Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
195 Cards in this Set
- Front
- Back
A term often used for an array of substances normally present in the body or formed there. Usually these active substances have a brief lifetime and act near their sites of synthesis. They are not neurotransmitters or hormones, but are sometimes called local hormones. It is a term sometimes used to refer to inflammatory mediators.
|
Autacoids
|
|
Antihistamines and leukotriene modifiers
target _______ mediator(s) |
a single
|
|
Anti-inflammatory steroids, NSAIDs target _______ mediator(s)
|
multiple
|
|
_______ inhibitors stop mediator production
|
Synthesis
|
|
Antagonists or inverse agonists ______ mediator action
|
stop
|
|
What mediator has these actions?
Vasodilation Increased vascular permeability Airway constriction Not chemotaxis |
HIstamine
|
|
What mediator has these actions?
vasodilate increase vascular permeability cause pain |
PGE and PGI
|
|
Which mediators cause bronchoconstriction?
|
PGD and TX
|
|
Which mediator causes platelet aggregation? Which opposes platelet aggregation?
|
TX
PGI |
|
Which leukotriene is chemotactic (PMNs) and reduces pain threshold?
|
LTB4
|
|
Which leukotrienes cause airway constriction, increased vascular permeability, chemotaxis (eosinophils)
|
LTC4, LTD4, LT3E4
|
|
Which mediator does everyting, especially vasodilation with hypotension... but not a major chemotactic agent
|
Kinins
|
|
Histamine, PGE2, PGI2, and Kinins all cause what symptom?
|
Redness (vasodilation)
|
|
Histamine, Peptidoleukotrienes, and kinins all cause what symptom?
|
Swelling - increased vascular permeability
|
|
PGE, PGI, LTB4, and Kinins all cause what side effect?
|
Pain - causes pain or reduces the pain threshold
|
|
LTB4 and Peptidoleukotrienes cause what symptom?
|
Chemotactic - directed migration of WBC.
LTB4 - neutrophils, etc Peptidoleukotrienes |
|
Which mediators induce fever?
|
PGEs
|
|
Histamine, Peptidoleukotrienes, Kinins, and PGD2 all cause what symptom?
|
Airway constriciton - bronchoconstriction (relevant for type 1 hypersensitivity)
|
|
Kinins and Histamines cause what symptom?
|
Hypotension = decreased bp (relevant in shock)
|
|
________ is a little, active, endogenous amine found in high concentrations in skin, lung, and stomach (portals of entry)
|
Histamine
|
|
There are two pools of histamine:
1) in ______ and _____ cells, within granules, bound by _____ bonds to heparin protein complex 2) Non mast cell histamine - rapid turnover, in CNS cells, epidermis, tissues undergoing rapid growth or repair |
basophils and mast cells
ionic bonds |
|
Histidine is coverted to Histamine in what kind of cells? Done by enzyme L-Histidine decarboxylase which does what action?
|
Basophils and mast cells
Takes off a carboxyl group |
|
Histamine metabolites have strong/moderate/weak pharmacological activity. Metabolism enzymes widely distributed, including histamine specific enzymes
|
weak - little or no pharmacological activity
|
|
If you eat histamine, large doses don't even cause effects because it's inactivated by histaminase in the _____ or intestinal wall. Intestinal ________ also convert it to N-acetylhistamine
|
liver
bacteria |
|
When you inject histamine into your skin you get _____ and pain first, then the triple response which includes localized _____, flare, and localized _____ (wheal formation)
|
itching
redness edema |
|
____ formation occurs in 1-2 min in the same area as the localized redness from histamine. Increased permeability with leakage of the postcapillary venules
|
wheal
|
|
Intranasal histamine causes intense itching, 2 reflexes?, and nasal blockage
|
sneezing and hypersecretion
|
|
IV administration of histamine leads to blood pressure ________
|
decrease -
vasodilation, increased capillary permeability and fluid loss. Sometimes there’s a secondary increase in blood pressure due to histamine-induced release of catecholamines from the adrenal medulla. |
|
IV administration leads to ______ heart rate.
|
Increased - reflex response elicited by the decrease in blood pressure
|
|
Bronchoconstriction, flushing of face, headache, wheal and flare, mucus and gastric acid secretion- are all from IV administration of what?
|
histamine
|
|
Antigen interaction with IgE antibody on mast cells and basophils caused enogenously released ________
|
histamine (either into bloodstream of locally)
|
|
Clinical uses of histamine are limited - inhale to assess _______ reactivity, use intradermally toa ssess integrity of ______ neurons
|
bronchial
sensory |
|
Antihistamines are ______ agonists, also known as ________ antagonists
|
Inverse
competitive |
|
Antihistamines shift the dose-response curve to the ____ because they are a _______ antagonist
|
right
competitive |
|
Stimulation of the __ receptor causes bronchoconstriction, contraction of __ smooth muscle, wheal formation, itch (pruritis), release of catecholamines from the ____ ______
|
H1
GI adrenal medulla |
|
Stimulation of the __ receptor causes gastric acid secretion, inhibition of IgE mediated basophil histamine release (feeds back on self), inhibition of t-cell cytotoxicity, suppression th2 cells and cytokines
|
H2
|
|
receptors __ and __ have no clinically useful agents. __ may be important for nerve cells and __ for immune cells
|
H3 and H4
H3 H4 |
|
Mixed H1 and H2 receptor cardiac effects:
_______ HR _______ force of contraction _______ arrhythmias _______ AV conduction |
increased
increased increased slows |
|
Vasodilator effects:
__ - rapid, short dilator response __ - slower and more sustained dilation |
H1
H2 |
|
Triple response caused by these histamine receptors:
Vasodilation (__ and __) _____ H1 (prob H2) Wheal - __ primarily |
H1 and H2
Flare H1 |
|
Nasal symptoms - stimulant action on nerve endings are generally __
|
H1
nasal blockage has some H2, mucus production H2 |
|
Classical, first generation antihistamines block __, muscarinic, alpha adrenergic and _____ receptors.
H1 receptors have 45% homology with _______ receptors |
H1
serotonin muscarinic |
|
The second generation antihistamines have minimal _______ properties and are non-sedating and no drying of secretions
|
anticholinergic
|
|
First generation antihistamines are well absorbed orally, distributed widely (even CNS), used as ophthalmic solution, but shouldn't be used _______ due to allergic response development
|
topically
|
|
First generation antihistamines stay in the CNS because they aren't recognized by _-________ efflux pumps on _______ cells
|
P-glycoprotein
endothelial |
|
Adverse effects of classical antihistamines:
Sedation - potentiate effect of CNS depressants __ Disturbances Drying of secretions - due to _______ properties |
G.I.
Anticholinergic |
|
Classic antihistamine poisoning leads to atropine-like symptoms (what are they?), excitiations, hallucinations, incoordination, convulsions, coma, cardioresp collapse
|
fixed-dilated pupils, flushed face, fever with dry mouth
|
|
Diphenydramine/Tripelennamine/Chlorpheniramine
Low incidence of GI side effects, sedation |
Diphenhydramine
|
|
Diphenhydramine, Tripelennamine, and Chlorpheniramine are all what?
|
Older antihistamines (first generation)
|
|
Diphenydramine/Tripelennamine/Chlorpheniramine
GI side effects common, feeble central effects, fewer anticholinergic effects than others |
Tripelennamine
|
|
Diphenydramine/Tripelennamine/Chlorpheniramine
Most suitable for daytime use |
Chlorpheniramine
|
|
Newer antihistamines (second generation) have minimal _______ properties, do not cause _______ or drying of secretions
|
anticholinergic
sedation |
|
Non-sedating Antihistamines penetrate the _____. Have affinity for the P-glycoprotein efflux pump. Do not potentiate the effects of CNS ______
|
CNS
depressants |
|
What class are these drugs: Cetirizine, Fexofenadine, Loratadine
|
Non-sedating antihistamines (second generation)
These are not cardiotoxic unlike the first non-sedating antihistamines made |
|
H1 antihistamines (new and old) are good against allergies: allergic rhinitis (relieve sneezing, itching, rhinorrhea), Urticaria (____), atopic dermatitis (poison ivy), NOT for ______
|
hives
asthma NO |
|
H1 histamines are good against allergies and ____ ______
|
motion sickness - older antihistamines
this is the antimuscarinic effect |
|
The only reason H1 antihistamines might help a cold would be what?
|
Older antihistamines dry secretions so could reduce rhinorrhea of common cold
|
|
What class are these?
Cimetidine, Famotidine, Ranitidine, Nizatidine They are inverse agonists |
H2 antihistamines
|
|
__ antihistamines inhibit histamine, _____ ___ secretion from decreasing muscarinic agonism and gastrin and pentagastrin-induction
|
H2, gastric acid
|
|
What are H2 antihistamines used for?
|
Ulcers and gastric hypersecretory states
|
|
What are Prostanoids?
|
Prostaglandins and Thromboxane - derivatives of prostanoic acid, a 20 C fatty acid containing a cyclopentane ring
|
|
What is the common precursor for Leukotrienes, Prostanoids, and Epoxygenase products?
|
Arachidonic acid made from Phospholipase A2 and phospholipids in the cell membrane
|
|
The availability of ________ is a control step in the production of PG and TX
|
arachidonic acid
|
|
PG1's (1 double bond) precursor is 8,11,14-eicosatrienoic acid.
PG2's (2 double bonds) precursor is ? |
arachidonic acid
|
|
ARACHIDONATE METABOLISM
Cyclooxygenase pathway makes: Lipoxygenase pathway makes? |
PG and TX
Leukotrienes |
|
Are PG stable/unstable, long/short half life, local/distal actions
|
short, unstable, local actions
|
|
_______ is the key enzyme for the two step synthesis of PGH2 in the cell
|
cyclooxygenase. Two isozymes COX-1 and COX-2
|
|
COX-_ is found in platelets and is constitutively expressed in most cells. Thought to protect gastric mucosa
|
COX-1
|
|
COX-_ not found in platelets, expressed constitutively in the brain and kidney and can be induced by some things at inflammation site. More important isozyme in the production of PG and TX in inflammation
|
COX-2
|
|
COX products degrade quickly via spontaneous chemical ______. Uptake into cells by transport protein and subsequent enzymatic degradation
|
hydrolysis
|
|
Sources of COX:
Numerous cell types and different stimuli ___ and ___ are synthesized on demand and liberated from cells |
PG and TX
prostaglandins and thromboxane |
|
Cells commonly produce more than one type of prostaglandin. The type of PG produced by particular cell type is influenced by expression pattern of ______.
|
enzymes
|
|
Platelets Prostacyclin
Endothelium PGD2 Mast Cells Thromboxane Which cell type goes with which prostaglandin? |
Platelets - Thromboxane (vaxoconstrictor)
Endothelium - Postacyclin (vasodilator) Mast cells - PGD2 (bronchoconstrictor) |
|
Action of COX product in a tissue determined by which _____ receptor. There are _ major types, they are 7 transmembrane G protein coupled receptors
|
Prostanoid
5 |
|
Match receptor with prostaglandin for which they have greatest affinity
DP PGI2 FP PGE IP PGF TP PGD EP (4 subtypes) TXA2 |
DP - PGD
EP - PGE (4 subtypes) FP - PGF IP - PGI TP - TXA2 |
|
Each receptor has a different G protein and therefore a different ____ _______
|
second messanger
|
|
PG and TX receptors are characterized in part by their ability to mediate ______ aggregation or _____ ______ constriction or dilation
|
platelet
smooth muscle |
|
Prostaglandins can induce fever with ___ being the most potent
IL-1 -> PG's -> fever |
PGEs
|
|
Increased vascular permeability and vasodilation due to what 2 prostaglandins?
|
PGEs and PGI2's
|
|
PGEs cause pain
PGEs and ___ lower pain threshold or sensitize pain receptors |
PGI2
|
|
Cytokines, Bradykinin, Other mediators cause _______ production and result in pain
|
Prostaglandin (PGE)
|
|
Therapeutic relevance of drugs that inhibit COX (cyclooxygenase)
|
Inflammation (redness, swelling, heat, pain), Fever, CV disease (PG and TX very important in balance of platelet aggregation)
|
|
NSAIDs, COX inhibitors, aspirin-like drugs, analgesic, anti-inflammatory, anti-pyretic drugs all have what action?
|
Inhibit cyclooxygenase
|
|
Drugs that inhibit COX 1 and 2:
Analgesia, Antipyretics, Anti _______ |
inflammatory
|
|
The analgesia of COX-1 and 2 inhibitors leads to pain of low intensity with little ____ _____ and no addiction compared to opioids. ___ lower pain threshold, so blocking them restores it
|
side effects
PG's |
|
The antipyretic effect of COX-1 and 2 can reduce body temp in febrile states
Inflammation -> IL-_ -> PGE2 -> Hypothalamus -> fever The action of ______ in hypothalamus results in elevated body temp |
IL-1
PGE2 |
|
What do Aspirin, Ibuprofen, Naproxen Diflunisal, Ketoprofen, Indomethacin, Sulindac, Piroxicam all have in common?
What makes Aspirin different form the other NSAIDs? |
They all inhibit cyclooxygenase (COX 1 and 2)
Aspirin irreversibly acetylates COX (need to produce new platelets before it's reversed) |
|
Aspirin ________ acetylates COX
|
irreversibly
|
|
In what respect is Ibuprofen better than Aspirin?
|
Ibuprofen has fewer GI side effects than aspirin
|
|
Recognize the following names as what?
Piroxicam, Sulindac, Indomethacin, Ketoprofen, Diflunisal, Naproxen and Ibuprofen (both OTC) |
Nonselective COX inhibitors - traditional NSAIDs
|
|
What is unique about Celecoxib? (Celebrex)
|
Selective COX2 inhibitors or "coxibs" (10-20x more selective for COX2)
|
|
Which common over the counter drug is NOT an NSAID, and is analgesic, antipyretic, but NOT anti-inflammatory?
|
Acetaminophen - weak inhibitor of COX. Inhibits COX in the brain but not at sites of inflammation
Hepatic injury with large doses (always associate tylenol with that!) |
|
Gastric or intestinal ulceration, prolonged gestation, renal function, hepatic function, and increased bleeding time are side effects of what drugs?
|
Drugs that inhibit cyclooxygenase
|
|
Gastric/intestinal ulceration from NSAIDs related to inhibition of ______ production by COX-1 which is thought to protect gastric mucosa. Sometimes secondary anemia from resultant blood loss. Reduced with _____ inhibitors
|
Prostaglandin
COX-2 inhibitors |
|
________ via COX-1 and -2 play a role in initiating labor
|
Prostaglandins
|
|
Being on a large dose of NSAIDs for years or abusing them can cause ______ problems.
|
kidney
|
|
What condition has been reported with sulindac, indomethacin, ibuprofen, and naproxen.
|
Hepatitis
|
|
Inhibition of COX 1 in the platelet prevents platelet aggregation and __ formation. This increases bleeding time.
|
TX (thromboxane)
|
|
Aspirin hypersensitivty is present in 3-10% of patients with what condition? Symptoms are rhinitis, urticaria, ______, and laryngeal edema
|
asthma asthma
|
|
Aspirin Hypersensitivity Mechanisms:
-Maybe block of COX shifts AA to lipoxygenase pathway -> _________ -> hypersensitivity -Inhibition of COX1 results in decreased PGE2 -> increased ________ -> hypersensitivity |
leukotriene production
leukotrienes |
|
COX-2 inhibitors are better than nonselective COX inhibitors because they are less likely to cause gastric ________, don't inhibit ________ function, and are less likely to cause ______ hypersensitivity
|
ulceration
platelet aspirin |
|
COX1 in ________ is not inhibited by COX2 inhibitors. Thus, platelets continue to make thromboxane (platelet aggregator). COX2 inhibitors reduce the production of _________(inhibits platelet aggregation) by endothelial cells.
|
platelets
prostacyclin |
|
_____ toxicity associated with Reye syndrome (encephalopathy and fatty liver follow viral infection with kids)
|
Aspirin
|
|
Anti-inflammatory doses of _____ are close to toxic doses
|
Aspirin
|
|
______ irreversibly inactivates platelet cyclooxygenase
|
Aspirin
|
|
Cyclooxygenase pathway makes ________ and ________
Lipoxygenase pathway makes ________ Both from Arachidonic Acid |
Prostaglandins and Thromboxane
Leukotrienes |
|
Limitation of the leukotriene pathway is availability of _______ _____
|
Arachidonic Acid
|
|
HETEs have ________ activity
|
chemotactic
|
|
Addition of ________ to peptidoleukotrienes (LTC4, LTD4, LTE4) which cause bronchoconstriction and asthma. "slow-reacting substance of ________"
|
glutathione
anaphylaxis |
|
5-lipoxygenase (5-LO) is a _______ enzyme which is translocated to membranes by binding to the protein 5-lipoxygenase activating protein (FLAP). In cell types of myelomonocytic origin.
|
cytosolic
|
|
Degradation of Lipoxygenase Products:
LTA4- short half life LTB4- oxidized by enzymes in ____ to inactive LTE4- low potency, excreted by urine or acetylated and excreted in the _____ |
PMN's
bile |
|
AA from PMN, Mast Cells, Basophils is transformed into ____ via 5-lipoxygenase
|
LTA4
|
|
LTA4 hydrolase transforms LTA4 into what?
|
LTB4
|
|
LTC4 formaiton can happen via:
1) LTC4 synthase in what kind of cells? 2) Glutathione S transferase in what kind of cells? |
1) mast cell or basophil
2) endothelial cell or smooth muscle cell |
|
LTA4 travels to other cell types where it can be converted to:
LTC4 in endothelial or _____ ____ cells LTB4 in platelets or _____ |
smooth muscle
RBC |
|
Receptor for which leukotriene is distinct from the other receptors?
|
LTB4
|
|
The CysLTR1 receptor is also known as the _____ receptor because it interacts preferentially with that leukotriene
|
LTD4
|
|
CysLTR2 is also known as the ______ receptor. It interacts with both ____ and LTD4
|
LTC4
LTC4 |
|
LTB4 through interaction with the LTB4 receptor can cause
- ________ of white cells - leukocyte adhesion, enzyme release, and production of ____ - hyperalgesia or reduction of pain threshold |
chemotaxis
ROS |
|
Peptidoleukotrienes interact wit the ______ to cause:
-bronchoconstriction -Eosinophil chemotaxis and cytokine secretion -increased vascular perm and mucous production -dendritic cell maturation and migration -smooth muscle proliferation |
CysLTR1
|
|
Peptidoleukotrienes interact with the _____ to cause:
-endothelial cell and macrophage activation -fibrosis |
CysLTR2
|
|
Which leukotrienes are imporant in ashtma?
Which leukotriene is found in the synovial fluid of pts with arthritis and gout? |
LTC4/LTD4
LTB4 |
|
Leukotriene inhibitors are used in the treatment of what?
|
Bronchial asthma
Used for chronic asthma but not acute |
|
Zileuton, Zafirlukast and Montelukast are all what type of drug?
|
Leukotriene Inhibitors
|
|
Zileuton inhibits 5-lipoxygenase and thus prevents synthesis of _______
|
leukotrienes - most importantly LTB4
|
|
Zileuton is metabolized by ________ ___ and may cause drug interactions
_________ inhibits that enzyme and may also cause significant drug interactions |
cytochrome P450
Zafirlukast |
|
Zafirlukast and Mantelukast are leukotriene receptor antagonists for what receptor?
|
LTD4 receptor, CysLTR1
|
|
Which leukotriene inhibitor requires monitoring for hepatic toxicity?
|
Zileuton
|
|
______ are synthesized extracellularly in blood or interstitial fluid, NOT in cell
|
Kinins
|
|
_______ and kallidin are kinins that cause:
Hypotension Pain Edema Important in BP control and ______ |
Bradykinin
inflammation |
|
Kallikrein inhibitors and kinin receptor antagonists being used in __ Inhibitor Deficiency (Hereditary angiodema)
|
C1 (complement - first step)
|
|
Activated Hageman Factor
Kallikrein Plasmin C1 esterase These 4 enzymes are key in what? |
Kinin, Complement, Coagulation and Fibrinolytic Pathways (which are all interrelated)
|
|
Bradykinin is just _____ with one less amino acid
|
Kallidin
|
|
C1 inhibitor inhibits C1 esterase, kallikrein, plasmin, Factor XIa and XIIa. Lacking in HAE. Critical event is lack of control of _____ by missing C1 inhibitor
|
kallikrein
If you don'ot have it, you have excessive production of kinins and swelling |
|
Kininase II = ________ converting enzyme (ACE) or Dipeptide hydrolase
|
Angiotensin
|
|
Kininase I - Carboxypeptidase N or anaphylatoxin inactivator removes the carboxy terminal _______.
|
arginine
|
|
Bradykinin (_ aa) and Kallidin (_aa) are mediators with inflammatory activities
|
9
10 |
|
B1 receptor - chronic inflammation, vasodilation, pain, ________ production, _____ recruitment
|
cytokine
WBC |
|
B2 receptor - Vasodilation, pain, _______ EXCRETION
|
sodium
|
|
Actions of Kinins via B1 and B2 receptor - Kallidin and Bradykinin are more active than when they have a terminal ____ attached
|
arginine
|
|
When Kallidin and Bradykinin bind the B2 receptor -
hyper or hypotension? edema algesic - cause pain contract smooth muscle release catecholamines from the ____ _____ release PGE |
HYPOTENSION
adrenal medulla |
|
When bradykinin and kallidin bind B1 receptor:
Chronic ______ effects Induced after ______ hypotension and pain |
inflammatory
trauma |
|
Deficiency of HMW kininogen or Prekallikrein results in clotting & fibrinolytic defects with decreased ____ formation
|
kinin
|
|
Kallikrein inhibitors and kinin receptor antagonists are useful in __ _______ deficiency
|
C1 inhibitor
|
|
Immunosuppressive drugs are used to dampen the immune response in organ _________, ________ disease, and hypersensitivity.
|
transplantation
autoimmune |
|
The goal of immunosuppression treatment is to avoid immune mediated ______ damage from the immune response and the ______ response
|
tissue
inflammatory |
|
The immune response is more likely to be inhibited if therapy is begun when?
|
After exposure to the immunogen
|
|
Are primary or secondary immune responses more effectively suppressed?
|
Primary
|
|
Limitations of immunosuppressive therapy:
Increased risk of ________ of all types Increased risk of ________ and related malignancies |
infections
lymphomas |
|
Major classes of immunosuppresants:
- Glucocorticoids - anti-inflammatory _____ - Cancineurin _________ -Antiproliferative/antimetabolic drugs -Anti_____ |
steroids
inhibitors bodies |
|
Primary clinical uses of immunosuppression:
________ disease Transplantation ________ anemia of newborn |
Autoimmune
Hemolytic |
|
Corticosteroids (21 carbons) and Androgens (19 carbons - body building) are synthesized by what?
|
Adrenal Cortex
|
|
The corticosteroids have 2 different types of activity
________ - carbohydrate metabolism regulating mineralcorticoid - ________ balancing activity |
Glucocorticoid
electrolyte |
|
Corticosteroids are secreted by the adrenal gland in response to stimulation by ____. Endogenous corticosteroids have varying degrees of mineral/glucocorticoid activity
|
ACTH (adrenocorticotrophic hormone)
|
|
In humans, ________ (cortisol) is the main glucocorticoid and _________ is the main mineralocorticoid
|
hydrocortisone
aldosterone |
|
Sodium retention is the ability of the steroid to reduce sodium excretion by the kidney in an adrenalectomized animal. Does aldosterone or cortisol exhibit this?
|
aldosterone (mineralcorticoid)
|
|
Cortisol is able to do liver glycogen deposition and ____ _______ activity
|
anti-inflammatory
Liver glycogen deposition, anti-inflammatory activity and involution of lymphoid tissue parallel one another. |
|
The HPA axis is made up of what?
What steroid results? |
Hypothalamus acting on Anterior Pituitary acting on Adrenal Cortex -> produces cortisol which is anti-inflammatory on the immune system
|
|
The hypothalamus communicates with the anterior pituitary with what hormone?
|
Corticotropin releasing hormone
|
|
The anterior pituitary acts on the adrenal cortex with what hormone?
What does the adrenal cortex then produce, which feeds back to turn off immune system? |
ACTH
Cortisol - negative feedback on endogenous inflammation |
|
When the immune system gets too active, we add exogenous __________ to turn it off because our endogenous can’t handle the job
We want to minimize drug action on the __________ receptor |
glucocorticoids
mineralocorticoid |
|
What is an anti-inflammatory, endogenous steroid that we have to know?
|
Cortisol
|
|
What do all of these drugs have in common?
Betamethasone, Dexamethasone, Methylprednisolone, Prednisone |
They are all synthetic steroids used as anti-inflammatory drugs
|
|
Glucocorticoids are administered how?
Where are they metabolized? Where are they excreted? |
Administered orally, parenterally, topically
Metabolized in the liver Excreted in the kidney |
|
Steroids act on ________ receptors. The glucocorticoid receptor binds and promotes _______ of proteins that inhibit the immune response. Can also inhibit proteins that help the response (NF-kB and AP-1)
|
intracellular
transcription |
|
Anti-inflammatory steroids cause more circulating _________, their release from bone marrow accelerated, their half time in circ increased, and blockage of their migration into inflammatory sites
|
Neutrophils
|
|
Anti-inflammatory steroids cause a profound, transient ________ in which the cells are not lysed, but move to extravascular compartments
|
lymphopenia (lack of lymphocytes)
|
|
Anti-inflammatory steroids cause increased/decreased monocytes and eosinophils in peripheral blood
|
decreased!
|
|
Steroids reduce the expression of COX_, inhibit release of _______ ____ from phospholipids - thus affecting PGE and LK production, inhibit degran of mast/basophils, inhibit synthesis and release of TNF, IL-_ and _, and IFN
|
COX2
arachidonic acid IL-1 and IL-2 |
|
Using glucocorticoids in anti-inflammatory therapy helps by reducing inflammation BUT
|
the underlying cause of the disease remains
|
|
After systemic administration - ____ _____ are common and life threatening.
Also, host ______ to microbial and fungal infection is lowered |
side effects
resistance |
|
How is dosing done for steroids? Does one dose or a few days of therapy have any bad effects? Does prolonged therapy have any bad effects? What happens if you just stop taking them after prolonged treatment?
|
Trial and Error
Virtually no harmful effects if one day, unlikely if a few days Prolonged therapy increases incidence of lethal effects Risk of adrenal insufficiency with abrupt cessation of prolonged, high dose |
|
Uses for Steroids in Nonendocrine diseases: arthritis, systemic lupus (collagen diseases), allergic diseases (not acute ______), bronchial asthma, eczema, malignancies, diseases of the ____, used to mask progression of _____ disesases
|
anaphylaxis
liver ocular |
|
Prolonged large doses of steroids administered systemically can lead to immunosuppression, peptric _______, behavioral disturbances, cataracts, osteoporosis, inihibiton of ______
|
ulcers
growth |
|
Withdrawl/discontinuation of long term use of ______ can cause fever, myalgia, athralgia, malaise, death with ___tension and shock
|
steroids
hypotension |
|
One major class of immunosuppressive drugs are ______ inhibitors, including cyclosporine and tacrolimus
|
Calcineurin
|
|
Inhibition of calcineurin activity blocks the _____________ events critical for cytokine gene expression and __ cell activation
|
dephosphorylation
T cell |
|
Both cyclosporine and tacrolimus bind to cytoplasmic receptor proteins to inhibit calcineurin activity.
Cyclosporine binds to ________ Tacrolimus binds to ____ |
cyclophilin
FKBP (FK506 binding protein) |
|
Cyclosporine is metabolized extensively in the ____. Potential for numerous drug interactions. Used for long term therapy for _________. BIG side effect is what?
|
liver
transplantation Nephrotoxicity - happens in as many as 75% of patients |
|
Tacrolimus is 100x more potent than _______. Its BIG side effect is what?
|
Also Nephrotoxicity
|
|
Antiproliferative and Antimetabolic drugs prevent the clonal expansion of _ and _ lymphocytes.
|
T and B lymphocytes
|
|
Sirolimus and Mycophenolate Mofetil are both what class of drugs?
|
Antiproliferative and Antimetabolic
|
|
Sirolimus (from Antiproliferative) and Tacrolimus (from Calcineurin inhibitors) both bind to what receptor?
|
FKBP receptor
|
|
Siromilus is used in combo therapy for organ transplant rejection. It binds to ____ receptor to inhibit a key enzyme in the cell cycle progression from __ to _ phase
|
FKBP
G1 to S phase |
|
What drug has these side effects?
Dose dependent increase in cholesterol and triglycerides, ________ when combined with cyclosporine, increased risk of lymphomas and infections, potential drug interactions because CYP3A4 is a substrate |
Sirolimus
combined with cyclosporine |
|
Mycophenolate mofetil is used for organ _______. A metabolite inhibits inosine monophosphate dehydrogenase which is used for guanine nucleotide synthesis. Which cells are dependent on this pathway for proliferation while other cell types can use salvage pathways??
|
B and T cells
|
|
Toxicity from mycophenolate mofetil includes hematologic - _____penia, and gastrointestional _____ and vomiting
|
leukopenia
diarrhea |
|
There is an overlap between drugs used for immunosuppression and those used for treatment of _____. Immune cells proliferate when there is an antigen while ____ cells proliferate unstimulated
Immune cell proliferation is partially synchronized while ____ cells are not. |
cancer x3
|
|
What is the difference in drug administration for immunosuppression versus cancer chemotherapy
|
Immuno - low dose daily - continuous blockade
Chemo - intermittently in high dose pulses to kill cells and allow immune system to rebound inbetween |
|
Antibodies have 2 functions:
Eliminate _______, done by anti-thymocyte globulin Affect _ cell function, done by Muromonab-CD3, Daclizumab, Basiliximab |
lymphocytes
T cell |
|
Daclizumab or Basiliximab – antibodies to ___ receptor so cytokine can’t bind
|
IL-2
|
|
Anti-thymocyte globulin binds to thymocytes in circulation resulting in ____penia and impaired _ cell immune responses
Toxicity due to Ig being recognized as foreign resulting in sickness and ____itis |
lymphopenia
T cell nephritis |
|
Muromonab-CD3 is used to prevent acute rejection of kidney, liver and ____ transplants. Mouse monoclonal Ab that binds to E chain of CD3 glycoprotein (part of _ ___ receptor) -> complex internalized preventing _____ recognition
|
heart
T-cell antigen |
|
______ release syndrome results from binding of muromonab CD3 to CD3 as well as crosslinking of Fc receptor. Administration of ______ prior to Muromonab reduces symptoms considerably. Working on humanized, non-Fc version
|
Cytokine
glucocorticoids |
|
Daclizumab or basiliximab bind to the __-_ receptor present on activated/resting T cells and blocks what?
What unique side effect does this drug have compared to anti-thymocyte globulin? |
IL-2
activated IL-2 mediated T cell activation events CAN have anaphylaxis |