Lecture 13: Anti-inflammatory drugs: disease-modifying anti-rheumatic drugs (DMARDs), Drugs used in gout & antihistamines

Question 1

Rheumatoid diseases

Answer 1

• Arthritic disease is one of the commonest chromic inflammatory conditions
• more than 6 million canadians have been diagnosed with arthritis.
• One in three patients likely to become severely disabled.
• autoimmune reaction (antigen?)
• comprise imflammation, proliferation of the synovium, and erosion of cartilage and bone.
• IL-1 & TNF-a major roles

Question 2

Describe the main classes of anti-rheumatoid drugs

Answer 2

• DMARDs= ‘disease modifying’ anti-rheumatic drugs
  –> may halt or reverse
  –> discrete groups

-NSAIDs (reduce symptoms)
- Cytotoxic drugs/immunosuppressants
-glucocorticoids
-Newer agents, with more specific actions (anticytokine drugs)

Question 3

DMARDs examples

Answer 3

• methotrexate
• auranofin
• penicillamine
• chloroquine

Question 4

DMARDs

Answer 4

• Improve symptoms
  -Reduce disease activiy
• not established - halt the long-term progress
• slow (months)
• unwanted effects and/or lack of efficacy

Question 5

Pharmacodynamics and pharmacokinetics for the main representitives of DMARDs

Answer 5

Auranofin =>
-organogold compound
MOA not known; through inhibition of IL-1 and TNF-a production, but multiple other molecular targets have been suggested.
Pharmacokinetics —————–
-Orally
- concentrated in the tissues
- Half-life 7 days initially
Unwanted effects —————–
-Skin rashes
-mouth ulcers
- non-specific flu-like symptoms
-skin turns blue
-if therapy stopped when symptoms appear, toxic effects low.

Penicillamine =>
- Does not have general anti-inflammatory effects- specific for rheumatoid diseases.
- Putative MOA
modify rheumatoid disease partly by decreasing the immune response.
partly by an effect on collagen synthesis, preventing the maturation of newly synthesized collagen.
Pharmacokinetics ———————
-orally; dosage is started low and increased
-only half dose administered is absorbed.
Unwanted effects ——————–
- up to 40% of patients therapy is stopped
-rashes, stomatitis, anorexia, fever, nausea and vomiting, disturbance in taste.
-may resolve if the dosage is lowered
-metal chelator, therefore it should not be given with gold compounds.

Cloroquine =>
-used in prevention & treatment of malaria
-DMARD
-Other treatments have failed
- effects do not appear until month or more, only half patients treated respond.
-systemic lupus erythematosus
-contraindicated in patients with psoriatic arthropathy
-MOA not fully understood
-lysosomotropic agent
-Putative anti-inflammatory effects:
-inhibits lymphocyte proliferation
-inhibits phospholipase A2
-inhibits release of enzymes from lysosomes
-inhibits release of reactive oxygen species from macrophages
-decreases production of IL-1
Pharmacokinetics ———————-
-orally, absorbed completely
-very high volume of distribution
-concentrated in parasitised red cells
-excreted in urine
Unwanted effects ———————-
- considered to be safe for pregnant women, safe at low prophylactic doses
-at high doses: nausea and vomiting, dizziness and blurring of vision, headache and urticarial symptoms, retinopathies can also occur.

Methotrexate (MTX)
- commonly a first-choice DMARD also immunosuppressant (amtimetabolitic agent)
-folate analogue
-versatile drug treating:
–rheumatoid arthritis
–psoriasis
–graft versus host disease
- more rapid onset of action (fatal blood dyscrasias)
-MOA:
–anti-inflammatory activity independent of cytotoxic action
–does not involve depletion of folate pools
–increasing levels of adenosine
-versatility = combined anti-neutrophil, anti-T-cell, and antihumoral effects.

Question 6

The pathogenesis of gout

Answer 6

• attacks single joint at a time
• Metabolic disease = plasma urate concentration is raised
  –> overproduction
• produced by deposition of crystals of sodium urate
  -inflammatory response
  -Neutrophils engulf the crystals
• production of IL-1 and other cytokines.

FOOT TRAP

Question 7

Pharmacodynamics and pharmacokinetics of the main classes of drugs that are used to treat gout

Answer 7

——-Inhibit uric acid synthesis
-> allopurinol (main prophylactic drug)
- Alloxanthine (metabolite)
- non-competitive inhibitor of the enzyme xanthine oxidase
- reduces concentration of the relatively insoluble urates and uric acid in tissues, plasma urine.
- Increases the concentration of the more soluble precursors, the xanthines and hypoxanthines.
- urate crystals in tissues
- renal stones
- drug of choice in the long-term treatment of gout
-ineffective in the treatment of an acute attack and may even exacerbate the inflammation.
PHARMACOKINETICS
- orally given
- well absorbed
- half-life is 2-3h
- metabolite half-life 18-30h
SIDE EFFECTS
- gastrointestinal disturbances
-allergic reaction (rashes)
- fatal skin diseases.

—- Increase uric acid excretion
-> uricosuric agents
- direct action on renal tubule.
- Initiated in combination with an NSAID and never during an acute attack.
-Acute attacks of gout occur commonly during the early stages of such therapy ( physicochemical changes in the surfaces of urate crystals)

—-Inhibit leukocyte migration into joint
-> colchicine
- prevents migration of neutrophils (biding to tubulin = depolymerisation of the microtubules)
- develop ‘drunken walk’
PHARMACOKINETICS
-given orally, well absorbed, reaches peak concentration in ~1h
-excreted in gastrointestinal tract & in urine

—– IL-1 targeting biopharmaceuticals
-> anakinra (recombinant human interleukin 1 receptor antagonist protein)
General anti-inflammatoy and analgesic effect
- NSAIDs
- Glucocorticoids

Question 8

SUMMARY OF DRUGS USED IN GOUT

Answer 8

• To treat acute attack:
  –> NSAIDs: anti-inflammatory action/reduce pain
  –> colchicine: reduces leukocyte migration into joints
  –> steroids: anti-inflammatory action
  –> anakinra: reduces IL-1 levels
  -For prophylaxis:
  –> allopurinol: inhibits uric acid synthesis
  –> uricosuric agents: increase uric acid excretion
  –> anakinra: reduces IL-1 levels.
• Drugs used for prophylaxis must not be started until the acute attack has resolved.
  (still being evaluated clinically)

Question 9

Three (4) types of histamine receptors and antihistamine drugs

Answer 9

• Histamine receptor: H1-4
• H1 receptor antagonists = affect inflammatory and allergic mechanisms.
• H2 receptor antagonists = inhibition of gastric secretion.
  -H3 agonists and antagonists available, may have use in CNS conditions.

CLINICAL USES antihistamines
H1:
- Allergic reactions:
-> non-sedating drugs
-> topical preparations
-> injectable formulations
- As antiemetics (gravol)
-> prevention of motion sickness
-> nausea
- For sedation

Question 10

Pharmacodynamics and pharmacokinetics of antihistamines

Answer 10

• Decrease - contraction f the smooth muscle
• inhibit - increases in vascular permeability
• effects in the CNS
  –> usually listed as side effects
• strong sefatives
• antiemetic
• antimuscarinic effects
• peripheral H1 is needed without the CNS effects = do not penetrate the BBB (terfenadine)
• tefenadine
  –> cause serious cardiac dysrhythmias (increased if taken w/ grapefruit juice or other agents that inhibit cytochrome P450

PHARMACOKINETICS
- orally, well absorbed quickly, half-life not long.

SIDE EFFECTS
- not clear which effects are unwanted
- treat allergies – sedative CNS effects are generally unwated.
- as sedatives – dizziness, tinnitus and fatigue are unwated.
- Peripheral antimuscarinic actions always unwated.
–> dryness of the mouth
–> blurred vision
–> constipation
–> tachicardia
- Unwanted effects that are not mechanism-based:
–> gastrointestinal disturbances
–> allergic dermatitis can follow topical application.