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Pharm + Thera > Anti-inflammatory drugs: NSAIDS + Glucocorticoids > Flashcards

Anti-inflammatory drugs: NSAIDS + Glucocorticoids Flashcards

1
Q

Pain and inflammation results

A

Substance P, Bradykinin, Phospholipases, Prostaglandins, and serotonin all get released immediately

They all have an ability to bind and activate receptors on nerve endings

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2
Q

Prostaglandins and Inflammation

A

Injection of prostaglandins mimic aspects of the inflam response

Highly reactive oxidants also contribute to the inflammatory response and the formation of these compounds is inhibited by NSAIDS

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3
Q

All NSAIDS inhibit

A

Cyclooxygenase (COX)

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4
Q

If a drug does not inhibit COX

A

Does not have any anti- inflammatory activity

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5
Q

FEVER and PGE2

A

Immune cells respond to infections which produce cytokines (TNF, IL-6)

Cytokines release PGE2 by CNS vascular endothelial cells

PGE2 stimulates firing of HYPOTHALAMIC NEURONS, which raise the temp (fever)

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6
Q

NSAIDs + Fever

A

NSAIDS will lover fever but not lower body temp and have no impact on temp rising from exercise

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7
Q

Inhibitors of prostanoid Synthesis

A

phospholipase inhibitors corticosteroids

Lipoxygenase inhibitors

receptor antagonists

Colchicine

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8
Q

Acetyl Salicylic Acid

A

-Irreversible
Therapeautic Effects: Analgesia (reduces fever) and antipyretic within an hour
-non-selective COX 1/2 inhibitor
-anti-inflammatory effects after days (may take weeks for some conditions)

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9
Q

Theraputic effects of Acetyl Salictylic acid

A

Analgesia
-within an hour
-PGE2 sensitization of nociceptors
Antipyretic
-within an hour
-PGE2 in hypothalamus
Anti-inflammatory
-within says (could be weeks for some conditions)
-PGE2-mediated edema and leukocyte recruitment
Cardiac Protection: low dose therapy
-platelet thromboxane A2(reduce ability for platelets to be aggravated)
-although aspirin undergoes first-pass metabolism, the effect is on platelets in the bloodstream (portal vein has a lot of platelets)

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10
Q

What is Acetyl salicylic acid

A

Asprin

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11
Q

How is Acetyl salic acid metabolized?

A

Absorbed in the stomach and distributed throughout body tissues

-rapidly metabolized to salicylic acid. In GI cells, plasma and live.

-Further salicylate metabolism occurs in the liver (mostly Phase II)

-excreted by kidney

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12
Q

Undesired Effects of Aspirin

A

GI toxicity: dyspepsia, bleeding, ulceration, perforation. ADDITION of misoprostol (synthetic PGE) to NSAID formulation can be considered in patients at high risk of GI toxicity

Renal toxicity: inhibition of intrinsic PG system:hypovolemic patients at greatest risk

Salicylism: CNS toxicity (dizziness, headache, confusion)

platelet inhibition (can be deisred in lowering risk of cardiovascular disease)

Hepatotoxicity (liver toxicity)

Hypersensitivity reactions

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13
Q

PDR warning for…

A

Aspirin + all others NSAIDs

-can develop suddenly

-Serious GI toxicity such as bleeding, ulceration

-happens in people treated chronically with NSAIDS

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14
Q

RISK for NSAID induced GI complications

A
  1. Past complicated Ulcer
  2. Multiple NSAIDs
  3. High dose NSAID
  4. Anticoagulant
  5. Past uncomplicated ulcer
  6. Age > 70
  7. Steroids
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15
Q

Drug interactions

A

anticoagulants- combined activity
Alcohol- addictive irritant effect on gastric mucosa
Uricosuric Drugs- hyperuricemia at lower poses
Antihypertensive agents- generalized decrease in anti-hypertensice efficacy
diuretics- decreased effects of diuretic agents, increased risk of acute renal failure (particularly in the elderly who may already have reduced renal function// kidney damage)

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16
Q

How are the NSAIDS ibuprofen and Naproxen similar

A

-Cyclooxygenase inhibition (well-absorbed)
-hepatic metabolism
-adverse effects: GI, CNS, Renal toxicity, blood elements
-contraindications: hypersensitivity, peptic ulcer, hepatic disease
-less severe sside effects bc they are reversible inhibitors of COX 1/2

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17
Q

what are first line for mild pain and inflammation

A

Ibuprofen Naproxen

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18
Q

NSAID/PHARMACODNAMIC/HALFLIFE

A

Aspirin: COX 1/2 irreversible, half-life= 20 minutes but irreversible

Ibuprofen: COX 1/2 reversible: half-life 2 hours

Naproxen: COX 1/2 reversible: half-life 15 hours

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19
Q

COX-1 (from arachidonic acid)

A

constitutively expressed; Prostaglandins (Homeostatic Effects)

-Renal homeostasis

-Gastric mucosal protection

-Platelet function

From Physiologic stimulus comes through; the stomach, kidneys, intestine, platelets, endothelium all can be impacted. Things that come from COX-1 are: PGE2, TxA, PGI2: these things can impact physiologic functions

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20
Q

COX-2 (from arachidonic acid)

A

inducible; Prostaglandins (Inflammatory Effects)

-Pain

-Inflammation

-Fever

-Limited Homeostatic Effects

From Inflammatory stimuli; inflammatory sites (macrophages, synoviocytes) impacts: Inflammatory PGs, Proteases, O2: these things can impact inflammation

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21
Q

What is COX-2 selectively inhibited by

A

Celocoxib

In cox-2 there is a side pocked that was added; it fits into COX-2 side pocket

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22
Q

CELECOXIB

A

COX-2 Specific inhibitors

Benefits:
lower incidence of GI toxicity vs non-selective NSAIDS
Risks:
-inhibition may increase chance of thrombosis in patients at risk for this disease; it could be a key in generation of the prostacyclin. A PG that decreases platelet aggregation

  • Rofecoxib (Vioxx): thrombotic cardiac events

-COX-2 active in kidneys, the recommended doses of COX-2 inhibitors causes renal toxicities similar to what is associated with traditional NSAIDs

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23
Q

COX-1 and COX-2 impacts on thrombosis (formation of blood clots)

A

they are different
COX-1 impacts thromboxane A2, which impacts TP receptors, which are pro-aggregatory, pro-adhesion, vasoconstrictor, increased vascular remodeling

COX1/2: impact prostacyclin- which impacts IP receptors- which are anti-aggregatory, anti-adhesion, vasodilator, reduced vascular remodelling, reduced cholesterol uptake

24
Q

What is Acetaminophen// paracetamol

A

tylenol

25
Q

Acetaminophen uses

A

effective analgesic(pain killing) -antipyretic(fever reducing) agent

-weak anti-inflammatory activity

-weak platelet inhibitor

CNS actions:
-inhibits cycooxygenase(enzyme that helps create the chemicals prostaglandin and thromboxane) in hypothalamus, this is where its analgesic(pain killing) + antipyretic(fever reducing) actions occur. (Prevents PGE2 production by CNS vascular endothelium)
-may inhibit COX-3
-May act on Cannabinoid receptors (CB1)

26
Q

Acetaminophen overdose+overuse

A

leading cause of acute liver failure in US

-dose-dependent hepatotoxity (liver damage) and possibly acute renal failure (kidney failure)

-chronic ingestion can lead to hepatotoxicity due to build-up of NAPQI or chonic analgesic nephropathy(kidney deterioration)

27
Q

Acetaminophen and toxicity + symptoms +treatment

A

-safe at normal dosages
-toxic to liver in overdose (more than 10g)
-Medical emergency
-Glutathione conjugation pathway(part of phase II of detoxification in the body) becomes overwhelmed
Alternate metabolite is TOXIC

SYMPTOMS:
-vomit, lethargy, uper right abdominal pain

TREATMENT
N-acetylcysteine (NAC//Acetadote)
-Detoxifies NAPQ( a toxic byproduct)
-restores glutathione (GSH)
-conjugates directly with NAPQI by serving as GSH substitute

28
Q

What do all NSAIDS try to do

A

Target pain, and inflammation

29
Q

Aspirin: Major indications, Mechanism, Adverse Effects, Distinctive PK + Notes

A

MI: pain+inflam, also antithrombotic (reduce blood clots) aget used in cardiovascular events

Mechanism: Irreversibly inhibitor of COX1/2

Adverse Effects: Gastric ulceration, tinnitus, renal failure, interstitial nephritis, reye syndrome in children w/ viral infection

Dinstincitive PK + notes: 20 minute half life, but irreversible. Overdose initially causes: hyperventilation (respitory alkalosis) and later a mixed metabolic acidosis/respiratory alkalosis

30
Q

Ibuprofen Major indications, Mechanism, Adverse Effects, Distinctive PK + Notes

A

MI: Pain + inflam
Mechanism: non-selective reversible COX inhibitor

Distinctive PK/Notes: Daily max of 3000 mg

31
Q

Naproxen MI, Mechanism, Adverse effects, and notes

A

MI: Pain + inflam

Mechanism: non-selective reversible COX inhibitor

notes: 15 hour half life BID dosing

32
Q

Celeoxib MI, Mechanism, Adverse effects, and notes

A

(celebrex)
Mechanism: selective reversible COX-2 inhibitor

Notes: Fewer GI ulcers

33
Q

Acetaminophen MI, Mechanism, Adverse effects, and notes

A

(Tylenol)

MI: fever, pain
Mechanism: Analgesic effect (pain relieving) not fully clear. Antipyretic effect from inhibition of hypothalamic heat-regulating center

Adverse effects: OD= liver failure. Hepatotoxic metabolie NAPQI concentrations increase with as little as daily max 4g/ day

Notes: 90% of normal dose is metabolized in the liver via glucuronidation and sulfate conjugation. Remaining 10% is metabolized by CYP2E1 to N-acetyl-p-benzoquinone imine (NAPQI)

34
Q

N-Acettylcyteine MI, Mechanism

A

(NAC)
MI: Acetaminophen overdose

Mechanism: replenishes glutathione necessary to conjugate with hepatotoxic metabolite NAPQI

35
Q

HPA feedback loop

A

Hypothalamus -Corticotrophin releasing factor CRF- anterior pituitary -ACTH adrenocorticotrophic hormone- Adrenal cortex- cortisol- which then increases blood glucose, BP, and amino acids… then cortisol exerts a negative feedback effect on the hypothalamus that inhibits further release of CRF.

36
Q

Short term stress response

A

elevated bp, breathing, metabolic reate… change in blood flow patterns with increased alertness, decreased digestive and kidney activity

37
Q

Long term stress response

A

Mineralocorticords
-retention of sodium ions +water by kindeys

Glucocorticoids:
-proteins+fats broken down and converted to glucose.. elevated blood glucose

-immune system supression

38
Q

Steroid hormones

A

-derived from cholesterol
-lipid soluble
-regulation involves control of enzymes

39
Q

Function of mineralocorticoids (aldosterone) also where it is produced

A

Adrenal cortex

Maintains blood volume and BP by increasing sodium reabsorption by kidney

40
Q

Glucocorticoids (cortisol) function + produced where?

A

Adrenal cortex; catabolic steroid. Promote gluconeogenesis; favor breakdown of fat and protein (fuel mobilization); anti inflammatory

41
Q

Progesterone function + where its produced

A

ovaries primarily; prepares uterus lining for implantation of ovum

42
Q

Androgens (strongest=testosterone) + where its produced

A

development of male secondary sex characteristics; prevents bone resorption

43
Q

how does glucocorticoid signal

A

diffuses across the membrane and binds to steroid receptor in cytoplasm… receptor dimerizes and enters nucleus- then binds to glucocorticoid response element… DNA binding enhances expression of anti-inflam proteins

44
Q

Glucocorticoids and inflamation

A

inhibit production of proinflammatory transcription factors, which results in less pro-inflam cytokines, adhesion molecules, and COX-2

45
Q

Clinical use of glucocorticoids

A

Allergy; anaphylazis/asthma/dermatitis, prednisone.
Endocrinology:
-addisons disease
-hydrocortisone
Gastroenterology
-colitis/chron’s disease
Hematology
-leukemia/lymphoma
-dexamethasone
Rheumatology
-arthritis

46
Q

Steroids

A

hydrocortisone, prednisone, dexamethasone

47
Q

Glucocorticoid effects of steroids in order of effect

A

Dexamethasone (most potent, longest duration of action)> prednisone> Hydrocortisone

48
Q

issues with glucocorticoid therapy

A

Long term (several weeks) can cause HPA suppression, and Cushings syndrome

49
Q

Recommended for glucocorticoid use

A

-short term for inflammatory flaire up
-not used for prevention of inflammation
-monitor symptoms for adrenal insufficiency/cushings
-metabolism through CYP450 enzymes, possible drug interactions with other metabolized by CYP
-taper dose to avoid adrenal insufficiency.

50
Q

What is hydrocortisone major indication

A

cortisol replacement, dermatitis

51
Q

what is hydrocortisones mechanism

A

activates glucocorticoid receptor, induces anti-inflam genes, suppresses inflammatory genes

52
Q

Hydrocortisone adverse effects

A

mild cushings syndrome

53
Q

Hydrocortisone pharmacokinetics and notes

A

LOW potency, short half-life CYP metabolism

54
Q

Prednisone Major Indication, Mechanism, adverse effects, pk + notes

A

MI: Allergy and inflammatory conditions

Mech:activates glucocorticoid receptor, induces anti-inflammatory genes, suppresses inflammatory genes

Adverse: Adrenal insufficiency, cushings syndrome

Pk/notes:Medium potency, medium half life, CYP metabolism taper dose.

55
Q

What is Dexamethasones major indications, mechanism, adverse effects, PK + notes

A

MI:Allergy and inflammatory conditions, immune cell cancers (leukemia/lymphoma)

Mechanism: Activates Glucocorticoid receptor induces anti-inflammatory genes, suppresses inflammatory genes, inhibits immune cell proliferation

adverse effects: Adrenal insufficiency, Cushing’s syndrome

Notes: High potency, long half life, CYP metabolism taper dose

Pharm + Thera (6 decks)

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