MindMap Gallery Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
- 171
- 3
- 1
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
This is a mind map of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). NSAIDs block the production of certain body chemicals that cause inflammation. NSAIDs are good at treating pain caused by slow tissue damage, such as arthritis pain. NSAIDs also work well in fighting back pain, menstrual cramps, and headaches.
Edited at 2022-12-18 17:52:37
- Recommended to you
- Outline
NSAIDS
Selectivity
nonselective proyotype : Ibuprofen
propionic acid derivatives : naproxen, fenoprofen, ketoprofen, flurbiprofen
Acetic acid derivatives : diclofenac, ketorolac, indomethacin, etodolac, sulindac, piroxicam, meloxicam, nabumetone, tolmetin, mefenamic acid, meclofenamate, flufenamic acid
Cyclooxygenase COX2 selective prototype : Celecoxib
others : rofecoxib, valdecoxib, etoricoxib
Inflammatory response
Transient local vasodilation and increased capillary permeability
Infiltration of leukocytes and phagocytic cells
Tissue degeneration and fibrosis
Molecules involved
Histamine
✓ One of the first identified mediators of the inflammatory process
✓ Are useful only for the treatment of vascular events in the early transient phase of inflammation
Bradykinin & 5hydroxytryptamine (serotonin, 5HT)
Ameliorate only certain types of inflammatory response
Leukotrienes
✓ Exert pro-inflammatory actions
✓ LT-receptor antagonists (montelukast and zafirlukast) approved for treatment of asthma
Prostanoids
Biosynthesis is significantly increased in inflamed tissue
includes the prostaglandins, leukotrienes, and prostacyclin; these are the products of cyclooxygenase cleavage of arachidonic acid
Eicosanoid Synthesis
COX
COX1
Constitutive enzyme: its levels remain relatively constant, and it is distributed widely throughout the body
COX-1 is thus believed to play a maintenance or protective role, responsible for production of cytoprotective mucus in the stomach and for platelet aggregation (clotting)
TXA2 activates platelets: COX-1 is primarily responsible for generating TXA2
COX2
Inducible enzyme: its levels and activity can increase rapidly and significantly in response to a stimulus
The main stimuli for COX-2 induction are inflammatory mediators, and thus COX-2 is typically associated with inflammation
PGI2 inhibits platelet activation.: COX-2 is responsible for generating PGI2
Aspirin & NSAIDS
Reversible competitive inhibitors of COX
CovaIently Irreversible inhibits COX
PAIN & FEVER
PAIN
MAIN COMPONENTS
1. Bradykinin
2. H+
3. Neurotransmitters such as serotonin and ATP
4. Neutrophins (nerve growth factor)
5. LTs
6. PGs
7. Cytokines appear to liberate PGs and some of the other mediators
FEVER
The hypothalamus regulates the set point at which body temperature is maintained
elevated in fever, reflecting an infection, or resulting from tissue damage, inflammation, graft rejection, or malignancy
enhance formation of cytokines such as IL-1, IL-6, TNF-, and interferons, which act as endogenous pyrogens
Cytokines increase the synthesis of PGE2/ Increase CAMP/ Triggers hypothalamus to elevate body temperature
NSAIDs suppress this response by inhibiting PGE2 synthesis
production of superoxide radicals
apoptosis
the expression of adhesion molecules
NO synthase
proinflammatory cytokines
o Modify lymphocyte activity
o Alter cellular membrane functions
Adverse effects
Pharmacokinetics
coadministered with PPI or Antacids
highly bound to PP--> highly DDI
distributed all over the body and can penetrate arthritic joints
synovial fluid concentrations half the plasma concentration (ibuprofen, naproxen, piroxicam)
Some substances yield synovial drug concentrations similar to (indomethacin), or even exceeding ( tolmetin), plasma concentrations
some NSAIDS have CNS analgesic effects
non selective COX : intermediate to short half life / selective cox2 : longer half life
Aspirin : 0,25 half life
Celexocib : twice daily instead of once daily
Celecoxib is lipophilic accumulates in fat and is readily transported into the CNS.
Available in topical dosage forms, including ophthalmic preparations of diclofenac, flurbiprofen, ketorolac, suprofen
Indomethacin is also available as a rectal suppository
Adverse effects
Non selecitive
Gastrointestinal effects occur because of the inhibition of COX- 1-mediated cytoprotective mucus in the stomach
Edema: PGs inhibit the reabsorption of Na+ and the activity of ADH, so PG inhibition leads to salt and water retention --> no for HF
Acute renal failure: Renal PGs often play a protective role (vasodilation) opposite to angiotensin 2 and vasopressin --> When PGs are reduced, glomerular afferent vasoconstriction activity is unopposed if have vasoconstriction, reducing renal blood flow and function
COX2 selective
Cardiovascular:a result of disruption of the balance between the platelet activating effects of COX-1 and the platelet-inhibiting effects of COX-2
All
Central nervous system (CNS):
Confusion, dizziness, depression, and hallucinations may occur
COX-2 is the most abundant in the CNS, and may play a role in neurotransmission
The frequency of CNS side effects appears to be higher with COX-2- selective inhibitors and possibly with indomethacin
GI system
Abdominal pain/Nausea/ diarrhea/ anorexia/ Anemia/ GI hemorrhage / Perforation/obstruction
o Gastric erosions/ulcers
Inhibition of COX-1 in gastric epithelial cells depresses mucosal cytoprotective PGs
These eicosanoids (PGE2 PGI2) inhibit acid secretion by the stomach, enhance mucosal blood flow, and promote the secretion of cytoprotective mucus in the intestine
Inhibition of PGI2 and PGE2synthesis may render the stomach more susceptible to damage and can occur with oral, parenteral, or transdermal administration of aspirin or NSAIDs
local irritation from contact of orally administered drug with the gastric mucosa
Local irritation allows back diffusion of acid into the gastric mucosa and induces tissue damage
minor with enteric coating,
It also is possible that enhanced generation of LOX products ( LTs) contributes to ulcerogenicity in patients treated with NSAIDs
Co-administration of the PGE1 analog, misoprostol, or proton pump inhibitors (PPIs) in conjunction with NSAIDs can be beneficial in the prevention of duodenal and gastric ulceration
Cardiovascular
Closure of ductus arteriosus, Myocardial infarction ,Stroke ,Thrombosis
o NSAIDS but NOT aspirin do not afford cardio protection due to their short t1/2
o Aspirin high dose may cause fecal blood loss Fe deficiency anemia
o Aspirin can cause mild degree of hemolysis
o Aspirin may cause hemorrhage especially in susceptible patients
o Best to stop Aspirin before surgery Usually 1 week
Nephropathy
use of high doses of combinations of NSAIDs and frequent urinary tract infections
Hypersensitivity
Vasomotor rhinitis, Angioneurotic, edema, Asthma, Urticaria, Flushing ,Hypotension, Shock
Aspirin intolerance is a contraindication to therapy with any other NSAID because cross-sensitivity can provoke a life-threatening reaction reminiscent of anaphylactic shock.
Salicylic acid is irritating to skin and mucosa
Aspirin resistance
All forms of treatment failure with aspirin have been collectively called aspirin resistance
CNS
Headache ,Vertigo, Dizziness ,Confusion ,Hyperventilation (salicylates)
Hepatic SE
o Hepatotoxicity could rarely happen
Renal SE
o Salt and water retention
o Edema, worsening of renal function in renal/cardiac and cirrhotic patients
o Decreased effectiveness of antihypertensive medications
o Decreased effectiveness of diuretic medications
o Decreased urate excretion (especially with aspirin)
o Hyperkalemia
Reye's syndrome
Aspirin and other salicylates are contraindicated in children and young adults<20 years of age with viral illness–associated fever
Characterized by the acute onset of encephalopathy, liver dysfunction, and fatty infiltration of the liver and other viscera.
Acetaminophen is the drug of choice as antipyretic in children, teens, and young adults
Salicylate toxicity
Mild (Salicylism)
Nausea, vomiting
Hyperventilation
Headache
Mental confusion
Dizziness
Tinnitus (ringing or roaring in the ears)
Ingestion of as little as 10 g of aspirin can cause death in children
Treatment
In mild cases, symptomatic treatment is usually sufficient Increasing the urinary pH enhances the elimination of salicylate
In serious cases, the intravenous administration of fluid, dialysis (hemodialysis or peritoneal dialysis), correction of acid-base and electrolyte balances
Severe
Restlessness
Delirium
Hallucinations
Convulsions
Coma
Respiratory and metabolic acidosis
Death from respiratory failure
Platelet
inhibited platelet activation/ /Propensity for bruising / Increased risk of hemorrhage
Uterus/pregnancy
Prolongation of gestation
Inhibition of labor
Increase risk of post partum hemorrhage
Aspirin is classified as FDA pregnancy category C risk during Trimesters 1 and 2 and category D during Trimester 3
Drug interaction
NSAIDS and low dose aspirin: GI adverse events
NSAIDS and ACE Inhibitors: ACE inhibitors stimulate PG production NSAIDs blocking the production of vasodilator and natriureticPGs Due to hyperkalemia, the combination of NSAIDs and ACE inhibitors also can produce marked bradycardia leading to syncope
NSAIDS and Corticosteroids or SSRIs: May increase the frequency or severity of GI complications
NSAIDs and warfarin: May augment the risk of bleeding in patients receiving warfarin Almost all NSAIDs suppress normal platelet function temporarily during the dosing interval Some NSAIDs increase warfarin levels by interfering with its metabolism Concurrent administration should be avoided
Many NSAIDs are highly bound to plasma protein
Patients taking lithium should be monitored because certain NSAIDs (piroxicam) can reduce the renal excretion of this drug and lead to toxicity, while others can decrease lithium levels (, sulindac)