Pharmacotherapy of inflammation Flashcards
H3 v(down arrow) cAMP
presynaptic autoreceptors
brain
myenteric plexus
Cox 1 vs 2
HPA axis and cortisol
Abatacept mechanism of action
blocking the costimulatory signal required for T cell activation
NSAID use
NSAID toxicities
What organ systems affected by histamine receptors
Cardiovascualr
pulmonary
nervous system
GI
Cox 2 derived PGs are involved in renal function; inhibition of COX-2…
reduced water and salt excretion byt the kidney, leading to peripheral edema, HTN, and exacerbation of pre-existing HTN
Rituxumab
inhibitor of B cell function
approved for pts that fail to respond to anti-TNF-a therapy
Approved for tx of nonhodgekins lymphoma
chimeric mab against CD20 antigen found on the surface of normal and malignant B lymphocytes. IgG1 and k immunoglobulin
2-1000mg IV infusions separated by 2 weeks
admin of glucocorticoid recommended prior to infusion to reduce incedence severity of infusion reaction
NSAID USE AND GI COMPLICATIONS
incidence of dyspepsia id >40% often amenable to tx with H2 receptor antagonist or a PPI
incedence of complicated or symptomatic ulcer is 2-5%. may be life treatening
How is the GI system affected by histamine receptors
increawse in acid secretion H2
PGE2
involved in all processes leading to the classical signs of inflammation: redness, swelling, and pain
glucocorticoid effects on the immune cells
ASA has been found to lower rates of what CA
colorectal cancer
NSAID side effects
asprin allergy
angioedema
anaphylazis
resp symptoms
skin rxns
increased leukotrienes
Abatacept
inhibitor of t cell activation
fusion protein of the extracellular domain of the CTLA4 molecule and the Fc doman of human IgG1
approved for pts who do not respond well to methotrexate and for pts who do not respond or cannot tolerate TNA antagonists
30 minute infusion given at 2 and 4 weeks after 1st infusion, every 4 weeks thereafter. Fixed dose. 10mg/kg
MOA: blocing the costimulatory molecule required for T cell activation B7 (CD80/86)
PGF2-alpha
high levels have been reported in patients suffereing from RA, OA,reactive arthritis, and psoriatic arthritis
PGI2
is rapidly produced following tissue injury and is an important mediator the the edema and pain associated with acute inflammation. It is the most abundant prostanoid in synovial fluid in human arthritic knee joints
AKA prostacycline
Autoimmune diseases being successfully treated with anti-TNA therapy
RA
crohns
ankylosing spondylitis
juvenile RA
psoriac arthritis
psoriasis
sarcoidosis
PGD2
produced by antigen presenting DCs and TH2 cells, suggesting a role in antigen-specific immune system responses
H2 (histamine receptor 2)
^ cAMP
gastric mucosa
blood vessels/ smooth muscle cells
mast cells
cardiac muscle cells
brain
H4 v(down arrow) cAMP
Eosinophils
Neutrophils
CD4 T cells
NSAID side effects
Reye’s syndome
varicella infection of influenza virus
liver damage and encephalopathy
Fexofenadine (allegra)
2nd/3rd generation H1 receptor competative antagonist
long duration (12-24 hours)
Little to no anticholinergic, and alpha-adrenergic, and anti-serotonergic actions
less sedation than 1st generation H1 blackers
not useful for N or motion sickeness
Zafirlukast and Montelukast
Leukotriene pathway inhibitor
LTD4 receptor antagonist
inhibits CYP3A4 and CYP2C9 -> increased warfarin t1/2
orally active
for mild to moderate asthma
considered an alternative to low dose inhaled corticosteroid
Cortisol
Cortisol is the primary glucocorticoid in hiumans
glucocorticoids exert a wide range of physioklogic effects, including regulation of immune fn, growth, and carbohydrate, fat, and protein metabolism
cortisol is synthesized from cholesterol
the secretion of cortisol follows a circadian rhythm ans is controlled by pulses of ACTH tht peak in the early morning and after meals
Chronic NSAID use linked to an increased risk of…
MI
Histidine ——> histamine
enzynme
histidine decarboxylase
Factors to conside (preexisting) when giving NSAIDs
stomach ulcer or bleeding
heart dz, inclduding MI or stroke
kidney dz/ HTN
co-administered meds/ supplements
chronic use of glucocorticoids is associated with…
high risk for adverse affects
Leukotriene pathways of arachadonic acid breakdown
Arachadonic acid and COX pathway
How is the nervous system affected by histamine receptors
stimulant of nerve endings H1
Laratadine (claratin)
2nd/3rd generation H1 receptor competative antagonist
long duration (12-24 hours)
Little to no anticholinergic, and alpha-adrenergic, and anti-serotonergic actions
less sedation than 1st generation H1 blackers
not useful for N or motion sickeness
Prednisone
glucocorticoid
short to medium acting
antiinflammatory 4x as much as cortisol
has high affinity for CBG and albumin
70-80 % protein bound
3 cell types affected by intradermal weal and flare response
1) dilation of vasculature in the microcirculation causing reddening
2) increased permeability pf capillary of venular endothelium causes edematous wheal (a smooth, slightly elevated patch)
3) stimulation of sensory nerve endings causes a red, irregular flare surrounding the wheal; may be accompanied by itching sensation
Apremilast
PDE-4 inhibitor
indicated for moderate to severe plaque psoriasis
increases intracellular cAMP, decreased TNAa production
Most common adverse affect N and D in first year of tx, nasopharyngitis, URI
Metabolized by CYP3A4 with subsequent glucuronidation and non-CYP mediated hydrolysis
excretion: 58% urine, 39% feces, severe renal impairment
associated with increased risk depression
Side effects of high dose or prolonged glucocorticoid therapy
Mechanism of histamine induced edema
contraction of endothelial cells happens along vasculature
Classic mechanism of glucocorticoid action
you have your glucocorticoid
comes and binds to receptor which has a head shock protein component that dissociates
GR and GCS go to nucleaus and upregulate and downregulate certain genes
Untoward effects of anti TNA therapy
TNFa is an important component of stress responses
TNA a is important for host defense mechanisms
pts on anti TNF therapy display increased incidence of infection, lupus, exacerbatiob of dymyelinating dz, and heart failure
may or may not be associated with increased risk of lymphoma
H1 (histamine receptor 1)
^ IP3/DAG
blood vessels
endothelial cells
sensory nerve endings
GI smooth muscle cells
broncial smooth muscle
brain
MAIN one that the drugs target. Think of inflammation when you think of this
How is the pulmonary system affected by histamine receptors
bronchoconstriction H1
How is the cardiovascular system affected by histamine receptors
vasodilation of arterioles and precapillary sphincters via H1 (some H2)
Increase vascular permeability H1 (hives) also edema
Increase heart rate (direct effect and reflex tachycardia)
Cetrizine (zyrtec)
2nd/3rd generation H1 receptor competative antagonist
long duration (12-24 hours)
Little to no anticholinergic, and alpha-adrenergic, and anti-serotonergic actions
less sedation than 1st generation H1 blackers
not useful for N or motion sickeness
Mechanism of histamine induced vasofilaiton
GC is guanylyl cyclase
influx of calcium happens
Tofacitinib
JAK inhibitor
Blocks JAK 1 and 3 and to a lesser degree 2
approved for moderate to severe RA for pts that do not respond well to methotrexate
Side effects: inflammation of nasal passages and upper pharynx, URI, Increased risk TB and lymphoma, HA
Metabolized by CYP3A4
diphenhydramine
1st generation H1 receptor competative antagonist
short duration (3-6 hours)
anticholinergic
anti a-adrenergic, anti serotonergic effeccts (penetration into CNS)
cause sedation
antiemetic, anti motion sickness
Asprin (Acetylsalicylic acid)
weak acid
analgesic (anti pain)
Antipyretic
anti-platelet
anti inflammatory
rapidly absorbed from the stomach and intestine in unionized form due to it being acidic
IRRIVERSIBLY inhibits prostaglandin biosynthesis by ACETYLATING the enxyme CYCLOOXYGENASE (COX)
How does ASA irriversibly inhibit prostaglandin biosynthesis
Acytelating COX
chloropheniramine
1st generation H1 receptor competative antagonist
short duration (3-6 hours)
anticholinergic
anti a-adrenergic, anti serotonergic effeccts (penetration into CNS)
cause sedation
antiemetic, anti motion sickness
Retuximan MOA
Histamine storage sites
blood basophils and tissue mast cells
gastric mucosal cells
neurotransmitter vessicles
Nabumetone
NSAID
Shows some selectivity for COX2 (in vitro)
Indomethacin
NSAID
associated with increase risk of CV event (mostly MI)
side effects : hypersensativity, GI, slight renal toxicity
depression. HA- similar to seratonin in structure
Tofacitinib MOA
Jak inhibitor
ultimately blocks transcription
Anakinra
cytokine blocker
inhibitor of IL-1
recombinant, nonglycosylated synthetic form of the human IL-1 receptor antagonist (IL-1Ra), an endogenous regularot of IL 1 action
Celecoxib
Cox 2 selective inhibitor
has not been shown to be any better than NSAIDS for upper GI (stomach) complications but has been shown to be associated with a significantly reddulced incidence of small bowel inflammatino and mucosal breaks than NSAIDS
It is a sulfonamide
t1/2 6-12 hours
Metabolized by CYP2c9
Inhibits CYP26( metabolism of metoprolol, SSRI, tricyclic antidepressants)
Significan 1st pass metabolism
RA and OA but not general pain
Acetaminophen
weak base
analgesic and antipyretic
NOT ANTI INFLAMMATORY
No anti platelet effefcts
Severe HEPATOTOXICITY with oversidage caused by reactive quinone metabolites. Normally these metabolites are rapidly inactivated by conjugation with glutathione. With high toic levels of the drug, hepatic glutathione becomes depleted. The drug N-acetylcysteine is used to prevent hepatotoxicity
Uses of H2 receptor antagonists
(H2 in the gut)
May be useful for reducing NSAID induced dyspepsia
Gastric and pepti ulcers ( most peptic ulcers due to h pylori. NSAID induced are usually gastric) there is no evidence that H2 antagonists prevent drug induced ulcers and their complications
esophageal reflux
few side effects
infrequent GI irritation
cimetidine is a potent inhibitor of P450 metabolism
Use of COX-2 inhibitors in pts with ASA induced asthma
5-20% of pts with chron asthma are hypersensative to ASA. Likely due to cox 1 inhibition, leading to lipoxygenase pathway activation and production of cysteinyl leukotrienes -> bronchospasm and nasal obstruction
Some ppl have been ok with COX2 inhibitors but there is still a warning label on med
Infliximab
cytokine blocker
inhibitor of TNF-a
chimeric mAb (human contant, mouse variable)
given IV
increased risk for TB
Functions of histamine
mediator of immediate allergic and inflammatory reactions
role in gastric acid secretion
neurotransmitter and neuromodulator
chemotactic factor for neutrophils, eosinophils, basophils, monocytes, and lymphocytes
Zileuton
Leukotriene pathway inhibitor
Inhibits 5-lipoxygenase
inhibits CYP3A4 can influence metabolism of terfenadine, warfarin, and theophulline
orally active
for mild to moderate asthma
considered an alternative to low dose inhaled corticosteroid
2 areas of inhibition for leukotriene pathway of arachadonic acid
NSAID side effects
Inhibition of COX-1
stomach irritation
prolonged bleed time
renal toxicity
CNS effects
entanercept
cytokine blocker
inhibitor of TNF-a
Human TNF receptor linked to the Fc portion of human IgG1
Basically sponge for TNF-a. Like a decoy recep.
Given 2x/ week
