NSAIDS/related drugs & steroids

Question 0

NSAIDS administration & elimination

Answer 0

Oral administration

Metabolized by liver & secreted in urine

Question 1

NSAIDS (MOA)

Answer 1

Completely inhibit COX-1/2 active sites thus inhibiting prostaglandin production resulting in antipyretic, analgesic, and anti inflammatory effects

Question 2

NSAIDS adverse effects

Answer 2

Anorexia, nausea, dyspepsia, abdominal pain & diarrhea
Gastric ulceration with regular use (inhibits prostaglandins which releases bicarbonate and reduces acid)
Renal failure (some conditions such as cardiac failure, hepatic cirrhosis, chronic renal disease, renal blood flow is dependent on the vasodilator effects of prostaglandins)
Coadministration of PGE1 analog, misoprostol, or proton pump inhibitors (omeprazole) can prevent duodenal & gastric ulcerations
Impairment of platelet function (prevents formation of TXA2 by platelets resulting in impairment of platelet aggregation and increased bleeding)
Hypersensitivity to NSAIDS can be fatal if they are used (less common in children, 10-25% adults with asthma and/or nasal polyps- symptoms are rhinitis, generalized urticaria to laryngeal edema, hypotension and circulatory collapse and death; thought to be due to blockade of COX leading to increased leukotrienes

Question 3

NSAIDS drug interactions

Answer 3

Glucocorticoids, low dose aspirin (for cardio protection)- increased risk for GI ulceration
Warfarin- increased bleeding risk (inhibit metabolism of warfarin and platelet function)

Question 4

NSAIDS contraindications

Answer 4

Hypersensitivity to aspirin or other NSAIDS

Question 5

3 Main NSAIDS

Answer 5

Celecoxib
Naproxen
Ibuprofen

Question 6

Celecoxib

Answer 6

NSAID
COX-2 selective with less severe GI toxicity than non-selective NSAIDS
Usual dosing has no effect on platelet aggregation

Question 7

Naproxen

Answer 7

NSAID

Longest half life of 3 main NSAIDS making twice a day dosing possible

Question 8

Ibuprofen

Answer 8

NSAID

Question 9

Aspirin MOA

Answer 9

Salicylate
Aka acetylsalicylic acid; converted to active compound salicylic acid in plasma by esterases
Covalently modify COX-1/2 irreversibly inhibiting activity
Duration of action varies depending on tissues COX turnover rate
Exhibits antipyretic, analgesic, and anti inflammatory effects by inhibiting prostaglandin production

Question 10

Aspirin administration & elimination

Answer 10

Oral & rectal suppository
Metabolized in liver, excreted in urine
Plasma half life of 20 min., 2-3 hrs for salicylate low dose, 30 hrs at toxic level
One of few drugs to exhibit zero order kinetics (disproportionate increase in plasma with increasing dose)
At low doses eliminated by first order processes, at high the liver enzymes become saturated increasing unmetabolized aspirin excretion in urine
Increasing urine pH hastens elimination of salicylic acid due to ion trapping

Question 11

Aspirin adverse effects

Answer 11

Same as NSAIDS
Bleeding time is especially increased due to irreversible inhibition of COX
Reye’s syndrome in children with viral infections- consists of acute noninflammatory encephalopathy, hepatic dysfunction, and various metabolic derangements

Question 12

Aspirin drug interactions

Answer 12

Same as NSAIDS

Question 13

Aspirin contraindications

Answer 13

Children w/ viral infections

NSAID hyper sensitivities

Question 14

Salicylate poisoning symptoms

Answer 14

Nausea, vomiting, diaphoresis, tinnitus which progresses to diminished auditory acuity with potential deafness as CNS conc. increases
Other CNS effects- vertigo, hyperventilation (due to uncoupling of oxidative phosphorylation increasing CO2) manifested as hyperpnea or tachnypnea, hyperactivity, agitation, delirium, hallucinations, convulsions, lethargy, stupor
Hyperthermia (due to uncoupling of oxidative phosphorylation)- preterminal sign of severe toxicity
Uncoupling also causes acidosis (decreased blood pH from increasing lactic and pyruvic acid levels)

Question 15

Salicylate poisoning treatment

Answer 15

Activated charcoal to absorb drug in GI

Sodium bicarbonate to increase urine pH and ion trap the weak acid

Question 16

Acetaminophen MOA

Answer 16

COX-1/2 weak inhibitor with analgesic, antipyretic effects similar to aspirin
Weak anti inflammatory (unable to inhibit COX in presence of high conc. of peroxides/sites of inflammation)
Does not inhibit platelets
Preferred drug for aspirin allergies

Question 17

Acetaminophen administration & elimination

Answer 17

Oral & rectal suppository
First line treatment for children
Metabolized in the liver- small fraction metabolized by cytochrome P450 system to a highly reactive metabolite NAPQI

Question 18

Acetaminophen adverse effects

Answer 18

At common daily doses it is devoid of the adverse effects assoc. w/ aspirin & NSAIDS (at high levels starts to mimic)
Overdose- sulfate & glucuronate pathways become saturated & increasing amounts are metabolized to NAPQI (eliminated by conjugation w/ glutathione which becomes depleted in overdose resulting in NAPQI binding covalently to cell macromolecules in liver leading to hepatic necrosis)

Question 19

Acetaminophen poisoning treatment

Answer 19

Activated charcoal to absorb drug in GI (within 4 hrs. to prevent necrosis)
N-acetylcysteine (orally or IV) to replete glutathione stores

Question 20

Acetaminophen drug interactions

Answer 20

Alcohol- may increase risk of liver damage

Question 21

Acetaminophen contraindications

Answer 21

Patients with alcoholic liver disease

Question 22

3 Main glucocorticoid drugs

Answer 22

Hydrocortisone
Dexamethasone
Prednisone

Question 23

Glucocorticoids MOA

Answer 23

Corticosteroid
Transported in blood bound to corticosteroid-binding globulin (CBG)
At target cell dissociates from CBG & crosses membrane- binds to glucocorticoid receptor (GR)- complex crosses the nuclear membrane binds to DNA at glucocorticoid response element (GRE) alterating protein synthesis
Interacts with numerous receptors (about 10 types) all of which are g-protein coupled
Inhibit cytokine induced expression of COX-2

Question 24

Glucocorticoids medicinal effects

Answer 24

Anti inflammatory- inhibit recruitment of leukocytes and monocyte-macrophages
Inhibit chemotactic substances, arachidonic acid metabolites (by stimulating annexin production which inhibit PLA2) and cytokines
Maintain capillary integrity and vascular tone
Immune modulating- inhibit macrophage functions- inhibit MIF (migration inhibitory factor) so macrophages do not accumulate at affected areas
Inhibit processing and display of antigens through inhibition of interferon
Inhibit synthesis and release of IL-1 & 2 decreasing activation and proliferation of T-cells- interfere with IL-2 & receptor on T-cells resulting in lymphocytopenia
Little to no effect on B-cells

Question 25

Glucocorticoid administration & elimination

Answer 25

Use minimum effective dose (a single large dose is virtually w/o harmful effects)
Administer locally (oral, intranasal, topically)
Avoid rapid withdrawal
Once in remission every other day therapy should be tried- steroid is administered every other AM to stimulate natural circadian rhythm
Not effective in more severe diseases
Metabolized in liver; water soluble conjugated excreted in urine

Question 26

Glucocorticoid diseases treated

Answer 26

Allergic, cerebral, collagen, hepatic, renal, respiratory, GI, arthritis & dermatological disorders
Shock
Rheumatic carditis

Question 27

Glucocorticoid adverse effects

Answer 27

Flare up of underlying disease trying to be controlled
Adrenal insufficiency due to rapid withdrawal where the HPA axis has been suppressed
Systematic effects:
Cardiovascular/renal- edema, hypokalemia, Na+ & H2O retention, hypertension
CNS- euphoria, depression, psychosis
Endocrine- growth failure (peds), suppression of HPA axis
GI- peptic ulcer, hemorrhage
Immune- susceptibility to infection
Metabolic- hyperglycemia, hyperlipidemia, negative N2 balance
Musculoskeletal- osteoporosis (glucocorticoids decrease Ca+ intestinal uptake increase it’s excretion & inhibit osteoblast- this cause parathyroid hormone secretion to attempt to counteract), osteonecrosis, myopathy
Opthalmological- glaucoma, cataracts

Question 28

Glucocorticoids drug interactions

Answer 28

Drugs that alter hepatic metabolism