Pharmocology Flashcards
1
Q
What are the non-selective Cyclooxygenase inhibitors? (7)
A
- aspirin*
- sodium salicylate
- indomethacin
- ibuprofen*
- naproxen*
- phenylbutazon
- diclofenac
2
Q
aspirin
A
- non-selective COX inhibitor (NSAID)
- irreversibly inhibits via covalent binding (acetylation)
- effect: decreases synthesis of thromboxanes and PGs
3
Q
indomethacin
A
Non-selective COX inhibitor (NSAIDs)
4
Q
ibuprofen
A
Non-selective COX inhibitor (NSAIDs)
5
Q
naproxen
A
Non-selective COX inhibitor (NSAIDs)
- trade name: Aleve
- long half-life (>6 hrs)
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
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
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)
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)
10
Q
etanercept
A
- anti-rheumatic
- TNF-alpha blocker
- often combined w methotrexate
11
Q
infliximab
A
- anti-rheumatic
- TNF-alpha blocker
- often combined w methotrexate
12
Q
anakinra
A
- anti-rheumatic
- inhibits IL-1 (IL-1 Ra analogue)
13
Q
What are the two fates of the arachidonic acid pathway, and what are each of their committed enzymes?
A
- Leukotrienes; formation is catalyzed by 5-lipoxygenase
2. Thromboxane A2, prostacyclin, prostaglandins (committed step catalyzed by cyclooxygenase 1 and 2)`
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)
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
16
Q
Generally, what is the purpose of both cyclooxygenases?
A
They convert arachidonic acid to various prostanoids in different tissues
17
Q
Which NSAIDs have a short half-life vs a long one?
A
Short (6 hrs): naproxen, salicylate, phenylbutazone
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
19
Q
What is the only drug that irreversibly inhibits cyclooxygenases?
A
aspirin
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)
21
Q
What interaction is problematic with acetominophen and why?
A
Mixture with ethanol causes increased production of NAPQI (hepatotoxin metabolite) via CYP2E1
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
Distinguish the two faces of treating arthritis, and which class of drugs are used for each.
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
What class of drugs do lefunomide and methotrexate belong to, and what are they used to treat? Distinguish their particular targets.
- 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
What class of drugs do etanercept and infliximab belong to, and what are they used to treat?
- TNF-alpha blockers
- used to treat rheumatoid arthritis (disease modifying)
- toxicity: cause increased incidence of infections and tumors
28
What class of drugs does anakinra belong to, and what are they used to treat?
IL-1 Receptor antagonist (IL-1 RA analog)
| - used to treat rheumatoid arthritis (disease modifying)
29
The ratio of what signalling molecules determines the rate of bone secretion/resorption, and what cell produces them?
RANKL and OPG, both produced by osteoblasts.
| The RANK receptor is made and expressed by osteoclasts.
30
What happens to bone maintenance with age?
- 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
How is osteoporosis defined clinically?
A BMD more than 2.5 standard deviations below the normal age reference.
32
Summarize the benefits of estrogen on bone density
- stimulates osteoclast apoptosis
- suppresses osteoblast and osteocyte apoptosis
- reduces pro-resporptive cytokines
33
What are the precursors of osteoblasts and osteoclasts?
- osteoblasts come from mesenchymal stem cells
| - osteoclasts come from hematopoietic stem cells
34
What is the mechanism of bisphosphonates and what is used to treat?
- binds to bone matrix and inhibits osteoclasts
- increases BMD
- used for osteoporosis (even prevention), Paget's, metastatic bone disease
35
Alendronate is a member of what class of drugs, and what is it used to treat?
- bisphosphonates
| - used for osteoporosis (even prevention), Paget's, metastatic bone disease
36
Why don't we give estrogen to treat osteoporosis?
It has an increased risk of breast cancer
37
What is the mechanism of SERMs
= 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
Raloxifene belongs to what class of drugs? Used to treat what?
- SERMs
- osteoporosis (reduces risk of vertebral fracture)
- reduces postmenopausal bone resorption
- reduces the recurrence of breast cancer
39
What is denosumab and what pathway does it effect?
Monoclonal antibody to RANKL
| - binds RANKL and prevents it from binding to RANK
40
What are the 3 hormones that affect plasma Ca2+? What are their end effects?
- PTH: increase serum Ca2+
- Calcitonin decreases serum Ca2+
- Vitamin D increases serum Ca2+
41
Terapatide is a derivative of what hormone, and to what class does it belong?
- 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
Generally, what do bone morphogenic proteins do?
Alter bone remodelling
43
What is the mechanism of parathyroid hormone?
- 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
What is the mechanism of Vitamin D?
- stimulates synthesis of Ca2+-binding transport protein in mucosal cells of gut
- increases reporption of Ca2+ from bone
45
What is the mechanism of calcitonin?
- produced by the C cells of thyroid
| - inhibits osteoclast activity and decreases Ca2+ resorption in kidney
46
What is the standard treatment for Paget's?
- Calcitonin injections
| - OR active bisphonates (alendronate)
47
Alendronate, risedronate, ibandronate, and zoledronic acid all belong to what class of drugs?
bisphosphonates
48
How do non-depolarizing neuromuscular junction blockers act, in general?
competitive Nicotinic Acetyl Choline Receptor antagonist
- cause weakness followed by flaccid paralysis
- surmountable with AChE inhibitors or increasing ACh concentrations
49
How do depolarizing neuromuscular junction blockers act, in general?
Nicotinic Acetyl Choline receptor agonist
- activate, open and desensitize the nAChRm
- resistant to AchE
50
What are the clinical uses of neuromuscular blocking drugs?
- surgical relaxation (they are selective for motor nicotinic receptors; don't affect autonomic)
- orthopedic procedures
- intubation
- control of ventilation
51
What is the prototypical non-depolarizing neuromuscular blocker?
d-tubocurarine (it's long-acting)
52
What is the prototypical depolarizing neuromuscular blocker?
Succinylcholine (very short acting)
53
Contrast how depolarizing and non-depolarizing neuromuscular blockers are affected by AcetylCholinesterases.
- non-depolarizing: effect can be surmounted with enough AChE
- polarizing: resistant to AChE
