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DEENT Exam 4 > Psoriasis Pharmacology > Flashcards

Psoriasis Pharmacology Flashcards

1
Q

Psoriasis Definition

A

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.

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2
Q

Cytotoxic Agents

A

Coal Tar
Shale Tar
Anthralin

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3
Q

Coal tar Products

A 
(made from coal)
Denorex, 
DHS Tar, 
Neutragena-T/Gel, 
Tegrin, 
Balnetar
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4
Q

Coal Tar MOA

A

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)

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5
Q

Coal Tar Side Effects

A

-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

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6
Q

Shale Tar Products

A

ichthammol

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7
Q

Shale Tar

A

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

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8
Q

Antralin Products

A

Antra-Derm,
Dithrocreme,
Lasan

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9
Q

Anthralin MOA

A

Cytotoxic Agent

Disruption of the DNA alpha helix by free radicals

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10
Q

Anthralin Pharmacological Effect

A

Suppresses hyperplastic keratinocyte cell growth

-Reduce growth and lessen the amount of plaques

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11
Q

Anthralin Side Effect

A

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

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12
Q

T-cell and Cytokine Suppressors

A 
Methotrexate
Mycophenolate mofetil 
Cyclosporin A
Tacrolimus
Pimeccrolimus
TNFa inhibitors
cytokine inhibitors
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13
Q

Methotrexate Products

A

Rheumotrex,
Amethopterin,
MTX,
Mexate

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14
Q

Methotrexate MOA

A

T-cell and cytokine suppressor
Reduces immune system

Inhibits dihydrofolate reductase

Promotes the apoptosis of activated T-cells (programmed death)

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15
Q

Methotrexate Pharmacological Effect

A

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

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16
Q

Methotrexate Side Effects

A

GI - diarrhea & ulcerative stomatitis
Blood dyscrasias (decease blood contents-any type of anemias)
Cirrhosis
Teratogenic

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17
Q

Mycophenolate mofetil products

A

myfortic

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18
Q

Mycophenolate mofetil MOA

A

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)

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19
Q

Mycophenolate mofetil Pharmacological Effects

A

Reduces the number of T-cells

Anti-inflammatory action

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20
Q

Mycophenolate mofetil side effects

A

Bone marrow suppression (reduction in RBC or WBC, GI upset, “flu-like” symptoms

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21
Q

Cyclosporin A products

A

Sandimmune

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22
Q

Tacrolimus Products

A

Prograf

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23
Q

Pimecrolimus Products

A

Elidel

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24
Q

Cyclosporin A, Tacrolimus, Pimecrolimus MOA

A

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

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25
Q

Cyclosporin A, Tacrolimus, Pimecrolimus Pharmacological Effect

A

Inhibits cytokine synthesis (IL 2,4,and 10)

Prevents release of mediators from mast cells

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26
Q

Cyclosporin A, Tacrolimus, Pimecrolimus Black Box Warning

A

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

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27
Q

Cyclosporin A, Tacrolimus, Pimecrolimus Side Effects

A 
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

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28
Q

TNFa inhibitor products

A

Etanercept (Enbrel)
Adalimumab (Humira)
Infliximab (Remicade)

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29
Q

TNFa MOA

A

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

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30
Q

cytokine inhibitor products

A

Ustekinumab (Stelera)

31
Q

cytokine inhibitor MOA

A

Inhibits IL-12 and IL-23 from binding to T-cells

32
Q

TNFa and Cytokine Inhibitor Pharmacological Effects

A

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

33
Q

TNFa and Cytokine Inhibitor Side Effects

A
  • 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
34
Q

Nuclear Receptor Binders

A

Acitretin
Tazarotene
Calcipotriene
Steroids

35
Q

Acitretin products

A

soriatane

36
Q

Acitretin MOA

A

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

37
Q

Acitretin Pharmacological Effect

A

Reduces proliferation and enhances differentiation of keratinocytes

Does not suppress sebum production as effectively as the other retinoids – not used in acne

38
Q

Acitretin Kinetics

A

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)

39
Q

Acitretin Dermatological Effects

A 
Lip inflammation
Alopecia
Peeling on palms, soles and fingertips
Dry nose and epitaxis 
Dry mouth and stomatitis
40
Q

Acitretin Other Side Effects

A 
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

41
Q

Acitretin in Pregnancy

A

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

42
Q

Tazarotene Products

A

Tazorac (topical retinoid)

43
Q

Tazarotene MOA

A

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

44
Q

Tazarotene Pharmacological Effects

A

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

45
Q

Tazarotene Side Effects

A

Pruritis, burning, stinging, erythema, irritation, rash, peeling and dry skin
Photosensitivity
No known systemic side effects

46
Q

Tazarotene in pregnancy

A

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

47
Q

Calcipotriene products

A

Dovonex

48
Q

Calcipotriene MOA

A

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

49
Q

Calcipotriene Pharmacological Effect

A

Inhibits proliferation and promotes epidermal differentiation

Decreases inflammation by decreasing inflammatory cytokine release

50
Q

Calcipotriene Side Effects

A

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

51
Q

Difference between glucocorticoid and mineralocorticoid activity

A

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

52
Q

Mineralocorticoids

A

Steroid
Aldosterone is the endogenous steroid

Acts on the kidneys to retain Na+ and thus retains water

These usually have little anti-inflammatory activity

53
Q

Glucocorticoids

A

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

54
Q

Steroid MOA

A

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

55
Q

Relative Potency of Topical Glucocorticoids

A

(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
56
Q

Effectiveness of Topical Glucocorticoids

A 
Depends on:
Concentration
Efficacy
Salt
Vehicle
Percutaneous absorption (Application) – goes through the plaque down into the skin to cause an effect
57
Q

Glucocorticoid Vehicles

A

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

58
Q

Percutaneous absorption

A
  • 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
59
Q

Permeability of skin

A

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)

60
Q

Immediate side effects of topical steroids

A

Increased risk of local infection and masking of infection (change the immune system)

61
Q

Long term use of topical steroids

A 
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)
62
Q

Systemic SE after topical or Oral Administration

A

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

63
Q

CorticosteroidsSystemic Side effects of oral or topical:

Adrenal Suppression

A

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.

64
Q

Phototherapy drugs

A

Methoxsalen

65
Q

Methoxsalen products

A

Oxsoralen

66
Q

Methoxsalen MOA

A 
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

67
Q

Methoxsalen Pharmacological Effect

A

Normalizes number and arrangement of ketatinocytes

Reorganizes cutaneous blood vessels

Cytotoxic to T-cells

Increases melanin pigmentation (darkens skin)

68
Q

Methoxsalen Side Effects

A 
Pruritus
Nausea
Erythema & Blistering (could get sunburn)
Hyperpigmentation
Increased skin aging
Increased risk of skin cancer
Cataracts
69
Q

PDE inhibitor

A

Apremilast

70
Q

Apremilast product

A

Otezla

71
Q

Apremilast MOA

A

Inhibits PDE4 which increases cAMP

72
Q

Apremilast Pharmacological Effect

A

Reduces plaques and psoriatic arthritis

73
Q

Apremilast Side Effects

A

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

DEENT Exam 4 (6 decks)

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