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OACNS Pharmacology

ConferenceManaging the Patient on Immunosuppressive Therapy

Melissa Craft, PhD APRN CNS AOCN

April 13, 2019

Definition of Immunosuppression: It’s all

about the t-cell.

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Immunosuppressive therapy

• Using drugs that inhibit or depress activity of the immune system; specifically t-lymphocytes.

• Indications for use:

• Graft rejection

• Autoimmune disorders

• Rh incompatibility

• Non-autoimmune inflammatory disease such as asthma

• Shared side effect with all immunosuppressive drugs is increased risk of infection. Because…. It’s all about the t-lymphocyte

Does this impact your practice?

• Do you work with patients who have received an organ or allogeneic stem cell transplant?

• Do you work with patients who have autoimmune disorders?

Name some autoimmune disorders

• Do you have any patients who might have Rh incompatibility?

• Do you have any patients who have non autoimmune inflammatory disorders?

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Medication

Class Mechanism

of Action

Indications/

Contraindications

Dosage Side Effects Prescribing

Pearls

Cyclosporin

Tacrolimus

Calcineurin

inhibitor (CNI)

Blocks

transcription

of IL-2

which

suppresses

T-cell

activation

Clinical

immunosuppressio

n

Variable

based on

indication

.

Transplan

t doses

are

dependent

on type of

transplant

and are

specific to

the

institution

.

Tremors, seizures,

posterior reversible

encephalopathy

syndrome,

hypertension,

hyperkalemia,

hypercholesterolemi

a, and

gastrointestinal

dysfunction

including diarrhea,

gingival hyperplasia,

hirsutism (less with

Tacrolimus) chronic

nephrotoxicity, new

onset diabetes

mellitus, alopecia

Drug interactions

with azoles and

drugs that

metabolize

cytochrome P450

3A4enzyme.

Tacrolimus is

similar to

cyclosporine in

efficacy but is

more potent so

lower doses are

required.

Sirolimus

Everolimus

mTOR

inhibitors

Blocks t-cell

proliferation

Used in place of

CNIs; mostly in

patients further out

from transplant;

less nephrotoxicity

but may have

higher risk of

rejection.

Variable

based on

indication

.

Impaired wound

healing after

transplant,

pneumonitis,

hyperlipidemia, new

onset diabetes

mellitus. Allergic

reaction, anemia,

diarrhea, nausea.

Metabolized by

CYP2A4 so

drugs such as

azoles increase

blood

concentration.

Inducers of

CYP3A4

decrease blood

levels.

Everolimus

usually

administered with

cyclosporine so

Fingolimod Sphingosine-1-

Phospate

Receptor (S1P-

R) Modulators

Inhibits

recirculation of

lymphocytes into

graft site and

peripheral

inflammation is

inhibited

First oral drug

approved for

multiple sclerosis

0.5mg once

daily

Symptomatic

bradycardia with

initial doses,

headache, diarrhea,

nausea

EKG is needed

before starting

drug and during

treatment

Belatacept

Abatacept

Inhibitors or

costimulatory

molecules of

T-cell

activation

Drugs generated

by recombinant

DNA

technology;

prevents

activation of

helper T-cells

Used in

combination with

basiliximab

induction,

mycophenolate

mofetil, and

corticosteroids

Used to treat

rheumatoid

arthritis

10 mg/kg

Dosing

according to

body

weight:

<60 kg: 500

mg

60-100 kg:

750mg

>100 kg:

1,000 mg

Increased risk for

posttransplant

lymphoproliferative

disorder (PTLD),

CMV infection,

progressive

multifocal

leukoencephalopathy

(PML).

Fatigue, sore throat,

dry cough, trouble

breathing, skin

irritation.

Dosing is based

on actual body

weight at time

of transplant.

Do not modify

dose unless

weight changes

by >10%.

Do not use in

combination

with other

drugs targeting

TNF-α.

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Mycophenolate

mofetil

Azathioprine

Methotrexate

Cytotoxic

Agents

Blocks the

production of

quanosine

nucleotides

required for

DNA synthesis

for B and T

lymphocytes.

Blocks cell

proliferation by

inhibiting

purine

synthesis.

Used for tissue

transplantation

in combination

with CNI or

sirolimus plus

glucocorticoids.

Prevent rejection

after

transplantation;

rheumatoid

arthritis.

Autoimmune

disorders

Variable

based on

indication

Variable

Diarrhea,

abdominal pain,

cough, edema,

drug-induced

fever, anemia.

Myelosuppression,

cancer, alopecia,

hepatotoxicity

Administering

with antacids

reduces

absorption.

Prophylactic agent

and is not used for

acute or chronic

rejection.

Myelosuppression

Risk is greater

when given with

angiotensin-

converting

enzyme inhibitors

or other drugs that

cause

myelosuppression.

Cortisone

Methylprednisolone

Glucocorticoids Inhibit acquired

or cell-

mediated

immunity.

Prevent rejection

after

transplantation;

prevent GVHD

Variable

based on

indication.

Hyperglycemia,

increased risk of

infection, ulcers,

GI bleeding,

muscle weakness

Discontinuation of

therapy requires

gradual reduction

of dose.

Anti-thymocyte

and Anti-

thymocyte

globulin

Polyclonal

Antibodies

Inhibit

lymphocyte

Prevent

rejection; treat

rejection; treat

aplastic anemia

1.5

mg/kg/day

Fever, chills, serum

sickness, increased

risk of infection,

cancer

Due to

increased risk of

infection and

risk of cancer

may not be used

as much as other

agents.

Rho (D)

immune

globulin

IgG

immunoglobulins

High Rh (D)-

specific titers

thus preventing

response in Rh-

mothers with

Rh+ fetus

Prevention of Rh

hemolytic

disease of the

newborn

Discomfort at

injection site, fever,

rarely anaphylactic

shock

Administered

IM with 3-4

week half-life

Muromonab

CD-3

Daclizumab

Basiliximab

Ustekinumab

Secukinumab

Infliximab

Adalimumab

Monoclonal

antibodies

Site-specific

interference

with specific

binding sites

involved with

immune cell

interactions,

signaling

mechanisms

and T-cell

proliferation

Prevent rejection

Treat psoriasis

Rheumatoid

arthritis, Crohn’s

disease,

psoriasis,

ulcerative colitis

Variable

45 mg sq

Variable

Cytokine release

syndrome

Increased risk of

infection

Flu-like syndrome,

increased risk of

infection, increased

risk of cancer

Cytokine release

syndrome, infection,

increased risk of

cancer

Contraindicated

in areas where

TB is high

Injection site

reaction with

Adalimumab

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Common major SEs

• Nephrotoxicity:• Dose limiting toxicity for CNIs

• Can be reduced by delaying use of CNIs immediately after transplant by using induction regimen with other less nephrotoxic agents

• Related to dose

• Maintain hydration and avoid use of other nephrotoxic agents

• Monitor patient for acute and chronic renal failure

• Neurotoxicity• Another dose limiting effect of CNIs

• Similar to nephrotoxic effect: is dose related

• Neurologic effects range from mild headache to seizure

Cardiovascular effects

Several of the drugs used for immunosuppressive therapy increase the risk for cardiovascular disease. This is due to an increased risk of:

• Hyperlipidemia

• Hyperglycemia

• Hypertension

• Monitor patients at risk and intervene as necessary.

• Encourage healthy lifestyle choices

• Note: Cyclosporin may increase statin concentration and toxicity such as myopathy. For this reason, start patients slow and on the lowest dose possible while monitoring them for toxicity.

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Infection due to immunosuppression

• Early post-transplant management of infection risk is focused on prophylaxis of opportunistic infections.

• Risk increases with degree of immunosuppression.

• Organisms such as Pneumocystis jirovecii, nocardia, aspergillus, and Cryptococcus.

• Reactivation of varicella zoster, herpes simplex, cytomegalovirus, hepatitis B and C as well as tuberculosis

• Do a careful history and physical prior to transplant and critically consider transplanting a patient with active infections

Infection Risk

Nosocomial or community acquired

• Bacterial

• Viral

• Parasitic

• Fungal infections

• Donor derived infections: examples include HIV, West-Nile virus, rabies, Chagas disease, and lymphocytic choriomeningitis virus

Use of vaccines in immunosuppressed

patients

• influenza vaccine each year, the Tdap vaccine and Pneumococcal vaccine for adults with a weakened immune system.

• See https://www.cdc.gov/vaccines/schedules for updated information.

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Cytokine Release Syndrome

• More common with biological agents such as monoclonal antibodies.

• Characterized by fever, hypotension, hypertension, tachycardia, dyspnea, urticaria and rash.

• Worse effects are noted with a higher rate of infusion.

• Risk and severity of the reaction is lowered through premedicatingwith acetaminophen, diphenhydramine and corticosteroids.

• It’s all about the t-lymphocytes…

Cancer

• Due to long term use of immunosuppressants, the immune system has a weakened defense against neoplastic processes.

• Cancers most commonly associated with chronic immunosuppression include skin cancer and lymphoproliferative disease.

• Routine skin examination is indicated for these patients.

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Managing patients on immunosuppressive

therapy

• Most important first step is to recognize that most providers have multiple patients on immunosuppressive agents

• Monitor patients for specific side effects related to the class of drug they are on

• Educate patients to know and report symptoms related to worsening complications

• Educate patients on healthy lifestyle choices including vaccination

• Recognize the balance on morbidity, mortality and QoL by effective use and management of immunosuppressive therapy.

Its all about the t-lymphocytes…

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Questions?

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