Transcript PHL 425 5th Lecture

Pharmacology-4 PHL 425
Fifth Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Management of Psoriasis
 Although there are no curative therapies for psoriasis, there are treatment options
that adequately suppress the disease process and sometimes afford short periods of
remission
 The spectrum of treatment options depends on the extent and severity as well as the
emotional response to the disease
 Management includes use of topical agents and systemic agents (orally or
percutaneously administered agents)
 All of these treatments may be used alone or in combination with one another
 Goal of treatment:
 Lubrication
 Removal of scales
 To slow down lesion proliferation
 Pruritus management
 To prevent complications
 Lessening patient stress
Treatment of Psoriasis
 Topical and systemic treatments
 Wide range of therapies for the treatment of moderate to severe psoriasis
 None induce a permanent remission
 Many have side effects that can place limits on their use
I. Topical preparations: They are first-line therapies for localized psoriasis. This
consists of a limited number of chronic stable psoriasis plaques. They include:
1. Corticosteroids
2. Pimecrolimus
3. Vitamin D3 analogues
4. Retinoids
5. Tar preparations
6. Keratolytics (salicylic acid)
7. Emollients
8. Photochemotherapy
9. Excimer laser-derived 308-nm ultraviolet (UV) B therapy
Management of Psoriasis, Topical preparations, contd.
1. Corticosteroids: They are the most commonly prescribed therapy for psoriasis in
North America
MOA includes anti-inflammatory effect, reducing itching & scaling, anti-proliferative
and immunosuppressive effects
Generally, corticosteroids range in strength from weak hydrocortisone to potent
corticosteroids, such as, betamethasone and clobetasol
Abrupt discontinuation of systemic corticosteroids should be avoided, otherwise a
rebound exacerbation of the condition may occur
Use of strong corticosteroids for long periods should be avoided
Topical corticosteroids are available in numerous vehicles including powders,
sprays, lotions, gels, foams, creams, emollient creams and ointments
Ointments: They help hydrate the lesion. They are good for dry, hyperkeratotic,
scaly lesions
Cream: For use on all areas. They are useful for infected lesions
Solutions: For scalp psoriasis. They often contain alcohols which can be painful
with open lesions
Management of Psoriasis, Topical preparations, contd.
Topical fluorinated glucocorticoids (e.g., fluocinolone acetonide, clobetasol
propionate) in ointment base are applied after the scales are removed by soaking
in water. Ointment is applied to wet skin, covered with plastic wrap and left on
overnight
Only weak preparations, such as hydrocortisone, should be used on the face,
perineum and flexural areas
 Side Effects
The major concerns with all corticosteroid preparations are dermal atrophy, skin
fragility, fast relapse times and tachyphylaxis
Systemic absorption  Suppression of the hypothalamic-pituitary-adrenal axis
Skin atrophy
Burning sensation
Poor wound healing
Pyogenic infections
Tachyphylaxis (medications that are highly effective initially, lose efficacy with
prolonged use)
 To avoid tachyphylaxis and the other side effects of topical corticosteroids, they
are applied twice daily for 2 weeks, after which they are applied on weekends
Management of Psoriasis, Topical preparations, contd.
2. Pimecrolimus and tacrolimus
They are potent immunosuppressants
They are calcineurin inhibitors which work mainly by inhibiting early activation of
T-lymphocytes
Pimecrolimus and tacrolimus ointments, compared with topical glucocorticoids, do
not cause skin atrophy, and therefore can be used safely in locations such as the
face
Burning, while occurring in some patients, appears to be less common with
pimecrolimus than with tacrolimus. In addition, pimecrolimus has less systemic
absorption
It is recommended that patients using pimecrolimus use sunscreen and avoid
excessive UV exposure; this may increase the incidence of lymphoma
Management of Psoriasis, Topical preparations, contd.
3. Vitamin D derivatives: Vitamin D3 analogues are good nonsteroidal antipsoriatic
topical agents and are not associated with cutaneous atrophy
 The second most commonly used group of psoriasis medications
 Calcipotriene (calcipotriol; 0.005%, ointment and cream) is a synthetic vitamin D3
derivative that has been shown to be effective in the treatment of plaque type
psoriasis of moderate severity
Trials with this formulation have shown efficacy rates equal to a medium-potency
steroid ointment, and it can be combined with the corticosteroids
It is available as cream, ointment and scalp lotion
inhibition of cell proliferation and induction of cell differentiation in psoriatic skin
It activates the vitamin D receptor, which belongs to the steroid/thyroid hormone
receptor superfamily (nuclear receptors). The receptor-vitamin D complex binds to
DNA and modulates the transcription of genes related to cell proliferation and
differentiation
 This results in inhibition of cell proliferation and induction of cell differentiation in
psoriatic skin
Management of Psoriasis, Topical preparations, contd.
3. Vitamin D derivatives (contd.):
 Side effects and interactions
Burning, pruritus, skin irritation, tingling of the skin
Potential risks include mild irritation and hypercalcemia, although this has not been
observed with the recommended doses
Phototherapy may inactivate vitamin D analogues and, conversely, vitamin D
analogues may block the therapeutic component of ultraviolet light; thus these
topical agents should be applied after phototherapy, not before
Topical salicylic acid inactivates calcipotriene. Thus, creams or ointments containing
salicylic acid should not be used with calcipotriene
Management of Psoriasis, Topical preparations, contd.
4. Topical Retinoids (Vitamin A derivatives)
 An important example is tazarotene: It is a third-generation retinoid approved for the
treatment of psoriasis
 It is the first topical retinoid approved by the FDA for the treatment of psoriasis
 MOA: It is a retinoid prodrug that is hydrolyzed by an esterase to its active form,
tazarotenic acid, which binds to retinoic acid receptors, resulting in modified gene
expression, thereby leading to:
Normalization of abnormal keratinocyte differentiation
Reduction in keratinocyte proliferation
A decrease in the expression of inflammatory markers
 Tazarotene gel, applied once daily to dry skin, may be used as monotherapy or in
combination with other medications e.g., topical corticosteroids for the treatment of
localized plaque psoriasis
 Side effects, contraindications and precautions:
Burning, itching, and skin irritation are relatively common
It is recommended that tazarotene should not be used by pregnant women. It is
prescribed with caution to women of childbearing age
Patients should avoid sun exposure
 Potentiation of photosensitizing medication may occur, and patients should be
cautioned to minimize sunlight exposure and to use sunscreens & protective clothing
Management of Psoriasis, Topical preparations, contd.
5. Coal Tar (‫)قطران الفحم‬: This old topical medication is a complex mixture of
substances produced during carbonization and distillation of coal
 The exact MOA of tar in psoriasis is not well characterized, but it includes:
Antiproliferative and antipruritic effects
Antibacterial effects
Anti-scaling effects : It decreases epidermal cell mitosis and scale development
Anti-inflammatory effects
 In the chronic stages of psoriasis, tar preparations are quite useful and offer an
alternative to the use of topical corticosteroids
5% coal tar concentration is most effective (range is 1%-6%)
It is used only on lesions that are well separated, not too big
It is used together with salicylic acid (keratolytic) for psoriasis of the scalp
Tar baths and shampoos are helpful
 Problems with coal tar:
Smell
Sting; irritation
Stain skin and fabrics
Sensitize, contact dermatitis
Management of Psoriasis, Topical preparations, contd.
5. Coal Tar (contd.)
 Goeckerman regimen: Tar is usually used in combination with UVB
phototherapy (the application of 1% crude coal tar in a hydrophilic ointment
before daily irradiation with UVB)
This is the oldest and used to be the most frequently used treatment for patients with
moderate-to-severe disease. It is effective within 2 to 3 weeks. This treatment leads
to remission of psoriasis in at least 80% of patients
The difficulties with this treatment are the time required for exposure to coal tar and
UVB, patients' dislike of the smelly, irritant coal-tar preparations and the expense of
the treatment. In rare cases, skin cancer has been induced by this treatment
This treatment is no longer popular because of its poorly tolerated side effects, and it
is not more effective than calcipotriene
6. Tree Bark Extracts
 Anthralin: It is a synthetic form of a tree bark extract that is considered to be
one of the most effective anti-psoriatic agents available
It slows the production of excess skin cells
Anthralin is combined with salicylic acid for psoriasis treatment
it can cause skin irritation and staining of clothing and skin
Management of Psoriasis, Topical preparations, contd.
7. Ultraviolet (UV) irradiation
 It is used for the control of psoriatic skin lesions
 Patients often notice improvement in skin lesions during the summer months
 UV radiation may act by slowing keratinization and anti-inflammatory effects
(inducing apoptosis of pathogenic T-cells)
 It has a potential to accelerate photo-damage and increase the risk of
cutaneous malignancy
8. Emollients and Moisturizers
 They soothe, smooth and hydrate the skin
 They are used for dry and scaly skin
 In case of scalp psoriasis, the scales may be thick and adherent
 Emollients are useful with other more specific treatment
 White soft paraffin ointment is an example
9. Topical salicylic acid
 Advantages of salicylic acid
Emollients containing keratolytic agents such as salicylic acid helps remove
scales and reduce hyperkeratosis
Ointments containing 2-10% salicylic acid are used with topical medications
to enhance absorption of other drugs
Management of Psoriasis,
Topical preparations, Conclusions
 There is not one topical drug that is best for all people with psoriasis.
Because each drug has adverse effects or becomes less effective over
time, it is common to rotate them
 Keratolytics are often added to these preparations to enhance their
penetration into the skin
 Some preparations should never be mixed together because they
interfere with each other. For example, salicylic acid inactivates
calcipotriene cream or ointment
 On the other hand, drugs such as anthralin (tree bark extract) may
require the addition of salicylic acid to work effectively
Management of Psoriasis, Phototherapy
Management of Psoriasis, Systemic Treatments
II. Systemic Treatments: Although the majority of patients with limited chronic
plaque psoriasis may be treated successfully with one or more topical agents,
approximately 20% require more aggressive treatment
Systemic treatment should be limited to patients with physically, socially, or
economically disabling psoriasis that has not responded to topical treatment
(severe, resistant, complicated forms of psoriasis)
They include:
 Psoralen and UVA
 Oral retinoids; acitretin
 Immunosuppressant therapy
Patients undergoing systemic treatment are required to have regular blood
and liver function tests because of the toxicity of the drugs
Pregnancy must be avoided for the majority of these treatments
Management of Psoriasis, Systemic Treatments
1. PUVA (Psoralen + Ultraviolet A): See before (2nd Lecture)
PUVA involves topical treatment with psoralen followed by UVA. Psoralen makes
the body more sensitive to UVA light. Psoralen is given 2 h before UVA irradiation
This treatment leads to symptomatic control of severe, disabling psoriasis, not
responsive to other therapy
Theories of MOA:
 Psoralen intercalates into DNA, inhibiting DNA replication and thus, inhibiting
epidermal cell hyper-proliferation
 Increased apoptosis of activated T-cells
PUVA is a highly effective treatment with a significant duration of remission. In over
85% of patients, skin lesions disappear after 20 to 30 treatments. Therapy is
usually given 2-3 times per week for several months. Maintenance therapy
involves as little as once every 2-4 weeks, with eventual discontinuation of
treatment
Most patients accept PUVA therapy because of the high likelihood of response and
the absence of need for topical medication between treatments
Management of Psoriasis, Systemic Treatments
1. PUVA (contd.)
Side effects
 The short-term side effects of PUVA are
 Nausea, burning, and pruritus
 increased risks of sensitivity to the sun, sunburn
 The long-term problems are:
 An increased risk of photodamage to the skin (premature aging) and of skin
cancer related to the cumulative exposure to UVA radiation
 Cataract: Protective glasses must be worn during and after treatment
 The therapeutic index of this treatment is high if the cumulative exposure to UVA
radiation is less than that likely to cause cancer or severe photodamage
 To minimize the cumulative dose of radiation, PUVA can be combined with the oral
retinoid etretinate (see later)
 Oral and topical retinoids are synergistic with oral PUVA, while reducing their dose
and the number of phototherapy treatments can be reduced, with the added benefit of
a potential reduction in skin carcinogenesis
Management of Psoriasis, Systemic Treatments
2.Oral retinoids:
They are vitamin A derivatives, and they have been used in the treatment of psoriasis
for the past two decades
Oral retinoids are approved for the treatment of severe psoriasis in adults resistant to
other form of therapies
Oral retinoids are especially effective in the treatment of erythrodermic and pustular
variants of psoriasis
Significant improvement can be achieved within 8 weeks of therapy
These synthetic hormones bind to nuclear retinoid receptors, thereby altering gene
transcription and returning keratinocyte proliferation and differentiation to normal
The original third generation retinoid used for psoriasis, etretinate, was superseded by
its natural metabolite, acitretin, which was shown to have similar efficacy with a better
pharmacokinetic profile
Since they are not immunosuppressive, retinoids might have a role in the treatment of
psoriasis in children, patients with HIV infection and those who are prone to cancer
Management of Psoriasis, Systemic Treatments
2.Oral retinoids (contd.):
Retinoids are considered excellent for use in combination with other treatments and
when used with UVB or PUVA, their dose and the number of phototherapy treatments
can be reduced, with the added benefit of a potential reduction in skin carcinogenesis
 This also will minimize the dose-related side effects of retinoids, such as dryness of
skin and conjunctiva, and pruritus
Systemic retinoid toxicity is similar to hypervitaminosis A; hence, mucocutaneous sideeffects (e.g., skin dryness, conjunctivitis, and hair loss) are common. Other side-effects
include hyperlipidaemia, osteoporosis and ligamentous calcifications
Contraindications
 Patients with severely impaired liver or kidney function
 Hyperlipidemia
 Pregnant females or those who intend to become pregnant
 Birth control must be continued for at least three years after the woman stops
taking acitretin because the drug stays in the body for a very long time and will
affect unborn babies
Management of Psoriasis, Systemic Treatments
3. Drugs affecting the immune response:
Systemic drugs acting on the immune system are generally used by
specialists in a hospital setting
 Examples:
a) Methotrexate
b) Cyclosporine
c) Mycophenolate mofetil
Management of Psoriasis,
Systemic Treatments, contd.
3. a) Methotrexate (MTX): It is an
antimetabolite. It is a folic acid analog and
the main folate antagonist
Methotrexate
Folic acid
 The uptake of MTX into the cell is mediated by
the reduced folate carrier (green) (1) and by an
endocytotic pathway activated by a folate
receptor (blue) (2)
 Once inside the cell, MTX is polyglutamylated by
the enzyme folylpolyglutamate synthase (3)
 Both MTX and its polyglutamates (Glu) are potent
inhibitors of dihydrofolate reductase, an enzyme
that converts dihydrofolate (FH2) to FH4 (4)
 The depletion of FH4, leads to an impairment of
both purine and thymidine synthesis, an inhibition
of DNA replication and cell death in rapidly
dividing tissues, including the hyperproliferative
psoriatic epidermis. MTX also stimulate apoptosis
and death of activated T lymphocytes
(immunosuppressive effect)
Management of Psoriasis, Systemic Treatments, MTX
Despite the advent of new therapies, MTX continues to play a central role as an
affordable, gold standard treatment for recalcitrant psoriasis and psoriatic arthritis
MTX is widely used for the treatment of rheumatoid arthritis and autoimmune
diseases, and it is one of the most widely used antimetabolites in cancer
chemotherapy
Dose: The cell cycle in psoriatic keratinocytes is rapid. Oral administration of MTX in
3 doses (usually 2.5 to 5 mg each) at 12-hour intervals, with the three doses given
once weekly, can inhibit the replication of these cells with minimal side effects
 When stability or adequate clearance is achieved, the lowest effective dose of MTX
should be sought by tapering the dose slowly by about 2·5 mg per month
 Administration can be by oral, intravenous, intramuscular, or subcutaneous routes
Contraindication & Side effects: The patient's hematologic status and
renal and liver function should be normal if methotrexate is to be given
Adequate renal function is necessary because 85% of the drug is
excreted through the kidneys, and patients with poor renal function
have sustained increases in plasma drug concentrations, leading to
acute side effects, including leukopenia and acute GI erosions
The chief long-term side effect of MTX therapy is cirrhosis; patients
with a history of liver disease or excessive alcohol intake and those
with abnormal liver function should not receive the drug
Management of Psoriasis, Systemic Treatments,
MTX, Contraindication & Side effects, contd.
Because of its teratogenicity, MTX is absolutely contraindicated during
pregnancy, and pregnancy should be avoided for at least 3 months
after discontinuing treatment with MTX. It is also contraindicated in
lactating mothers
Bone marrow suppression is the most common cause of MTX-related
death; hence, appropriate screening every 1–3 months is essential
MTX is contraindicated in pre-existing severe anemia, leukopenia,
thrombocytopenia
A number of drugs, including sulphonamides and their derivatives,
may potentiate the risk of bone marrow suppression
Like pregnancy, alcohol abuse is an absolute contraindication
It should not be also used in patients with immunodeficiency or active
infectious disease
Side effects include BM suppression, nausea, vomiting, stomatitis and
development of megaloblastic anemia (folate supplementation!)
 MTX-induced DHFR inhibition makes cells megaloblastic, as a consequence of the
impairment of DNA synthesis, whereas RNA and protein synthesis are less affected
 Folic Acid is effective in the treatment of megaloblastic anemias due to a deficiency
of folic acid resulting from MTX treatment & other causes
 MTX antagonizes both mammalian and microbial DHFR, whereas
diaminopyrimidines such as trimethoprim bind to the bacterial DHFR but not
mammalian DHFR
Management of Psoriasis, Systemic Treatments
3. b) Cyclosporine:
Cyclosporine is a potent immunosuppressant
It is a calcineurin Inhibitor (as discussed before) and results in inhibition of Tcell activation
Hypertension and renal dysfunction are the major adverse effects
3. c) Mycophenolate mofetil:
It is an antiproliferative immunosuppressant approved for prophylaxis of organ
rejection in patients with renal, cardiac and hepatic transplants
It inhibits the enzyme inosine monophosphatase dehydrogenase, thereby
depleting guanosine nucleotides essential for DNA and RNA synthesis
 Inosine monophosphate dehydrogenase is the rate-limiting enzyme in de
novo synthesis of guanosine nucleotides
 T- and B-lymphocytes are more dependent on this pathway than other cell
types are. This is the principal mechanism by which mycophenolate mofetil
exerts immunosuppressive effects
Management of Psoriasis, Systemic Treatments
4. Monoclonal antibodies:
Infliximab is a monoclonal antibody administered intravenously for treating
several chronic inflammatory diseases
Infliximab works by blocking the effects of tumor necrosis factor alpha (TNFalpha)
It is used for treating the inflammation due to psoriasis and psoriatic arthritis
Adalimumab is another TNF-alpha inhibitor
5. Phosphodiesterase (PDE) 4 inhibitors:
Apremilast is a new oral agent for the treatment of moderate severe plaque
psoriasis
MOA: It is a PDE4 inhibitor with TNF-α inhibitory activity. It reduces production
of multiple cytokines involved in the pathogenesis of psoriasis
 PDE4 is a key enzyme involved in modulating production of inflammatory
mediators by immune cells