HIS16 Immunosuppressive And Immunomodulatory Drugs Flashcards
Immune disorders
- Autoimmunity
- Immunodeficiency
- Hypersensitivity
- Transplant rejection
Histamine
Histamine:
- Amine formed by Decarboxylation of Histidine by Histidine decarboxylase (expressed in Mast cells, Basophils)
- Stored in intracellular granules, complexed with acidic protein and heparin
- Released from Mast cells, Basophils in allergic conditions, bacterial infections, trauma etc.
- if Histamine not stored / released —> rapidly inactivated by Amine oxidase enzymes
- Location: practically all tissues, but unevenly distributed with high amounts in Lung, Skin, Blood vessels, GI tract
- Also function as NT in brain
Stimuli for Histamine release
- Destruction of cells as a result of cold
- Toxins from organisms
- Venoms from insects
- Trauma
- Allergy / anaphylaxis
Histamine mechanism
Produces effects by acting on H1, H2, H3, H4 seven transmembrane GPCR
- **H1:
- **Vasodilation (release of NO from vascular endothelium), but **Coronary vasoconstriction
- ***↑ capillary permeability
- ***Smooth muscle contraction (other than blood vessel) —> Bronchoconstriction, Intestinal cramps
- Itching, pain
- ***Mucus secretion
- Enhance secretion of pro-inflammatory cytokines
(H2:
- Vasodilation (release of NO from vascular endothelium)
- ↑ capillary permeability
- ***Positive chronotropism + inotropism
- ***Gastric acid secretion)
Type I hypersensitivity
Immediate / Anaphylactic hypersensitivity
- ***Sensitisation phase: APC —> Th2 cell —> IL-4, IL-5 etc. —> prime Naive B cell —> IgE-secreting plasma cell —> IgE bind to Mast cell / Basophil (via Fcε receptor) —> mast cell primed to respond to allergen
- ***Effector phase: Allergen cross link IgE and cause clustering of Fc receptor on Mast cell —> Signal transduction —> Degranulation —> Histamine + Serotonin, Leukotrienes, other chemotactic factors etc.
Early phase:
- within mins of exposure to allergen
- lasts for 30-90 mins
Late phase:
- begins 4-8 hours later
- lasts for several days
- often lead to chronic inflammatory disease
Effect depend on Site and Rate of Mediators release:
- Mild / Localised reaction:
- Allergic rhinitis
- Atopic dermatitis
- Conjunctivitis
- Bronchoconstriction
- Urticaria (Hives)
- Gastroenteritis - Severe / systemic:
- Asthma
- Anaphylactic shock
Antihistamine (H1 receptor blockers)
MOA:
Prevent histamine-mediated effects at H1 receptor (reversible H1 antagonist / inverse agonist)
Therapeutic use:
- Allergic and inflammatory conditions
- control allergic rhinitis, urticaria
- control cough due to cold / allergy
- ineffective in treating bronchial asthma (only Histamine only one of mediators, instead use β2-agonist to treat / epinephrine to treat systematic anaphylaxis) - Motion sickness and nausea (prophylaxis)
- Antiemetic due to blockade of **Central H1, M1 receptors
- prevents / diminish vomiting and nausea (mediated by chemoreceptors, vestibular pathway)
- not effective if symptoms already present, taken before expected travel
- Diphenhydramine, **Cyclizine, Meclizine (also for vertigo), ***Promethazine - Somnifacients (induce sleep)
- 1st generation antihistamine (e.g. ***Diphenhydramine, Doxylamine) —> strong sedative effect —> treatment of insomnia
- CI in people with jobs to operate machines (e.g. pilot)
Drug interactions:
- Potentiation of effects of ALL other CNS depressant (e.g. alcohol) (∵ Anticholinergic)
- Should not take with ***MAOI —> enhance Sedative, Anticholinergic effect of Antihistamine
- ↓ effectiveness of ***AChE in Alzheimer’s (∵ Anticholinergic)
Overdoses:
- CNS poisoning (e.g. hallucinations, excitement, ataxia, convulsion)
—> if untreated —> coma, collapse of CVS
1st Generation vs 2nd Generation Antihistamine
1st generation:
- effective
- inexpensive
- short duration —> require multiple dosing
- **penetrate CNS —> **Sedation, CNS impairment
- low specificity —> also act on
- **1. Muscarinic cholinergic receptor (Anticholinergic)
- **2. α-adrenergic receptors
- **3. Serotonin receptors as well (apart from H1)
Drugs:
- Diphenhydramine
- Chlorphenamine
- Promethazine
- Cyclizine
SE:
- weak Anticholinergic, Antiadrenergic SE (e.g. dry mouth, urinary retention, dizziness, blurred vision)
—> some may be unwanted / of therapeutic value
2nd generation:
- modification of 1st generation to eliminate SE
- specific for ***peripheral H1 receptor —> little / no anticholinergic SE
- ***more polar by adding COOH —> not cross CNS —> less CNS toxicity (e.g. Less sedative)
- rapidly onset
- longer duration —> less frequent dosing
Drugs:
- ***Fexofenadine (eliminated anticholinergic and antiadrenergic effects via bulky group + cannot cross BBB with polar COOH, OH group)
- Loratadine
- Cetirizine
- Mizolastine
Diphenhydramine (Benadryl)
Indication:
- Relieve allergic rhinitis (seasonal allergy) symptoms (e.g. sneezing, runny nose, itching, watery eyes)
- Relieve itching + swelling (in uncomplicated allergic skin reactions)
- Control cough (in cold / allergy)
Properties:
- Act on Muscarinic cholinergic receptor (Anti-muscarinic)
- Ability to penetrate BBB due to relative lipophilicity
SE:
- Sedation
- Fatigue
- Dizziness
- Tremor
- Lack of coordination
Immunosuppressants
Reduce activation / efficacy of immune system
MOA:
Alter Lymphocyte function —> Drugs / Ab against immune proteins
Indication:
- Autoimmune diseases
- Type 1 DM (pancreatic beta cell protein)
- Multiple sclerosis (oligodendrocyte protein)
- RA (synovial membrane protein)
- Autoimmune haemolytic anaemia
- Idiopathic thrombocytopenia purpura (ITP)
- Acute glomerulonephritis
- SLE (DNA, histones, RBC, platelets) - Allograft rejection
- selectively inhibit rejection of transplanted tissue while preventing individual from immunologically compromised
SE:
- severe toxicity —> use combination of immunosuppressants at lower doses
Mechanisms of Allograft rejection: Role for T cells
T cell:
- crucial for both initiation and coordination of rejection response
- T cell recognition of foreign Ag on Allograft —> Rejection response
- Induction phase:
Ag presentation by APC
—> T cell activation
—> Clonal expansion - Effector phase:
Cytokine production by T cell (IL-2, TNFα etc.)
—> Cytotoxic effects (Macrophage, CTL) + Ab production (B cells)
***3 Signal model (interactions between APC and T cell)
- MHC/peptide complex bind to TCR
—> T cell activation at CD3 receptor complex by Ag on APC - Binding of CD80/86 (on APC) to **CD28 (on T cell)
—> ↑ intracellular Ca
—> initiate Signal cascades
—> **Calcineurin pathway
—> Gene transcription (NFAT bind to DNA)
—> **Cytokine production and release (esp. **IL-2)
(—> Activation enhanced by CD40/CD40L + ICAM-I/LFA-I interactions) - Cytokines (e.g. IL-2) stimulate T cell proliferation
- **IL-2 bind to IL-2R (CD25)
—> Signal 3
—> **mTOR
—> promote translation of mRNA
—> promote transition from G1 to S phase in cell cycle
—> ***T cell proliferation
Microbial products - Inhibitors of cytokine production and function
- Calcineurin inhibitors —> inhibit IL-2 production
- Cyclosporin
- Tacrolimus
—> share same MOA, metabolite route —> never given together (Additive Nephrotoxicity) - mTOR inhibitors —> cell cycle arrest —> inhibit T cell proliferation
- Sirolimus
- Everolimus
- Cyclosporin
MOA:
Bind to Cyclophilin (CpN) (a cytoplasmic receptor protein)
—> inhibit **Calcineurin (CaN) phosphatase (Ca-dependent)
—> prevent activation of nuclear factor (*NFATc)
—> inhibit synthesis of IL-2
—> inhibit T cell activation
Indication:
- lipophilic cyclic polypeptide (11 a.a.)
- 1st line in prophylaxis treatment of transplant rejection (e.g. kidney, liver, heart allogenic transplant)
- combined in Double-drug / Triple-drug regimen with Corticosteroids, Antimetabolites
- alternative for treatment of severe autoimmune disease not responding to other therapies (e.g. RA, recalcitrant psoriasis)
Pharmacokinetics:
- Orally (poor absorption) / IV infusion
- CYP3A metabolism (affected by inducer / inhibitor of P450)
SE:
- ***Nephrotoxicity
- ***Infections (may be life-threatening)
- ***Lymphoma
- Hypertension, **Hyperkalaemia, Tremor, **Hirsutism, Glucose intolerance, ***Gum hyperplasia
- Tacrolimus
Preferred over Cyclosporin due to ↓ rate of Allograft rejection, ↓ SE
MOA:
Bind to FKBP (also Cyclophilin (CpN))
—> inhibit **Calcineurin (CaN) phosphatase (Ca-dependent)
—> prevent activation of nuclear factor (*NFATc)
—> inhibit synthesis of IL-2
—> inhibit T cell activation
Indication:
- macrolide isolated from soil fungus
- prevention of rejection of solid organ transplants
- given with Corticosteroids +/- Antimetabolite
- 10-100 fold more potent than Cyclosporin —> lower dose of Corticosteroids needed
SE:
- ***Nephrotoxicity
- ***Neurotoxicity (tremor, seizure, hallucination)
- Post-transplant insulin-dependent DM
- Lower incidence of CVS toxicities (hypertension, hyperlipidaemia)
- Sirolimus (Aka Rapamycin)
MOA:
Bind to cytoplasmic **FKBP (but does not inhibit CaN pathway)
—> Sirolimus-FKBP complex **inhibit mTOR (serine-threonine kinase controlling T cell proliferation)
(—> inhibit Signal 3)
—> inhibit translation of mRNA
—> **T cell arrest in G1 phase (cannot progress to S phase)
—> **Block T cell proliferation / clonal expansion in response to IL-2
Indication:
- macrolide obtained from fermentations of soil mould
- together with Cyclosporin / Tacrolimus + Corticosteroids —> ↓ dose of Calcineurin inhibitors —> ↓ Nephrotoxicity
- kidney / heart transplantation
- ***Sirolimus coated stent —> ↓ endothelial proliferation —> inhibit restenosis of blood vessels
Pharmacokinetics
- Longer t1/2 (OD)
- Orally, high fat diet reduce absorption
- Liver metabolism extensively
SE:
- ***Hyperlipidaemia
- hypertension
- leukopenia
- thrombocytopenia
- infection
Drug interactions:
- ↑ Cyclosporin-induced ***Renal dysfunction
- Cyclosporin ↑ Sirolimus-induced ***Hyperlipidaemia
Antimetabolite and Cytotoxic agents
- Azathioprine
- Mycophenolate mofetil
- Cyclophosphamide
- Methotrexate
- Azathioprine
MOA:
Azathioprine
—> 6-Mercaptopurine
—> **6-Thioinosinic acid (TIMP) (nucleotide analogue)
—> incorporated into nucleic acid chains
—> block De novo **purine synthesis (Adenine, Guanine) (required for lymphocyte proliferation)
—> prevent elongation of DNA
Indication:
- combination with Corticosteroids + Cyclosporin / Tacrolimus
- kidney transplantation
- Autoimmune disorder (e.g. Haemolytic anaemia)
Pharmacokinetics:
- PO / IV
SE:
1. **Myelosuppression
—> individuals with **defective TPMT (thiopurine methyltransferase)
—> ↑ risk for life-threatening myelosuppression when give standard dose
—> ↓ dose 10-15 fold in TPMT poor metabolisers
- ***Allopurinol
—> ↓ dose of Azathioprine by 75% to avoid accumulation of Azathioprine - ↑ cancer risks, GI irritation
- Mycophenolate mofetil
Immunosuppressive antimetabolite isolated from Penicillum spp.
2 forms:
- Mycophenolate mofetil (prodrug)
- Mycophenolic acid (MPA) - enteric coated tablet (↓ GI upset)
Indication:
- combination with Cyclosporin / Tacrolimus +/- Corticosteroids
- sole agent for heart, kidney, liver transplants
- largely replaced Azathioprine due to better safety profile
MOA:
Rapidly hydrolysed in GI tract
—> **Mycophenolic acid (MPA)
—> inhibit **IMP dehydrogenase (Inosine monophosphate dehydrogenase) (reversible non-competitive inhibitor)
—> block De novo formation of ***GMP (Guanosine monophosphate)
—> deprive T / B cell of component for nucleic acid synthesis
SE:
- diarrhoea
- N+V
- abdominal pain
- leukopenia
- anaemia
Polyclonal / Monoclonal Antibodies
- Anti-lymphocyte globulins
- IV immunoglobulins
- IL-2 receptor antagonists (Daclizumab, Basiliximab)
- Alemtuzumab, Rituximab etc.
Antibodies
Prepared either by
1. Immunisation of rabbits / horses / mouse with human lymphoid cells
2. Hybridoma technology
—> producing large quantities of Ag-specific monoclonal Ab
3. Recombinant DNA technology used to “humanise” Ab —> less antigenic
Administration:
- IV must
SE:
- ***Acute pulmonary oedema (dyspnea, chest pain, wheezing)
(Muro-mab: murine Ab
Zu-mab: humanised Ab
Xi-mab: Chimeric Ab)
- Anti-lymphocyte globulins
Prepared by immunisation of rabbits / horses with human thymocytes
—> isolating γ-globulin fraction of serum
—> Anti-thymocyte globulins (Polyclonal Ab)
Indication:
- combination with other immunosuppressants
- use at time of transplantation
- prevent early allograft rejection
- prevent severe rejection episodes
MOA:
**Ab-dependent cytotoxicity (ADCC)
—> Ab-bound **T cells are depleted in liver and spleen
—> depletion of circulating T cells + apoptosis of activated T cells
Pharmacokinetics:
- IV infusion (premedication with Corticosteroids, Paracetamol, Antihistamine reduce infusion-related reaction)
- t1/2: 3-9 days
SE:
- ***infections
- ***PTLD
- chills, fever
- leukopenia
- thrombocytopenia
- skin rashes
- IV immunoglobulins
Ig prepared from human plasma pooled from many donors
MOA:
- unclear
- High dose Induce **B cell apoptosis + **Modulate B cell signalling
Indication:
- Autoimmune disease
- Pre-transplant desensitisation
- ***Ab-mediated rejection
SE:
- headache
- fever, chills
- myalgias
- hypo/hypertension
- aseptic meningitis
- acute renal failure
- thrombotic events
- IL-2 receptor antagonists (Daclizumab, Basiliximab)
MOA:
Monoclonal Ab (Daclizumab, ***Basiliximab)
—> Anti-CD25 (IL-2R) Ab
—> bind to α chain of IL-2 receptor on activated T cell
—> inhibit IL-2 mediated T cell activation / proliferation
Basiliximab: Chimeric Ab (25% murine, 75% human sequence)
Daclizumab: Humanised Ab (90% human sequence)
Indication:
- combination with Corticosteroids / Cyclosporin A (↓ nephrotoxicity)
- ***Induction therapy in transplantation (∵ not T-cell depleting), effective in ↓ incidence of acute rejection
- Prophylaxis against acute rejection of kidney transplantation
- NOT used to treat ongoing rejection
Pharmacokinetics:
- IV
SE:
- well-tolerated, no SE
Corticosteroids
MOA:
Non-specific anti-inflammatory agents
—> inhibition of **Nuclear factor kappa B activation + bind to **Glucocorticoid response elements in promoter regions of cytokine genes
—> inhibit **Cytokine production by **T cells / ***Macrophages
—> disrupt T cell activation / Macrophage-mediated tissue injury
Indication:
- Prednisone / Methylprednisolone (in transplantation)
- Acute rejection
- Chronic graft-vs-host disease
- Autoimmune diseases (e.g. RA, SLE)
SE:
- diabetogenic
- hypercholesterolemia
- cataract
- osteoporosis
- hypertension
Immunosuppressants choice
Induction therapy —> require more potent immunosuppressants
1. Monoclonal Ab
2. Polyclonal Ab
—> powerfully suppress immune system at time of transplantation
—> allow new organ to start functioning in recipient
—> prevent early graft rejection
Maintenance therapy
E.g. Calcineurin inhibitor, mTOR inhibitor, Mycophenolate, Corticosteoid
—> provide long term immunological protection for transplanted organ
—> less potent
—> lower risk of infection
—> usually combined regimen
—> maintain adequate immunosuppression + minimise SE
***Summary
- Destruction of T + B lymphocytes —> Acute pulmonary edema
- Anti-lymphocyte globulins (Anti-T cell)
- IV immunoglobulin (Anti-B cell) - Calcineurin inhibitor (inhibit IL-2 synthesis)
- Cyclosporin —> Nephrotoxicity
- Tacrolimus —> Nephrotoxicity, Neurotoxicity - IL-2 antagonist (Anti-CD25, Monoclonal Ab)
- Daclizumab
- Basiliximab - mTOR inhibitor (prevent progression into cell cycle)
- Sirolimus —> Hyperlipidaemia
- Everolimus - Purine synthesis inhibitor (prevention of cell proliferation)
- Azathioprine (6-MP —> TIMP —> inhibit Purine synthesis)
- Mycophenolate (MPA —> inhibit IMP dehydrogenase —> inhibit GMP synthesis) - Other drugs
- Antihistamine (block H1 receptor)
- Corticosteroids (inhibit Nuclear factor kappa B activation + bind to Glucocorticoid response elements —> inhibit Cytokine production)
