Anti-inflammatory & Immunosuppressive Drugs. Regal. 05.05 & 05.06 2009.
Redundancy- many difft substances or mediators can cause the sxs of inflammation.
Acute Inflammation:
-arteriolar dilation  ↑ed flowstasis… redness & heat
-postcapillary venules leak…swelling
-leukocyte infiltration thru postcapillary venules…chemotaxis
(pain-nerve endings stimulated by mediators or ↑ed P)
Acute Inflammation is caused by any variety of mediators depding on the sitn.
Inflammatory mediators
Histamine- limited clinical use. Inhalation- assesses bronchial reactivity. Intradermally to
assess integrity of sensory neurons.
Synthesis: Histidine – L-histidine decarboxylase Histamine
-Site: MOST stored in mast cells & basophils (SLOW TURNOVER). Bound to heparin-protein
complex w/in granules via ionic bonds. SMALL AMT in CNS nerve endings, epidermis, &
BM/wounds (RAPID TURNOVER).
-Endogenous release: by immunological stimuli (Ag + IgE ab on mast cells & basophils from
Previous exposure  ASTHMA, HAYFEVER, ATOPIC ECZEMA)
-Release by other substances: Non-cytolytic release (SIGNIFICANT IF DRUGS GIVEn IV IN
HIGH DOSES) includes basic substances, C3a/C5a (anaphylatoxins), kinins, protamine
(heparin antagonist), dextrans & plasma substitutes, morphine, & curare alkaloids. Cytolytic
release includes mechanical/thermal insult & venoms w/ enzymes like PLA.
Serious symptoms of acute inflammation:
-Airway constriction
-Hypotension- seen in shock
-Fever
Summary by Symptoms:
Redness - Vasodilation
Histamine
PGE2
PGI2
Kinins
Swelling - Increased vascular permeability
Histamine
Peptido leukotrienes
Kinins
Pain - Causes pain or reduces the pain threshold
PGE
PGI
LTB4
Kinins
Degradation (Metabolism): N-methyltransferase & diamine oxidase(histaminases) are specific
for histamine. Metabolites have little activity, enzymes widely distributed, non-specific enzymes exist
too.
Chemotactic - Directed migration of white blood cells
-In oral dose it’s INACTIVATED by diamine oxidase in intestinal wall or liver; additionally
Intestinal bacteria convert it to N-acetylhistamine.
LTB4 (neutrophils, etc)
Peptido leukotrienes (eosinophils)
Biological activities: redness, heat, swelling, hypotension & airway constriction
NOT CHEMOTAXIS.
-In intracutaneous dose a “triple response” results  itching, pain, redness (fast),
wheal (edema) & flare (fast)(urticaria/hives). Ag-ab rxn too.
-In intranasal dose (Hayfever)intense itching, sneezing, hypersecretion, nasal blockage
-In IV dose: hypotension, ↑ vascular permeability & fluid loss, sometimes secondary
Hypertension due to histamine-induced release of catecholamines from adrenal medulla.
Tachycardia due to hypotension, bronchoconstriction (asthmatics), flushing of face,
headache (cerebrovascular dilation), urticaria/hives, mucus & gastric acid secretion.
FEVER
PGEs induce fever
Airway constriction = Bronchoconstriction (Relevant
for Type 1 hypersensitivity in lungs)
Histamine
Peptido leukotrienes
Kinins
PGD2
Hypotension = Decreased blood pressure (Relevant
in shock)
Kinins
Histamine
Receptors: FcR of IgE on mast cells & basophils. H1, H2, H3, H4.
H1: bronchoconstriction, contraction of GI SM, ↑ed capillary permeability (wheal), itch, &
release of catecholamines from the adrenal medulla.
H2: gastric acid secretion, inhibition IgE-mediated basophil histamine release (histamine release by ag feeds back to turn off its own release,
antagonist not relative for whole body), inhibition of T lymphocyte mediated cytotoxicity, & suppression of Th2 cells & cytokines.
H3 & H4: on histaminergic nerve terminals (H3) & many immune cells (H4:eosinophils, dendritic cells, T cells, neutrophils). No clinical significance
yet.
Mixed H1 & H2 responses: cardiac effects (↑HR, ↑ F of contraction, ↑ arrhythmias, & slows AV conduction (primarily H1)), vasodilator effects
(H1- rapid dilator response that is short-lived & H2- a dilation that develops more slowly & is more sustainedtherefore an antagonist of just one
won’t get rid of all vasodilation), triple response (H1 & H2- vasodilation, H1- flare, primarily H1- wheal), & nasal symptoms (H1-intense itching,
sneezing, hypersecretion, & nasal blockage; H2- nasal blockage & mucous production).
Synthesis:
AA comes from phospholipids in the cell membrane.
PLA2 is needed. In future may see PLA2 inhibitors.
IMPT limiting step.
Note: OOH & epoxide in first two steps.
FLAP- transport of 5-lipoxygenase from cytosol to the
membrane
LTC 4 synthase (mast cell or basophil) OR glutathione
S transferase (endothelial cell, SM cell, etc)
Site: lipoxygenase products are in many cells & tissues. Other enzymes are found in
myelomonocytic origin as well as endothelial cells/platelets, which do not have
5-lipoxygenase.
LTA4 is made in 5-lipoxygenase containing cells & has 3 difft fates:
-LTB4 formation in a cell which contains LTA4 hydrolase (PMN).
-LTC4 formation in a cell which contains either LTC4 synthase (mast cell or basophil) or
glutathione S transferase (endothelial cell, SM cell).It is then transported out of cell &
converted to LTD4 or LTB4.
-transcellular metabolism in other cells to LTC4 (endothelial cell, SM cell) or LTB4 (rbc &
platelet).
LTB4
Biological activities: chemotactic (PMNs), leukocyte adhesion, enzyme release, ROS
production & ↓es pain threshold. Found in synovial fluid of RA & gout.
Degradation: oxidized by enzymes in PMN’s & other oxidative enzymes to inactive cmpds.
Receptors: LTB4 Receptor on other cell types.
LTC4, LTD4, LTE4 (Peptido leukotrienes)
Biological activities: Cys LTR1bronchoconstriction, ↑ vascular permeability (swelling), chemotaxis (eosinophils), ↑ mucous production,
dendritic cell maturation & migration, SM proliferation. Cys LTR2 endothelial cell & macrophage activation, as well as fibrosis. LTC4/LTD4impt in asthma. SLOW REACTING SUBSTANCE OF ANAPHYLAXIS (SRS-A).
Degradation: LTE4 is excreted in the urine or acetylated & excreted in the bile.
Receptors: Cys LTR1 preferentially w/ LTD4  airway constriction; is blocked by current receptor antagonists, while cys LTR2 preferentially w/
LTC4 & LTD4 cell activation.
Phospholipids in
cell membrane
Prostanoids
Synthesis: By phospholipase A2, which takes off the FA at C2. Other acylhydrolases
release AA from memb phospholipids. The availability of AA is a control step in the
production of prostaglandins & thromboxane; these are derivatives of prostanoic acid
(20C FA w/ cyclopentane ring). Subscripts = # doubles bonds. For PG2’s the precursor
is AA. For PG1’s the precursor is 8,11,14 – eicosatrienoic acid (ddddihomo-gammalinolenic acid).
COX-1: found in platelets, CONSTITUTIVELY EXPRESSED in most cells & protects gastric
Mucosa.
COX-2: Not found in platelets, expressed constitutively in brain & kidney, but can be
INDUCED BY certain serum factors, cytokines, & gfs in other tissues & at sites of inflam.
MORE IMPT ISOZYMEPROSTAGLANDINS & THROMBOXANE in inflammation.
Prostaglandins can also be the mediators of the mediators.
Degradation of cyclooxygenase products: unstable molecules w/ short half lives.
Spontaneous chemical hydrolysis. Uptake into cells by transport protein & subsequent
enzymatic degradation.
Biological activities: local actions (autocoids).
Receptors: On cell membrane- dictate action of cyclooxygenase product.
Five major types of receptors for prostaglandins (seven transmemb G protein coupled)
-DP (PGD), FP (PGF), IP (PGI2), TP (TXA2) & EP (PGE).
-Unique Gs,GiGq G-proteins for difft PG receptor subtypes
-Unique second messangers for difft PG receptor subtypes
Phospholipase A2
Epoxygenase products
(vasodilators)
Isoprostanes
(vasoconstrictors?)
Cyt P450
Arachidonic Acid
Cyclooxygenase
COX
Prostanoids
(PG & TX)
Lipoxygenase
LOX
Leukotrienes
PGD2
Synthesis: produced by MAST CELLS
Biological activities: bronchoconstriction
Receptor: DP
PGE2
Biological activities: vasodilate (redness), ↑ vascular permeability (& synergize w/
PGI2), CAUSE pain (lower threshold- synergizes w/ PGI2), & FEVER (IL-1Pg’sFever).
Receptor: EP
PGF2
Direction PGH2 goes dpds on what is in the cell.
Cytokines
Bradykinin
Receptor: FP
Prostaglandins
Pain
Other
mediators
PGI2 (prostacyclin)-
Synthesis: produced by ENDOTHELIUM
Biological activities: vasodilate (redness), ↑ vascular permeability (& synergize w/ PGE), CAUSE pain (lower threshold- synergizes w/ PGE),
OPPOSE platelet aggregation, & vasodilation (SM dilation). Second messanger is cAMP.
Receptor: IP, Gs
TXA2 (thromboxane)-
Synthesis: produced by PLATELETS.
Biological activities: bronchoconstriction, CAUSE platelet aggregation & vasoconstriction. Second messanger is IP3/DAG/Ca2+.
Receptor: TP, Gq
Kinins- relevance to be detmd. Deficiency of HMW kininogen or prekallikreinclotting & fibrinolytic defects w/ ↓ kinin.
Kallikrein inhibitors & kinin receptor antagonists are useful in C1 inhibitor deficiency (HAE)- recurrent episodes of localized
edema in skin, GI, or larynx. C1INH is primary inhibitor of kallikrein. Excess kinin also is assoctd w/ pain in dental extractions,
nasal allergy or rhinitis assoctd w/ rhinoviral infection.
Interrelationship btwn Kinin, complement, coagulation & fibrinolytic pathways- all intertwined.
Synthesis-NOT in cells rather in extracellular blood or interstitial fluid. Injury initiates this pathway.
HFa
Plasmin
Prekallikrein
Plasma kallikrein
HMW kininogen
Kininase I & II
Tissue kallikrein
LMW kininogen
Hfa=activated Hageman factor, part of clotting
cascade.
Plasmin digests fibrin.
Bradykinin (9 a.a.)
Kallidin (10 a.a.)
Biological activities: everything + strong vasodilator resulting in hypotension. NOT A MAJOR CHEMOTACTIC AGENT.
Degradation: Kininase I- Carboxypeptidase N or anaphylatoxin inactivator removes the carboxy terminal arginine
Kininase II- Angiotensin converting enzyme (ACE) or dipeptide dihydrolase cleaves btwn Pro-Phe. Works at both sites, inhibiting vasoconstriction &
allowing vasodilation.
Bradykinin (Arg….ProPheArg)
Biological activities: Mediators w/ inflammatory activities.
Kallidin (LysArg…..ProPheArg)
Biological activities: Mediators w/ inflammatory activities.
Receptors:
Via B2 Receptor: Kallidin & Bradykinin more active than w/o removal of arg. Potent vasodilators, hypotension, ↑ed capillary permeability &
edema formation, CAUSE pain, slowly contract the gut SM, bronchoconstriction, release catecholamines form the adrenal medulla, & release
PGs.
Via B1 Receptor: Des-arg Bradykinin & Kallidin are more active. Chronic inflammatory effects, induced after trauma, maybe involved in cytokine
production & more long term effects, hypotension & pain.
Antihistamines (H1)
Mechanisms of action- target a single mediator & are inverse agonists (preferential affinity for inactive state of histamine 1 Gprotein receptor”nothing happens”) Note: historically referred to as competitive antagonists of histamine. THINK OF SHIFT
DOSE RESPONSE CURVE. NO BENEFITS FOR COLDS!
Mostly, antihistamines shift the agonist doseresponse curve to the right & look like a
competitive antagonist.
Response
Histamine
Old Antihistamines:
Mechanism of action: blockade of H1, muscarinic, alpha adrenergic, & SE receptors. Used as ophthalmic solutions, for allergies (allergic rhinitis,
urticaria, atopic dermatitis), motion sickness, & NOT FOR ASTHMA.
Side effects:
-Sedation including potentiation of CNS depressants such as barbs or alcohol, dizziness, incoordination, blurred vision, nervousness, insomnia,
tremors, & may interfere w/ learning or work productivity.
-Drying of secretions: due to anticholinergic properties (atropine-like)
-GI disturbances: reduced by giving the drug w/ meals & not necessarily related to H1 antagonism.
Distribution: Well absorbed orally, widely distributed including CNS. Not recognized by the P-glycoprotein efflux pump on the endothelial cells in
the vasculature of the CNS. Therefore, they are NOT PUMPED OUT OF THE CNS.
Metabolism/excretion: transformed to inactive metabolites in the liver & excreted in the urine.
Toxicity: topical application not recommended bc allergic dermatitis can devp. Acute poisoning resembles atropine poisoning w/ fixed-dilated
pupils, flushed face, fever, & dry mouth; also includes excitation, hallucinations, incoordination, convulsions; terminal use results in coma &
cardiorespiratory collapse. Tx for acute poisoning is symptomatic and supportive.
Diphenhydramine - Tylenol PM: low incidence of GI side effects & sedation. Good for motion sickenss (has to do w/ ACh antagonis) bc of
antimuscarinic properties. Use if want sedation.
Tripelennamine – GI side effects are common, less central effects, fewer anti-cholinergic effects.
Chlorpheniramine – Suitable for daytime use.
Newer Non-sedating Antihistamines:
Mechanism of action: Used for allergies (allergic rhinitis, urticaria, atopic dermatitis), & NOT FOR ASTHMA.
Side effects:
-Minimal anticholinergic properties
-No sedation or drying of secretions
-Do not potentiate effects of CNS depressants such as alcohol or barbs.
Distribution: ONLY SMALL AMTS CROSS THE BBB. These do have an affinity for P-glycoprotein efflux pump in endothelium of vasculature in
CNS, therefore they are pumped out.
Toxicity: CARDIOTOXICITY W/ ORIGINAL NON-SEDATIN ANTIHISTAMINES, drugs currently used are NOT cardiotoxic.
Cetirizine
Fexofenadine
Loratadine (now over the counter)
Newer H2 antihistamines: used for ulcers & gastric hypersecretory states. Inverse agonists.
Leukotriene modifiers
Mechanism of action- target a single mediator/inhibitors. Tx of chronic bronchial asthma & allergic rhinitis.
Zileuton
Mechanism of action- INHIBITS THE ENZYME 5-LIPOXYGENASE & thus prevents synthesis of LTB4 as well as the peptide-leukotrienes. Second
line for tx of chronic asthma.
Metabolism/Elimination: cyt P450
Toxicity: drug interactions, hepatic toxicity.
Zafirlukast
Mechanism of action- leukotrine receptor antagonists (esp LTD4 receptor, Cys LTR1). INHIBITS CYT P450 isozyme. Use in chronic asthma.
Toxicity: drug interactions
Montelukast
Mechanism of action- leukotrine receptor antagonists (esp LTD4 receptor, Cys LTR1). Use of asthma.
NSAID
Mechanism of action- target multiple mediators, but mostly stop cyclooxygenase synthesis & inhibit COX-1 & COX-2.
Analgesic, antipyretic (Inflammationcytokines (IL-1)PGE2HypothalamusFever, so inhibit PGE2 production to prevent
fever), & anti-inflammatory (don’t arrest the progression of pathological injury).
Side effects:
-GI ulceration bc of inhibition of PG synthesis, sometimes a secondary anemia can result, alcohol increases GI bleeding, can be
reduced w/ COX 2 inhibitors)
-Prolongation of gestation bc PGs help initiate labor & inhibiting COX1 or COX2 PREVENTS LABOR.
-COX1 inhibition in the plateletPREVENTS PLATELET AGGREGATION & TXA FORMATION. INCREASES BLEEDING
TIME.
-COX2 inhibition does not do this to same extent.
Toxicity- Large daily doses for years can result in analgesic abuse nephropathy- fluid retention, diminished sodium excretion,
nitrogen retention, hyperkalemia, oliguria (scanty urine), anuria. May lead to papillary necrosis & chronic interstitial neprhritis.
Hepatitis can happen too.
Acetylsalicylate (aspirin)
Mechanism of action: Irreversibly acetylates COX 1 (inactivates). The platelet cannot make more cyclooxygenase. The effect of aspirin lasts the
lifetime of the platelet (8-10 days).
Toxicity: Hypersensitivity- in 3-10% of asthmatics, sxs include rhinitis, urticaria, asthma, & laryngeal edema. Possible mechanisms include shift to
lipoxygenase pathway resulting in increase leukotriene production. Have also seen upregulation of Cys LTR1. Decreases in PGE2 may also
decrease the blockage of 5-lipoxygenase. Also associated w/ REYE SYNDROME bc anti-inflammatory does are close to toxic dosesencephalopathy & fatty liver following viral infection in kids. Can result in central hyperventival & intoxication & tinnitus w/ overdose.
Ibuprofen-OTC
Side effects: fewer GI than aspirin
Toxicity: Hepatitis.
Naproxen-OTC
Toxicity: Hepatitis
Diflunisal (also a salicylate)
Indomethacin
Most potent NSAID, severe frontal headache & blood dxs
Toxicity: Hepatitis
Sulindac
Toxicity: Hepatitis
Ketoprofen- related to Ibuprofen
Piroxicam- once a day administration, can cause serious GI bleeding
Drugs that inhibit cyclooxygenase:
-NSAIDs
-Cyclo-oxygenase inhibitors
-Aspirin-like drugs
-Analgesic, anti-inflammatory, anti-pyretic.
Names of drugs that Inhibit COX:
-Aspirin
-tNSAIDs
Ibuprofen (OTC)
Naproxen (OTC)
Diflunisal
Indomethacin
Sulindac
Ketoprofen
Piroxicam
-Selective COX2 inhibitors: Celecoxib
-Acetaminophen- not antiinflammatory
COX2 Inhibitor
Celecoxib-risk of thrombosis 200mb/day
Mechanism of action: 10-20X MORE SELECTIVE FOR COX2 inhibition. Safe in aspirin hypersensitive indls. No inhibition of platelet fxn, so
thromboxane can be produced. Less likely gastric ulceration & intolerance.
Toxicity: Reduce the production of prostacyclin (inhibitor of platelet aggregation) by endothelial cells. Balance favors platelet aggregation due to
↓ed PGI2 (prostacyclin).
Acetaminophen-not anti-inflammatory, not a NSAID.
Mechanism of action: Analgesic & antipyretic. Very weak inhibitor of cyclcooxygenase. Effectively inhibits COX in the BRAIN, but not at sites of
inflammation.
Toxicity: SERIOUS hepatic injury w/ large doses. Analgesic abuse nephropathy.
Anti-inflammatory steroids- Glucocorticoids
Mechanism of action- Target multiple mediators. We want to minimize drug
Action on the mineralcorticoid receptor. In response to ACTH
adrenal cortex synthesizestwo classes: corticosteroids & androgens.
Corticosteroids have glucocorticoid (carb metabolism regulating) activity
(& immune systemfamilies are regulated) & mineralcorticoid (electrolyte
balance regulating) activity. Given orally, parenterally, & topically.
Major Classes of Immunosuppressive Drugs:
-Glucocorticoids – anti-inflammatory steroids
-Calcineurin Inhibitors
-Antiproliferative/antimetabolic drugs
-Antibodies.
Primary uses:
-Autoimmune dx
-Transplantation
-Hemolytic anemia of the newborn
Activity
Prototype
Compound
Sodium
Retention
Liver
Glycogen
Deposition
AntiInflammatory
Mineralocorticoids
Glucocorticoids
Aldosterone
Cortisol
+
-
+
+
Inhaled glucocorticoids- enhanced uptake & prolonged tissue binding in airway w/ nearly
CRH=corticotrophin releasing
complete hepatic first pass inactivation.
hormone
Steroid GR complex also interacts w/ transcription factors such as NF-kB & AP-1 to repress gene expression.
Numerous effects on the immune system:
-cell movt: neutrophils (↑, yet blockage into inflammatory sites), lymphocytes (↓- moved to spleen, LNs, BM), monocytes
& eosinophils (↓ peripheral blood).
-synthesis &/or release of inflammatory mediators: ↓ expression of COX 2, inhibits AA from phospholipids ↓ing PG &
leukotriene formation, inhibits degranulation of mast cells & basophils, & inhibits synthesis & release of TNF, IL 1, IL 2 & IFN.
UNDERLYING CAUSE OF THE DX REMAINS, W/ SYSTEMIC ADMINSTRATION, SIDE EFFECTS ARE COMMON & CAN
BE LIFE-THREATENING. Also lowers resistance to microbial & fungal infections.
Numerous uses in NONENDOCRIN DXs: arthritis, renal dxs, systemic lupus, bronchial asthma, eczema, malignancies, etc.
Elimination/metabolism: In general, metabolized in liver & excreted by kidney.
Receptors: steroid receptors- time lag
Toxicity: prolongation of th ↑es the incidence of potentially lethal effects. There is also risk of adrenal insufficiency w/ abrupt
cessation of prolonged, high-dose thfever, myalgia, arthralgia, malaise, & death w/ hypotension & shock.
Primarily assoctd w/ SYSTEMIC ADMINISTRATION & large doses ↑ED SUSCEPTIBILITY TO INFECTIONIMMUNOSUPPRESSIVE, peptic ulceration, bxal disturbances, cataracts, osteoporosis & vertebral compression fractures, &
inhibition of growth.
Cortisol/Hydrocortisone- main glucocorticoid in humans.
Mechanism of action- endogenous. T ½= 8-12 hrs.
Betamethasone
Mechanism of action- synthetic, good anti-inflammatory. T ½= 36-72 hrs.
Dexamethasone
Mechanism of action- synthetic, good anti-inflammatory. T ½= 36-72 hrs.
Methylprednisolone
Mechanism of action- synthetic, okay anti-inflammatory. T ½= 12-36 hrs.
Prednisone
Mechanism of action- Synthetic, okay anti-inflammatory. T ½= 12-36 hrs Drug of choice for autoimmune dxs (ITP), autoimmune hemolytic
anemia, & acute glomerulonephritis. Also used for “autoreactive” tissue dxs & renal, heart, liver, & BM transplantation.
Immunosuppressive drugs
Mechanism of action- Target multiple mediators. Dampen the immune response (primary more so than secondary) in organ
transplantation, autoimmune dx, & hypersensitivity. The immune response is more likely to be inhibited if th is begun before
exposures to immunogen. Limitations include ↑ed risk for infections & lymphomas/malignancies.
Calcineurin Inhibitors: two drugs that stop T-cell activation
Cyclosporine
Mechanism of action- used in “autoreactive” tissue dxs. Also used in long term th for renal, heart, liver, & BM transplantation.
Binds to cytoplasmic receptor protein called cyclophilin, resulting in the inhibition of calcineurin activity. This blocks the dephosphorylation
events critical for cytokine gene expression & T cell activation.
Metabolism/Elimination: Metabolized in the liver.
Toxicity: potl for numerous drug interactions. RENAL TOXICITY, which must be distinguished from GRAFT REJECTION IN KIDNEY
TRANSPLANTATION. In as many as 75% of patients txd w/ cyclosporine.
Tacrolimus (FK506)
Mechanism of action- Used in renal, heart, liver, & BM transplantation. Binds to cytoplasmic receptor protein called FKBP, resulting in inhibition of
calcineurin activity. This blocks the dephosphorylation events critical for cytokine gene expression & T cell activation. 100X MORE POTENT
THAN CYCLOSPORINE.
Toxicity: ~ to cyclosporine w/ nephrotoxicity.
Muromonab CD3
Anti IL-2 abs
T cell w/ TCR.
↓

Antiproliferative/Antimetabolic Drugs: prevent the clonal expansion of both B & T lymphocytes
Sirolimus (also known as rapamycin)
Mechanism of action- Used in combination th for renal, heart, liver, & BM transplant rejection.
Binds to FKBO to inhibit a key enzyme in cell cycle progression (mammalian kinase target of rapamycin, mTOR), blocking cell cycle progression
from G1 to S phase.
Toxicity: Dose dpdt ↑ in cholesterol & triglycerides. NEPHROTOXICITY in combination w/ CYCLOSPORINE. ↑ed risk of LYMPHOMAS &
INFECTIONS. A substrate for cytochrome CYP3A4 w/ potl for DRUG INTERACTIONS.
Mycophenolate mofetil
Mechanism of action- Used in organ transplantation. A metabolite that is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an
impt enzyme in the de novo pathway of guanine nucleotide synthesis. B & T CELLS ARE HIGHLY DEPDT on this pathway for cell proliferation,
while other cell types can use salvage pathways.
Toxicity- Hematologic & GI. LEUKOPENIA, DIARRHEA, & VOMITING.
A RELATIONSHIP EXSISTS BTWN IMMUNOSUPPRESSIVE TH & CANCER CHEMOTHERAPY. For cancer drugs are
administered in high dose pulses.
Anti-thymocyte globulin (ATG)
Mechanism of action- Purified Igs prepared commercially from hyperimmune serum of animals following immunization w/ human thymocytes.
The Ig binds to the thymocytes in circulation, resulting in LYMPHOPENIA & impaired T cell immune responses.
Toxicity- when Ig is recognized as foreign resulting in serum sickness & nephritis. Anaphylaxis is rare.
Muromonab-CD3
Mechanism of action- Used to prevent acute rejection of kidney, liver & heart transplants. A mouse monoclonal ab that binds to the ε chain of
CD3 glycoprotein that is part of the TCR complex on T lymphocytes. When this happens, the TCR complex is internalized preventing further ag
recognition. Initial interactions leads to cytokine release by activating T cells (CYTOKINE RELEASE SYNDROMEmild flu-like illness to lifethreatening shock). Administration of glucocorticoids prior reduces symptoms.)
Toxicity: repeated use can cause immune response. Newer drug that lacks Fc portion is being devpd to prevent cross-linking & cytokine release
syndrome.
Daclizumab & Basiliximab
Mechanism of action- Renal & heart transplantation. ANTI-IL-2 RECEPTOR ABS, “humanized” in part. Bind to the IL-2 receptor present on
activated, but not resting, T cells & block IL-2 mediated T cell activation events.
Toxicity: No cytokine release syndrome. Lower incidence of lymphoproliferative dxs & opportunistic infections than many other
immunosuppressive drugs. Anaphylactic rxns can occur.
Site of Action of Selected Immunosuppressive Agents on T Cell Activation
DRUG
SITE OF ACTION
Glucocorticoids
Glucocorticoid response elements in DNA
(regulate gene transcription)
Muromonab-CD3
T-cell receptor complex (blocks antigen recognition)
Cyclosporine
Calcineurin (inhibits phosphatase activity)
Tacrolimus
Calcineurin (inhibits phosphatase activity)
Mycophenolate Mofetil Inosine monophosphate dehydrogenase (inhibits activity)
Daclizumab,
Basiliximab
Sirolimus
IL-2 receptor (block IL-2-mediated T-cell activation)
Protein kinase involved in cell-cycle progression
(mTOR) (inhibits activity)
MEDIATORS:
1.Synthesis
Know the pathway for synthesis including the important
enzymes and the primary site of synthesis.
2.Degradation
Know how the mediator is inactivated, whether by enzymes
or unstable chemical structure, as well as where the
degradation occurs.
3.Biological Activities
Know the important biological activities of the mediator as
they relate to inflammation.
4.Receptors
Know which receptor the mediator activates to result in the
biological activity.
DRUGS:
1.
Generic name of the drugs in the drug class
i.e. diphenhydramine is a H1 antihistamine
2.
Mechanism of action
Learn the general mechanism of action of the drug
class and be able to associate a certain drug with the
drug class
3.
Distribution - how it may affect the use of the drug
i.e. non-sedating antihistamines do not cross the
blood brain barrier and thus are not as likely to cause
sedation
4.
Elimination - how it dictates the use of the drug
5.
Toxicity - major toxicities which limit the usefulness
of each drug class
Example: Systemic use of the anti-inflammatory
steroids is limited by major side effects such as
increased susceptibility to infection and osteoporosis.
6.
Identify differences between individual drugs in
each class or unique pharmacological properties
of particular drugs in a class.
Example: Indomethacin is the most potent NSAID
and can cause severe frontal headache.