Immune Suppression Flashcards
Carprofen
COX inhibitor - Humans = COX-1 Selective Horses = COX-1 + COX-2 Dogs + Cats = COX-2 Selective Arylpropionic acid derivative Photoallergen in humans - photo allergic contact dermatitis
What gene results in Cat’s sensitivity to paracetamol?
UGT1A6 gene is a pseudogene therefore lack glucuryonaly transferase - more paracetamol is metabolised to NAPQ1 and Para-amino-phenol. Cat lack N-acetyltransferase 2 enzyme therefore cannot convert PAP back to paracetamol (Dogs lack NAT1 + NAT2) - causes Methaemoglobinaemia
What is the cause of Ibroprufen toxicity?
Dogs half life ~4.5hrs (rather than humans 2hrs), drug is excreted via the urine but also the bile which means ibroprufen enters the enter-hepatic circulation, seen to accumulate in the proximal GI tract - ulceration and acute renal failure
Dicourmarol
Result of Coumaurin fermentation in silage, compound from which Warfarin metabolised therefore Anti-coagulant, cause of sweet clover disease
Warfarin
Anti-coagulant, structrally similar to vitamin K, therefore competitive inhibitor of Vit K Epoxide reductase - depletes levels of vitamin K and therefore reducing Y-carboxylation of glutamate residues in Vit K dependent enzymes:
Factor II
Factor VII
Factor IX + Factor X
Theobromine
Toxic alkaloid in chocolate for dogs, methylxanthine, overdose causes: aggitation, hyper excitability, tremours, convulsions and cardiotoxicity
Competitive antagonist of Adenosine receptor, stimulate Ryanadine receptors increasing Ca release, and inhibit phosphodiesterase’s (breaks down CAMP)
Toxicity in dogs a result of metabolites + 3-MX
Toxicity not seen in cats, lack sweet taste receptor TasLr2
Omalizumab
Monoclonal antibody against IgE
Used in the treatment of Dermatographic utercaria
Sodium Cromoglycate
Inhibits mast cell degranulation through the inhibition of inward Cl- channels required to maintain the Ca influx for histamine release
Used in the treatment of Utercaria and Mastocytosis, and Hay fever
Salbutamol
B2 adrenoreceptor agonist - Rising levels of C-AMP seen to decrease mast cell degranulation and hence prevent histamine release
Used in the treatment of asthma
Salmeterol
B2 adrenoreceptor agonist - rising C-AMP reduces mast cell degranulation and hence histamine release
Used in the treatment of asthma
Theopylline
Phosphodiesterase inhibitor - rising levels of C-AMP seen to reduce mast cell degranulation and therefore histamine release
Used in the treatment of asthma
Mepyramine
First generation H1 histamine antagonist
Rapidly crosses blood brain barrier resulting in drowsiness
Promethazine
First generation H1 histamine antagonist
Used for morning sickness, as a sedative (as could cross blood brain barrier), and motion sickness
Terfenadine
Second generation anti-histamine H1 histamine receptor antagonist, does not cross blood brain barrier, but seen to inhibit the K11.1v / hERG channel responsible for repolarisation of the AP therefore caused Long QT syndrome - sudden death
Activated by cytochrome p450 into Fexofenadine
Fexofenadine
Second generation antihistamine - H1 receptor antagonist, does not cross BBB but can cause Long QT syndrome and hence sudden death
Loratadine
Third generation antihistamine - H1 antagonist, non-drowsy and lack of cardiac side effects
Imatinib
Small molecule inhibitor, targets receptor tyrosine kinases, used in the treatment of mastocytosis, only effective in patients without the c-KIT mutation
Progluminde
Inhibits CCK2 receptors reducing gastric acid secretion - CCK2 receptors acts to stimulate histamine release form ECL cells following Gastrin activation
Cimetidine
H2 Histamine receptor antagonist
Used in the treatment of peptic ulcers
Seen to inactive cytochrome P450 however
Ranitidine
H2 Histamine receptor antagonist
Used in the treatment of peptic ulcers
Omeprazole
Proton pump inhibitor
Used for treatment of peptide ulcers
Arthrotec
Combination drug of Diclofenac (Nsaid) and Misoprotol (anti-inflammatory), used for patients prone to peptic ulcers
C1 - Esterase inhibitor
Endogenous inhibitor of enzyme Kallikrien (bradykinin production)
Hereditary angioedema = mutation in gene resulting in excess bradykinin therefore pain
Icantibant
B2 bradykinin receptor antagonist
Used in the treatment of Hereditary angiodema
Ecallantide
Kallikrien antagonist
Used in the treatment of hereditary angioedema
Tanezumab
Monoclonal antibody targeted against TrKA and NGF which both act to sensitive nerves during inflammation
Under clinical trials for treatment of inflammatory pain
Zileuton
5-Lipooxygenase inhibitor (Leukotrine production)
Used in the treatment of Asthma
Zarfirlukast
Cystl- leukotrine receptor antagonist
Used in the treatment of asthma
Lexipafant
PAF receptor antagonist, used in the treatment of pancreatitis
Rupatadine
Combination H1 (histamine) receptor antagonist and PAF receptor antagonist, used in the treatment of Hay fever and utercaria
Ibruprofen
Non-selective Cox inhibitor, hydrogen bonds with arginine at position 120, inhibiting production of prostaglandins, reversible
Naproxen
non-selective COX inhibitor therefore inhibiting production of prostaglandins, form hydrogen bond with arginine at position 120, reversible
Etoricoxib
Selective COX-2 inhibitor
Misoprostol
Prostaglandin E2 analogue
Aspirin
Marginally COX-1 selective, acetylates the COX enzyme at a serine position 530 and hence irreversibly inhibits prostaglandin production, only a small dose required for anti-thrombotic effect - inhibits both TXA2 = thrombotic and PGI2 = anti-thrombotic but seen as platelets are seen to only express COX-1 and TX synthase they are the major source of thromboxane and their replacement is slower than that of the epithelium - produces PGI2 hence aspirin overall anti-thrombotic effect
acetylyates COX-2 into 15-RHETE can be converted by 5-LO into Aspirin triggered lipoxin A4 which has similar mode of action - anti-inflammatory
Rey’s syndrome + salicylism associated
Paracetamol
Inhibits both COX-1 and COX-2, acts by reducing active site of enzyme required to produce PGH2 and PGG2, poor anti-inflammatory but anti-pyretic and analgesic
Dog also inhibits COX-3 = expressed in brain
Ondansetron
5-HT3 receptor antagonist
Used in the treatment of Emesis (HT3 receptors present in CTZ + vomiting centres in medulla)
Scopolamine
Non-selective muscarine antagonist, anti-emetic through actions on M1 receptors - inhibits inputs from the labyrinth ?
Aprepitant
Neurokinin-1 receptor antagonist
Anti-emetic - prevents signalling of emetic stimuli
Metoclopramide
Dopamine D2 receptor antagonist
Anti-emetic - prevents sensing of toxic stimuli in gut
Pheothiazines
Dopamine D2 receptor antagonists
Anti-emetics = prevents signalling of toxic stimuli from gut
Summatriptan
5-HT1b/d/f receptor agonist
Used in the treatment of Migranes
Inhibits nociceptor activity and causes vasoconstriction
Associated with coronary disease as causes constriction in small vascular bed also, poorly absorbed, short duration of action and cannot cross the BBB
Naratriptan
5-HT1b/d/f receptor agonist
Used in the treatment of migranes
Inhibits nociceptor activity and causes vasoconstriction
Can cross the BBB and has no cardiac associated side effects
Telcagepant
Calcitonin gene related peptide receptor antagonist
Clinical trials for treatment of migranes
CGRP is a potent vasodilator and carrier of nociceptive information - activated by TNF and iNOS
Topiramate
Anti-migrane
Acts on Ion channels, GABA receptor and voltage gated sodium channels - reducing nocioceptive transmission
Methylsergide
5-HT2 receptor antagonist
Used in the treatment of migranes
Dexamethasone
Synthetic corticosteroid, acts to suppress immune response, biological half life over 48hrs
Prednisolone
Glucocorticoid / Corticosteroid - acts to suppress immune system, anti-inflammatory
Fludrocortisone
Mineralocorticoid agonist - actions on salt and water metabolism
Metyrapone
Acts to inhibit the action of ACTH on adrenal cortex and hence the production of glucocorticoids
Mitotane
Acts to inhibit the action of ACTH on adrenal cortex and hence the production of glucocorticoids
Trilostane
Acts to inhibit the action of ACTH on adrenal cortex and hence the production of glucocorticoids
Formoterol
B2 adrenoreceptor agonist, used prophylatially in asthma to relieve bronchospasm by vasodilation through inhibition of myosin light chain kinase
Long acting due to lipophillic tail inserting into plasma membrane
Indancaterol
B2 adrenoceptor agonist, used prophylatcially in asthma but also for chronic pulmonary obstructive disorder, dilates bronchi through inactivation of myosin light chain kinase, long lasting action due to lipophillic tails inserting into membrane - drug reservoir
Beclametasone
Inhaled corticosteroid
used prophetically in the treatment of asthma, act to suppress underlying inflammation
Fluticasone
Inhaled corticosteroid
Used prophetically in the treatment of asthma, acts to suppress underlying inflammation
Clenbutarol
Prescribed to horses suffering with recurrent airway obstruction acts as a bronchodilator
Methotrexate
DMARD - Anti-proliferative
Inhibits folic acid synthesis reducing tetrayhrofolate production required for nucleotide synthesis in the proliferating cells - T cells
Reducing immune response - effects after 8-10 weeks
Can result in low leukocyte count however
Sulfasalzine
DMARD - Converted into sulfapyridine by colonic bacteria, thought to retrieve ROS from neutrophils therefore reducing their potential damage
3 months to see effects
Also used in Inflammatory bowl disease, and cause GI disturbances, stains tears yellow
Penicillamide
DMARD - Hydrolysis product of penicillin, decreases Il-1 synthesis as well as collagen generation and maturation
Also has reactive thiol group which can act as a cheltalator for heavy metal poisoning and in Wilson’s disease
Can cause rashes and disturbances in taste
Sodium Aurothiomalate
DMARD - Gold compound, mechanism uncertain, thought to inhibit / reduce Il-1 and TNF-a induction, can accumulate in tissues increasing half life, takes months to show affect
side effects include cyriasis, mouth ulcers, grey discolouration
IM administration
Auranofin
DMARD - Gold compound, mechanism uncertain, thought to inhibit / reduce Il-1 and TNF-a induction, can accumulate in tissues increasing half life, takes months to show affect
side effects include cyriasis, mouth ulcers, grey discolouration
Oral administration
Hydroxychloroquine
DMARD but also anti-malarial treatment, lipophilic weak base, seen to accumulate in acid cytoplasmic vesicles and inhibit both antigen presentation and ROS generation
Used when refractory to other DMARD’s
Etanercept
DMARD - Fusion protein of soluble TNF-a receptor and FC portion of IgG used to mop up excess TNF-a
Infliximab
Chimeric antibody against TNF-a , used as a treatment in rheumatoid arthritis
Adalimumab
Humanised monoclonal antibody against TNF-a, used as a treatment in rheumatoid arthritis
Anakinra
Recombinant IL-1 receptor antagonist, used in the treatment of rheumatoid arthritis
Rituximab
Monoclonal antibody against CD20 expressed on B-cells leading to their destruction
Tolcilizumab
Monoclonal antibody against Il-6, used in the treatment of rheumatoid arthritis
Cyclophosphamide
Immunosuppressant - Cross links guanine in DNA preventing its replication and hence immune cell proliferation, pro-drug which must first be converted via cytochrome p450 into phosphoramide mustard which has two alkylating groups, can cause bone marrow suppression and bladder irritation
Ciclosporin A
Immunosuppressant - cyclic 11 amino acid protein, acts to inhibit Il-2 synthesis and hence activation and clonal expansion of T-cells
Binds to cytoplasmic protein cyclophillin which as a complex inhibits calcinurin
Calcinurin is a serine-threonine phosphatase which would act on the Nuclear factor of the T-cell promoting its translocation to the nucleus to promote IL-2 synthesis
Used in transplants and against canine atopic dermatitis
Tacrolimus
Immunosuppressant - Macrolide antibiotic, binds to FK-binidng protein in cytoplasm which acts to inhibit Calcinurin and therefore IL-2 synthesis
Basiliximab
Immunosuppressant - Monoclonal antibody against the CD25 region of the IL-2 receptor, acts and an antagonist preventing activation of T and B cells, used to prevent transplant rejection
Sirolimus
Macrolide antibiotic, binds to FK-binding protein within cytoplasm and acts to inhibit mTOR ( a serine threonine kinase involved in cell cycle progression), this results in decreased T-cell proliferation
Used as an immunosuppressant and for restenosis
Rapamycin
Macrolide antibiotic, binds to FK-binding protein within cytoplasm and acts to inhibit mTOR ( a serine threonine kinase involved in cell cycle progression), this results in decreased T-cell proliferation
Used as an immunosuppressant and for restenosis
Azathioprine
Immunosuppressant - used to inhibit T and B cell protein synthesis and hence proliferation
First converted in TIMP which is then converted by TPMT into meTIMP which inhibits de novo protein synthesis
TIMP can also be converted via IMPDH into 6-guaninucleotides which are inserted into the DNA and inhibit synthesis - selective for cells without a salvage pathway such as B and T cells
Used in the treatment of rheumatoid arthritis and irritable bowl disease
Alemtuzumab
Humanised monoclonal AB against CD52 found on mature lymphocytes, targets them for destruction, used in the treatment of chronic lymphocyte leukaemias and cutaneous T-cell lymphoma
Catumaxomab
Rat/ Mouse hybrid bispecific AB, targets both the CD3 + epithelial-CAM on the tumour cell and T-cells, the FC region then binds to macrophages, this allows the killing machinery to be localised and T-cells activated
