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Drug Question
New Height Clinic Pharmacy
Ted Williams 2008
Introduction
New Height Clinic does not provide opioid analgesics for pain. We rely heavily on
NSAIDS, particularly ibuprofen to manage pain. COX-2 inhibitors like Vyoxx and
Celebrex have been derided for increasing the risk of cardiovascular events. To what
extent do other non-opioid analgesics introduce cardiovascular risks?
Pathophysiology
Non-steroidal anti-inflammatory (NSAID) medications block the activity of
cyclooxygenase (COX) enzymes. Isoenzymes COX-1 and COX-2 have differing effects,
with COX-2 being the more inducible form and COX-1 more active at a basal level.
Therapeutic effects of analgesia, antipyresia, and anti-inflammation are attributable to
both COX-1 and COX-2.1 Most side effects of NSAIDs and COX inhibition are
associated with inhibition of COX-1, including platelet aggregation, Gastrointestinal (GI)
side effects, renal function changes, and hypersensitivity reactions. GI and renal effects
are primarily due to the inhibition of prostaglandin and prostacycline production.
Prostaglandins are responsive for regulating GFR, Choloride ion reabsorption in the renal
tubules, vasopressin release, and Endothelin-1 release.2
Prostaglandins regulate afferent arteriole tone and thereby
regulate GFR. Increases in prostaglandin synthesis
produce afferent arteriole smooth muscle relaxation and
subsequent vasodilation, leading to increased GFR. In
otherwise healthy adults, prostaglandin inhibition is
compensated for by the renin-angiotensin system, which
also regulates GFR in the renal arterioles.3 In the
hypertensive patient, the rennin-angiotensin system is
either compromised or its compensatory capacity is
compromised. Most antihypertensive medication also
work either in the renal tubules (diuretics), on the reninFigure 1. Prostaglandin Cascade
angiotensin system (ACE Inhibitors, Angiotensin II
affecting hemodynamics
Receptor Blockers, Beta Blockers), or affect vascular
smooth muscle (non-dihydropyridine calcium channel
blockers), further limiting compensatory mechanisms of maintaining GFR.
Trials and Studies
The Vyoxx debacle gave a bad name to COX-2 selective inhibitors due to their increased
risk of cardiovascular events.4 Non-selective COX inhibitors continue to be used widely
in patients with and without hypertension. Interestingly, at least one study demonstrated
that non-selective COX inhibitors (naproxen) and selective COX-2 inhibitors (celecoxib)
have similar effects on prostaglandin levels.2
In normotensive patients, NSAIDs do not cause a clinically or statistically significant
increase in blood pressure at doses of 1200mg of ibuprofen daily for 8 days.3
Drug Question
New Height Clinic Pharmacy
Ted Williams 2008
In hypertensive patients, risk of hypertension due to NSAID use appears to be associated
with frequency and duration of therapy and somewhat with dose.3 The Nurses Health
Study (NHS) I and II evaluated the use of NSAIDs in women with hypertension from age
31-50years. Relative risk ratio increased in both studies when frequency exceeded 5 days
per month and plateaued after 2 weeks of therapy.5,6 These increases were seen with
doses as low as 400mg/day. Two seminal meta-analyses by Pope et al7 and Johnson et
al8 found that in patients with well controlled hypertension, on low sodium diets, NSAID
increased blood pressure by 3.2mmHg. Other studies have reported increases as high as
10mmHg and 12mmHg.3 Although these increase are small, sustained changes of 56mmHg over several years can increase the risk of stroke 67% and CAD 15%. 9 It is
important to note that comparable changes in blood pressure are found with other
commonly used medications like oral contraceptives (5mmHg).3
Acute renal failure is also a concern when taking NSAIDs, due to selective inhibition of
efferent arteriole vasodilation. One large scale nested case-control study from the UK
evaluated the effects of prescription NSAID use and the risks of ARF.10 Relative risk of
ARF while using NSAIDs is 3.2. This increases with the concurrent use of diuretics
(11.6RR), CCB (7.8). Patients with HF and HTN taking NSAID saw an increase in risk
of ARF (7.63RR, 6.12RR) when taking NSAIDs vs. HF and HTN patients not taking
NSAIDS (2.82RR, 2.09RR).
Although most research has been focused on COX-2 seletive inhibitors and NSAIDs,
acetaminophen is also a COX inhibitor. Acetaminophen’s effects on renal function have
been demonstrated to be similar to other NSAIDs.11 In a study simiar to the NHS design,
the hypertensive effects of acetaminophen, NSAIDs, and Asprin were evaluated in
otherwise healthy men.12 The results were similar to the NHS results, showing a
significant increased risk of hypertension with increasing frequency of use of NSAIDs.
Importantly, these risks also increased with the use of NSAIDs and Acetaminophen..
Conclusions
Non-opioid and non-steroidal analgesics all work by inhibition of COX enzymes. This
shared mechanism leads to similar analgesic effects and side effects for NSAIDs and
APAP. Blood pressure is not significantly changed in normotensive patients, but there
are statistically and clinically significant changes in patient with hypertension. The risk
of ARF is increased in all patients using NSAIDs, with the greatest increases in patients
with Heart Failure, Hypertension, and on medications treating hypertension. Patients
requiring a non-steroidal, non-opioid analgesic should be monitored carefully when
taking either NSAIDs or APAP for fluid retention, increases in blood pressure, and renal
function.
1
Goodman and Gilman Chapter 26 Burke, A., Smyth, E., and FitzGerald, G.A., ANALGESICANTIPYRETIC AGENTS; PHARMACOTHERAPY OF GOUT.
2
Gaziano, JM. Nonnarcotic Analgesics and Hypertension. American Journal of Cardiology 2006;97
Suppliment 10E-16E.
3
Wilson, S, Poulter, N. The effects of non-steroidal anti-inflammatory drugs and other commonly used
non-narcotic analgesics on blood pressure level in adults. Journal of Hypertension 2006:24:1457-1469
Drug Question
New Height Clinic Pharmacy
Ted Williams 2008
4
Sequence of Events with VIOXX, since opening of IND
http://www.fda.gov/OHRMS/DOCKETS/AC/05/briefing/2005-4090B1_04_E-FDA-TAB-C.htm
5
Dieder, J, et al. Nonnarcotic analgesic use and the risk of hypertension in US women. Hypertension
2002:604-608
6
CurhanGC, Willett WC, Rosner, B, Stampfer, MJ. Frequency of Analgesic Use and Risk of Hypertension
in Younger Women. Archives of Internal Medicine 2002;162:2207
7
Pope, JE, Anderson, JJ, Felson, DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory
drugs on blood pressure. Archive of Internal Medicine 1993; 153:477-484
8
Johnson AG, Nguyen TV, Day RO. DO nonsteroidal anti-inflammatory drugs affect blood pressure? A
meta-analysis. Annals of Internal Medicine 1994;121:289-300
9
MacMahon, S, Peto, R, Culter, J, Collins, R, Sorlie, P, NEaton, J et al. Blood pressure, stroke, and
coronary heart disease. Part 1. Prolonged differences in blood pressure: prospective observational studies
corrected for the regression dilution bias. Lancet 1990; 335:765-74
10
Huerta, C, Castellsague, J, Varas-Lorenzo, C, Rodrigues, LAG, Nonsteroidal anti-inflammatory drugs
and risk of ARF in the general population.
11
Fored, CM, et al. Acetaminophen, Aspirin, And Chronic Renal Failure. New England Journal of
Medicine. 2001;345:25
12
Forman, JP, Rimm, EB, Curhan, GC. Frequency of Analgesic Use and Risk of Hypertension Among
Men. Archives of Internal Medicine. 2007;167:394-399