Module E

Question 1

List 4 important classes of autocoids

Answer 1

Histamine, serotonin, prostaglandins, leukotrienes

Question 2

Compare and contrast the locations and functions of H1, H2, and H3 receptors

Answer 2

H1: Found throughout the body (CNS, skin, airways). Activation causes alertness (hence drowsiness with antihistamines). Peripheral activation causes hives/rashes, erythema, pruritis, edema, cough, and bronchoconstriction

H2: Found in glandular and smooth muscle tissue of GIT, uterus, and vasculature. Activation causes gastric acid release and smooth muscle relaxation

H3: Autoregulatory inhibitory histamine receptor found throughout the nervous system

Question 3

Antihistamines ______ (are / are not) effective once an allergic reaction is underway.

Answer 3

are not!

they should be used prophylactically to reduce frequency, severity, and duration of allergic reactions

Question 4

The major difference between first and second generation antihistamines is:

Answer 4

first generation antihistamines cross the blood-brain barrier and cause sedation/hypnosis, second generation antihistamines do not

Question 5

The major clinical use of H2 receptor antagonists is:

Answer 5

reduce gastric acid production in GERD (ex: Zantac (ranitidine))

Question 6

Benadryl (Diphenhydramine)

Answer 6

• First-generation antihistamine, H1 receptor antagonist
• Blocks H1 receptors systemically, including the CNS
• Used to manage symptoms of allergy, but may cause unwanted sedation/hypnosis

Question 7

Allegra (Fexofenadine)

Answer 7

• Second-generation antihistamine, H1 receptor antagonist
• Blocks peripheral H1 receptors, does not closs blood-brain barrier
• Alleviates allergy symptoms without causing significant sedation/hypnosis

Question 8

Claritin (Loratadine)

Answer 8

• Second-generation antihistamine, H1 receptor antagonist
• Blocks peripheral H1 receptors, does not closs blood-brain barrier
• Alleviates allergy symptoms without causing significant sedation/hypnosis

Question 9

Zantac (Ranitidine)

Answer 9

• H2-receptor antagonist
• reduces gastric acid secretion to reduce dyspepsia/gastroenteritis in GERD

Question 10

Tagamet (Cimetidine)

Answer 10

• H2-receptor antagonist
• reduces gastric acid secretion to reduce dyspepsia/gastroenteritis in GERD

Question 11

3 important endogenous sources of serontonin (5-HT) are:

Answer 11

platelets, neurons, GI cells

Question 12

Describe the PNS effects of serotonin

Answer 12

• Platelet aggregation
• Vasoconstriction
• Bronchoconstriction

Question 13

Describe the biosynthesis of eicosanoids, list the three main classes, and generally describe their effects

Answer 13

Arachidonic acid is cleaved from membrane phospholipids by phospholipase A2 (ex: following injury). This then follows one of two pathways; cyclooxygenase (COX) initiates a metabolic pathway leading to production of prostaglandins and thromboxanes. 5-Lipoxygenase initiates a pathway leading to production of the Leukotrienes. These local hormones have varied and often opposing effects (ex: vasoconstriction and vasodilation)

Question 14

Group the prostaglandins/thromboxanes by vaso/bronchodilating vs. contricting effects

Answer 14

PG_F, PG_D, and TXA₂ all cause bronchoconstriction and vasoconstriction

PG_E and PG_I (prostacyclin) cause bronchodilation and vasodilation

also note that TXA₂ causes platelet aggregation, while prostacyclin (PG_I) inhibits it

Question 15

Leukotrienes produce _______ (opposite / similar / greater) effects compared to histamine

Answer 15

similar and greater!

leukotrienes are responsible for the late phase reaction in anaphylaxis

Question 16

Briefly describe the effects of PGE and PGE analogues and how they are used therapeutically

Answer 16

• cause vasodilation, bronchodilation, and smooth muscle contraction in the uterus
• used to treat PAH and ED, maintain a patent ductus arteriosus, and induce labour.

Question 17

Briefly outline causes and treatments of PAH

Answer 17

• could be due to NO or PGI deficiency, or overabundance of endothelin-1 (ET1)
• non-specific treatments include oxygen, diuretics, cardiac glycosides
• specific therapies include CCBs, PGI (epoprostenol), NO donors, ET1 receptor antagonists, etc.

Question 18

Contrast the roles of COX-1 and COX-2 in the body

Answer 18

COX-1 is a “housekeeping” enzyme, it is continuously expressed in gastric tissues and promotes mucus production with inhibited gastric acid secretions

COX-2 is an “inducible” enzyme, it is up-regulated in most tissues as a result of tissue injury causing prostaglandin/TXA2 production and inflammation

Question 19

Describe the role of eicosanoids in inflammation

Answer 19

eicosanoids are produced by the COX and 5-lipoxygenase pathways in response to tissue injury. They cause vasodilation, platelet aggregation, chemotaxis, heat production, and increased sensitization of pain receptors

Question 20

Aspirin (ASA)

Answer 20

• NSAID, non-specific COX inhibitor
• causes irreversible inhibition of platelet COX enzymes. Reduces PG and TXA2 production in a dose-dependent fashion
• used for anti-inflammation, anti-inflammatory, analgesic, and anti-platelet effects
• Has an anti-platlet effect which is longer-acting than analgesia
• Increased risk of GI bleeding, ulcers, can cause tinnitus, respiratory alkalosis, and asthma
• may potentiate Reye’s syndrome in children with viral infection

Question 21

Contrast the antiplatelet and antiinflammatory actions of aspirin

Answer 21

antiplatelet action is provided by irreversible addition of an acetyl group to the active site of COX (the acetyl from ASA)

The remaining salicylate moiety acts as a competitive COX inhibitor providing the inti-inflammatory effects.

Question 22

Motrin/Advil (Ibuprofen)

Answer 22

• NSAID, non-selective COX inhibitor
• competitively inhibits COX enzymes, reducing PG and TXA2 synthesis in inflammation
• used to reduce pain, inflammation
• May cause GI, hepatic, and renal side effects due to COX-1 inhibition
• does not produce the anti-platelet effects of ASA

Question 23

Celebrex (Celecoxib)

Answer 23

• NSAID, selectie COX-2 inhibitor
• Reduces PG production associated with inflammation without causing gastric irritation
• used in management of pain and inflammation
• increased risk of cardiovascular events (MI, CVA)

Question 24

Tylenol (Acetaminophen)

Answer 24

• Not strictly an NSAID; non-opioid analgesic/antipyretic
• MOA not udnerstood, but may involve COX-3. Does not affect COX-1 or COX-2
• reduces pain and fever associated with inflammation
• No associated GI effects or Reye’s syndrome
• causes hepatic toxicity in overdose that rapidly escalates with higher doses as toxic metabolites accumulate

Question 25

Compare and contrast non-selective NSAIDs, coxibs, and acetominophen

Answer 25

* Ibuprofen/naproxen: effective anti-inflammatories and analgesics. No anti-platelet effect. cause GI/renal side effects * ASA: effective anti-inflammatory and analgesic with anti-platelet effect. Causes GI side effects and increases risks of bleeding. * Coxibs: COX-2 selective. Highly effective anti-inflammatories and analgesics without GI side effects. Increased risk of adverse CV events * Acetominophen: not an NSAID, MOA unknown. Analgesic and antipyretic. No GI side effects, hepatotoxic in overdose.

Question 26

Describe how exogenous corticosteroids affect the HPA axis

Answer 26

hypothalamus recognizes exogenous CS drugs as endogenous and down-regulates CRH production. This leads to decreased ACTH expression and decreased activation of the adrenals. Prolonged use may lead to adrenal hypoplasia

Question 27

Describe the circadian rhythm of corticosteroids

Answer 27

Corticosteroids are usually produced mainly during sleep and are at a maximum level in the morning after waking. They gradually decline in concentration during the day, reaching a minmum concentration at midnight.

Question 28

Describe the effects of corticosteroids on glucose metabolism

Answer 28

CS drugs increase circulating glucose by inhibiting insulin, promoting glycogenolysis (in muscles), and promoting gluconeogensis. Gluconeogenesis is promoted by increased muscle wasting, freeing amino acids for glucose production.

Question 29

Corticosteroids bind to __________ (intracellular / extracellular) receptors

Answer 29

intacellular ## Footnote *glucocorticoids are hydrophobic and cross the plasma membrane freely. They are transported in blood by binding to albumins and globulins.*

Question 30

The two major clinical uses of corticosteroids are:

Answer 30

anti-inflammation, treatment of adrenal insufficiency (esp. Addisonian crisis)

Question 31

If available, the preferred routes of corticosteroid administration for inflammation are:

Answer 31

topical, inhalational

Question 32

Give an example of a short-acting, intermediate-acting, and long-acting corticosteroid

Answer 32

* Short: Hydrocortisone, cortisone (8-12 hrs.) * Intermediate: Prednisone (12-36 hrs.) * Long: Dexamethasone, Betamethasone (24-72 hrs.)

Question 33

Describe the anti-inflammatory effects of corticosteroids

Answer 33

* broadly inhbiit eicosanoid (PG, TXA, LT) production by producing inhibitory proteins for phospholipase A₂. This inhibits release of arachidonic acid. * Inhibit production of pro-inflammatory cytokines, reducing eosinophil recruitment and chemotaxis * Decrease production and recruitment of inflammatory cells like macrophages, T-lymphocytes, neutrophils, eosinophils, mast cells * Decreases histamine synthesis and release by stabilizing mast cell membranes * cause constriction of microvasculature

Question 34

If a prolonged regimen of corticosteroids is required, why must the dose be slowly tapered off at the end of treatment?

Answer 34

CS drugs disrupt the HPA axis and decrease endogenous CRH, ACTH, and CS production. Dose must be reduced slowly to restore equilibrium and prevent adrenal insufficiency (addisonian) crisis

Question 35

Describe how alternate-day therapy for CS drugs is used

Answer 35

for prolonged regimens of high-dose or high-potency CS drugs, they may be given on alternating days to limit disruption of the HPA axis while still producing their therapeutic effect. This limits the possibility of iatrogenic adrenal insufficiency

Question 36

Describe metabolic adverse effects of prolonged corticosteroid administration

Answer 36

* Through various effects may cause hyperglycemia (steroid diabetes) * causes peripheral muscle wasting and increased central fat deposition; face, back of neck, supraclavicular region, leading to a cushingoid appearance.

Question 37

Describe electrolyte and water disturbances associated with long term corticosteroid administration

Answer 37

* Increased sodium and water retention which may lead to hypertension * increased potassium excretion * increased calcium excretion which may lead to osteoporosis

Question 38

Describe adverse effects of CS administration on the CNS, GI, and respiratory systems

Answer 38

* CNS: may cause behavioural disturbances, euphoria, psychosis * GI effects: peptic ulcers * Respiratoy: decreased surfactant production in neonates

Question 39

**Deltasone** (Prednisone)

Answer 39

* Intermediate acting corticosteroid * Causes broad anti-inflammatory effects * Decreases eicosanoid production * Decreases inflammatory cytokine production * Decreases inflammatory cell produciton and recruitment * Reduces histamine production and release * Used to treat cancer, inflammation, allergy, and autoimmune disorders * Prolonged use may disrupt HPA axis and lead to addisonian crisis when withdrawn

Question 40

**Cortef / Solu-Cortef** (Hydrocortisone)

Answer 40

* Short-acting corticosteroid * Causes broad anti-inflammatory effects * Decreases eicosanoid production * Decreases inflammatory cytokine production * Decreases inflammatory cell produciton and recruitment * Reduces histamine production and release * Short-acting CS mainly used in CS-replacement therapy (addison's) or as topical anti-inflammatory * Prolonged use may disrupt HPA axis and lead to addisonian crisis when withdrawn

Question 41

**Decadron** (Dexamethasone)

Answer 41

* Long-acting, high-potency corticosteroid * Causes broad anti-inflammatory effects * Decreases eicosanoid production * Decreases inflammatory cytokine production * Decreases inflammatory cell produciton and recruitment * Reduces histamine production and release * Used in dexamethasone suppression test and in long-term anti-inflammation, anti-immune treatment * Prolonged use may disrupt HPA axis and lead to addisonian crisis when withdrawn

Question 42

Describe the three common biologic pathways involved in the development of PAH

Answer 42

* **Nitric Oxide**: NO-producing enzymes (eNOS) is decreased in PAH patients * **Prostaglandin**: Decreased presence of PGI₂ (prostacyclin) producing enzyme * **Endothelin**: Increased ET₁ (endothelin) production All of these pathways lead to smooth muscle contraction and vasoconstriction in the pulmonary arteries. This may lead to thromboembolism in situ

Question 43

The 5 common treatment modalities of PAH are:

Answer 43

* CCBs * Prostacyclin * Endothelin receptor antagonists * Nitric oxide donors * PDE-5 inhibitors (sildenafil)

Question 44

The preferred route of drug administration when treating PAH is:

Answer 44

inhalational

Question 45

Describe the use of iNO in PAH management

Answer 45

* Given as an inhaled gas (iNO = inhaled NO) * Any NO that diffused into blood is bound to Hb and deactivated (little to no systemic effects) * NO causes pulmonary arterial vasodilation and inhibits platelet aggregation

Question 46

The chemical mediators that are most associated with production of pain, inflammation, and fever are:

Answer 46

The prostaglandins (PG)