Pharmacodynamics of Immunosuppressive Agents
Session 14: Pharmacodynamics of Immunosuppressive Agents
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe mechanism of action of Immunosuppressive agents
Describe drug interactions associated with Immunosuppressive agents
Describe side effects of Immunosuppressive agents
Describe contraindications of Immunosuppressive agents
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and projector
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning Tasks
Introduction, Learning Tasks
2
2
45 minutes
45 minutes
Presentation/
Mechanism of Action of Immunosuppressive
Mechanism of Action of Immunosuppressive
2
2
45 minutes
45 minutes
Buzzing
Agents
Agents
Buzzing
Agents
Agents
3
3
20 minutes
20 minutes
Presentation/
Drug Interactions Associated With
Drug Interactions Associated With
3
3
20 minutes
20 minutes
brainstorming
Immunosuppressive Agents
Immunosuppressive Agents
brainstorming
Immunosuppressive Agents
Immunosuppressive Agents
4
4
20 minutes
20 minutes
Presentation
Side Effects of Immunosuppressive Agents
Side Effects of Immunosuppressive Agents
5
5
20 minutes
20 minutes
Presentation/
Contraindications of Immunosuppressive
Contraindications of Immunosuppressive
5
5
20 minutes
20 minutes
Brainstorming
Agents
Agents
Brainstorming
Agents
Agents
6
6
05 minutes
05 minutes
Presentation
Key Points
Key Points
7
7
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 114 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Mechanism of Action of Immunosuppressive Agents (45 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
How do Immunosuppressive Agents produce their pharmacological effects?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
Calcineurin inhibitors
Ciclosporin
o It inhibits the production of interleukin-2 (IL-2) and other cytokines by activated lymphocytes through its binding to a cytosolic protein cyclophilin. This conjugate subsequently interacts with a Ca2+–calmodulin dependent Calcineurin complex and inhibits its phosphorylase activity.
o This impairs access to the nucleus of the cytosolic component of the transcription promoter nuclear factor of activated T cells (NF-ATc), which in turn reduces the transcription of messenger RNA for IL-2, other pro-inflammatory lymphokines and IL-2 receptors.
Tacrolimus
o Tacrolimus (FK506) is another calcineurin inhibitor with the same mechanism of action to ciclosporin.
o It is more potent than ciclosporin and often used in patients who are refractory to ciclosporin.
PST 05104 Pharmacology & Therapeutics 115 NTA Level 5 Semester 1 Facilitator Guide
Target of Rapamycin (mTOR) Inhibitors
Sirolimus,
o mTOR (mammalian target of rapamycin) is a serine-threonine protein kinase activated by several growth factors after receptor binding.
o Sirolimus binds a protein called FKBP 12 (FKBP stands for FK506 binding protein) in the cytoplasm. The drug-protein complex then binds and inhibits mTOR.
o Inhibition of mTOR blocks cell-cycle progression at the G1 → S phase transition.
o mTOR regulates important functions of the cell, including proliferation, angiogenesis (blood vessel formation), cell survival, protein synthesis, and transcription. It is recognized as a key point in many cellular functions.
Glucocorticosteroids
Prednisolone and others
o inhibits expression of pro-inflammatory cytokines IL-2, 3 and 6, TNF, GM-CSF and IFN-γ;
o inhibits production of adhesion molecules – ICAM-1,E-selectin and vascortin – leading to reduced vascular permeability
o reduces synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes) and reduces histamine release
Anti-Proliferative Immunosuppressants
Azathioprine
o Azathioprine is a prodrug and is converted to 6-mercaptopurine (6-MP) by the liver.
Mycophenolate Mofetil
o In vivo the active entity, mycophenolic acid, inhibits inosine monophosphate dehydrogenase (a pivotal enzyme in purine synthesis). Hence, it suppresses proliferation both of T and B lymphocytes.
o In addition, mycophenolic acid inhibits the production of pro-inflammatory cytokines.
Monoclonal Antibodies
Anti-CD3 Antibody (Muromonab-CD3)
o Anti-CD3 antibodies bind CD3 protein, blocking antigen binding to the T-cell antigen–recognition complex, and decreasing the number of circulating CD3-positive lymphocytes.
o In addition, binding of anti-CD3 to its receptor causes cytokine release. The overall effect is to reduce T-cell activation in acute solid-organ graft rejection.
Polyclonal Antibodies
Antilymphocyte Globulin
The major effect is probably to prevent antigen from accessing the antigen-recognition site on the T-helper cells.
PST 05104 Pharmacology & Therapeutics 116 NTA Level 5 Semester 1 Facilitator Guide
STEP 3: Drug Interactions Associated with Immunosuppressive Agents (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are drug interactions associated with Immunosuppressive agents?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Calcineurin inhibitors
Ciclosporin
o These include allopurinol, cimetidine, ketoconazole (and other azoles), erythromycin, diltiazem (and other calcium channel blockers), anabolic steroids, norethisterone and other inhibitors of cytochrome P450 3A4, which reduce the hepatic clearance of ciclosporin leading to increased toxicity.
o Phenytoin and rifampicin increase hepatic clearance, thus reducing plasma concentrations.
o Concomitant use of nephrotoxic agents such as aminoglycosides, vancomycin and amphotericin increases nephrotoxicity.
o Concomitant use of ACE inhibitors increases the risk of hyperkalaemia.
Tacrolimus
o The drug–drug interaction profile of tacrolimus is similar to that of ciclosporin, but it may cause more neurotoxicity and nephrotoxicity.
Target of Rapamycin (mTOR) Inhibitors
Sirolimus
o Although sirolimus is not nephrotoxic alone, coadministration with a calcineurin inhibitor (another drug used for renal transplants) results in greater kidney damage than with a calcineurin inhibitor alone. Therefore there is some interaction with calcineurin inhibitors that potentiates the renal damage induced by the calcineurin inhibitor, and the two drugs should not be coadministered.
Glucocorticosteroids
Prednisolone and others
o Details are found on pharmacodynamics of drugs acting on respiratory system .
PST 05104 Pharmacology & Therapeutics 117 NTA Level 5 Semester 1 Facilitator Guide
STEP 4: Side Effects of Immunosuppressive Agents (20 minutes)
Calcineurin inhibitors
Ciclosporine and others
o Increased risk of infections, especially opportunistic infections Fungal, Viral: Epstein-Barr virus (EBV), cytomegalovirus (CMV), Atypical bacterial: Nocardia, Listeria, mycobacterial
o Increased risk of neoplasm: Cancer is often detected and eradicated by the immune system in its very early stages.
o Nephrotoxicity: Kidney damage is a common problem with administration of cyclosporine. This is the most important side effect. It is possibly mediated through renal arteriolar vasoconstriction. Renal damage often limits administration of cyclosporine.
o Hypertension: The exact mechanism is unknown, but cyclosporine has been shown to increase sympathetic nervous system activity, which would result in increased blood pressure.
o CNS problems: Tremors and headaches may occur, usually seen with larger doses.
o Tacrolimus only: Hyperglycemia (diabetes) may occur as a result of pancreatic beta cell inhibition.
o Cyclosporine Only: Hirsutism or hypertrichosis (hair growth): a cosmetic problem and Gum hyperplasia
o Tacrolimus Only: Alopecia (paradoxically, the opposite of hypertrichosis)
Glucocorticosteroids
Prednisolone and others
o Details are found on pharmacodynamics of drugs acting on respiratory system
Antimetabolites
Methotrexate and others
o Details are found on pharmacodynamics of anticancer drugs
Tumor Necrosis Factor (TNF)–α Inhibitors
Infliximab, adalimumab, certolizumab o Injection site irritation
o Acute inflammatory reaction: Because of the ability of TNF to influence the immune system, extensive inflammatory reactions can occur within 24 hours (usually within 6 hours) after administration.
o They are characterized by fever, hypotension, tachycardia, itching, chest pain, and shortness of breath. These reactions are relatively common (10% of the time), but only rarely are they severe enough to discontinue treatment.
o Delayed inflammatory reaction: Signs and symptoms that occur within 2 weeks after the injection are probably mediated by antibodies to the drug. Symptoms of these
PST 05104 Pharmacology & Therapeutics 118 NTA Level 5 Semester 1 Facilitator Guide
reactions include fever, rash, urticaria (itching), myalgia (muscle pain), arthralgia (joint pain), jaw tightness, and edema.
o Infection: Because of the immune suppression, common bacterial and also opportunistic infections are more common in patients receiving TNF suppression:
Bacterial sepsis (widespread inflammatory response caused by bacterial infection in
the blood)
Fungal infections
Latent TB (previous TB can be reactivated); patients must be screened for previous TB infections before starting anti-TNF therapy
Herpes zoster
Severe but rare side effects include heart failure, liver failure, and demyelinating
disorders of the central nervous system (CNS).
Cancer: Another function of the immune system is to provide surveillance of early cancer cells and to destroy them early. A blunted immune system therefore can increase the potential for development of cancer.
STEP 5: Contraindications of Immunosuppressive Agents (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are the contraindications of Immunosuppressive Agents? ALLOW few students to respond?
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Antimetabolites
Methotrexate and others
o Details are found on pharmacodynamics of anticancer drugs (session )
o Mycophenolate is contraindicated in pregnancy, whereas azathioprine is not. o An active, severe infection is a contraindication.
Tumor Necrosis Factor (TNF)–α Inhibitors
Infliximab, adalimumab, certolizumab
o Latent TB: TB can be reactivated if the immune system is suppressed.
o Patients who are immunocompromised: Combination with additional immunosuppression increases the risk of infection.
o Active infection: The immune system must remain intact to fight the current infection before treatment with an immunosuppressant begins.
PST 05104 Pharmacology & Therapeutics 119 NTA Level 5 Semester 1 Facilitator Guide
STEP 6: Key Points (5 minutes)
Tacrolimus is more potent than ciclosporin, but cause more neurotoxicity
Various drugs are immunosuppressive through different mechanisms
Immunosuppressants have many indications
STEP 7: Evaluation (5 minutes)
What are indications of immunosuppressants?
What are the general side effects of immunosuppressants?
What are the contraindications of immunosuppressants
PST 05104 Pharmacology & Therapeutics 120 NTA Level 5 Semester 1 Facilitator Guide
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).
Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.
PST 05104 Pharmacology & Therapeutics 121 NTA Level 5 Semester 1 Facilitator Guide
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