Module E Flashcards
List 4 important classes of autocoids
Histamine, serotonin, prostaglandins, leukotrienes
Compare and contrast the locations and functions of H1, H2, and H3 receptors
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
Antihistamines ______ (are / are not) effective once an allergic reaction is underway.
are not!
they should be used prophylactically to reduce frequency, severity, and duration of allergic reactions
The major difference between first and second generation antihistamines is:
first generation antihistamines cross the blood-brain barrier and cause sedation/hypnosis, second generation antihistamines do not
The major clinical use of H2 receptor antagonists is:
reduce gastric acid production in GERD (ex: Zantac (ranitidine))
Benadryl (Diphenhydramine)
- 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
Allegra (Fexofenadine)
- Second-generation antihistamine, H1 receptor antagonist
- Blocks peripheral H1 receptors, does not closs blood-brain barrier
- Alleviates allergy symptoms without causing significant sedation/hypnosis
Claritin (Loratadine)
- Second-generation antihistamine, H1 receptor antagonist
- Blocks peripheral H1 receptors, does not closs blood-brain barrier
- Alleviates allergy symptoms without causing significant sedation/hypnosis
Zantac (Ranitidine)
- H2-receptor antagonist
- reduces gastric acid secretion to reduce dyspepsia/gastroenteritis in GERD
Tagamet (Cimetidine)
- H2-receptor antagonist
- reduces gastric acid secretion to reduce dyspepsia/gastroenteritis in GERD
3 important endogenous sources of serontonin (5-HT) are:
platelets, neurons, GI cells
Describe the PNS effects of serotonin
- Platelet aggregation
- Vasoconstriction
- Bronchoconstriction
Describe the biosynthesis of eicosanoids, list the three main classes, and generally describe their effects
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)
Group the prostaglandins/thromboxanes by vaso/bronchodilating vs. contricting effects
PGF, PGD, and TXA2 all cause bronchoconstriction and vasoconstriction
PGE and PGI (prostacyclin) cause bronchodilation and vasodilation
also note that TXA2 causes platelet aggregation, while prostacyclin (PGI) inhibits it
Leukotrienes produce _______ (opposite / similar / greater) effects compared to histamine
similar and greater!
leukotrienes are responsible for the late phase reaction in anaphylaxis
Briefly describe the effects of PGE and PGE analogues and how they are used therapeutically
- cause vasodilation, bronchodilation, and smooth muscle contraction in the uterus
- used to treat PAH and ED, maintain a patent ductus arteriosus, and induce labour.
Briefly outline causes and treatments of PAH
- 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.
Contrast the roles of COX-1 and COX-2 in the body
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
Describe the role of eicosanoids in inflammation
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
Aspirin (ASA)
- 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
Contrast the antiplatelet and antiinflammatory actions of aspirin
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.
Motrin/Advil (Ibuprofen)
- 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
Celebrex (Celecoxib)
- 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)
Tylenol (Acetaminophen)
- 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
Compare and contrast non-selective NSAIDs, coxibs, and acetominophen
- 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.
Describe how exogenous corticosteroids affect the HPA axis
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
Describe the circadian rhythm of corticosteroids
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.
Describe the effects of corticosteroids on glucose metabolism
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.
Corticosteroids bind to __________ (intracellular / extracellular) receptors
intacellular
glucocorticoids are hydrophobic and cross the plasma membrane freely. They are transported in blood by binding to albumins and globulins.
The two major clinical uses of corticosteroids are:
anti-inflammation, treatment of adrenal insufficiency (esp. Addisonian crisis)
If available, the preferred routes of corticosteroid administration for inflammation are:
topical, inhalational
Give an example of a short-acting, intermediate-acting, and long-acting corticosteroid
- Short: Hydrocortisone, cortisone (8-12 hrs.)
- Intermediate: Prednisone (12-36 hrs.)
- Long: Dexamethasone, Betamethasone (24-72 hrs.)
Describe the anti-inflammatory effects of corticosteroids
- 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
If a prolonged regimen of corticosteroids is required, why must the dose be slowly tapered off at the end of treatment?
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
Describe how alternate-day therapy for CS drugs is used
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
Describe metabolic adverse effects of prolonged corticosteroid administration
- 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.
Describe electrolyte and water disturbances associated with long term corticosteroid administration
- Increased sodium and water retention which may lead to hypertension
- increased potassium excretion
- increased calcium excretion which may lead to osteoporosis
Describe adverse effects of CS administration on the CNS, GI, and respiratory systems
- CNS: may cause behavioural disturbances, euphoria, psychosis
- GI effects: peptic ulcers
- Respiratoy: decreased surfactant production in neonates
Deltasone (Prednisone)
- 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
Cortef / Solu-Cortef (Hydrocortisone)
- 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
Decadron (Dexamethasone)
- 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
Describe the three common biologic pathways involved in the development of PAH
- 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
The 5 common treatment modalities of PAH are:
- CCBs
- Prostacyclin
- Endothelin receptor antagonists
- Nitric oxide donors
- PDE-5 inhibitors (sildenafil)
The preferred route of drug administration when treating PAH is:
inhalational
Describe the use of iNO in PAH management
- 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
The chemical mediators that are most associated with production of pain, inflammation, and fever are:
The prostaglandins (PG)
