SPRING 2014 NSAIDS Prostaglandins Marty Foster MSN, CRNA.

SPRING 2014

NSAIDS

Prostaglandins

Marty Foster MSN, CRNA

Normal Immune Response (cont'd)

• Cells involved in immune response– Mononuclear phagocytes– Lymphocytes

• B lymphocytes• T lymphocytes

– T cytotoxic cells– T helper cells

• Natural killer cells

– Dendritic cells

Fig. 14-6

• Inflammation:

• Mediated by neutrophils, macrophages, monocytes,eosinophils and basophils

• Stage l: vascular, brief vasoconstriction

• Stage ll: hyperemia, edema

• Stage lll: tissue repair Inflammation

Inflammatory Response

• Vascular response

• Cellular response– Neutrophils– Monocytes– Lymphocytes– Eosinophils and basophils

Fig. 13-1

Fig. 13-2

Fig. 13-3

Inflammatory Response (cont'd)

• Chemical mediators– Complement system– Prostaglandins and leukotrienes

Fig. 13-4

Fig. 13-5

Inflammatory Response (cont'd)

• Exudate formation

• Clinical manifestations– Fever

• Types of inflammation– Acute– Subacute– Chronic

Fig. 13-6

• Prostaglandins

• Classification: Eicosanoids/autocoids

• History: 1930, Euler of Sweden

• Chemistry: 20 carbon fatty acid chain

• Nomenclature:

• PG=prostaglandin

• 3rd letter=structure of cyclopentane ring

• Subscript=number of double bonds

• Are Statins Anti-Inflammatory?• Decreased:• Natural T cells• Number of rejections after heart transplant• Thrombus formation• IL-6 and TNF• C-reactive protein• Serum amyloid beta protein found in AD

Pain Mechanisms Transduction

• Conversion of a mechanical, thermal, or chemical stimulus into a neuronal action potential– Occurs at the nociceptors

Pain Mechanisms Transduction

• Noxious stimuli cause release of a “biologic soup” of chemicals– These substances activate nociceptors and

lead to generation of an action potential carried to the spinal cord

Pain Mechanisms Transduction

• Inflammation increases the likelihood of transduction– Peripheral sensitization

Pain Mechanisms Transduction

• Two types of pain– Nociceptive

• Activation of peripheral nociceptors

– Neuropathic• Abnormal processing of stimuli by the nervous

system

• Synthesis of PGs:

• Arachidonic acid is the precursor

• MOA: PG increase cAMP (2nd messenger, adenylate cyclase), releasing protein kinase A and intracellular Ca++ (vascular relaxation)

• Metabolism of PGs: via enzymes found in lungs, kidneys, liver and G.I. tract

• 95% of infused PGE-2 inactivated in one passage through the lungs (protective filter for CVS and other organs/local hormone)

• TXA elimination half life is 30 seconds so that effects are felt only in the micro-environment.

• Prostacyclin: half life 3 minutes

• PG effect on organ systems:• Blood:• TXA---PLT aggregation and

vasoconstriction/hemostatic plug• Prostacyclin---PLT inhibition and vasodilation• Normal TXA/Prostacyclin ratio important r/t PLT

activity and coagulation• Increased ratio leads to increased TXA resulting

in decreased BF, ischemia or infarction in brain, kidney or heart

• Blood continued:• Increased ratio in venous system:

thromboembolism• Prostacyclin may yet have a role in

extremity pain, healing in PVD, M.I.• PLT COX(TXA) more sensitive to ASA

than endothelial COX (PGI)• Large doses of ASA inhibits both TXA and

PGI

Prostaglandin Analogues and Inhibitors

• Prostacyclin (PGI2, Epoprostenol)• Intense vasodilation• Potent inhibitor of PLT aggregation• Elimination half-life, 6 minutes• Protect IV solution from light• May decrease pulmonary and SVR resulting in intrapulmonary

shunting• Can be used in HD for PLT inhibition• Limited d/t hypotension• With CPB; less thrombocytopenia, post-op bleeding• Used for pulmonary artery hypertension with improved

hemodynamics and 6-minute walk distance• Used in inhaled for in ARDs with limited success

• Epoprostenol continued

• Requires indwelling CVP catheter with related risks of infection, air embolism and thrombosis.

• Potential for rebound pulmonary hypertension is abruptly discontinued.

• Unstable at room temperature; requires ice packs around the medication cassette

• Inhaled PGI2 and NO equal in ability to decrease PAP and increase PaO2 (cheaper, no risk of metHb)

• Iloprost• Analogue of PGI• PLT inhibitor: PLT activity returns in 30 minutes• Less hypotension but still may be resistant to

phenylephrine• Pulmonary Hypertension: via inhaler 2.5-5 mcg q

2-4hrs (brand name Ventavis)• IV administration shows improved PVR, CO,

PAPs, and exercise tolerance

• Treporostinil• Stable analog of epoprostenol that does not

require refrigeration• Approved for continuous IV or SQ use• Half life of four hours• Injection site pain the most dose-limiting side

effect• Studies being done for an aerosolized drug

delivery system to assess safety and efficacy with promising results

• Desmopressin:• Anti-diuretic, procoagulant• Synthetic Vasopressin analogue/ADH• Indicated in diabetes insipidus (10 mcg nasal

spray), CPB• Acts as a general endothelial stimulant via PG

resulting in PLT adhesiveness• Increases Factor 8, von Willebrand’s (hemophilia

A) factor; 0.3 mcg/kg/IV pre-op

• PG effect on CVS:• PGs promote vasodilation in most vascular beds and

enhance Na+ excretion• PGE produces chronotropy, ionotropy and inhanced

SNS activity• IV prostacyclin decreases SVR and SBP. Not inactivated

in the lungs so an effective IV vasodilator• PGE and prostacyclin responsible for transition of fetal

circulation to that of nml neonate. PG inhibitors (Indocin) aids closure of PDA (TXA:PGI)

• PG effect on CVS cont:• Mesenteric txn during aortic surgery produces

facial flushing and hypotension, probably mediated by PGI

• Inhaled prostacyclin decreases pulmonary vascular resistance without the hypotension associated with NO…less expensive and no metHb

• PGF enhances vasoconstriction in the atelectatic lung potentiating HPV…improved ventilation:perfusion

• Alprostadil (PGE1, Prostin VR Pediatric)• Vasodilator of vascular smooth muscle• PLT inhibitor• Maintains PDA until surgical shunt done• Rapid metabolism mandates continuous infusion• Dilute in NS or D5W• .05-0.1 mcg/kg/min• Many side effects/use for shortest time and lowest dose

possible• Theoretical use in erectile dysfunction, ARDS, ARF

• PG effect on Lungs: • Major site of PG synthesis• Abnml TXA:PGI may contribute to asthma• Leukotrienes 1000x more powerful than

histamine (note the ineffectiveness of anti-histamines in asthma)

• ASA induced asthma may be r/t inhibition of COX pathway, more arachidonic acid available for lipo-oxygenase pathway

• For pulmonary hypertension (see Iloprost)• Flolan:prostacyclin• Permanent central line: ice pack• Exercise tolerance is improved• Many SE and potential adverse rxns• Start at 2ng/kg/min• Other prostacyclin analogues: Uniprost,

Beraprost, Treprostinil (latter does not require refrigeration)

• Remodulin:• Continuous SQ infusion• Small quiet pump• Stable at room temp• Bosentan:• P.O. competitive antagonist of endothelin-1• Expensive• Not easily available

• Kidneys:• Intrarenal release of PGs modulate RBF, GFR• Major site of PG synthesis• Mediates renin-aldosterone system• Influences afferent and efferent arterioles• NSAIDs do not affect renal hemodynamics in the

normal kidney• If renal vasoconstriction exists, NSAIDS may

increase vasoconstriction

• Mistoprostol:

• PGE1 analogue

• Decreases incidence of acute rejection in kidney transplant

• Gastric acid inhibitor: can be used with NSAIDS though H2 blockers, PPIs preferred(Cytotec)

• Can provoke abortion/miscarriage

• Uterus:

• PGs important for the initiation of labor

• TXA:PGI imbalance may lead to PIH

• PGs may cause dysmenorrhea

• Carboprost (Hemabate) (PGF)

• Used in post-partum hemorrahge after IV oxytocin, uterine massage and IM ergot

• 250 mcg (1mL) deep IM

• Total dose: 2 mg

• May have fever: distinguish from endometritis

• Not stable at room temperature

• Order of Therapy for Postpartum Hemorrhage:• Oxytocin• Ergonovine• Methlyergonovine• Carboprost• Mistoprolol• Uterine vessel ligation• Internal Iliac artery ligation• B-lynch suture• Arterial embolization• Emergency peripartum hysterectomy

• Immune system:• PG accentuates pain and edema via bradykinins• Other PGs suppress allergic reactions• Certain tumors may produce PGs and thereby

suppress the immune system (wounded tissue produces hydrogen peroxide. Some cancer cells do the same, co-opting the immune system into protecting their growth)

• Pain

• PGs lower the threshold for nocioception

• Leukotrienes produce hyperalgesia

• Aspirin• Classification: Salicylate• History:• Hippocrates, 5000BC, extracted powder

from the bark of a willow tree• 1857: sodium salicylate developed for pain• 1875: German chemist, Hoffman, working

for Bayer concocted a less acidic salicylate, acetylsalicylic acid

• Chemistry:

• ASA is an ester of acetic acid

• Mechanism of action:

• Irreversible acetylation of the COX enzyme

• Resultant decreses in the synthesis and production of PG

• PLT life about 10 days so ASA must be dc’d 2 weeks prior to surgery

• At low levels ASA inhibits TXA synthesis

• At higher levels, ASA inhibits PGI

• ASA is a weak inhibitor of renal PG

• Analgesic/antipyretic dose fro adults is 325-650 mg q 4hrs. plasma concentration of 60ug/mL. half-life 2-3hrs

• Anti-inflammatory dose is 4-6 g daily. plasma concentration of 150-300 ug/mL. half-life 12 hrs

• Fatal dose is 10-30 g.plasma concentration 450 ug/mL. half-life 15-30 hrs

• Aspirin pharmacokinetics• Rapidly absorbed from G.I. tract • Distributed through most body tissues• 80-90% bound to plasma proteins.competing for

binding sites with thyroxine, PCN, phenytoin, NSAIDs

• Hydrolyzed in blood and liver to salicylic acid. Half-life 15 minutes

• Inactivation occurs mainly in the liver through the formation of conjugates that are excreted in the urine

• Clinical use• Analgesic effect in headache, OA and RA• Antipyretic: prevents pyogen-induced release of PG• Anti-inflammatory; inhibits PGs peripherally• TIA and stroke prevention• PIH; corrects TXA/PGI imbalance • Alzheimer's; 1/08 large CV health study showed less risk

of AD only in those with certain genetic markers• Cancer; for colorectal,prostate,lung ASA may decrease

tumor progression, invasion and mets

• Adverse effects• G.I.• Hematologic• Hepatic• Endocrine• Obstetric• Allergic rxns• Renal• Glucose6PD deficiency

• G.I.

• Direct drug effect on stomach; nausea, heartburn

• Hematologic:• PLT inhibition leads to prolonged bleeding

time and PT• Liver dx, Vitamin K deficiency, hemophilia

and ASA use may result in hemorrhage• Bruising, melena, epitaxis more common

with ASA use• Pre-op ASA use can increase CT drainage

following CABG

• Increased liver enzymes associated with ASA usually reversible

• Large doses of ASA may increase blood sugar

• ASA not associated with ESRD unlike acetominophen

• CNS/Respiratory:

• Aspirin toxicity-Salicylism

• Mild intoxication with aspirin

• Experienced when the dose exceeds 4 g

• S&S are tinnitus, high frequency hearing loss. Headache, nausea, dimness of vision

• Symptoms reversible 2-3 days after withdrawal of the drug

• Aspirin toxicity: changes in acid-base balance

• Increased O2 consumption and CO2 production as a result of the uncoupling of oxidative phosphorylation

• Increased CO2 stimulates respiratory balancing production and maintenance of plasma CO2

• Salicylates stimulate the respiratory center in the medulla resulting in hyperventilation

• Respiratory alkalosis results

• Kidneys excrete bicarb to compensate

• After toxic doses or prolonged exposure the medulla is depressed, leading to respiratory and metabolic acidosis

• Aspirin toxicity treatment:

• Gastric lavage

• Activated Charcoal

• IV to restore pH, fluids and electrolytes

• Hemodialysis, exchange transfusion

Obstetric:• DC ASA before expected time of delivery

to avoid prolonged labor and postpartum bleeding (reflecting nml uterine effects of PGs)

• No evidence of fetal damage with maternal ASA use

• Long term ingestion is associated with low birth weights

• Salicylate use in children:

• Reyes syndrome is associated with a virally induced fever/varicella or influenza and concomitant use of Aspirin

• No causal evidence but strong epidemiologic evidence

• S&S of Reyes syndrome:

• Cerebral edema

• Encephalopathy

• Disorientation, confusion

• Combativeness

• Liver damage, failure

• Fatty infiltration of brain and liver

• Glucose-6-phosphate dehydrogenase deficiency:• ASA causes mild hemolysis with this deficiency• Decreased amounts of glutathione leads to precipitation

of Hb in RBCs and hemolysis• Hematuria and hypotension may result • Asian, Mediterranean and African males more likely to

be affected• These patients are susceptible to fava beans, sulfa, anti-

malarials, methylene blue, prilocaine and nitroprusside.• Protect RBF with fluids and diuretics

• Anesthetic consideration:

• History: ID those at risk, note all meds including herbals

• Feverfew, ginko bilboa, evening primrose increase risk of bleeding with ASA use

• DC ASA 1-2 wks prior to surgery

• Bleeding time to assess PLT has little value

• Allergic reaction rare but can be life-threatening

• Hypersensitive reaction not immunologic

• Patients who are allergic to ASA cross react to all PG inhibitors and are advised to avoid all NSAIDs

• Allergic reaction• Tachycardia• Hypotension• CVS collapse• Cardiac arrest• Urticaria• Flushing• Wheezing• Increased PIP• Hypocarbia• Decreased SaO2

• Pulmonary edema• Laryngeal edema

• To treat:• Stop causative agent• Secure airway• FiO2 100%• DC anesthesia• Increase volume 20 mL/kg• Epinephrine• H1 and H2 blocker/Benadryl/Zantac• Beta 2 agonist/albuterol, terbutaline• Aminophylline• Steroid• Sodium bicarb

• ASA-induces asthma occurs in 8-20 % of all asthmatic adults

• Incidence greater in those with rhinosinusitis or a history of nasal polyps

• Can be accompanied by life-threatening bronchospasm and hypotension

• Not an allergy, a hypersensitive response not immunologic

• NSAIDs:

• One of the most frequently prescribed meds in the U.S.

• More $$ spent developing NSAIDS

• Elderly consume a disproportionate share of these meds

• Clinical uses for NSAIDS:• Pre-operative• Adjunct during GA, MAC and post-op pain mgt• Cancer pain• Chronic pain• Dysmenorrhea• Thrombosis prevention• Gout• Fever• Vascular headache relief• Eye inflammation• Gum disease• Familial polyposis• Prevention of Alzheimer’s

NSAIDS are analgesic agents

• Reduces capillary permeability

• Stabilizes the mast cell

• Inhibits PG production (lowers threshold of the C fiber nocioceptors

• Stops bradykinin from stimulating pain receptors

• NSAIDs are anti-inflammatory

• Mediators of inflammation:

• PGs

• Histamine

• Thromboxanes

• Leukotrienes

• NSAIDS are anti-pyretic• Inhibiting the effects of PGS on the

thermoregulatory center's (TRC) set point• Lowering the TRC set point that is

elevated during fever• The concentration of cytokines (ILs,

interferons, TNF) elevated during inflammation which stimulates PGE2 near the hypothalamus

• NSAIDS are anti-coagulants:

• Prolongation of clotting time

• Clotting factors inhibited

• PLT aggregation inhibited

• Injury:

• Increased intracellular CA++

• Cascade

• Activation of phospholipase A2

• Release of Arachodonic Acid

• COX-1:

• Constitutive

• Promotes PG production

• Protects GI tract

• Hemostasis

• COX-2• Inducible• Expressed mainly at sites of injury• Mediates pain, fever, inflammation and

carcinogenesis(liberates free radicals with direct oncogenic effect)

• May facilitate tumor invasion, angiogenesis, and mets

• COX-2 up-regulation in the spinal cord as a result of surgical inflammation may be important to central sensitization

• Chemistry:

• Organic acid

• History:

• 1971:

• Vane et al show low concentrations of ASA and Indocin inhibit production of PGs

• It was known at that time that PGs involved in pain and inflammation

• Pharmacodynamics:• COX inhibition with resultant decrease in

peripheral and central synthesis of PGs• Most inhibit COX-1 and COX-2. • Recent ID of third isoform, COX-3,that may be

blocked by acetaminophen• Selective COX-2 inhibitors spare COX-1

cytoprotection• NSAIDS may enhance suppressor t cell activity

thus suppressing rheumatoid factor

• Merck & company withdrew Vioxx from the market after FDA found it associated with 140K cases of heart disease and as many as 56,000 deaths during the 5 yrs it was on the market 9/04

• This study used data collected fro Kaiser Permanente, Ca. collected over a 3 year period

• Bextra withdrawn 4/05• Only Celebrex left/give shortest time and lowest

dose possible

• Pharmacokinetics:• Well-absorbed in G.I. tract• Low 1st pass hepatic extraction• 95% protein bound• Lipid soluble NSAIDS cross BBB with potential

for change in cognition, mood• Weakly acidic. pH favors preferential

sequestering in the synovium of inflamed joints• 6-10 hr half lives• Hepatic and renal biotransformation and

excretion

• Adverse reactions:• Dyspepsia; peptic ulceration rare• Renal adverse effects often unrecognized; those with

hypertension and/or CHF at risk for ARF• Skin reactions frequent• Increased post-op bleeding• Aseptic meningitis; may follow ibuprophen and H2

blocker. women with autoimmune dx at greater risk. Recovery with withdrawal of drug

• Hepatic dysfunction with some NSAID classes; at greater risk if Hep C +

• Bone healing impaired; not recommended for spinal fusion patients

• G.I. effects:• PGs are cytoprotective; blocking them will

interfere with normal G.I. fxn• More leukotrienes available to contribute to

ulceration• Some correlation with H pylori infection• Anti-ulcer tx recommended but adaptation may

occur• Unwise for those with hx of gastric bleeding• Can still have gastric perf with Celebrex even

with brief use

• Renal effects:• None in the healthy• NSAIDS can produce renal ischemia in the diseased kidney• ARF can be precipitated in those with CHF, cirrhosis with ascites

(hepatorenal failure) or hypovolemia• Water and salt retention promoted by NSAIDS affect HTN tx though

effect is small (5 mm Hg)• Acetaminophen associated with 8-10% of ESRD• No NSAID other than low dose ASA can be prescribed with absolute

safety r/t adverse renal effects• Cautious use in elderly r/t CRF• For CHF use lowest dose possible for symptom relief for the

shortest course possible as NSAIDS put these patients at risk for AKI, hyperkalemia and volume overload

• Coagulation effects:• Non-specific NSAIDS inhibit COX-1 impairing

the ability of the PLT to aggregate• Platelets do not contain COX-2 such that COX-2

inhibitors have no effect on PLT aggregation, bleeding time or post-op blood loss (Stoelting 2006)

• Thrombotic events may occur more frequently with COX-2 inhibitors reflecting suppression of vasoprotective PGI2

• Cutaneous effects:

• Rare

• Erythema multi-form

• Steven-Johnson syndrome

• Toxic epidermal necrolysis

• Obstetric:

• Inhibition of uterine motility; prolongation of gestation

• May increase the risk of miscarriage

• Geriatric:

• Elderly at risk for concommitent organ system dysfunction

• Patients greater than 70 should start with ½ the usual dose and increase only if no toxicity

• Consider polypharmacy

• Pediatric:• Indocin; powerful COX inhibitor. May be

used with LBW babies to close PDA. PDA allows fetal blood to bypass non-functioning lungs and pick up O2 from mom’s blood

• Conversely, PGs may be given to babies with congenital heart defects to keep ductus open until surgery can be done

• Tylenol:• Strong central inhibition of PG confers analgesic and

anti-pyretic properties• 10-15 mg/kg q 6-8 hrs• Some recommend 20-40 mg /kg rectally prior to surgery

and half that dose later. Do not exceed 5 doses in 24 hrs• Overdose most common cause of acute liver failure• Overdose tx is lavage, charcoal and mucomyst (anti-

oxidant highly effective if given within 8 hrs of overdose• New IV acetamenophen, Ofirmev, is opiod sparing. Give

over 15 minutes. May mask fever.

• Consider pediofen in healthy kids prior to surgery and post-op.5-10 mg/kg

• Give round the clock post-op

• Can alternate with Tylenol

• Max dose is 50 mg/kg/day. use lowest effective dose. Short tx duration only

• NSAID Families:

• Fenamates

• Acetic acid derivatives

• Propionic acid derivatives

• Oxicam derivatives

• Drug interactions

• Anticoagulants

• K+ sparing diuretics

• Antihypertensives

• Phenytoin

• Probenicid

• Anesthetic implications:

• Decreases post-op pain in ambulatory surgical cases (lap procedures)

• May be used intrathecally in future

• Pre-op: DC NSAIDs 24-96 hrs (5 elimination half lives effect of NSAID on PLT only while in the system.

• In the O.R. Torodol/Ketorolac;• Max dose 120 mg/24 hrs• Less than 65 yrs give 30 mg IM and 30 mg IV when

closing. Especially effective in gyn and ortho procedures. Then 30 mg IM x 6 doses. Use only 30 mg preservative free vial for IV use.

• Less than 50 kg or >65, or with impaired renal fxn, max dose 60 mg/24 hrs

• 30 mg compares to 10 mg Morphine/100 mg Demoral• Available in intranasal form.• Oral dose also time limited.

• IV rate of administration, over 1-2 minutes• Onset 30-60 mins, T1/2 3.8-8.6 hrs, based on age and clinical condition.

duration 6-8 hrs. peak after IV administration in 45 minutes.• Post-op: may give 10 mg p.o. qid; don’t give > 5 days• Contra-indications: NSAIDor ASA allergy,compromised renal fxn, history of

easy bleeding, previous PUD, triad of nasal polyps (common in cystic fibrosis), rhinitis and asthma.

• Pregnancy drug risk Category C; safety for use not established• Not for children <16 yrs• Drug interactions:• Potentiates salycilates, Lithium, Methotrexate• Additive: NMB• Probenicid inhibits clearance so plasma level of NSAID is increased• Has been associated with seizures in patients taking Tegretol or Dilantin• Opiod use decreased 20-50 % with NSAID

• Bleeding time increased by a single IV dose to patients with spinal anesthesia

• Bleeding time not increased in pts with GA

• Hypercoagulable state produced by neuro-endocrine response to surgical stress during GA not spinal anesthesia.

• Ketorolac not given for spinal or epidural anesthesia

• Parecoxib:

• COX-2 inhibitor

• More potent than Torodol; 20-40 mg compares to 30-60 mg of Torodol

• Like other COX-2 inhibitors may be pro-thrombotic. Adverse CV effects following CABG in 2 studies