Histamine and Inflammation drugs

Question 1

H1 receptor antagonist

Answer 1

Class: ___
Mech: H1 receptor antagonist; rapidly absorbed orally, widely distributed, rapidly metabolized via liver microsomes
Thera: Allergic reactions (rhinitis, urticaria, conjunctivitis), motion sickness, nausea and vomiting in pregnancy, sleep aids
Important SE’s: Sedation, anti-muscarinic action, poisoning (especially children) with convulsions, allergy, local anesthesia (has actions not ascribable to H1 blockade because of muscarinic cholinoceptor, a-adrenoceptor, serotonin, local anesthetic receptor sites)
Misc: Older agents cross CNS to cause central effects

Question 2

Diphenhydramine (Benadryl)

Answer 2

Class: Ether/ethanolamine derivitive
Mech: H1 receptor antagonist
Important SE’s: Anti-muscarinic, sedating

Question 3

Tripelennamine (Pyribenzamine)

Answer 3

Class: Ethylenediamine derivitive
Mech: H1 receptor antagonist
Thera: OTC sleep aid; moderate sedation

Question 4

Meclizine (Marezine)

Answer 4

Class: Piperazine derivative
Mech: H1 receptor antagonist
Thera: Motion sickness

Question 5

Promethazine (Phenergan)

Answer 5

Class: Phenothiazine derivative
Mech: H1 receptor antagonist
Thera: Antiemetic
Important SE’s: Anti-muscarinic, sedating (because of cholinergic receptors, dry mouth, urinary retention, sinus tachy; because of alpha-adre, hypotension, dizziness, reflex tachy)

Question 6

Chlorpheniramine (Chlor-Trimeton)

Answer 6

Class: Alkylamine derivitive
Mech: H1 receptor antagonist
Thera: Component of “cold” medications
Important SE’s: Less sedating

Question 7

Loratadine (Claritin)

Answer 7

Class: Piperidine derivitive
Mech: 2nd generation H1 receptor antagonist
Thera: Allergic rhinitis
Important SE’s: No sedation
Other SE’s: Cardiovascular effects (rare, with high doses)
Misc: Poorly crosses BBB, so fewer central and side effects; once daily dosing

Question 8

Fexofenadine (Allegra)

Answer 8

Class: Piperidine derivitive
Mech: 2nd generation H1 receptor antagonist
Thera: Allergic rhinitis
Important SE’s: No sedation
Other SE’s: Cardiovascular effects (rare, with high doses)
Misc: Poorly crosses BBB, so fewer central and side effects; once daily dosing

Question 9

Azelastine (Astelin)

Answer 9

Mech: 2nd generation H1 receptor antagonist
Thera: Allergic rhinitis (intranasal spray), allergic conjunctivitis (ophthalmic solution)
Important SE’s: No sedation
Misc: Poorly crosses BBB, so fewer central and side effects

Question 10

Cetirizine (Zyrtec)

Answer 10

Mech: 2nd generation H1 receptor antagonist
Thera: Allergic rhinitis
Important SE’s: No sedation
Misc: Poorly crosses BBB, so fewer central and side effects

Question 11

Cimetidine (Tagamet)

Answer 11

Mech: H2 receptor antagonist; blocks gastric acid secretion (more so with nocturnal acid secretion than meal secretion)
Thera: Dyspepsia, duodenal and gastric ulcers, hypersecretory conditions
Important SE’s: Antiandrogen (causing impotence and gynecomastia), inhibition of P450 enzymes
Other SE’s: CNS dysfunction possible
Misc: Most side effects of H2-blocker class

Question 12

Ranitidine (Zantac): how different from cimetidine?

Answer 12

Important SE’s: Liver toxicity

Question 13

Famotidine (Pepcid): how different from cimetidine?

Answer 13

No Important SE’s or misc

Question 14

Nizatidine (Axid): how different from cimetidine?

Answer 14

Misc: Least side effects of H2-blocker class

Question 15

Cyproheptadine (Periactin)

Answer 15

Mech: Antihistaminic and antiserotinergic
Thera: Skin allergies (urticaria, anti-5HT1), diarrhea of carcinoid syndrome (anti-5HT2)
Other SE’s: Sedation, antimuscarinic

Question 16

Ketanserin

Answer 16

Mech: Selective 5HT2A,2C receptor antagonist, as well as α1 and H1 receptor antagonist
Thera: Antihypertensive (relaxes vascular and tracheal smooth muscle), antiplatelet aggregation

Question 17

Odansetron (Zofran)

Answer 17

Mech: 5HT3 receptor antagonist
Thera: Nausea and vomiting in chemotherapy

Question 18

Ergot alkaloids

Answer 18

Mech: Agonist and antagonist actions at 5HT and α-adrenergic receptors
Important SE’s: Powerful hallucinations, smooth muscle contraction (vascular and uterine, latter leading to abortion)

Question 19

Ergotamine (Ergomar)

Answer 19

Class: Ergot alkaloid
Mech: Nonspecific partial agonist at all 5HT1,2 receptors; partial agonist at α-adrenergic receptors
Thera: Prodrome of migraines
Other SE’s: N/V, cumulative and prolonged vasoconstriction

Question 20

Methysergide (Cycloset)

Answer 20

Class: Ergot alkaloid
Mech: Partial agonist at all 5HT1 receptors, antagonist at 5HT2
Thera: Prophylaxis of migraines
Other SE’s: GI disturbances, inflammatory fibrosis (chronic use), hallucinations
Misc: Withdrawn from U.S. market

Question 21

Ergonovine

Answer 21

Class: Ergot alkaloid
Thera: Postpartum hemorrhage (Oxytocic)

Question 22

Bromocriptine (Sansert)

Answer 22

Class: Ergot alkaloid
Mech: Dopamine agonist (D2)
Thera: Hyperprolactinemia (suppress prolactin secretion from pituitary cells)

Question 23

Triptans (Suma, nara, riza, zolmi)

Answer 23

Class: Non-ergot serotonin analogs
Mech: 5HT1B,D receptor agonist
Thera: Effective (70%) migraine treatment

Question 24

Acetylsalicylic acid (ASA, Aspirin)

Answer 24

Class: Salicylate
Mech: Acetyl-salicylic acid irreversibly acetylates COX-1 and -2; metabolite (salicylic acid) reversibly inhibits COX-1 and -2
Thera: Antiplatelet (inhibit TXA2 synthesis; 80-160 mg), analgesic (inhibition of eicosanoid-induced sens of pain receptors and transmission to relay neurons in dorsal horn; 650-975 mg) and antipyretic (blocks pyrogen-induced eicosanoid synthesis, PGE2, in vicinity of hypo; 650-975 mg), and anti-inflammatory (inhibit eicosanoid formation; 3-6 g) (in ascending order of amount taken); often taken as a “baby aspirin” to prevent MI, CVA
Important SE’s: GI irritation (lose PGE2 and PGI2, dyspepsia), bleeding and anemia, hepatotoxicity (Reye’s syndrome), and salicylate toxicity
Other SE’s: Nephrotoxicity in elderly or hypovolemic patients (renal failure with less vasodilation and lack of renal vasodilator eicosanoids); rare hypersensitivity reaction (aspirin-induced airway hyperactivity and bronchoconstriction and urticaria)
Misc: peak plasma salicylate level 1-2 hrs; rapidly absorbed by passive diffusion from stomach (non-ionized) and upper small intestine (ionized)

Question 25

Diflunisal (Dolobid)

Answer 25

Class: Salicylate Mech: Difluorophenyl derivitive of salicylic acid, which reversibly inhibits COX-1 and -2 Thera: Osteoarthritis, musculoskeletal strains/sprains, pain after dental extraction, and postepisiotomy pain Important SE's: Fewer GI side effects and less effect on platelets than aspirin Misc: analgesic, weak antipyretic activity, and longer half life;

Question 26

Acetaminophen (Tylenol)

Answer 26

Class: Para-amino phenol Mech: Reversibly inhibits COX-1 and -2 (favors COX-1) Thera: Analgesic and antipyretic effect similar to aspirin, but weak anti-inflammatory effects Important SE's: Renal tubular necrosis if chronically abused with other NSAIDs; hepatic necrosis with overdose Other SE's: GI irritation (less than aspirin) Misc: Poor function in presence of peroxides (as found in sites of inflammation); mostly metabolized via conjugation, but minor pathway via P450 enzymes may lead to toxic intermediate (N-acetyl-benzoquinoneimine); used in more combo products than any other drug

Question 27

Indomethacin (Indocin)

Answer 27

Class: Indole Mech: Reversibly inhibits COX-1 and -2 (favors COX-1) Thera: Rhematoid arthritis (10X as potent as aspirin), ankylosing spondylitis, osteoarthritis, acute gout Important SE's: At times, thrombocytopenia, aplastic anemia, and severe frontal headaches Other SE's: Nephrotoxicity in elderly or hypovolemic patients Misc: Toxicity causes >25% of patients to discontinue use

Question 28

Sulindac (Clinoril)

Answer 28

Class: Indole Mech: Reversibly inhibits COX-1 and -2 (favors COX-1) Thera: Rhematoid arthritis, ankylosing spondylitis, osteoarthritis, acute gout Important SE's: At times, thrombocytopenia, aplastic anemia, and severe frontal headaches Other SE's: Nephrotoxicity in elderly or hypovolemic patients Misc: Half as potent as indomethacin; side effects less frequent

Question 29

Ibuprofen (Advil, Motrin)

Answer 29

Class: Proprionic acid dervitive Mech: Reversibly inhibits COX-1 and -2 (favors COX-1) Thera: Rheumatic disorders, osteoarthritis, ankylosing spondylitis, postpartum pain, dysmenorrheal pain, and many types of surgeries Important SE's: GI irritation; hepatotoxicity (less frequent than aspirin)

Question 30

Flurbiprofen (Ocufen)

Answer 30

Class: Proprionic acid dervitive Mech: Reversibly inhibits COX-1 and -2 (favors COX-1) Thera: Rheumatic disorders, osteoarthritis, ankylosing spondylitis, postpartum pain, dysmenorrheal pain, and many types of surgeries Important SE's: GI irritation; hepatotoxicity (less frequent than aspirin)

Question 31

Naproxen (Aleve)

Answer 31

Class: Proprionic acid dervitive Mech: Reversibly inhibits COX-1 and -2 (favors COX-1) Thera: Rheumatic disorders, osteoarthritis, ankylosing spondylitis, postpartum pain, dysmenorrheal pain, and many types of surgeries Important SE's: GI irritation; hepatotoxicity (less frequent than aspirin) Misc: Longer half-life than most proprionic acid derivitives (13 hours vs. 1-2 hours)

Question 32

Oxaprozin (Daypro)

Answer 32

Class: Proprionic acid dervitive Mech: Reversibly inhibits COX-1 and -2 (favors COX-1) Thera: Rheumatic disorders, osteoarthritis, ankylosing spondylitis, postpartum pain, dysmenorrheal pain, and many types of surgeries Important SE's: GI irritation; hepatotoxicity (less frequent than aspirin) Misc: Much longer half-life than most proprionic acid derivitives (50 hours vs. 1-2 hours)

Question 33

Piroxicam (Feldene)

Answer 33

Class: Enolic acid Mech: Reversibly inhibits COX-1 and -2 (favors COX-1) Thera: Long-term treatment of rheumatoid arthritis or osteoarthritis; also, ankylosing spondylitis, acute musculoskeletal disorders, acute gout Other SE's: Same as aspirin Misc: Very long half-life (45 hours) permits single daily dose

Question 34

Ketorolac (Toradol)

Answer 34

Class: Heteroaryl acetic acids Mech: Reversibly inhibits COX-1 and -2 (favors COX-1) Thera: Post-operative pain; inflammatory eye conditions Other SE's: Same as aspirin; relatively nonirritating Misc: Injectable (one of few NSAIDs available for this)

Question 35

Celocoxib (Celebrex)

Answer 35

Class: COX-2 inhibitor Mech: Selectively inhibits COX-2 (too bulky to reliably interact in COX-1 site); 10-20 fold greater selectivity for COX-2 to COX-1 Thera: Same anti-inflammatory, antipyretic, and analgesic effects as NSAIDs Important SE's: Less GI toxicity than traditional NSAIDs Misc: Contraindicated in patients with heart problems/pregnancy

Question 36

Etoricoxib (Arcoxia)

Answer 36

Class: COX-2 inhibitor Mech: Selectively inhibits COX-2 (too bulky to reliably interact in COX-1 site) Thera: Same anti-inflammatory, antipyretic, and analgesic effects as NSAIDs Important SE's: Less GI toxicity than traditional NSAIDs Misc: Contraindicated in patients with heart problems/pregnancy

Question 37

Inflammatory processes occur in three distinct phases:

Answer 37

1. acute transient phase (local vasodilation and increased capillary permeability) 2. Delayed, subacute phase (infiltration of leukocytes and phagocytotic cells) 3. Chronic proliferative phase (tissue degen and necrosis)

Question 38

Histamine is a biologically ____, an ____, synthesized from ____ and stored primarily in _____ in many tissues; it is a mediator of what reactions? How does it act?

Answer 38

active amine; autacoid; histidine; mast cells and basophils; immediate type I hypersens reactions; 1. increases blood flow by capillary dilation 2. causes edema by increasing pcv permeability 3. Causes itching by sensitizing primary sensory neurons

Question 39

Kinins are ____ that are formed from _____. Enzymes responsible for their formation, the ____, are released from ____ or activated by _____ in plasma. Kinins have what effects?

Answer 39

two related peptides; plasma globulins (kininogens); kallikreins; tissues; clotting factors; 1. acute: excitation of primary sensory neurons 2. chronic: capillary dilation, increase in pcv perm, and activation of AA release (slower to act than histamine!!

Question 40

Cytokines are released from ___ and ____, and the major players are what? What do these players do?

Answer 40

lymphoid; non-lymphoid cells; IL-1: made particularly by macrophages and induces inflamm responses (increases eicosanoid synthesizing enzymes, collagenase), regulates B and T cells, induces fever IL-8 and chemokines: powerful chemotactic agents; TNF: regulates production of other cytokines and induces fibrosis and tissue catabolism

Question 41

AA is released from ____ and is metabolized by either ____ to make what, and _____, to make what?

Answer 41

phopholipids of cell membrane; lipooxygenase, to make leukotrienes; cyclooxygenase, to make prostaglandines, prostacyclines, thromboxanes

Question 42

COX-1 is produced _____, and is involved in? PRIG

Answer 42

constitutively; 1. gastric cytoprotection 2. initiation of parturition 3. renal blood flow autoregulation 4. Platelet aggregation

Question 43

COX-2 is induced _____; it makes ____ at the sites of inflammation and/or tissue damage; what are both COX-1 and -2 inhibited by?

Answer 43

during inflammation; prostaglandins; | NSAIDs

Question 44

COX-2 constitutive and inducible functions are what?

Answer 44

Constitutive: 1. renal electrolyte homeostasis 2. Renal blood flow maintenance Inducible: 1. Pain 2. Fever 3. Inflammation

Question 45

Largest concentration of histamine is found where?

Answer 45

Skin, lungs, GI and nasal mucosa, and blood

Question 46

Histamine is stored where and can be synthesized rapidly in what circumstances?

Answer 46

1. Mast cells and basophils | 2. With appropriate stimuli, the paracrine cells of the gastric fundus and histaminergic neurons

Question 47

Stimuli that can help with release of histamine from mast cells?

Answer 47

1. Antigens and anaphylatoxins (IgE crosslinking on surface of sensitized mast cells and membrane Ca channels opened to activate enzymes leading to histamine release) 2. Certain basic drugs that increase GTP (morphine, codeine, tubo) 3. Chemical or mech injury: degranulation usually due to increased Na

Question 48

All histamine receptors have ___ membrane-spanning regions and G protein use; what G proteins are used by each receptor type?

Answer 48

7; H1 with Gq, H2 with Gs, H3 and H4 with Gi

Question 49

Most important physiological effect on humans regarding histamine? Other effects?

Answer 49

Peripheral vasodilation with H1 and H2, which can lead to pronounced drop in BP and anaphylactic shock!! 1. Bronchiolar smooth muscle with minor effect on bronchoconstriction unless asthmatic 2. GI tract with gastric acid and pepsin secretion via H2 3. Nervous system: sensory nerve endings stimulated and itching (H1); also H3 receptors are presynaptic autoreceptors on histaminergic neurons

Question 50

What can you give to counter histamine effects?

Answer 50

Epi, cromolyn sodium (prophylactic treatment of exercise or seasonal asthma); ALSO HISTAMINE RECEPTOR ANTAGONISTS

Question 51

Pharmacologic actions of 5-HT?

Answer 51

1. GI tract contraction; look for carcinoid syndrome with 5-HT and autacoid release; high 5-HIAA in urine is diagnostic 2. Cardiovascular system: vasoconstrictor in smooth muscle, vasodilator in skeletal muscle and heart; have platelet aggregation with 5-HT2 3. Nervous system: peripheral (sensory nerve endings stimulated with pain and itching), central (involved in mood, food intake, sleep, reg of pituitary secretions)

Question 52

How is there regulation with serotonin?

Answer 52

1. Auto-reg with 5-HT1A receptor (somatodendritic autoreg) | 2. Auto-reg with 5-HT 1D/1B receptor (presynaptic autoreg)

Question 53

Aspirin is effective in treating what types of pain, but NOT one particular type?

Answer 53

Joint inflammation, myalgias, headaches, arthralgias, dysmenorrhea, but NOT visceral pain!!!

Question 54

Key adverse effects of giving antihistamines (particularly H1 receptor antagonists?)

Answer 54

Sedation; atropine like effects: blurred vision, dry mouth, urinary retention, constipation; poisoning; CNS stimulation at high doses (convulsions), allergy, local anesthetic!!