Dr.Siddharth Dhanaraj,BDS.,MDS.

, Lecturer Dept of Oral & Maxillofacial Surgery Faculty of Dentistry MAHSA University

INTRODUCTION
Analgesics are drugs that relieve pain due to multiple causes. Drugs that relieve pain due to a single cause, e.g. ergotamine (migraine), glyceryl trinitrate (angina pectoris) are not classified as analgesics!

CLASSIFICATION OF ANALGESICS
Analgesics are classified into 2 main groups: Opioid (Narcotic) Analgesics Are the most powerful analgesics that can relieve any type of pain except itching. Act mainly at the level of the cortex. Can produce addiction. Example: Morphine and codeine. Non-opioid Analgesics (analgesics- antipyretics) Are mild analgesics and effective in mild types of pain as 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

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 to block prostaglandin biosynthesis by inhibiting cyclooxygenase 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.

1. A suggested treatment algorithm (American Journal of Medicine 105, 53S-60S, 1998) Moderate-to-severe pain Moderate pain Opioids or Tramadol

NSAIDs or Tramadol

Mild-to-moderate pain

Acetaminophen or Ibuprofen

Classification of NSAIDs
I. Non-selective COX inhibitors: These NSAIDs inhibit the constitutive COX-1 and the inducible COX-2 so are liable to be associated with gastrointestinal tract upset and renal impairment on long term use. This group is further classified according to chemical structure into: 1) Salicylates e.g. acetyl salicylic acid. 2) OtherNSAIDs:
o o o o a) b) c) d) Ibuprofen. piroxicam Diclofenac . Indomethacin.

II. Selective COX-2 inhibitors: These NSAIDs selectively inhibit COX2 and are less liable to be associated with side effects. Example: Celecoxib: Celecoxib is a selective COX-2 inhibitor that spares COX-1, so it does not inhibit the synthesis of the protective prostaglandin in the gut. Hence, its anti-inflammatory effect is associated with less gastrointestinal adverse effects.

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 a pain reliever in 1899, at that time it was used in doses of 650 mg every 4 hours

History - Salicylates

History
In 1899 Aspirin acetylsalicylic acid was named; the "a" --- acetyl grouping and the "spirin" -- botanical genus spiraea, from which salicylates could be extracted. Now, more than 30 million people consume NSAIDs daily and of these 40% of the patients are more than 60 years of age. In 1969 the first association between prostaglandin production and the actions of aspirin- like drugs In 1992 new enzyme was cloned & was called cyclooxygenase 2 (COX- 2) or PGH 2 synthase 2

NSAIDs
Mechanism 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.

PHARMACOLOGICAL ACTIONS OF

ASPIRIN
Pharmacological Actions of Salicylates (Sodium salicylate and acetyl salicylic acid): (1) Analgesic action Salicylates act on subcortical level to produce their analgesic action: 1. By raising the threshold to painful stimuli relayed from the thalamus to the sensory cortex. 2. Through its anti-inflammatory action because 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.

 (3) Anti-inflammatory and anti-rheumatic action Relieves muscular pain. Relieves joint pain and swelling. This effect is due to decreasing the synthesis of prostaglandins.

1. Antipyretic Effects
"normal" temperature: slightly affected "elevated" temperature: reduced

The higher temperature, the more potent

Blocks pyrogen-induced prostaglandin production in thermoregulatory center (CNS)

Mechanisms of Antipyretic Action

Prostaglandins pGE2

Pyrogen

thermoregulatory center set point heat production Heat dissipation

NSAIDs
Antipyretic Mechanism

Block prostaglandins production Sites of action: Central Nervous System

Fever

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.

Analgesic Effects
Pain may arise from: Musculature, dental work , vascular , postpartum conditions, arthritis , bursitis Sites of action: peripherally -- sites of inflammation subcortical sites

NSAIDs
Prostaglandins
pGE2 pGF2
factors

+
Nerve ending of pain

Bradrkinin histamine

block prostaglandins production

Sites of action: peripheral tissue

Pain

3. Anti-inflammatory Effects
NSAIDs only inhibit the symptoms of inflammation But they neither arrest the progress of the disease nor do they induce remission

Anti-inflammatory Effects
Reduced synthesis: --eicosanoid mediators Interference: --kallikrein system mediators --inhibits granulocyte adherence --stabilizes lysosomes --inhibits leukocyte migration

How can NSAIDs inhibit the prostaglandin production?

The Mechanism of NSAIDs

Mechanism of action
The principal pharmacological effect of NSAIDs is due to their ability to inhibit prostaglandin synthesis by blocking the cyclooxygenase COX activity of both COX-1 and COX-2. NSAIDs----- acetylation of COX

(reversible or irreversible)

NSAIDs
Prostaglandins pGE2 pGF2 Inflammatory factors

+
Symptoms of inflammation Red, swelling, Heating, Pain

Bradrkinin
Histamine 5-HT

block prostaglandins production

Sites of action: peripheral tissue

PGE2 vasodilatation, pain sensitization, gastric cytoprotection [mucous/HCO3 secretion], fever

PGF2 bronchoconstriction, uterine contraction

PGI2 inhibition of platelet aggregation, gastric cytoprotection TXA2 platelet aggregation

Therapeutic Uses
o Fever (non-specific). o Analgesic (headache, toothache, myalgia and arthralgia). o Common cold (lowers fever and relieves headache and 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. antithrombotic.

Differences between NSAIDs and Acetaminophen

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 acidosis stimulates medullary respiratory center respiratory alkalosis

 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

Aspirin Toxicity - Salicylism

Reye's syndrome: In which there is severe hepatic injury and encephalopathy may occur following the use of salicylates to control fever in viral infections in children. Long term abuse of analgesic mixtures may lead to nephropathy.

Aspirin Toxicity - Treatment

Gastric lavage. Correction of hyperthermia by cold water fomentation. Correction of dehydration by I.V. fluids. For hemorrhage: Vitamin K or blood transfusion. Alkalinization of urine by intravenous injection of Na HCO3 to increase the excretion of salicylates. Hemodialysis in severe cases.

Paracetamol
It is an analgesic-antipyretic with no antiinflammatory action. It effectively inhibits PG synthesis in the CNS resulting in analgesic and antipyretic effects but it is a weak PG inhibitor in peripheral tissue thus has no antiinflammatory effect. Actions: Analgesic antipyretic (inhibits COX enzyme centrally). No anti-inflammatory effect (does not inhibit this enzyme peripherally). No uricosuric effect.

Paracetamol
Therapeutic Uses: Paracetamol is a commonly used analgesic antipyretic instead of aspirin in cases of: Peptic or gastric ulcers (it causes no GIT disturbances) Bleeding tendency, (it does not affect platelet function) Allergy to salicylates. Viral infections in children (to avoid Reye syndrome).

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 severe hepatotoxicity, resulting in centrilobular hepatic necrosis.

 Paracetemol no 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.

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 RxGastric lavage, activated charcoal N-acetylcysteine 150mg/kg i.v over 15 mins followed by same dose over 20 hrs.

Propionic acid derivatives (Ibuprofen)

Inhibit PG synthesis Adverse effects:
o Ibuprofen and all its congeners are better tolerated than aspirin. Gastric erosion and occult blood loss are rare. o Rashes, itching and other hypersensitivity phenomena are infrequent. However, these drugs precipitate aspirin-induced asthma. Use:
o Ibuprofen is used as a simple analgesic and antipyretic in the same wav as low dose of aspirin.

o Dose of ibuprofen is 200- 400 mg, ketoprofen 50100 mg (also inhibit LOX), flurbiprofen 5 mg.

Enolic acid derivatives (Piroxicam)

Long acting potent NSAID with similar antiinflammatory action of indomethacin. Reversible inhibitor of COX; decrease the production of IgM rheumatoid factor and leucocyte 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 for rheumatoid and osteo-arthritis. Also used for acute bout, musculoskeletal injuries in dentistry. Dose: 10, 20 mg cap.

Acetic acid derivatives (Ketorolac)

Potent analgesic but moderate antiinflammatory agent Efficacy is similar to morphine; inhibits PG synthesis PK: rapidly absorbed; 60% protein bind nature, metabolized by liver (glucuronidation); plasma t1/2 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 days is not recommended. Topical preparation used for non-infective ocular conditions. Dose: 10 mg tab, 30 mg inj, 0.5% eye drops

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 by kidney; plasma t1/2 is 2-5 hours ADR: high incidence of (up to 50%) GIT and CNS side 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

 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 and bile, plasma t1/2 is approx. 2 hr. ADR: mild ADRs. Epigastric pain, nausea, headache, dizziness, rashes. Diclofenac can increase the risk of heart ach and stroke. Kidney damage is rare. Use: most extensively used NSIDs. Rheumatoid, and osteo-arthritis, ankylosing spondylitis, renal colic, post-traumatic and post-operative inflammatory condition. Dose: 50 mg entrecoted tab, 100 mg SR, 1% topical ointment, 1% eye drops.

Preferential COX-2 inhibitors (Diclofenac)

Selective COX-2 inhibitors (Celecoxib)

Selective COX-2 inhibitor Its exerts with anti-inflammatory, analgesic and antipyretic actions with low ulcerogenic potential. ADR: Tolerability of celecoxib is better than traditional NSAIDs. Still abdominal pain, dyspepsia and mild diarrhea are common side effects. PK: slow absorbed, 97% plasma protein bound and metabolized primarily by CYP2C9 with t1/2 of approx. 10 hr. Dose: 100 and 200 mg cap.

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 preventing arachidonic 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 COX2, but not that of COX-1.

 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 they do not inhibit platelet aggregation. Thus,.. should not be given to patients with CV disease Role in Cancer prevention Role in Alzheimers disease

Selective COX-2 Inhibitors

Common pharmacological effects

These drugs show the same pharmacological effects
antipyretic effect analgesic effect anti-inflammatory effect

References
Basic & Clinical Pharmacology (11th edition), 2010. Goodman & Gilmans the pharmacological basis of therapeutics (12th), 2010. Text book of Medical/Dental Pharmacology by Dr.K.D.Tripati.