Case 1 Pharmacology Table, FIRST SET

prednisone MOA: (2)

INHIBITORS OF GENE EXPRESSION

Mechanism—Inhibit COX-2 expression;

induce lipocortins and activate endogenous anti-inflammatory pathways,

GLUCOCORTICOID RECEPTOR AGONISTS

Mechanism—Mimic cortisol function by acting as agonists at the glucocorticoid receptor

prednisone uses (2)

- inflammatory conditions in many different organs

- autoimmune diseases

prednisone contraindications: (2)

- Hypersensitivity to drug

- Systemic fungal infection

prednisone side effects:

Cushing's syndrome, pulmonary toxicity, increased risk of infection (shared adverse effects);

impaired wound healing, psychotic disorder (prednisone, prednisolone, methylprednisolone, dexamethasone, hydrocortisone, and triamcinolone only);

cardiotoxicity, seizure, muscle atrophy (prednisone, prednisolone, methylprednisolone, dexamethasone, and hydrocortisone only);

decreased body growth (prednisone, methylprednisolone, dexamethasone, flunisolide, and triamcinolone only);

electrolyte imbalance (prednisone and methylprednisolone only); thromboembolic disorder, aseptic necrosis of bone (prednisone only) Hypertension, edema, weight gain, osteoporosis, mood disturbance, headache

prednisone notes: how does it act, why taper doses, what form reduces systemic adverse effects, intrinsic activity of a glucocorticoid, which have longest duration of action?

Pharmacologic glucocorticoid therapy does not correct the underlying disease etiology but rather limits the effects of inflammation.

Chronic glucocorticoid treatment should be tapered slowly; abrupt withdrawal of systemic glucocorticoids can lead to acute adrenal insufficiency.

Intranasal and inhaled formulations greatly reduce systemic adverse effects; do not switch abruptly from high-dose oral to inhaled glucocorticoids.

The intrinsic activity of a glucocorticoid is especially important for topically administered drugs because the skin does not possess appreciable amounts of 11β-HSD 1.

Glucocorticoid agents with higher anti-inflammatory potency typically have a longer duration of action.

mycophenolate mofetil: MOA (1)

inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the formation of guanosine

mycophenolate mofetil: uses

solid organ transplantation

mycophenolate mofetil: contraindications

Hypersensitivity to mycophenolate mofetil

mycophenolate mofetil: side effects

Gastrointestinal hemorrhage, leukopenia, myelosuppression, neutropenia, increased risk of infection or lymphoma, leukoencephalopathy, pleural effusion, pulmonary fibrosis Hypertension, edema, hypercholesterolemia, electrolyte imbalance, gastrointestinal disturbance, headache, anxiety, asthenia, paresthesia

mycophenolate mofetil: note (1)

Avoid concurrent administration of oral iron because it markedly reduces the bioavailability of mycophenolate mofetil.

leflunomide: MOA

inhibits dihydroorotate dehydrogenase (DHOD), leading to inhibition of pyrimidine synthesis

leflunomide: use

rheumatoid arthritis

leflunomide: contraindications (2)

- hypersensitivity to leflunomide

- pregnancy

leflunomide: side effects:

Stevens-Johnson syndrome, toxic epidermal necrolysis, pancytopenia, hepatotoxicity, interstitial lung disease Alopecia, diarrhea, rash, mouth ulcer, dizziness, headache, infection

leflunomide: notes (2) why is there a prolonged pharmacologic effect, what does it hae antiviral activity against?

Leflunomide undergoes significant enterohepatic circulation, resulting in a prolonged pharmacologic effect.

Leflunomide has antiviral activity against cytomegalovirus (CMV) and can be used to treat resistant CMV and CMV in transplant patients.

azathioprine: MOA (1)

INHIBITORS OF PURINE METABOLISM:

Mechanism—Drug metabolites inhibit IMPDH and other synthetic enzymes, thereby interfering with AMP and GMP synthesis

azathioprine: uses (2)

- immunosuppression in renal transplantation

- Rhematoid arthritis

azathioprine: contraindications (3)

- pregnancy

- hypersensitivty to azathioprine

- rheumatoid arthritis with prior treatment with alkylating agents

azathioprine: side effects

Pancreatitis, myelosuppression, hepatotoxicity, increased risk of infection or malignancy, pericarditis, leukoencephalopathy, Gastrointestinal upset

azathioprine: notes (3), effectiveness/toxicity..., less tox than...., used for...

Effectiveness and toxicity increased by allopurinol.

Azathioprine is a less toxic prodrug of 6-mercaptopurine.

Azathioprine is used for immunosuppression of autoimmune diseases.

cyclosproine: MOA(1)

SPECIFIC LYMPHOCYTE-SIGNALING INHIBITORS:

Cyclosporine binds to cyclophilin, and the resulting complex inhibits the phosphatase activity of calcineurin, a cell-signaling protein that mediates T-cell activation. Cyclosporine inhibits the production of IL-2 by activated T cells.

cyclosporine: uses (2)

- solid organ transplantation

- Keratoconjunctivitis sicca (topical cyclosporine)

cyclosporine: contraindications (10)

Hypersensitivity to cyclosporine,

Abnormal renal function,

Uncontrolled hypertension,

Malignancies (rheumatoid arthritis and psoriasis patients), Concomitant PUVA or UVB therapy,

methotrexate,

immunosuppressive agents,

coal tar,

radiation therapy (psoriasis patients),

Active ocular infection (topical cyclosporine)

cyclosporine: side effects (many)

Hyperkalemia, hypomagnesemia, nephrotoxicity, neurotoxicity, hepatotoxicity, Hypertension, gingival hyperplasia, hirsutism, headache, tremor, eye irritation, infection

cyclosporine: notes (2)

- Danazol and other androgens can increase serum cyclosporine level

- Rifampin and St. John's wort decrease serum cyclosporine level

tacrolimus: MOA (1)

SPECIFIC LYMPHOCYTE-SIGNALING INHIBITORS: Tacrolimus binds to FK-binding protein (FKBP), and the tacrolimus-FKBP complex inhibits calcineurin.

tacrolimus: uses (2)

- Organ transplantation

- Atopic dermatitis (topical tacrolimus)

tacrolimus: contraindications (2)

- Hypersensitivity to tacrolimus

- Hypersensitivity to hydrogenated castor oil (IV formulation)

tacrolimus: side effects (many)

Prolonged QT interval, atrial fibrillation, heart failure, diabetes mellitus, hyperkalemia, hypomagnesemia, gastrointestinal perforation, hepatotoxicity, neurotoxicity, nephrotoxicity, acute respiratory distress syndrome, increased risk of lymphoma or infection. Edema, alopecia, rash, gastrointestinal upset, anemia, leukocytosis, thrombocytopenia, headache, insomnia, paresthesia, tremor

tacrolimus: notes (2)

- Topical tacrolimus is used widely to treat atopic dermatitis and other eczematous dermatitis.

- Rifampin and St. John's wort markedly decrease serum tacrolimus level.

etanercept: MOA (1)

TUMOR NECROSIS FACTOR INHIBITOR,

Mechanism—Etanercept is a soluble TNF receptor dimer

etanercept: uses (5)

Rheumatoid arthritis

Juvenile idiopathic arthritis

Plaque psoriasis

Psoriatic arthritis

Ankylosing spondylitis

etanercept: contraindications (1)

sepsis

etanercept: side effects (many)

Heart failure, myelosuppression, necrotizing fasciitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatotoxicity, optic neuritis, reactivation of tuberculosis, increased risk of infection or malignancy, demyelinating disease of central nervous system. Injection site reaction, upper respiratory infection, rhinitis

etanercept: notes (2) TB, any pt developing an infection while taking a...

All patients should undergo screening for tuberculosis before initiating therapy with a TNF inhibitor because of a greatly increased risk of reactivating latent tuberculosis.

Any patient developing an infection while taking a TNF inhibitor should undergo evaluation and aggressive antibiotic treatment.

infliximab: MOA (1)

TUMOR NECROSIS FACTOR INHIBITOR,

infliximab are anti-TNF antibodies

infliximab: uses (6)

- rheumatoid arthritis

- ankylosing spondylitis

- psoriatic arthritis

- Crohn's disease

- Ulcerative colitis

- Plaque psoriasis

infliximab: contraindications (2)

- Hypersensitivity to infliximab

- Moderate to severe heart failure (infliximab doses >5 mg/kg)

infliximab: side effects (similar to..., and 1 other)

additionally, GI upset

similar to etanercept:

Heart failure, myelosuppression, necrotizing fasciitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatotoxicity, optic neuritis, reactivation of tuberculosis, increased risk of infection or malignancy, demyelinating disease of central nervous system. Injection site reaction, upper respiratory infection, rhinitis

infliximab: notes (1)

infliximab is a partially humanized mouse antibody against human TNF-a

anakinra: MOA

INTERLEUKIN-1 INHIBITORS,

Mechanism—Anakinra is a recombinant IL-1 receptor antagonist

anakinra: uses (3)

Rheumatoid arthritis

Cryopyrin-associated periodic syndromes, including neonatal-onset multisystem inflammatory disease

anakinra: contraindications (1)

hypersensitivity to anakinra or E.coli-derived proteins

anakinra: side effects (4)

- Cardiorespiratory arrest

- neutropenia

- increased risk of infection or malignancy

- Injection site reaction

anakinra: notes (2) .. reduces .... avoid administration of....

- Reduces bony erosions, possibly by decreasing metalloproteinase release from synovial cells.

- Avoid administration of live vaccines.

rituximab: MOA

DEPLETION OF SPECIFIC IMMUNE CELLS;

Rituximab is a partially humanized anti-CD20 antibody

rituximab: uses (4ish)

Chronic lymphocytic leukemia,

B-cell non-Hodgkin's lymphoma,

Rheumatoid arthritis,

Granulomatosis with polyangiitis and microscopic polyangiitis

rituximab: contraindications

none

rituximab: side effects (many)

Anemia, significant immunosuppression, leukoencephalopathy, tumor lysis syndrome, bowel obstruction, hepatitis, infusion reaction, cardiac arrhythmia, heart failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, keratitis, nephrotoxicity, pulmonary fibrosis, angioedema. Rash, fever, fatigue, gastrointestinal upset, hypotension, night sweats, arthralgia, myalgia, shivering.

rituximab: notes (1)

avoid administration of live vaccines

belimumab: MOA (1)

DEPLETION OF SPECIFIC IMMUNE CELLS;

Fully human monoclonal antibody that inhibits B lymphocyte stimulator (BLyS), a factor that is required for the survival of B cells.

belimumab: use (1)

systemic lupus erythematosus

Belimumab: contraindications (1)

previous anaphylaxis to belimumab

belimumab: side effects (7)

Susceptibility to infection or malignancy,

infusion reaction,

leukoencephalopathy,

depression,

Gastrointestinal upset,

nasopharyngitis,

fever

abatacept: MOA (1)

INHIBITION OF COSTIMULATION:

Mechanism—Abatacept is a CTLA-4 analogue fused to an IgG1 constant region. By forming a complex with cell surface B7 molecules, the drugs prevent delivery of a costimulatory signal and the T cell develops anergy or undergoes apoptosis.

abatacept: uses (2)

- Rheumatoid arthritis

- juvenile idiopathic arthritis

abatacept: contraindications

none

abatacept: side effects (many)

Cellulitis, sepsis, pyelonephritis, pneumonia, acute exacerbation of chronic obstructive lung disease, susceptibility to malignancy Nausea, headache, urinary tract infection, nasopharyngitis, upper respiratory infection

abatacept: notes (3)

- Abatacept should not be administered concurrently with TNF inhibitors due to increased risk of serious infection.

- Avoid administration of live vaccines.

- All patients should undergo screening for tuberculosis before initiating therapy

natalizumab: MOA (1)

BLOCKADE OF CELL ADHESION:

Mechanism—Natalizumab is a monoclonal antibody against alpha-4 integrin that inhibits immune cell interaction with cells expressing VCAM-1 and MAdCAM-1

natalizumab: uses (3)

Multiple sclerosis, relapsing forms, Crohn's disease

natalizumab: contraindications (2)

- Hypersensitivity to natalizumab,

- History of progressive multifocal leukoencephalopathy (PML) or existing PML

natalizumab: side effects: (many)

Progressive multifocal leukoencephalopathy, bowel obstruction, hepatotoxicity, herpes encephalitis and meningitis, depression, suicidal ideation, pneumonia; Rash, gastrointestinal upset, arthralgia, headache, urinary tract infection, respiratory tract infection, fatigue

natalizumab: notes (1)

infusion-related rxns may occur

eculizumab: MOA (1)

INHIBITOR OF COMPLEMENT ACTIVATION:

Mechanism—Humanized monoclonal antibody against C5, a complement protein that mediates late steps in complement activation and assembly of the membrane attack complex

eculizumab: uses (2)

- Paroxysmal nocturnal hemoglobinuria (PNH)

- atypical hemolytic uremic syndrome (aHUS)

eculizumab: contraindications (3)

- Hypersensitivity to eculizumab,

- Neisseria meningitidis infection,

- No vaccination against N. meningitidis

eculizumab: side effects (many)

Infections, leukopenia, anemia; Hypertension, gastrointestinal upset, headache, insomnia, nasopharyngitis, fever

eculizumab: notes (2) pts need to be monitored for....

All patients who discontinue eculizumab need to be monitored for signs and symptoms of intravascular hemolysis, including evaluation of serum lactate dehydrogenase levels.

Ipilimunab: MOA (1)

INHIBITION OF IMMUNE CHECKPOINTS:

Mechanism—Ipilimumab is a humanized monoclonal antibody against CTLA-4. By inhibiting the interaction of CTLA-4 with their ligands B7-1/B7-2, the drugs release checkpoint pathway-mediated inhibition of the anti-tumor immune response.

Ipilimunab: uses (1)

unresectable or metastatic melanoma

Ipilimunab: contraindications

none

Ipilimunab: side effects (many)

Pericarditis, endocrine disorder, enterocolitis, eosinophilia, anemia, hepatotoxicity, myositis, encephalitis, neuropathy, renal failure, iritis, uveitis, pneumonitis; Rash, diarrhea, fatigue

Ipilimunab: notes (1)

Administered intravenously every 3 weeks for a total of four doses.