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PoD - E4 > Anti-pyretics, Anti-inflammatory, and Analgesics > Flashcards

Anti-pyretics, Anti-inflammatory, and Analgesics Flashcards

1
Q

Eicosanoids

A

Members of a family of oxygenated products of polyunsaturated fatty acids. Includes:

  • Prostaglandins (PGs)
  • Thromboxanes (TBs)
  • Leukotrienes (LTs)
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2
Q

Prostaglandins include

A

PGD2, PGF2alpha, PGI2

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3
Q

Thromboxanes include

A

TXA2

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4
Q

Leukotrienes include

A

LTC4, LTD4, LTE4

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5
Q

Eicosanoid fatty acid precursors

A
  • Dihomo-gamma- linoleic acid
  • Arachidonic acid
  • Eicosapentaenoic acid

The nature of the precursor PUFA affects the function of the eicosanoid synthesized

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6
Q

Arachidonic acid

A
  • Most abundant and most important precursor of eicosanoids
  • Synthesized from linoleic acid (essential fatty acid)
  • Arachidonic acid = eicosa tetraenoic (5, 8, 11, 14) acid
  • 20 carbons, 4 unsaturated bonds
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7
Q

Prostanoids refers to

A

Products of cyclooxygenase:

  • Prostacyclins
  • Prostaglandins
  • Thromboxanes
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8
Q

COX-1

A
  • Constitutive form
  • Found in endothelial cells, stomach and kidney
  • House keeping functions (always present), widely distributed: ↑ stomach mucus → protection of stomach mucosa from HCl
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9
Q

COX-2

A
  • Inducible form
  • Elevated by inflammation and by cytokines
  • Constitutively expressed in brain and kidney
  • Immediate early response gene product in inflammatory/ immune cells (inflammation in rheumatoid arthritis)
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10
Q

Prostanoids - Mechanism of Action

A
  • Act locally (short half-lives) - paracrine or autocrine
  • Have cell surface receptors (GPCRs)
  • Activate G proteins ( ↓ intracellular calcium) or phosphatidyl inositol metabolism (↑ intracellular calcium)
  • Major effects are on 4 types of smooth m.: vascular, gastrointestinal, airway and reproductive
  • Other targets: platelets, monocytes, kidneys, CNS, sensory nerve endings, endocrine organs, and the eye (this may involved smooth m.)
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11
Q

Prostacyclin (PGI2) - Vascular Action

A
  • Synthesized by both smooth m. cells and endothelial cells (major contributor - COX2)
  • Relaxes vascular smooth m.
  • POWERFUL VASODILATOR: ↑ cAMP, ↓ intracellular calcium
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12
Q

Prostacyclin (PGI2) - Airway Action

A
  • POWERFUL BRONCHODILATOR (most potent)
  • Used clinically to treat pulmonary (induced by hypoxia) and portopulmonary hypertension

Portopulmonary = portal + pulmonary hypertension

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13
Q

Prostacyclin (PGI2) - GI Action

A
  • Inhibits gastric acid secretion

- Increased mucus secretion

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14
Q

Prostacyclin (PGI2) - Renal Action

A
  • Increases GFR and renal blood flow
  • Increases water and sodium excretion
  • Stimulates renin release (cortex)
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15
Q

Prostacyclin (PGI2) - Reproductive Action

A
  • Relaxes uterine muscle
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16
Q

Prostacyclin (PGI2) - Pain Action

A
  • Induces pain by lowering threshold of nociceptors
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17
Q

Prostacyclin (PGI2) - Receptors

A
  • IP (Gs - cAMP)
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18
Q

Prostaglandin (PGE2) - Vascular Action

A

Vasodilator

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19
Q

Prostaglandin (PGE2) - Platelet Action

A

- [High]: inhibits platelet aggregation

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20
Q

Prostaglandin (PGE2) - Airway Action

A
  • Relaxes respiratory smooth m.

- POWER BRONCHODILATOR

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21
Q

Prostaglandin (PGE2) - GI Action

A
  • Inhibits gastric acid secretion

- Increases stomach mucus secretion

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22
Q

Prostaglandin (PGE2) - Renal Action

A
  • Increases GFR
  • Increases renal blood flow
  • Increases water and sodium excretion
  • Stimulates renin release (cortex)
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23
Q

Prostaglandin (PGE2) - Reproductive Action

A

Dysmenorrhea = painful menstruation

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24
Q

Prostaglandin (PGE2) - Pain Action

A
  • Induces pain by lowering the threshold of nociceptors
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25
Q

Prostaglandin (PGE2) - Fever Action

A
  • Induces fever in hypothalamus (DIRECT PYROGEN)

- Cytokines can stimulate PGE2

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26
Q

Prostaglandin (PGE2) - Receptor

A

EP1 - EP4 (Gs, Gq)

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27
Q

Thromboxane (TXA2) - Synthesis

A

Synthesized by platelets, lung and kidney

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28
Q

Thromboxane (TXA2) - Vascular Action

A
  • POTENT VASOCONSTRICTOR
  • SMC mitogen

SMC = smooth muscle cell

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29
Q

Thromboxane (TXA2) - Platelet Action

A
  • MAJOR PRODUCT OF PLATELET COX1
  • STIMULATES PLATELET AGGREGATION
  • Also acts as an amplification signal for other more potent agonists such as thrombin and ADP
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30
Q

Thromboxane (TXA2) - Airway Action

A
  • Constricts airway smooth m.
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31
Q

Thromboxane (TXA2) - Renal Action

A
  • Intra-renal vasoconstriction (perhaps an ADH-like effects) resulting in decline in renal function
  • Normal kidney synthesizes very little TXA2
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32
Q

Thromboxane (TXA2) - Reproductive Action

A
  • Uterine muscle contraction
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33
Q

Thromboxane (TXA2) - Receptor

A

TP (PLC)

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34
Q

Prostaglandin F2alpha (PGF2alpha) - Vascular Action

A
  • Vasoconstrictor
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35
Q

Prostaglandin F2alpha (PGF2alpha) - Airway Action

A
  • Contracts airway smooth m.
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36
Q

Prostaglandin F2alpha (PGF2alpha) - Reproductive Action

A
  • CONTRACTS UTERINE MUSCLE (similar to PGE2 can terminate pregnancy)
  • In combination with oxytocin can induce labor, causes dysmenorrhea
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37
Q

Prostaglandin F2alpha (PGF2alpha) - Eye Action

A
  • Decreases intraocular pressure
  • Used to treat glaucoma - a condition associated with a loss of COX2 expression in the pigmented epithelium of the ciliary body
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38
Q

Misoprostol

A
  • PGE1 analog
  • INHIBITS GASTRIC ACID SECRETION (increasing production of gastric mucus and mucosal secretion of bicarbonate)
  • Adjunct to NSAID therapy to reduce ulcer formation in high risk patients (i.e. elderly and patients with concomitant debilitating disease)
  • Should be taken for the duration of the NSAID therapy
  • Contraindication in pregnancy (may induce uterine contractions and induce labor)
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39
Q

Latanoprost

A
  • PGF2alpha analog
  • Ophthalmic preparation
  • Used for OPEN ANGLE GLAUCOMA to LOWER INTRAOCULAR PRESSURE (increases aqueous humor outflow)
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40
Q

Alprostadil

A
  • PGE1 analog
  • TEMPORARILY MAINTAINS PATENT DUCTUS ARTERIOSUS in newborns until surgery can be done
  • Administer by IV infusion
  • Increase pulmonary blood flow (vasodilator), IMPROVES BLOOD OXYGENATION
  • Other uses: erectile dysfunction
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41
Q

Leukotriene

A
  • Products of lipoxygenases

- Arachidonic acid converted by lipoxygenase pathway to leukotrienes

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42
Q

5-HETE (5-HPETE) and Leukotriene B4 (LTB4)

A
  • Lipoxygenase product
  • CHEMOTACTIC AGENT for polymorphonuclear leukocytes, eosinophils and monocytes
  • LTB4 can also produce hyperalgesia
  • Human colonic epithelial cells synthesize LTB4
  • Patients with IBD contains substantial amounts of LTB4
Hyperalgesia = abnormally heightened sensitivity to pain
IBD = inflammatory bowel disease
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43
Q

Cysteinyl Leukotrienes (LTC4/C4, LTD4/D4, LTE4/E4)

A
  • Chemoattractant for eosinophils
  • POTENT BRONCHOCONSTRICTORS (act principally on airway smooth muscle cells)
  • INCREASE VASCULAR PERMEABILITY (1000x more potent than histamine)
  • COMPONENTS OF SLOW REACTING SUBSTANCE OF ANAPHYLAXIS (SRS-A) that is secreted in asthma and anaphylaxis
44
Q

4 current approaches to anti-leukotriene drug development

A
  1. Leukotriene receptor antagonists
  2. 5-LOX inhibitors
  3. Inhibitors of FLAP (5-lipoxygenase activated protein)
  4. Phospholipase A2 inhibitor
45
Q

Competitive, Leukotriene D4 receptor antagonists (Cys-LT1)

A
  • Zafirlukast

- Montelukast

46
Q

5-Lipoxygenase inhibitors

A
  • Zileuton
47
Q

Zafirlukast and Montelukast - Mechanism of Action and Uses

A
  • Competitive, reversible LTD4 (cysteinyl leukotriene 1) receptor antagonist
  • Inhibit the leukotriene mediated effects on bronchoconstriction and vascular permeability
  • PROPHYLACTIC TREATMENT OF ASTHMA - not used for acute asthmatic attacks, used in children and adults, m > 1 yo, z > 5 yo
  • Exercise induced bronchoconstriction (m > 15 yo)
  • Allergic rhinitis
  • Aspirin sensitivity induced asthma (m only)
48
Q

Zafirlukast - Adverse Effects

A
  • Headache
  • Pharyngitis
  • Rare cases of increased liver enzymes
49
Q

Zafirlukast - Drug Interactions

A
  • Inhibits CYP3A4 and CYP2C9
  • Numerous drug interactions (i.e. warfarin)
  • Take on empty stomach (food reduces bioavailability by 40%)
50
Q

Montelukast - Adverse Effects

A
  • Headache
51
Q

Montelukast vs Zafirlukast

A
  • Montelukast - 1x per day
  • Zafirlukast - 2x per day
  • Zafirlukast must be taken on empty stomach
  • Zafirlukast inhibits CYP3A4 and CYP2C9
  • Montelukast can be used in children
52
Q

Zileuton - Mechanism of Action

A
  • Inhibitor of 5-lipoxygenase

- Inhibits the synthesis of LTA4, B4, C4, D4, D4 and E4

53
Q

Zileuton - Uses

A
  • Prophylaxis for asthma (>12 yo)
54
Q

Zileuton - Adverse Effects

A
  • Must monitor hepatic function (hepatic transaminase may increase up to 3x of normal)
  • Cannot be used in those with liver disease
55
Q

Zileuton - Drug interactions

A
  • Increase response: theophylline (blood levels double), warfarin, propranolol
  • Ergot alkaloids contraindicated - severe vomiting, vasospasms
56
Q

NSAID

A
  • Chemically diverse class of drugs
  • Most frequently prescribed drugs
  • Many available OTC
  • Mechanism of action: inhibits cycloxygenase
57
Q

Non-selective NSAIDs

A
  • Inhibit both COX1 and COX2

Salicylates:
- Aspirin (irreversible inhibitor)

58
Q

Traditional NSAIDs

A

Propionic acid:

  • Ibuprofen
  • Naproxen
  • Oxaprozin

Acetic acid:

  • Indomethacin
  • Sulindac
  • Ketoralac
  • Diclofenac
59
Q

Selective NSAIDs

A
  • COX2 specific inhibitor
  • Celecoxib
  • Valdecoxib
  • Rofecoxib
60
Q

Common therapeutic actions of NSAIDs

A
  • ANTIPYRETICS: inhibit PGE synthesis in the hypothalamus (lowering of an elevated temperature)
  • ANALGESICS: reduction of mild to moderate pain, pain associated with inflammation
  • Good ANTI-INFLAMMATORY properties: inhibits prostaglandin synthesis in localized areas
61
Q

Common side effects associated with NSAID

A
  • Increased risk of GI ulcers and pain
  • Increased risk of bleeding (inhibit platelet aggregation)
  • Inhibit prostaglandin mediated effects in kidney (sodium and water retention)
  • Cross sensitivity with aspirin (aspirin sensitivity is a contraindication)
62
Q

Aspirin - Mechanism of Action

A
  • Salicylate
  • Also called acetyl salicylate
  • IRREVERSIBLE inhibitor of cyclooxygenase
  • ACETYLATES the enzyme (ser 530 in COX1, ser 516 in COX2)
63
Q

Aspirin - Uses

A
  • Antipyretic, anti-inflammatory and analgesic agent
  • Analgesic activity at localized area and in brain but DOES NOT interact with opioid receptor
  • Therapeutic limitation for arthritis (rheumatoid and osteoarthritis) - therapeutic dose approaches side effect dose
64
Q

Aspirin - Effect on Platelets

A
  • IRREVERSIBLY INHIBITS platelet COX
  • Low does can irreversibly inhibit TXA2 production in platelets (effect lasts 8-10 days - the life of the platelet)
  • This prolongs bleeding time
65
Q

Aspirin - Clinical Uses

A
  • Decreases incidence transient ischemic attacks, unstable angina, coronary artery thrombosis with MI and thrombosis after CABG
  • Reduces risk of preeclampsia in women (administered late 1st trimester for women with history and after 34 weeks for women who show high risk)
  • Long term use may lower incidence of colon cancer
66
Q

Salicylate preparations

A
  • Aspirin (acetyl salicylate): buffered, enteric coated effervescent (very high sodium level)
  • Topical salicylate: methyl salicylate (oil of wintergreen), choline magnesium salicylate
  • Mesalamine (5-aminosalicylic acid, Asacol): treatment of inflammatory bowel disease
67
Q

Aspirin - Side Effects

A
  • GI PAIN, BLEEDING AND ULCERS
  • Variable urate excretion (decreased 5 g)
  • Reye’s syndrome (do not give to children with influenza or varicella)
  • SALICYLISM: mild intoxication with aspirin and salicylates; commonly experienced when daily does exceeds 4 g; characterized by TINNITIS (high frequency hearing loss), headache, nausea, dimness of vision; symptoms are usually reversible within 2-3 days after withdrawal of drug
68
Q

Propionic acid derivatives

A
  • Ibuprofen

- Naproxen

69
Q

Heteroarylacetic acid derivatives

A
  • Ketorolac
70
Q

Phenylacetic acid derivatives

A
  • Diclofenac
71
Q

Indole derivatives

A
  • Indomethacin
72
Q

Selective COX2 inhibitors

A
  • Coxibs
73
Q

Propionic acid and Arylacetic acid derivative - Uses

A
  • Competitive, REVERSIBLE active-site inhibitors of COX1 and COX2

Uses:

  • Mild to moderate pain
  • Anti-pyretic
  • Symptoms of rheumatoid and osteoarthritis
  • Less GI ulcers and problems than aspirin
74
Q

Ibuprofen - Uses

A
  • Fever in children
  • Dysmenorrhea
  • Acute migraine attacks
  • Rheumatoid and osteoarthritis
75
Q

Naproxen - Uses

A
  • Greater inflammatory action, can be used the same as ibuprofen
  • Osteoarthritis, rheumatoid
  • Acute gout
  • Tendonitis (shoulder)
  • Ankylosing spondylitis
76
Q

Naproxen - Adverse Effects

A
  • Clearance is reduced in liver disease
  • Increased risk of stroke/heart attack with prolonged use
  • ACE inhibitors - NSAIDs seem to diminish the anti-hypertensive effects of ACE inhibitors (due to inhibitor of vasodilator and natriuretic PGs)
  • Antacids and Sucralfate (Al and Mg containing agents) - delays absorption
77
Q

Ketorolac - Uses

A
  • Excellent analgesic action
  • NSAID used for postoperative pain (moderate to severe)
  • Analgesia, comparable to morphine (short term alternative)
  • Administer IM, IV, oral
  • Advantage to morphine - not habit forming
  • Given 5 days max
  • Analgesic > anti-inflammatory activity
  • Inhibits platelet aggregation
78
Q

Ketorolac - Adverse Effects

A
  • GI bleeding
  • Bleeding (inhibits platelet aggregation)
  • Hepatic (monitor AST/ALT levels)
  • Lower dose in patients under 110 lbs or over 65 yo or ELEVATED CREATININE
79
Q

Ketorolac - Contraindications

A
  • History of peptic ulcer or presence of GI bleeding
  • Must stop before surgery
  • CONCURRENT USE WITH ASPIRIN OR NSAID
  • Use in renal disease
  • Combined with probenecid (used in treatment of gout)
  • Active bleeding (GI, cerebrovascular)
  • During labor/delivery or during lactation
80
Q

Diclofenac - Uses

A
  • Rheumatoid, osteoarthritis, and ankylosing spondylitis
  • Primary dysmenorrhea (diclofenac potassium only)
  • Ophthalmic: postoperative pain and inflammation following cataract surgery
  • Arthrotec: DICLOFENAC + MISOPROSTOL used in patients with risk of gastric or duodenal ulcers (contraindicated in pregnancy)
  • Low dosage: mild to moderate acute pain
81
Q

Diclofenac - Adverse Effects

A
  • GI pain, nausea cramps, diarrhea
  • Modest elevation of ALT
  • Dizziness
  • Headache
  • ARTHROTEC CONTRAINDICATED DURING PREGNANCY
  • METABOLIZED BY CYP2C9
82
Q

Indomethacin - Uses

A
  • Oral: acute gouty arthritis, rheumatoid (moderate to severe), osteoarthritis (moderate to severe), tendinitis, ankylosing spondylitis
  • IV: nonsurgical repair of patent ductus arterioles (close PDA)
83
Q

Indomethacin - Side Effects

A
  • GI pain (take with food)
  • Severe frontal headache
  • Displacement of bilirubin from albumin
  • Decreased urine output
  • Contraindications: hyperbilirubinemia, renal failure
84
Q

Celecoxib - Uses

A
  • Rheumatoid and osteoarthritis
  • Akylosing spondylitis
  • Primary dysmenorrhea
85
Q

Celecoxib - Interactions

A
  • Metabolized by P450 CYP2C9

- Monitor dose carefully when given with FLUCONAZOLE (inhibits CYP2C9)

86
Q

Celecoxib - Adverse Effects

A
  • GI pain

- Nausea

87
Q

NSAIDs and Pregnancy

A
  • Inhibit uterine motility (PGE and PGF)
  • Induce bleeding in last trimester
  • Premature closing of ductus arteriosus
88
Q

Prostaglandin with high risk of acute renal failure

A

Indomethacin

89
Q

Water and sodium retention mechanism - PGI2 and PGE2

A
  • Increase GFR
  • Increase renal blood flow
  • PGE2: inhibits Cl- reabsorption in thick ascending limb of the loop of Henle
90
Q

Water and sodium retention mechanism - NSAIDs

A
  • Lower PGI2, PGE2, TXA2
  • Resulting in decreased renal blood flow and glomerular filtration rate, increase tubular reabsorption of water, Cl, and Na
91
Q

Hyperkalemia likely to occur with NSAID use when

A
  • Used in elderly, diabetics and other situations of diminished renal function
  • Individuals should monitor weight in order to assess whether water retention is occurring

Combination with:

  • Propranolol (less renin and aldosterone)
  • Potassium sparing diuretics
  • ACE inhibitors (decreases kinins which decrease renin release)
92
Q

Hyperkalemia and water retention mechanism - PGI2 and PGE2

A
  • Stimulate renin release

- PGE2: inhibits the effect of anti-diuretic hormone (ADH) on collecting tubules

93
Q

Hyperkalemia and water retention mechanism - NSAIDs

A
  • Will lower renal PG levels
  • Result in enhanced ability of ADH to increase permeability of collecting tubules to water (water retention)
  • Decrease K secretion (K+ retention)
94
Q

Acetaminophen - Uses

A
  • Alternative drug in people that are aspirin sensitive
  • Active metabolite of phenacetin
  • Excellent antipyretic and analgesic (mild to moderate pain, osteoarthritis) activity comparable to aspirin
  • Weak anti-inflammatory agent
  • DOES NOT alter platelet function
  • Less GI upset
95
Q

Acetaminophen - Mechanism of Action

A
  • Weak inhibitor of cycle-oxygenase (COX1 and COX2)
  • Mechanism - COX3 inhibitor?????
  • Activates cannabanoid receptor
96
Q

Acetaminophen - Interactions

A
  • Ethanol
97
Q

Acetaminophen - Adverse Effects

A
  • Hepatic toxicity (acute) - #1 cause of drug induced liver failure in US
  • Renal toxicity (chronic)
98
Q

Gold Salts

A
  • Auranofin

- Gold sodium thiomalate

99
Q

Auranofin and Gold sodium thiomalate - Uses

A
  • Used for ACTIVE rheumatoid arthritis that are not responding to NSAIDs
  • Not first line due to side effects
  • GST: administer IM, used for more aggressive treatment
100
Q

Auranofin and Gold sodium thiomalate - Mechanism of Action

A
  • Inhibit function and maturation of T cell
  • Decreased level of rheumatoid factor (IgM)
  • Inhibits phagocytosis by macrophages
101
Q

Auranofin and Gold sodium thiomalate - Adverse Effects

A
  • Develop rash and/or skin lesions of mucous membrane
  • CHRYSIASIS: gold deposit in skin, gray color esp. upon sun exposure
  • PROTEINURIA AND GLOMERULONEPHRITIS
102
Q

Gold Sodium Thiomalate - Adverse effects

A
  • Greater risk of chrysalis and mucosal lesions
  • Anemia and thrombocytopenia
  • Anaphylactic reaction to injection
  • CONTRAINDICATIONS: renal disease, lupus, eczema, gold sensitivity
103
Q

What is arachidonic acid cleaved by

A

Phospholipase A2 and C

104
Q

Prostaglandin synthetase is a combination of

A

Cyclooxygenase + peroxide

105
Q

Enzymes that use prostaglandin as a substrate

A
  • Prostacyclin synthase
  • Thromboxane synthase
  • Endoperoxide isomerase
  • Endoperoxide reductase
106
Q

Kind of pyrogen PGE2 is in hypothalamus

A
  • DIRECT
  • PMNs release cytokines (IL-1) which cross into the hypothalamus
  • IL-1 increases PGE2 levels
107
Q

What is thromboxane a major product of

A

Platelet COX1

PoD - E4 (5 decks)

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