Unit 6 Immune Suppressants

Front 1

Methotrexate uses

Back 1

Used in treatment of rheumatoid arthritis, asthma, Crohn’s disease and
multiple sclerosis, psoriasis

Front 2

Methotrexate mechanism

Back 2

Inhibits dihydrofolate reductase (DHFR), which converts DHF to
tetrahydrofolate
 Lack of tetrahydrofolate blocks purine synthesis and the conversion of
dUMP to dTMP, consequently DNA, RNA and protein synthesis are
inhibited
 Net Effect: Inhibition of cell proliferation (cancer cells, bone marrow,
B-cells, T-cells, etc.)
Other important facts
 Methotrexate is taken up into cells by the folate transporter
 Like folate, becomes polyglutamated, which increases potency
and traps the drug in the cell prolonging its duration of action,
 Effect of methotrexate can be reversed by “leucovorin rescue”

Front 3

LEUCOVORIN

Back 3

Administered 24 hr after high-dose methotrexate
 Taken up by reduced-folate transporter competes with methotrexate
 Converted to N5,N10 methylene-THF and bypasses need for dihydrofolate
reductase
 Allows DNA, RNA and protein synthesis at a slow rate
 Review: Potentiation of Fluorouracil Therapy
 dUMP + N5,N10 methylene-THF  dTMP
 FdUMP + leucovorin blocks thymidylate synthesis

Front 4

AZATHIOPRINE mechanism

Back 4

Prodrug converted to 6-mercaptopurine, which blocks DNA and
RNA synthesis

Front 5

AZATHIOPRINE important drug interaction

Back 5

Allopurinol blocks xanthine oxidase and allows accumulation of 6-
mercaptopurine – potentiates toxicity
 If allopurinol used, dose of azathioprine must be lowered

Front 6

AZATHIOPRINE uses

Back 6

Treatment of severe RA, IBD, lupus nephritis, Wegener’s
granulomatosis, as well as prevention of rejection of renal transplants

Front 7

LEFLUNOMIDE mechanism

Back 7

 Prodrug converted to active form in gut or liver
 Inhibits dihydro-orotate dehydrogenase an enzyme catalyzing a key
step in pyrimidine synthesis, thus blocks RNA and DNA synthesis.
 Has a long half-life (2 weeks) due to entero-hepatic
cycling.
Cholestyramine can be used to shorten half-life to 1
day.

Front 8

GOLD THERAPY OR “CHRYSOTHERAPY” THERAPY FOR RA.

Back 8

Due to toxicity, use is reserved for cases in which response to standard
therapies (NSAIDs, MTX) is inadequate.
 Auranofin: Oral administration
 Deacetylated in GI tract, only 25% absorbed
 Aurothioglucose: IM administration
 Water soluble, higher plasma levels obtained
MECHANISM
 Mechanism unknown - may inhibit macrophages?

Front 9

HYDROXYCHLOROQUINE

Back 9

Danger of irreversible retinal damage
USES
 Chronic discoid and systemic lupus erythematosus
 RA, if not responsive to other therapies

Front 10

MYCOPHENOLATE MOFETIL mechanism

Back 10

MECHANISM
 Reversible but non-competitive inhibition of IMP (inosine
monophosphate) dehydrogenase, the rate limiting step in GMP
synthesis.
 Blocks proliferation, adhesion and migration of T and B cells, and
antibody production by B cells

Front 11

MYCOPHENOLATE MOFETIL adverse effects

Back 11

ADVERSE EFFECTS –RELATIVELY FEW
 GI effects –diarrhea vomiting are the most common >10% patients
 Bone marrow toxicity is less than azathioprine
 Nephrotoxicity minimal (contrast cyclosporine)
 Pregnancy category D (need pregnancy test, reliable contraception)

Front 12

CORTICOSTEROIDS

Back 12

These drugs are important in
the short-term treatment of flare-ups of rheumatoid arthritis, but are not very useful for the
long-term treatment of RA and other chronic inflammatory diseases due to toxic side effects.
They also played a key role in making kidney transplants possible in the 1960’s.
Mycophenolate moiety
Immunosuppressants
7
Mechanism
 Switch on synthesis of I-B, and hence inhibit activation of NF-B
 Active corticosteroid receptors block action of NF-B
 Switch on synthesis of lipocortins which inhibit PLA2
 Inhibit proliferation of inflammatory cells

Front 13

ETANERCEPT

Back 13

Etanercept is a genetically engineered recombinant fusion protein that has the
soluble form of the TNF receptor (p75) attached to the Fc portion of human IgG1
and as a consequence forms dimers.

Front 14

INFLIXIMAB

Back 14

Infliximab is a genetically engineered chimeric (man-mouse) monoclonal
antibody against TNF. Binds soluble/free and membrane associated TNF. It is
also been approved for the treatment of Crohn’s disease and ulcerative colitis.

In RA, it is administered with methotrexate, which appears to limit the
generation of antibodies against infliximab that otherwise reduce the
benefits of subsequent treatments

Front 15

CYCLOSPORINE main uses

Back 15

 Prevent rejection in renal, liver and heart transplants
VERY IMPORTANT
 Autoimmune diseases RA, IBD, myasthenia gravis

Front 16

CYCLOSPORINE mechanism

Back 16

Mechanism of action of cyclosporine (CSA). T-cell becomes activated when an
antigen-presenting cell presents an antigen to the T-cell receptor. Signal transduction involves
an increase in cytosol Ca2+, which activates calcineurin (Cal), a phosphatase that
dephosphorylates NF-AT (nuclear factor of activated T-cells), which then enters the nucleus
and turns on synthesis of cytokines such as interleukin-2, which induces T-cell proliferation.
Cyclosporine binds to a cyclophilin (CP) and inhibits calcineurin, thus inhibiting T-cell
activation/proliferation.

Front 17

CYCLOSPORINE pharmacokinetics

Back 17

 Administration
 Due to insolubility in water, it is usually administered orally as
solution in an ethanol/corn oil/castor oil derivative mix in
capsules or diluted into orange or apple juice to produce a
“microemulsion”
 Variable absorption 20-50% -Neoral® > Sandimmune®
 1st pass metabolism significant - metabolized by CYP 3A4
 Many drug interactions
 Significant toxic effects
 IV: - only if oral administration not possible
 RESULT: Need to assay blood levels to establish appropriate dose

Front 18

CYCLOSPORINE toxicity

Back 18

 Nephrotoxicity most common and important (20-38% in allografts).
Difficult to distinguish from kidney rejection in kidney transplant
patients
Immunosuppressants
11
 Others
 hypertension
 hirsutism
 hypercholesterolemia
 Little effect on bone marrow

Front 19

CYCLOSPORINE drug interactions

Back 19

DRUG INTERACTIONS - IMPORTANT
 Drugs that inhibit cytochrome P450 3A4 may potentiate toxicity
 ketoconazole, itraconazole, (antifungals)
 erythromycin, clarithromycin, grapefruit juice, etc.
 Drugs that induce the P450 system may lead to organ rejection
 Phenobarbital - CNS depressant
 Carbamazepine - anticonvulsant
 Rifampin - antimicrobial
 Omeprazole - inhibits gastric acid secretion
 St. John’s Wort - dietary supplement - “antidepressant”
 Other nephrotoxic drugs
 e.g. amphotericin B, aminoglycosides, NSAIDs etc
 Cyclosporine can inhibit metabolism of drugs by blocking CYP 3A4
 E.g. lovastatin – increases risk of rhabdomyolysis

Front 20

TACROLIMUS

Back 20

Another hydrophobic cyclic compound produced by fungi that inhibits
calcineurin
 Properties very similar to cyclosporine, BUT has different receptor - “FK
binding protein” (FKBP25)
 Approved for heart, liver and kidney transplants

Front 21

SIROLIMUS

Back 21

Another hydrophobic cyclic compound, related to tacrolimus produced by
fungi, BUT different mechanism and little nephrotoxicity, hence it is used
synergistically with cyclosporine and prednisone.
 Not for liver transplant - hepatic artery thrombosis risk

Front 22

Retinoic effect on epithelial structures

Back 22

1. Retinoic acid promotes generation of goblet cells and mucus production
2. Retinoic acid inhibits keratinization of the epithelium.

Front 23

TRETINOIN

Back 23

 Topical application for treatment of acne
 In acne treatment, Retin-A® is comedolytic and inhibits keratinization
- promotes expulsion of open comedones
 Decreases cohesiveness of epithelial cells in follicle
 Decreases thickness of stratum corneum
 Other Effects – diminishes fine lines and wrinkles (Renova®)
 Promotes dermal collagen synthesis
 Promotes new blood vessel formation
 Promotes thickening of epidermis
 ADVERSE EFFECTS
 No systemic effects as only 10% is absorbed into circulation
 Increases susceptibility to sunburn, use sunscreen (15SPF) and
protective clothing
 Not usually prescribed to pregnant patients (see below)

Front 24

ISOTRETINOIN uses and mechanism

Back 24

 Systemic/oral therapy reserved for treatment of severe nodular
acne in patients who are unresponsive to conventional therapy,
including systemic antibiotics - very effective treatment
MECHANISM:
 Decreases sebum production
 Decreases sebaceous gland size
Immunosuppressants
18
 Decreases keratinization
 Decreases inflammation

Front 25

ISOTRETINOIN side effects

Back 25

SIDE EFFECTS
Similar to those of hypervitaminosis A
1) SIDE EFFECTS ON EPITHELIA
 Dryness of skin and mucous membranes - results in
 Dry itchy eyes, nose, mouth
 Nose bleeds Most common
 Inflammation of lips (cheilitis)
 Hair loss, peeling of skin from palms and soles
 Sensitivity to UV light, use protection against sun
 Inflammatory bowel disease
2) HYPERLIPIDEMIA – 25%
 Elevation of tri-glyceride levels
 Sometimes increase in cholesterol (LDL) and decrease in
HDLs - needs to be monitored
3) EFFECTS ON BONE FORMATION
 Long-term therapy- calcification of ligaments and tendons
 Decreased bone mineral density
 Pain in joints muscles
4) SUDDEN REDUCTION IN NIGHT VISION
 Seems paradoxical
5) PSEUDOTUMOR CEREBRI - RARE
 Benign cerebral hypertension, can be mistaken for a tumor
 Leads to edema of optic disk (papilledema), which can lead to
permanent blindness
 More likely if tetracycline co-administered
6) DEPRESSION - RARE, BUT…
 Depression and suicidal ideation may be associated with
retinoids. Since 1989, 12 patients have committed suicide
 Must be discussed with patient, so that any signs or symptoms
are reported to physician and therapy stopped

Front 26

ISOTRETINOIN big time contraindication

Back 26

CONTRAINDICATION: PREGNANCY
Isotretinoin is a pregnancy category X drug and should not be
taken during pregnancy. There is a very high risk of birth defects, e.g.
 Skull abnormalities
 External ear malformation
 Facial malformation
 Cleft palate
 CNS abnormalities
 CV abnormalities
IMPORTANT: To prevent birth defects isotretinoin must be prescribed under the iPLEDGE
program, which was introduced march 1, 2006 and replaced the S.M.A.R.T. program.

Front 27

ACITRETIN AND ETRETINATE - SYNTHETIC ANALOGS

Back 27

They are approved for systemic treatment of psoriasis.
Their side effects and contraindications are similar to isotretinoin.
 Acitretin (Soriatane®, 1996) is the active metabolite of etretinate (Tegison®,
1986-2003). Etretinate accumulates in adipose tissue and has a very long
half-life (120 days) compared with acitretin (49 hours). Because this
increases risk of birth defects etretinate has been removed from market
(2003).
 However, if ethanol is consumed by patients taking acitretin, etretinate is
synthesized, consequently, alcohol should be avoided during therapy up to 2
months after the last dose.
 Also, patients should not become pregnant for at least 3 years after the last
dose
LONG HALF LIVES

Front 28

TAZAROTENE

Back 28

It is a prodrug, which is hydrolyzed to produce a carboxylic acid – tazarotenic
acid – the active drug. It is used topically for the treatment of both acne and
psoriasis. First topical retinoid approved for psoriasis