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MSK Final > Pharmocology > Flashcards

Pharmocology Flashcards

1
Q

What are the non-selective Cyclooxygenase inhibitors? (7)

A
  • aspirin*
  • sodium salicylate
  • indomethacin
  • ibuprofen*
  • naproxen*
  • phenylbutazon
  • diclofenac
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2
Q

aspirin

A
  • non-selective COX inhibitor (NSAID)
  • irreversibly inhibits via covalent binding (acetylation)
  • effect: decreases synthesis of thromboxanes and PGs
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3
Q

indomethacin

A

Non-selective COX inhibitor (NSAIDs)

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4
Q

ibuprofen

A

Non-selective COX inhibitor (NSAIDs)

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5
Q

naproxen

A

Non-selective COX inhibitor (NSAIDs)

  • trade name: Aleve
  • long half-life (>6 hrs)
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6
Q

Distinguish acetaminophen from the mechanism of NSAIDs.

A

reversibly inhibits cyclooxygenase (mostly in CNS - inactivated peripherally)

  • antipyretic and analgesic, not anti-inflammatory
  • drug of choice for fever/headache in infants
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7
Q

celecoxib

A

AKA celebrex

  • the only COX-2 specific inhibitor that’s still on the market
  • used particularly for rheumatoid arthritis, osteoarthritis, and ulcers
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8
Q

methotrexate

A
  • folic acid analog (dihydrofolate reductase inhibitor)
  • anti-rheumatic
  • immunosuppressant
  • inhibits T and B cell proliferation (arrests cell growth in G1 phase)
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9
Q

leflunomide

A
  • anti-rheumatic
  • immunosuppressant
  • blocks pyrimidine synthesis by inhibiting dihydroorate dehydrogenase (reduces T and B cell proliferation)
  • given as pro-drug (must be metabolized into active form)
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10
Q

etanercept

A
  • anti-rheumatic
  • TNF-alpha blocker
  • often combined w methotrexate
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11
Q

infliximab

A
  • anti-rheumatic
  • TNF-alpha blocker
  • often combined w methotrexate
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12
Q

anakinra

A
  • anti-rheumatic

- inhibits IL-1 (IL-1 Ra analogue)

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13
Q

What are the two fates of the arachidonic acid pathway, and what are each of their committed enzymes?

A
  1. Leukotrienes; formation is catalyzed by 5-lipoxygenase

2. Thromboxane A2, prostacyclin, prostaglandins (committed step catalyzed by cyclooxygenase 1 and 2)`

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14
Q

Generally, what are the targets of corticosteroids vs NSAIDs?

A
  • corticosteroids inhibit phospholipase A2 (which catalyzes the formation of arachidonic acid from membrane phospholipids)
  • NSAIDs inhibit cyclooxygenase 1 and 2 (which catalyze the formation of thromboxane A2, prostacyclin, and prostaglandins from arachidonic acid)
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15
Q

Contrast the functions of cyclooxygenase 1 and 2.

A

COX-1: protective/ maintenance function throughout the body; generates low PG levels

  • gastric mucosa
  • platelet aggregation
  • uterine contraction

COX-2: expression has to be induced by inflammatory mediators; expressed in kidneys and brain; generates high PG levels;

  • local inflammation
  • wound healing
  • resistance to infection
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16
Q

Generally, what is the purpose of both cyclooxygenases?

A

They convert arachidonic acid to various prostanoids in different tissues

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17
Q

Which NSAIDs have a short half-life vs a long one?

A

Short (6 hrs): naproxen, salicylate, phenylbutazone

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18
Q

Which NSAIDs are COX-2 specific, and what is the main toxicity concern? (2)

A

Celecoxib (Celebrex, only one still on the market)* and Rofecoxib (Vioxx)

  • increased risk of thrombosis
  • other COX2 inhibitors pulled for cardiovascular effects
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19
Q

What is the only drug that irreversibly inhibits cyclooxygenases?

A

aspirin

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20
Q

What are the toxicity concerns associated with NSAIDs? (3)

A
  • interstitial nephritis
  • gastric ulcer (PGs protect gastric mucosa)
  • renal ischemia (PGs vasodilate afferent arteriole)
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21
Q

What interaction is problematic with acetominophen and why?

A

Mixture with ethanol causes increased production of NAPQI (hepatotoxin metabolite) via CYP2E1

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22
Q

Which drug is most appropriate for treating fever/headache and why?

A

Acetominophen, particularly in young children. Aspirin can cause Reye’s syndrome

23
Q

What are the long-term benefits of daily, low-dosage (80mg/day) intake of aspirin, and explain the mechanism.

A
  • cardiovascular benefits: reduction of clotting and myocardial infarction
  • reduced incidence of cancer (colorectal and others)
  • mech: reduced platelet aggregation (bc of inhibited COX-1) and uninhibited vasodilation (doesn’t inhibit COX-2 as much as the COX-2 specific inhibitors or other nonspecific)
24
Q

Why do COX-2 selective inhibitors cause cardiovascular problems? (Explain mech.)

A
  • doesn’t inhibit COX-1 –> platelet aggregation (plaques)

- inhibits COX-2 –> no vasodilation

25
Q

Distinguish the two faces of treating arthritis, and which class of drugs are used for each.

A

Relief of symptoms: anti-inflammatory (aspirin, NSAIDs, COX-2 selective inhibitors)

Disease modifying anti-rheumatic drugs: “biologic agents” including immunosuppressant agents (particularly methotrexate), TNF-alpha blockers, IL-1 receptor agonist, IL-6 monoclonal antibody, and immune modulators

26
Q

What class of drugs do lefunomide and methotrexate belong to, and what are they used to treat? Distinguish their particular targets.

A
  • immunosuppressant agents
  • used to treat rheumatoid arthritis (disease modifying)
  • methotrexate: inhibits dihydrofolate reductase (is a folic acid analog)
  • leflunomide: inhibits dihydroorate dehydrogenase (in pyrimidide synthesis pathway); reduces lymphocyte proliferation
27
Q

What class of drugs do etanercept and infliximab belong to, and what are they used to treat?

A
  • TNF-alpha blockers
  • used to treat rheumatoid arthritis (disease modifying)
  • toxicity: cause increased incidence of infections and tumors
28
Q

What class of drugs does anakinra belong to, and what are they used to treat?

A

IL-1 Receptor antagonist (IL-1 RA analog)

- used to treat rheumatoid arthritis (disease modifying)

29
Q

The ratio of what signalling molecules determines the rate of bone secretion/resorption, and what cell produces them?

A

RANKL and OPG, both produced by osteoblasts.

The RANK receptor is made and expressed by osteoclasts.

30
Q

What happens to bone maintenance with age?

A
  • Rate of turnover increases
  • osteoblasts decrease in number and activity (unbalanced resorptive); leads to normal, progressive degeneration of bone (osteoporosis is even more extreme)
31
Q

How is osteoporosis defined clinically?

A

A BMD more than 2.5 standard deviations below the normal age reference.

32
Q

Summarize the benefits of estrogen on bone density

A
  • stimulates osteoclast apoptosis
  • suppresses osteoblast and osteocyte apoptosis
  • reduces pro-resporptive cytokines
33
Q

What are the precursors of osteoblasts and osteoclasts?

A
  • osteoblasts come from mesenchymal stem cells

- osteoclasts come from hematopoietic stem cells

34
Q

What is the mechanism of bisphosphonates and what is used to treat?

A
  • binds to bone matrix and inhibits osteoclasts
  • increases BMD
  • used for osteoporosis (even prevention), Paget’s, metastatic bone disease
35
Q

Alendronate is a member of what class of drugs, and what is it used to treat?

A
  • bisphosphonates

- used for osteoporosis (even prevention), Paget’s, metastatic bone disease

36
Q

Why don’t we give estrogen to treat osteoporosis?

A

It has an increased risk of breast cancer

37
Q

What is the mechanism of SERMs

A

= Selective Estrogen Receptor Modulators

  • act as an agonist for estrogen receptors in most tissues (including bone), but an antagonist for receptors in breast tissue (no increased risk of breast cancer)
  • difference is by differential recruitment of the co-repressors or co-activators available in different tissues
38
Q

Raloxifene belongs to what class of drugs? Used to treat what?

A
  • SERMs
  • osteoporosis (reduces risk of vertebral fracture)
  • reduces postmenopausal bone resorption
  • reduces the recurrence of breast cancer
39
Q

What is denosumab and what pathway does it effect?

A

Monoclonal antibody to RANKL

- binds RANKL and prevents it from binding to RANK

40
Q

What are the 3 hormones that affect plasma Ca2+? What are their end effects?

A
  • PTH: increase serum Ca2+
  • Calcitonin decreases serum Ca2+
  • Vitamin D increases serum Ca2+
41
Q

Terapatide is a derivative of what hormone, and to what class does it belong?

A
  • PTH
  • anabolic drugs
  • stimulates osteoblasts and increases BMD (reduces risk of spinal fracture)
  • can only be given for two years bc of perceived risk of osteosarcoma
42
Q

Generally, what do bone morphogenic proteins do?

A

Alter bone remodelling

43
Q

What is the mechanism of parathyroid hormone?

A
  • affects both osteoblasts and osteoclasts
  • at low concentrations, stimulates bone growth
  • at high concentrations, increases serum Ca2+ by stimulating osteoclasts
  • increases renal tubular resorption of Ca2+
  • stimulates 1-alpha-hydroxylase in kidney to increase synthesis of activated Vit D (absorbs more Ca2+ from GI tract)
44
Q

What is the mechanism of Vitamin D?

A
  • stimulates synthesis of Ca2+-binding transport protein in mucosal cells of gut
  • increases reporption of Ca2+ from bone
45
Q

What is the mechanism of calcitonin?

A
  • produced by the C cells of thyroid

- inhibits osteoclast activity and decreases Ca2+ resorption in kidney

46
Q

What is the standard treatment for Paget’s?

A
  • Calcitonin injections

- OR active bisphonates (alendronate)

47
Q

Alendronate, risedronate, ibandronate, and zoledronic acid all belong to what class of drugs?

A

bisphosphonates

48
Q

How do non-depolarizing neuromuscular junction blockers act, in general?

A

competitive Nicotinic Acetyl Choline Receptor antagonist

  • cause weakness followed by flaccid paralysis
  • surmountable with AChE inhibitors or increasing ACh concentrations
49
Q

How do depolarizing neuromuscular junction blockers act, in general?

A

Nicotinic Acetyl Choline receptor agonist

  • activate, open and desensitize the nAChRm
  • resistant to AchE
50
Q

What are the clinical uses of neuromuscular blocking drugs?

A
  • surgical relaxation (they are selective for motor nicotinic receptors; don’t affect autonomic)
  • orthopedic procedures
  • intubation
  • control of ventilation
51
Q

What is the prototypical non-depolarizing neuromuscular blocker?

A

d-tubocurarine (it’s long-acting)

52
Q

What is the prototypical depolarizing neuromuscular blocker?

A

Succinylcholine (very short acting)

53
Q

Contrast how depolarizing and non-depolarizing neuromuscular blockers are affected by AcetylCholinesterases.

A
  • non-depolarizing: effect can be surmounted with enough AChE
  • polarizing: resistant to AChE

MSK Final (15 decks)

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