Back to Basics Practical Pharmacology – part deux Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team March 2013 [email protected]
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Back to Basics Practical Pharmacology – part deux Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University.
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Back to BasicsPractical Pharmacology – part deux
Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team
2. Fibrates • (The exact mechanism of action of gemfibrozil is unknown; Theories re:
the VLDL effect; it can inhibit lipolysis and decrease subsequent hepatic fatty acid uptake as well as inhibit hepatic secretion of VLDL; together these actions decrease serum VLDL levels; increases HDL-cholesterol; the mechanism behind HDL elevation is currently unknown)
• (Inhibits absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1)).
4. Niacin5. Cholestyramine
• (Bile acid sequestrant)
Efficacy – Endpoints?
• Hard Endpoints– Reduction in mortality
• Fatal MI, Fatal stroke
– Reduction in morbidity• Non-fatal MI, non-fatal stroke, reduction in hospitalization
• Soft Endpoints– Reduction in plaque size– Reduction in lipid panel values– etc
Efficacy
• Only statins have any proven reduction in hard endpoints.
The End.
Who cares about lipid panel numbers going up and down if they don’t affect morbidity or mortality?
So….why bother with the Toxicity, Cost orInconvenience of any others?
Can J Cardiol Vol 25 No 10 October 2009
Cdn Dyslipidemia Guidelines 2009
Can J Cardiol Vol 25 No 10 October 2009
Cdn Dyslipidemia Guidelines 2009
Can J Cardiol Vol 25 No 10 October 2009
Pharmacotherapy
• “The majority of patients will be able to achieve target LDL-C levels on statin monotherapy.”
• “Clinical outcome data on the incremental benefit of combination therapy with statin plus ezetimibe, niacin or fibrate, versus statin monotherapy are lacking, although clinical trials are underway to examine this issue.”
• So….• If equivalent LDL lowering with non-statin
drugs have no effect on morbidity or mortality then LDL may only be a surrogate marker of the pleiotrophic effects of statins.
Bottom Line• Being on any statin at any dose is the most
important thing.• Being on the highest dose of statin that a
patient can tolerate is secondary.– Doubling the statin dose only lowers LDL by 6%– Pushing the statin dose to levels that result in side
effects is just not worth it. Non-compliance will result.
• The LDL target is just your guide.
Exceptions• Gemfibrozil
– Two trials that show reduction in CVD events• Helsinki Heart Study (HHS)• Veterans Administration HDL Intervention Trial (VA-HIT)
– Never combine it with statins• Serious risk of rhabdomyolysis
• N.B. Fenofibrate– No effect on CVD events
• Fibrates for high TGs – reduce risk of pancreatitis• Fibrates for high TGs – treatment of gout
Statin + Fibrate (ACCORD-Lipid Trial)
• No difference in vascular (hard) outcomes. – Almost a difference in lipids values (ie. soft outcomes)– ?Possible vascular harm in women? [9.1% vs 6.6%]
• No hard endpoints reported.• Even intima-media thickness non-significant
– IMPROVE-IT Trial still ongoing (expected 2013)– “Dr Steven Nissen (Cleveland Clinic, OH) questioned whether
the trial would be completed because more than 5000 hard clinical end points are needed for the study to reach statistical significance, an unusually high number given that past studies required a few hundred events.” (see: http://www.theheart.org/article/1064755.do )
Rxfiles.ca. ENHANCE Trial Summary, June 2008. Accessed Apr 26/12.
• Earlier Statin + Niacin studies had only showed reduction in soft endpoints. – Eg. Regression of carotid atherosclerosis
Statin + Niacin(AIM-HIGH Trial)
Michael O'Riordan. AIM-HIGH fell short, leaving experts looking for reasons in new review. Heart.org APR 19, 2012. Accessed Apr 25/12Rxfiles.ca. AIM-HIGH Trial Summary, Dec 2011. Accessed Apr 29/12.
Treatment Populations
• Who gets statins? – Secondary prevention – Primary prevention?– Moderate risk??– Put it in the water???
Secondary Prevention
• Clear efficacy• Reduction of
mortality• Reduction of
morbidity• Benefit in as
little as one year – (usually 4-5
years)
Primary Prevention
• Clear efficacy in High Risk Framingham
• Reduction in morbidity
• No effect on mortality
Primary Prevention(never had an MI or Stroke)
• High risk Framingham patients with history of:– Diabetes– CKD– CHF– Angina– PVD– CABG or PCI– Metabolic syndrome– Score > 20%
Moderate Risk
• Likely not worthwhile…• BUT, the JUPITER trial = reduction in hard
endpoints!– Patients with low/normal cholesterol and high CRP– Relative Risk Reduction ~ 50%!– But the Absolute Risk Reduction was tiny!– hsCRP can differentiate between higher- and lower-
risk Moderate Category Framingham patients
Ridker PM, et al. the JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med. 2008 Nov 9.
JUPITER trialN Engl J Med 2008;359:2195-207.
Rosuvastatin:22/8901 (0.28%) of non-fatal MI
Placebo: 62/8901 (0.70%) of non-fatal MI
Relative vs Absolute Risk
Time to Benefit
• How old is too old to start therapy?– Upper ages of trials ~ 80-83 yrs old. – …Add time to divergence of survival curves
• ~ 4 to 6 years…plus• ?Prognosis
• Older than 85y.o, don’t start?– Already on it, don’t stop, but don’t bother
checking LDL either.
Pharmacotherapy
• “The majority of patients will be able to achieve target LDL-C levels on statin monotherapy.”
• “Clinical outcome data on the incremental benefit of combination therapy with statin plus ezetimibe, niacin or fibrate, versus statin monotherapy are lacking, although clinical trials are underway to examine this issue.”
Can J Cardiol Vol 25 No 10 October 2009
“…Trials (were) Underway…”
• Statin + Niacin trials:• AIM-HIGH trial
– Stopped early. No benefit from niacin in HDL raising.
• See: http://www.theheart.org/article/1231453.do
– Known risk of hepatotoxicty with Niacin and significant flushing.
• HPS2-THRIVE trial (statin + ER Niacin/Laropiprant)
– No benefit (n = 25673)• See: http://www.theheart.org/article/1515533.do
Pharmacist, Bruyere Academic FHTAssistant Professor, Dept Family Medicine, U of Ottawa
March 2013
Objectives
Pain: Somatic vs Neuropathic
Somatic• WHO Pain Ladder:
1. Acetaminophen2. NSAID3. Acetaminophen or NSAID +
“weak” opioid (eg. Codeine)
• Eg. Tylenol #2, Tyl#3, 222’s,
4. Pure “strong” opioid• Hydromorphone• Oxycodone• Morphine• Codeine
Neuropathic• TCA
– Nortriptyline– Amitriptyline
• Gabapentin• Pregabalin• Anti-epileptics
– CBZ– VPA– Phenytoin
Acetaminophen• MOA: unknown
– (NAPQI metabolite may interfere w/ TRPA1 mediated pain transmission in the spine)
• Efficacy – Equivalent analgesia and antipyresis to NSAIDs
• Eg. OA, non-inflammatory pain
• Toxicity– Much less GI upset vs NSAIDs, no PUD, no ARF– Liver toxicity in overdose – N.B. combo OTC products!
• Cost– Cheap!
• Convenience– Q4h dosing, same as NSAIDs
Choosing NSAIDs
As ever, work through the 4 steps: 1. EFFICACY: What are the endpoints of interest?
1. Analgesia2. Anti-inflammation3. Antipyresis
• All NSAIDs are generally considered equivalent for each endpoint.
• Few useful comparative trials published
Efficacy - Analgesia• Efficacy vs placebo
– Clearly beneficial– Lots of evidence (RCTs, meta-analyses etc)
• Efficacy vs other NSAIDs– Indirect evidence of differences in analgesia.
• Single dose studies only• Acute pain only• Limited number of indications & comparators
– Ass-u-me-s we are able to extrapolate data
• See Oxford League Table (Table 1) – here: http://www.clinmedres.org/content/5/1/19.long – N.B. ONLY compares EFFICACY
Ong CKS et al. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. ClinMedRes 2007;5(1):19-34 see: http://www.clinmedres.org/content/5/1/19.long Accessed Oct 31, /11
Ong CKS et al. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. ClinMedRes 2007;5(1):19-34 see: http://www.clinmedres.org/content/5/1/19.long Accessed Oct 31, /11
– Heavy Metal Poisoning – Mercury, Lead, Arsenic, Bismuth
– Lithium
Toxicity – Renal Triple Whammy!
Katarzyna K Loboz and Gillian M Shenfield. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol. 2005 February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/ Accessed Oct 31/11
N.B. There is no correlation between symptoms of dyspepsia and GI mucosal damage as seen on endoscope.
Toxicity - Gastrointestinal• GI ULCER Risk: ~annual risk 1-4% • Elevated odds ratio (OR) with: (Consider adding PPI)
– Hx of ulcer complication OR =13.5– Multiple NSAID OR = 9– High dose NSAID OR = 7 – Concomitant anticoagulant OR = 6.4– Age≥70 OR = 5.6 – Age ≥60 OR = 3.1– Concomitant steroid OR = 2.2 – Hx heart dx OR = 1.8
NSAID comparison chart. p69 Oct 11 – Access Nov 11/11 www.Rxfiles.ca
Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I study. Am J Med 2006; 119:255-266
Landmark CLASS trial(Celebrex® / Celecoxib)
• “… an interim report of the first 6 months of data from 2 trials that lasted 12 and 16 months.” – “… at …16 months there was no difference in GI adverse
effects between celecoxib and traditional NSAID groups.” • Discovered because crucial info was posted on FDA
2. Pharmacodynamic (PD)– What the drug does to the body
PK – 1) Absorption Interactions
• Important in family practice: – Chelation (binding interactions)
• Less commonly clinically relevant:– Alteration of gastric pH– Alteration of GI motility
1. Aymard JP et al. Med Toxicol Adverse Drug Exp 1988;3:430-48.2. Murray J.J. et al. JAMDA 1991;1:p.3. Lomaestro BM et al. Drug Intell Clin Pharm 1991;25: 1249-58.
PK – 1) Absorption InteractionsChelation
1. Fluoroquinolones or Tetracyclines plus minerals [Minerals = calcium (Ca2+) , magnesium (Mg2+) , iron (Fe3+) , aluminum (Al3+)] [Almost all buffering antacids (TUMS, Gaviscon, Milk of Magnesia, Rolaids, etc.), as well as MVITs, iron tabs etc.]
– Risk of treatment failure!
2. Bisphosphonates plus minerals– Risk of osteoporotic fracture
3. Phenytoin plus minerals– Potential loss of seizure control
Separate administration by 2 hours
PK – 1) Absorption Interactions
• Alteration of gastric pH– Increased pH
• Eg. Iron / Ketoconazole / Vit B12 absorption is reduced• Administer with OJ or Coca-cola
• Alteration of GI motility– Decreased motility
• Eg. Decreased absorption of Levodopa– Increased metabolism at intestinal brush border
– Increased motility• Eg. Decreased absorption of Digoxin
PK – 2) Distribution Interactions
• Displacement Reaction – (from protein binding sites)– Rarely significant – Often need:
• Highly bound drug – (98% bound to 96% bound = 100% increase in free concentration)
• PLUS, you often need inhibition of metabolism (or elimination) to allow enough time for these effects before redistribution to a new steady state.
PK – 2) Distribution Interactions
• Eg. Warfarin + Septra– Displacement of warfarin off protein binding sites
• (plus inhibition of metabolism and Vitamin K synthesis by gut flora)
• Eg. Phenytoin + Valproic acid– Displacement of phenytoin off binding sites
• (plus inhibition of metabolism and zero order kinetics (enzyme saturation kinetics) of
phenytoin)
Hogan M.J. et al. DNS Aug. 30, 1999 http://www.findarticles.com/p/articles/mi_m3374/is_13_21/ai_55693815/pg_4 Accessed Apr 18/12
PK – 3) Metabolism Interactions
• Metabolism occurs in many places– Skin, lung, intestine, serum, kidney, liver– Most metabolism occurs in the liver
• Few interactions with non-oxidative metabolism – (ubiquitous enzymes)
– Not everything is P450• P-glycoprotein poorly understood so far
– Genetic variability becoming more important• Isoniazid, codeine
PK – 3) Metabolism Interactions
• Cytochrome P450 isoforms – so many!• Family - Subfamily - Genotype (eg. 2-C-19) (18) (42) (60)
– Substrates, inhibitors, & inducers for each isoform!– 3A4 - most common
• Inducers:
• Ask: Time to effect?– ~ 2 weeks to kick in– ~ 2 weeks to fade out
Katarzyna K Loboz et al. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol. 2005 February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/pdf/bcp0059-0239.pdf Accessed Apr 18/12
Katarzyna K Loboz and Gillian M Shenfield. Drug combinations and impaired renal function – the ‘triple whammy’. Br J Clin Pharmacol. 2005 February; 59(2): 239–243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/ Accessed Oct 31/11
2) NSAIDs vasoconstrict afferent arterioles (inh of PG synthesis)
1) Diuretics reduce forward flow into kidney
Result:
Reduced GFR & Acute Renal Failure!
Rarities (that never seem rare enough)
Serotonin Syndrome
– Hyperstimulation of 5-HT 1A & 2A receptors• Peripherally and centrally
– Concentration dependent symptoms • Mild - tremors and diarrhea • Severe – hyperthermia and rigidity, even death.
– Rare in monotherapy• Usually with polypharmacy
Rastogi, Rahul et al. Case Scenario: Opioid Association with Serotonin Syndrome: Implications to the Practitioners. Anesthesiology: December 2011 - Volume 115 - Issue 6 - p 1291–1298 see: http://journals.lww.com/anesthesiology/Fulltext/2011/12000/Case_Scenario___Opioid_Association_with_Serotonin.24.aspx Accessed Apr 18/12.