Glucocorticoid and NSAIDs Flashcards
1
Q
what synthesizes Arachidonic Acid?
A
Phospholipase A2 breaks down membrane phospholipids
2
Q
Arachidonic acid is the precursor for…
A
prostaglandins, thromboxane, and leukotriene
3
Q
Cycooxygenase -1
A
constitutive enzyme, path of arachidonic acid break down involved in prostaglandin and thromboxane synthesis
4
Q
Cycooxygenase -2
A
enzyme that is both induced with inflammation and constitutive, part of arachidonic acid break down, involved in prostaglandin synthesis
5
Q
COX-1 ubiquitously located and has these functions …
A
Gastroprotection, platelet aggregation, renal function
6
Q
COX-1 gastroprotection
A
Decreased pepsin/acid synthesis; increase mucosa and bicarbonate synthesis. This COX1 pathway is gastro-protective. (prostaglandin)
7
Q
Cox-1 Platelet aggregation
A
pro aggregatory, increased clot formation (thromboxane)
8
Q
Renal Function - Cox 1
A
Increase renal blood flow to promote diuresis (prostaglandin)
9
Q
Side effects when COX-1 is inhibited?
A
Gi ulceration and dyspepsia (bleeding), prolonged bleeding, acute renal failure
10
Q
COX 2 has these functions..
A
Pain, Fever, Inflammation, Renal Function, Endothelial vasodilation, Uterine contractions, Ductus Arteriosus prolongation
11
Q
COX-2 Pain
A
potentiation of bradykinin (prostaglandin)
12
Q
COX-2 Fever
A
Increased heat generation and decreased heat loss (prostaglandin)
13
Q
Cox -2 Inflammation
A
Enhanced edema and leukocyte infiltration
14
Q
Cox-2 Renal Function
A
Maintenance of renal blood flow
15
Q
Endothelial Cells - Cox2
A
Vasodilation and antiaggregatory;
16
Q
Uterus - Cox 2
A
Labor contraction
17
Q
Ductus arteriosus
A
prolonged opening
18
Q
Side Effects when COX2 is inhibited?
A
Acute renal failure, thrombosis/increased risk of MI and stroke, prolonged gestation, premature closure of ductus arteriosus
19
Q
Therapeutic Effect of COX2 inhibition?
A
Antipyretic, anti-inflammatory, analgesic
20
Q
Aspirin CoX 1 or 2? Reversible or Irreversible?
A
Cox 1/2 Irreversible
21
Q
NSAIDs CoX 1 or 2? Reversible or Irreversible?
A
Cos 1/2, Reversible
22
Q
Acetaminophen CoX 1 or 2? Reversible or Irreversible?
A
COX 2 reversible in the CNS
23
Q
Celecoxib
A
COX2 reversible
24
Q
Therapeutic Analgesia
A
inhibition of inducible COX2 at site of injury
25
Antipyretic Therapeutic Effect
inhibition of inducible COX2 in hypothalamus
26
Anti-inflammaotry Therapeutic Effect
Inhibition of inducible COX-2 at sites of inflammation
27
Anti-thrombogenesis Therapeutic Effect
Inhibition of constitutive COX1 in platelets
28
GI side effects are due to…
inhibition of constitutive COX-1 in gastric cells
29
Increased bleeding is due to…
inhibition of constitutive COX-1 in in platelets
30
Renal Side Effects are due to..
Inhibition of constitutive COX-1 or Induced COX-2 in kendey cells
31
Uterine side effects are due to..
inhibition of induced COX-2 in uterine smooth muscle
32
Increased thrombotic events are due to..
unopposed inhibition of COX3 in vascular endothelial cells
33
Aspirin Therapeutic Effects
Analgesic, Antipyretic, Anti-inflammatory, Anti-plaetlet
34
NSAIDs therapeutic effects
Analgesic, Antipyretic, Anti-inflammatory
35
Acetaminophen therapeutic effects
Analgesic, Antipyretic,
36
Celecoxib therapeutic effects
Analgesic, Antipyretic, Anti-inflammatory
37
which COX1 and COX 2 inhibitors are analgesic?
ALL
38
which COX1 and COX 2 inhibitors are antipyretic?
All
39
which COX1 and COX 2 inhibitors are antiinflammatory?
All except acetaminophen
40
which COX1 and COX 2 inhibitors are anti—platelet?
Only aspirin
41
Aspirin side Effects
GI Upset, Increased bleeding, Renal Failure, Decreased Labor
42
NSAIDs Side Effects
GI upset, Increased Bleeding, Renal Failure, Decreased Labor
43
Acetaminophen Side Effects
None
44
Celecoxib Side Effects
Renal Failure, Decreased labor, increased clotting, closure of ductus arteriosus
45
Which medications cause GI upset?
Aspirin and NSAIDs
46
Which medications cause Increased bleeding?
Aspirin and NSAIDs
47
Which medications cause increase renal failure?
Aspirin, NSAIDs, Cox-2 selective
48
Which medications cause decreased labor/contractions?
Aspirin, NSAIDS, COX-2 selective
49
What medications cause increased clotting?
COX-2 selective
50
NSAID dose for Pain/Fever reducer
Moderate
51
NSAID dose for Inflammation
high
52
Which is more effective for acute pain - NSAID, Aspirin, Acetaminophen?
NSAIDs
53
Toradol
IM or IV NSAID used to treat post-surgical pain
54
what should dysmenorrhea be treated with?
NSAIDs
55
Which is more effective for fever - NSAID, Aspirin, Acetaminophen?
all equal
56
Contraindications of NSAIDs
Advanced age, prior NSAID gastropathy or history of peptic ulcer disease, concurrent glucocorticoid use; anti-coagulent agent, patients with heart failure, hypertension, diabetes
57
Solutions of GI upset of NSAIDs
food or antacids; PPI to protect against gastroduodenal toxicity
58
Bleeding Effects Aspirin vs. NSAID
less bleeding in NSAID (around 2 days active); Aspirin is active 4-7 days
59
GI upset Aspirin vs. NSAID
Less GI upset compared to aspirin
60
Renal dysfunction Aspirin vs. NSAID
greater for NSAID, causes Renal blood flow, increased fluid retention and BP
61
What NSAID would you prescribe to a person at risk of GI bleed?
Ibuprofen because it has greater COX2 inhibition than COX1
62
What NSAID would you prescribe to a person at risk of cardiac problems?
Naprozen because it has greater COX1 inhibition over COX2
63
NSAID use in pregnancy
not established, not recommended especially in 3rd trimester
64
Celecoxib - what is selectivity of COX2 compared to COX 1?
5-7x more inhibition of COX2
65
Celecoxib metabolism
in liver with renal excretion; metabolized by CYP2C9; long half life allowing 1-2 times per day dosing
66
Clinical uses of Celecoxib
rheumatoid arthritis, osteoarthritis, dysmenorrhea, acute pain; benefits outweigh risks for those who cannot use NSAIDs due to GI bleeding risk
67
Adverse Reactions with Celecoxib
prothrombotic potential to increase MI risk
68
Pain reflief Celecoxib vs. NSAIDs
less effective for acute pain than NSAIDs
69
Inflammation relief Celecoxib vs. NSAIDs
equal for osteo and rheumatoid arthritis
70
GI upset in Celecoxib vs. NSAIDs
Less than NSAIDs at low dose, but equal at high dose.
71
avoid use of Celecoxib in these patients…
Chronic renal insufficiency, severe heart disease, volume depletion, hepatic failure
72
Celecoxib in pregnancy
not recommended, especially in 3rd trimester
73
Acetaminophen limitations
Not-antiinflammatory; limited to 4g/day due to hepatotoxicity.
74
Pain/fever dose for acetaminophen
moderate; less effective than NSAIDs for moderate pain
75
Adverse Effects of Acetaminophen
Hepatotoxicity - liver damage
76
what dose of acetaminophen causes toxicity
single 6 mg dose; also 5-8 mg/day for several weeks or 3-4 g/dy for 1 year
77
How does alcohol influence acetaminophen toxicity
alcohol induces CYP2E1 to produce toxic metabolite; thus may achieve toxicity at lower doses
78
Treatment of acetaminophen toxicity
N-Acetylcysteine (substitute glutathione in inactive toxic metabolite)
79
Max dose for acetaminophen
4000 mg/24 hours
80
Pregnancy and acetaminophen
safe in all stages, but only for therapeutic short term use
81
Aspirin - what type of pain does it work with?
inflammatory origin, less effective in visceral pain
82
Antipyretic effect of aspirin
reduced elevated body temperature (not normal)
83
Aspirin Anti-platelet function
low dose aspirin has larger effect on circulating platelet COX1 than tissue endothelial COX 2 - resulting in decreased tendency for clotting
84
Warfarin and Heparin interactions
inhibit platelet function - hemorrhage
85
Alcohol with additive gastric irritation
internal bleeding
86
Glucocorticoids
principally involved in carbohydrate and protein metabolism and anti-inflammatory response through cortisol
87
Mineralcorticoids
principally involved in Na Retention through Aldosterone
88
Dihydroandrostenedione (DHEA)
works with androstenedione to have weak androgenic active, but some DHEA is converted to testosterone and estradiol outside of adrenal gland.
89
ACTH
Adrenocorticopropic hormone - release from pituitary and under the control of the Corticotropin release factor from hypothalamus. Controls synthesis and secretion of clutocorticoids
90
Negative feedback in the hypothalamic pituitary adrenal axis
circulating corticosteroids (both endogenous and exogenous) act on hypothalamus AND pituitatary to decrease ACTH release.
91
Adrenal Crisis
chronic glucocorticoid can suppress HPA axis and results in adrenal atrophy and insufficient adrenal release
92
Stress and the HPA axis
injury, hemorrhage, infection, surgery, hypoglycemia, cold, pain, fear, override negative feedback loop to produce increased levels of steroid.
93
Cortisol Binding Globulin
binds to free cortisol in plasma and enters cells as free molecule.
94
What does cortisol in cytoplasm bind to?
HSP90
95
what does binding to HSP90 to cortisol do?
allows dimerization of S-R complex and entry into the nucleus to bind to glucocorticoid response element on DNA.
96
What genes dos Gluccocortcoid Response Element control?
transcription of genes that bring about the delayed hormone response.
97
Secretion of natural cortisol is highest…
during the early AM and after meals
98
Which is more active, bound cortisol or free?
Free, 75% of cortisol is bound
99
Half life of Cortisol
60-90minutes; prolonged in stress
100
changes to cortisol in glucocorticoid drugs?
altered protein binding, prolonged half life, separation of mineralocorticoid activity from glucocorticoid activity
101
Metabolic Effects of Glucocorticoids
Stimulates gluconeogenesis to increase blood glucose and glyocogen synthesis; increase Amino acid uptake in liver and kidney for decreased protein synthesis (transfer of AA to liver) can lead to muscle wasting; inhibit glucose uptake by fat to stimulate glycolysis (increased lipogenesis); net result maintenance of glucose supply to brain
102
Carbohydrate effect of glucocorticoids
increased blood sugar and glyocogen synthesis for diabets like state
103
Protein effect of glucocorticoids
increased uptake of AA into liver and kidney for overall decreased protein synthesis and muscle wasting
104
Lipid effect of glucocorticoids
inhibit uptake of glucose by fat cells to stimulate lipolysis (net effect though is lipogenesis) that leads to centripetal obesity (abdominal fat)
105
Mechanism of Mineralocorticoids
aldosterone binds to cytosolic receptor and migrate to nucleus to induce formation of mRNA for synthesis of Na/K ATPase channels for reabsorption of Na and increased secretion of H and K.
106
Pharmocologic reasoning for glucocorticoids
suppress inflammation and immune response
107
Anti-inflammatory Glucocorticoids
decreased synthesis of inflammatory and immune mediators; decreased production/action of cytokines; reduced generation of leukotrienes and prostalandinds vis decreased COX-2 and inhibition of phospholipase A2
108
Immunosuppresive Effects of Glucocorticoids
reduction in chronic inflammation and autoimmune reactions, but decreased healing and diminution of protective aspects of immune system
109
Four actions of glucocorticoids
1) suppress Tcell activation 2) suppress cytokine production 3) preventing mast cells and eosinophils form release chemical mediators of inflammation
110
Mast cells release
histamine, prostaglandins, leukotrienes
111
Eosinophils release
histamine, leukotrienes, cationic proteins
112
What do mediators of inflammation cause
tissue damage, vasodilation, edema
113
Glucocorticoid vascular effects
reduced vasodilation, decreased fluid exudation
114
GLucocorticoid effects on cellular events
decrease in accumulation and activation of cells
115
glucocorticoids on acute inflammation
decrease number and activity of leukoctyes; neutrophils increase in circulation, but movement into peripheral tissues is decreased
116
Glucocorticoids on chronic inflammation
decreased activity of monocytes and lymphocytes, decreased proliferation of Blood vessles, less fibrosis
117
Glucocorticoids on lymphoid areas
decreased clonal expansion of T and B cells, decrease cytokine secreting cells
118
11-hydroxy
glucocorticoids are physiologically active
119
11-keto
glucocorticoids are prodrugs that must be activated - prednisone and cortisone
120
11Beta-Hydrozysteroid dehydrogenase
converst to active or inactive glucocorticoids depending on lcoations
121
11Beta-HSD1 in liver
converts cortisone to cortisol (prednisone to prednisolone) in Activating step
122
11Beta-HSD2 in kidney
converts Cortisol to cortisone - inactivating step
123
11Beta-HSD2 in fetus
inactivating form is active in fetus, but 11Beta HSD1 is not functional in liver. Thus can treat mother with glucocorticoids without effect on fetus because placental enzymes can covert active drug back to prodrug
124
Treating fetus with glucocorticoids
poor substrate for 11beta-HSD2 (betamethasone)
125
Cortisol
hydrocortisone - use in physiologic doses for replacement therapy and emergencies; activated from cortisone in liver
126
Cortisol Glucocorticoid:mineralcorticoid acitivty
1 to 1
127
Cortisol forms
Orally, injectable, topical
128
Prednisone
use for steroid burst therapy; not activated until first pass from liver
129
Prednisone Glucocorticoid:mineralcorticoid acitivty
13 gluco to 1 mineral
130
Prednisone forms
Orally
131
Methylprednisolone
use of parenteral administration during steroid burst
132
Methylprednisolone Glucocorticoid:mineralcorticoid acitivty
NO mineralcorticoid activity
133
Methylprednisolone forms
Oral, Injectable
134
Dexamethasone
most potent antiinflammaotry, used in cerebral edema, chemo induced vomiting
135
Dexamethasone Glucocorticoid:mineralcorticoid acitivty
most potent antiinfalmmatory, no mineralocorticoid
136
Triamcinolone
potent systemic agent, excellent topical, no mineralcorticoid
137
Dosage of Glucocorticoid
determined by trial and error; considered by minimal amount for desired effect, duration of therapy; alternative day schedule; tapered otherwise might cause rebound of disease or adrenal insuffienciency
138
Acute affects of mineralocorticoid overdose
edema, increased BP, hypokalemia
139
Acute affects of glucocorticoid overdose
glucose intolerance, mood changes, insomnia, GI upset
140
High dose sustained Glucocorticoid therapy >2 weeks
Iatrogeni cushing’s syndrome, hypothalamic pituitary adrean axis suppression, mood disturbance, impaired wound healing; increased suseptabillty to infection
141
Iatrogenic Cushing Syndrome
hyperglycemia, protein wasting in muscle, lipid deposion (weight gain) in diabetes like state.
142
Hypothalamic-Pituitary Adrenal Axis Suppresion
insufficient response to stress, decreased ACTH, GH, TSH, LH, sex steroids
143
Possible side effects of large cumulative doses of glucocorticoids
Osteoporosis; posteror capsular cataracts, skin atrophy, growth retardation in children, peptic ulceration
144
Osteoporosis in glucocorticoid use
decrease in osteoblast, blockage of Vitamin D3, decrease calcium aborsption and increase PIH release.
145
Skin atrophy in glucocorticoid use
loss of collagen support
146
Growth retardation in children with glucocorticoids
decreased growth hormone secretion and impaired somatomedins.
147
Fludrocortisone
glucocorticoid with high anti-inflammatory (10), but extra high mineralocorticoid activity (250). only available in oral form.
148
Which glucocorticoids have no topical activity?
cortisone and prednisone
149
Potency of Glucocorticoids.
most potent is dexamethasome, leas is hydrocortisone; in between is methylprednisolone and triamcinolone.
150
which glucocorticoids have topical activity
hydrocortisone, triamcinolone, dexamethasone
