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1
 Anti-inflammatory
drugs

Dr Devinder Arora
2020PHM; Pharmacology for Oral Health
Following this lecture you should be able to:

• Describe the main clinically used NSAIDs.

• Explain the mechanism of NSAIDs.
• Describe the important pharmacological properties, adverse effects and
drug interactions of NSAIDs.
• Describe the doses and max. dose limits of commonly used NSAIDs in
dental practice.
• Explain the role of corticosteroids in dental and oral health specific issues
• Understand the basics of gout and immunosuppressant drugs
Causes of common types of dental pain:

Australian Prescriber Vol. 24 No. 6 2001

Prostaglandins:
 Non-steroidal Anti-Inflammatory Drugs (NSAIDs): COX-1/2
• It is a large family of weak acidic
drugs
• All NSAIDs block COX enzyme
• most NSAIDs are non-specific COX
blockers
• two isoforms (COX-1 & COX-2)
• COX-1 – beneficial (housekeeping
role: haemostatic function – PG
production for gastro-protection,
renal blood flow autoregulation,
parturition initiation)
• COX-2 - inflammatory

• therefore blocking both of the enzymes is not good !!

COX…

Aspirin & COX inhibition:

Common indications of NSAIDs:
• Rheumatoid arthritis
• Osteoarthritis
• Other inflammatory arthropathies
• Ankylosing spondylitis, psoriatic arthritis

• Acute gout
• Pain
• Inflammation, tissue injury
• Period pain, metastatic bone pain, renal colic, headache, migraine,
postoperative pain…
Classification of NSAIDs

Acetic Acids Fenamates Propionic Oxicams Salicylates Coxibs

Acids

Diclofenac Mefenamic Ibuprofen Meloxicam Aspirin Celecoxib

acid

Indomethacin Ketoprofen Piroxicam Parecoxib

Ketorolac Naproxen Etoricoxib

Sulindac
Drug Half-life (hours) Oral doses/day Routes Comments
1 available without prescription / 2 active metabolite / 3 controlled release forms

0.25 nonselective; analgesic and antiplatelet agent (inhibits platelet COX for
aspirin1 3 or 4 oral
(2–19)2 life of platelet unlike other nonselective NSAIDs)

celecoxib 4–15 1 or 2 oral selective COX-2 inhibitor

diclofenac1 1–2 2 or 3 oral, rectal, topical nonselective; risk of cardiovascular events appears highest

etoricoxib 22 1 oral selective COX-2 inhibitor; severe hypertension appears more common

ibuprofen1 2–2.5 3 or 4 oral, IV, topical nonselective

indometacin 4.5–6 2–4 oral, rectal nonselective
ketoprofen 1.5–2 13 oral nonselective
ketorolac 4–6 4 IM, IV, oral nonselective
mefenamic acid1 3–4 3 oral nonselective
meloxicam 20 1 oral selective COX-2 inhibitor (at low dosage)

naproxen1 12–15 2 (1)3 oral nonselective; risk of cardiovascular events appears lowest

3.5–4
parecoxib IM, IV selective COX-2 inhibitor; single perioperative dose
(6.5–7)2

piroxicam 30–50 1 oral, topical nonselective; severe skin reactions may be more common

sulindac 7 (16)2 1 or 2 oral nonselective

AMH, 2018
 NSAIDs:
Pharmacological effects: Adverse effects:

• Anti-inflammatory effect: • Gastric irritation (from simple

discomfort to ulcer formation)
modification of the inflammatory
• An effect on renal blood flow in the
reaction
compromised kidney
• Analgesic effect: reduction of • A tendency to prolong bleeding through
certain types of pain (especially inhibition of platelet function

inflammatory) • COX-2 selective drugs may increase

the likelihood of thrombotic events
• Antipyretic effect: lowering of
such as myocardial infarction by
body temperature when this is
inhibiting prostaglandin (PGI2)
raised in disease (fever) synthesis
NSAIDs and paracetamol
 NSAIDs:
Analgesic effect

Anti-inflammatory effect ▪ decreased sensitisation of

▪ Block the peripherally generated COX-2 PGs nociceptive nerve endings to

▪ the decrease in PGE2 and prostacyclin inflammatory mediators (bradykinin,
reduces vasodilatation and, indirectly, oedema 5-HT)
▪ low doses of NSAIDs are usually sufficient to ▪ relief of headache is probably a
treat mild to moderate pain and counteracts
result of decreased prostaglandin-
fever
mediated vasodilatation
▪ high doses are generally required to relieve
Antipyretic effect
inflammation associated with arthritic
disorders and injuries Blockade of hypothalamic COX-2
generated PG inhibition
Antiplatelet action
Reduced platelet COX-1 generated TXA2
Gastrointestinal system:

❑ COX-1 → local PGE1 →  stomach mucus secretion

-mucus protects mucosa from damage by acid

❑ COX-2 inhibition →  mucus

↓PGE1/PGE2

❑ NSAIDs or corticosteroids → COX-1 activity →  local PGE1/2 → mucosal

damage by acid → ulcer
❑ Synthetic PGE1 “misoprostol” is used to prevent ulcer in NSAID treated patients

❑ Side effects of misoprostol: abdominal discomfort and diarrhea

Understanding the importance of PPIs and H2 receptor antagonists in
gastric acid secretion:
General unwanted effects of NSAIDs
➢ Inhibition of the constitutive housekeeping enzyme COX-1

➢ Dyspepsia, nausea and vomiting

➢ ↑ risk of ulcerations (*PGE1 and Misoprostol)

➢ Reversible renal insufficiency

➢ analgesic-associated nephropathy

➢ Skin reactions

➢ Liver toxicity,

➢ Bronchospasm (seen in 'aspirin-sensitive' asthmatics)

 Aspirin:
• Acetylsalicylic acid

• Anti-inflammatory actions

• Antiplatelet actions (at lower doses)

• Colonic & rectal cancer preventions

• Alzheimer disease

• Radiation induced diarrhoea

• Weak acid and absorbed orally

• Hydrolysed to salicylate

• 75% metabolized in liver

Aspirin: adverse effects
• Gastritis with focal erosion and bleeding
• (therefore contraindicated in patients with peptic
ulcer)

➢ Salicylism: tinnitus; dizziness; decreased

hearing, nausea and vomiting
➢ Hypersensitivity reaction
➢ skin rash to anaphylaxis
➢ Reye’s syndrome Dose dependent pharmacological & toxicological effects of aspirin

➢ Hepatic encephalopathy

➢ Hyperventilation: respiratory alkalosis and metabolic acidosis

➢ Hyperpyrexia (very high body temperature)
➢ Increase in warfarin action
Drug interactions with salicylates:
Paracetamol:
• Acetaminophen
• Non-narcotic analgesic-antipyretic drug
• Weak anti-inflammatory effect
• No gastric and platelet side effects
• may be a COX-3 inhibitor !!
• Active orally and metabolized in liver
• by glucuronide/sulphate
conjugation
• Fatal hepatotoxicity occurs at higher
doses (> 4g/day)
• NAC
Coxibs:
❑ Celecoxib
❑ Anti-inflammatory actions similar to conventional NSAIDs ❑ Etoricoxib
❑ may be even less effective analgesics & similarly ❑ Parecoxib
effective in inflammation ❑ Meloxicam

❑ Little or no effect on platelets – TXA2

❑ Suppress the production of vasodilatory and anti-aggregating PGI2 by blood

vessels → exposes the TXs to exert greater unwanted cardiovascular effects

❑ The CV effects need to be weighed against the gastro-protective effects !

Pain management strategies: principles
• Effective pain management begins with an accurate diagnosis and an
appropriate treatment plan using principles of ‘3 Ds’:
• Diagnosis
• Dental treatment
• Drugs

• If analgesics are required for post-treatment pain: 5 questions before Rx

• Is the pain nociceptive in origin?
• Is the pain mild, moderate or severe?
• Has the appropriate dental treatment been provided?
• Can the patient use NSAIDs
• Can the patient take medications via the oral route?
Post-treatment pain management in adults:
For mild pain: For moderate pain: For severe pain:

• Ibuprofen 400 mg orally, • Ibuprofen 400 to 600 mg • Ibuprofen 400 to 600 mg orally,
every 4 hours (to a max. of orally, every 4 hours (to a every 4 hours (to a maximum
2400 mg/24 hours) maximum of 2400 mg/24 of 2400 mg/24 hours)
hours) PLUS
OR
PLUS • Paracetamol + codeine
• Aspirin 600 to 900 mg orally,
every 4 hours (to a max. of • Paracetamol 1000 mg orally, 1000+60 mg orally, every 4
3600 mg/24 hours) every 4 hours (to a maximum hours (to a maximum
of 4 g/24 hours) paracetamol dose of 4 g/24
OR (if NSAIDs are hours)
contraindicated) OR (if NSAIDs are
contraindicated) OR (if NSAIDs are
• Paracetamol 500 to 1000 mg contraindicated)
orally, every 4 hours (to a • Paracetamol + codeine
max. of 4 g/24 hours) 1000+60 mg orally, every 4 • Paracetamol+ codeine 1000+60
hours (to a maximum mg orally, every 4 hours (to a
paracetamol dose of 4 g/24 maximum paracetamol dose of
hours). 4 g/24 hours).
 NSAID + Codeine
• Ibuprofen 200 mg + Codeine 12.8 mg
• 1-2 tabs q4h PRN
• Up to of max 6 tabs daily
• Aspirin 300-900 mg + Codeine 30-60 mg
• 1-2 tabs q4h PRN
• Max Codeine 240 mg in 24 hours
• Paracetamol 500 mg + Codeine 8, 15 or 30 mg
• Every q4h or q6h PRN
• Up to of max 8 tabs daily
Combination analgesics in adults

(Aust Prescr 2010;33:113–5)

❑ Combining ibuprofen with paracetamol (or paracetamol + codeine) for
enhanced pain management in adults:
 Post-treatment pain in children:
• Ibuprofen 5 to 10 mg/kg orally (to a max. of 2400 mg/24 hours)
OR
• Paracetamol 15 mg/kg orally or rectally, 4 to 6 hourly (to a max. of 4 g/24
hours)
• As the main action of ibuprofen is local, and pcm works centrally, they can be
combined.
• Aspirin should not be used in children < 16 years of age

Dose is calculated →
Other analgesics used in practice:
• Step 1:
• Hydrocodone 5-10 mg +
• Ibuprofen 400-800 mg
Paracetamol 500 mg
tid/qid or equivalent NSAID
– 1-2 tabs q4h PRN
• Acetaminophen 500-1000
mg qid • Oxycodone 5-10 mg +
Paracetamol 500 mg
• Step 2:
– 1-2 tabs q4h PRN
• Add any of the following to
step 1 regimen→ • Tramadol 50 mg +
Paracetamol 500 mg
• Oxycodone 5-10 mg or
Morphine 15 mg 1 or 2 – 1-2 tabs q4h PRN
tabs q4h PRN (as needed)

• Tramadol 50 mg 1 tab q4h

PRN
Corticosteroids:
Glucocorticoids:

Anti-inflammatory effects
glucocorticoids…
Topical corticosteroid ointments used in oral conditions:
Drug Strength Form * Clinical potency Oral uses
on oral mucosa**
hydrocortisone acetate 1% ointment mild minor mucosal inflammation, cheilitis (not
suitable for angular cheilitis)
triamcinolone acetonide 0.02% ointment moderate inflammatory mucosal conditions
betamethasone valerate 0.02% ointment moderate inflammatory mucosal conditions (e.g.
0.05% aphthous ulceration, lichen planus) (use with
caution)
betamethasone valerate 0.1% ointment potent inflammatory mucosal conditions (e.g.
aphthous ulceration, lichen planus) (use with
caution)
betamethasone 0.05% ointment potent inflammatory mucosal conditions (e.g.
dipropionate aphthous ulceration, lichen planus,
pemphigoid, pemphigus) (use with caution)
methylprednisolone 0.1% ointment moderate inflammatory mucosal conditions (e.g.
aceponate aphthous ulceration, lichen planus) (use with
caution)
mometasone furoate 0.1% ointment potent severe inflammatory mucosal conditions
(e.g. erosive lichen planus) (use with caution)
* In the mouth, ointments are preferred, as creams are less effective in enhancing contact time.
** Potencies of corticosteroids when applied to the oral mucosa are not the same as when they are applied to the skin.
 Systemic corticosteroids in oral conditions:
• Systemic corticosteroids are usually inappropriate for general dental practice
• The major limiting factor in the use of systemic corticosteroids is the
development of adverse effects
• Some oral inflammatory mucosal conditions, however, do require systemic
corticosteroids
• should only be used in patients who have been assessed as suitable for treatment
• severe postoperative swelling
• severe trauma
• periapical nerve sprouting
• acute apical periodontitis following removal of acutely inflamed pulp
➢ All of these conditions usually require specialist management
 Corticosteroids + antibiotics for intradental application
• Clindamycin or demeclocycline + triamcinolone acetonide
• Pulp and periapical disease
• water soluble paste or a hard setting cement

• Paste is used as an intracanal medication during endodontic treatment

• The paste can be used as an initial medication for rapid pain relief associated
with irreversible pulpitis.
• to reduce periapical inflammation and pain
• associated with irreversible pulpitis and infected root canal system

• to prevent and manage several forms of inflammatory root resorption

• Internal inflammatory resorption
• External inflammatory resorption

• External lateral inflammatory resorption

• Reduction in external replacement resorption following tooth evulsion,

intrusive luxation injuries
 Corticosteroids + antibiotics for intradental application

• Corticosteroid – antibiotic cements

• Used within the crown of a tooth as a part of cavity lining or base
• As an indirect/direct pulp cap
• As a pulpotomy agent before restoration of cavities in teeth that have
reversible pulpitis
• Other substances
• Calcium hydroxide, zinc oxide, eugenol

• Cement is presented as powder or liquid

• Mixed to form a paste that is placed on the dentine or exposed pulp → sets to form
a hard cement
Points to consider when prescribing topical intraoral corticosteroids

• Corticosteroids are best applied with the pad of a washed finger

• Applicators, including cotton tips, are fibrous and may inadvertently damage the fragile atrophic mucosa.

• Corticosteroids should be applied to wet mucosa

• Drying the tissues before application is a natural instinct, but tissue trauma must be balanced against any
benefit of drying (which is minimal).

• Prolonged avoidance of food and drink after topical corticosteroid application seems
logical, but is not required as corticosteroid absorption is reasonably rapid
• A convenient time for application is after oral hygiene in the morning and at night
• Patients readily become frustrated when ointments do not adhere effectively
• This is overcome by frugal application, brief gentle rubbing with the finger pad, and reassurance that this
method of application is adequate.

• Patients using special methods of application (e.g. sprays, adhesives) require additional
written explanation
Common adverse effect to intraoral corticosteroids
• Secondary oral candidosis
Local skin effects:
• Nausea
• loss of dermal collagen, leading to skin atrophy,
formation of striae, fragility and easy bruising
• Intolerability
• telangiectasia (development of prominent blood
• because of unpleasant taste vessels)
• promotion of infection
• Refractory response • idiosyncratic reactions (e.g. allergic contact
dermatitis, perioral dermatitis).
• Mucosal atrophy
• Delayed healing
• Rebound withdrawal with high potency drugs
• tapered dose reduction to complete cessation
• Should not be used in the presence of infection
• or suspected infection or viral disease
• The tissue atrophy on the tongue caused by some oral mucosal diseases like lichen planus,
can persist even with lesion resolution or enter into a quiescent phase
Sites of action of gout drugs:

Allopurinol

Probenecid
Calcineurin inhibitors
• Cyclosporin
• Tacrolimus
• Immunosuppressant
• Prevention of transplant rejection
• Rheumatoid arthritis
• Nephrotic syndrome
• Psoriasis or atopic dermatitis

❑Gingival hyperplasia, nephrotoxicity

❑ CYP inducers reduce plasma conc. of cyclosporin