Anti-Inflammatory Pharmacology

Front 1

Histamine receptors

Back 1

H1 Gq smooth muscle (pain and itching, vasodilation, bronchoconstriction)
H2 Gs stomach, heart, mast cells (negative feedback – important!)
H3 Gi CNS
H4 Gi leukocytes and mastcells

Marker in the urine of excess histamine: Imidazole acetic acid

Front 2

Effects of H1 receptor activation

Back 2

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

Front 3

Effects of H2 receptor activation

Back 3

Increased gastric acid secretion (ulcers), positive inotropism

Front 4

H1 antagonist drugs

Back 4

1st Generation
Diphenhydramine
Chlorpheniramine
Cyclizine

2nd Generation
Cetirizine
Fexofenadine
Loratadine

Front 5

Effects of H1 First and Second generation

Back 5

1st Gen. (older)
- CNS, PNS

- Active on serotonin, alpha, muscarinic, histamine receptors

-Highly sedative
-lipid soluble
-Autonomic receptor-blocking effects
-Anti-motion sickness

-Potent local anesthetic effect
-First generation shorter duration of action, but faster onset.
Admin: Oral, topical, parenteral

USED:
· antiemetic
· anti-motion
· anaphylaxis
· sleep pills
· local anesthetics
SE: sedation
dry mouth
blurred vision


2nd Gen.
-Autonomic receptor-blocking effects
-PNS
- Active on histamine receptors
Admin: Oral, topical
USED:
· anti-inflammatory
· urticaria

Front 6

Uses of H1 antagonists

Back 6

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

Front 7

Adverse effects of H1 antagonists

Back 7

M block and sedation, GI distress, allergic reactions.

Front 8

Substances that increase proton pump activity

Back 8

ACh, gastrin, histamine (H2 receptors)

Front 9

H2 antagonist drugs

Back 9

Cimetidine, ranitidine, Famotidine, Nizatidine

Front 10

H2 antagonists
Effect

Back 10

MOA: They reduce the secretion of gastric acid from parietal cells.
USE: · peptic ulcer
· duodenal ulcer
· Zollinger-Ellison syndrome

cimetidine: P450 inhibitor

Front 11

MOA of H2 antagonists

Back 11

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

Reversible block of H2receptors ↓ H+secretion by parietal cells

Front 12

Uses of H2 antagonists

Back 12

Peptic ulcer disease, GERD, Zollinger-Ellison,
gastritis, mild esophageal reflux.

Front 13

Side effects of H2 antagonists

Back 13

GI distress, dizziness, sommnolence; Cimetidine: inhibits P450 --> increases effects of quinidine, phenytoin, TCAs, warfarin; also decreases androgens --> prolactinrelease, gynecomastia, impotence, ↓ libido in males
Can cross BBB (confusion, dizziness, headaches) & placenta. Cimetidine& Ranitidine ↓ Renal excretion of creatinine.

Front 14

H3 antagonists

Back 14

Clobenproprit
-Stim. release of GABA

Front 15

Omeprazole

Back 15

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

Front 16

Misoprostol

Back 16

PGE1 analog, increases mucus and bicarbinote, decreases HCL secretion.

Use: NSAID-induced ulcers also used to induce labor.

Maintenance of PDA (Alprostradil);

Toxicity: Diarrhea. Contraindicated in childbearing women (abortifacient)

Front 17

Sulcralfate

Back 17

A prodrug,
Requires acidic PH
Polymerizes in stomach to form gel like coating of ulcers. Increases healing and decreases ulcer recurrence.

Front 18

Drugs that require acid stomach pH to be absorbed

Back 18

Azoles, fluoroquinolones, warfarin

Front 19

Drugs used as antiemetics

Back 19

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

Front 20

Metabolism of serotonin

Back 20

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

Front 21

Buspirone

Back 21

Partial 5HT1a agonist used for generalized anxiety disorder

Front 22

Sumatriptan

Back 22

5HT1d agonist in cerebral vessels, used for migraine

Front 23

Olanzapine

Back 23

Atypical antipsychotic, 5HT2a receptor antagonist, decreases psychosis

Front 24

Cyproheptadine

Back 24

5HT2 antagonist used in carcinoid

Front 25

Ondansetron

Back 25

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

Front 26

Ergonovine

Back 26

Uterine muscle contraction after placental delivery

Front 27

Ergotamine

Back 27

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

Front 28

Prophylaxis of migraine headaches

Back 28

Propranolol, verapamil, amitriptyline, valproic acid

Front 29

PGE2

Back 29

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

Front 30

Prostacyclin (PGI2)

Back 30

Vasodilation and inhibits platelet aggregation

Front 31

COX1

Back 31

Constitutive enzyme synthesizes GI PGs and TxA2

Front 32

COX2

Back 32

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

Front 33

Zileuton

Back 33

Lipoxygenase inhibtor used in asthma

Front 34

Zafirlukast and -lukasts

Back 34

Leukotriene receptor antagonist used in asthma

Front 35

MOA of aspirin

Back 35

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

Front 36

Actions of aspirin

Back 36

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

Front 37

Effects of aspirin on acid-base and electrolytes

Back 37

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

Front 38

Side effects of aspirin

Back 38

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

Front 39

Aspirin overdose management

Back 39

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

Front 40

Celecoxib

Back 40

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

Front 41

Acetaminophen

Back 41

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.

Front 42

Hydroxychloroquine

Back 42

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

Front 43

Methotrexate

Back 43

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

Front 44

Sulfasalazine

Back 44

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

Front 45

Glucocorticoids

Back 45

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

Front 46

Gold salts

Back 46

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

Front 47

Penicillamine

Back 47

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

Front 48

Etanercept

Back 48

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

Front 49

Infliximab

Back 49

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

Front 50

Anakinra

Back 50

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

Front 51

Colchicine

Back 51

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

Front 52

Allopurinol

Back 52

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.

Front 53

Probenecid

Back 53

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

Front 54

Glucocorticoid drugs

Back 54

Cortisol, prednisone, triamcinolone, betamethasone, dexamethasone

Front 55

MOA of glucocorticoids

Back 55

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

Front 56

Uses of glucocorticoids

Back 56

Antiinflammatory and immunosuppressive

Front 57

Side effects of glucocorticoids

Back 57

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.

Front 58

Role of beta agonists in asthma

Back 58

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

Front 59

Ipratropium

Back 59

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

Front 60

Theophylline

Back 60

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.

Front 61

Role of glucocorticoids in asthma

Back 61

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.

Front 62

Zafirlukast, mentelukast

Back 62

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

Front 63

Zileuton

Back 63

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

Front 64

Drugs used in Peptic Ulcer Disease
NAME

Back 64

H2Antagonist
Proton Pump Inhibitors
Bismuth, Sucralfate
Misoprostol
MuscarinicAntagonists
Metoclopramide
Infliximab
Sulfasalazine
Laxatives
Antacids
Antidiarrheals

Front 65

Proton Pump Inhibitors

Back 65

Omeprazole, Lansoprazole; Irreversibly inhibit H+/K+ATPasein stomach parietal cells.
Used for peptic ulcers (better than H2blockers), gastritis, esophageal reflux, Zollinger-Ellison syndrome.

Front 66

MuscarinicAntagonists

Back 66

Propantheline, Pirenzepine;
Block M1 receptors on ECL cells (↓ histamine secretion) & M3 receptors on parietal cells (↓ H+secretion).

Used for peptic ulcers (rarely). Caused tachycardia, dry mouth, difficulty focusing eyes.

Front 67

Metoclopramide

Back 67

D2receptor antagonist. ↑resting tone, contractility, LES tone, motility. Does NOT influence colon transport time.
Used in Diabetics & post-surgery gastroparesis.
Toxicity: ↑ parkinsonianeffects. Restlessness, drowsiness, fatigue, depression, nausea, diarrhea. Drug interaction with Digoxin& Diabetic agents. Contraindicated in patients with small bowel obstruction

Front 68

Infliximab

Back 68

A monoclonal Abto TNF,proinflammatorycytokine.
Used Crohn’sdisease (IBD), rheumatoid arthritis.
Toxicity: Respiratory infection (including activation of latent TB), fever, hypotension.

Front 69

Sulfasalazine

Back 69

A combination of Sulfapyridine(antibacterial) & 5-aminosalicylic acid (anti-inflammatory). Activated by colonic bacteria.

Used ulcerative colitis (IBD) & Crohn’sdisease (IBD).

Toxicity: malaise, nausea, sulfa allergy, reversible oligospermia.

Front 70

Laxatives

Back 70

MgSO4: waterretaining–↑ intraluminalpressure.

Bisacodyl: direct intestinal wall stimulant.

Methylcellulose: collects water & swells –↑ bulk.

Docusate: detergent –stool softener

Mineral oil: lubricant

Lactulose: hyperosmotic(also indicated for systemic encephalopathy)

Front 71

Antacids

Back 71

Antacids: (all cause hypOkalemia)

Can affect absorption, bioavailability or urinary excretion of other drugs by altering gastric & urinary pH or by delaying gastric emptying.

↑ Oral absorption of weak bases (quinidine); ↓ oral absorption of weak acids (warfarin), azoles, fluoroquinolones& tetracylines(via chelationby Ca carbonate)
Overuse can also cause the following problems:

1.AluminiumHydroxide Constipation & hypOphosphatemia; proximal muscle weakness, osteodystrophy, seizures.

2.Magnesium Hydroxide Diarrhea, hyporeflexia, hypotension, cardiac arrest.

3.Calcium carbonate Hypercalcemia, rebound acid ↑.

Front 72

Antidiarrheals

Back 72

Loperamide& diphenoxylate(with atropine) are opioidsthat are poorly absorbed
Adsorbants: kaolin, pectin

Front 73

Antiemetics

Back 73

5-HT3antagonist:
Ondansetron(caused headache & constipation), and Granisetron
DA antagonists:
Prochlorperazine& Metoclopromide
H1antagonists:
Diphenhydramine, Meclizine, Promethazine
Muscarinicantagonists:
Scopolamine
Cannabinoids:
Dronabinol
NK1-receptor antagonist:
Aprepitant(NK1is a receptor to substance P)

Front 74

Serotonin
Agonists

Back 74

5-HT1(a-h):
Found in CNS (inhibitory) & smooth muscle (excitatory/inhibitory)
BUSPIRONE(agonist of 5-HT1a) anxiolytic& GAD.
SUMATRIPTAN(agonist of 5-HT1d) ↓ migraine pain.
5-HT4:
TEGASEROD(agonist of 5-HT4) used in IBS when associated with constipation)

Front 75

Serotonin
Antagonists

Back 75

5-HT2 (a-c):
Found in CNS (excitatory) “too (2) excited”
OLANZEPINE(antagonist at 5-HT2a) ↓ psychosis symptoms.
CYPROHEPTADINE(antagonist at 5-HT2) used in carcinoidtumors, postgastrectomy& anorexia nervosa. Also has H1blocking action (used in seasonal allergies).
5-HT3:
ONDANSETRON (antagonist at 5-HT3) antiemesis.

Front 76

Drugs used in migraine headaches:

Back 76

Ergot alkaloid:
Ergotamine:
Partial agonist at α& 5-HT2receptors.
Vasoconstrictiveactions –↓ pulsation in cerebral vessels
Used in acute migraine attacks
Side effects: GI distress, prolonged vasoconstictionischemia & gangrene, abortion near term.
Analgesics:
ASA, other NSAIDs, acetaminophen, oral or injectableopioidanalgesics & butorphanol(spray).
Prophylaxis:
Propanolol, verapamil, amitriptyline, valproicacid.

Front 77

Aspirin:

Back 77

Irreversibly inhibits COX ↓ TXAs & PGEs
Low dose (<300 mg/day) to ↓platelet aggregation; intermediate dose (300 –2400 mg/day) as antipyretic & analgesia; high dose (2400 –4000 mg/day) as anti-inflammatory.
Toxicity: gastric upset. Chronic use acute renal failure, intestinal nephritis, & upper GI bleeding. Reye syndrome in children with viral infection (use Acetaminophen instead).

Front 78

NSAIDs

Back 78

Ibuprofen, Naproxen, Indomethacin, Ketorolac, Sulindac(causes Steven-Johnson Syndrome).
Reversibly inhibits COX-1 & COX-2. Block PGE synthesis.
Used as antipyretic, anti-inflammatory. Indomethacinto close PDA.
Toxicity: renal damage (except Sulindac), fluid retention, aplasticanemia, GI distress, ulcers.

Front 79

Acetaminophen

Back 79

Reversibly inhibits COX (mostly in CNS). Inactivated peripherally.
Used as antipyretic, analgesia. Lack anti-inflammatory properties.
Toxicity: hepatic necrosis (depleted GSH). N-acetylcysteineis antidote –regenerates GSH.

Front 80

COX-2 inhibitors (celecoxib)

Back 80

Reversibly inhibits COX-2 helps maintain gastric mucosa.
Used in RA and OA.
Toxicity: ↑risk of thrombosis. Sulfa allergy.

Front 81

Anti-leukotrienes(LTs)

Back 81

Zileuton–a 5-lipoxygenase pathway inhibitor. Blocks conversion of arachidonicacid to LTs.
Zafirlukast, montelukast–block LT receptors. Especially good for aspirin-induced asthma.

Front 82

Prostaglandins (PGs)

Back 82

PGE1Misoprostol(used in NSAID-induced ulcers); Alprostadil(Maintain PDA open & causes vasodilationin male impotence)
PGE2Dinoprostone(causes cervical “ripening” –used as abortifacient)
PGE2αCarboprost(abortifacient); Latanoprost(txof glaucoma –↓ IOP)
PGI2(prostacyclin) Epoprostenol(platelet stabilizer –used in pulmonary HTN)
PGE2 & PGE2αBoth ↑ in primary dismenorrhea.

Front 83

Thromboxanes(TXAs)

Back 83

TXA2Platelet aggregator & causes bronchoconstriction& vasoconstriction.

Front 84

Drugs used in treatment of Gout

Back 84

Acute Gout:
Colchicine:
Binds & stabilizes tubulinto inhibit polymerization, impairing leukocyte chemotaxis& degranulation. GI side effects, especially if given orally (Note: Indomethacinis less toxic & is also used in acute gout).
Chronic Gout:
Probenecid:
Inhibits reabsorptionof uric acid in PCT (also inhibits secretion of penicillin –synergistic).
Allopurinol:
Inhibits xanthineoxidase, ↓ conversion of xanthineto uric acid. Also used in lymphoma & leukemia to prevent tumor lysis–associated uratenephropathy. ↑ concentrations of azathioprine& 6-MP (both normally metabolized by xanthineoxidase).
Probenecid& Allopurinolshould not be used to treat acute gout.
Do not give salicylates. All but the highest doses depress uric acid clearance. Even high doses (5 –6 g/day) have only minor uricosuricactivity.

Front 85

Drugs used in RA
name

Back 85

Hydroxychloroquine
Methotrexate
Sulfasalazine
Glucocorticoids
Gold Salts
Penicillamine
Etanercept
Infliximab
Leflunomide
Anakira

Front 86

Drugs used in RA

Back 86

Drug Mechanism(s) Side Effects
Hydroxychloroquine Stabilizes lysosomes& ↓chemotaxis GIdistress, dizziness, blurred vision, tinnitus, pruritus(cinchonism), hemolysisin G6PD def.
Methotrexate Cytotoxicto lymphocytes Hemototoxic, mucositis,crystalluria
Sulfasalazine Sulfapyridineà↓ B-cellfunctions; 5-ASA possibly inhibits COX GI distress, rash, hemolysisin G6PD def, SLE-like syndrome.
Glucocorticoids ↓ LTs, Ils, & PAF ACTH suppression, cushingoidstate, osteoporosis, GI distress, glaucoma.
Gold Salts ↓ lysosomal& macrophage functions Dermatitis, hematotoxic, nephrotoxic.
Penicillamine SupressesT cells & circulating Rheumatoid factor Proteinuria, hematotoxic, autoimmunedisease
Etanercept Binds TNF Hypersensitivity,injection site reaction, infections.
Infliximab Monoclonal Abto TNF Infusion reactions, infections
Leflunomide Inhibits DHOD à↓ UMP à↓ ribonucleotidesàarrests lymphocytes in G1 Alopecia, rash,diarrhea, hepatotoxic, rarely Steven-Johnson Syndrome.
Anakira IL-1 receptor antagonist Infection, injection-sitereaction.

Front 87

Glucocorticoids

Back 87

· prednisone
· dexamethasone
· triamcilolone
· beclomethasone
· budesonide

↓ the production of LTs & PGs by inhibiting phospholipaseA2& expression of COX-2.
Used in Addison disease, inflammation, immune suppression, asthma.
Side effects: iatrogenic Cushing’s syndrome –buffalo hump, moon facies, truncleobesity, skin thinning & easily bruised, osteoporosis, adrenocorticalatrophy, peptic ulcers & even diabetes (with chronic use). Also cause ↑ in IOP.

Front 88

Drugs used to treat asthma

Back 88

Non-specific β-agonist:
Isoproterenolrelaxes bronchial smooth muscle (β2); adverse effect is tachycardia (β1)
β2-agonist:
Albuterolrelaxes bronchial smooth muscle (β2); use during acute attack !!
Salmeterollong-acting for prophylaxis; adverse effects: tremors & arrhythmia.
Methylxanthines:
Theophyllinecauses bronchodilationby inhibiting PDE, thereby ↓cAMPhydrolysis. Narrow therapeutic index (cardio-& neurotoxicity). Metabolized by CYP450. Blocks action of adenosine.
Muscarinic antagonist:
Ipratropium bromide competitive muscarinicblock, prevents bronchoconstriction. Also used in COPD.

Cromolyn& Nedocromil:
Prevents release of mediators from mast cells. Effective ONLY for ASTHMA PROPHYLAXIS (not during acute attack). Toxicity is rare.
Corticosteroids:
Beclomethasone, prednisone inhibits the synthesis of virtually all cytokines. Inactivates NF-κB, the transcription factor that induces the production of TNF-α, among other inflammatory agents. 1stline therapy for chronic asthma.
Antileukotrienes:
ZileutonA 5-lipoxygenase pathway inhibitor. Blocks conversion of arachidonicacid to LTs.
Zafirlukast, montelukastBlocks LT receptors. Especially good for aspirin-induced asthma.