Drugs inflammator and relared disorder_ Eicosanoid pharmacology Flashcards
_______ are cell-regulating polyunsaturated fatty acids
Eicosanoids
Eicosanoids is synthesized from ______ and released by actions of __________ from lipid membranes
Arachidonic acids; phospholipase A2
Eiconsanoids are present in ______ concentration in most cells but synthesized and released on demand in response to stimuli
Low
Stimulus that triggers release of eicosanoids
IgE-mediated reactions (HSR type I); inflammatory mediators, trauma, heat; and toxins
eicosanoids interact with specific receptors, which are ________ effector systems
G-protein coupled to 2nd messenger
membrane phosplipids “____________” ——> arachidonic acid which gives
- cyclooxygenase (COX1, COX2) —->endoperoxides: giving PGI2; PGD2, PGE2, PGF2alpha
- Lipooxygenase (LOX) —->hydroperoxides: giving Leukotrienes
phospholipase A2;
Prostaglandins (PGs) are _________ in stomach, dilates renal vasculature, contracts uterus and maintains ductus arteriosus
Cytoprotective
TxA2 causes
platelet aggregation
GI PGs and platelets TxA2 are synthesized via
COX1 (constitutive)
________ synthesizes PGS involved in inflammation; fever, and pain
COX2 (inducible)
both enzymes _____ and ______ synthesizes renal PGs which increases RBF
COX1 and COX2
_______ are formed via hydroperoxides from LOX on arachidonic acid
Leukotrienes (LTs)
________ inflammatory mediator leading to neutrophil chemoattractant; activates PMNS(polymorphonuclear leukocytes); increase free radical formation - cell damage
LTB4
LTB4 (inflammatory mediators)
neutrophil chemoattractant; activates PMNS(polymorphonuclear leukocytes); increase free radical formation - cell damage
LTA4; LTC4 and LTD4 causes
anaphylaxis and bronchoconstriction (role in asthama)
Leukotrienes are targets for ?
- Glucocorticoids: decreases phopholipase A2 activity leading to both antiinflammatory and immunosuppressive actions
- Zileuton: inhibits lipooxygenase leading to decrease LTs used in Rx of asthma
- Zafirlukast and “lukasts” : LT-receptor antagonists used in Rx of asthma
inhibits lipoxygenase leading to decrease LTs used in Rx of asthma
Zileuton
ecreases phopholipase A2 activity leading to both antiinflammatory and immunosuppressive actions
Glucocorticoids
LT-receptor antagonists used in Rx of asthma
Zafirlukast and “lukasts”
__________ are formed via endoperoxides from actions of cyclooxygenases (COXs)
Prostaglandins
_______ is expressed in most tissues: platelets, stomach; and acts to synthesize TxA2 and cytoprotective PGs
COX1
_______ is expressed in brain and kidney and sites of inflammation
COX2
_______ are drugs of PGE1
Misoprostol: ( used previously in Rx of NSAID induced ulcers; protective action on gastric mucosa)
Alprostadil: ( maintains patency of ductus arteriosus; vasodilates, used in male impotence) - CI in preg unless used as abortifacient (misoprostol + miferprsitone combined)
used previously in Rx of NSAID induced ulcers; protective action on gastric mucosa
Misoprostol
maintains patency of ductus arteriosus; vasodilates, used in male impotence) - CI in preg unless used as abortifacient (misoprostol + miferprsitone combined)
Alprostadil
_______ used to close ductus arteriosus
Indomethacin
PGE2 causes
uterine smooth muscle contraction
uses of PGE2
dinoprostone used for “Cervical ripening” and as abortifacient
abortifacient means
combination of misoprostol + miferprsitone
used for “Cervical ripening” and as abortifacient
dinoprostone
PGF2-alpha actions
causes uterine and bronchiolar smooth muscle contraction
drugs of PGF2-alpha are
Carbopros (used as abortifacient)
latanoprost (Rx glaucoma (decrease intraocular pressure)
_______Rx glaucoma (decreases intraocular pressure
latanoprost
PGI2 (prostacyclin) uses
pulmonary HTN
PGI2 actions
platelet stabilizer and vasodilators
Drugs of prostacyclin (PGI2) include
epoprostenol
Prostacylin
Vasodilator (PGI2)
PGE2 and PGF2-alpha
both increases in primary dysmenorrhea
Therapeutic effects of NSAIDs may be due to inhibition of their synthesis
Thromboxanes (TxAs) (TxA2)
platelet aggregator (inhibition of synthesis underlines protective role of acetylsalicylic acid (ASA) post-MI))
Nonsteroidal anti-inflammatory drugs (NSAIDs)
most are non-selective inhibitors of cyclooxygenases, acting on COX 1 and COX2 isoforms to decrease formation of PGs and TxA2
most are non-selective inhibitors of cyclooxygenases, acting on COX 1 and COX2 isoforms to decrease formation of PGs and TxA2
Nonsteroidal anti-inflammatory drugs (NSAIDs)
______ are analgesic, antipyretic and antiinflammatory and have anti-platele effects
NSAIDs
Acetylsalicylic acid (ASA) is prototype of ________ which includes more than 20 individual drugs
NSAIDs
Platelet stabilization via PGI2
activation of PGI2 receptors —>stimulation of adenylate-cyclase —–>increase cAMP —> increase activity of internal Ca2+ “pumps” —> decrease free Ca2+ => platelet stabilization
Platelet aggregation via TxA2
activation of TxA2 receptors —>stimulation of phospholipase C —> increase PIP2 hydrolysis —> PIP3 ——>mobilization of bound Ca2+ —-> increase free ca2+ => platelet aggregation
Acetylsalicylic acid (ASA: Aspirin) causes
irreversible inhibition of COXs; covalent bond via acetylation of Serine hydroxyl group near the active site
covalent bond via acetylation of Serine hydroxyl group near the active site
Acetylsalicylic acid (ASA: Aspirin)
Actions of ASA is dose dependent:
- antiplatelet aggregation: low dose, used in post-MI prophylaxis to reduce risk of transient ischemic attack (TIAs)
- analgesia and antipyresis: moderate dose
- antiinflammatory: high doses
- uric acid elimination:
- Low to moderate doses –> decreases tubular
secretions —> hyperuricemia - High-doses: decrease tubular reabsorption
=>uricosuria
- Low to moderate doses –> decreases tubular
- Acid-Base and Electrolyte balance:
- High therapeutic: mild uncoupling of oxidative phosphorylation —> increase respiration —> decrease PCO2 —-> respiratory alkalosis —-> renal compensation —–> increase HCO3- elimination —> compensated respiratory alkalosis (pH = normal; decrease HCO3- ; decrease PCO2)
- Adults: stable condition but in children it increases
toxicity - Toxic dose: inhibits respiratory center —> decrease respiration —-> increase PCO2 —-> respiratory acidosis (decreased pH, decrease HCO3- and normalization of PCO2) plus inhibition of Krebs cycle and severe uncoupling of oxidative phosphorylation (decreases ATP)—-> metabolic acidosis, hyperthermia and hypokalemia (decrease K+)
Side effects of ASA (aspirin)
GI irritation, ulcer and bleeding;
salicylism ( tinnitus, vertigo, decrease hearing —often 1st
sign of toxicity)
Brochoconstriction : exacerbates asthma
Hypersensitivity, especially “triad”: asthma, nasal polyps, rhinitis
Reye Syndrome: encephalopathy
increase bleeding time (antiplatelet)
chronic use: - associated with renal dysfunction Drug interactions: - ethanol (increase GI bleeding) - OSUs and warfarin (increase effects) - uricosurics (decrease effects)
aspirin overdose management
extensions of the toxic actions, + at high dose vasomotor collapse occurs, with respiratory and renal failure
management: no antidote; managed via gastric lavage (+/- activated charcoal); + ventilatory support and symptomatic manangement of acid-base/ electrolyte imbalance and hyperthermia and resulting dyhration
increase urine volume and its alkalinization facilitates ASA renal elimination; ASA follows zero-order elimination at toxic doses
ASA follows _______elimination at toxic doses
zero-order
other examples of NSAIDs that are reversible inhibitors of COX 1/2 with analgesic, antipyretic, and antiinflammatory actions include
Ibuprofen Naproxen indomethacin ketorolac sulindac
comparison with ASA:
analgesia: ketorolac > ibuprofen/naproxen> ASA
GI irritation: < ASA(but still occurs use misprostol)
minimal effects on acid-base balance, no effect on uric acid elimination
allergy: common (cross HS with ASA)
Renal: chronic use, nephritis, nepheritic syndrome, acute failure (via decrease PGE2 and PGI2, which normally maintains GFR and RBF) does not occur with sulindac
which PGs normally maintains GFR and RBF
PGE2 and PGI2
toxicities of Indomethacin
thrombocytopenia, agranulocytosis and >CNS effects
toxicities of sulindac
Steven-johnson syndrome, hematotoxcity
Selective COX 2 inhibitors
Celecoxib
_______ not as effective as antiflammatory compare to other NSIADs; less GI toxicity; less antiplatelet actions
Celecoxib
may possibly exert prothrombotic effects via inhibition of endothelial cell function (MI and strokes)
Celecoxib
Cross-hypersensitivity between ________ and _________
Celecoxib and sulfonamides
NSAIDs are associated with _________?
increased risk of thrombotic events such as MI and stroke
_________ has no inhibition of COX in peripheral tissues and lacks sign. antiinflammatory effects
Acetaminophen
Equivalent analgesic and antipyretic activity to ASA due to inhibition of cyclooxygenases in CNS
Acetaminophen
Comparison of Acetaminophen to ASA
no antiplatelet action; no Reye syndrome; no effects on uric acid; not bronchospastic (safe in NSAID HS and asthmatic) and GI distress is minimal at low-moderate dose
Acetaminophen toxicity effects
Hepatotoxicity:
- its metabolized mainly by liver glucuronyl transferase to form inactive conjugate
- at P450 it results in formation of reactive metabolite (N-acetylbenzoquinoneimine), which is inactivated by glutathione (GSH)
- in overdose: finite stores of GSH is depleted resulting in metabolite reacting with hepatocyte causing nausea and vomiting, abdominal pain, liver failure due to centrilobular necrosis
- chronic use of ethanol enhances liver toxicity via induction of P450
management of hepatotoxicity: N-acetylcysteine (supplies -SH groups), preferably within 1st 12 hrs
________ (supplies -SH groups), preferably within 1st 12 hrs in hepatotoxicity
N-acetylcysteine
N-acetylcysteine also used as
mucolytic in CF disease
“Tot” toxicity
young children are gustatory explorers; therefore compounds responsible for toxicity in children age of 3 years are : aspirin, acetaminophen (ppl know about reye syndrome), supplementary iron tablets
aspirin, acetaminophen (ppl know about reye syndrome), supplementary iron tablets
“Tot” toxicity