Immunomodulatory & Anti-Inflammatory Drugs Flashcards
1
Q
Target of anti-inflammatory agents
A
Inhibit innate immunity
2
Q
Target of disease-modifying antifheumatic agents (DMARDs)
A
both innate and adaptive but more often affect inflammatory cytokines (innate)
3
Q
Receptor protein for IL-2 on activated T cells
A
CD25
4
Q
Importance of IL-2
A
clonal expansion
5
Q
TH1 response
A
- Interferon-gamma (IFN-y)
- Increases cell mediated cytotoxicity
- Effective against intracellular pathogens
6
Q
TH2 response
A
- IL-4
- Humoral response, associated w/ production of IgE type antibodies
- Effective against multicellular parasites
- Associated w/ allergic diseases
7
Q
TH17 response
A
- IL-17
- Inflammatory responses
- Effective against extracellular bacteria & fungi
- Associated w/ autoimmune diseases
8
Q
Immunostimulants
A
promote activation of the immune system
9
Q
Adverse effects of immunostimulants
A
systemic inflammatory reactions & flu-like symptoms (fever, chills, etc.)
10
Q
Applications of immunostimulants
A
- enhanced vaccination response (adjuvants)
- chronic infectious disease
- immunodeficiency disorders
- cancer
11
Q
Limitations of immunostimulants
A
- don’t promote specific immune reactions
- alternative therapies more effective
- cytokines require parenteral administration, have short half-lives, expensive
12
Q
Types of immunostimulants
A
adjuvants & cytokines
13
Q
Two adjuvants
A
Alum & BCG
14
Q
Alum adjuvant
A
- aluminum salts
- MOST COMMON ADJUVANT IN HUMAN VACCINES
- support prolonged exposure to developing immune reactions
- may directly increase activity of APCs
- few side effects
15
Q
BCG adjuvant
A
- live attenuated bacillus calmette-guerin
- interact directly w/ PRRs and increase APC activity
- used as an anti TB vaccine & ppl who get this test will test + for TB
- useful in some cancer therapies (bladder cancer)
- direct activation of leukocytes can produce a systemic inflammatory response and septic shock
16
Q
Cytokine immunostimulants
A
IL-2 (aldesleukin), interferons
17
Q
IL-2 (aldesleukin) cytokine immunostimulant
A
- increased proliferation of activated T cells, production of IFN-y, & cytotoxic killer cell activity
- treatment of metastatic melanoma & renal cell carcinoma
- associated w/ serious capillary leak syndrome, hypotension, reduced organ perfusion…CAN BE FATAL
18
Q
Interferon cytokine immunostimulants
A
- INF-y: stimulates cell mediated cytotoxic immune response; treat sever infections
- IFN-alpha & beta: produced by most cells in response to viral infection; useful in treating chronic viral infection (hepatitis)
19
Q
Clinical indications for suppression of immune responses
A
- organ transplantation
- treatment of inflammatory disorders
- treatment of autoimmune disorders
- selective immunosupression
20
Q
Adverse effects common to ALL general immunosuppressants
A
- increased infection risk
- increased risk of cancer: loss of immune surveillance & increased susceptibility to tumor-promoting pathogens
- other adverse effects are mechanism specific
21
Q
Cyclophosphamide
A
- immunosuppression via cross linking DNA & killing proliferating cells thus preventing expansion of antigen specific lymphocytes
- uses: auto-immune diseases, bone marrow transplant
- adverse effects: myelosupression, nausea, vomiting, infertility
22
Q
Azathiopurine
A
- metabolized to 6-mercaptopurine & 6-thioguanine
- inhibit purine synthesis & cause DNA damage when incorporated into DNA as thio-guanine nucleotide
- inactivated by xanthine oxidase (decreased when combined with allopurinol-requires reduced dosage)
- uses:renal & other tissue transplantation, auto-immune disorders (lupus, rheumatoid arthritis)
- adverse effects: myelosuppression, nausea, vomiting
23
Q
Mycophenolate Mofetil
A
- hydrolyzed to mycophenolic acid
- inhibits inosine monophosphate dehydrogenase preventing purine synthesis
- uses: solid organ transplant as an alternative to cyclosporine, auto-immune diseases
- adverse effects: myelosuppression, nausea, vomiting
24
Q
Methotrexate
A
- inhibits dihydrofolate reductase
- direct inhibition & accumulated inhibitory intermediates prevent synthesis of thymidine as well as purine nucleotides
- uses: RHEUMATOID ARTHRITIS, auto-immune diseases
- adverse effects: nausea, mucosal ulcers, modest hepatotoxicity, myelosuppression
25
Leflunomide
- metabolized to A77-1726
- inhibits dihydroorotate dehydrogenase leading to decrease PYRIMADINE synthesis
- suject to enterohepatic recirculation & has half-life of 19 days
- uses: similar to methotrexate
- adverse effects: diarrhea, modest hepatotoxicity, myelosuppression
26
Glucocorticosteroid effects (Prednisone)
- anti-inflammatory
| - immunosuppressive
27
Prednisone mechanisms
- induced transcription: annexins (lipocortins) --inhibition of PLA2, & synthesis of lipid derived mediators
- repressed transcription: IL-1,2,3,5, TNF, IFNy, GM-CSF -- reduced T helper cell mediated response, B cell antibody production, cytotoxic response
- repressed transcription: cyclooxygenase, NO synthase, PLA2 -- reduced mediator release
- repressed transcription: IL-8, other chemotaxins -- reduced recruitment of leukocytes
28
Prednisone usage
- solid organ & hematopoetic stem cell tranplant
| - combined anti-inflammatory/immunosuppressant activity (asthma, allergic reactions, systemic inflammation)
29
Prednisone adverse effects
- only with greater than 2 weeks daily systemic administration
- cushings syndrome, glucose intolerance, ocular disturbance, GI disturbances, NO SERIOUS MARROW TOXICITY, osteoporosis, hypertension, psychiatric disturbances
30
Target of immunomodulatory agents
T & B cells
31
Role of calcineurin in T cell signaling
de phosphorylates NF-AT so then it can activate transcription in the nucleus
32
Calcineurin inhibitors
cylcosporine - binds w/ cyclophilin and inhibits
| tacrolimus (FK506) - binds w/ FKBP12 & inhibits
33
Cyclosporine
- often combined w/ other immuno-suppressants
- useful in kidney, liver, & cardiac transplants
- useful in rheumatoid arthritis, & inflammatory diseases (ABD, asthma)
- adverse effects: nephrotoxicity, increased cancer incidence documented
34
Tacrolimus (FK506)
- same uses and toxicities as cyclosporine
| - 10-100 TIMES MORE POTENT than cyclosporine
35
IL-2 receptor signaling pathway
- uses mTOR
| - takes 45 min
36
Sirolimus (rapamycin)
- usually combined w/ other agents
- inhibits mTOR in IL-2 signaling pathway
- useful in steroid resistant graft versus host disease in hematopoetic stem cell transplants
- antagonizes tacrolimus but synergizes w/ cyclosporine
- adverse effects: myelosuppression (not combined with anti metabolite due to syngergy), hyperlipidemia, HTN, edema, hepatotoxicity
37
Use of therapeutic antibodies
- provides "passive immunity" before host adaptive immune responses can be effective (hepatitis, rabies, tetanus), or when host immunization is unwanted (Rho[D]) -- acts like host adaptive immunity
38
Administration of therapeutic antibodies
- All applications require parenteral administration, but long half-lives can allow weekly - monthly dosing for continuous effect
39
Human derived antibody (Rh(D) immune globulin, adalimumab)
- activate human complement leukocytes: YES
- induce anti-antibody response: NO
- adverse effects: few
40
Animal derived antibody (ATG, OKT3)
- activate human complement leukocytes: YES
- induce anti-antibody response: YES
- adverse effects: on repeated use antibody destruction allergic reaction serum sickness
41
Chimeric "humanized" derived antibody (basiliximab, alemtuzumab, infliximab)
- activate human complement leukocytes: YES
- induce anti-antibody response: NO
- adverse effects: few
42
Fc-fusion protein derived antibody (belatacept, etanercept)
- activate human complement leukocytes: variable, usually not complement, Fc confers extended half life (weeks)
- induce anti-antibody response: NO
- adverse effects: few
43
Treatment of Rh hemolytic disease
- Rh(D) immune globulin (BayRho-D, WinRho SDF)
- maternal administration of immune globulin prevents initiation of maternal immune response to fetal Rh(D) antigen
- works through opsonization, also inhibit naive Rh(D) reactive B cells, & T cell responses are NOT affected but are not harmful to fetus
44
Blocking receptors preventing T cell activation
- anti-T cell globulin (ATG): targets T cells for destruction
- Belatacept: immunosuppressant approved for kidney transplantation
45
Belatacept
- fusion protein of B7 ligand (CTLA4) w/ an IgG Fc domain
- second generation version of abatacept w/ higher affinity for B7
- FDA approved for kidney transplantation 2011
- prevents interaction b/w B7 on APC and CD28 on T cell
- adverse effects: anemia, neutropeina, peripheral edema, posttransplant lymphoproliferative disorder (PTLD)
46
Anti-T cell globulin (ATG)
- blocks T cell surface receptors & opsonizes T cells
- adverse effects: cytokine release syndrome, CAN BE REDUCED BY PRE-TREATMENT WITH ACETAMINOPHEN & ANTIHISTAMINE
- produces prolonged T cell depletion (more than a year), potential for late rejection as lymphoid system recovers
47
Anti-CD52
- surface protein expressed on T & B cells, monocytes, macrophages, and NK cells
48
Alemtuzumab
- humanized anti-CD52 antibody
- depletes broad variety of cells involved in immune reactions
- adverse effects: myelosuppression, flu-like symptoms
- effect: produces prolonged depletion of T cell and other cells of immune system (one year)
49
Basiliximab
- anti CD25 (IL-2 receptor)
- blocks and opsonizes alpha chain of CD25 on ACTIVATED T cells
- adverse effects: well tolerated
- effect: depletes only activated T cells, moderate compared to ATG (more appropriate for patients w/ low to moderate risk of rejection)
- reduced immune depletion is associated w/ reduced incidence of infection (particularly chronic CMV infection) & malignancy
50
Anti-TNF alpha agents
- infliximab
- adalimumab
- etanercept
51
Infliximab
- humanized antibody to TNF alpha
- applications: inflammatory disease involving TNFalpha, PARENTERAL ADMINISTRATION REQUIRED, rheumatoid arthritis w/ methotrexate, & crohn's disease w/ azathioprine
- complications: increased frequency of infections
52
Adalimumab
- human antibody to TNF alpha
| - similar to infliximab
53
Etanercept
- fusion protein containing ligand binding domain of TNFalpha receptor & the Fc domain of human IgG
- similar to infliximab
54
Anti IL-1 agents
- anakinra
55
Anakinra
- competitive IL-1 receptor antagonist
- uses: rheumatoid arthritis
- short half life, daily injection required
- complications: increased infection susceptibility
56
Protein required by cytokine receptors
Jak
57
Jak inhibitor
tofacitinib
58
Tofacitinib
- jak kinase inhibitor
- uses: rheumatoid arthritis 2012, second line for those failing methotrexate
- administration: oral
- mechanism: inhibits activity of cytokines required for adaptive immunity (IL-2, IL-4, IL-6)
- adverse effects: anemia, neutropenia, myelosuppressino, increased risk of infection (HERPES ZOSTER)
59
Mediators released from activated leukocytes
- prostaglandins, leukotrienes
| - histamine
60
Prednisone
- increase annexin production
- annexin inhibits PLA2 inhibiting production of prostaglandins/leukotrienes
- decreased recruitment of leukocytes
61
NSAIDS
- inhibit cyclooxygenase
| - lowers prostaglandin levels decreasing inflammation
62
Zileuton
- inhibits lipoxygenase
| - lowers leukotriene levels decreasing inflammation
63
Comolyn & Nedocromil
- inhibit histamine release
| - decreases inflammation
64
Degradation of histamin requires two enymes
- imidazol N methyltransferase
| - diamine oxidase
65
Importance of diamine oxidase
- histamine intolerance results from deficiency or reduced activity of diamine oxidase
- anything that effects activity of diamine oxidase will effect half life of histamine
66
Sites of histamine production and storage
- synthesized in most tissues
- stored: complexed with sulfated polysacchrides, mast cells/basophils (heparin), fibroblasts (chondroitin sulfate)
- IgE antibody reactions promote histamine release from mast cells in type I hypersensitivity reactions (allergy, anaphylaxis)
67
Histamine & CNS
- neurotransmitter
- neurons in posterior hypothalamus
- projections to: neuroendocrine releasing neurons, cardiovascular areas, thermoregulatory regions, "AROUSAL" REGIONS (promotes wakefulness)
68
Histamine receptors
- H1: smooth muscles, enothelium, cardiac muscle, sensory nerve terminals, CNS post synaptic; Gq coupled
- H2: gastric parietal cells, mast cells, cardiac muscle, CNS post synaptic; Gs coupled-INCREASED cAMP
- H3: CNS pre synaptic; Gi coupled-DECREASED cAMP
- H4: CD4 T cells, eosinophils, neutrophils; Gi coupled-DECREASED cAMP
69
Vascular smooth muscle histamine response
- H1/H2 receptor
- NO release promotes smooth muscle relaxation & vasodilation
- symptom: hypotension, flushing, headache, anaphylaxis
70
Endothelium histamine response
- H1 receptor
- induced actin/myosin contraction, separation of endothelial cells
- symptom: edema
71
Cardiac muscle histamine response
- H1/H2 receptor
- H1: decreased rate and atrial contractility
- H2: increased rate and contractility
- symptom: unclear
72
Bronchiolar smooth muscles histamine reaction
- H1 receptor
- constriction
- symptom: decreased airway size leading to breathing difficulty
73
Uterine smooth muscle histamine resoponse
- H1 receptor
- constriction
- symptom: premature labor w/ anaphylaxis
74
Gastric smooth muscle histamine response
- H1 receptor
- constriction
- symptom: diarrhea
75
Sensory nerves histamine response
- H1 receptor
- stimulation
- symptom: pain, itching
76
CNS hypothalamus histamine response
- H1 receptor
- arousal
- symptom: increased wakefulness
77
CNS emetic center histamine response
- H1 receptor
- emesis
- symptom: nausea, vomiting
78
CNS histamine response
- H1/H2 receptor
| - effects on thirst, blood pressure, perception of pain
79
Gastric secretion histamine response
- H2 receptor
- increased acid production, pepsin, intrinsic factor
- symptom: mucosal erosion, ulceration
80
Histamine "triple response"
- "wheal and flare" response
- wheal = edema
- reddening from dilation of small vessels
- flare = axon reflex; histamine stimulation of sensory nerve terminals cause release of vasodilators at other branches
- ithcing
81
Ways to antagonize histamine effects
- physiologic: epinephrine
- release inhibitors: cromolyn & nedocromil inhibit Ca2+ dependent release (asthma)
- receptor antagonist: competitive antagonist of H1 or H2 receptors
82
Comolyn & Nedocromil
- poorly soluble salts: must be topically absorbed (inhaled)
- only effective prophylactially as part of long term therapy for asthma
- mechanism: inhibits degranulation of mast cells through inhibition of Ca channels, inhibition of Cl- may also contribute to reduced nerve activity & inhibition of cough
83
H1 receptor antagonists
- act as inverse agonists; reduce basal levels of activity
- uses: allergic rhinitis & utricaria, motion sickness/emesis
- adverse effects: sedation w/ first generation, Non H1 effects:dry mouth, urinary retention, tachycardia (anticholinergic), orthostatic hypotension (adrenoreceptor), increased appetite (serotonin block), blocks sodium channels (local anesthesia)
84
First generation antihistamines
- diphenhydramine: motion sickness
- dimenhydrinate: motion sickness
- cyclizine: motion sickness
- promethazine: antiemetic
85
Second generation antihistamines
- poor penetration into CNS reducing sedative effects
| - loratadine, cetrizine, fexofenadine
86
Role of phospholipase A2 (PLA2)
- enzyme that turns membrane phospholipids (phosphatidylcholine) into aracadonic acid
87
Role of cyclooxygenase
- enzyme that turns AA into prostaglandins
88
Role of lipoxygenase
- enzyme that turns AA into leukotrienes
89
Prostanoid synthesis & degradation
- short half lives and lack to stored products make prostanoid activity synthesis dependent
- membrane permeable and passively released after synthesis
- autocrine and paracrine activity
90
Prostanoids
- prostacyclin (PGI2)
- prostaglandin (PGE2)
- thromboxane (TXA2)
91
PGE2
- prostaglandin
- synthesis: most tissues
- half life: 30 sec
92
PGI2
- prostacyclin
- synthesis: endothelium, vascular smooth muscle
- half life: 3 min
93
TXA2
- thromboxane
- synthesis: platelets, macrophages
- half life: 30 sec
94
PGE2 Gs receptor effects
- blood vessels: dilate
- smooth muscle: relax
- platelets: none
- pain: hyperalgesia
- hypothalamus: increased body temp
95
PGE2 Gq receptor effects
- blood vessels: none
- smooth muscle: constrict (uterine)
- platelets: none
- pain: none
- hypothalamus: increased body temp
96
PGI2 Gs receptor effects
- blood vessels: dilate
- smooth muscle: relax (bronchial/uterine)
- platelets: inhibits aggregation
- pain: hyperalgesia
- hypothalamus: none
97
TXA2 Gq receptor effects
- blood vessels: constrict
- smooth muscle: constrict (bronchial)
- platelets: stimulates aggregation
- pain: none
- hypothalamus: none
98
Cyclooxygenase-1 (COX-1)
- substrates: narrow specturm-arachidonate
| - indelibility: not inducible, constitutively expressed
99
Cyclooxygenase-2 (COX-2)
- substrates: broader spectrum-arachidonate, linolenic, unsaturated C22 FAs
- indelibility: highly inducible, inducers: IL-1, TNFalpha, LPS; inhibitors: IL-4, IL-10, IL-13
100
Compare COX-1 & COX-2
- steady state for most cells, COX-1>>>>>>>>>>>>>>>>>COX-2
- COX-2 has larger role in kidney & uterus
- elevated prostanoid production associated w/ inflammation due to COX-2
101
Non-selective NSAID therapeutic applications
- fever
- analgesia
- inflammation due to injury or stress
- rheumatoid & osteoarthritis
- cardiovascular prophylaxis, reduced platelet aggregation (aspirin only)
102
Aspirin (Acetylsalicylic Acid, ASA)
- metabolism: rapidly converts to salicylic - acetyl group is active part of ASA and is what separates it from other NSAIDs
- more COX-1 inhibition, so if you give enough to get COX-2 will always get COX-1 inhibitions too
- biochemical effects: ASA acetylates & IRREVERSIBLY inhibits, while salicylic acid REVERSIBLY inhibits
103
Keotolac
- NSAID
- 395 selectivity
- post surgical analgesic
104
Indomethacin
- NSAID
- 10 selectivity
- arthritis, anti imflammatory
105
Aspirin
- NSAID
- 4.4 selectivity
- cardiovascular prophylaxis
106
Naproxen
- NSAID
- 3.8 selectivity
- anti inflammatory
107
Ibuprofen
- NSAID
| - 2.6 selectivity
108
Diclofenac
- NSAID
- .3 selectivity
- arthritis/anti inflammatory
109
Etodolac
- NSAID
- .1 selectivity
- arthritis
110
Meloxicam
- NSAID
- .04 selectivity
- arthritis
111
NSAID anti inflammatory effects
- block production of prostanoids by inhibition of COX
| - COX-2 primarily responsible for prostanoid production during inflammation
112
NSAID analgesic effects
- reduced PGE2 & PGI2 induced hyperalgesia
- general reduced inflammation
- not effective against non inflammatory pain (distention of hollow organs)
- not as efficacious as other analgesic
113
NSAID antipyretic effects
- inhibits PGE2 production in CNS stimulated by cytokines (IL-1, IL-6, & TNFalpha)
- reduced peripheral prostanoids may also reduce cytokine expression from macrophages
- does NOT influence body temp when elevated by non inflammatory factors (exercise, environmental change)
114
NSAID anti platelet effects
- inhibit platelet COX-1
- increase bleeding time (increase surgical bleeding)
- potentiates GI bleeding
115
NSAID (aspirin) cardiovascular protection
- irreversibly inhibits platelet COX-1 (no TXA2 made for life of platelet)
- platelet COX-1 activity only restored through replacement of platelets over 5-7days
- other NSAIDs inhibit platelet COX-1, but effect is REVERSIBLE
- antagonize irreversible anti-platelet activity of ASA, for cardiovascular protection should be taken 30 min before or after other NSAID elimination
116
NSAID GI effects
- inhibition of COX-1 causes lysis of epithelium (misoprostol, PGE1 analog, protects against COX-1 inhibition)
- GI infection of inflammation induces COX-2
117
NSAID GI toxicity
- dyspepsia: upper abdominal pain, bloating nausea (35%)
- ulcers: gastric more common than duodenal (16%)
- GI bleeding: anemia
- prevention: H2 receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine), PPIs (omeprazole, lansoprazole), misoprostol blocks NSAID induced ulcers but not other anti inflammatory effects
118
NSAID kidney effects
- renal vasoconstriction, water/salt retention (edema, HTN)
- acute renal failure (.5-1%)
- at risk patients: CHF, cirrhosis/ascites, age
119
NSAID uterus effects
- both COX-1/2 present
- PGE2 contracts, PGI2 relaxes
- NSAIDs can delay premature labor
- NSAIDs can reduce dysmenorrhea (menstrual cramps)
120
Aspirin intolerance
- salicylism: hypersensitivity to ASA; hyperventilation, tinnitus, vertigo, emesis, sweating
- reye's syndrome: ASA used in children w/ viral illness; acute encephalopathy, fatty liver degeneration
121
Acetaminophen
- Non selective COX inhibitor
- usage: analgesic/antipyretic ONLY, no anti inflammatory activity
- tolerance: HEPATOTOXICITY with overdose
122
COX-2 selective NSAIDS
- retain COX-2 specific effects: anti inflammatory, antipyretic, analgesic, renal toxicity
- lack COX-1 effects: platelet, cardio protective, GI side effects
- usage: osteoarthritis, rheumatoid arthritis
- expensive
123
NSAID COX-2 selectivity comparison
meloxicam
124
Vioxx (rofecoxib) debacle
- reduced incidence of GI effects (only in patients not taking aspirin)
- adverse effects: increased incidence of cardiovascular events
- result: Celecoxib (available), rofecoxib (withdrawn), valdecoxib (withdrawn), parecoxib:injectible pro drug of valdecoxib available in europe
125
NSAID cardiovascular risk
- ALL NSAIDS (accept ASA) APPEAR TO BE ASSOCIATED W/ SOME LEVEL OF INCREASED RISK
- naproxen may be safer
- mechanism: loss of COX-2 antagonism of platelet activity
126
Leukotrienes
LTB4, LTC4, LTD4
127
LTB4 effects
- blood vessels: none
- smooth muscle: none
- leukocytes: neutrophil chemotaxis
128
LTC4 effects
- blood vessels: decreased coronary blood flow, increased permeability
- smooth muscle: bronchial constriction
- leukocytes: eosinophil chemotaxis & degranulation
129
LTD4 effects
- blood vessels: decreased coronary blood flow, increased permeability
- smooth muscle: bronchial constriction
- leukocytes: eosinophil chemotaxis & degranulation
- primary mediator of bronchial smooth muscle constriction and edema in asthmatic airways
130
Zileuton
- leukotriene (LTB4, LTD4) synthesis inhibitor
- oral asthma therapy
- adverse effects: liver toxicity (lower metabolism of other drugs)
131
Zafirlukast & Montelukast
- leukotriene receptor antagonist
| - oral asthma therapy
132
Aspirin induced asthma
- 5-10% of asthmatics exhibit sensitivity to aspirin & other NSAIDs
- NOT A DRUG ALLERGY
- sensitivity caused by shifting of AA metabolism from prostaglandin to leukotriene synthesis
