Anti-inflammatory drugs: NSAIDS + Glucocorticoids Flashcards
Pain and inflammation results
Substance P, Bradykinin, Phospholipases, Prostaglandins, and serotonin all get released immediately
They all have an ability to bind and activate receptors on nerve endings
Prostaglandins and Inflammation
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
All NSAIDS inhibit
Cyclooxygenase (COX)
If a drug does not inhibit COX
Does not have any anti- inflammatory activity
FEVER and PGE2
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)
NSAIDs + Fever
NSAIDS will lover fever but not lower body temp and have no impact on temp rising from exercise
Inhibitors of prostanoid Synthesis
phospholipase inhibitors corticosteroids
Lipoxygenase inhibitors
receptor antagonists
Colchicine
Acetyl Salicylic Acid
-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)
Theraputic effects of Acetyl Salictylic acid
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)
What is Acetyl salicylic acid
Asprin
How is Acetyl salic acid metabolized?
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
Undesired Effects of Aspirin
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
PDR warning for…
Aspirin + all others NSAIDs
-can develop suddenly
-Serious GI toxicity such as bleeding, ulceration
-happens in people treated chronically with NSAIDS
RISK for NSAID induced GI complications
- Past complicated Ulcer
- Multiple NSAIDs
- High dose NSAID
- Anticoagulant
- Past uncomplicated ulcer
- Age > 70
- Steroids
Drug interactions
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)
How are the NSAIDS ibuprofen and Naproxen similar
-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
what are first line for mild pain and inflammation
Ibuprofen Naproxen
NSAID/PHARMACODNAMIC/HALFLIFE
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
COX-1 (from arachidonic acid)
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
COX-2 (from arachidonic acid)
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
What is COX-2 selectively inhibited by
Celocoxib
In cox-2 there is a side pocked that was added; it fits into COX-2 side pocket
CELECOXIB
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
COX-1 and COX-2 impacts on thrombosis (formation of blood clots)
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
What is Acetaminophen// paracetamol
tylenol
Acetaminophen uses
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)
Acetaminophen overdose+overuse
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)
Acetaminophen and toxicity + symptoms +treatment
-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
What do all NSAIDS try to do
Target pain, and inflammation
Aspirin: Major indications, Mechanism, Adverse Effects, Distinctive PK + Notes
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
Ibuprofen Major indications, Mechanism, Adverse Effects, Distinctive PK + Notes
MI: Pain + inflam
Mechanism: non-selective reversible COX inhibitor
Distinctive PK/Notes: Daily max of 3000 mg
Naproxen MI, Mechanism, Adverse effects, and notes
MI: Pain + inflam
Mechanism: non-selective reversible COX inhibitor
notes: 15 hour half life BID dosing
Celeoxib MI, Mechanism, Adverse effects, and notes
(celebrex)
Mechanism: selective reversible COX-2 inhibitor
Notes: Fewer GI ulcers
Acetaminophen MI, Mechanism, Adverse effects, and notes
(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)
N-Acettylcyteine MI, Mechanism
(NAC)
MI: Acetaminophen overdose
Mechanism: replenishes glutathione necessary to conjugate with hepatotoxic metabolite NAPQI
HPA feedback loop
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.
Short term stress response
elevated bp, breathing, metabolic reate… change in blood flow patterns with increased alertness, decreased digestive and kidney activity
Long term stress response
Mineralocorticords
-retention of sodium ions +water by kindeys
Glucocorticoids:
-proteins+fats broken down and converted to glucose.. elevated blood glucose
-immune system supression
Steroid hormones
-derived from cholesterol
-lipid soluble
-regulation involves control of enzymes
Function of mineralocorticoids (aldosterone) also where it is produced
Adrenal cortex
Maintains blood volume and BP by increasing sodium reabsorption by kidney
Glucocorticoids (cortisol) function + produced where?
Adrenal cortex; catabolic steroid. Promote gluconeogenesis; favor breakdown of fat and protein (fuel mobilization); anti inflammatory
Progesterone function + where its produced
ovaries primarily; prepares uterus lining for implantation of ovum
Androgens (strongest=testosterone) + where its produced
development of male secondary sex characteristics; prevents bone resorption
how does glucocorticoid signal
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
Glucocorticoids and inflamation
inhibit production of proinflammatory transcription factors, which results in less pro-inflam cytokines, adhesion molecules, and COX-2
Clinical use of glucocorticoids
Allergy; anaphylazis/asthma/dermatitis, prednisone.
Endocrinology:
-addisons disease
-hydrocortisone
Gastroenterology
-colitis/chron’s disease
Hematology
-leukemia/lymphoma
-dexamethasone
Rheumatology
-arthritis
Steroids
hydrocortisone, prednisone, dexamethasone
Glucocorticoid effects of steroids in order of effect
Dexamethasone (most potent, longest duration of action)> prednisone> Hydrocortisone
issues with glucocorticoid therapy
Long term (several weeks) can cause HPA suppression, and Cushings syndrome
Recommended for glucocorticoid use
-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.
What is hydrocortisone major indication
cortisol replacement, dermatitis
what is hydrocortisones mechanism
activates glucocorticoid receptor, induces anti-inflam genes, suppresses inflammatory genes
Hydrocortisone adverse effects
mild cushings syndrome
Hydrocortisone pharmacokinetics and notes
LOW potency, short half-life CYP metabolism
Prednisone Major Indication, Mechanism, adverse effects, pk + notes
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.
What is Dexamethasones major indications, mechanism, adverse effects, PK + notes
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
