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Musculoskeletal System > 1 - Pharmacology > Flashcards

1 - Pharmacology Flashcards

1
Q

What are the 3 categories of lipid derived eicosinoids?

A

Prostaglandins
Thromboxanes
Leukotrienes

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2
Q

Most prominent precursor for eicosanoids?

A

Arachidonic Acid (AA)

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3
Q

What is the rate limiting step in eicosanoid generation?

A

Arachidonic Acid Release Cascade -

Stimulus increases IC calcium which activates PLA2 —> allows AA to enter

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4
Q

Describe the actions of PGE2

A
  • Vasodilator and is responsible for cell homeostasis
  • Mediates vasodilatory effect of bradykinin
  • Essential** for the regulation of gastric acid production
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5
Q

Treatment of ocular hypertension and open-angle glaucoma by increasing outflow of aqueous humor (DRUG OF CHOICE)

A

Latanoprost, travoprost, unoprostone - eicosanoid analog (PGF-alpha)

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6
Q

Describe the 3 tissue locations where histamine plays a major role and predict actions of histamine based on type of H receptors and 2nd messengers in those tissue locations.

A
  1. Mast cells are especially rich at sites of potential tissue injury (nose mouth, feet, internal body surfaces; blood vessels)
  2. Non-Mast cell histamine is found in the brain and functions as neurotransmitter
  3. Non-neuronal site of histamine storage and release is the enterochormaffin-like (ECL) cells of the fundus of the stomach, which release histamine to acitvate acid producing parietal cells of the mucosa
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7
Q

How is histamine synthesized?

A

one-step reaction where “histidine decarboxylase” removes CO2 from histidine to form histamine

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8
Q

Once synthesized, where is histamine stored in the body?

A

sequestered in bound granules in mast cells and basophils

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9
Q

What are the possible side effects of diphenhydramine?

A

Diphenhydramine (OTC antihistamine)-benadryl

could cause sedation, antimuscarinic effects (mydriasis, dry eyes/mouth, urinary retention)

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10
Q

Describe the different mechanisms of release of histamine. (2)

A
  1. Immunologic Release - immune activation casues B cells to secrete IgE, which bind mast cells Fc receptors. Bound IgE causes degranulation (release of histamines)
  2. Chemical and Mechanical Release - certain drugs (morphine, tubocurarine) can penetrate mast cells adn displace histamine.

Also, chemical or mechanical injury damaging the mast cell and causing degranulation
(i.e. EC Na+ enters free granules and causes histamine release)

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11
Q

What is the triple response of histamine?

A
  1. Red Spot: during infection or intradermal injection –> histamine-induced post-capillary venule dilation engorges the local microvasculature with blood (increased immune cells/response reaches the area)
  2. Wheal: histamine induced endothelial cell contraction and separation, resulting in release of plasma proteins and fluid form post-capillary venules, causing localized edema
  3. Flare: histamine directly depolarizing afferent nerve terminal resulting in itch/pain sensation
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12
Q

What is the signaling mechanism/tissue distribution of H1 receptors?

A

Gq - inc. IP3/DAG/Ca2+
Smooth muscle, vascular endothelium, brain
activates NFkB which promotes the expression of adhesion molecules and inflammatory cytokines

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13
Q

What is the signaling mechanism/tissue distribution of H2 receptors?

A

Gs - increased cAMP
gastric parietal cells, cardiac muscle, mast cells, brain
mediates gastric acid secretion in the stomach (prilosec/zantac?)

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14
Q

What is the signaling mechanism/tissue distribution of H3 receptors?

A

Gi - decreased cAMP
CNS and some Peripheral nerves
limit the synthesis and release of histamines and other NTs

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15
Q

What is the signaling mechanism/tissue distribution of H4 receptors?

A

Gi - decreased cAMP
Hemipoetic cells, gastric mucosa
mediates histamine-induced LTB4 production, adhesion molecule up regulation, and chemotaxis of mast cells, eosinophils, and dendritic cells

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16
Q

Describe the general characteristics of 1st generation antihistamines?

A

NEUTRAL at physiologic pH (readily cross BBB) and can block H1 receptors in the CNS – drowsy effect
may additionally bind cholinergic (less selective than 2nd gen.), alpha adrenergic, and serotonergic receptors at standard doses (dry mouth) ~anticholinergic effect

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17
Q

Describe the general characteristics of 2nd generation antihistamines?

A

IONIZED at physiologic pH (doesn’t x BBB —> non-drowsy)

H1 selective, less dry mouth (anticholinergic effect)

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18
Q

Describe diphenhydramine and what its used for

A

aka benadryl, is a first generation ethanolamine

  • Given parentally to improve anti-psychotic-induced parkinsonism movement disorder (sedative)
  • Indicated for atopic dermatitis, mostly for sedative effects to distract/reduce awareness of itch
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19
Q

Describe dimenhydrinate and what it is used for

A

1st gen ethanolamine similar to diphenhydramine

- used recreationally as OTC hallucinogen due to a narrow Ti

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20
Q

Describe chorpheniramine and its uses

A

1st gen alkylamine

  • least sedating* of the 1st gen antihistamines
  • most widely used antihistamine for allergic reations

(other widely used allergic rxn drugs are 2nd gen and very expensive)

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21
Q

Describe promethazine and its uses

A

1st gen phenothiazine
has an alpha receptor blockade effect
used for allergic reations and motion sickness
could cause orthostatic hypotension in some susceptible individuals

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22
Q

What 3 antihistamines are indicated for motion sickness and vestibular disturbances?

A

Dimenhydrinate (only indication for this drug)
Diphenhydramine
Promethazine

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23
Q

Which antihistamine is indicated for insomnia?

A

diphenhydramine

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24
Q

Describe Cyproheptadine and its uses?

A

1st gen piperidine
strong serotonin receptor antagonist
promoted as an antiserotonin agent

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25
Q

Describe Loratadine and its uses

A

2nd gen piperidine

metabolized by the liver CYP (3A4, 2D6) to form other metabolites

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26
Q

Describe Fexofenadine and its uses

A

3rd gen piperidine
not metabolized by liver CYP
eliminated in the feces

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27
Q

Describe Cetrizine

A

2nd gen piperazine (zyrtec)
not metabolized by liver CYP
eliminated in the urine

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28
Q

What are the major clinical indications of H1 antihistamines? (4)

A
  • 2nd line for allergic rhinitis (hay fever),
    - 1st line is nasal glucocorticoids
  • 1st line for urticaria (hives)
  • Motion sickness and Vestibular Disturbances (dimenhydrinate, diphenhydramine, promethazine)
  • Insomnia (diphenhydramine)
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29
Q

What are the major adverse effects of H1 antihistamines?

A

1st Gen - sedation, antimuscarinic effects

  • Hallucinations, irritability, and convulsions before progressing to resp. failure and cardio collapse
  • Postural hypotension
  • FDA advises against use in children less than 2 because children and elderly are more susceptible to side effects
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30
Q

What drug interactions exist with H1 antihistamines?

A

May compete with other agents that are metabolized by the same enzymes in the liver (2D6 and 3A4) and increase adverse effects

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31
Q

Describe and list the H2 antagonists, and their uses (4 drugs)

A

Reversible, competitive antagonists of histamine binding H2 receptors on gastric parietal cells to reduce gastric acid secretion.

  • Cimetidine
  • Ranitidine (Zantac)
  • Famotidine (Pepsid)
  • Nizatidine
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32
Q

What drug (histamine antagonist) prevents mast cell degranulation? Mech of action? Indications?

A

Cromolyn
inhibits chloride channels from opening (thus not allowing shape changes that allow for degranulation)
indicated for allergic rhinitis, systematic mast cell disease ***

33
Q

Which drug is a functional antagonist of histamine? Indications

A

Epinephrine
Adrenergic agonist that induces bronchodialation and vasoconstriction
- counters anaphylactic shock symptoms caused by histamine

34
Q

What are the 3 major eicosanoid pathways?

A

Arachidonic Acid Release
Cyclooxygenase Pathway/ Prostanoids
Lipoxygenase Pathway

35
Q

What eicosanoid derivative is formed through non-enzymatic oxidation of AA

A

Isoprostanes

36
Q

What do COX-1 and COX-2 do?

A

known as prostaglandin H (PGH) synthases, catalyze two reactions:

  1. oxygen-dependent cyclization of AA to PGG2
  2. peroxidase reduction of PGG2 to PGH2
37
Q

What are the characteristics of PGG2 and PGH2 (effects of the body)

A

Potent vasoconstrictors and platelet aggregators

38
Q

PGH2 can be converted to different eicosanoid products (prostanoids) in a tissue specific manner.

List the various PGH2-derived Prostanoids and their effects. (5)

A 
PGE2
PGF2
PGD2
PGI2
TxA2
39
Q

Describe PGE2

A

Vasodilation, hyperalgesia, fever, diuresis, immunomodulation. *Essential for regulation of gastric acid production, mediates vasodilatory effects of bradykinin

40
Q

Describe PGF2

A

Smooth muscle contractions
Bronchoconstriction
Abortion
(uterus/bronchi)

41
Q

Describe PGD2

A

Smooth muscle contractions
Inhibits platelet aggregation
(brain, mast cells)
Plays a role in inflammation

42
Q

Describe PGI2 (prostacyclin)

A

Vasodilation
Inhibits platelet aggregation
Opposite effects of TxA2
(Endothelium)

43
Q

Describe TxA2

A

Vasoconstriction
Platelet activation
(Platelets)

44
Q

List the two PGE1 eicosanoid analogs and their indications

A

Misprostol: prophylactic for NSAID-induced gastric uclers. Also, used for abortion or to induce labor

Alpostadil: used to maintain patency of ductus arteriosus. 2nd line for erectile dysfunction by relaxing smooth muscle of the corpus cavernosa

45
Q

PGF2alpha analog and its indications?

A

Latanoprost (travoprost, unoprostone) - treatment of choice for open angle glaucoma (over beta blockers), mech of action is to increase outflow of aqueous humor

46
Q

What is 5-HPETE?

A

An intermediate compound in the transformation of AA to LTA4. LTA4 has the capability of being transformed into LTB4 or LTE4

47
Q

What is the major action of LTB4

A

Major pro-inflammatory mediator. Strong chemoattractant for inflammatory cells and it also plays a part in activation of neutrophils.

48
Q

What enzymes are involved in the transformation of diacylgycerol or phospholipids to AA

A

PLC and PLA2

49
Q

What are the major actions of LTC/D/E4?

A

Increased vascular permeability (for infiltration of inflammatory cells), also responsible for symptoms of anaphylaxis (bronchoconstriction, vasoconstriction)

50
Q

Which AA derivatives are responsible for the resolution of inflammation?

A

LXA4 and LXB4

51
Q

Describe the actions of NSAIDs

A

They are COX inhibitors, block the action of cyclooxygenase in the formation of PGG2 from AA

52
Q

What is the only irreversible COX inhibitor and is it selective or non-selective?

A

acetylsalicylic acid (aspirin) and its derivatives
It is non-selective, and works by acetylating serine residues—> which:
1. Irreversibly binds/inactivates COX-1 (TXA2
2. Switches the catalytic activity of COX-2 (PGI2)

53
Q

Why is aspirin commonly used as an anti-platelet medication? How does it produce these effects?

A

It inhibits both TXA2 (platelet coagulation factor) and PGI2 (endothelial anticoagulent factor), the reason it works is that the endothelium has a nucleus and can regenerate the effected PGI2 to recover the anticoagulent effects, while RBCs dont have a nucleus —- Bottom line: net less TXA2 and relatively more PGI2, (resulting in increased anti-thromic activity)

54
Q

Explain how fish oil promotes antinflammatory pathways.

A

DHA in fish oil forms EPA which shifts the balance towards the generation of COX and LOX mediated anti-inflammatory molecules. (PGH3 instead of PGH2)

55
Q

Explain the pharmacokinetics of acetylsalicylic acid (Aspirn)

A

It is a pro-drug – biotransformed into salicylates which are highly bound to plasma proteins
Kidney excretion is highly variable (depends on dose) T1/2 = 15-30hrs at high dosing becasue it switches to 0order kinetics

Note- liver can’t handle high doses of aspirin so it is unable to transform it into excretable derivatives (salicyluric and phenolic acids)

56
Q

What are the possible adverse effects of aspirin?

A
  • GI bleeding, Nephrotoxicity, Tinnitus (ear ringing)
  • Aspirin-induced airway hyper-reactivity: may be due to a shift from COX to LOX pathway (athsma patients)
  • Reye’s Syndrome: Sweling and damage to liver and brain tissue in young children and teens recovering from viral infections (VZV)
57
Q

What is the accepted treatment for salixylate toxicity?

A

Alkaline diuresis

58
Q

To avoid reyes syndrome in kids and teens w/ viral infections, what is most commonly recommended for fever/pain?

A

acetominophen

59
Q

Describe acetominophen, is it an NSAID?

A

Acetominophen is not an NSAID, it is just commonly classified with them. In the peripheral tissues, high levels of peroxides render it ineffective in COX inhibition.

However, in the brain peroxide levels are low, allowing COX inhibition. Therefore, it is not anti-inflammatory because it has no effect in the regions of inflammation outside the CNS. It is a pain reliever and anti-pyretic agent though.

60
Q

How do you treat liver toxicity caused by acetominophen? What produces the toxic effects?

A

Toxicity is due to the production of high levels of NAPQIs when it saturates glucuronidation, sulfation, and GSH conjugation reactions in the liver.

Treated with N-acetylcysteine

61
Q

What are the acetic acid derivative NSAIDs and what is notable about them (3)

A

Indomethacin - GI toxicity
Diclofenac - Reduce IC AA, more potent than above
Ketorolac - strong analgesic, only NSAID approved for maternal use; only used short term due to side-effects
They inhibit COX as well as reduce the availability of AA for COX and LOX to form inflammatory derivatives
Not used often.. many side-effects

62
Q

What is the only NSAID approved for maternal use?

A

Ketorolac - only used short term becasue of side-effects

63
Q

What are the proprionic acid derivatives?

A

Ibuprofen (advil, motrin)

Naproxen (aleve)

64
Q

What is a good predictor of the response provided by NSAIDs?

A

PHarmacodynamics

65
Q

What are the common indications for the use of Ibuprofen?

A 
Rheumatoid arthritis
Osteoarthritis
Ankylosing spondylitis
Primary dysmenorrhea
 - It is better tolerated than the acetic acid derivatives (indomethacin)
66
Q

What is so great about naproxen?

A

Long plasma 1/2life, 20x more potent than aspirin, directly inhibits leukocyte function, and causes less GI effects

67
Q

Whan is naproxen commonly indicated?

A

It is indicated for the same reasons as ibuprofen, but especially in patients resistant to other propionic acid derivatives becasue it is present in its pure active isomer while others are inactive isomers that need to be activated (variable in certain patients)

68
Q

What are the oxicam derivatives?

A

Piroxicam is the major player

69
Q

What are the indications/benefits of piroxicam?

A

It works as well as aspirin, naproxen, and ibuprofen in the treatment of arthritis, (BETTER TOLERATED)

It also inhibits collagenase, proteoglycanase, adn oxidative burst to modulate neutrophil function

Extremely long 1/2life - PO 1xdaily

70
Q

What is the basis for COX-2 Inhibitors

A

Knowing there are 2 COX isoforms, 1 is thought of as good/hemostatic, while 2 is thought of as inflammatory/bad.

However COX2 is important for the formation of PGI2 (antiplatelet from TXA2, and essential kidney function)

71
Q

What is the major selective COX 2 inhibitor used today? Indications? Adverse effects

A

Celecoxib - antiinflammatory without the antiplatelet effects

Indications - same as all NSAIDS

Adverse effects - RISK OF MI/STROKE, peripheral edema, athsma exacerbation, GI bleeds

72
Q

What are LOX inhibitors? Indications? Adverse Effects?

A

LOX inhibitors are not commonly prescribed
Zileuton
ONLY used for athsma, but not even commonly used because of low F, potency, and liver loxicity

73
Q

What are the common LOX pathway drugs that are used? Mech of action? Names?

A

LOX inhibitors are rarely used but LT receptor antagonists are used.
They block the receptors for LTC/D/E4
- Montelukast: Indicated for athsma, allergies
- Zafilukast: indicated for athsma

74
Q

How do cytokine inhibitors work? What are the two classes?

A

Bind to cytokines to prevent them from activating the eicosanoid pathway of inflammation

Anti-TNFs — (Etanercept, Infliximab, adalimab, golimumab)

Anti-IL — (anakinra)

75
Q

What is a draw-back of cytokine inhibitors?

A

They increase the risks of serious infections

76
Q

How to glucocorticoids work? Known as?

A

Known as corticosteroids (steroidal anit-inflammatory)
They inhibit PLA2 and prevent AA release from cellular phospholipids (aka block rate-limiting step in eicosanoid inflammation pathway)

Prednisone, prednisolone, dexamethasone

77
Q

What are some adverse effects of corticosteroid use?

A

Mostly seen with chronic use
Osteoporosis
muscle wasting
abnormal carbohydrate metabolism

78
Q

Are glucocorticoids direct inhibitors of PLA2?

A

No, they induce lipocortins which inhibit PLA2, inhibit inflammation by activating LOXA4 receptor, repress COX2 gene expression, AND repress cytokine expression that would activate COX2

Musculoskeletal System (21 decks)

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