Immunosuppression Flashcards
Omalizumab
Monoclonal antibody against IgE, used to treat urticaria (exaggeration of triple response) and allergic asthma. Omalizumab is built on an IgG framework and so does not activate FcεRI itself.
Sodium cromoglycate
Reduces Ca2+ influx into mast cells by inhibiting a Cl- conductance that is usually needed to maintain a negative potential for Ca2+ influx.
Prevents degranulation, eye drops for hay fever/allergic rhinitis, also used for mastocytosis, asthma.
Not useful to treat RAO (asthma equivalent in horses) since neutrophils play a larger role than mast cells.
β2-adrenoceptor agonists + PDE inhibitors
Raising [cAMP] inhibits mast cell degranulation.
Mepyramine
1st generation H1 antagonists. Causes drowsiness. Used topically for insect bites
Terfenadine
2nd generation anti-histamine, inhibited Kv11.1/hERG causing long QT syndrome/torsades de points syndrome. Prodrug (with respect to its anti-histamine action) metabolised by CYP3A4 to fexofenadine.
Fexofenadine
3rd generation anti-histamine (non-drowsy), used to treat hay fever, allergy, urticaria
Loratadine
3rd generation anti-histamine (non-drowsy, no cardiac side-effects), used to treat hay fever, allergy, urticaria
Adrenaline
Used for anaphylaxis. Counteracts systemic vasodilation, increases cAMP to inhibit mast cell degranulation, relieves bronchospasm. Noradrenaline is not used as it’s such a strong vasoconstrictor that it causes reflex bradycardia.
Imatinib
Receptor tyrosine kinase inhibitor used to treatment mastocytosis (ineffective in people with common c-kit/D816V mutation).
Oclacitinib
JAK inhibitor, used to treat allergic dermatitis in dogs
Proglumide
CCK2 receptor antagonist. Inhibits histamine release from ECL cells.
Cimetidine
H2 receptor antagonist but inhibits CYP enzymes.
Ranitidine
H2 receptor antagonist.
Omeprazole
Proton pump inhibitor. Treats peptic ulcers.
Converted to their active form in the acidic environment of the parietal cell and form disulphide bonds with the K+/H+ pump.
Issues: Broken down by H+, have a slow onset to maximal effectiveness, predominantly metabolised by CYP2C19, which exhibits significant genetic polymorphism.
Vonoprazan
Potassium-competitive acid blocker (P-CAB). Treats peptic ulcers.
Competes with the K+ binding site, has greater stability than PPIs in H+, CYP2C19 is less vital in its metabolism
Gaviscon
Antacid that neutralises stomach pH
Misoprostol
PGE1 analogue. Treats peptic ulcers.
Action of PGE2 include:
(1) Acts on EP2/3 receptors on ECL cells to decrease histamine release.
(2) Acts on EP4 receptor to increase mucin release
(3) Acts on EP1/2 receptors to increase bicarbonate release.
Arthrotec
Diclofenac (a NSAID) + misoprostol. Misoprostol acts to prevent NSAID-induced ulceration.
Diclofenac
NSAID: Non-selective COX inhibitor, used in treating chronic inflammation. Used to lessen pain and inflammation in rheumatoid arthritis and lessen pain in osteoarthritis and SLE.
Icatibant
B2 receptor antagonist used in the treatment of HAE.
Tanezumab
Anti-NGF antibody, in clinical trials for pain relief for osteoarthritis.
Montelukast
CysLT1 receptor antagonist, use in treatment of asthma.
Ibuprofen
NSAID: Non-selective COX inhibitor, used as analgesic, antipyretic and anti-inflammatory.
Etoricoxib
COX-2 selective inhibitor, used for chronic inflammation in patients that don’t have a substantial cardiovascular risk.
All NSAIDs have following side effects: GI bleeding (COX-2 selective inhibitors show lower GI side effects), renal insufficiency, increased myocardial infarction risk (also with COX-2 selectives since COX-2 is constitutively expressed in coronary VSMCs), bronchospasm (mechanism unknown).
Aspirin
Irreversibly inhibits COX by acetylating Ser530, and turns into salicylate, a reversible COX inhibitor. Weakly COX-1 selective.
Used to reduce risk of platelet aggregation.
Irreversible means that low doses can be used to minimise side effects.
Acetylated COX-2 forms ATL (15R-epi-lipoxin A4) which has similar functions to LXA4 so aspirin is also an anti-inflammatory.
Reye’s syndrome: Hepatic encephalopathy that occurs in children.
Salicylism: Metabolic acidosis due to disrupted carbohydrate metabolism. Leads to respiratory depression and coma. Treatment: (1) administer fluids, (2) bicarbonate to enhance aspirin elimination, (3) activated charcoal to adsorb aspirin, (4) haemodialysis.
Don’t use in cats.
Paracetamol
Analgesic, anti-pyretic, poor anti-inflammatory. Weakly COX-2 selective, but COX-3 selective in canines. Acts by reduction of active site in COX enzymes required to produce PGH2 from PGG2.
Metabolised by glucuronidation, sulphonation, or CYP2E1. Sulphonation first to saturate, then glucuronidation. CYP2E1 converts paracetamol to NAPQI which causes hepatotoxicity and is detoxified by glutathione. Alcohol upregulates CYP2E1 and fasting decreases glutathione levels.
Don’t use in cats and dogs.
N-acetylcysteine
Increases hepatic glutathione production .
Phenylbutazone
NSAID used mainly in horses, many side effects in humans.
Robenacoxib
COX-2 selective inhibitor used in cats and dogs.
Firocoxib
COX-2 selective inhibitor used in dogs and horses.
Ondansetron
5-HT3 antagonist. Anti-emetic.
Cyclizine
H1 receptor antagonist. Anti-emetic.
Metoclopramide
D2 receptor antagonist. Anti-emetic. Can cause acute dystonia due to striatal D2 receptor inhibition.
Scopolamine
Non-selective muscarinic receptor antagonist, acts via M1 as an anti-emetic.
Sumatriptan
5-HT(1B/D/F) agonist used for migraine. 5-HT(1B) causes vasoconstriction and 5-HT(1D/F) inhibits nociceptor activity.
Vasoconstriction can be bad so sumatriptan is contraindicated in coronary disease.
Can’t be taken orally and doesn’t cross BBB.
Lasmiditan
5-HT(1F) agonist being developed for potential migraine treatment.
Naratriptan
5-HT(1B/D/F) agonist used for migraine. Longer half life than sumatriptan, can cross BBB, fewer side effects.
Botulinum toxin A
Decreased neurotransmitter release from nociceptors due to SNARE cleavage.
Erenumab
Monoclonal antibody against the CGRP receptor, used for migraine.
Hydrocortisone
Short acting corticosteroid, anti-inflammatory. Inhibits neutrophil degranulation (mechanism unknown).
Use of corticosteroids in general: Asthma, inflammatory skin conditions, autoimmune conditions, reduce cerebral oedema, Addison’s disease (primary adrenal insufficiency).
Side effects of corticosteroids: Opportunistic infection, oral thrush, muscle wasting, stomach ulcer, hyperglycaemia, osteoporosis, avascular necrosis of femoral head, psychiatric effect.
Betamethasone
Long acting corticosteroid, anti-inflammatory. Reduces nasal itching within 10 minutes (mechanism unknown).
Beclomethasone
Regular inhaled corticosteroid for asthma. Not for acute attacks as corticosteorids effect gene transcription.
Theophylline
PDE inhibitor producing increased cAMP, used prophylactically for mast cell stabilisation and bronchodilation in treatment of asthma and COPD (NOT for acute attacks).
Raising cAMP levels in neutrophils can also prevent its degranulation.
Fluticasone
Corticosteroid, can be used as anti-inflammatory in cats and horses.
Clenbutarol
β2-adrenoceptor agonist, used to treat recurrent airway obstruction in horses.
LABA + LAMA, no corticosteroids
Fibroblast proliferation means bronchoconstriction is irreversible. So SABA + SAMA not effective.
Peroxynitrite (ONOO-) nitrates HDAC2, causing its ubiquitination. Lack of HDAC2 means increased acetylation of GRα, preventing it from inhibiting NFκB-induced inflammation.
Roflumilast
Selective PDE type IV inhibitor used for COPD since PDE type IV is the main PDE in neutrophils, T cells, and macrophages.
Naproxen
Non-selective COX inhibitor.
Methotrexate
DHFR inhibitor used as a DMARD. Targets rapidly proliferating cells such as immune cells. Taken weekly (NOT daily since it can cause bone marrow suppression).
Often used with a ‘biological DMARD’ to reduce risk of neutralising antibodies developing.
Sulfasalazine
DMARD. Broken down to sulfapyridine and 5-aminosalicylic acid. 5-aminosalicylic acid scavenges ROS from neutrophils.
Hydroxychloroquine
DMARD and anti-SLE drug. Reduce macrophage antigen presentation and neutrophil ROS generation for RA, and reduces interferon production for SLE (TNFα, IL-6, interferon, BlyS upregulated in SLE).
Leflunomide
DMARD. Inhibits dihydroorotate dehydrogenase and thus pyrimidine synthesis. Inhibits rapidly dividing B and T cells.
Etanercept
DMARD. Fusion protein of the soluble TNFα receptor and Fc portion of IgG1 to mop up TNFα.
Can cause drug-induced lupus and MS.
Infliximab
DMARD. Anti-TNFα mAb.
Can cause drug-induced lupus and MS.
Adalimumab
DMARD. Anti-TNFα mAb. Can cause MS.
Tocilizumab
DMARD. Anti-IL-6 receptor mAb. IL-6 drives production of acute phase proteins by hepatocytes like CRP.
Rituximab
DMARD. Anti-CD20 mAb. CD20 is expressed by B cells. Can cause PML due to reactivation of JC virus. NOT useful for SLE since CD20+ B cells are not important in SLE.
Also treats non-Hodgkin’s lymphoma and Hodgkin’s disease.
Abatacept
DMARD. Synthetic fusion protein of CTLA-4 and Fc ragment of IgG1. Binds to B7 on dendritic cells to prevent naive T cell co-stimulation.
Belatacept is NOT a DMARD
Anakinra
DMARD. Recombinant IL-1 receptor antagonist. Binds to IL-1 receptor with a higher affinity than IL-1 itself.
Capsaicin
TRPV1 agonist to cause depolarising block of nociceptors. Used in osteoarthritis.
IRAP
IL-1 receptor antagonist protein, used to treat osteoarthritis in horses. IL-1, IL-6, TNFα levels are upregulated in osteoarthritis (but it’s a NON-inflammatory disorder due to low leukocyte count).
Lispro
Insulin analogue made by swapping lysine and proline at C-terminus end of B chain reduces hexamer formation. Monomeric insulin is very fast acting.
Actrapid
‘Normal’ insulin - short acting. Forms hexamers then dissociates.
Neutral protamine hagedorn (NPH)
Suspension of protamine and insulin which forms relatively insoluble crystals, slowing absorption. Intermediate acting.
Glargine
Amino acid changes causes isoelectric point to shift upwards to a more neutral pH. Forms a precipitate of stable hexamers and higher aggregates. Long acting.
Metformin
Activates AMPK which: Decreases hepatic gluconeogenesis Increased skeletal muscle glucose uptake Decreased carbohydrate absorption Decrease VLDL, LDL production (many diabetics are obese) Decrease appetite, decrease weight.
Metformin does NOT cause hypoglycaemia (unlike injecting insulin), but causes lactic acidosis as it inhibits hepatic lactate uptake. Contraindicated in alcoholics or those with renal insufficiency (usually the elderly).
Glibencamide, Glipizide, Tolbutamide
Bind to SUR1 subunit to close K(ATP) channels.
Glipizide is broken down into inactive products, glibencamide is not, so is contraindicated in those with renal failure (usually the elderly). Also contraindicated in pregnancy.
Can cause hypoglycaemia and increase appetite to cause weight gain.
Repaglinide
Bind to SUR1 subunit to close K(ATP) channels. Have faster onset and offset kinetics than SUs.
Less likely to cause hypoglycaemia. Also increases appetite and cause weight gain.
Exenatide
GIP and GLP-1 are incretins secreted by K and L cells of the gut respectively. They increase insulin secretion and decrease glucagon secretion, and decrease rate of food absorption in the gut. GLP-1 also decreases appetite and decrease weight.
Exendin-4 mimics GLP-1, and exenatide is a synthetic version of exendin-4.
Sitagliptin
Inhibits DPP-4. GIP and GLP-1 are brokendown by DPP-4.
Dapagliflozin
SGLT2 inhibitor, so increases renal excretion (so causes weight loss) and decreases GI glucose absorption.
Causes unexplained increase in ketone production in liver.
Pioglitazone
PPARγ agonist. Increases GLUT4 transcription. Increases Na+ reabsorption via ENaC channels so increases weight.
Contraindicated in those with heart failure, which a lot of diabetics also have!
PPARγ (and PPARα) also upregulates LXR which upregulates ABCA1. ABCA1 controls cell’s phospholipid and cholesterol efflux into lipid-poor HDLs (HDL brings this cholesterol back to liver).
Acarbose
α-glucosidase inhibitor. Slows breakdown of starch into glucose so slows rate of GI glucose absorption and reduces weight.
Belimumab
Anti-BlyS, reduces B cell activity. Used for SLE.
Azathioprine
Prodrug for 6-mercaptopurine. Turns into TIMP then
(1) MeTIMP which inhibits de novo purine synthesis
(2) 6-TGN which inhibits nucleotide and protein synthesis.
Targets cells that lack a ‘salvage pathway’ to synthesise nucleotides such as B and T cells.
Used to prevent rejection of transplanted organs and in IBD, RA.
Mycophenolic acid
Inhibits IMPDH, an enzyme important for de novo guanosine synthesis. Like azathioprine, has greatest effect on B and T cells.
Used to prevent rejection of transplanted organs and in MS.
Cyclophosphamide
Nitrogen mustard alkylating agent. Converted to aldophosphamide then to phoshporamide mustard by CYP enzymes.
Alkylating guanine results in inter- or intrastrand crosslinks, preventing DNA replication. If the second side chain reacts with H2O instead of a guanine, a monoalkylated guanine is produced, which can base pair with thymine. Hence there’s a G-C to A-T base pair change. Also strand scission may occur when DNA repair systems try to repair alkylated DNA.
Has greatest effect on B and T cells. Can cause bladder cancer via the metabolite acrolein, and other side effects via reactions with other nucleophilic groups in DNA, RNA, protein.
Treats autoimmune conditions and cancer.
Ciclosporin A
Binds to cyclophilin. CsA-CpN complex inhibits calcineurin, preventing NFAT dephosphorylation and entering nucleus. Usually NFAT goes to nucleus to upregulate IL-2 production.
Used to prevent rejection of transplanted organs.
Tacrolimus (FK506)
Binds to FKBP. FK506-FKBP complex inhibits calcineurin, preventing NFAT dephosphorylation and entering nucleus. Usually NFAT goes to nucleus to upregulate IL-2 production.
Used to prevent rejection of transplanted organs.
Basiliximab
mAb against CD25, the α subunit of IL-2 receptor. Used to prevent rejection of transplanted organs.
Belatacept
Synthetic fusion protein of CTLA-4 and Fc ragment of IgG1. Binds to B7 on dendritic cells to prevent naive T cell co-stimulation.
Used to prevent rejection of transplanted organs.
Belatacept is NOT a DMARD.
Theralizumab (TGN1412)
Anti-CD28 agonist. Activation of CD28 alone can cause proliferation of Treg cells. Need low doses or else memory inflammatory T cells are also activated causing a cytokine storm.
Sirolimus
Binds to FKBP. Sirolimus-FKBP complex inhibits mTOR1. Decreases T cell proliferation. Used to prevent rejection of transplanted organs and for drug-eluting stents.
Muromonab-CD3
Targets CD3 present on T cell co-receptor. Used to prevent rejection of transplanted organs.
Alemtuzumab
Targets CD52, an antigen on mature lymphocytes but not stem cells. Treats T cell lymphomas.
Catumaxomab
Bi-specific antibody. Binds EpCAM on tumour cells and CD3 on T cells. Tri-functional because Fc receptor can activate target cell.
Trastuzumab emtansine (T-DM1)
Trastuzumab binds and disrupts HER2 signalling, whilst DM1 disrupts tubulin polymerisation.
Caplacizumab
Nanobody against VWF, treats thrombotic thrombocytopenic purpura (caused by lack of ADAMTS13).
