NSAIDs

Vocabulary flashcards covering NSAIDs, COX enzymes, mechanisms, eicosanoids, pharmacokinetics, clinical uses, adverse effects, and acetaminophen.

NSAIDs

Non-steroidal anti-inflammatory drugs

inhibit COX, which inhibits prostaglandins

aspiring is prototype

Characteristics of NSAIDs

no CNS depression, respiratory depression, or drug dependence

inhibit prostaglandin synthesis (COX inhibition)

low dose aspirin is anti-platelet

analgesics and antipyretics

dose depending uricosuric action

Non-selective NSAIDs

Inhibit both COX-1 and COX-2

Irreversible COX inhibitors

Drugs that permanently acetylate COX in platelets

Examples of Irreversible COX inhibitors

salicylic acid derivatives (aspirin, na salicylic acid, sulfasalazine, methylsalicylate)

Reversible COX inhibitors

NSAIDs that temporarily inhibit COX enzymes and reverse with drug clearance

Examples of Reversible COX inhibitors

diclofenac, piroxicam, mefenamic acid

propionic acid derivatives (ibuprofen, ketoprofen, oxaprozin, naproxen)

indole derivatives (sulindac, ketorolac, indomethacin)

Preferential COX-2 inhibitors

NSAIDs with higher COX-2 inhibition relative to COX-1

not fully COX-2 selective

Examples of Preferential COX-2 inhibitors

MEN:

meloxicam

etodolac

nimesulide

Selective COX-2 inhibitors

Drugs that selectively inhibit COX-2

no GIT side effects

can cause renal toxicity

Side effects of selective COX-2 inhibitors

cause increased prothrombotic events like heart attacks and stroke

celecoxib has warning for heart/stroke liabilities

Examples of Selective COX-2 inhibitors

coxibs

Nabumetone

COX1=COX2 inhibitor

COX3 inhibitor

acetaminophen

Pro-Inflammatory effects of eicosanoids mediated by COX2

flushing

swelling

dull, aching pain, with hyperalgesia and allodynia

Eicosanoids

inflammation mediators:

prostaglandins

leukotrienes

Relationship between COX inhibitors and Eicosanoids

COX inhibitors stop production of eicosanoids

Eicosanoids effect on platelets

platelet aggregation by TXA2 synthesis via COX1

Eicosanoids effect on GI

prostaglandins I2 and E2 exert gastroprotective effect

Eicosanoids effect on body temp

fever

Eicosanoids effect on kidneys

prostaglandins I2 and E2 increase renal blood flow via COX

renoprotective effect (increase salt and water loss)

Eicosanoids effect on ductus arteriosus

maintains patency of ductus in fetal life

Eicosanoids effect on uterus

initiate and stimulate labor

Eicosanoids effect on airway

allergic bronchospasm

Prostaglandin Synthesis

occurs from tissue injury

prostaglandins cause inflammation, pain, erythema (vasodilation), and edema (increase capillary permeability)

Mechanism NSAIDs

inhibit COX enzyme and decrease prostaglandin synthesis

lead to pain relief, fever relief, anti-inflammatory effects, GI side effects, and renal side effects

COX1

constitutive enzyme

always present in most cells

housekeeping function

inhibition causes analgesic, antipyretic, and antiplatelet effects

COX2

non-constitutive enzyme (except in kidney)

induced by inflammation via endotoxins, cytokines, and TNF

pro inflammatory function

inhibition causes anti inflammatory effects

NSAID Dose Dependence

low dose has antiplatelet effects

increasing dose leads to pain relief, fever reduction, and decreased inflammation

extremely high doses lead to shock, coma, respiratory/renal failure, and death

tinnitus is definitive for aspirin OD

NSAID Effects

antiplatelet

analgesia

antipyresis

anti-inflammatory

urate excretion

renal effects

NSAIDs & antiplatelet

low doses irreversibly inhibit TXA2 synthesis in platelets via COX1

effects last 1 week

NSAIDs & urate excretion

low dose (<2g/day) causes urate retention

high dose (>5g/day) causes urate excretion

NSAIDs & GIT

gastric erosion

necrosis

ulceration

bleeding via COX1 inhibition

NSAIDs & ductus arteriosus

prescribing near term pregnancy is avoided because it may cause premature closure of ductus arteriosus

NSAIDs & hypersensitivity

inhibition of COX pathway causes diversion to lipooxygenase pathway, which increases production of leukotrienes

NSAIDs & parturition

delay or retard labor by prostaglandin synthesis inhibition

NSAIDs & renal effects

significant with diuretics or antihypertensives in cases of CHF, hypovolemia, liver cirrhosis, renal disease

chronic consumption leads to analgesic neuropathy and renal papillary necrosis

Benefits of Prostaglandin Synthesis Inhibition (NSAIDs)

analgesia

antipyresis

anti-inflammatory

antithrombotic

closure of patent ductus arteriosus in newborn

Toxic Effects of Prostaglandin Synthesis Inhibition (NSAIDs)

gastric mucosal damage

bleeding

delay or prolongation of labor

asthma or anaphylactoid reactions

nephropathy

NSAID Kinetics

therapeutic doses follow first order

becomes zero order at toxic doses

switches from first to zero order

Therapeutic Uses of NSAIDs

pain

fever

inflammation

menstrual cramps

Therapeutic Uses of Aspirin

low dose is antiplatelet

Therapeutic Uses of Acetaminophen

pain

fever

Uncommon Therapeutic Uses of NSAIDs

cystic fibrosis

patent ductus arteriosis

niacin induced cutaneous flush and pruritis

Use of Methylsalicylate

counter irritant in balms

Use of Salicylic Acid

keratolytic agent for corns/warts

Use of Sulfasalazine

inflammatory bowel disease

NSAID CNS adverse effects

tinnitus

aseptic meningitis

NSAID renal adverse effects

decreased renal blood flow

sodium and water retention (leads to HTN)

renal papillary necrosis

renal ischemia and renal failure

NSAID CVS adverse effects

fluid retention

hypertension

edema

NSAID hypersensitivity adverse effects

asthma

urticaria

angioedema

rhinitis, and nasal polyps (in asthma or aspirin exacerbated respiratory disease)

NSAID blood adverse effects

aplastic anemia

thrombocytopenia

neutropenia

NSAID black box warnings

cardiovascular risk

GI risk

Aspirin adverse effects

Asthma

Salicylism (aspirin poisoning)

Peptic ulcer disease

Intestinal blood loss

Reye’s syndrome

Idiosyncracy

Noise (tinnitus)

Reye’s syndrome

Rare and fatal

hepatic damage and encephalopathy

seen in children given aspirin for flu or VZV

aspirin avoided in children under 12

Acute salicylate poisoning symptoms

vomiting, dehydration

restlessness, delirium, hallucinations, tinnitus

hyperventilation

hyperpyrexia

convulsions, coma, death

Acute salicylate poisoning treatment

forced alkaline diuresis with sodium bicarbonate

TXA2

causes vasoconstriction and promotes platelet aggregation

formation of TXA occurs via COX1

PGI2

causes vasodilation and inhibits platelet aggregation

formation of PGI2 via COX2

Aspiring & clotting

irreversible inhibition of COX2 via covalent acetylation of serine at low doses causes clotting

high doses can lead to bleeding because it inhibits more COX1

Co-administration of aspiring with other NSAIDs

other NSAIDs compete for COX1 binding, which interferes with anti-thrombotic efficacy of aspirin

NSAIDs contraindications

peptic ulcer or GI bleeds

chronic liver disease

CHF

diabetes

bleeding disorders

pregnancy

hemolysis in G6PD deficiency

Mechanism of Acetaminophen

inhibition of COX3 only in CNS

no peripheral COX inhibition, so no anti-inflammatory action

Therapeutic Uses for Acetaminophen

decreased opioid requirement in combination with opioids

increased effectiveness in combination with NSAIDs

Acetaminophen is preferred in patients who?

allergic to aspirin

have bronchial asthma

have bleeding disorders

take anticoagulants

have history of peptic ulcer disease

in children under 12

Acetaminophen adverse effects

nephrotoxicity

Acetaminophen metabolism

major pathway is gluconuride/sulfate conjugation

minor pathway is MFOs forming NAPQI

NAPQI

N-acetyl P-benzoquinone imine

toxic metabolite from acetaminophen metabolism

NAPQI detoxification

glutathione pathway

Acute Acetaminophen Poisoning

minor metabolism can be preferred

infants and elderly at risk of lower level of gluconuridation

medications, chronic alcoholism, and smokers at risk of CYP induction

Acetaminophen toxicity

results from depleted glutathione

poor nutrition or alcoholism, compromised liver function, acetaminophen overdose

Acute Acetaminophen Poisoning Treatment

N-acetylcysteine (IV) or oral methionine

Ketorolac (Toradol)

parenteral administration

used instead of morphine for mild to moderate post surgical pain

used with opioids to reduce the required dose

Meloxicam

COX2 preferential, but less selective than celecoxib

low doses associated with fewer GI side effects compared to nonselective drugs

Celecoxib

lower incidence of GI ulceration

spares platelet function because it is prothrombotic

renal side effects same as nonselective drugs

increased risk of CV events due to COX2 inhibition associated thrombosis