Psoriasis Pharmacology Flashcards
Psoriasis Definition
Psoriasis is a disease characterized by keratinocyte hyperproliferation and incomplete differentiation resulting caused by cytokines (IL-1 & TNFa) released from infiltrating activated T-cells.
Evidence points to an immune-mediated disorder, possibly an organ-specific autoimmune disease of skin.
Cytotoxic Agents
Coal Tar
Shale Tar
Anthralin
Coal tar Products
(made from coal) Denorex, DHS Tar, Neutragena-T/Gel, Tegrin, Balnetar
Coal Tar MOA
Cytotoxic Agent
Suppresses DNA synthesis which decreases epithelial cell proliferation
Photosensitizing agent (more sensitive to sun; use prior to light treatment to enhance)
Don’t use immunological drugs except for the VERY severe cases
Psoriasis is treated by UV radiation so photosensitizing is better for psoriasis (NOT good in acne)
Coal Tar Side Effects
-Irritation, stinging and burning (tar smarks)
-Folliculitis particularly of the axilla and groin (hair follicles become inflammed – similar to prickly heat) – tar acne
-Contact dermatitis
Photosensitizing
-Carcinogenic (coal miners and chimney sweeps – scrotal cancer)
-Systemic side effects do not occur
-Will stain light skin and hair – brownish-black discoloration
-Unpleasant odor – sulfur smell
Shale Tar Products
ichthammol
Shale Tar
Cytotoxic but the exact mechanism of action is unknown
No clinical studies have demonstrated its effectiveness, but it is safe and gives symptomatic relief
It is less irritating and has no photosensitizing activity unlike coal tar
Also used for treatment of eczema, rosacea and acute otitis externa
Antralin Products
Antra-Derm,
Dithrocreme,
Lasan
Anthralin MOA
Cytotoxic Agent
Disruption of the DNA alpha helix by free radicals
Anthralin Pharmacological Effect
Suppresses hyperplastic keratinocyte cell growth
-Reduce growth and lessen the amount of plaques
Anthralin Side Effect
Local irritation – only put on affected area
Erythema on normal skin around lesions
Severe conjunctivitis with eye contact
Systemic side effects do not occur
Will stain skin, hair and clothes a dark brown or black color
T-cell and Cytokine Suppressors
Methotrexate Mycophenolate mofetil Cyclosporin A Tacrolimus Pimeccrolimus TNFa inhibitors cytokine inhibitors
Methotrexate Products
Rheumotrex,
Amethopterin,
MTX,
Mexate
Methotrexate MOA
T-cell and cytokine suppressor
Reduces immune system
Inhibits dihydrofolate reductase
Promotes the apoptosis of activated T-cells (programmed death)
Methotrexate Pharmacological Effect
Reduces keratinocyte hyperproliferation
Reduces the number of T-cells
Methotrexate is a chemotherapeutic agent– used for autoimmune diseases –Chrone’s disease, rheumatoid arthritis , psoriasis, or other autoimmune diseases
Methotrexate Side Effects
GI - diarrhea & ulcerative stomatitis
Blood dyscrasias (decease blood contents-any type of anemias)
Cirrhosis
Teratogenic
Mycophenolate mofetil products
myfortic
Mycophenolate mofetil MOA
Inhibits purine synthesis
Inhibits cytokine production
(If you can’t make purines, the T-cells can’t reproduce
Cytokines are the cause of inflammation by transcription factor activation
Reduces IL-1 and IL-2 – found most around the psoriasis plaques)
Mycophenolate mofetil Pharmacological Effects
Reduces the number of T-cells
Anti-inflammatory action
Mycophenolate mofetil side effects
Bone marrow suppression (reduction in RBC or WBC, GI upset, “flu-like” symptoms
Cyclosporin A products
Sandimmune
Tacrolimus Products
Prograf
Pimecrolimus Products
Elidel
Cyclosporin A, Tacrolimus, Pimecrolimus MOA
Binds to proteins called immunophilins and prevents binding to calcineurins (immunophilin-drug complex inhibits calcinuerin)
Cyclosporin binds Cyclophilin (CP) A
Tacrolimus & Pimecrolimus: FK binding protein 12 (FKBP-12)
Without calcineurins, T-cells cannot make interleukins and cytokines
Cyclosporin A, Tacrolimus, Pimecrolimus Pharmacological Effect
Inhibits cytokine synthesis (IL 2,4,and 10)
Prevents release of mediators from mast cells
Cyclosporin A, Tacrolimus, Pimecrolimus Black Box Warning
Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression
Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infection
Cyclosporin A, Tacrolimus, Pimecrolimus Side Effects
Nephrotoxicity (long term use) Hypertension Upper respiratory tract infections Burning and irritation of skin at application site Cough and headache
Cyclosporin only: Gingival hyperplasia (gum overgrowth also occurs with phenytoin) Multiple drug interactions through P450 3A4
Anti-rejection drugs – given to patients who have organ transplant – suppress the immune system so the organ will not be rejected
Ensure that the patient is not sick – opportunistic infections may arise
TNFa inhibitor products
Etanercept (Enbrel)
Adalimumab (Humira)
Infliximab (Remicade)
TNFa MOA
Binds free TNFa and reduces inflammation
TNFa (keeps us from getting cancer, but in autoimmune diseases TNFa is too active) is a cytokine that kills off cells in our bodies – if it occurs in higher than normal levels, kills off cells that are not harmful
cytokine inhibitor products
Ustekinumab (Stelera)
cytokine inhibitor MOA
Inhibits IL-12 and IL-23 from binding to T-cells
TNFa and Cytokine Inhibitor Pharmacological Effects
Reduces the number and size of the plaques
Really work! But are expensive and not especially safe (can be lethal) yet advertised frequently like they are aspirin
TNFa and Cytokine Inhibitor Side Effects
- Injection reactions – chills and site pain and inflammation
- Serious infections and malignancies (make sure the person does not have any serious illness – TB)
- Blood dyscrasias (reduces the # of RBC/WBC)
- Upper respiratory tract infections and headache
- Can worsen Chrone’s disease
Nuclear Receptor Binders
Acitretin
Tazarotene
Calcipotriene
Steroids
Acitretin products
soriatane
Acitretin MOA
Binds to either RAR or RXR retinoid receptors
A homodimer or heterodimer is formed which alters DNA transcription (Direct) binding RARE
A single receptor complex binds to a transcription factor to alter DNA transcription (indirect) stops TRE binding
Acitretin Pharmacological Effect
Reduces proliferation and enhances differentiation of keratinocytes
Does not suppress sebum production as effectively as the other retinoids – not used in acne
Acitretin Kinetics
Half life is 49 hours
Drug is still detectable in the serum from 1 to 3 years after discontinuation
You can’t give blood for 1 month after discontinuing accutane
Cannot give blood or get pregnant for 3 years if you have taken soriatane (therefore is typically used in older, post menopausal)
Acitretin Dermatological Effects
Lip inflammation Alopecia Peeling on palms, soles and fingertips Dry nose and epitaxis Dry mouth and stomatitis
Acitretin Other Side Effects
Ophthalmic: Eye irritation Dryness or thickening of conjunctiva Blurred vision Loss of eyelashes or brow
Pseudotumor cerebri (benign intercranial pressure)
Smaller changes in blood lipids than isotretinoin (good for older patients)
Everything dries up
SEs are less severe than accutane
Acitretin in Pregnancy
Teratogenic
Should not be given to woman in child bearing years
More teratogenic than isotretinoin
Should not become pregnant or give blood up to 3 years after use
Warnings
Do not drink alcohol with this drug – increases the half-life
Do not use any of the retinoids in patients with atopic dermatitis – further skin drying
RAR – in the skin
RXR – one that involves reproduction
These drugs bind to both (RXR linked to teratogenicity)
Soritane is oral
Tazarotene Products
Tazorac (topical retinoid)
Tazarotene MOA
Same as Acitretin
Binds to either RAR or RXR retinoid receptors
A homodimer or heterodimer is formed which alters DNA transcription (Direct) binding RARE
A single receptor complex binds to a transcription factor to alter DNA transcription (indirect) stops TRE binding
Tazarotene Pharmacological Effects
Same as Acitretin
Reduces proliferation and enhances differentiation of keratinocytes
Does not suppress sebum production as effectively as the other retinoids – not used in acne
Tazarotene Side Effects
Pruritis, burning, stinging, erythema, irritation, rash, peeling and dry skin
Photosensitivity
No known systemic side effects
Tazarotene in pregnancy
Teratogenic
Do not use in pregnancy
While it doesn’t cross the skin, it should not be used in pregnancy to be safe
Basically topical soritane
Calcipotriene products
Dovonex
Calcipotriene MOA
Calipotriene-VDR complex forms a heterodimer with retinoid receptors to alter DNA function – see nuclear receptor mechanism
Binds with GRE, RAR, RXR, TRE
Vitamin D drug
The VDR binds RAR or RXR to form a heterodimer which then binds the RARE
Calcipotriene Pharmacological Effect
Inhibits proliferation and promotes epidermal differentiation
Decreases inflammation by decreasing inflammatory cytokine release
Calcipotriene Side Effects
Topical side effects:
Burning, itching, erythema, dry skin
Hypercalcemia (Vit D regulates calcium)
6% of drug is absorbed through the skin
Rare side effects:
Skin atrophy, hyperpigmentation and folliculitis
Pretty good drug – not as many side effects as retinoids
Synthetic derivative of vitamin D3 which can cause an increase in calcium absorption and cause hypercalcemia
Difference between glucocorticoid and mineralocorticoid activity
Steroids are called corticosteroids because they are formed in the adrenal cortex (WATCH FOR TEST SAYING MEDULLA=INCORRECT)
Corticosteroids have two main effects
- Na+ retention: mineralocorticoids
- Hepatic glycogen storage: glucocorticoid
Most corticosteroids have a mixture of these activities
Mineralocorticoids
Steroid
Aldosterone is the endogenous steroid
Acts on the kidneys to retain Na+ and thus retains water
These usually have little anti-inflammatory activity
Glucocorticoids
Steroid
Cortisol and cortisone are the endogenous steroids
Have significant effect on metabolism to help the body through stressful times (mobilize sugars) such as trauma, surgery, car accident etc
These compounds usually have greater anti-inflammatory action
Steroid MOA
Glucocorticoids modulate inflammation either directly or indirectly by increasing the transcription of anti-inflammatory proteins or decreasing the transcription of inflammatory proteins
Direct Mechanism – a homodimer binds to the Glucocorticoid Response Element (GRE) in the DNA
Indirect Mechanism – a single receptor/steroid complex binds to AP-1 and NF-kB and prevents binding to the TRE
Relative Potency of Topical Glucocorticoids
(Efficacy)
A vasoconstrictor assay is used to measure efficacy
7 degrees of potency :
Steroids in each class have the same relative efficacy (they are all at a concentration that produces maximal response) Exception: Cutivate (clobetasol) – the strongest steroid = highest efficacy
Effectiveness of Topical Glucocorticoids
Depends on: Concentration Efficacy Salt Vehicle Percutaneous absorption (Application) – goes through the plaque down into the skin to cause an effect
Glucocorticoid Vehicles
Optimized cream (propylene glycol) or ointment (highest efficacy)
Ointment with less propylene glycol than optimized
Cream less propylene glycol than optimized
Alcoholic lotion (shampoo)
Solution (shampoo) (lowest efficacy)
Note: Sometimes the vehicle is more important than the drug itself
The vehicle list is highest to lowest efficacy
Percutaneous absorption
- Proportional to the duration of use, area of coverage and thickness of skin (thin skin= increased absorption)
- Abraded or inflammed skin is more permeable than regular skin
- Occlusive dressing can enhance percutaneous absorption by as much as 10 fold (patient may be told to put saran wrap or an occlusive dressing over the affected area)
- The skin acts as a reservoir so frequent dosing is not needed
Permeability of skin
High - scalp, axilla, face, eyelids, neck, perineum & genitalia (use low absorption drugs on highly permeable)
Low - back, palms, and soles
(use high absorption drugs on low permability)
Immediate side effects of topical steroids
Increased risk of local infection and masking of infection (change the immune system)
Long term use of topical steroids
Atrophy of the dermis and epidermis (thin skin) Striae (stretch marks) Purpura (black and blue marks) Telangiectasia (spider veins) Acne Hypertrichosis (hair growth on face) Alopecia (hair loss on head) Cataracts and glaucoma (more frequent when steroids are used in inhalers)
Systemic SE after topical or Oral Administration
Topical glucocorticoids can be absorbed in sufficient quantities to produce systemic side effects
Usually only occurs under extreme use like when high potency with occlusive dressing are used over a large area of the body for a long period of time
Long term oral use may cause round stomach distention
Cushing’s Syndrome – excess steroids (almost entirely drug induced)
- Rounding, puffiness and plethora of the face (moon face)
- Fat redistributes to the face and trunk (buffalo hump)
- Fine hair grows over the thighs, face and trunk
- Alopecia
Addison’s Syndrome – too little steroid (congenital or caused by abrupt discontinuation of overused steroids)
Weakness & fatigue
Weight loss
Hyperpigmentation
Hypotension
Electrolyte imbalance
Possible death if discontinued to rapidly
Growth suppression in children
CorticosteroidsSystemic Side effects of oral or topical:
Adrenal Suppression
Important!!
Adrenal Suppression aka HPA axis suppression:
Naturally release steroids when under stress
Stress signals hypothalamus
Hypothalamus releases CRH CGR stimulates anterior pituitary
anterior pituitary releases ACTH
ACTH stimulates of adrenal cortex
adrenal cortex releases cortisol
cortisol causes metabolic effects
metabolic effects cause negative feedback to turn off hypothalamus
If we introduce steroids into the system, the brain thinks there are enough and doesn’t produce any more=adrenal gland atrophy (gets smaller) – if you don’t use it, you lose it adrenal cortex will atrophy to the point that it will not function – may be lethal
Adrenal suppression can occur at 14 days after beginning steroid therapy – use step-therapy
Can not take for extended periods because it will kill us. Adrenal cortex is a lazy gland and if you don’t use it, it will atrophy and basically die off. If you don’t use it, you will lose it. When you need it such as in a stressful situation, it won’t work to make the steroids you need, and you die.
Phototherapy drugs
Methoxsalen
Methoxsalen products
Oxsoralen
Methoxsalen MOA
Belongs to the chemical class psoralens -Chromophore – a drug that is excited by a specific wavelength of light
The drug does not have activity until excited
After exposure to UVA, methoxsalen combines with the DNA in epidermal cells by forming covalent linkages with pyrimidines (the linkages keep DNA from being made)
Therapy with psoralens is called PUVA therapy
Methoxsalen Pharmacological Effect
Normalizes number and arrangement of ketatinocytes
Reorganizes cutaneous blood vessels
Cytotoxic to T-cells
Increases melanin pigmentation (darkens skin)
Methoxsalen Side Effects
Pruritus Nausea Erythema & Blistering (could get sunburn) Hyperpigmentation Increased skin aging Increased risk of skin cancer Cataracts
PDE inhibitor
Apremilast
Apremilast product
Otezla
Apremilast MOA
Inhibits PDE4 which increases cAMP
Apremilast Pharmacological Effect
Reduces plaques and psoriatic arthritis
Apremilast Side Effects
Diarrhea, nausea and headache
Use cautiously in depressed patients (screen for antidepressants etc)…could cause patient to commit suicide
Weight loss (could lose 5% body weight-significant)
Don’t use with strong cytochrome P450 enzyme inducers
