Antipyretics, antiinflammatory and analgesics aspirin, non steroidal antiinflammatory drugs, acetaminophen and gold

Question 1

Prostaglandins and leukotrienes general

Answer 1

Family of oxygenated products of polyunsaturated fatty acids

Prostaglandins (PGs): PGD2, PGF2alpha, PGI2
Thromboxanes (TX): TXA2
Leukotrienes (LTs): LTC4, LTD4, LTE4

Question 2

Prostaglandins and leukotrienes general 2

Answer 2

nature of the precursor fatty acids affects the function of the eicosanoid:

arachadonic acid forms PGI2, PGE2, TXA2

Eicosapentaenoic acid: PGI3, PGE3, TXA4

Question 3

Phosopholipase A2 and C

Answer 3

Arachadonic acid cleaved by the phosopholipids

AA > (cyclooxygenase) PGG2 > (Peroxidase) PGH2 > PGI2, TXA2, PGE2, PGF2alpha

Question 4

Prostaglandin synthetase

Answer 4

Cox-1 and Cox-2

Cox-1 found in blood vessels, stomach and kidney. House keeping functions- always present and wildy distributed. Increased stomach mucus > protects mucosa from HCl.

COX-2 infolved in inflammation, levels elevated by ifnlammation and cytokines, decreased by administration of glucocorticoids (Look at slides)

COX-3

Question 5

MoA prostaglandins

Answer 5

Act locally (short half life)- paracrine or autocrine

prostagladins exert their action by interacting with a receptor (GPCRs)

post receptor events following prostaglandin binding to receptor include -increaes or decreased adenylate cyclase and stimulation of phosphatidlinositol

major effects on smooth muslce; other effects on platelets, kidne, CNS, endocrine organs, eye

Question 6

Prostacycline (PGI2)

Answer 6

Synthesized by both vascular smooth muscle cells and endothelial cells (major contributor of COX2)

Circulation: powerful vasodilator and inhibits platelet aggregation

airways: powerful bronchodilator

GI: inhibits gastric acid secretion; increase mucus secretion

renal: enhances renal excreton fo sodium and water
reproductive: relaxes uterine muscle
pain: induces pain by lowering the threshold of nociceptors.

Question 7

Prostaglandin (PGE2)

Answer 7

Vascular: vasodilator

Platelet: low conc- enhances and high conc inhibits platelet aggregation

Airway: bronchodilator

GI: inhibits gastric acid secretion and stimulates gastric mucus secretion (misoprostol (arthrotec, cytotec) used to prevent ulcers produced by NSAID)

Renal: promotes renal salt and water excretion

Reproduction: unterine smooth muscle, increases contraction

fever and inflammation: induces hyperalgesia, erythema, swelling (vasodilator) at a localized area. Fever: PGE2 is a direct pyrogen in hypothalamus. PMN’s release cytokines (IL1) which cross into hypothalamus; interleukin-1 increases PGE2 levels.

Question 8

Thromboxane (TXA2)

Answer 8

synthesized by platelets, lung, kidney and other sites

vascular vasocontriction

stimulates platelet aggregation (major product of platelet (COX1)

Question 9

PGF2alpha

Answer 9

vascular vasoconstrictor

airway contracts airway smooth muscle cells

reproductive- contracts uterine smooth muscle/dysmenorrhea

eyes-decreased intraocular pressure

Question 10

Misoprostol (cytotec)

Answer 10

PGE1 analogue

Use: inhibits gastric acid secretion, reduces risk of peptic ulcer in patients taking NSAID

Contra: Pregnancy, women of childbearing age must use contraceptive measures

Question 11

latanoprost (xalatan)

Answer 11

penyl substituted prostaglandin F2 alpha analogue

Use opthalmic prepartion for open angle glaucoma

mecahnism: increases uveoscleral outflow which lowers intraocular pressure

Question 12

Alprostadil (prostin) PGE1

Answer 12

Use: temporarily maintain patency of the ductus arteriosus for adequate blood oxygenation until surgery.

PGE1, vasodilator; increase pulmonary blood flow

constant IV infusion

Question 13

Leukotriene biosynthesis and actions

Answer 13

1. lipoxygenase pathway forms 5 hydroxyeicosatetraenoic acid (5-HETE)
2. 5 HETE and LTB4 are chemotactic agents
3. LTC 4 and LTD4 (LTE4): potent bronchoconstrictor and increase vascular permeability. Components of slow reacting substance of anaphylaxis (SRS-A). LTC, LTD4, and LTE4 are known as cystinyl leukotrienes

Question 14

Zafirlukast (accolate) and MOntelukast (singulair)

Answer 14

Zafirlukast (accolate) and MOntelukuast (singulair): Mechanism competitive luekottire LTD4 (cysteinyl Luekotriene 1) receptor antagonist.

Inhibit leukotriene mediated bronchoconstriction and vascular permeability.

Use: prophylactic agent in treatment of astham in adults: Note not indicaed for acute astham attacks. Zafir age >5 and Monte > 1.

Allergic rhinits

aspirin sensitivity induced asthma montelukast only.

Comparison: Montelukast allows once daily dosing (zafir 2x per day)

zafirluakst must be taken 1-2 hour before eating

zafil inhibits cyp 2c9 and cyp 3a4

montelukast can be used in children 1 year old.

Question 15

Zafirlukast AE, Drug-drug, drug food interaction

Answer 15

AE: HA and pharyngitis

drug drug: zafirlukast inhibits p450 isozyme cyp 2C9 and CYP 3A4. warfarin

Drug food interaction: take on empty stomach, 1-2 hours prior to food. Food reduces bioavailability to 40%

Question 16

Montelukast AE

Answer 16

AE: HA

Question 17

Zileuton (zyflo)

Answer 17

MoA: Inhibitor of 5 lipoxygenase

use: prophylaxis for asthma in adults and children (12 yr and older) not indicated for acute asthma attacks

AE: Elevated liver enzymes; must monitor ALT

Contra: active liver disease. Combination with ergot alkaloids (cafergot), used for migraines

Drug interactions: decrease clearance of theophylline, warfarin, and propranolol

Question 18

NSAID: names and MOA

Answer 18

Preparations: nonselective: aspirin, iuprofen, naproxen, oxaprozin, indomethacin, sulindac, ketorolac, diclofenac.

Selective cox 2 inhibitors: celecoxib, rofecoxib, valdecoxib

MoA: Inhibit cyclo-oxygenase. Aspirin irreversible inhibitor. All other NSAIDs are coemptitive, reversible inhibitors. Non selective inhibits cox 1 and 2 and the cox 2 more selective for cox 2.

Question 19

NSAID: Theraputic and SE

Answer 19

Actions: antipyretic, inhibit PGE synthesis in hypothalamus. Analgesics for mild to moderate pain. Good antiinflammatory activity. Inhibit prostaglandin synthesis at localized area.

SE: Gi irritation, pain, and ulcer. Bleed, inhibits paltelet aggregation. Inhiit uterine motility, avoid use in the last trimester of pregnancy. Cross sensitivity with aspirin (contra). FLuid retention

Question 20

Salicylates Aspirin: MoA, Uses

Answer 20

MoA: irrevesible cyclooxygenase inhibitor. acetylates the enzyme.

Therapeutic action: Analgesic (mild to moderate), antipyretic and antiinflammatory activity. Rheumatoid and osteoarthritic good agent for initial therapy (side effects limit use0. Low dose (60-80mg) aspirin irreversibly inhibits TXA2 production in platelets * prevents MI but bit prolong bleeding.

Low dose aspirin recommended for preeclampsia beginning in the late first trimester for women with historyof early onset preeclampsia and preterm delivery at <34 week gestation or preeclamsia in more than one prior pregnancy.

Question 21

Salicylates Aspirin: Prep and AE

Answer 21

Prep: aspirin preparations include buffered, enteric coated and effervescent. Effervescent: high sodium. 2016 durlaza (a 24 hour extended relase aspirin 162.5 mg capsules) (avaible only by prescription) for secondary prevention of MI and stroke.

AE: GI pain, hemorrhage and ulcers (high incidence). Urate excretion varies with dose. <2 gm aspirin ddecreased urate excretion. >5gm/day increased urate excretion

additional contra: viral infection with or without fever due to risk of reyes syndrome in children.

Question 22

Proprionic and arylacetic acids

Answer 22

Agents: Ibuprofen, naproxen, oxaprozin, ketoprofen, fenoprofen

Mechanism: reversible inhibition of cyclo oxygenase

uses: mild to moderate pain, symptoms of rheumatoid and osteoarthritis, antipyretic

AE: less GI ulcer and problems than aspirin

Ibuprofen: antipyretic, can be used in children. Rheumatoid and osteoarthritis, acute migraine attacks, primary dysmenorrhea.

Naproxen (aleve): Rheumatoid osteoarthritis and ankylosing spondylitis. Acute gout. Primary dysmenorrhea. Acute migraine attacks. tendonitis. Naproxen clearance reduced in liver cirrhosis. FDA: increased risk of stroke/cardiovacular event.

Question 23

Ketorlac Use

Answer 23

use: ophtalmic seasonal allergy and for inflammation following cataract removal.

Moderate to severe pain, poster operative pain IV, IM, oral. ONly NSAID approved for moderate to severe pain. In jected form is comparableto morphine. Advantage over morphine is non habit forming and longer duration. Used for short term use for < 5 days. Analgesic activity than antiinflammatory activity.

Question 24

Ketorlac AE and contra

Answer 24

AE: Bleeding inhibits platelet aggregation. Hepatic monitor ALT/AST levels. Lower dose in patients under 110 lbs or > 65 years old or elevated creatnine.

contra: history of peptic ulcer or presence of GI bleeding,
renal disease, presence of situations with increased bleeding (hemophilia) must stop prior to surgery, cerebrovascular bleeding, concurrent use of probenecid, during labor/delivery or during lactation, concurrent use of other NSAIDs.

Question 25

Diclofenac Use

Answer 25

rheumatoid osteoarthritis and ankylosing spondylitis

primary dysmenorrhea (diclofenac potassium only)

opthalmic prepartion for pain and inflammation from cataract surgery

artotec combination dicofenac and misoprostol for patients with high risk of gastric and duodenal ulcers.

2014 FDA approved a low dose diclofenac for mild to moderate acute pain

2015: IV diclofenac: mild to moderate pain or in combination with opioid for moderate to severe pain.

Question 26

Diclofenac AE

Answer 26

Metabolized by cyc2c9. GI pain, nausea, cramps, diarrhea, diziness, HA, artotec contraindicated during pregnancy.

Question 27

Indomethacin uses

Answer 27

uses: oral: Rheumatoid or osteo arthritis, ankylosing spondylitis, acute gout attacks, tendinitis.

IV: closure of patent ductus arteriosus.

Nonsurgical close of patent ductus arteriosus: Indomethacin (iv) high sucess of closure without surgery. AE: Bilirubin displacement from plasma albumn Diminished renal function.

Question 28

Indomethacin AE and contra.

Answer 28

Contra: hyperbilirubinemia and renal failure.

AE: Gi pain (take with food) and HA

Question 29

Cox-2 inhibitor celecoxib , rofecoxib, and valdecoxib: MoA and Use

Answer 29

MoA: selective cox 2 competitive reversible inhibitor.

Therapeutic concentrations have less effect on COX-1

Use: celecoxib: rheumatoid and osteo arthritis

Rofecoxib: voluntarily withdrawn from market.

Valdecoxib: rheumatoid and osteoarthritis.

Question 30

Cox-2 inhibitor celecoxib , rofecoxib, and valdecoxib: Drug drug and AE

Answer 30

Drug drug: celecoxib metabolized by p450 cyp2c9. Monitor dose carefully when given with fluconazole (inhibits CYp2c9)

AE: Gi pain, nausea. FDA alert december 2004. increased risk of cardiovascular and troke even with high dose for prolonged time.

Question 31

General considerations for the use of NSAID

Answer 31

1. cross sensitivity with aspirin, higher incidence in asthma.
2. most common AE is GI pain and ulceration. Worse aspirin and indomethacin
3. Avoid in last trimester of pregnancy. premature closure of patent ductus arteriosus (decrease oxygenation) and bleeding during labor.
4. Altered renal functions with NSAIDs. Salt and water retention. Acute renal fialure worse for indomethacin. Occurs in conditions with decreased renal perfusion live failure, nephortic syndrome. Premature infans, elderly. Hyperkalemia most liekly to occur in eldery, diabetes mellitus, renal insufficiency. Drugs that icrease risk of hyperkalemia, propranolol, potassium sparing diuretics, ACE inhibitors.

Question 32

APAP

Answer 32

Alernative to aspirin. Antipyretic, analgesic for mild to moderate pain, osteoarthritis, alternative to aspirin less gi upset and does not affect platelets.

Activity: possesses comparable activity to aspirin for antipyretic and anagesic action. Poor antiinflammatory activity.

MoA: Weak Cox 1 and Cox3 and Cox 2 inhibition.

AE: Hepatotoxicity (Acute) and renal toxicity associated more wth chronic use.

Question 33

Gold salts: Drug names and moA

Answer 33

Auranofin (oral) and gold sodium thiomalate (given IM)

a disease modifying antirhematic drug (DMARD)

use early active rheumatoid arthritis not responding to NSAIDs.

MoA: inhibit maturation and function of mononuclear phagocytes and T cells. Decrease levels of rheumatoid factor. Inhibits migration and phagocytosis of macrophages (gold taken up by macrophages)

Question 34

Gold salt: AE and contra

Answer 34

can be delayed for months after cessaton of therapy.. Stomatitis. Nephrotic syndrome, same in auranofin. ANaphylactic rxn to IM injection. Gray pigmentation of skin (chrysiasis), exfoliatve dermatitis, pruritus. Anemia and thrombocytopenia.

Contra: lupus, presence of kidney or renal disase, sensitivity to gold, presence of skin disorder of eczema or urticarial.