Unit 1 Flashcards
What is the biosynthetic pathways for production of prostaglandins, prostacyclin, thromboxane, and leukotrienes?
Arachidonic acid –> Prostaglandins + Leukotrienes
Enzyme for leukotriene formation: 5-lipoxygenase
Cyclooxygenase (COX-1 and COX-2) –> Prostaglandins + Prostacyclin (PGI2, from endothelial cells) + Thromboxane A2 (TXA2, from platelets)
What is the source of the precursor arachidonic acid and what are the specific enzymes involved?
Cell membrane phospholipids –> arachidonic acid
Enzyme = phospholipase
COX-1: tissue locations, physiologic role, inhibitors?
Tissue locations: GI tract, platelets, kidneys, vascular smooth muscle
Physiologic role:
o GI TRACT: ↓ acid/pepsin secretions, ↑ mucus/bicarb production (cytoprotective effects)
o PLATELETS: Pro-aggregatory effect
o KIDNEYS: ↑ renal blood flow –> promotion of diuresis
Inhibitors: Aspirin, tNSAIDs, glucocorticoids
COX-2: tissue locations, physiologic role, inhibitors?
Tissue locations: Kidneys, endothelial cells, uterine smooth muscle, ductus arteriosus
Physiologic role:
o KIDNEYS: up-regulated –> adaptation to stress via maintenance of renal blood flow
o ENDOTHELIAL CELLS: up-regulated by shear stress
• Vasodilation and anti-aggregatory platelet effect (PGI2) –> decrease platelet aggregation
o UTERINE SMOOTH MUSCLE: contributes to labor contractions near parturition
o DUCTUS ARTERIOSUS: maintenance of PDA via vasodilation
o Tissue damage –> pain, inflammation
o Hypothalamus –> fever
Inhibitors: Aspirin, tNSAIDs, acetaminophen (in CNS!), Celecoxib, glucocorticoids
If you inhibit COX-2, you’ll increase clotting, risk of MI, etc.
What are the effects of prostaglandins on vascular smooth muscle, platelets, GI tract smooth muscle and secretory cells, kidney cells, uterus, and inflammatory cells?
Vascular smooth muscle: prostaglandins vasodilate, TXA vasoconstricts
Platelets: pro-aggregatory effect (COX1) and anti-aggregatory effects (COX2)
GI tract: ↑ mucus/bicarb secretions, ↓ acid/pepsin secretion (cytoprotective); ↑ smooth muscle contractions
Kidney cells: ↑ renal blood flow (COX1), adaption to stress via maintenance of renal blood flow (COX2)
Uterus: ↑ smooth muscle contractions, contributes to labor contractions near parturition
Inflammatory cells: COX2 causes pain & inflammation via vasodilation, leukocyte infiltration
Common side effects:
- GI ulceration, bleeding: COX1 in gastric cells
- Increased bleeding risk: COX1 in platelets
- Renal dysfunction: COX1 and COX2 in kidneys
- Delay labor: COX2 in uterine smooth cells
- Increased thrombotic events: COX2 in endothelial cells
What are the effects of leukotrienes on inflammatory cell function and pulmonary/vascular smooth muscle?
Leukotrienes lead to increased vascular permeability, vasoconstriction, and bronchospasm.
What are the functional interactions of prostacyclin and thromboxane A2 with relation to physiologic effects on vascular smooth muscle and platelets?
Prostacyclin (PGI2) causes vasodilation & inhibits platelet aggregation.
Thromboxane A2 (TXA2) causes vasoconstriction & promotes platelet aggregation.
Soooooo… they’re opposites.
Compare and contrast the effects of aspirin, acetaminophen, NSAIDs, and COX-2 selective inhibitors on the cyclooxygenase enzymes 1 and 2 as the relation to therapeutic uses and adverse reactions.
Therapeutic uses:
- Analgesia: COX-2 at sites of tissue injury
o Intermediate doses (prn)
- Antipyrectic: COX-2 in hypothalamus
o Intermediate doses (prn) - Anti-inflammatory: COX-2 at sites of tissue injury
o High doses - Antithrombotic: COX1 in platelets
o Low doses – daily
Aspirin: irreversible inhibitions of COX-1 and COX-2
tNSAIDs: reversible inhibition of COX-2 and COX-2
Acetaminophen: reversible inhibition of CNS COX-2
Celecoxib: reversible selective inhibition of COX-2
NSAIDs that inhibit COX-2 would result in:
- Therapeutic actions: relief of pain - reduction of fever - reduction of inflammation
- Potential side effects: acute renal failure - thrombotic events (COX-2 selective agents) -
prolonged gestation
NSAIDs that inhibit COX-1 would result in:
- Potential side effects: GI ulceration - prolonged bleeding time - acute renal failure
Describe the mechanism whereby low-dose, but not high-dose, aspirin is able to exert an anti-thrombotic / cardioprotective effect (is COX-1 selective)
Platelets don’t have nuclei, whereas endothelial cells do. If you wipe out COX-1 irreversibly in a platelet, you need to make more platelets to make COX-1 –> make TXA2 –> clotting. If you wipe it out in an endothelial cells, nuclei will just upregulate COX-2.
Acetylsalicylic acid is highest in concentration in portal vein, just prior to being broken down by esterases in liver. In this location, a constant concentration of acetylsalicylic acid (daily low dose) will see ALL platelets, only some EC.
ASPIRIN
Therapeutic uses? Metabolism and excretion? Common side effects at therapeutic doses? Overdose toxicities and their treatment? Contraindications to use? Drug-drug interactions?
Therapeutic uses: analgesic effects (pain of inflammatory origin), antipyretic effects, anti-inflammatory effects, anti-platelet effect
Metabolism and excretion: Acetylsalicylic acid rapidly hydrolyzed to salicylate by esterases in blood. Salicylate then more slowly eliminated by glycine or glucuronide conjugations. Excreted into urine.
Common side effects at therapeutic doses: gastric irritation, bleeding, renal dysfunction, delay onset of labor, Reye’s syndrome
Overdose toxicities and their treatment: hyperventilation and respiratory alkalosis (6-10); fever, dehydration, and metabolic acidosis (10-20 g); shock, coma, resp failure, death. Treatment: Na bicarb, cooling blankets, gastric lavage & charcoal
Contraindications to use: ulcer patients, patients on oral anticoagulants, use caution w/ chronic renal insufficiency (elderly), avoid during pregnancy, avoid in children s syndrome)
ACETAMINOPHEN
Therapeutic uses? Metabolism and excretion? Common side effects at therapeutic doses? Overdose toxicities and their treatment? Contraindications to use? Drug-drug interactions?
Therapeutic uses: mild to mod pain, antipyretic, some use in osteoarthritis. NOT ANTI-INFLAMMATORY
Metabolism and excretion: metabolized to sulfate and glucuronide (phase II conj). Small % metabolized to hepatotoxic metabolite (P2E1) - detoxified by GSH conjugation (phase II)
Common side effects at therapeutic doses: little or no effects on peripheral COX 1-2. Hepatotoxicity major concern!!!
Overdose toxicities and their treatment:
Contraindications to use:
Drug-drug interactions: w/ alcohol :(
TRAD NSAIDS (ibuprofen/naproxen/ketorolac) Therapeutic uses? Metabolism and excretion? Common side effects at therapeutic doses? Overdose toxicities and their treatment? Contraindications to use? Drug-drug interactions?
Therapeutic uses: analgesic (also together with opioids for post-op pain), antipyretic, anti-inflammatory
Common side effects at therapeutic doses: better tolerated; safer in overdose. GI irritation, bleeding transient and reversible. Safety in pregnancy not established.
CELECOXIB
Therapeutic uses? Metabolism and excretion? Common side effects at therapeutic doses? Overdose toxicities and their treatment? Contraindications to use? Drug-drug interactions?
Therapeutic uses: 5-7 fold selectivity for COX-2 over COX-1. Analgesic, antipyretic, and anti-inflammatory effects
Indicated for INFLAMMATORY CONDITIONS: RA, ankylosing spondylitis, acute pain, primary dysmenorrhea
Metabolism and excretion: metabolized by the liver with metabolites eliminated by renal excretion
Common side effects at therapeutic doses: inhibit uterine labor contractions; fewer ulcers than other NSAIDs; renal side effects same as NSAIDs; no prolonged bleeding time
IMPORTANT: increased risk of CV thrombotic events = selectively inhibit anti-aggregatory PGI2 in EC
Overdose toxicities and their treatment:
Contraindications to use: Benefits outweigh risks in pts who cannot use NSAIDs b/c of GI side effects. Risks outweigh benefits in pts with underlying CV disorders*
Drug-drug interactions: possible inhibition of warfarin metabolism –> increased bleeding
Describe the regulation of glucocorticoid secretion by the hypothalamic-pituitary-adrenal gland axis
From hypothalamus, corticotropoid-releasing hormone (CRH) –> causes corticotropoid (ACTH) to be released from anterior pituitary –> causes release of adrenal hormones cortisol [GC] and aldosterone [MC]
Describe the metabolic and mineralocorticoid effects associated with glucocorticoids and explain how these effects can result in serious adverse effects when they are used as pharmacotherapeutic agents
*GC metabolic effects:
CARBOHYDRATES: ↑ gluconeogenesis –> ↑ blood glucose (excess = diabetes-like state)
PROTEINS: ↓ protein synthesis –> ↑ AA to glucose (excess = muscle wasting, CT/skin atrophy)
FAT: ↑ lipolysis (periph) –> ↑ free fatty acids (excess = ↑ lipogenesis centrally via insulin –> obesity)
Excess = iatrogenic Cushing’s Disease
*MC metabolic effects (aldosterone):
↑ Na+ reabsorption at kidney –> ↑ blood volume and BP
(excess = fluid retention, HTN, hypoK, metabolic alkalosis)
[GC side effects]:
adrenal gland suppression
iatrogenic Cushing’s disease
[MC side effects]:
HTN
Hypokalemia
metabolic alkalosis
Explain the rationale for alternate day therapy and tapered withdrawal following chronic therapy with glucocorticoids
Chronic therapy = suppression of adrenal gland & release of ACTH.
If you taper, you give the adrenal glands time to recover.
Also, to prevent the disease from flaring back up
What are the mechanisms of the anti-inflammatory and and immunosuppressive effects of GCs?
(1) Reduced vasodilation; ↓ fluid exudation
(2) overall ↓ in accumulation & activation of inflammatory and immune cells
(3) decrease in infl/imm mediator synthesis
Prednisone
Needs to be activated by liver into prednisolone!
GC:MC 5:1
Dosing considerations of GCs
Most potent: Dexa
Moderately potent: Methylpred, Triam
Least potent: Hydrocortisone
Triamcinolone
Potent, excellent topical activity
No MC action
Dexamethasone
Most potent anti-inflammatory agent
Use: cerebral edema; chemotherapy-induced vomiting
Minimal MC action; greatest suppression of ACTH
Compare and contrast the relative salt-retaining vs anti-inflammatory activities vs ACTH suppression and routes of administration for the drugs below.
Salt-retaining:
Methylpred, Triam, and Dexa are all NOT s-r
Anti-inflammatory:
ACTH suppression:
Routes of administration:
Topical = hydrocortisone, Triam, & Dexa
Oral ONLY = prednisone, Fludro (need to be metabolized by liver)
Methylprednisolone
IV for steroid burst
Minimal MC action
Toxicities (acute vs. chronic vs. withdrawal)
ACUTE
[MC]: salt + water retention, edema, HTN, hypoK
[GC]: glucose intolerance in diabetics; mood changes, insomnia, GI upset
CHRONIC [GC]: Cushing's syndrome (hyperglycemia, protein/muscle loss, lipid deposition/weight gain, diabetes-like state Adrenal suppression --> loss of hormones Mood disturbances --> initial euphoria, then psychic letdown or psychosis (rarely) when dose reduced Impaired wound healing Increased susceptibility to infection Osteoporosis Posterior capsular cataracts Skin atrophy, loss of collagen support Growth retardation in children Peptic ulceration
What is the difference between exertional heat stroke and classic heat stroke?
Exertional heat stroke: hot, dry skin, usually (not always) there is cessation of sweating. Usually lactic acidosis. May lead to rhabdomyolysis (breakdown of skeletal muscle fibers), AKI, disseminated intravascular coagulation (DIC), multi organ failure.
Classic heat stroke - young, elderly, obese in hot humid weather. Hot, dry skin. No lactic acidosis, but respiratory alkalosis. Hypotension, coma. AKI and DIC are very uncommon.
How do you distinguish alcoholic hepatitis morphologically?
In alcoholic hepatitis, we see swollen hepatocytes, death of occasional hepatocytes, an infiltrate of PMNs, and a ropy, eosinophilic material within the cytoplasm of some hepatocytes called “alcoholic hyaline” (representing aggregates of cytokeratin filaments).
How do free radicals arise?
Oxygen therapy
Acute inflammation (PMNs have myeloperoxidases)
Reperfusion (Xanthine oxidase, which is produced from proteolysis during hypoxia)
How does the body get rid of free radicals?
Superoxide dismutase (SOD) gets rid of superoxide (O2-) by converting to hydrogen peroxide
Glutathione peroxidase is a very important enzyme – catalyzes:
o GSH is a reducing agent in the cell that gets rid of radicals
Antioxidants (uric acid, Vitamin E) can eliminate radicals
What type of metaplasia occurs in the esophagus after chronic gastric acid exposure?
Chronic reflux esophagitis leads to replacement of the stratified squamous epithelium along the distal esophagus by a columnar type of intestinal epithelium.
Stratified squamous –> columnar
What type of metaplasia occurs in the lungs after chronic smoke exposure?
Replacement of the pseudostratified columnar epithelium of the bronchus by stratified squamous epithelium
Columnar –> stratified squamous
What are the cell membrane changes that occur during injury?
↓ Na pump
↑ influx of Ca and Na ions & water
↑ efflux of K ions
leads to cellular swelling
Coagulative necrosis
Dead cell remains a ghost-like remnant of its former self – classically seen in an MI
Pyknosis
Nucleus is intensely dark staining and shrunken –> seen in a necrotic (dead) cell
Karyorrhexis
Fragmentation of pyknotic nucleus
Karyolysis
Extensive hydrolysis of the pyknotic nucleus with loss of staining. Represents breakdown of the denatured chromatin.
