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PHARM L21: NSAIDS and Corticosteroids

Terms in this set (39)

List the important properties of NSAIDS.

What is the prototype drug?
1. analgesic = pain relief
2. antipyretic = anti-fever
3. anti-inflammatory

ASPIRIN
Describe the mechanism of action for all NSAIDS.
• inhibit the enzyme cyclooxygenase (COX)
• COX responsible for synthesis of prostaglandins
• PGs contribute to inflammatory processes
What are the actions and side effects of COX-1 inhibitors?

Name the drugs in this category.
Selectivity?
• reduce fever and inflammation
• produce ulcers and cardiac side effects

NAPROXEN, KETOPROFEN, IBUPROFEN, ASPIRIN**
• non-selective or slightly COX-1 > COX-2
• reversible inhibition of COX
*aspirin irreversibly inhibits COX-1 and COX-2
What are the actions and side effects of COX-2 inhibitors?

Name the drugs in this category.
Selectivity?
• reduce fever and inflammation
• reduced ulcers BUT produce cardiac side-effects

celecoxib, rofecoxib, and valdecoxib
• COX-2 >> COX-1
Describe the mechanism of action for aspirin
covalently (irreversibly) inhibits COX 1&2
• Platelets cannot synthesize new COX, so inhibition is irreversible.
NSAIDs inhibit __________ formation (via blockade of _____)
prostaglandin, COX
What are the functions of PGE2 and PGI2?
• vasodilation
• increase vascular permeability
• important mediators of localized erythema and edema
• recruit immune cells

• sensitize primary afferent fibers
- increased sensitivity to painful stimulation
When NSAIDs are used for analgesia, pain from _____________ is relieved but pain from ____________ is not.

What are NSAIDs combined with to provide greater pain relief than 1 drug alone?
integumental structures, hollow viscera

opioids
(T/F): NSAIDs are useful for prevention/treatment of post-op pain.

(T/F): NSAIDs have opioid effects of respiratory depression and development of tolerance/dependence.
True

False
Which part of the brain contains the temperature control center?

What agents lead to higher temperature set points (fever)?

Metabolism (increases/decreases) and vasodilation (increases/decreases).

How do NSAIDs affect body temperature?
hypothalamus

pyrogens (cytokines)

metabolism (heat generation) INCREASES, vasodilation (heat loss) DECREASES

NSAIDs that can cross BBB can suppress this increase in body temperature (antipyresis)
Describe the role of prostaglandins in the GI tract.

How do NSAIDs affect the GI tract?
Protective!
• PGE2 inhibits gastric acid secretion
• PGE2 and PGF2a stimulate synthesis of bicarbonate and mucus; PGI2 also involved
• PGE2 promotes mucosal blood flow

inhibit all effects -> GI irritation
Which conditions can be treated with NSAIDs to provide symptomatic relief for pain/fever of low-to-moderate intensity?
• headache
• dysmenorrhea
• arthralgia
• myalgia
• neuralgia
Which inflammatory conditions can be treated with NSAIDs?
• rheumatoid arthritis
• osteoarthritis
• seronegative spondyloarthropathy
• gout
• SLE
• bursitis, tendonitis
What are the uses of aspirin?
• analgesic, antipyretic, anti-inflammatory
• anti-platelet effects:
- prophylaxis of MI, stroke, etc.
- but prolonged bleeding
Aspirin can reduce the risk of colon cancer but only in people with a _________ gene mutation
PIK3CA
Describe the adverse effects associated with aspirin
• GI irritation
• prolonged bleeding (anti-platelet)
• Reye's Syndrome (swelling in liver and brain)
Describe the symptoms of mild aspirin toxicity - salicylism.
• nausea, vomiting, **tinnituss***, hyperventilation, headache, mental confusion, dizziness
• salicylates found OTC: muscle/chest rubs (Ben-Gay), oil of wintergreen, Peptobismol, etc.
Describe the signs and symptoms of aspirin overdose.
Which population is particularly vulnerable?
• acute medical emergency
• fever, dehydration, delirium, hallucination, convulsions, coma, respiratory and metabolic acidosis, death
• children
What are the uses for modern NSAIDs?

List the drugs.
• Reversible, non-selective COX inhibition
• Analgesic, antipyretic, anti-inflammatory
• Do not effect platelets
• Safe for children (no Reyes syndrome)

IBUPROFEN
KETOPROFEN
NAPROXEN
What are the issues associated with modern NSAIDS?
• Better tolerated than aspirin, but still have gastric irritation when taken for long periods
• Increased risk of GI bleeding if use SSRIs
CELECOXIB:
• selectivity?
• GI effect?
• platelet effect?
• risks/disadvantages?
• COX-2 inhibitor
• significantly fewer GI ulcers
• no effect on platelets and bleeding time
• expensive, increased risk of serious adverse CV event (but no greater risk than non-selective NSAIDs)
What are the advantages of NSAIDs over aspirin?

Disadvtanges?
• more potent, more efficacious at tolerated doses
• less GI irritation or other side effects
• longer duration of action so taken less frequently

• more expensive
• some more toxic
ACETAMINOPHEN:
• uses?
• GI effect?
• platelet effect?
• Reye's syndrome?
• advantages?
• non-narcotic analgesic & antipyretic
• very weak anti-inflammatory activity (NOT an NSAID)
• no GI effcet
• no platelet effect
• no Reye syndrome
• useful analgesic, antipyretic for kids
• well tolerated, cheaper, fewer side effects
Toxic doses of acetaminophen lead to _________________.

How does acetylcysteine protect the liver?
hepatic necrosis
- drug travels down minor path once major path overwhelmed

• maintain or restore glutathione levels
• act as alternate substrate for reactive metabolite
____________corticoids in the outer layer of the adrenal cortex regulate fluid and electrolyte levels.

____________corticoids in the middle later regulate carbohydrate metabolism and contribute to anti-inflammatory responses.
mineralo

gluco
Corticosteroids inhibit __________
PLA2
What is the role of glucocorticoids on metabolism?
• Regulate carbohydrate, protein, lipid metabolism
• Increase resistance to stress
• Redistribution of blood cells
- decrease most WBCs
- increase RBCs, platelets
What is the role of glucocorticoids in the immune system?
• inhibition of inflammatory mediators (PGs, leukotrienes, COX-2)
• decrease mast cell degranulation (less histamine)
• decrease peripheral lymphocyte and macrophage activation and function
Describe the anti-inflammatory actions of glucocorticoids.
• Increase vasoconstriction and decrease capillary permeability
• Limit cytotoxic effects of inflammation
- suppress activation of T-cells
- suppress/redistribute leukocytes
- block release of compounds from neutrophils, eosinophils, mast cells (inhibit cytokine production and release of mast cell stuff)
Why is topical/inhalation administration of glucocorticoids preferred?

What disease results from too little glucocorticoid?
Too much?
reduces systemic adverse effects
- Important homeostatic regulatory hormones: body keeps a balance

Addison's disease
Cushing's syndrome
Which glucocorticoids can be used to treat asthma and allergic rhinitis?
BECLOMETHASONE
TRIAMCINOLONE
Glucocorticoids can be used for which arthritic/autoimmune disorders?

Chronic inflammatory disorders?
• rheumatoid arthritis
• spondylopathies
• SLE
*flare-ups and when NSAIDs stop working

• ulcerative colitis
• Crohn's disease

**systemic uses
- also acute adrenal crises or allergic reactions
What is prednisone used for?
powerful broad-spectrum immunosuppressant
What kind of drug is prednisone?
How does its potency compare to cortisol?
• synthetic corticosteroid (highly lipophilic)
• prodrug for prednisolone (the active form, liver)
• more potent
Describe the adverse effects of prednisone.

How can these adverse effects be prevented?
• suppresses the adrenals after ~7 days use
• suppresses both ACTH & CRH secretion
• dependence develops
• withdrawal (Severe fatigue, weakness, body aches, nausea or vomiting, low blood pressure; adrenal crisis)

tapered off to allow ACTH & CRH levels to normalize
Describe the symptoms of prednisone toxicity with systemic administration
• Hyperglycemia
• Hypertension
• Peptic ulcers
• Myopathy
• Behavioral changes
• Cataracts
• Osteoporosis
• Growth retardation
Describe the symptoms of prednisone toxicity with LONG-term administration
• HPA axis suppression and withdrawal
• Continued use of high dose steroid
- HPA suppression
- Immunosuppression
- poor wound healing
- opportunistic infections
• Cushing's syndrome
Describe alternate day therapy for prednisone toxicity
• Use drug with shorter half-life (e.g., prednisone)
• Give drug every other day
• Minimizes HPA suppression
Describe pulse therapy for prednisone toxicity
• life-threatening or serious disease
• initial dose large
• if insufficient benefit quickly, double or triple the dose
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