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Eicosanoid Pharmacology

4

Learning Objectives

Demonstrate understanding of NSAIDs

Differentiate leukotrienes, prostaglandins, and thromboxanes

OVERVIEW

λEicosanoids are cell-regulating polyunsaturated fatty acids primarily synthesized from arachidonic acid and released by the action of phospholipase A2 from lipids in cell membranes.

λEicosanoids are present in low concentrations in most cells but are synthesized and released “on demand” in response to stimuli, including IgEmediated reactions, inflammatory mediators, trauma, heat, and toxins.

λEicosanoids interact with specific receptors, which are G-proteins coupled to second messenger effector systems.

 

 

 

 

Membrane

 

 

 

 

 

 

 

 

 

 

 

phospholipids

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

–

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Glucocorticoids

 

 

 

 

 

Phospholipase A2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Arachidonic acid

 

 

 

 

 

 

 

 

–

 

 

 

 

 

 

 

 

–

 

 

 

 

 

 

 

 

 

 

NSAIDs

 

 

 

 

 

 

 

 

 

 

 

 

Cyclooxygenases Lipoxygenase

 

 

Zileuton

 

 

 

 

 

–COX1 COXib COX2

–

Endoperoxides Hydroperoxides

Glucocorticoids

 

 

 

 

 

 

Receptors blocked

Leukotrienes

 

 

 

 

by –lukasts

 

 

 

 

 

Bridge to Physiology

Prostaglandins (PGs) are cytoprotective in the stomach, dilate renal vasculature, contract the uterus, and maintain the ductus arteriosus. Thrombaxane (TxA2) causes platelet aggregation. GI PGs and platelets TxA2s are synthesized

by COX 1 (constitutive). COX 2 (inducible) synthesizes PGs involved in inflammation, fever, and pain. Both enzymes synthesize renal PGs →↑ RBF.

PGI2

 

PGD2

PGE2

 

TXA2

 

PGF2α

 

 

 

 

 

Figure VI-4-1. Drugs Acting on Eicosanoids

229

Section VI λ Drugs for Inflammatory and Related Disorders

Note

Indomethacin is used to close a patent ductus arteriosus.

LEUKOTRIENES (LTs)

λFormed (via hydroperoxides) from the action of lipoxygenases on arachidonic acid

–LTB4:

ºMechanism of action: inflammatory mediator → neutrophil chemoattractant; activates PMNs; ↑ free radical formation → cell damage

–LTA4, LTC4, and LTD4

ºCause anaphylaxis and bronchoconstriction (role in asthma)

λLeukotrienes are “targets” for the following:

–Glucocorticoids: →↓ phospholipase A2 activity → contributes to both antiinflammatory and immunosuppressive actions

–Zileuton: inhibits lipoxygenase →↓ LTs and is used in treatment of asthma

–Zafirlukast and “–lukasts”: LT-receptor antagonists used in treatment of asthma

PROSTAGLANDINS (PGs)

λPGs are formed (via endoperoxides) from the actions of cyclooxygenases (COXs).

λCOX 1 is expressed in most tissues, including platelets and stomach, where it acts to synthesize thromboxane and cytoprotective prostaglandins, respectively.

λCOX 2 is expressed in the brain and kidney and at sites of inflammation.

PGE1

λDrugs:

–Misoprostol (analog) used in treatment of NSAID-induced ulcers (protective action on gastric mucosa)

–Alprostadil

ºMaintains patency of ductus arteriosus

ºVasodilation; used in male impotence

λContraindicated in pregnancy, unless used as an abortifacient (misoprostol in combination with mifepristone)

PGE2

λMechanism of action: uterine smooth muscle contraction

λUses: dinoprostone can be used for “cervical ripening” and as abortifacient

PGF2α

λMechanism of action: uterine and bronchiolar smooth muscle contraction

λDrugs:

–Carboprost used as abortifacient

–Latanoprost for treatment of glaucoma (↓ intraocular pressure)

230

Chapter 4 λ Eicosanoid Pharmacology

PGI2 (Prostacyclin)

λPlatelet stabilizer and vasodilator

λDrug: epoprostenol

λUses: pulmonary hypertension

PGE2 and PGF2α

λBoth ↑ in primary dysmenorrhea

λTherapeutic effects of NSAIDs may be due to inhibition of their synthesis

THROMBOXANES (TXAs)

TXA2

λPlatelet aggregator (inhibition of synthesis underlies protective role of acetylsalicylic acid [ASA] post-MI)

Bridge to Physiology and Biochemistry

Platelet Stability and Eicosanoids

Activation of TxA2 receptors → stimulation of phospholipase C →↑

PIP2 hydrolysis →↑ IP3 → mobilization of bound Ca2+ →↑ free Ca2+ → platelet aggregation.

Activation of PGI2 receptors → stimulation of adenylyl cyclase →↑ cAMP →↑ activity of internal Ca2+

“pumps” →↓ free Ca2+ → platelet stabilization.

NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDs)

λMost NSAIDs are nonselective inhibitors of cyclooxygenases, acting on both COX 1 and COX 2 isoforms to decrease formation of PGs and thromboxanes.

λThey are analgesic, antipyretic, and antiinflammatory and have antiplatelet effects.

λAcetylsalicylic acid (ASA) is the prototype of the group, which includes more than 20 individual drugs.

Acetylsalicylic Acid (ASA; Aspirin)

λCauses irreversible inhibition of COX

λCovalent bond via acetylation of a serine hydroxyl group near the active site

λActions are dose-dependent:

–Antiplatelet aggregation. Low dose, the basis for post-MI prophylaxis and to reduce the risk of recurrent TIAs

–Analgesia and antipyresis. Moderate dose

–Antiinflammatory. High doses

–Uric acid elimination

ºLow to moderate doses: ↓ tubular secretion → hyperuricemia

ºHigh doses: ↓ tubular reabsorption → uricosuria

–Acid-base and electrolyte balance

ºDose-dependent actions

ºHigh therapeutic: mild uncoupling of oxidative phosphorylation

→↑ respiration →↓ pCO2 → respiratory alkalosis → renal compensation →↑ HCO3– elimination → compensated respiratory alkalosis (pH = normal, ↓ HCO3–, ↓ pCO2)

231

Section VI λ Drugs for Inflammatory and Related Disorders

ºIn adults, this can be a stable condition; in children →↑ toxicity.

ºToxic doses: inhibits respiratory center →↓ respiration →↑ pCO2 → respiratory acidosis (↓ pH, ↓ HCO3–, normalization of pCO2) plus inhibition of Krebs cycle and severe uncoupling of oxidative phosphorylation (↓ ATP) → metabolic acidosis, hyperthermia, and hypokalemia (↓ K+).

λSide effects:

–Gastrointestinal irritation: gastritis, ulcers, bleeding

–Salicylism: tinnitus, vertigo, ↓ hearing—often first signs of toxicity

–Bronchoconstriction: exacerbation of asthma

–Hypersensitivity, especially the “triad” of asthma, nasal polyps, rhinitis

–Reye syndrome: encephalopathy

–↑ bleeding time (antiplatelet)

–Chronic use: associated with renal dysfunction

–Drug interactions: ethanol (↑ gastrointestinal bleeding), OSUs and warfarin (↑ effects), and uricosurics (↓ effects)

λAspirin overdose and management:

–Extensions of the toxic actions described above, plus at high doses vasomotor collapse occurs, with both respiratory and renal failure.

–No specific antidote. Management includes gastric lavage (+/– activated charcoal) plus ventilatory support and symptomatic management of

acid-base and electrolyte imbalance, and the hyperthermia and resulting dehydration. ↑ urine volume and its alkalinization facilitate salicylate renal elimination. (Note: ASA follows zero-order elimination kinetics at toxic doses.)

Other NSAIDs

Types

λReversible inhibitors of COX 1 and COX 2, with analgesic, antipyretic, and antiinflammatory actions, include:

–Ibuprofen

–Naproxen

–Indomethacin

–Ketorolac

–Sulindac

λComparisons with ASA:

–Analgesia: ketorolac > ibuprofen/naproxen > ASA

–Gastrointestinal irritation: < ASA, but still occurs (consider misoprostol)

–Minimal effects on acid-base balance; no effects on uric acid elimination

–Allergy: common, possible cross-hypersensitivity with ASA

–Renal: chronic use may cause nephritis, nephritic syndrome, acute

failure (via ↓ formation of PGE2 and PGI2, which normally maintain GFR and RBF)—does not occur with sulindac

232

λSpecific toxicities:

–Indomethacin: thrombocytopenia, agranulocytosis, and > CNS effects

–Sulindac: Stevens-Johnson syndrome, hematotoxicity

Selective COX 2 Inhibitors: Celecoxib

λCompared with conventional NSAIDs, it is no more effective as an antiinflammatory agent.

λPrimary differences are:

–Less gastrointestinal toxicity

–Less antiplatelet action

λHowever, it may possibly exert prothrombotic effects via inhibition of endothelial cell function (MI and strokes).

λCross-hypersensitivity between celecoxib and sulfonamides

Chapter 4 λ Eicosanoid Pharmacology

Clinical Correlate

NSAIDs are associated with an increased risk of adverse

cardiovascular thrombotic events such as MI and stroke.

OTHER DRUGS

Acetaminophen

λMechanisms

–No inhibition of COX in peripheral tissues and lacks significant antiinflammatory effects

–Equivalent analgesic and antipyretic activity to ASA due to inhibition of cyclooxygenases in the CNS

λComparisons with ASA:

–No antiplatelet action

–Not implicated in Reye syndrome

–No effects on uric acid

–Not bronchospastic (safe in NSAID hypersensitivity and asthmatics)

–Gastrointestinal distress is minimal at low to moderate doses

λOverdose and management:

–Hepatotoxicity—Acetaminophen is metabolized mainly by liver glucuronyl transferase to form the inactive conjugate. A minor pathway (via P450) results in formation of a reactive metabolite (N-acetylbenzoquinoneimine), which is inactivated by glutathione (GSH). In overdose situations, the finite stores of GSH are depleted. Once this happens, the metabolite reacts with hepatocytes, causing nausea and vomiting, abdominal pain, and ultimately liver failure due to centrilobular necrosis. Chronic use of ethanol enhances liver toxicity via induction of P450.

–Management of the hepatotoxicity: N-acetylcysteine (supplies –SH groups), preferably within the first 12 hours (N-acetylcysteine is also used as a mucolytic for cystic fibrosis)

Clinical Correlate

“Tot” Toxicity

Young children are gustatory explorers.

Among the compounds responsible for toxicity in youngsters under the age of 3 years are three items commonly found in households with “tots”: aspirin, acetaminophen (people know about Reye syndrome!), and supplementary iron tablets.

233

Источник: https://studfile.net/preview/16445239/

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