Anti-Inflammatory Pharmacology

Front 1

Effects of H1 receptor activation

Back 1

Increased capillary dilation and permeability (hypotension, edema), bronchoconstriction, activation of nociceptive receptors (pain, pruritus)

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Effects of H2 receptor activation

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Increased gastric acid secretion (ulcers), positive inotropism

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H1 antagonist drugs

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Diphenhydramine, promethazine, chlorpheniramine, meclizine, hydroxyzine, loratadine, fexofenadine

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Uses of H1 antagonists

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Hay fever, rhinitis, urticaria, motion sickness and vertigo (meclizine), nausea in pregnancy

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Adverse effects of H1 antagonists

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M block and sedation, GI distress, allergic reactions.

Front 6

Substances that increase proton pump activity

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ACh, gastrin, histamine (H2 receptors)

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H2 antagonist drugs

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Cimetidine, ranitidine

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MOA of H2 antagonists

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Indirectly decrease proton pump activity (histamine increases proton pump activity)

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Uses of H2 antagonists

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Peptic ulcer disease, GERD, Zollinger-Ellison

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Side effects of H2 antagonists

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GI distress, dizziness, sommnolence; Cimetidine: inhibits P450 --> increases effects of quinidine, phenytoin, TCAs, warfarin; also decreases androgens --> gynecomastia

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Omeprazole

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Direct, irreversible proton pump inhibitor. Uses: PUD, GERD, Zollinger-Ellison, H. pylori. Side effects: decreases bioavailability of weak acids (fluoroquinolones, ketoconazole), inhibits P450

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Misoprostol

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PGE1 analog, increases mucus and bicarbinote, decreases HCL secretion. Use: NSAID-induced ulcers.

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Sulcralfate

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Polymerizes in stomach to coat ulcers. Increases healing and decreases ulcer recurrence.

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Drugs that require acid stomach pH to be absorbed

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Azoles, fluoroquinolones, warfarin

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Drugs used as antiemetics

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5HT3 antagonists (ondansetron), DA antagonists (metoclopramide), H1 blockers (diphenhydramine, meclizine), muscarinic blockers (scopolamine)

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Metabolism of serotonin

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5HT is metabolized by MAOa to 5-hydroxyinolacetic acid (marker for carcinoid)

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Buspirone

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Partial 5HT1a agonist used for generalized anxiety disorder

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Sumatriptan

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5HT1d agonist in cerebral vessels, used for migraine

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Olanzapine

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Atypical antipsychotic, 5HT2a receptor antagonist, decreases psychosis

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Cyproheptadine

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5HT2 antagonist used in carcinoid

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Ondansetron

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5HT3 antagonist, used as antiemetic in chemotherapy, radiation and post-op. 5HT3 receptors are found in area postrema

Front 22

Ergonovine

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Uterine muscle contraction after placental delivery

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Ergotamine

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Partial 5HT2 and alpha agonist causes vasoconstriction to decrease pulsation in migraine acute attack. Side effect is vasoconstriction (prinzmetal)

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Prophylaxis of migraine headaches

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Propranolol, verapamil, amitriptyline, valproic acid

Front 25

PGE2

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Vasodilation in kidneys, increases renal blood flow, increases gastric mucosal blood flow (mucoprotection), activates osteoclasts, fever, pain, maintains ductus arteriosus

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Prostacyclin (PGI2)

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Vasodilation and inhibits platelet aggregation

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COX1

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Constitutive enzyme synthesizes GI PGs and TxA2

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COX2

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Inducible enzyme synthesizes PGs involved in inflammation, fever and pain.

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Zileuton

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Lipoxygenase inhibtor used in asthma

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Zafirlukast and -lukasts

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Leukotriene receptor antagonist used in asthma

Front 31

MOA of aspirin

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Nonselective, irreversible COX inhibitor via acetylation of serine near active site

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Actions of aspirin

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Low dose: antiplatelet aggregation (post-MI); moderate dose: analgesia, antipyeresis, hyperuricemia; High dose: antiinflammatory, uricosuria

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Effects of aspirin on acid-base and electrolytes

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Antiinflammatory doses: uncoupling of ETC --> increases respiration --> decreased pCO2 --> resp. alkalosis --> renal compensation via HCO3 excretion --> compensated respiratory alkalosis. Toxic doses: inhibits respiratory center --> decreases respiration --> resp. acidosis plus ETC uncoupling --> metabolic acidosis, decreases ATP, hyperthermia, hypokalemia

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Side effects of aspirin

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Gastritis, ulcers, bleeding, tinnitus, vertigo, decreased hearing, bronchoconstriction, hypersensitivity (asthma, nasal polyps, rhinitis), Reye syndrome, increased bleeding time, renal dysfunction at high doses

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Aspirin overdose management

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Gastric lavage, alkalinization of urine (zero-order kinetics at toxic doses)

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Celecoxib

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Selective COX-2 inhibitor. Antiinflammatory. Increases PT when used with warfarin, prothrombotic. Cross hypersensitivity with sulfonamides. Potential cardiotoxicity resulted in withdrawal of rofecoxib.

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Acetaminophen

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Inhibits COX in CNS only. No antiplatelet activity, not implicated in Reye syndrome, no effects on uric acid, no bonchoconstriction. Metabolized via P450. Hepatotoxic due to reactive metabolite N-acetylbenzoquinonemine, which is inactivated by GSH. Upon GSH depletion, metabolite damages hepatocytes, nausea, vomiting, abdominal pain, centrilobular necrosis. Inducers of P450 enhance toxicity. Management of hepatotoxicity: N-acetylcysteine.

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Hydroxychloroquine

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Used for rheumatoid arthritis. Stabilizes lysosomes and decreases chemotaxis. Side effects: GI distress, visual dysfunction, hemolysis in G6PDH deficiency

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Methotrexate

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Used for rheumatoid arthritis. Cytotoxic to lymphocytes. Side effects: hematotoxicity, mucositis, crystalluria

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Sulfasalazine

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Used for rheumatoid arthritis. Decreases B cell function, possibly inhibits COX. Side effects: GI distress, rash, hemolysis in G6PDH deficiency, drug-induced lupus

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Glucocorticoids

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Used in rheumatoid arthritis. Decrease LTs and platelet activating factor (PAF). Side effects: ACTH suppression, Cushingoid state, osteoporosis, GI distress, glaucoma

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Gold salts

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Used in rheumatoid arthritis. Decreases lysosomal and macrophage functions. Side effects: dermatitis, hematotoxicity, nephrotoxicity

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Penicillamine

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Used in rheumatoid arthritis. Suppresses T cells and circulating rheumatoid factor. Side effects: proteinuria, hematotoxicity, autoimmune disease.

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Etanercept

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Used in rheumatoid arthritis. Binds TNF. Side effects: hypersensitivity, injection site reactions, infections

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Infliximab

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Used in rheumatoid arthritis. Monoclonal antibody to TNF. Side effects: infusion reactions, infections

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Anakinra

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Used in rheumatoid arthritis. IL-1 receptor antagonist. Side effects: infections, injection site reactions

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Colchicine

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Used in acute gout. Binds tubulin --> decreases microtubular polymerization ; decreases LTB4 and leukocyte/granulocyte migration. Side effects: diarrhea, GI pain, hematuria, myelosuppression, neuropathy

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Allopurinol

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Prodrug converted by xanthine osidase into alloxanthine which inhibits the enzyme --> decreases purine metabolism --> decreases uric acid. Side effects: GI distress, neuropathy, rash, vasculitis, stones.

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Probenecid

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Inhibits tubular reabsorption of urate. Interactions: inhibits secretion of acidic drugs (cephalosporins, fluoroquinolones). Side effects: GI distress, rash, nephrotic syndrome, crystallization

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Glucocorticoid drugs

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Cortisol, prednisone, triamcinolone, betamethasone, dexamethasone

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MOA of glucocorticoids

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Inhibits leukocyte migration, phagocytosis and capillary permeability, decreases PGs, LTs, expression of COX2, PAF and interleukins

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Uses of glucocorticoids

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Antiinflammatory and immunosuppressive

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Side effects of glucocorticoids

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Suppression of ACTH --> cortical atrophy, shock if abruptly withdrawn, cushingoid syndrome, hyperglycemia (increased gluconeogenesis), osteoporosis with vertebral fractures, gastric acid secretion (ulcers), Na+ and H2O retention with edema and hypertension, hypokalemic alkalosis, hypocalcemia, inhibits bone growth in children, decreases wound healing (infections), increased sorbitol (glaucoma, cataracts), mental dysfunction.

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Role of beta agonists in asthma

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Selective β2 agonists: Relief of acute bronchoconstriction (albuterol, metaproterenol, terbutaline) and prophylaxis of nightime attacks (salmeterol). Side effects include anxiety, tremors and CV toxicity

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Ipratropium

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Muscarinic blocker causes bronchodilation in acute asthma. Safer than β2 agonists in patients with cardiovascular disease. DOC in bronchospasm induced by β-blockers.

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Theophylline

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Inhibits phosphodiesterase --> increases cAMP --> bronchodilation. Also antagonizes adenosine (broncoconstrictor). Narrow therapeutic index. Side effects: nausea, diarrhea, increases HR, arrhythmias. Increased toxicity with erythromycin, cimetidine and fluoroquinolones.

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Role of glucocorticoids in asthma

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Decreases reactivity by decreasing PGs, LTs and Ils; May cause oropharyngeal candidiasis and retarded bon growth with chronic use; low doses prevent desensitization of β receptors.

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Zafirlukast, mentelukast

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LTD4 antagonists with slow onset. Used prophylactically for antigen, exercise or drug-induced asthma.

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Zileuton

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Selective inhibitor of lypoxygenases --> decreased Ils. Rapid onset, adjunct to steroids.