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Module 2: MSK > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What are two critical mediator pathways of inflammatory conditions?

A
  1. Nuclear Factor Kappa B (NF-kB)
  2. Arachidonic Acid Cascade
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2
Q

What are stimuli and target genes for NF-kB?

A
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3
Q

What is the arachidonic acid cascade?

A

Arachidonic acid is cleaved from membrane phospholipids by Phospholipase A2

It is used to in the lipoxygenase pathway to make leukotrienes and the Cyco-oxygenase pathway to make prostaglandins, prostacyclin, and thromboxane A2

Pathways are determined by the tissue/cell

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4
Q

What pathway do NSAIDs inhibit?

A

COX-1 and COX-2 pathways

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5
Q

What are characteristics of the COX-1 pathway?

A
  • Constitutively expressed in many tissues
  • generates thromboxanes
  • Generates low levels of prostaglandins
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6
Q

What are characteristics of the COX-2 pathway?

A
  • Most responsive for inflammatory response
  • Inducible form of enzyme; expressed in high levels after induction by inflammatory mediators
  • Generates high levels of prostaglandins and thromboxanes

Functions:
local inflammation
wound healing
resistance to infection

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7
Q

What are functions of prostaglandins?

A
  • protective (i.e. gastric mucosa)
  • maintains local blood flow / vasodilation (i.e. kidney)
  • platelet aggregation
  • uterine contraction
  • muscle growth
  • modulation of synaptic transmission
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8
Q

Thromboxanes are dependent on which enzyme for their synthesis?

A

COX-1

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9
Q

What are some non-selective COX inhibitors?

A

aspirin (irreversible)

ibuprofen

naproxen

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10
Q

What are some toxic side effects of NSAIDs?

A

- Gastrointestinal tract

- Renal effects

- Hypertension

- Impaired hemostasis

- Allergic hypersensitivity rxns

- CNS toxicity

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11
Q

What are some GI side effects of NSAIDs?

A

Dyspepsia

Ulcers

Inflammation

Gastric erosion, hemorrhage

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12
Q

What are some renal side effects of NSAIDs?

A

Glomerular filtration rate reduced

Edema

Necrosis

Nephritis

Hyperkalemia

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13
Q

What are some pharmacokinetic interactions of NSAIDs that increase NSAID toxicity?

A

potentiation of drugs bound to plasma proteins
(warfarin, phenytoin, sulfonylureas, methotrexate)

Inhibition of drug metabolism
(phenylbutazone)

Inhibition of acid transport in kidney
(by probenecid)

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14
Q

What are some pharmacodynamic intereactions of NSAIDs that increase their toxicity?

A

Increased risk of bleeding after alcohol

Reduced effects of anti-hypertensive agents
(beta-adrenergic antagonists, ACE inhib., diuretics)

Inhibition of renal clearance of Lithium

Sudden hyperkalemia with K+-sparing diuretics

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15
Q

What are the half lives of NSAIDs?

A

Short half-life (< 6 hr)
aspirin
ibuprofen (Motrin, Advil)
indomethacin

Long half-life (> 6 hr)
naproxen (Aleve)
salicylate
phenylbutazone

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16
Q

What are COX-2 selective inhibitors?

A

celecoxib (celebrex)

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17
Q

What are other analgesic/anti-inflammatory (non-NSAID) agents?

A

Glucocorticoids

Acetaminophen (tylenol)

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18
Q

What are characteristics of glucocorticoids?

A
  • effective anti-inflammatory agents
  • inhibit Phospholipase A2, reduce arachidonic acid levels
  • inhibit production of inflammatory cytokines (IL-1, TNFalpha, IFNgamma)
  • inhibit NF-kB signaling and thus inhibit COX-2 inhibition
  • significant side effects limit use
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19
Q

What are characteristics of aceteminophen?

A
  • analgesic, antipyretic agent
  • less effective anti-inflammatory agent
  • a weak inhibitor of COX-1 and COX-2
  • exact mechanism unknown
  • drug of choice for fever, headache in infants
20
Q

What about COX-2 specific inhibitors has led to their removal from the market?

A

They have increased cardiovascular risk, thought to be because they alter the balance between thromboxanes and prostacyclins, by inhibiting pathways leading to prostacyclin synthesis

21
Q

What are possible drug treatment options for arthritic conditions?

A

Relief of symptoms:
NSAIDs

Disease modifying anti-rheumatic drugs (DMARDs)

22
Q

What are the different categories of DMARDs?

A

Synthetic Drugs:

Immunosuppresant agents

Biologics:

TNFalpha Blockers

IL-6 mAb

IL-1 Receptor antagonist

Immune Modulators

23
Q

What are some notable Immunosuppressant DMARDs?

A

Methotrexate
Leflunomide

24
Q

What are some notable TNFalpha blockers?

A

etanercept
infliximab

25
What are some notable IL-1 receptor antagonists?
anakinra
26
What are some notable immune modulator DMARDs?
abatacept rituximab
27
What are characteristics of methotrexate?
- Immunesuppressant: dihydrofolate reductase inhibitor - Effectiveness is dose-related - Slow onset of effects - Side effects: anorexia, vomiting, abdominal cramps mucosal ulcers, hepatotoxicity mild leucopenia, thrombocytopenia - may be used in combination with other disease modifying drugs
28
What are characteristics of leflunomide?
- Inhibits pyrimidine synthesis by inhibiting dihydroorate dehydrogenase - reduces lymphocyte proliferation - potent immunosuppressant - pro-drug (active metabolite) - long half-life - long-term effectiveness/toxicity unkown - inhibits CYP2C9 - Adverse Effects: hepatotoxicity hypertension teratogenic may cause fetal death
29
What are characteristics of etanercept?
TNF-alpha blocker - a chimeric TNF receptor, blocks binding of TNF-alpha - reduces joint swelling - combined with methotrexate - long-term effectiveness/toxicity unknown - increased risk of latent TB activation
30
What are characteristics of Infliximab?
TNF-alpha antibody - blocks stimulation by TNF-alpha - combined with methotrexate - long-term effectiveness/toxicity unknown
31
What is the target for rituximab?
CD20+ B cells - rituximab prevents development and proliferation of B cells
32
What are the two types of cholinesterases?
Acetylcholinesterase Plasma cholinesterase
33
What is a cholinesterase inhibitor?
Molecules that look like ACh to AChE, ultimately blocking AChE's ability to cleave ACh
34
What are the types of cholinesterase inhibitors?
**Quarternary alcohols, Carbamates:** Clinical use; choice depends on desired site and duration of action **Organophosphates:** Slowly reversible or irreversible: few clinical uses (except glaucoma) Found in insecticides and nerve agents
35
What are medical uses of anticholinesterases?
Myasthenia Gravis Anesthesia Alzheimer's Disease Glaucoma Emergency Medicine Bladder control Dry mouth
36
What's the difference between carbamates and organophosphates that determines their reversibility?
Both act as intermediates of the AChE rxn, blocking the rxn Carbamate can be dislodged by H2O as a nucleophile Organophosphates need nucleophiles stronger than H2O initially, then undergo aging which makes them completely irreversible and new AChE must be produced
37
What is Edrophonium?
Used for diagnosis of Mysathenia Gravis and reversal of neuromuscular blockade by non-depolarizing muscle relaxants Bioavailability: IV or IM injectable Active for ~30min Metabolism: renal Adverse effects minimal due to fast elimination
38
What is Pyridostigmine?
Myasthenia Gravis treatment (Also, organophosphate poisoning prophylaxis) Bioavailability: oral treatment Peak after 30min active ~4 hrs Metabolism: renal Adverse effects: GI symptoms of nausea, vomiting or diarrhea sweating and flushing increased salvation tearing and constricted pupils bronchial secretions
39
What is Donezipil?
Alzheimer's treatment Bioavailability: oral treatment Peak concentration after 4hrs accumulates in brain 2x plasma levels active ~ 80hr Extreme half life requires increasing dose slowly, including a 1 week titration, to avoid adverse effects Metabolism: renal
40
What is cholinergic crisis?
Can occur by overdose of anti-AChE drugs: **SLUDS: Salivation, lacrimation, urination, defication, sweating** - Miosis - profuse secretion - bronchial constriction - defecation/urination - bradycardia - hypotension - muscle twitches - convulsions - respiratory failure
41
What is Physostigmine?
Used for Emergency medical reversal of anticholinergics or antihistamines: Anticholinergics = atropine, scopolamine antihistamines = diphenhydramine, dimethylhydrinate "recreational" Jimson weed Bioavailability: oral or injectable peak concentration ~10-30min Transdermal patch for 24hr exposure Metabolism: liver metabolism, renal elimination Adverse effects: S.L.U.D.S. **NOTE:** also used to treat xerstoma (dry mouth)
42
What is the intermediate syndrome of organophosphate poisoning?
May occur for up to 1 week after exposure modifications in function of nicotinic receptors Symptoms **do not** respond to: atropine 2-PAM Symptoms resolve on own in week or two Treatment is supportive (respirator)
43
What is Organophosphate-induced delayed polyneuropathy (OPIDP)?
**Symptoms:** muscle weakness headaches psyciatric problems memory problems Cause not established; likely chronic exposure to OPs No established pharmaceutical therapy
44
What is pralidoxime (2-PAM)?
hydroxylamine derivative with a cationic head that is able to regernate AChE active site after organophosphate exposure Not indicated for carbamate overdose
45
What is used to treat organophosphate poisoning?
Remove all sources of agent (clothes, etc) atropine - immediately to stop secretions pralidoxime (2-PAM) - immediately to regenerate enzyme diazepam to reduce convulsions Supportive measures (i.e. respirator)
46
What is the current protection to organophosphate poisoning?
Prophylactic opportunity with pyridostigmine: Inhibit a fraction of AChE with *spontaneously reversible* anti-AChE before exposure This is possible b/c poisoning effects appear after \> 50% enzyme is inhibited

Module 2: MSK (11 decks)

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