Immunology: Anti-histamines and Immunosuppressant drugs

Part 1: Anti-histamines

What is histamine?

-Naturally occuring amine that is found in most body tissues in a inactive bound form (histamine+heparin+protein)

-Important component of mast cell granules and released in response to stimuli such as physical trauma or antigen-antibody reactions.

-Various chemicals such as tubocurarine, morphine, some anti-histamines,  snake venome and proteolytic enzymes can cause release as well.

-The triple response of Lewis is a cutaneous response that occurs from firm stroking of the skin, which produces an initial red line, followed by a flare around that line, and then finally a wheal. [Subtypes involved: H1 and H2 receptors]

Physiological function of histamine:

1. In body epithelia, it is released in repsonse to invasion by foreign substances.

2. In glands, mediates part of the normal secretory process.

3. In most cells near blood vessels where it plays a role in regulating microcirculation.

Action of histamine

Smooth muscles: Cause smooth muscles to contract (not including arterioles but larger arteries). Stimulation of human uterus is insignificant. Brisk attack of bronchospasm may be induced in subjects who have allergy esp. asthma.

1. Dilate arterioles, with a consequent fall in blood pressure.

2. Dilate capillaries

3. Pruritic (Cause itchiness)

4. Gastric secretion (Increased acid and pepsin concentration in gastric juices)

5. Metabolism (Formed from the amino histidine and metabolised minaly by deamination and by methylation)

  • Types of Histamine receptors (H1, H2, H3)

h1: Anti-histamine usually refers to H1-receptor antagnoists (which is affects various allergic and inflammatory mechanisms)

h2: Recently developed, main effect is on gastric secretion (e.g. cimetidine)-‘Cement ti dine’

h3: Experimental and investigational tools.

1.1 H1 antagonists (Anti-histamines)

-Considerable structural similarity to histamine, adrenaline, serotonin and acetylcholine. Thus, may affect or block one another.

-H1 anti-histamines have sedative, antimuscarinic or even alpha antagonist effects.

-As such, H1-anti-histamines can be used as hypnotics, antitussives, expectorants, in motion sickness and in parkinson’s disease.

-if used for its anti-histamic effect, the above uses will become adverse effects.,

1. 2Mechanism of action: 

  • Decrease histamine-mediated contraction of smooth muscles in the bronchi, the intestine and in the uterus.
  • Reduce the increased vascular permeability caused by histamine.
  • Sedation
  • Prevent motion sickness

1.3 Clinical Uses/Indications:

-For allergic reactions including hay fever, urticaria, insect bites, drug hypersensitivities. Drugs that lack sedative effect are preferred (e.g. fexofenadine-(Fatso fiend-a dine) or cetirirzine)

-Used as anti-emetics for the prevention of motion sickness or other causes of nausea, especially those with associated with vertigo (e.g. labyrinthine disorders) [Loratadine]

-For sedation (e.g. promethazine found in Phenergen)

1.4 Side effects

-Depends on the effects that the drug is prescribed for. This means that if a drug is used for peripheral actions, the CNS activity is unwanted and vice versa.

-When used for their sedative or anti-emetic actions, some of the CNS effects are dizziness, tinnitus and fatigue are unwanted.

Precautions: Excessive doses may cause excitation and convulsions in children. (!st generation anti-histamines) For children, sedation may be induced and learning ability will be affected. Severe effects are unusual following ovedoses of 1st generation anti-histamines.

-Altering the structure of some drugs may prevent them from entering BBB and less unwanted Adverse effects (e.g. loratadine)—>More polar


*Peripheral actions on CNS activity is always unwanted!!! When used for sedative or anti-emetic actions (eg. dryness of the mouth, blurred vision, constipation, retention of urine)

*Gastrointestinal disturrbances and Allergic dermatitis can follow after application

1st generation anti-histamines: Hydroxyzine, Bromazine, Mepyramine

2nd generation anti-histamines (Agents with no sophoric effect): Loratadine, Cetirizine, Mizolastine, Terfenadine, Astemizole (Terfenadine and astemizole are non-sedating alternatives to first-generation compounds, inhibits several ion channels) *Disturbing arrhythmias were described for these two drugs.

3rd generation anti-histamines (Non-cardiotoxic, non-sedative agents): Fexofenadine (Children who have overdose can be managed at home)

Part 2: Immunosuppressant drugs

2. 1Generabl Mechanism of action:

1. Inhibits IL-2 production or action (e.g. cyclosporin, tacrolimus, sirolimus/rapamycin)

2. Inhibitors of cytokine gene expression (e.g. corticosteroids)

3. Act by cytotoxic mechanisms (e.g. cyclophosphamide, chlorambucil)- Prevents cell proliferation

4. Inhibits purine or pyrimidine synthesis (e.g. azothioprine, myclophenolate mofetil)

5.  Blocks cytokines and receptors mediating immune responses (e.g. antibodies)

2.2 Clinical Indications

1. To suppress tissue regection after transplant

2. To suppress graft versus host disease in bone marrow transplant.

3. To treat autoimmune diseases (psoriasis, ulcerative colitis, systemic lupus erythematosus/SLE, idiopathic thrombocytopenic purpura/ITP)

2.3 Types of immunosuppressant drugs

1. Cyclosporin

-Fungal peptide (cyclic 11 amino acids, invaluable role in organ transplant)

Mechanism of action:

  • Decreased clonal proliferation of T cells, primarily by inhibiting IL-2 release and decreasing expression of IL-2 receptor
  • Reduced induction of and clonal proliferation of cytotoxic T-cells from precursor CD8+ cells
  • Reduced function of effector T-cells that mediate cell-mediated responses
  • Some reduction of T-cell dependent responses

***Main effect by preventing IL-2 transcription

Antigen binds to T-cell receptor–>Increase in intracellular Ca2+–>Ca2+ plus calmodulin stimulates phosphatase, calcineurin, that activates various transcription factors–>Transcription of IL-2 genes–>Cyclosporin binds with a cystolic protein called cyclophilin–> The resulting complex inhibits calcineurin–>Inhibits IL-2 production and T-cell proliferation does not occur.

Unwanted effects:

1. Nephrotoxicity (probably due calcineurin inhibition)-Limiting factor in certain patients (Esp with renal failure)

2. Hypertension

3. Hepatotoxictiy

4. Less crucial side effects (Anorexia, lethargy, hirsuitism, tremor, parasthesia, gingival hyperplasia, gastrointestinal disturbances)

+No depressant effects on bone marrow

2. Tacrolimus

Mechanism of action: Macrolide antibiotic with a similar mode of action to cyclosporin but the internal receptor is not cyclophilin but immunophilin known as FKBP/FK binding protein. The complex inhibits calcineurin in the same way. 

Side effects:

-Similar to cyclosporin. Hypertension and Nephrotoxicity not that serious here.

-Thrombocytopenia and hyperlipidemia may occur but reversible by reducing the dose.

3. Glucocorticoids-Discusssed previously

4. Azathioprine

-Interfers with purine synthesis and is cytotoxic. Used widely for the control of tissue rejection in transplants. Drug is metabolised to give mercaptopurine (analogue which inhibits DNA synthesis)

-Both cell-mediated and antibody-mediated immune reactions are depressed by this drug since it inhibits clonal proliferation in the induction phase of the immune response by cytotoxic effects on dividng cells. Main unwanted effect is depression on bone marrow.

5. Alkylating agents

-Two alkyl groups which can form covalent bonds with cell substituents. Can cross link two nucleophilic sites such as N7 of guanine in DNA.

Mechanism of action: During DNA replication, the result is base substitution, base excision or chain breakage. Eventually, cell dies by apoptosis.

(a) Cyclophosphamide-Cytotoxic agent with powreful immunosuppressive effects. Particular action on lymphocytes during the clonal proliferation phase and inhibits both anti-body and cell-mediated immunity

(b) Chlorambucil-Similar in action and effects to cyclophosphamide

6. Mycophenolate mofetil

-Derivative of fungal antibiotic.

-Metabolised into mycophenolic acid in the body which inhibits proliferation of both T and B lymphocytes by inhibiting inosine monophosphate dehydrogenase (enzyme needed for purine biosynthesis)

-T-cells and B-cells need this pathway. So inhibiting this pathway has rather specific effects.

*When used with cyclosporin and steroids, it is effective in suppressing kidney transplant rejection.

7. Immunoglobulins

-Antibodies against human lymphocytes or their surface proteins.

-When derived from animal sources, the antibodies themselves are potent antigens which limits their usefulness.

-Using genetic engineering, the antibodies can be humanised to combine the Fab region to the Fc region.

8. Polyclonal

-Anti-lymphocyte immunoglobulin and anti-thymocyte immunoglobulin are obtained from horses which are immunised against human lymphocytes or feotal thymus tissue respectively.

-Binding of the antibodies cause complement activation and lysis of target cells.

-Unwanted effects: Due to the presence of foreign proteins and subsequent immune response. Anaphylaxis can occur and immune complexes can lodge into kidney causing nephritis.

9. Monoclonal

-Directed against surface components of T-cells.

CD3-Group of peptides responsible for epxression of T-cell receptors at the cell surface.

CD4-Essential co-receptor on T-helper cells

IL-2 receptor-Needed for clonal proliferation of T-cells

-Initial doses of anti-CD3 can cause severe side effects. Fever, hypotension, pulmonary edema, nephropathy and encephalopathy which is thought to be due to cytokine release can occur. Pre-treatment with steroids is required to mitigate these effects.

10. Anti-TNF humanised antibodies

Clinical uses: Ankylosing Sponylitis, Crohn’s disease, Psoriasis, Psoriatic arthritis, Rheumatoid arhritis

-Very effective though the vary in effectiveness with different disease, adverse reactions are unusual but as they inhibit immunity some increase in infections have been noted.

*It is advised that a patient suffering from infections to stop Adalimumab (Humira) treatment.

*Increased in liver enzymes (AST and ALT) and formation of autoantibodies similar to early SLE have been reported.

(a) Infliximab (Remicade): Mouse-Human antibody to TNF-a

(b) Etanercept (Enbrel): Construct of human TNF receptor and IgG which binds to TNF-a and prevents its action. Effectiveness may decrease over time, perhaps due to antibody formation and less effective in obese patients, maybe due to adipocytes being a source of TNF-a.

(c) Adalimumab (Humira): Fully human monoclonal antibody to TNF-a. Slightly more effective than Enbrel in psoriasis and injections are once a fortnight as compared to once a week with Enbrel.

(d) Efalizumba (Raptiva): Recombinant humanized monoclonal to CD11a. Part of the integrin molecule LFA-1 involved in immune cell extravsation. Withdrawn from market due to progressive multifocal leukoencephalopathy (PML)

11. Rapamycin (Sirolimus)

-Macrolide antibiotic like tacrolimus

Mechanism of action: Binds to intracellular immunophilin, FKBP. However, complex does not bind to calcineurin nor does it affect IL-2 gene transcription. Interferes with IL-2 signal transduction pathway, blocking the cell cycle of activated T cells in G1 phase.

-It also competes with tacrolimus for FKBP but their effects are additive.

-Nephrotoxicity and hypertension not serious problems. Hyperlipidemia and ITP responds to reduction in dosage.

12. Future drug developments 

a) Sulphated polysaccharides

-Sulphated glycosaminoglycans (GAGs) such as chondroitin sulphate and heparan are major constituents of cell membranes and extracellular matrix (ECM)

-GAGs represent the endogenous ligand for the sulphated polysaccharide receptors on cells.

*Sulphated polysaccharides, phospho-sugars and the oligosaccharide-processing inhibitor castanospermine represent promising new drugs with a novel mode of action.

Mechanism of action of drugs above: Inhibition of migration across vascular endothelium and entry into tissue parenchyma at sites of inflammation. Prevents the accmuluation of leukocytes in inflammatory foci. The drugs may halt the progression of inflammatory dieases such as rheumatoid arthritis.

b) Immunosuppressants

Brequinar sodium: An anti-metabolite that inhibits de-novo (on the spot) pyrimidine synthesis

Mizoribine: An inibitor of purine synthesis

-Monoclonal antibodies: To cytokines, cytokine receptors and adhesion molecules. There is also the possiblity of inducing specific tolerance to donor antigens by blocking T-cell activation and inducing T-cell apoptosis.

c) Anti-rheumatoid agents

-Cytokine-targeted therapies including anti-TNF-a antibodies, soluble TNF receptor to remove TNF-a.

d) 5-lipooxygenase inhibitors

-Prevents the conversion of arachidonic acid to 5-HPETE. Thus, they prevent leukotriene production. Useful for asthma treatment.

e) Phosphodiesterase inhibitors

-To increase cAMP concentrations in cells thus reducing activation.


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