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IHO Week 5 - WLB > Anti-Inflammatory Drugs - Regal > Flashcards

Anti-Inflammatory Drugs - Regal Flashcards

1
Q

What inflammatory mediators are involved in redness (due to vasodilation)?

A
  • Histamine
  • PGE2
  • PGI2
  • Kinins
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2
Q

What inflammatory mediators are involved in swelling (due to increased vascular permeability)?

A
  • Histamine
  • Peptido leukotrienes (LTC4, LTD4, LTE4)
  • Kinins
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3
Q

What inflammatory mediators are involved in pain (causes pain/reduces pain threshold)?

A
  • PGE
  • PGI
  • LTB4
  • Kinins
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4
Q

What inflammatory mediators are chemotactic (direct migration of white blood cells)?

A
  • LTB4 (neutrophils, etc.)
  • Peptido leukotrienes (eosinophils)
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5
Q

What inflammatory mediators are involved in fever?

A

PGEs induce fever

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6
Q

What inflammatory mediators are involved in airway constriction/bronchoconstriction?

A
  • Histamine
  • Peptido leukotrienes
  • Kinins
  • PGD2
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7
Q

What inflammatory mediators are involved in hypotension/decreased blood pressure (relevant in shock)?

A
  • Kinins
  • Histamine
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8
Q

What is the pathway for synthesis of Histamine?

A
  • Histidine → Histamine
    • via L-histidine decarboxylase
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9
Q

What is the primary site of Histamine synthesis?

A
  • Mast cells
  • Basophils
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10
Q

How is histamine inactivated/degraded? Where?

A
  • Histamine → N-methylhistamine
    • via N-methyltransferase
  • Histamine → Imidazoleacetic acid
    • via Diamine Oxidase
  • Where
    • Enzymes for metabolism are widely distributed
      • small intestinal mucosa
      • skin
      • kidney
      • liver
      • thymus
      • WBCs
      • etc.
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11
Q

What are the important biological activities of Histamine as they relate to inflammation?

A
  • Itching/pain
    • due to stimulation of nerve endings
  • Localized redness
    • due to arteriolar dilation
  • Localized edema
    • due to increased capillary permeability with leakage of the postcapillary venules
  • Airway constriction/bronchoconstriction
    • stimulates mucous secretion
    • vasodilation & edema
  • Flare (diffuse redness around/beyond the original redness)
    • nerves dilating neighboring arterioles
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12
Q

What is the result of H1 receptor stimulation by Histamine?

A
  • H1
    • ​bronchoconstriction
    • contraction of GI smooth muscle
    • increased capillary permeability (wheal)
    • pruritis (itch) and pain
    • release of catecholamines from the adrenal medulla
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13
Q

What is the result of H2 receptor stimulation by histamine?

A
  • Gastric acid secretion
  • Inhibition of IgE-mediated basophil histamine release
    • histamine release by antigen feeds back to turn off its own release
  • Inhibition of T lymphocyte mediated cytotoxicity
  • Suppression of Th2 cells and cytokines
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14
Q

Where are H3 and H4 receptors? What effect does histamine have on these?

A
  • Histaminergic nerve terminals (H3)
  • Many immune cells (H4)
    • eosinophils
    • dendritic cell
    • T cells
    • neutrophils
  • Histamine can regulate the activity of all of these cells through stimulating the receptor(s).
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15
Q

What is the general MOA of classical first generation antihistamines?

A
  • Block:
    • H1 receptors (inverse agonists)
    • muscarinic receptors
    • alpha adrenergic
    • serotonin receptors
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16
Q

What are the generic names of the two “Old” H1 Antihistamines that we need to know?

A
  • Diphenhydramine (OTC)
  • Chlorpheniramine (OTC)
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17
Q

What is the distribution of “Old” H1 Antihistamines?

A
  • Well absorbed orally
  • Widely distributed
    • including CNS
  • Not recognized by the P-glycoprotein efflux pump on the endothelial cells in the vasculature of the CNS
    • i.e. they are not pumped out of the CNS
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18
Q

How are the “Old” H1 Antihistamines eliminated?

A
  • Transformed to inactive metabolites in the liver
  • Excreted in the urine
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19
Q

What are the major toxicities of “Old” H1-Antihistamines?

A
  • Sedation
  • Drying of secretions (due to anticholinergic properties)
  • GI disturbances
  • Acute poisoning - treatment is symptomatic & supportive
    • resembles atropine poisoning (fixed-dilated pupils, flushing, fever, dry mouth)
    • Dominant effect: excitation, hallucinations, incoordination, convulsions
    • Terminally: coma & cardiorespiratory collapse
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20
Q

What are the difference between the two “Old” H1 Antihistamines that we need to know?

A
  • Diphenhydramine (OTC)
    • low incidence of GI side effects
    • sedative
  • Chlorpheniramine (OTC)
    • most suitable for daytime use
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21
Q

What is the general MOA of “Newer” Non-Sedating Antihistamines?

A
  • Inverse agonist of H1 receptor
    • appear as competitive inhibitors of the actions of histamine
  • Minimal/No anticholinergic properties
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22
Q

What are the generic names of the three “Newer” Non-sedating H1 Antihistamines that we need to know?

A
  • Cetirizine (OTC)
  • Fexofenadine
  • Loratadine (OTC)
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23
Q

What is the distribution of “Newer” Non-Sedating H1 Antihistamines?

A
  • Widely distributed
  • Penetration into the CNS
    • only small amounts cross the BBB
    • cause less sedation that first gen
      • have affinity for P-glycoprotein efflux pumps in endothelium of vasculatrue in CNS
      • pumped out of CNS
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24
Q

What are the major toxicities of “Newer” Non-Sedating H1 Antihistamines?

A
  • Cardiotoxicity with original non-sedating antihistamines
    • Cardiotoxicity with overdosage for one of the first non-sedating antihistamines led to the development of the newer drugs that are not cardiotoxic
      • Cetirizine
      • Fexofenadine
      • Loratadine
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25
Q

What are the therapeutic uses of H1 Antihistamines?

A
  • Allergy
    • Allergic rhinitis
    • Hay fever - relieve sneezing, rhinorrhea, & itching
    • Urticaria (hives)
    • Atopic dermatitis (poison ivy)
    • NOT for asthma
  • Motion sickness (older antihistamines)
  • Sleep aid
  • Colds?
26
Q

How are Prostanoids (Prostaglandins and Thromboxanes) synthesized?

A
  • Phospholipids in cell membrane broken down by Phospholipase A2
    • Release Arachidonic Acid
  • Arachidonic Acid broken down by Cyclooxygenase (COX)
    • Release Prostanoic acid
  • COX breaks down Prostanoic acid further into:
    • Prostaglandins
    • Thromboxane
    • Prostacyclin
27
Q

How are prostaglandins and thromboxanes degraded?

A
  • Spontaneous chemical hydrolysis OR
  • Rapid enzymatic degradation
  • Uptake into cells by a transport protein
    • subsequent degradation
  • Short half lives to limit their systemic effects
28
Q

What are the important biological activities of prostaglandins and thromboxanes as they relate to inflammation?

A
  • Often have opposing effects, dictated by what receptor is present in particular tissue
  • PGE2 & PGI2
    • vasodilate
    • increase vascular permeability
    • cause pain (sensitize receptors)
  • PGD2 & Thromboxane
    • cause bronchoconstriction
  • TXA2
    • causes platelet aggregation
    • vasoconstriction
  • PGI2
    • opposes platelet aggregation
    • vasodilation
  • PGE
    • fever
      ​
29
Q

Which receptors are activated by Prostaglandins and Thromboxanes in inflammatory response?

A
  • PGD2 → DP
    • Gs → cAMP
    • +/- smooth muscle tone
  • PGF2 → FP
    • ​Gq → IP3/DAG/Ca2+
    • smooth muscle constriction
  • PGI2 → IP
    • ​Gs → cAMP
    • smooth muscle dilation
  • TXA2 → TP
    • Gq → IP3/DAG/Ca2+
    • platelet aggregation
    • smooth muscle constriction
  • PGE2 → EP (four subtypes EP1-EP4)
30
Q

What is the general MOA of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

A
  • inhibit cyclooxygenase
    • stop the conversion of arachidonic acid into prostaglandins/thromboxanes
31
Q

What are the generic names of the 8 NSAIDs that we need to know?

A
  1. Aspirin (acetylsalicylate) (OTC)
  2. Ibuprofen (OTC)
  3. Naproxen (OTC)
  4. Ketorolac
  5. Ketoprofen
  6. Indomethacin
  7. Sulindac
  8. Piroxicam
32
Q

What is the distribution of NSAIDs?

A
  • They are well absorbeell from the stomach and intestinal mucosa.
  • They are highly protein-bound in plasma (typically >95%), usually to albumin, so that their volume of distribution typically approximates to plasma volume.
  • (according to Wiki)
33
Q

How are NSAIDs eliminated?

A

Most NSAIDs are metabolized in the liver by oxidation and conjugation to inactive metabolites that typically are excreted in the urine, though some drugs are partially excreted in bile.

Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage.

34
Q

What are the major toxicities of NSAIDs?

A
  • Gastric or intestinal ulceration
    • due to inhibition of PG synthesis
    • alcohol will increase GI bleeding produced by salicylates
  • Prolongation of gestation
    • PGs are thought to play a role in initiating labor
  • Increased bleeding time (not TX in platelets)
  • Abnormal hepatic function
  • Renal function
    • analgesic abuse nephropathy
    • large daily doses → reduced tubular function
      • fluid retention, diminished sodium excretion, nitrogen retention, hyperkalemia, oliguria (scanty urine), and anuria (no urine)
35
Q

What are the differences or unique pharmacological properties of Aspirin compared to other NSAIDs?

A
  • irreversibly acetylates COX
    • prevents TX formation (platelet aggregation) in platelets for 8-10 days (lifetime of platelet)
  • associated with Reye syndrome
    • encephalopathy and fatty liver following viral infection in children
  • anti-inflammatory doses are close to toxic doses
36
Q

What are the differences or unique pharmacological properties of Ibuprofen compared to other NSAIDs?

A

fewer GI side effects than aspirin

37
Q

What are the differences or unique pharmacological properties of Ketorolac compared to other NSAIDs?

A

promoted primarily for analgesia but is also anti-inflammatory

38
Q

What are the differences or unique pharmacological properties of Indomethacin compared to other NSAIDs?

A
  • most potent NSAID
  • can cause:
    • severe frontal headache
    • blood disorders
39
Q

What are the differences or unique pharmacological properties of Piroxicam compared to other NSAIDs?

A

once a day administration

can cause dose-related serious GI bleeding

40
Q

What are the differences or unique pharmacological properties of Celecoxib (Celebrex) compared to other NSAIDs?

A
  • selectively inhibits COX-2
  • less likely to cause:
    • gastric ulceration and intolerance
    • inhibition of platelet function
    • aspirin hypersensitivity
  • Increase risk of thrombotic cardiovascular events
    • due to reduced prostacyclin, which inhibits platelet aggregation
41
Q

What are the differences or unique pharmacological properties of Acetaminophen compared to other NSAIDs?

A

NOT AN NSAID!

  • Analgesic, antipyretic, but NOT anti-inflammatory
  • weak inhibitor of cyclooxygenase in the brain, but not at sites of activity
  • Overdose can cause serious hepatic injury
42
Q

How are leukotrienes synthesized?

A
  • FLAP (5-lipoxygenase activating protein) activates 5-lipoxygenase
  • Arachidonic Acid → 5-HPETE
    • via 5-lipoxygenase
  • 5-HPETE → Leukotriene A4
    • via 5-lipoxygenase
  • LTA4 → LTB4
    • via LTA Hydrolase
  • LTA4 → LTC4
    • via LTC4 synthase (mast cell/basophil)
    • OR via Glutathione S transferase (endothelial cell, smooth muscle cell, etc.)
43
Q

Where are leukotrienes predominantly generated?

A

Leukocytes

  • cell types of myelomonocytic origin:
    • PMNs primarily make LTB4
    • Mast cells & basophils primarily make peptido-leukotrienes (LTC4, LTD4, LTE4)
  • Some cells which lack 5-lipoxygenase (endothelial cells & platelets) can also generate leukotrienes by transcellular metabolism.
44
Q

How are leukotrienes degraded?

A
  • LTA4 has a short half life
  • LTB4 is oxidized by enzymes in PMN’s and other oxidative enzymes to inactive compounds
  • LTE4 is excreted in the urine or acetylated and excreted in the bile
45
Q

What are the important biological activities of leukotrienes as they relate to inflammation?

A
  • LTB4
    • chemotactic (white cells/PMNs)
    • reduces pain threshold
  • LTC4, LTD4, LTE4
    • bronchoconstriction
    • increased vascular permeability
    • chemotactic (eosinophils)
46
Q

What receptors are activated by leukotrienes during inflammatory response?

A
  • LTB4 → LTB4 receptor
    • chemotaxis of white cells
  • LTC4, LTD4, LTE4 →
    • Cys LTR1 receptor
      • bronchoconstriction
      • eosinophil chemotaxis and cytokine secretion
      • increased vascular permeability
      • increased mucous production
    • Cys LTR2 receptor
      • endothelial cell and macrophage activation
      • fibrosis
47
Q

What is the MOA of Zileuton?

A
  • inhibits the enzyme 5-lipoxygenase
    • prevents the synthesis of LTB4 as well as the peptide-leukotrienes (LTC4, LTD4, LTE4)
48
Q

What is the MOA of Zafirlukast and Montelukast?

A
  • leukotriene receptor antagonists of:
    • LTD4 receptor
    • Cys LTR1
49
Q

What are Leukotriene Inhibitors/Leukotriene Modifiers used for?

A
  • Treatment of bronchial asthma
    • used for chronic asthma
    • not recommended for treatment of acute asthma (the immediate bronchoconstriction)
  • May be useful in other anti-inflammatory disorders
    • inflammatory bowel disease
  • New uses emerging
50
Q

How is Zileuton eliminated?

A
  • metabolized by cytochrome p450
    • may cause drug interactions
  • requires monitoring for hepatic toxicity
51
Q

What are the differences or unique pharmacological properties of Zileuton compared to other Leukotriene Inhibitors?

A
  • may decrease the need for the use of beta-agonists in asthma
  • modestly effective for the maintenance treatment of chronic asthma
52
Q

What are the differences or unique pharmacological properties of Zafirlukast compared to other Leukotriene Inhibitors?

A
  • inhibits a cytochrome p450 isoenzyme
  • may cause significant drug interactions
53
Q

What are the differences or unique pharmacological properties of Montelukast compared to other Leukotriene Inhibitors?

A
  • Prescribed more because of once daily administration without restrictions with regard to meals
54
Q

Where are Kinins synthesized?

A

Extracellular in blood or interstitial fluid

(not in cells)

55
Q

What is the pathway of kinin synthesis?

A
  • Prekallikrein → Plasma kallikrein
    • via HFa Plasmin
      • HFa = activated Hageman factor (part of clotting cascade)
      • Plasmin = enzyme that digests fibrin
  • HMW kininogen →​ Bradykinin
    • via Plasma kallikrein
    • or via Tissue Kallikrein
  • LMW kininogen → Kallidin
    • via Tissue kallikrein
  • Kallidin → Bradykinin
    • via Kininase I & II
56
Q

How are the kinins degraded?

A
  • Kininase I
    • Carboxypeptidase N or anaphylatoxin inactivator removes the carboxy terminal
  • Kininase II
    • Angiotensin converting enzyme (ACE) or Dipeptide hydrolase
57
Q

What are important biological activities of Kinins as they relate to inflammation?

A
  • Strong vasodilator (results in hypotension)
  • Redness
  • Swelling
  • Heat
  • Pain
58
Q

Which receptor does Kallidin and Bradykinin activate to result in hypotension, increased capillary permeability, edema formation, pain/stimulation of nerve endings, contraction of gut smooth muscle, contraction of airway smooth muscle, release of catecholamines from the adrenal medulla, and release of prostaglandins?

A

B2 receptor

(more active without the terminal arginine - des-arg kinins)

59
Q

Which receptor does Kallidin and Bradykinin activate/induce after trauma to result in chronic inflammatory effects, hypotension, pain, cytokine production, and more long term effects?

A

B1 receptor

(more active without the terminal arg - des-arg kinins)

60
Q

What is the relevance of Kinin inhibitors?

A
  • To be determined
  • Kinin receptor antagonists are useful in C1 inhibitor deficiency and show promise for use in pain
    • C1INH is the primary inhibitor of kallikrein
  • Various other pathological conditions have been associated with excess kinin formation
    • pain in dental extractions
    • nasal allergy/rhinitis associated with rhinoviral infection

IHO Week 5 - WLB (6 decks)

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