Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

MSII Pharmacology > Unit 2 - Drug Therapy of Inflammation > Flashcards

Unit 2 - Drug Therapy of Inflammation Flashcards

1
Q

what are the three distinct phases of the inflammatory response?

A
  1. acute transient phase, characterized by local vasodilation and increased capillary permeability
  2. delayed, subacute phase, most prominently characterized by infiltration of leukocytes and phagocytic cells
  3. chronic proliferative phase, in which tissue degeneration and necrosis occur
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what is histamine? what does it do?

A

autacoid amine made from histidine and stored in mast cells and basophils in many tissues in the body

  • released from storage sites in response to injury and Ag
  • mediator of immediate (type I) allergic reactions
  • acute inflammatory response actions:
  • -locally increases blood flow by capillary dilation
  • -causes edema by increasing post-capillary venule (PCV) permeability
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what are kinins? what do they do?

A

two related peptides (bradykinin and kallidin) formed from plasma globulins (kinnogens) by kallikreins in blood or in tissues at sites of injury, allergic reaction, viral infections, etc.

  • kallikreins released from tissues or activated by clotting factors in plasma
  • kinins have:
  • -acute effects (pain) due to excitation of primary sensory neurons
  • -chronic effects due to capillary dilation, increase in PVC permeability, and activation of arachidonic acid release through stimulation of PLA2 (similar to histamine, except chronic)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what are cytokines? what are the major players?

A

polypeptides that orchestrate inflammatory process and defense mechanisms in general

  • released from lymphoid and non-lymphoid cells, and have multiple actions
  • major players are IL-1, IL-8, TNF, and chemokines
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what is IL-1? where is it made most? what does it do?

A

cytokine made particularly by macrophages

  • induces inflammatory response
  • -increases eicosanoid synthesizing enzymes, collagenase, and adhesion molecule expression
  • regulates B and T cells
  • induces fever due to action on brain (endogenous pyrogen)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is IL-8?

A

powerful chemotactic agents

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what does TNF do?

A

regulates production of other cytokines and induces fibrosis and tissue catabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what are eicosanoids? what do they do?

A

metabolites of arachidonic acid that play central and complex role in inflammation

  • released from phospholipids of cell membrane in response to mechanical or chemical injury or agonists that activate PLA2 or diacylglycerol lipase
  • AA is metabolized by either lipoxygenase (makes leukotrienes) or cyclooxygenase (makes prostagladins, prostacyclins, and thromboxanes)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

describe COX-1

A

cyclooxygenase (makes prostaglandins, prostacyclins, and thromboxanes) produced constitutively in all tissues

  • gastric cytoprotection
  • platelet aggregation
  • renal blood flow autoregulation
  • initiation of parturition
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

describe COX-2

A

induced during inflammation

-produces prostaglandins at the sites of inflammation and/or tissue damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what is the origin of

  • histimine
  • kinins
  • cytokines
  • eicosanoids
A
  1. mast cells, basophils
  2. kinin system (kininogen)
  3. primarily lymphoid cells
  4. lymphoid and non-lymphoid cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what are the general actions of

  • histamine
  • kinins
  • cytokines
  • eicosanoids
A
  1. capillary dilation, increase in venule permeability, sensitization
  2. as above; effects more chronic than histamine
  3. immunoregulation, inflammation, fever, chemotaxis, tissue catabolism, induction of COX-2, etc.
  4. vasodilation, increase venule permeability, sensitization, contraction/relaxation, etc.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what are the primary goals of treating patients with inflammation?

A
  1. relief of pain (presenting symptom and major continuing complaint of the patient)
  2. slowing or (in theory) arrest of tissue damaging process
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is the general mechanism of NSAIDs?

A

inhibit COX enzymes (thus inhibiting synthesis of prostaglandins, prostacyclins, and thromboxanes, but NOT leukotrienes)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

explain the chemistry and pharmacokinetics of aspirin (salicylates)

A
  1. pKa = 3.5; ester of acetic acid that can acetylate proteins, thus irreversibly blocking synthesis of eicosanoids by acetylating COX-1/2
  2. orally administered aspirin is rapidly absorbed by passive diffusion from stomach (non-ionized) and upper SI (ionized) yielded peak plasma level within 1-2 hours
  3. liver is principal site for biotransformation of salicylates by microsomal and mitochondrial enzymes
    - aspirin is first hydrolyzed to salicylic acid and then converted to metabolites that are excreted in urine
    - cannot acetylate COX-1/2, but can still reversibly inhibit
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what are the pharmacological effects of aspirin?

A
  1. antiinflammatory effects
  2. analgesic effects
  3. antipyretic effects
  4. antiplatelet effects
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

how do aspirin anti-inflammatory effects work?

A

inhibit eicosanoid formation and thus vasodilation, PCV permeability, luekocyte chemotaxis, etc.

  • reduces inflammation in joint tissues and surrounding structures
  • much higher dose needed VS analgesia
  • treats symptosm of rheumatic and CT disorders
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

how do aspirin analgesic effects work?

A

inhibition of eicosanoid-induced sentization of pain receptors (indirectly antagonizes effects of histamine, kinins, etc.) and transmission to relay neurons in dorsal horn

  • frequently combined with codeine or other narcotic analgesics to obtain more pain relief
  • alleviates pain such as headache, myalgia, arthralgia, dysmenorrhea
  • not effective in alleviating visceral pain (acute abdomen, renal colic, pericarditis)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

how do aspirin antipyretic effects work?

A

reduces elevated temperature by blocking pyrogen-induced eicosanoid synthesis in vicinity of hypothalamus (PGE2)

20
Q

how do aspirin antiplatelet effects work?

A

increases bleeding time by inhibiting TXA2 synthesis and thus platelet aggregation

  • irreversibly acetylates COX-1/2, and since platelets cannot make new proteins, this inhibition lasts for the life of the platelet (8 days)
  • in lower doses than for analgesic effects good therapy and prophylactic for thrombosis (coronary and cerebral)
21
Q

what are major adverse (non-therapeutic) side effects of aspirin?

A
  1. GI irritation
  2. nephrotoxicity
  3. bleeding and anemia
  4. hepatotoxicity
  5. hypersensitivity reactions
  6. salicylate toxicity
22
Q

how does GI irritation occur from aspirin?

A
  • dyspepsia in 10-20% of patients
  • creation of, or exacerbation of peptic ulcer symptoms including GI hemorrhage (blood loss from ulcers)
  • -mechanism is topical injury and loss of cytoprotective effect of PGE2 and PGI2, and increased bleeding time
23
Q

what is cytoprotection? what does it come from? what loses it?

A

decreased acid secretion, increased mucosal blood flow, increased mucus secretion, due to PGE2 and PGI2
-lost with taking aspirin

24
Q

how does nephrotoxicity occur from aspirin?

A

inhibits synthesis of renal vasodilator eicosanoids, decreases renal blood flow, and may cause renal failure
-particularly a problem in elderly, hypovolemic, or analgesic-abusing patients

25
Q

how does bleeding/anemia occur from aspirin?

A

prolongs bleeding time contributing to GI hemorrhage and is contraindicated during anticoaglant therapy (warfarin) or hemophilia

  • inhibits TXA2 synthesis, thus platelet aggregation
  • also causes gastric ulcers, which cause bleeding
26
Q

how does hepatotoxicity occur from aspirin?

A

often in patients with CT disorders

-may contribute to rare Reye’s syndrome

27
Q

what is Reye’s syndrome

A

rare childhood hepatitis/cerebral edema associated with viral infection, but can be induced with aspirin

28
Q

how does hypersensitivity occur from aspirin?

A

incidence is ~0.2% normally, 10% in asthmatics (aspirin-induced airway toxicity)
-manifested as bronchoconstriction, urticaria, or angioneurotic edema (due to increased leukotrienes)

29
Q

how does salicylate toxicity occur from aspirin?

A

uncoupler of oxidative phosphorylation causes metabolic acidosis and respiratory alkalosis

30
Q

what is difunisal?

A

difluorophenyl derivative of salicylic acid

  • competitive inhibitor of COX-1/2
  • analgesic and weak antipyretic activity
  • longer half-life
  • better tolerated than apsirin b/c fewer GI side effects and less effect on platelets
  • effective in OA, cancer pain with bone metastases, dental pain, post-episiotomy pain
31
Q

what is general information about acetaminophen?

A

para-amino phenol (Tylenol)

  • analgesic and antipyretic effects similar to aspirin, but only weak anti-inflammatory properties or adverse GI effects
  • poor ability to inhibit COX in presence of high [peroxide] (sites of inflammation)
  • COX inhibition is disproportionately pronounced in brain (antipyretic efficacy)
32
Q

explain acetaminophen metabolism?

A

conjugation with sulfate and glucuronide

  • minor pathway involves oxidation of acetaminophen by cytochrome P450 enzymes to form potentially toxic intermediate (N-acetyl-benzoquinoneimine)
  • -when therapeutic dose is taken, NAB is conjugated with glutathione and excreted in urine
33
Q

what is unique about Tylenol?

A

used in more combination products than any other drug

34
Q

what are adverse effects of Tylenol?

A
  1. at ordinary doses, free of any significant ASE (no gastric irritation)
  2. renal tubular necrosis is rare complication associated with chronic abuse
  3. potentially fatal hepatic necrosis may occur from overdose (>10 g) b/c glutathione stores are depleted, so NAB attacks hepatic cell macromolecules, causing hepatic necrosis
    - -acetylcysteine (MUCOMYST) treats this overdose by protecting liver by maintaining/restoring glutathione levels, or by acting as alternate substrate for conjugation with, and thus detox, of reactive metabolite
35
Q

what is indomethacin?

A

indole to treat RA, ankylosing spondylitis, OA, gout

  • 10x more potent than aspirin
  • contraindicated in children, except for closure of ductus arteriosus
  • serious ASE: thrombocytopenia, aplastic anemia, severe frontal headaches in 25-50% of patients (>25% discontinue)
36
Q

what is sulindac?

A

prodrug indole that is half as potent as indomethacin

  • less frequent side effects with long term use
  • no renal toxicity
37
Q

what are propionic acid derivatives and analogs

A
  1. ibuprofen
  2. flurbiprofen - obtains high synovial concentration, and available in topical ophthalmic formulation
  3. naproxen - 20x more potent than aspirin, with long half-life (13 hours) to treat arthritis in 2x/day
  4. oxaprozin - can be given once a day b/c 50 hour half-life
38
Q

what are general facts about propionic acid derivatives/analogs?

A
  1. half short T 1/2 (1-2 hours) except Naproxen (13 hours) and Oxaprozin (50 hours)
  2. symptomatic treatment of rheumatic disorders, OA, ankylosing spondylitis
  3. effective analgesics to releive postpartum pain, dysmenorrheal pain, and oral, ophthalmic, or other types of surgery
  4. usual range of adverse effects
  5. better tolerated than aspirin or indomethacin
39
Q

what is piroxicam?

A

enolic acid recommended for long-term treatment of RA or OA b/c of long half-life (45 hr) allowing single daily dose

  • slow onset faction
  • used in treatment of ankylosing spondylitis, acute musculoskeletal disorders, and acute gout
40
Q

what is ketorolac?

A

heteroaryl acetic acid that is injectable (one of few NSAIDs approved parenteral)

  • T 1/2 = 4-6 hours
  • for postoperative pain (single-dose analgesic efficacy equal or superior to standard opioid agents
  • relatively non-irritating to tissues, so can be used t opically for inflammatory conditions in eye
41
Q

what are “coxibs”? how do they compare to NSAIDs?

A

COX-2 inhibitors (highly selective for COX-2 over COX-1)

  • “better” anti-inflammatory drugs as COX-2 is more associated with inflammation
  • have the same anti-inflammatory, antipyretic, and analgesic benefits as tNSAIDs, but with less GI toxicity
  • -also have no impact on platelet aggregation, thus don’t offer cardioprotective effects of other NSAIDs
42
Q

what is the mechanism of coxibs?

A

hydrophobic sulfonic acid derivatives that block hydrophobic channel to active site of COX-2
-larger molecules than NSAIDs, thus inhibit 2 > 1, as COX-2’s channel is larger (too bulky to access COX-1 channel)

43
Q

what is celecoxib?

A

first drug specifically developed as COX-2 selective inhibitor
-displays 10-20x greater selectivity for COX-2 as compared to COX-1

44
Q

what is etoricoxib?

A

newer inhibitor that displays 100x greater selectivity for COX-2 over COX-1
-available in Europe, still in FDA testing

45
Q

why were newer coxibs pulled from the market?

A

increased risk for stroke, MI, thrombosis

MSII Pharmacology (43 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions