IBD Pharmacology

Name 5-Aminosalicylic Acids

1. sulfasalazine (Azulifidine)

2. mesalamine (Asacol)

3. olsalazine (Dipentum)

4. balsalazide (Colazal)

What is the MOA of 5-Aminosalicylic Acids?

- Modulates inflammatory response from cyclooxygenase and lipooxygenase pathways decreasing the synthesis of prostaglandins and leukotrienes

- Interfere with production of inflammatory cytokines by reducing the activity of nuclear factor KB (NF-KB) and inhibition of tumor necrosis factor (TNF), cellular functions of mucosal lymphocytes, macrophages, and NK cells

- Act as a free radical scavenger and an antioxidant

What are some key side effects of 5-Aminosalicylic Acids?

- N/V

- HA

- Rash

- Anemia

- Pneumonitis

- Hepatotoxicity

- Nephritis

- Thrombocytopenia

- Lymphoma

What side effects are key for mesalamine?

N/V and HA

What are some important things to note regarding specific mesalamine products?

- Where the patients disease is occurring along their GI tract (different products can release the active drug in specific locations)

- Inter-patient variability in pH (affects product release)

Name 5 corticosteroids used for IBD

1. budesonide

2. budesonide MMX

3. Methylprednisolone

4. Hydrocortisone

5. Prednisone

What are the 2 dosage forms of budesonide (plus brand names)?

1. Enterocort = EC capsule 6-9 mg PO qd

2. Uceris = rectal foam 2 mg PR qd

What are 2 brand names and dosing for budesonide MMX?

- Cortiment tablet

- Uceris tablet

- 6-9 mg PO qd

What is the difference between budesonide and budesonide MMX?

- MMX = multi-matrix system

- MMX dissolves at higher pH

- MMX ulcerative colitis as it covers the entire colon

- Regular targets the ileum and right colon

- Regular more for ileocecal crohn's disease

Methylprednisolone dosing

40-60 mg IV q6-8h

Hydrocortisone dosing

100 mg IV q6-8h

Prednisone dosing

40-60 mg PO qd

What is the MOA of corticosteroids for IBD?

- Suppress acute inflammation when given parenterally, orally, or rectally

- Modulates immune system and inhibits production of cytokines and mediators

What are some common side effects with systemically acting steroids?

- Hyperglycemia

- Dyslipidemia

- Osteoporosis

- Hypertension

- Acne

- Edema

- Infection

- Myopathy

- Psychosis

Budesonide given PO in a controlled-release formulation is designed to...

release in the terminal ileum or the colon depending on the product, or as a rectal foam. It undergoes extensive first-pass metabolism so systemic exposure is minimized

Name 2 Thiopurines used for IBD

1. azathioprine (Imuran, Azasan)

2. mercaptopurine (Purinethol, Purixan)

What is the MOA of Thiopurines?

- Immunomodulator

- Following uptake by transporter molecules, 6-mercaptopurine (6-MP) is metabolized to 6-thioguanine nucleotides (6-TGNs), the active metabolites

- 6-TGNs incorporate into lymphocyte DNA inducing apoptosis of active T-cells as well as exerting direct cytotoxic effects at higher doses

- 6-TGTP inhibits activity of GTPase Rac1 resulting in suppression of T-cell dependent immune response

- Azathioprine is a purine analog that's converted to active metabolites 6-MP and 6-TGN

What are the 2 types of side effects of Thiopurines and what is included?

Type A (dose related): malaise, nausea, infection, hepatitis, myelosuppression

Type B (idiosyncratic): fever, rash, arthralgia, pancreatitis

Thiopurines take effect in about ________

6-8 weeks

What is an important pharmacogenomic consideration before giving a Thiopurine?

Thiopurines are catabolized to an inactive form by thiopurine methyltransferase (TPMT). Test for TPMT activity. Can also predict risk for side effects including bone marrow suppression and liver toxicity

Name a AICAR Transformylase Inhibitor

Methotrexate

What is the MOA of methotrexate?

- Immunomodulator

- Inhibits enzyme AICAR transformylase, leading to hindrance in adenosine and guanine metabolism

- Increased adenosine accumulation creates repression of T-cell activation, down-regulation of B-cells (increasing activated CD-95 T-cell sensitivity), repression of methyltransferase activity (inhibits binding of beta-1 interleukin to its cell surface receptor)

What are some key side effects for methotrexate?

- Bone marrow suppression

- Pancreatitis

- Pneumonitis

- Pulmonary fibrosis

- Hepatitis

Methotrexate is used in...

Crohn's disease

What is an important BBW for methotrexate?

Pregnancy category X - inhibits dihydrofolic acid reductase (DNA synthesis), leads to birth defects including microcephaly, craniosynostosis, limb abnormalities, etc.

What are 3 brand names for cyclosporine?

1. Gengraf

2. Neoral

3. Sandimmune

What is the MOA of cyclosporine?

- Immunomodulator

- Inhibits release of mitochondrial factors that stimulate the production of type 1 interferons by innate immune cells, results in altered T-cell responses and reduces inflammation in acute, severe disease

What are 2 key side effects of cyclosporine?

1. Nephrotoxicity

2. Neurotoxicity

When is cyclosporine used?

In an effort to avoid emergent colectomy in severe UC

Name 4 Anti-TNF-alpha biologics

1. infliximab

2. adalimumab

3. certolizumab (Cimzia)

4. golimemab (Simponi)

What is the MOA of infliximab?

- Anti-TNF-alpha biologic

- Monoclonal antibody (chimeric IgG1 kappa) with specific activity for human tumor necrosis factor alpha

- Binds with high affinity to TNK-a receptors neutralizing inflammatory effects

- Lyses activated T-cells and macrophages and induces T-cell apoptosis

What is the MOA of Adalimumab and Golimumab (Simponi)?

- Anti-TNF-alpha biologics

- IgG1 antibody to TNF-a, but is fully humanized

- Contains no murine sequences providing theoretical benefit for reduced risk of antibody formation against the drug

What is the MOA of Certolizumab (Cimzia)?

- Anti-TNF-alpha biologic

- A humanized pegylated FAB fragment directed against TNF-a

What are some key side effects for Anti-TNK-alpha biologics?

- Infection

- HF

- Optic neuritis

- Demyelination

- Injection site reaction

- Anti Drug antibody formation (decreased effectiveness and increased adverse reactions)

What is a side effect specific to infliximab?

Infusion reaction - anti drug antibody formation can increase risk of serious infusion-related reactions

What is key to check before starting an anti-TNF-a biologic?

PPD - no tuberculosis!

Name 2 selective adhesion-molecule inhibitors

1. natalizumab (Tysarbi)

2. vedolizumab (Entyvio) - preferred

What is the MOA of natalizumab (Tysarbi) and vedolizumab (Entyvio)?

- Inhibit leukocyte adhesion and migration by targeting the apha4 subunit of integrin

- Vedolizumab is more specific for the alpha-4-beta-7 subunit which targets leukocyte trafficking in the gut

What are some side effects for natalizumab (Tysarbi) and vedolizumab (Entyvio)?

- Infusion related reactions

- HA

- Fatigue

- UTIs

- depression

- arthralgia

- rash

- gastroenteritis

- vaginitis

What is a side effect specific to natalizumab (Tysarbi)?

- Opportunistic viral infection of the brain resulting from reactivation of the John Cunningham virus

- Leads to oligodendrocyte destruction and demyelination in the CNS

Name 4 Interleukin 12/23 and Interleukin 23 inhibitors

1. ustekinumab (Stelara)

2. ustekinumab-srlf (Imuldosa)

3. guselkumab (Tremfya)

4. mirikizumab-mrkz (Omvoh)

5. Risankizumab-rzaa (Skyrizi)

What are Interleukin 12/23 and Interleukin 23?

2 key cytokines responsible for promoting and perpetuating bowel inflammation in IBD

What is the MOA of ustekinumab (Stelara)?

Monoclonal IgG1 kappa antibody directed against the shared p40 subunit of IL12 and IL23 blocking their interaction with their receptors

What is the MOA of guselkumab (Tremfya)?

Monoclonal IgG1 lambda antibody that inhibits the p19 subunit of IL-23

What is the MOA of mirikizumab-mrkz (Omvoh)?

Humanized IgG4 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 and inhibits its reaction with its receptor

What is the MOA of risankizumab-rzaa (Skyrizi)?

Humanized IgG1 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 and inhibits its reaction with its receptor

Inhibiting IL-23 and/or IL-12 leads to...

the inhibition of downstream Th-17 signaling pathways and interferes with the triggering of inflammatory response

What are some side effects of IL23/12 inhibitors?

- Infections

- Skin cancers

- Elevated liver transaminases (rare, screen LFTs, bilirubin)

- Hypersensitivity

- Posterior reversible leukoencephalopathy syndrome (PRES) (rare, sudden onset of HA, vision disturbances, mental status changes, seizures, encephalopathy)

What is a key counseling point for IL23/12 inhibitors?

Avoid live vaccines, evaluate patient for Tb and complete all required vaccines PRIOR to initiation of therapy

Name 2 Janus Kinase Inhibitors

1. tofacitinib (Xeljanz, Xeljanx XR)

2. upadacitinib (Rinvoq)

What is the MOA of Janus Kinase Inhibitors?

- JAKs are intracellular enzymes that transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane

- Upon cytokine binding, JAKs form heterodimers with other JAKs than phosphorylate and activate signal transducers and activators of transcription (STATs), which modulate intracellular activity, including gene expression

- The JAK/STAT pathway is therefore an important mechanism by which many cytokines exert their effect on biological processes, including those involved in the pathogenesis of IBD

- Modulate signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs

What are some side effects of JAKs?

- Infection

- Thrombosis

- Lymphoma

- Elevated cholesterol

- CPK elevation

- Elevated LFTs

- Lymphopenia

- Neutropenia

- Anemia

What side effect has been reported with the use of XR JAKs?

GI perforation

What are some key counseling points for JAKs?

- Avoid live vaccines

- Screen for Tb and CBC abnormalities at baseline

- Drug interactions with CYP3A4 and 2C19 inhibitors

Name 2 S1P Receptor Modulators

1. etrasimod (Velsipity)

2. ozanimod (Zeposia)

What is the MOA of S1P Receptor Modulators?

- Bind with high affinity to S1P receptors on lymphocytes

- Partially and reversibly block the capacity of lymphocytes to egress (leave) from lymphoid organs

- Reduces the number of lymphocytes in the peripheral blood. Thought to result in improvement to symptoms because there is a reduction in the number of lymphocytes available to migrate into the intestines

Etrasimod binds to...

S1PR1, S1PR4, and S1PR5

Ozanimod binds to...

S1PR1 and S1PR5

What are some common side effects of S1P Receptor Modulators?

- HA

- Elevated LFTs

- Dizziness

- Risk of serious infections increased

- Bradyarrhythmia and AV conduction delays

- Macular Edema

- Skin Cancer

- Reduced pulmonary function

- Hypertension

- Posterior Reversible Encephalopathy Syndrome (PRES)

What kinds of infections can occur with S1P Receptor Modulators?

- Zoster

- Cryptococcal meningitis

- Progressive Multifocal Leukoencephalopathy (PML) (ozanimod)

- CHECK CBC

Due to the bradyarrhythmia and AV conduction delay risk, in which populations should S1P Receptor Modulators be avoided?

Recent MI, unstable angina, stroke, TIA, HF (hospitalization, Class III/IV), and those with AV conduction issues without presence of pacemaker

Which foods should be avoided when taking Ozanimod?

High tyramine containing foods (cured/smoked/processed meats, sauerkraut, pickled foods, soy sauce)

What is an important vaccine counseling point for S1P Receptor Modulators?

Give any needed live vaccines a month prior to initiating therapy