PHARM: Non-steroidal Anti-Inflammatory Drugs (NSAIDS) and Acetaminophen

Cyclooxygenase (COX)

an enzyme responsible for formation of prostanoids (including prostaglandins)

Prostaglandins

a group of lipids made at sites of tissue damage or infection that are involved in dealing with injury and illness

Prostaclyclin

inhibits platelet activation and is also an effective vasodilator

Thromboxane

a vasoconstrictor and a potent hypertensive agent, facilitates activation of new platelets and aggregation

COX-1 role on stomach

Helps reduce gastric acid secretion, increase secretion of HCO3 and cytoprotective mucus and maintain submucosal blood flow

COX- 1 role in neonates

Keeps ductus arteriosis patent

COX - 1 role on kidney

Maintains renal blood flow

COX-1 role in blood

Promotes platelet aggregation

COX- 2 role on tissue injury

promotes inflammation and pain sensation

COX-2 role on brain

Mediate fever and contribute to perception of pain

COX- 2 role on kidney

Maintains renal blood flow Promotes tumor growth and metastasis (especially colon & prostate cancers)

COX- 1 components

Prostaglandins

Thromboxanes

what does COX-1 cause

Gastroprotection (↓acid production, ↑mucus production)

Increased platelet aggregation

Renal protection

Vasodilation

Bronchodilation

COX- 2 components

Prostaglandins

what does COX-2 cause

Inflammation

Pain

Fever

Decreased platelet

aggregation

where do NSAIDs blck

after arachidonic acid befor COX 1 and 2

where do selective cox 2 inhibitors block

before arachidonic acid goes to COX-2

therapeutic actions: analgesia

both centrally and peripherally – results from inhibition of PG synthesis in inflamed tissues; produces analgesia for mild to moderate pain; much less than analgesia produced by opioids

therapeutic actions: antipyretic action

fever, heat stroke, inc. temp are hypothalamic problems releasing interleukins

therapeutic actions: anti-inflammatory action

PGs in inflammation lead to vasodilation and inc. vascular permeability; inhibition of PGs by NSAIDS attenuates inflammation; inhibit leukotriene pathway

therapeutic actions: antiplatelet action

inhibits platelet aggregation

NSAID Adverse Effects: GI

Stomach upset, heartburn, nausea - thoughtto be due to direct irritation

ulcers - Decreased protective barriers, decreased platelet aggregation

how to help Stomach upset, heartburn, nausea

EC or SR does not seem to help

Take with full glass of water and food

how to help ulcers

Anti-ulcer meds - H2 receptor antagonists (Pepcid,

etc), PPIs (Prilosec, etc.)

NSAID adverse effect: renal impairment

 Both COX-1 and COX-2 maintain renal blood flow; can cause acute renal impairment

↑risk in underlying kidney disease, concomitant conditions which reduce blood flow (elderly, dehydration, heart failure)

 Increased sodium and water retention - edema

NSAID adverse effects cardiovascular effects

Use with caution in high risk cardiovascular patients

NSAID adverse effects: bleeding

 Non-selective NSAIDS inhibit platelet aggregation - platelets do not express COX-2

 Drug interaction with warfarin, alcohol

NSAID adverse reaction in category

Category D; risk of anemia, postpartum hemorrhage, suppress spontaneous uterine contractions, premature closing of ductus arteriosus in fetus

NSAID and ASTHMA

can increase the risk of acute brinchospasm

NSAID and anti-coagulant drug interaction

mechanism: Displacement – additive effect

effect: Increased anticoagulant effect by displacement; some non-steroidals affect platelet function

NSAID and Lithium drug interaction

mechanism: NSAIDs inhibit renal excretion of lithium

effect: Elevated serum lithium levels, increased risk of lithium toxicity

NSAIDS and anti hypertensives

mechanism: NSAIDs may cause fluid retention and edema

effect: Decreased antihypertensive effects

non-selective NSAID: Ibuprofen (Advil, Motrin)

treatment of muscle pain

• Interactions – warfarin, phenytoin, sulfonamides, cephalosporins, lithium

non-selective NSAID: Indomethacin (Indocin)

Used for treatment of acute gout attacks

• Increased GI and anti-platelet side effect

non-selective NSAID: Ketorolac (Toradol)

powerful analgesic, short term use only (< 5 days); IV followed by PO if needed

non-selective NSAID: Meloxicam (Mobic)

pain of osteoarthritis, musculoskeletal;

• less GI and anti-platelet effect

non-selective NSAID: Naproxen (Naprosyn, Aleve)

musculoskeletal pain,

• longer half-life so less frequent dosing

what to ask about before patient starts taking NSAIDS

all over the counter products

why would you inform dentisit if taking NSAIDS

because they inhibit of platelet aggregation

with prolonged used of NSAIDS there is

an increased risk of adverse effects

NSAID and efficacy

Efficacy of one drug over another has been found to be equivocal – difference in effect is really the individual’s response to meds

if one NSAID isnt effective

another drug may be

how to dose NSAIDs especially in ELDERLY

Lowest dose possible for shortest period – especially in older adults

what to educate patient when talking about nsaids: reporting and advice

Report any adverse effects to provider – GI effects most common -always take with food; Avoid alcohol use

what is aspirin

Non-selective COX inhibition

aspirin has what platelet inhibition

IRREVERSIABLE platelet inhibition

what is aspirin used for

Clot prevention (stroke, MI, angina, etc)

aspirin days of inhibition

 8 days inhibition (life of platelet)

 DC ASA 1 week prior to surgery

when to use caution with aspirin

Coumadin + ASA (aspirin)

aspirin drug interaction: ibuprofen

may block access of ASA to COX-1 in platelets

aspirin drug interaction: glucocorticoids

promote gastric ulceration

aspirin drug interaction: other NSAIDS

ASA decreases blood level of NSAID’s

aspirin absorption

Absorbed rapidly and completely in small intestine

in aspirin the rate of salicylic acid inactivation depends on

amount present

• half life varies from 15 minutes to 20 hours)

aspirin distribution

80 - 90% protein bound, distributed to all body tissues and fluids

aspirin excretion

kidney

the excretion of aspirin is dependent on

urine pH

• (alkaline promotes → OD treatment)

adverse effects of aspirin: GI

gastric distress, heartburn, nausea

Occult bleeding with chronic use

Gastric ulceration - not only from decrease effects of prostaglandins but from irritation by ASA - more likely with extended release

how to treat gastric distress, heartburn, nausea

Take with full glass of water, milk, food - useenteric coated ASA

aspirin adverse effects

• Bleeding

• Renal failure in predisposed patients

• hypersensitivity

aspirin adverse effect: reyes syndrome

 Not used in children< 12 yrs

 ASA + children who had chickenpox or influenza - increased risk

aspirin adverse effect in pregnant people

 Anemia - Post-partum hemorrhage

 Prolongation of labor

 Premature closure of ductus arteriosus in infant, low birth weight, stillbirth, intracranial hemorrhage

adverse effect os aspirin: TINNITUS

hearing loss, vision dimness, H/A, dizziness, confusion, drowsy, sweating, N/V/D, increased heart rate

aspirin overdose treatment

 Decrease absorption - activated charcoal, emetics, gastric lavage

 Enhance excretion – ion trapping (alkalinize urine), forced diuresis, hemodialysis

 Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose

Aspirin patient teaching

 Inform dentist if taking aspirin

 Discontinue ASA 7 days before surgery or as recommended by surgeon

 Keep away from children - poison control

 Take with food, milk, fluids

Selective COX-2 Inhibitors example

Celecoxib (Celebrex)

Celecoxib (Celebrex) characterisitcs

GI risk less, except if taking ASA

Can still cause renal dysfunction, but less

Does not inhibit platelet aggregation

Can cause premature closing of ductus arteriosus

what does Celecoxib (Celebrex) contain

sulfa group -sulfa allergy cross- sensitivity

what does Celecoxib (Celebrex) cause a potential increased risk for

CV events - may be pro-thrombotic

what is acetaminophen

A non-opioid with analgesic and antipyretic effects

acetaminophen mechanism of action

Inhibits synthesis of prostaglandins and peripherally blocks pain impulse generation (oxycodone binds to opiate receptors in CNS)

what does Acetaminophen act on

hypothalamus and reduces temperature (vasodilation and  peripheral blood flow)

Acetaminophen has weak

anti-inflammatory effects

Acetaminophen absoroption

readily absorbed after oral administration

Acetaminophen max dosage

Max dose in 24hrs is 4,000mg

how is Acetaminophen metabolized

by liver via two pathways

liver metabolism: major pathway

acetaminophen undergoes conjugation to form nontoxic metabolites

liver metabolism: minor pathway

oxidized by a P-450 containing enzyme into a highly toxic substance which is normally converted to a nontoxic form using glutathione

Acetaminophen overdose

more is processed via minor pathway, glutathione depleted and toxic metabolite accumulates in liver (damage)

adverse effects of acetaminophen

Rare at therapeutic doses (not > 4 gm/day)

overdose of acetaminophen can cause

severe liver damage

if you use acetaminophen with alcohol

there is an increase risk of liver injury

• Alcoholics often have liver damage - unable to tolerate injury caused by acetaminophen

• moderate consumption: increase risk with normal doses of acetaminophen

if you use acetaminophen with warfarin

it inteferes with metabolism

early signs of overdose/toxicity of Acetaminophen: early signs

N/V/D, sweating, abdominal pain

early signs of overdose/toxicity of Acetaminophen: hepatic necrosis

overt symptoms appear 48 to 72 hours after ingestion

hepatic necrosis symtoms

 Dark urine, clay colored stools, jaundice, anemia

 Pruritis, abdominal pain, cyanosis

 Delirium  convulsions, vascular collapse, coma, death

early signs of overdose/toxicity of Acetaminophen: chronic overdose

bleeding, bruising, malaise, sore throat

early signs of overdose/toxicity of Acetaminophen: chronic poisoning

rapid, weak pulse, dyspnea, cold, clammy extremities

how to minimize damage of Acetaminophen overdise

with acetylcysteine - substitutes depleted glutathione

how to treat Acetaminophen overdose

 Best if given soon after ingestion, but can protect liver if within 24 hours - early serum levels may not indicate toxicity

 10 - 20% solutions diluted to 5 %

 Mucomyst diluted in fruit juice, water, or cola

 Initial dose is 140 mg/kg, additional doses of 70mg/kg given q4h for the next 72 hours

 Very unpleasant odor and may induce vomiting - give through oroduodenal tube