DENT 3005: Introduction to Pharmacology¹

Immunomodulators & anti-inflammatory

Dr Thuy Linh Truong thuy.truong@uwa.edu.au

Acknowledgement of country²

The University of Western Australia acknowledges that its campus is situated on Noongar land, and that Noongar people remain the spiritual and cultural custodians of their land, and continue to practise their values, languages, beliefs and knowledge.

Artist: Dr Richard Barry Walley OAM

THE UNIVERSITY OF WESTERN AUSTRALIA

Learning Outcomes³

Learning objectives

Understand the different types of immunomodulators and anti-inflammatory drugs
Broad understanding of RA, OA and gout and the pharmacological agents used in these conditions
Recognise oral and dental side effects of these drugs
Understand drugs interactions with dental medications
Applied knowledge to clinical scenarios

Immunomodulators⁴

Stimulate or suppress immune system
- Tx autoimmune & inflammatory diseases: RA, psoriasis, UC, Crohn’s, SLE, organ transplantation
Rheumatoid arthritis (RA): autoimmune disease attacking healthy tissue in joints
- Tx rationale: provide sx relief, maintain level of function, and prevent damage to bones, joints, and other organs
Osteoarthritis (OA): deterioration of cartilage at the ends of bones in the joints
- Tx rationale: Relieve symptoms (pain and stiffness) and improve joint function to enable the patient to exercise and increase strength and mobility

Rheumatoid Arthritis⁵

What is it?
- Autoimmune disease, inflammatory disorder
- Chronic & progressive
- Systemic, significant morbidity and mortality
Pathophysiology
- Lymphocyte mediated inflammatory disease
- Stimulating antigens $\to$ abnormal inflammatory response
- Inflammatory mediators (cytokines)TNF- $α$ , IL-1, IL-6
- Synovial membrane hypertrophies $\to$ synovial pannus
- Cytokine rich synovial fluid $\to$ damage to adjacent supporting structures

Rheumatoid Arthritis: treatment⁶

Non-pharmacological
- Exercise, diet, footcare, massage, heat/cold packs etc
Pharmacological
- Analgesics: paracetamol, NSAIDs, opioids
  - Manage symptoms but do not alter course of disease
- Corticosteroids: not first line, short duration of tx due to adverse effects
  - Anti-inflammatory, immunosuppressant and disease modifying effects
- DMARDs: biologicals and non biologicals
  - DMARDs: aka conventional antirheumatic drugs
  - Biological DMARDs: TNF alpha antagonists and cytokine modulators

(DMARDs) Conventional antirheumatic drugs⁷

Generic name (brand name)	Drug class	Selected ADR	Drug interactions (dentally related)
Azathioprine (Azapin, Imuran)	Purine antimetabolite	Dose-related myelosuppression, infection, GI irritation, mouth ulceration	Nil
Ciclosporin (Neoral)	Calcineurin inhibitors	Gingival hyperplasia, opportunistic infections	Increases toxicity risks of calcineurin inH: Azole antifungals, clarithromycin, erythromycins, NSAIDs
Hydroxychloroquine (Plaquenil)	Anti-inflammatory and immunosuppressive Antimalarial	Retinal damage, rash, GI irritation	Drugs that prolong QT interval: clarithromycin, erythromycin, fluconazole
Leflunomide (Arava, Ataris)	Pyrimidine synthesis inhibitor	(common) pharyngitis, dyspnea (infrequent) oral candidiasis, stomatitis, taste disturbance	Hepatotoxic, adhere strict dosage for paracetamol to prevent increase risk of hepatotoxicity
Methotrexate (Methoblastin)	Antimetabolite	Myelosuppression, mucosal ulcers, GI irritation, infections	Hepatotoxic May increase risks of MTX toxicity: NSAIDs, penicillins, nitrous oxide
Sulfasalazine (Salazopyrin, Pyralin)	5-aminosalicylate	Myelosuppression, rash (infrequent) yellowing of skin	Nil
Auranofin (Ridaura)	Gold Salt	Dyspepsia, stomatitis, mouth ulcers, dry mucous membranes, gingivitis	Nil

Calcineurin inhibitors⁸

MOA: form complexes with cytoplasmic immunophilins
- Block the action of calcineurin in activated T cells
- Prevents production of interleukin-2 and other cytokines
Ciclosporin: gingival hyperplasia [common in children & adolescent]
Tacrolimus: gingival hyperplasia a [rare ADR]
Drug interactions: increases toxicity risks of calcineurin inH
- Azole antifungals
- Clarithromycin & erythromycins
- NSAIDs

Generic name	Brand Name
Ciclosporin	Neoral
Tacrolimus	Prograf

Corticosteroids⁹

Recap: we have discussed a few in respiratory & adrenal insufficiency
MOA: regulate gene expressions (glucocorticoid & mineralocorticoid effects)
ADR: remember $steroids adverse reactions$ slide
Drug interactions
- ( $Methylprednisolone, dexamethasone$ ) $+$ azole: increase steroid adverse effects
- $Aspirin: decrease salicylate concentration$
- $NSAIDs: increase risk of gastric ulceration$

Generic name	Brand Name
Betamethasone	Celestone inj
Cortisone	Cortate
Dexamethasone	Dexmethsone
Hydrocortisone	Solu-Cortef Inj
Methylprednisolone	Solu-Medrol inj
Prednisolone	Predsolone…
Triamcinolone	Kenacort-A inj

Corticosteroids: ADRs¹⁰

Infection
Delayed wound healing
Steroid rosacea
Perioral dermatitis
Skin atrophy
Bruising
Acne
Facial flushing
Pupura
Depigmentation
Telangiecstasia
Steroid induced crushing’s

Janus Kinase (JAK) inhibitors¹¹

MOA: inh Janus kinase (JAK) $\to$ suppress immune response
ADR: infections (serious and opportunistic)
Drug interaction
- Azoles, clarithromycin, erythromycin: increase toxicity risk of tofacitinib & upadacitinib

Generic name	Brand Name
Baricitinib	Olumiant inj
Tofacitinib	Xeljanz inj
Upadacitinib	Rinvoq inj

(bDMARDs) TNF alpha antagonists¹²

MOA: Bind to TNF alpha and inhibit its activity.
ADR: [common >1%]
- Infections (opportunistic or serious)
- Mouth ulcers, sore that do not heal, pain or excessive bleeding of gums
Drug interactions: not dentally related drugs (phew)
- Not to be used with other bDMARDs

Generic name	Brand Name
Adalimumab	Humira inj
Certolizumab	Cimzia inj
Etanercept	Enbrel inj
Golimumab	Simponi inj
Infliximab	Remsima inj

(bDMARDs) Cytokine modulators¹³

Abatacept: binds to CD80 and CD86 on antigen-presenting cells
- Prevent full activation of CD28 T lymphocytes $\to$ reducing cytokine production and inflammation
Anakinra: neutralises the activity of IL-1
Rituximab: reduce T cell activation and resulting cytokine production
Tocilizumab: inhibits the activity of IL-6
Drug interactions: not dentally related drugs (phew)
- Not to be used with other bDMARDs

Generic name	Brand Name
Abatacept	Orencia inj
Anakinra	Kineret inj
Rituximab	Riximyo inj
Tocilizumab	Actemra inj

Selected ADR
Dizziness
Infections (opportunistic or serious)
Mouth ulcers
Vertigo

Additional reading: for fun!¹⁴¹⁵

Not to be assessed ☺
- Systemic Lupus Erythematosus (SLE)
- Spondyloarthropathies (seronegative arthritis)
- Ankylosing spondylitis
- Psoriatic arthritis
- Juvenile arthritis
- Fibromyalgia
- Infectious arthritis (chronic and acute)
- Osteomyelitis
- Raynaud’s syndrome

Rheumatoid arthritis drugs: Dental implications

DMARDs: dose related myelosuppression
- Patient at risks of infections
- Check slide 6 for selected ADR
Calcineurin inhibitors
- Ciclosporin: gingival hyperplasia in youth
- Check slide 8 for selected ADR
Corticosteroids: interactions and ADRs
ADRs relating to dental
- JAK inh (slide 11)
- Gold Salt (slide 7)
- bDMARDs: TNF alpha antagonists & cytokine modulators (slide 12, 13)

Osteo-arthritis¹⁶

What is it?
- Gradual breakdown of cartilage, the smooth, protective tissue that covers the ends of bones in joints
- Commonly affects joints in your hands, knees, hips and spine
Pathophysiology
- “wear and tear”
- Breakdown of cartilage, destruction of articular cartilage
- Remodelling of bone
- Loss of joint space $\to$ bone rub on bone

Osteo-arthritis: treatment¹⁷

Non-pharmacological
- Exercise, diet, footcare, massage, heat/cold packs etc
Pharmacological
- Supplements
- Paracetamol: preferred drug cf to NSAIDs
- NSAIDs
  - Topical can be use but costly
  - Oral: aim for the lowest effective dose for the shortest duration
- Opioids
- Intra-articular corticosteroids
  - Short-term relief of pain for moderate-to-severe flare of symptoms
  - Adjunct to oral therapy

Rheumatoid arthritis Vs Osteo-arthritis¹⁸

Features	Rheumatoid arthritis	Osteoarthritis
Affected joints	Smaller, multiple, proximal finger, bilateral	Large, often one, distal finger, unilateral
Age of onset	30-50	Typically older population
Inflammation	Yes	Maybe
Other associated sx	Systemic illness involving other organs	None
Blood tests	Usually elevated ESR, CRP, RF and anti-CCP	Usually none
Pharmacological treatment	NSAIDs, DMARDs, bDMARDs, corticosteroids	Paracetamol, maybe NSAIDs & opioids

Prostaglandin & COX enzymes¹⁹

Prostaglandin
- Synthesized from AA
- Present at site of inflammation
- Augment action of histamine, vasodilation, increase vascular permeability
Cyclooxygenase enzymes
- Convert AA $\to$ prostaglandin & TxA2
- COX 1: constitutive
  - Homeostasis
  - Regulate renal blood flow
  - Platelet aggregation
  - Stomach mucous production
  - Regulate stomach acid secretion
- COX 2: inducible
  - Inflammation

graph TD A[MEMBRANE PHOSPHOLIPIDS] -->|Phospholipase A₂| B[ARACHIDONATE] B --> C(5-Lipoxygenase); B --> D(Cyclo-oxygenase); D --> E[Cyclic endoperoxides]; E --> F[PGF₂\nVasodilator, stops\nplatelet aggregation,\nhyperalgesic]; E --> G[TXA₂\nPlatelet aggregator,\nvasoconstrictor]; E --> H[PGD₂\nVasodilator,\nstops platelet\naggregation,\nrelaxes most\nsmooth muscle\nbut contracts\nbronchi]; E --> I[PGE₂\nVasodilator,\nhyperalgesic,\nincreases mucus\nand decreases\nacid secretion in\nstomach, contracts\npregnant uterus]; E --> J[PGF₂α\nSpasmogen,\nluteolytic]; C --> K[5-HPETE]; K --> L[Leukotrienes]; D --> M(Inhibitors:\nNSAIDs);

subgraph enzymes N[5-HPETE = 5-hydroperoxyeicosatetraenoic acid] end

NSAIDs²⁰

Nonselective NSAIDs (COX1&2-Inh)

Generic name	Brand Name
Aspirin	Solprin
Diclofenac	Voltaren
Ibuprofen	Nurofen
Indomethacin	Arthrexin, Indocid
Ketorolac	Toradol
Mefenamic Acid	-
Naproxen	Inza, Naprosyn
Piroxicam	Feldene-D, Mobilis

Selective NSAIDs (COX2-Inh)

Generic name	Brand Name
Celecoxib	Celebrex
Etoricoxib	Arcoxia
Meloxicam	Melobic, Mobic
Parecoxib	Dynastat inj

NSAIDs: Precautions and Interactions²¹

Precautions

Existing renal impairment
- Worsen renal function
Existing platelet disorder
- Affect coagulation → ↑ bleeding risks
Existing cardiac disease
- Na and H2O retention → HTN, peripheral oedema, worsening HF
Existing GI conditions
- Ulceration & ↑ bleeding risks
Existing asthma: ↑ bronchospasm

Interactions (MANY)

Anticoagulants
- E.g. warfarin, clopidogrel
Renally excreted drugs
- E.g. lithium, ACE inhibitors, digoxin
K+ sparing drugs
- E.g. ACE inhibitors, "sartans", spironolactone
Antihypertensives
Bisphosphonates
- E.g. alendronate
Corticosteroids
"Triple whammy"
- NSAID + diuretic + ACE/ARB

NSAIDs ADR²²

Serious ADR
- Vomiting blood or material that looks like coffee grounds
- Bleeding from your back passage (rectum), black sticky motions or bloody diarrhoea
- Swelling of the face, lips or tongue which may make swallowing or breathing difficult
- Asthma, wheezing, shortness of breath
- Sudden or severe itching, skin rash, hives
- Pain or tightness in the chest
Dental related
- Sore mouth/tongue
- Aphthous ulcers
- Lichenoid drug eruptions
- Drug induced pemphigus
- Prolonged bleeding

NSAIDs: Dental implications²³

Common ADRs

Gastrointestinal: upset stomach, ulcers, bleeding
Renal: oedema, hypertension, kidney damage
Respiratory: bronchospasm, asthma exacerbation
Cardiovascular: increased risk of heart attack, stroke

Dental ADRs

Sore mouth/tongue
Aphthous ulcers
Lichenoid drug eruptions
Drug-induced pemphigus
Prolonged bleeding during procedures

Considerations

Monitor for bleeding risk (esp. during surgery)
Check for gastrointestinal and renal issues
Assess for asthma history
Be aware of drug interactions with other medications (e.g., anticoagulants)

Drugs for gout²⁴

What is it?
- Progressive inflammatory disease
Pathophysiology
- Persistent hyperuricaemia: serum urate >0.42mmol/L
- Formation monosodium urate crystals
Treatment rationale
- Acute flare: provide sx relief
- Chronic gout: lower serum urate
Pharmacological
- NSAIDs: except aspirin
- Colchicine
- Corticosteroids: oral, IM, IV
- Urate lowering drugs
  - Xanthine oxidase inH
  - Uricosurics

Xanthine oxidase inhibitors²⁵

Allopurinol & febuxostat
- MOA: Inhibit xanthine oxidase $\to$ reduce production of uric acid
Drug interactions
- Allopurinol & Amoxicillin: increase risks of rash
ADR (infrequent)
- Allopurinol: altered taste sensation

Generic name	Brand Name
Allopurinol	Allosig, Progout
Febuxostat	Adenuric

Other drugs for gout²⁶

Colchicine

MOA: inhibits neutrophil migration, chemotaxis, adhesion and phagocytosis in inflamed tissue
Drug interactions
- Clarithromycin, erythromycin& azole antifungals: increase colchicine concN
- NSAIDs: monitor in patients w/ reduced renal function
ADR (common)
- Diarrhoea, nausea, abdominal discomfort, vomiting, pharyngo-laryngeal pain

Generic name	Brand Name
Colchicine	Colgout, Lengout

Probenecid²⁷

MOA: Increases renal excretion of uric acid by blocking its renal tubular reabsorption
Drug interactions
- Aspirin: reduced uricosuric effect of probenecid
- Cephalosporins & penicillins: increases half-life and prolongs activity of cephalosporin
- Indomethacin & ketorolac: increases concN of these drugs
ADR (infrequent)
- Sore gums

Generic name	Brand Name
Probenecid	Pro-cid

Drugs for gout: Dental implications²⁸

NSAIDs: monitor for gastric ulcers and bleeding risks during procedures
Colchicine: monitor for gastrointestinal discomfort and interactions with antibiotics
Corticosteroids: monitor for delayed healing, oral thrush and infection
Allopurinol: altered taste and oral irritation
Probenecid: sore gums may occur, monitor for oral discomfort
Drug Interactions: review interactions, especially with antibiotics and NSAIDs, in patients with renal issues

References²⁹

Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Robinson E, editors. Rang & Dale’s pharmacology. 10th ed. Edinburgh: Elsevier; 2023
Australian Medicines Handbook Online [Internet]. Adelaide (AU): Australian Medicines Handbook Pty Ltd;2000. Immunomodulators and Anti-inflammatories; [updated 2025; cited 2025]. Available from: UWA Onesearch
Pharmaceutical Society of Australia. Australian Pharmaceutical Formulary and Handbook: A Guide to Best Practice. 25th ed. Canberra: Pharmaceutical Society of Australia; 2021
Ali K. Clinical dental pharmacology. 1st ed. Oxford: Wiley-Blackwell; 2023
Bullock S, Manias E. Fundamentals of pharmacology. 8th ed. Frenchs Forest, NSW: Pearson Australia; 2017
MIMS Australia. eMIMSelite: Consumer medicine information, specific clinical monograph [Internet]. Sydney: MIMS Australia; [updated 2025; cited 2025 Apr 17]. Available from: UWA Onesearch

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DENT 3005: Introduction to Pharmacology1

Immunomodulators & anti-inflammatory

Acknowledgement of country2

Learning Outcomes3

Learning objectives

Immunomodulators4

Rheumatoid Arthritis5

Rheumatoid Arthritis: treatment6

(DMARDs) Conventional antirheumatic drugs7

Calcineurin inhibitors8

Corticosteroids9

Corticosteroids: ADRs10

Janus Kinase (JAK) inhibitors11

(bDMARDs) TNF alpha antagonists12

(bDMARDs) Cytokine modulators13

Additional reading: for fun!1415

Osteo-arthritis16

Osteo-arthritis: treatment17

Rheumatoid arthritis Vs Osteo-arthritis18

Prostaglandin & COX enzymes19

NSAIDs20