Immunosuppressants Question And Answers

Immunosuppressants

Question 1. Classify the immunosuppressants used in therapy. Describe briefly the actions and uses of any two of them. Write short notes on

1. Cyclosporine

2. Azathioprine 

3. MMF 

4. Immunostimulants.

Answer:

Overview:

• Drugs influencing the immune system include immunosuppressants, immunostimulants, and immunomodulators.
• Vaccines and antisera also act by stimulating or supplementing the immune system.
• Immunosuppressants are drugs that inhibit immunity.

Read And Learn More: Pharmacology Question And Answers

• They may suppress cell-mediated or humoral immunity or both.
• It is necessary to suppress immune reactions in organ transplantation (to prevent graft rejection) and in autoimmune disorders.

Immunosuppressants are classified as:

Immunosuppressants Classification:

1. Calcineurin inhibitors: Cyclosporine, tacrolimus
2. Antiproliferative drugs: Sirolimus, everolimus, mycophenolate mofetil
3. Cytotoxic drugs: Azathioprine, methotrexate, cyclophosphamide, chlorambucil, leflunomide, teriflunomide.
4. Glucocorticoids
5. Immunosuppressant antibodies: Muromonab CD3, anti-lymphocyte globulin, anti-thymocyte globulin, anti-Rh (D) immune globulin, adalimumab, infliximab, etanercept, basiliximab, daclizumab.
6.  Others: Hydroxychloroquine, thalidomide, lenalidomide, pomalidomide.

Calcineurin Inhibitors

1. Cyclosporine: Cyclosporine is a cyclic peptide antibiotic produced by the fungus Beauveria nivea.

Cyclosporine Actions:

• Cyclosporine acts at an early stage, selectively inhibits T-cell proliferation, and suppresses cell-mediated immunity.
• It can be given orally and intravenously.

Cyclosporine Mechanism of Action:

• Cyclosporine binds to cyclophilin (an immunophilin) and this complex binds to and inhibits phosphatase calcineurin.
• This results in the inhibition of T-cell activation and IL-2 production. T cells do not respond to specific antigenic stimulation.
• Cyclosporine also suppresses the proliferation of cytotoxic T cells.

Cyclosporine Pharmacokinetics:

Cyclosporine is metabolized by microsomal enzymes cytochrome P450 in the liver → can interact with many drugs given concurrently.

Cyclosporine Adverse effects:

• Including nephrotoxicity, hepatotoxicity, anorexia, gum hypertrophy, and increased susceptibility to infections, hypertension, hyperglycemia, hyperlipidemia, and hirsutism.
• An increased incidence of lymphoma and other cancers has been noted.

Cyclosporine Uses:

• In organ transplantation: Effective for the prophylaxis and treatment of graft rejection in organ transplantation surgeries—like kidney, liver, bone marrow, and other transplants.
• Autoimmune disorders: Like rheumatoid arthritis as an alternative to methotrexate.
• Cyclosporin is also tried in severe psoriasis, uveitis, atopic dermatitis, inflammatory bowel disease, and nephrotic syndrome.

2. Tacrolimus: Tacrolimus is a macrolide antibiotic obtained from Streptomyces tsukubaensis. The mechanism of action is similar to cyclosporine except that it binds to a different immunophilin and inhibits
calcineurin.

Tacrolimus Adverse effects: Nephrotoxicity, GI disturbances, hypertension, hyperglycemia, tremors, and seizures.

Tacrolimus Uses: In organ transplantation similar to cyclosporine.

Antiproliferative Drugs

1. Sirolimus: Sirolimus is obtained from Streptomyces hygroscopicus.

Sirolimus Mechanism of action:

• Sirolimus inhibits the activation and proliferation of T cells.
• Sirolimus forms a complex with an immunophilin and the complex inhibits a protein kinase (mTOR) which is involved in cell growth and proliferation.
• Sirolimus is given orally, rapidly absorbed, and has a t½ of ~60 hours.
• It is metabolized by the same cytochrome enzyme (CYP3A4) as cyclosporine and tacrolimus when used with these drugs the dose of sirolimus should be adjusted.

Sirolimus Adverse effects:

Hyperlipidemia, GI disturbances, and an increased risk of infections and lymphomas.

Sirolimus Uses:

• Organ transplantation: Prophylaxis of organ transplant rejection as an alternative to calcineurin inhibitors. The functioning of the kidney graft may be delayed because of its antiproliferative effects.
• Psoriasis: Topical sirolimus is used.
• Chorioretinitis: Sirolimus is used with cyclosporine
• Coronary stents: Sirolimus is incorporated into cardiac drug-eluting stents to inhibit local cell proliferation and reduce restenosis.

2. Everolimus: Everolimus is similar to sirolimus.

• Mycophenolate mofetil (MMF):
  • MMF is a prodrug, converted to mycophenolic acid which inhibits guanine nucleotide synthesis.
  • B and T cells depend on this pathway for cell proliferation and thus mycophenolate selectively inhibits the proliferation and functions of lymphocytes.

MMF can be given both orally and intravenously.

Everolimus Adverse effects:

Include headache, GI disturbances, hypertension, and bone marrow suppression.

Everolimus Uses:

• Organ transplantation: As an alternative to calcineurin inhibitors.
• Other uses: MMF is also tried in autoimmune diseases like rheumatoid arthritis, inflammatory bowel disease, lupus nephritis, and psoriasis.

Cytotoxic Drugs

Cytotoxic drugs like azathioprine and methotrexate inhibit cell-mediated immunity, while cyclophosphamide predominantly suppresses humoral immunity.  They are used in the prevention of graft rejection and in autoimmune disorders.

Azathioprine:

• Azathioprine is a prodrug of mercaptopurine which is a purine analog.
• It is a cytotoxic immunosuppressive agent used in maintaining renal and other tissue transplants.
• It is also useful in SLE, glomerulonephritis, rheumatoid arthritis, Crohn’s disease, and multiple sclerosis and is being tried in idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia.
• Azathioprine is preferred to mercaptopurine because it is a better immunosuppressant, converted to mercaptopurine in the immune cells, and also has a better bioavailability.

Cyclophosphamide and Methotrexate are used for immunosuppressive properties. Pentostatin is now tried as an alternative to prevent graft rejection. Leflunomide is an orally effective prodrug. The active metabolite is an inhibitor of pyrimidine synthesis. It is used in rheumatoid arthritis and is also being studied for other autoimmune indications.

Glucocorticoids:

Glucocorticoids have potent immunosuppressant activity and are used in the prevention of organ transplant rejection and in autoimmune disorders with immunosuppressant drugs.

Immunosuppressant Antibodies

1. Muromonab CD3:

• Muromonab CD3 is a monoclonal antibody to CD3 antigens on T lymphocytes.
• On intravenous administration, T cells disappear from circulation within minutes.
• It is used with other immunosuppressants in organ transplantation.
• Fever, chills, and pulmonary edema may occur.

2. Antilymphocyte and anti-thymocyte antibodies:

• Antilymphocyte globulin (ALG) and anti-thymocyte globulin (ATG) are used to induce immunosuppression in solid organ transplants and bone marrow transplantation.
• They may be used along with cyclosporine to prepare the patient for transplantation by immunosuppression.
• Allergic reactions and pain at the injection site are common.

3. Infliximab: Infliximab is a monoclonal antibody and etanercept is a protein that blocks TNF-α. Etanercept inhibits TNFα-mediated inflammation.

• They are useful in rheumatoid arthritis, Crohn’s disease, ulcerative colitis, and psoriatic arthritis.
• Adalimumab is an anti-TNF monoclonal antibody that brings remission in rheumatoid arthritis.
• Abatacept is a protein that blocks the activation of T cells and is useful in rheumatoid arthritis.
• Anti-IL-2 receptor antibodies, basiliximab, and daclizumab block the binding of interleukin-2 to the lymphocytes and halt the immune process—used in organ transplantation.

Other monoclonal antibodies:

Efalizumab is used in psoriasis, omalizumab in bronchial asthma, and abciximab to prevent platelet aggregation.

Anti-Rh (D) immunoglobulin:

• Anti-Rh (D) immunoglobulin: Anti-Rh (D) immunoglobulin is human IgG with a high titer of antibodies to the Rh (D) antigen of the red blood cell.
  • When Rh negative mother delivers an Rh-positive baby (or aborts), the Rh-positive antigens from the red cells of the fetus enter into the maternal bloodstream.
  • This sensitizes the mother to produce antibodies against Rh-positive cells.
  • In subsequent pregnancies, the maternal antibodies against Rh-positive cells reach the fetus and may result in hemolytic disease of the newborn.
• Injection of anti-Rh (D): Injection of anti-Rh (D) immunoglobulin to the mother at the time of childbirth (or after abortion) will bind the antigens on the RBCs of the baby which have entered the maternal circulation.
  • This will prevent the formation of antibodies in the Rh-negative mother against the Rh-positive RBCs.
  • Thus subsequent pregnancies would not be affected. The immunoglobulin should be given within 24–72 hours of childbirth.

Dose: 300 mg IM.

Antibodies Others:

1. Hydroxychloroquine: Hydroxychloroquine an antimalarial drug like chloroquine also has immunosuppressant and anti-inflammatory properties for which it is used in rheumatoid arthritis and SLE.
2. Thalidomide: Thalidomide is  seen immunostimulant

Immunostimulants

Immunostimulants and immunomodulators are drugs that modulate the immune response and can be used to increase the immune responsiveness of patients with immunodeficiency as in AIDS, chronic illness and cancers.

This is still a developing field of pharmacology. The drugs currently used for this purpose are:

1. BCG
2. Cytokines
3. Thalidomide
4. Thymosin
5. Levamisole
6. Inosiplex
7. Interferons
8. Immunization

1. BCG: BCG vaccine used in tuberculosis has been tried in cancers.

2. Cytokines:

• Interferons are cytokines with antiviral and immunomodulatory properties.
• Recombinant interferons α, β and γ are available for clinical use. They bind to specific receptors and bring about immune activation and increase host defenses.
• There is an increase in the number and activity of cytotoxic and helper T cells and killer cells. Interferon alpha and beta are mainly used for antiviral effects, while interferon α for its immunomodulating actions.
• Interferons are used in tumors like malignant melanoma, hairy cell leukemia, lymphomas,
• Kaposi’s sarcoma, condylomata acuminata, and viral infections.

3. Thalidomide: The teratogenic hypnotic of the 1960s is now being tried in many clinical conditions.

• It has anti-inflammatory and immunomodulatory properties—inhibits angiogenesis, and enhances cell-mediated immunity by action on T cells.
• Thalidomide is used in multiple myeloma, lepra reactions, and in lupus erythematosus.
• Adverse effects include teratogenicity, peripheral neuropathy, hypothyroidism, and constipation.
• Because of the increased risk of deep vein thrombosis, an anticoagulant cover is needed. Lenalidomide and pomalidomide are similar to thalidomide.

4. Thymosin: Thymosin is synthesized in the thymus and purified from bovine and human thymus glands for therapeutic use. It induces the maturation of precursor T cells and is tried in hepatitis B and C.

5. Levamisole: Levamisole used in helminthiasis, increases cell-mediated immunity in humans. It has also been tried in some cancers.

Classification Of Immunizing Agents:

Immunization

Vaccines and antisera are used for immunization against bacterial- and viral infections.

Vaccine:

• Vaccines stimulate the host immune system, while antisera supplement and support the immune system with readymade antibodies.
• Vaccines are suspensions of microorganisms (dead or live-attenuated) that stimulate the immunological defense of the host by developing antibodies.

Toxoids:

• Toxoids are bacterial exotoxins modified to remove toxicity but retain antigenicity.
• Antisera contain antibodies against a particular microorganism—they provide passive immunity.
• Antisera like tetanus antitoxin, gas gangrene, antitoxin, diphtheria and antirabies sera are obtained from sera of horses which are actively immunized against the specific organism.
• Sensitivity tests should be done before giving antisera. Allergic reactions may occur because of the animal source.

Immunoglobulins:

• Immunoglobulins are human gammaglobulins that carry the antibodies like a normal human
• Vaccine Type of agent ROA
• Primary gammaglobulin, tetanus Ig, rabies Ig, anti-diphtheria Ig, and hepatitis-B Ig. Allergic reactions including serum sickness and anaphylaxis can occur with antisera, while it is uncommon with Igs.

Active immunization:

• Active immunization is the administration of antigens to the host in order to induce antibody production.
• Vaccines are used for active immunization. They impart active immunity which takes some time to develop and are, therefore, used prophylactically.
• The antibodies are so developed that they destroy the specific microorganism when it enters the body.
• Some commonly used vaccines are given in Table.

Vaccines for Japanese encephalitis, Kyasnur forest disease (KFD), and epidemic typhus are also available now.

1. Passive immunization: Passive immunization is imparting immunity to a host passively by the transfer of antibodies, for example, Aantisera and Ig. This affords immediate protection because readymade antibodies are available
2. Primary immunization: Primary immunization provides primary immunity and is usually given in children, for example, DPT (triple antigen given to infants).
3. Secondary immunization: Secondary immunization is done to reinforce primary immunity by giving booster doses.

Question 2. Vaccines in common use and their recommended schedules
Answer:

Vaccines in common use and their recommended schedules:

 

Question 3. Passive immunization
Answer:

Passive Immunization:

Conditions for which passive immunization is available:

Chelating Agents

• Heavy metals bind to and inactivate the essential tissue enzyme and thereby interfere with normal cell functions. Heavy metals cannot be metabolized in the body.
• Chelating agents or heavy metal antagonists bind the heavy metal ions and make them nontoxic.
• The chemical complex formed is called chelate (Chele = claw in Greek). The process of complex formation is chelation.
• The complex so formed is water-soluble and is eliminated by the kidneys. The clinically useful chelating agents are CaNa₂ EDTA, dimercaprol, D-penicillamine, desferrioxamine, deferiprone, and deferasirox Prussian blue.

Uses, routes of administration, and toxicity of chelating agents:

Treatment Of Poisoning

Toxicology: Toxicology is the science that deals with the study of poisons, their source, properties, actions, detection, and treatment of poisoning.

• A poison may be defined as any substance which if administered or comes in contact with a living being, produces ill-health, disease, or death.
• Every drug in a high dose can be poisonous. Poisoning could be accidental, suicidal or homicidal.
• When treated on time with appropriate drugs, considering the toxicokinetics and toxicodynamics, the treatment of poisoning can be successful.
• No time should be lost in identifying the exact poison.
• Treatment should be started immediately with supportive measures.

Steps in the treatment of poisoning are:

1. Stop the source of poison: Shift the patient away from the source.

2. Limit the absorption of poison: If taken orally—induce vomiting or stomach wash may be given to prevent further absorption of the poison.

• Cathartics or bowel irrigation may be tried.
• If poisoning is through the skin, for example, by organophosphorus compounds, the clothing should be changed and the skin should be washed with soap and water.

3. Supportive therapy: Emergency stabilization of the cardiovascular and respiratory system:

• Airway, Breathing, and Circulation (ABC) of poisoned Airway to be cleared of any mucus or vomitus.
• The patient should be put in a lateral position. Suction to clear the air passages and if required an endotracheal tube may be inserted.
• If breathing is depressed, artificial ventilation should be given. Oxygen may be needed.
• Circulation:
  • Circulatory status should be assessed by pulse rate, blood pressure, and urine output. Suitable IV fluids should be given.
  • Generally, 1 liter of normal saline with 1 liter of dextrose is injected in the first 24 hours
  • If hypotension is present, the foot end of the bed should be raised.  If the patient is in a coma, nothing should be given orally.
  • Blood glucose should be estimated to rule out hypoglycemic coma. In all comatose patients with signs of CNS depression, administration of IV ‘coma cocktail’ is routinely recommended
• Naloxone 2 mg + Thiamine 100 mg + Dextrose 50 mL of 50% solution

These are given because if the poison is an opioid, naloxone overcomes the respiratory and

• CNS depression. Naloxone also overcomes the effects of opioids released in the body in pain; dextrose helps if the coma is due to hypoglycemia.
• Thiamine helps to prevent Wernicke’s encephalopathy in alcoholics.

4. Specific therapy:

Specific antidotes, antivenoms, and antitoxins should be used whenever available. For some poisons, specific therapies may be available though they are

5. Other measures:

• Forced diuresis, peritoneal dialysis, hemodialysis, hemoperfusion, exchange transfusion, and similar procedures are carried out in certain cases of poisoning only if indicated.
• The excretion of acidic drugs like salicylates can be increased by forced alkaline diuresis—using frusemide, sodium bicarbonate, and IV fluids. Excretion of basic drugs like amphetamines
  maybe increased by forced acid diuresis using frusemide, ascorbic acid, and IV fluids.
• However, these procedures may lead to volume overload and also expose the kidneys to a high dose of the toxin. The excretion of drugs like amphetamines, barbiturates, ethyl and methyl
  alcohol, phenytoin, salicylates, theophylline, and lithium can be effectively carried out by hemodialysis. Hemoperfusion can be done in some fat-soluble poisons.

Some Specific antidotes for drugs and chemicals:

Cardiopulmonary Resuscitation

Management of a collapsed patient requires early assessment and restoration of the circulation, airway, and breathing (CAB) using basic life support (BLS) so that circulation is maintained until definite treatment with advanced life support can be made available.

Some important steps in cardiopulmonary resuscitation (CPR) are:

• Chest compression rate at least 100/min.
• Compression depth at least 2 inches (5 cm).
• Allow complete chest recoil after each compression.
• Minimal interruptions in chest compressions.
• Avoidance of excessive ventilation.
• 2 breaths to be given after every 30 chest compression

Enzymes In Therapy

Enzymes are proteins which catalyze several biochemical reactions. Some substances act with specific enzymes and are called coenzymes. Enzymes used in therapy are:

Mammalian Enzymes

1. Hyaluronidase:

• Hyaluronidase is obtained from mammalian testes. It depolymerizes hyaluronic acid of connective tissue.
• Given subcutaneously, it increases tissue permeability and enhances the rate of absorption of subcutaneously administered fluids and drugs.
• Hyaluronidase can produce allergic reactions. It should not be injected around an infected site to avoid the spread of infection.

Hyaluronidase Uses:

• For hypodermoclysis in infants and children when large volumes of fluids are given subcutaneously.
• To hasten resorption of fluids and blood in a hematoma.
• Along with local anesthetics—to increase the effectiveness of local anesthesia.
• Radiography: Hyaluronidase enhances the absorption of radio-opaque substances.

2. Trypsin:

Trypsin is obtained from the bovine pancreas. It is a proteolytic enzyme that directly hydrolyses natural proteins. It digests dead tissue, bacteria, and debris. Trypsin may be used topically, sublingually, or intramuscularly. Allergic reactions can occur.

Trypsin Uses:

• Topically for debridement of necrotic tissues.
• Topically for liquefaction of coagulated blood and exudates.
• Trypsin-containing gelatin capsules are inserted into sinuses and fistulae that cannot be adequately irrigated.
• For irrigation of nasal cavities.
• Used sublingually for thrombophlebitis, deep contusions, and skin ulcers.

Chymotrypsin, alpha chymotrypsin, and pancreatic dornase.

 Enzymes used in therapy and antioxidants:

Bacterial Enzymes

1. Streptokinase:

Streptokinase is obtained from beta-hemolytic streptococci (see Page 257).

2. Streptodornases:

Streptodornase is a group of proteolytic enzymes that catalyze the depolymerization of nucleoproteins like deoxyribonucleic acid that are present in dead cells of the pus. Thus streptodornase liquifies viscous and purulent material. It has no effect on living cells.

Streptokinase and Streptodornases Uses:

• Streptokinase + streptodornase are used both topically and for instillation into body cavities.
• They are used topically to liquefy clotted blood, and pus and to clear the debris in chronic
  ulcers, osteomyelitis, and other wounds and lesions.

3. Serratiopeptidase:

• Serratiopeptidase from the Serratia species was administered orally to relieve inflammatory edema in the soft tissues.
• It is claimed to digest necrotic tissue, exudates, and clots which are cleared faster from the site of trauma. However, adequate evidence to prove its efficacy is currently not available.

Serratiopeptidase is tried as an adjuvant in a wide variety of conditions associated with inflammation like rheumatoid arthritis, osteoarthritis, cervical spondylosis, ankylosing
spondylitis, fractures.

Other musculoskeletal disorders; sinusitis, otitis, bronchitis, bronchial asthma, and pulmonary tuberculosis to facilitate expectoration; subconjunctival hemorrhage and hyphema; Postoperative patients, traumatic injury, following tonsillectomy, episiotomy, perineal laceration; Dental infections.

L-asparaginase is obtained from E.coli cultures for commercial use.

Plant Enzymes:

Papain: Papain obtained from the unripe fruit of Carica papaya is a proteolytic enzyme used topically for debriding wound surfaces

Vitamins

Sources recommended daily allowances (adults) and deficiency symptoms of vitamins in the diet: