114 terms

Anti-Inflammatory Pharmacology #1

Dr. Gayer's 10.17.12 Lecture
STUDY
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What are the six major classes of anti-inflammatory drugs?
1) Eicosanoids 2) Glucocorticoids 3) NSAIDS 4) DMARDS 5) Drugs for gout 6) Immunopharmacology
What are the three types of eicosanoids?
1) Prostaglandins 2) Thromboxanes 3) Leukotrienes
What are glucocorticoids?
Steroidal anti-inflammatory drugs
What are NSAIDS?
Non-steroidal anti-inflammatory drugs
What are DMARDS?
Disease modifying anti-rheumatic drugs
What are the five main causes of inflammation?
1) Burns 2) Chemical irritants 3) Toxins 4) Infection by pathogens 5) Physical injury
What cells are involved in the immune response?
Lymphocytes, monocytes, macrophages, neutrophils, etc
What are the two main goals of anti-inflammatory treatment?
Relief of pain and reduction of inflammation
What is the major precursor molecule for eicosanoids?
Arachidonic acid
What is another name for arachidonic acid?
5,8,11,14-eicosatetraenoic acid
What is the role of arachidonic acid?
Arachadonic acid (AA) is enzymatically modified to form fatty acids signaling molecules (prostaglandins, thromboxane, leukotrienes)
What is the role of the eicosanoid fatty acid signaling molecules?
They activate g-protein coupled receptors located on platelets, smooth muscle, bone, immune and nerve cells.
What is the general structure of arachidonic acid?
A 20-carbon fatty acid with four double bonds
From what cell component is arachadonic acid (AA) primarily formed?
AA is released from membrane phospholipids (phosphatidyl-choline and -ethanolamine)
What enzyme catalyzes the cleavage of arachidonic acid from membrane phospholipids?
Phospholipase A2
What the three forms of the cleavage enzymes phospholipase A2?
Secreted, cytosolic, and calcium activated
What activates phospholipase A2?
Cell damage and chemical stimuli
Is arachadonic acid an omega-3 or omega-6 fatty acid? Why?
Omega-6, because the last double bond is six carbons from the free end of the molecule
Why is a diet high in omega-3 fatty acids recommended?
O-6 fatty acids produce more active inflammatory molecules
What is the second, minor pathway for formation of arachidonic acid?
Cleavage of phosphoinositides
What enzymes cleaves phosphoinositides? What enzyme must modify the product to form arachidonic acid?
1) Phospholipase C 2) Diacylglycerol lipase
What important drug class inhibits phospholipase A2 AND diacylglycerol lipase, thus inhibiting arachidonic acid production?
Corticosteroids (glucocorticoids)
What are the four different pathways that arachidonic acid can enter?
Two we will discuss in detail - lipoxygenases and PGH synthase (COX I&II) - plus epoxygenases and isoeicosanoids
What happens if one pathway for arachidonic acid is inhibited? Give an example.
The arachidonic acid will be shunted to another pathway - cause of NSAID-induced asthma
What is the product of PGH synthase (this enzyme is also known as cyclooxygenase 1&2)?
PGH2
What drugs inhibit PGH synthase?
Aspirin and other NSAIDs
What are the six products formed when PGH2 is metabolized?
Prostaglandins (PGF2a, PGD2, PGE2, PGE1); PGI2 (prostacyclin), TXA2 (thromboxane A2)
What are the characteristics of COX1?
Constitutive (continuously expressed), in all tissues, platelets, gut; involved in GI mucosal integrity, platelet aggregation, and renal function.
What are the characteristics of COXII?
Expression is inducible, found in inflammatory cells, bone, kidney & endothelial cells, involved in mitogenesis and grown, female reproductive regulation, bone formation, renal function and REDUCES platelet aggregation.
What chemicals upregulate COXII transcription?
Inflammatory cytokines
What are the products of COXII?
Pro-inflammatory prostaglandins and prostacyclin
What is an important function of both COX isotypes?
Maintenance of renal blood flow
What enzymes catalyzes the formation of leukotrienes from arachdonic acid?
5-Lipoxygenase
What is one general action of leukotrienes?
Bronchoconstriction
Is 5-lipoxygenase inhibited by NSAIDS?
No, except for ketoprofen
What is the effect of leukotrienes on the cardiovascular system?
Vascular smooth muscle chemoattractant, reduce heart contractility and coronary blood flow
What is the effect of leukotrienes on the airways?
Potent bronchoconstriction, induce plasma exudation, mucus secretion; primary components of slow-reacting substance of anaphylaxis (SRS-A)
What is the effect of leukotrienes on blood cells?
Chemoattractants for PMN and eosinophils, promote eosinophil adherance and degranulation; pathogenesis of inflammation
What are the characteristics of 5-lipoxygenase (5-LOX)?
Central mediator of inflammation, active in stimulated inflammatory cells (PMN, basophils, mast cells, eosinophils, macrophages), significant in asthma & anaphylactic shock; major target for drug action
What receptors do PGI2, PGD2 and PGE1 bind to? What intracellular cascade results? What is the end result?
1) IP, DP1 and EP2,4 2) Gs - Increased cAMP, decreased MLCK activity 3) Smooth muscle relaxation
What receptors does PGE2 bind to? What are their effects?
EP1-4; 2&4 produce SM relaxation, 1&3 produce SM contraction
What receptors to TXA2, PGF2a, and LTB bind to? What intracellular cascade results? What is the end result?
1) TP, FP, BLT1, DP2 2) Gq and Gi - Increased IP3 or decreased cAMP, increase intracellular calcium, increased MLCK activity 3) Smooth muscle contraction
What is the role of leukotrienes in inflammation?
Phagocyte attraction and activation, T cell modulation, increased vascular permeability, endothelial cell gaps (swelling) and secretion
What is the role of PGE2 and PGI2 in inflammation?
Increased vascular permeability, endothelial cell gaps (swelling) and secretion; increased vasodilation and capillary fluid outflow; increased TXA2 and PGD2 production
What is the role of TXA2 and PGD2 in inflammation?
Immune cell chemoattraction and activation, T cell modulation
Which eicosanoids produce smooth muscle contraction?
PGF2a and TXA2
Which eicosanoids produce smooth muscle relaxation?
PGD2, PGE2, PGE1, and PGI2
Which eicosanoid produces increased platelet aggregation?
TXA2
Which eicosanoid produces inhibition of platelet aggregation?
PGI2
Which eicosanoids produce GI smooth muscle contraction?
TXA2, PGE2 (EP3), PGF2a (FP), LTs
Which eicosanoid produces gastric mucosa cytoprotection and decreased acid release?
PGE1
Which eicosanoids produce lung smooth muscle relaxation?
PGE2 and PGI2
Which eicosanoids produce lung smooth muscle contraction and increased mucosal secretion?
TXA2, PGD2, PGF2a, LTs
Which eicosanoids produce vasodilation, Na+ regulation, and renin release in the blood vessels of the kidneys?
PGE2 and PGI2
Which eicosanoids produce uterine smooth muscle contraction and have roles in ovulation, luteolysis, fertilization and labor induction?
TXA2, PGE2 (EP3), and PGF2a (FP)
Which eicosanoid produces relaxation of vascular smooth muscle of the corpora cavernosa of the penis?
PGE1
Which eicosanoid produces increased body temperature through the CNS?
PGE2 (EP3)
Which eicosanoids produce decreased NE release in sympathetic neurons and increased pain sensation peripheral neurons?
PGD2, PGI2, PGF2
Which eicosanoid produces increased bone turnover to aid in healing?
PGE2 (EP4)
Which eicosanoid produces increased aqueous humor outflow in the eye?
PGF2a (FP)
Which eicosanoid is pro-oncogenic in the breast and colon?
PGE2 via the COX-2 pathway
How do PGE2 and PGI1 maintain glomerular blood pressure in the kidneys when blood volume is low?
Direct dilation of the afferent vessels and renin release, which produces angiotensin II and constriction of the efferent vessels
What is the generic drug name for PGE2?
Dinoprostone
What is the clinical application of PGE2 (Dinoprostone)?
Uterine contraction and cervical softening. Used for pregnancy termination, cervical ripening, and labor facilitation.
What are the trade names for dinoprostone preparations?
Gel = Prepidil, suppository = Cervidil
What other prostaglandin drug is used for pregnancy termination?
A combination of PGE1 (misoprostol) and antiprogestin (mifepristone)
What drug inhibits PGE2 and PGF2a production to ease dysmenorrhea?
NSAIDS
What are the systemic adverse effects of PGE2 use?
Severe: vomiting, diarrhea, fever, bronchoconstriction. Other: hypotension, hypertension, syncope, dizziness, flushing.
What is the generic drug name for PGE1?
Alprostadil
What are the clinical applications for PGE1 (Alprostadil)?
Male impotence and cardiovascular uses
What are the two preparations of alprostadil used for male impotence? What are their adverse effects?
Injection - Caverject, Pellet - Muse; Adverse effects - pain and prolonged erection
What is the trade name of alprostadil used for maintaining patency of the fetal ductus arteriosus prior to surgery?
Prostin VR Pediatric; vasodilation and inhibition of platelet aggregation
What drug is used to close the ductus arteriosus without surgery?
Indomethacin
What eicosanoid is used to treat pulmonary hypertension? What is its generic name?
IV prostacyclin (PGI2); Epoprostenol and Treprostinil
What two eicosanoids have effects on platelet aggregation?
TXA2 and PGI2
Which eicosanoid increases platelet aggregation?
TXA2
Which eicosanoid decreases platelet aggregation?
PGI2
What disease results from a deficiency of cyclooxygenase enzyme?
Bleeding disorder
What is the effect of aspirin on platelet aggregation and thrombus formation?
Aspirin decreases platelet aggregation and inhibits thrombus formation, decreasing death due to infarction. However, risks of GI bleeding and stroke are increased.
Why is aspirin the preferred drug for inhibition of platelet aggregation?
It is an irreversible, nonspecific COX 1 AND 2 inhibitor, and it inhibits prostacyclin synthesis (thereby inhibiting TXA2 synthesis)
What is the clinical application of PGE1 in the GI system?
Cytoprotection against gastric ulcers caused by steroids and NSAIDS
What is the generic and trade name for PGE1 used against gastric ulcers? What is the name of an analog?
Misoprostol (Cytotec); enprostil
What are the adverse effects of misoprostol?
Abdominal discomfort, diarrhea, bone pain
What new drug would eliminate the need for misoprostol?
A COX-II selective inhibitor would not disturb the local COX-1 synthesis of cytoprotective PGE2
What are the other clinical applications of misoprostol?
Chronic constipation, cervical ripening, pregnancy termination
Analogues of what prostaglandin are used in glaucoma treatment?
PGF2a
What are the names of the PGF2a analogues used in glaucoma treatment?
Latanoprost (Xalatan), bimatoprost, travoprost, and unoprostone
What is the action of latanoprost and the other PGF2a analogues?
Eye drops increase aqueous humor outflow via uveoscleral vasoconstriction
What prostaglandin is used in asthma treatment?
Aerosol PGE2 is a potent vasodilator
What drug inhibits 5-LOX in asthma treatment?
Zileuton (Zyflo)
What drugs are used to treat asthma by inhibiting leukotriene receptors?
Zafirlukast (Accolate) and Montelukast (Singulair)
Aspirin and other NSAIDs are used to treat general inflammation. What other drugs are used to treat general inflammation and how do they function?
P-lipase A2 inhibitors (Prednisone and hydrocortisone) inhibit production of arachidonic acid
What is the physiologic function of glucocorticoids?
Increased gluconeogenesis, stress resistance, immune dampening, decreased response to catecholamines
What are the two major anti-inflammatory actions of glucorticoids?
Decreased number and activity of immune cells, decreased arachidonic acid cascades
What is the action of glucocorticoids at the cellular level?
They bind to glucocorticoid response element (GRE) and decrease transcription of pro-inflammatory proteins, while increasing transcription of anti-inflammatory proteins. Slow and long-lasting effects. Also directly activates annexin 1 and MapK phosphatase, which quickly inhibit P-lipase A2 and COX2.
What protein carries glucocorticoids in the blood? What protein complexes with glucocorticoids in the cytosol?
1) Corticosteroid binding globulin (CBG) 2) Heat-shock protein 90 (hsp 90)
What are the six short- to medium-acting glucocorticoids?
Hydrocortisone (cortisol), cortisone, prednisone, prednisolone, methylprednisolone, meprednisone
What are the three intermediate-acting glucocorticoids?
Triamcinolone, paramethasone, fluprednisolone
What are the two long-acting glucocorticoids?
Betamethasone, dexamethasone
What are the two mineralcorticoids?
Fludrocortisone, desoxycorticosterone acetetate
Which seven glucocorticoids are low potency anti-inflammatory drugs (1-5 times hydrocortisone activity)?
Hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, meprednisone and triamcinolone
Which two glucocorticoids are medium potency anti-inflammatory drugs (10-15 times hydrocortisone activity)?
Paramethasone and fluprednisone
Which two glucocorticoids are high potency anti-inflammatory drugs (25-40 times hydrocortisone activity)?
Betamethasone and dexamethasone
What are the five general categories of clinical applications for glucocorticoids?
Immunosuppression, anti-inflammatory, anti-allergic, pain relief, decrease in blood vessel permeability
What types of disorders are glucocorticoids used for?
Allergic reactions, collagen vascular disorders, eye diseases, blood disorders such as leukemia and hemolytic anemia, systemic inflammation, arthritis/bursitis, neurologic auto-immune (MS), transplant management, asthma, renal and thyroid disorders, hypercalcemia, mountain sickness
What constitutes appropriate use of glucocorticoids?
Smallest effective dose for shortest duration of time possible. Gradual tapering off if used for long periods.
What are side effects of glucocorticoid use in the immune, musculoskeletal, and central nervous systems?
Infection, myopathia, osteoporosis, osteonecrosis, neuropsychiatric effects and HPA insufficiency
What are the side effects of glucocorticoid use in metabolism?
Weight gain/obesity, fluid retention/edema, Cushingoid appearance, impaired glucose metabolism, peptic ulcers
What are the side effects of glucocorticoid use in the skin, eyes, and vasculature?
Skin thinning, ecchymoses, cataract, glaucoma, cardiovascular effects
What is the preferable duration of glucocorticoid use?
Two weeks or LESS
What signs should the physician monitor for during glucocorticoid use?
Hyperglycemia, glycosuria, sodium retention, hypertension, hypokalemia, peptic ulcer, osteoporosis and hidden infections
What is a major concern of prolonged glucocorticoid use?
Feedback suppression of endogenous adrenal production of cortisol (Lowered resistance to stress of trauma, surgery; increased intensity of symptoms upon cessation of medication). Fatalities have occurred in asthmatic patients during switch from systemic to aerosol steroids.
Which six anti-inflammatory glucocorticoid drugs do we need to know?
Cortisone, betamethasone, dexamethasone, hydrocortisone, prednisolone, triamcinolone
Which 13 therapeutic eicosanoids do we need to know?
Alprostadil, bimatoprost, carboprost, dinoprostone, epoprostenol, iloprost, latanoprost, misoprostol, travoprost, treprostinil + three anti-leukotrienes: montelukast, zafirlukast, zileuton.