use: long-term anti-inflammatory agent used forrheumatoid and osteo-arthritis. Also used for acutebout, musculoskeletal injuries in dentistry.

Dose: 10, 20 mg cap.


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Acetic acid derivatives (Ketorolac)

Potent analgesic but moderate anti-

inflammatory agent Efficacy is similar to morphine; inhibits PG

synthesis

PK: rapidly absorbed; 60% protein bind nature,metabolized by liver (glucuronidation); plasmat1/2 is 5-7 hours

ADR: nausea, abdominal pain, loose stools,pain in injection site.

Use: used in postoperative (concurrently with

morphine); continuous use for more than 5 daysis not recommended. Topical preparation usedfor non-infective ocular conditions.

Dose: 10 mg tab, 30 mg inj, 0.5% eye drops


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Acetic acid derivatives (Indomethacin)

Potent anti-inflammatory drug with prompt

antipyretic action. Highly potent inhibitor of PG synthesis and

suppress neutrophil.

PK: well absorbed orally; 90% protein bind

nature, metabolized by liver and excreted bykidney; plasma t1/2is 2-5 hours

ADR: high incidence of (up to 50%) GIT and CNSside effects. Increase bleeding due to decrease

platelet aggregability. Use: arthropathies, psoriatic arthritis and acute

gout

Dose: 25 mg cap, 75 mg cap, 1% eye drop


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Preferential COX-2 inhibitors (Diclofenac) An analgesic-antipyretic-anti- inflammatory

drug

Inhibits PG and some what COX-2 selective PK: well absorbed orally, 99% protein bound,

metabolized and excreted through urine andbile, plasma t1/2 is approx. 2 hr.

ADR: mild ADRs. Epigastric pain, nausea,headache, dizziness, rashes. Diclofenac canincrease the risk of heart ach and stroke. Kidneydamage is rare.

Use: most extensively used NSIDs. Rheumatoid,

and osteo-arthritis, ankylosing spondylitis, renalcolic, post-traumatic and post-operativeinflammatory condition.

Dose: 50 mg entrecoted tab, 100 mg SR, 1%topical ointment, 1% eye drops.

)


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Selective COX-2 inhibitors (Celecoxib) Selective COX-2 inhibitor

Its exerts with anti-inflammatory, analgesicand antipyretic actions with low ulcerogenicpotential.

ADR: Tolerability of celecoxib is better thantraditional NSAIDs. Still abdominal pain,dyspepsia and mild diarrhea are commonside effects.

PK: slow absorbed, 97% plasma proteinbound and metabolized primarily byCYP2C9 with t1/2of approx. 10 hr.

Dose: 100 and 200 mg cap.

Mechanism of Action on the Active Site of COX


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Mechanism of Action on the Active Site of COX

Possess a long channel (COX-2 channel is wider than

in COX-1).

Non-selective NSAIDs enter channel (but not aspirin).

Block channels by binding with H-bonds to an arg

half of the way in.

This reversibly inhibits the COX by preventingarachidonic acid from gaining access.

Aspirin acetylates COX (at ser530) and is, therefore,

irreversible.

Selective COX-2 inhibitors generally more bulky

molecules - can enter and block the channel of COX-

2, but not that of COX-1.


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Selective COX-2 Inhibitors Anti-inflammatory with less adverse

effects, especially GI events. Potential toxicities: kidney and platelets -

? increased risk of thrombotic events.

Assoc with MI and stroke because theydo not inhibit platelet aggregation.Thus,.. should not be given to patients

with CV disease Role in Cancer prevention

Role in Alzheimers disease


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Common pharmacological effects

These drugs show the same pharmacological effects

antipyretic effect

analgesic effect

anti-inflammatory effect


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References Basic & Clinical Pharmacology (11th edition), 2010.

Goodman & Gilmans the pharmacological basis oftherapeutics (12th), 2010.

Text book of Medical/Dental Pharmacology byDr.K.D.Tripati.

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Analgegics & Anti Inflammatories in OS-Dr.siddHARTH