Module 3.1.1 (Pharmacology of Immunosuppressants used in Psoriasis) Flashcards
For coal tars;
A) What is the most effective component?
B) What activity does it have?
C) What is the MOA?
D) Why is not really used now?
A)
- Carbazole thought to be most effective component
B)
- Anti-angiogenic activity
C)
- Activates aryl hydrocarbon receptor (AhR), resulting in induction of epidermal differentiation
- AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients
> AhR antagonists increased inflammation
D)
- Carniogens –> mostly reduced in modern preps
- Stains, unpleasant odour –> other treamtnets more common now
For topical corticosteroids (CS);
A) Why are they used in psoriasis?
B) What are examples of mild CS? Dose?
C) What are examples of moderate CS? Dose?
D) What are examples of potent CS? Dose? How to reduce tolerance and adverse effects?
A)
- Most common treatment for Psoriasis
B)
- Hydrocortisone 0.5 – 1% creams (give bd)
C)
- 0.02 – 0.05% betamethasone, triamcinolone, desonide, clobetasone (use up to twice a day)
D)
- 0.1% betamethasone, mometasone, methylprednisolone or 0.05% Clobetasol (use once per day)
Apply on alternate days (or on off periods eg, 5 on 2 off) if possible –> reduces tolerance and adverse effects
For topical corticosteroids (CS);
A) What is their key pharmacological property?
B) What forms do they come in? Why do they come in these forms?
C) Which CS to use in children? What caution to exercise?
D) What type to use on the face, armpits or groin? List some examples.
E) Examples of fluroinated CS
E) What patients must caution be exercised in?
A)
- MOST potent antiinflammatory available topically
> cause vasoconstriction –> limits immigration of immune cells to the area
B)
- Creams, ointments, lotions –> lipophilic, therefore easy to prepare different forms
C)
- Hydrocortisone –> significant systemic absorption occurs in topical forms for kids/infants
D)
Non-fluorinated: methylprednisolone, prednisolone and hydrocortisone
E)
Fluorinated: dexamethasone, betamethasone
F)
- Delayed wound healing –> caution in diabetic and immunosuppressed patients.
What is the dose of methotrexate used in psoriasis?
Usual dose 7.5 to 15 mg once a week (similar regime to RA patients)
For cyclosporin A (CsA);
A) What form is it available in?
B) What is the MOA?
C) Examples of drugs?
D) What improves oral absorption?
E) M and E?
F) 1/2 life?
G) When is it used?
A)
Only available orally
B)
- Inhibition of T-lymbopcytes
- Binds cyclophilin
- Complex binds calcineurin –> calcineurin inhibitor
- Suppresses early cell response to antigens
C)
- Sandimmune and Neoral
D)
- Microemulsion improves oral absorption
E)
- Metabolised in liver (and small intestine) – CYP3A –> many metabolites
- Mostly Faecal route excretion
F)
- ½ life = 6 h (healthy) – 20 h (hepatic damage)
G)
- Used in severe Psoriasis
For cyclosporin A (CsA);
A) What must be it be used orally (systematically)?
B) What are other countries using? Topical or oral?
A)
- High MW –> no effect when used topically
B)
- Other countries trialing Tacrolimus as topical application
- Pimecrolimus is a smaller MW drug with similar MoA to cyclosporine A –> adverse effects as for CsA except for cutaenous atropy (CsA only has his AE).
What are the adverse effects of Cyclosporin A (CsA)?
- Nephrotoxic –> 2-3 month checks
- Hypertension, hyperlipidemia, tremor, hirsutism, general G.I. issues, gum hyperplasia, & excreted in breast milk.
- Paraesthesia (Burning/tingling sensation on hands/feet) , increase in skin malignancies
- Hypomagnesaemia, hyperkalaemia, tremor
- Convulsions
- Muscle cramp
- Some increase infection (less than others – more lymphocyte targeted)
For monoclonal antibody drugs;
A) What are some examples?
B) What is the MOA? What dosage form?
C) When is it used?
D) Adverse effects?
A)
- Infliximab / Adalimumab (TNF-a monoclonal) –> immunosuppression use in Psorasis
- Etanercept as TNF-α fusion protein also useful in psoriasis
B)
- Prevents TNF-α from attaching to receptors
- Dosage form: injection
C)
- All reserved for when other therapies have not worked – NOT 1st line
D)
- 15% patients infusion reaction-within 1-2 h
- Fever, urticaria, hypotension, dyspnea
What are FOUR examples of other monoclonal antibody drugs? What is their MOA and what adverse effects do they share?
- Ustekinumab = immunosuppression use in psoriasis. Anti IL-12 and IL-23 monoclonal (binds to P40 sub unit)
- Guselkumab. Anti IL23 (binds to p19 sub unit of this cytokine)
- Secukinumab. Monoclonal against Anti-IL17a
- Ixekizumab. Humanised monoclonal against IL-17A
For Apremilast;
A) What is the MOA?
B) How to long to see effects?
C) 1/2 life?
D) BA?
E) Metabolism?
F) Excretion?
G) What does it work on?
A)
- Apremilast is selective phosphodiesterase 4 (PDE4) inhibitor –> increases cAMP levels.
- Increased cAMP levels = increase in anti-inflammatory cytokines
- Not as potent as the biologic drugs (TNF-α drugs) –> lower risk of infection though.
- Ultimately ⇩ TNF-α, IL-12, IL-23 and ⇧ IL-10 (PBMCs). Decrease in stimulation of T-cells.
B)
- Effects are seen between 1 to 2 weeks after initiating
C)
- Plasma ½ life of 6-9h, peak plasma after oral = 2.5h –> taken twice a day
D)
- 73%
E)
- CYP3A4 metabolised + non-CYP hydrolysis
F)
- 58% kidney excreted
G)
- Works on monocytes, T-cells, keratinocytes, synovial fibroblasts
What are the adverse effects of apremilast? What are some precautions?
Adverse: NVD. 15% have Diarrhoea. Abdominal pain, headache, back pain, anorexia, GORD, upper respiratory tract infections
- Severe renal impairment – reduce dose to once a day
- Avoid strong CYP3A4 inhibitors/inducers
What is the MOA of Dithranol? What dosage form does it come in?
MOA
- Possible DNA synthesis inhibition
- Possible oxidative metabolism blocking potential – could limit ATP production – and therefore have a general suppressive activity of energy driven processes – slowing down epidermal cell growth
Dosage form
- Only to be used topically and only to psoriatic lesions, not intact skin
What are the adverse effects of dithranol?
- Skin irritation
- Discolouration of skin – brown (affects fair-skinned patients more)
- Stains clothes - permanent
How is methoxsalen involved in the use of phototherapy? How is it activated?
Part of Phototherapy (can be used orally as well as topically)
- Topically may include a whole body bath in 2.6 mg/L soln
- Topical is 30 min before UVA light exposure
UVA activated – then binds to DNA – inhibiting further synthesis
> inert when UV light removed
What is the mechanism of action of methoxsalen?
clue: regulatory t cell induction (3 ways)
AMH states mechanism as probably binds DNA
Current evidence suggests more to do with regulatory T cell induction (Tregs) –> 3 populations of T helper cells
- IL17 producing ones – turn into Th17 cells – contribute to the inflammatory problem of Psoriasis (non-Treg)
- Resting Treg cells - mild suppressive effect on Tcell mediated damage (rTreg)
- Activated Treg cells have strongest suppressive activity on Tcell mediated effects (aTreg)
MORE aTREG and rTREG, and less non T-reg cells = reverse Tcell mediated inflammation.
