http://www. nlm. nih. gov/medlineplus/
2.
http://www. blackmores. com. au/products/joint-formula-with-glucosamine-chondroitin
http://www. naturesway. com/
3. Interaction between health supplements and prescription medication
Part A is answered for interaction between various agents
Fish oil and aspirin A clinical study was carried on 10 healthy patients to investigate the effect of omega 3 fatty acid prescription in combination with aspirin on the platelet aggregation effect and bleeding time. Aspirin alone inhibited platelet aggregation in presence of low concentration of collagen. Omega3 fatty acid treatment did not inhibit platelet aggregation under the experimental condition; however combination of aspirin and omega 3 fatty acid inhibited blood platelet aggregation. This study demonstrated the efficacy of prescribing omega-3 fatty acid (fish oil) with aspirin to enhance its anti-platelet effect. This clinical study describes a synergistic interaction between aspirin and omega -3 fatty acid, making this a “ Pharmacodynamic” interaction between two agents. ( Larson MK, Ashmore JH, Harris KA, Vogelaar JL, Pottala JV, Sprehe M, Harris WS. Effects of omega-3 acid ethyl esters and aspirin, alone and in combination, on platelet function in healthy subjects. Thrombosis and homeostasis. 2008: 100(4): 634-41.)
Ginkgo biloba and Omeprazole: The active ingredient of ginkgo biloba had been demonstrated to induce CYP2C19. A study was initiated on eighteen healthy subjects to evaluate the effect of combination of ginkgo biloba on a CYP2C19 substrate omeprazole. The concentrations and other pharmacokinetic analyses was performed on omeprazole and its metabolites, 5-hydroxyomeprazole and omeprazole sulfone isolated from urine and blood. The plasma concentration of omeprazole and omeprazole sulfone was decreased while 5- hydroxy omeprazole level was elevated when supplement of ginkgo was co-administered. It was determined from the study that ginkgo supplement enhanced the metabolism (hydroxylation) of omeprazole by induction of CYP2C19.
As a result a decrease in the activity of omeprazole was observed when taken in conjunction with ginkgo supplement. It can be classified as a ‘ Pharmacokinetic interaction’. The metabolism and clearance of omeprazole was enhanced due to induction of its metabolizing ennzyme b. This study was a clinical study. (Yin OQ, Tomlinson B, Waye MM, Chow AH, Chow MS. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics. 2004 Dec; 14(12): 841-50)
Interaction between St. John’s Wort and Oxycodone. Oxycodone is metabolized by CYP450 enzymes. A. The CYP3A4 metabolic pathway is the major while CYP2D6 is the minor pathway for oxycodone metabolismSt. John’s Wort is known to induce the enzymatic activity of CYP450 pathway. St. John’s Wort lowered the effective concentration of oxycodone. This would mean that the patient is getting less analgesic benefit from oxycodone. It can be classified as a ‘ Pharmacokinetic interaction’ (Söderberg Löfdal KC, Andersson ML, Gustafsson LL. Cytochrome p450-mediated changes in oxycodone pharmacokinetics/pharmacodynamics and their clinical implications. Drugs. 2013 May; 73(6): 533-43.)
St. John’s Wort with Zocor: A study was performed to evaluate the effect of co-treating St. John’s Wort supplement with Simvastatin (Zocor). The authors describe the study to be “ Controlled, randomized, crossover study.” Following study completion it was demonstrated that the LDL levels in patients treated with Hypericum perforatum were increased as opposed to control. Similarly elevated level of total-cholesterol was also observed. This loss of drug activity was observed once again due to induction of CYP3A4, the enzyme pathway responsible for metabolism and clearance of Simvastatin. It can be classified as a ‘ Pharmacokinetic interaction’ (Eggertsen R, Andreasson A, Andrén L. Effects of treatment with a commercially available St John’s Wort product (Movina) on cholesterol levels in patients with hypercholesterolemia treated with simvastatin. Scand J Prim Health Care. 2007 Sep; 25(3): 154-9.)
The common theme observed is the induction of CYP450 induced metabolic pathway which results in increased metabolism and inactivation of many of the drugs. This could result in decreased effectiveness of a number of medications for our patient Howard Bloom.
b. The various studies identified in this process are all clinical trials and a meta- analysis. They utilize robust statistical analyses and employ adequate controls in addition to the intervention. The sample sizes for most of the studies are however very small. They have 10-24 participants. It would be more useful to perform studies with larger sample size. However, the patient should be informed of these interactions and recommended to stop taking the supplements. Larson MK,
Larson, Ashmore JH, Harris KA, Vogelaar JL, Pottala JV, Sprehe M, Harris WS. Effects of omega-3 acid ethyl esters and aspirin, alone and in combination, on platelet function in healthy subjects. Thrombosis and homeostasis. 2008: 100(4): 634-41.)-Clinical trial
Yin OQ, Tomlinson B, Waye MM, Chow AH, Chow MS. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics. 2004 Dec; 14(12): 841-50-Clinical trial
Söderberg Löfdal KC, Andersson ML, Gustafsson LL. Cytochrome p450-mediated changes in oxycodone pharmacokinetics/pharmacodynamics and their clinical implications. Drugs. 2013 May; 73(6): 533-560 Meta Analysis
Eggertsen R, Andreasson A, Andrén L. Effects of treatment with a commercially available St John’s Wort product (Movina) on cholesterol levels in patients with hypercholesterolemia treated with simvastatin. Scand J Prim Health Care. 2007 Sep; 25(3): 154-9. Clinical Trial
4. The drug allocated to me for part 2 is “ Atenolol”.
Atenolol is indicated for hypertension or elevated blood pressure. It is also used to treat chest pain (angina) and it is useful in improving the survival rate following a heart attack. It is also indicated for myocardial infarction. Myocardial infarction may have led to heart failure in Mr. Bloom. Atenolol is a beta blocker. It specifically targets the beta-1(-1) adrenoreceptors. The -1 receptors are activated by norepinephrine. Activation of -1receptors results in increased rate and force of contraction of heart postsynaptically. By inhibiting the rate of contraction of heart atenolol lowers blood pressure. At the pre-synaptic level atenolol inhibits the release of norepinephrine, which essentially triggers -1receptor activation. Atenolol also effectively result in vasodilation and reduce cardiovascular stress.
Fig1. Demonstration of effect of beta blocker on heart contraction and vasodilation
(Source: www. studyblue. com)
5. Studies demonstrating clinical efficacy of Atenolol.
The first study that I have identified is a “ Multicenter Study of Perioperative Ischemia Research Group”. The study was performed to evaluate the efficacy of Atenolol in patients who were at risk for cardiovascular disease and were undergoing non-cardiac surgery. The study recruited 200 patients. Of these 200 patients, 91 received atenolol while the other 101received placebo control. Patients who had received atenolol as opposed to placebo had a better rate of survival 6, 12 and 24 months post surgery. Event free survival was observed in 83% of atenolol treated patients as opposed to 60% of patients who received placebo over two year observational period. This conclusion from this clinical study was that atenolol improves the survival rate in patients who are at risk for cardiovascular disease and undergoing non cardiac surgery. It also reduces the heart related complications post surgery. (Mangano, D. T., Layug, E. L., Wallace, A. & Tateo, I. for the Multicenter Study of Perioperative Ischemia Research Group. Effect of Atenolol on Mortality and Cardiovascular Morbidity after Noncardiac Surgery. N Engl J Med 1996; 335: 1713-1721DOI: 10. 1056/NEJM199612053352301)
– The second study was performed to evaluate the efficacy of atenolol in patients with asymptomatic ischemia. It was a randomized, double-blind, placebo-controlled study. The study recruited 306 patients who suffered from mild or no angina due to coronary artery disease. The patients were randomized to receive placebo or 100 mg dose of atenolol daily. The measure of outcome was reduction in events one year following treatment. Four weeks following treatment the number and duration of ischemic episodes went down in patients getting atenolol and demonstrated better event free survival in patients who took longer to have first adverse event as compared to placebo. This study demonstrated that patients have asymptomatic ischemia arising from coronary heart disease were at a better chance of adverse event free survival and low risk of adverse outcome following atenolol treatment as opposed to placebo. (Hansson L, Aberg H, Karlberg BE, Westerlund A. Controlled study of atenolol in treatment of hypertension. Br Med J. 1975 May 17; 2(5967): 367-70).
b. Based on these two clinical studies atenolol is an effective treatment of choice for hypertension, long term management of angina and myocardial infarction. It can also be indicated for asymptomatic ischemia.
6. Effect of GTN on survival benefit.
The first study was a randomized prospective evaluated the efficacy of GTN in improvement of clinical symptoms or preservation of ischemic myocardium. GTN was administered IV for 48 hours after incidence of myocardial infarction and compared to the effect seen with placebo control. The size of the study sample was 104, with 56 patients assigned to GTN treatment group and 48 patients received placebo control treatment. When retrospective division of patients was done to early and late treatment (who received treatment at less than 10 hours or 10 hours after onset of symptoms of myocardial infarction), early GTN was associated with fewer events (heart failure, death, etc) and mortality. The conclusion demonstrated from this study was that GTN was effective in lowering rate of mortality and heart failure only when administered within 10 hours of appearance of symptoms and in patients with small to mid size myocardial infarctions only. (Flaherty, J. T., Becker, L. C., Bulkley, B. H., Weiss, J. L, Kallman, C. H., Silverman, K. J. and Weisfeldt, J. L.(1983). A randomized prospective trial of IV nitroglycerin in patients with acute myocardial infarction. Circulation, 68, pp. 576–588)
The second study was an initial double blind study that was performed on 140 patients with acute myocardial infarction who received intravenous infusion of GTN or placebo for 48 hours. Within 12 hours of symptom onset patients were randomly divided into treatment or control group. GTN treatment group had improvement in diastolic blood pressure. Reduction in mortality rate was also observed, however the reduction was not very significant. At the three month follow up 83% patients treated with GTN resumed to normal activities as opposed to 60% of placebo treated group. This was preliminary study that documented the usefulness of glyceryl trinitrate in patients with acute myocardial infarction. (Y. Lis, D. Bennett, G. Lambert, D. Robson. A preliminary double-blind study of IV nitroglycerin in acute myocardial infarction. Intensive Care Med, 10 (1984), pp. 179–184)
b. Glyceryl trinitrate sublingual spray is converted to nitric oxide that increases the vasodilation of contracted blood vessels, making it easier to pump blood to heart. Sublingual administration allows for quick relief from angina pain and quick vasodilation effect. It also improves the amount of oxygen delivered to the heart. This form of medication also used in prophylaxis of anticipated heart attack.
7.
a. Preexisting conditions to be considered, blood pressure, allergies, presence of erectile dysfunction( if exists), fluid retention and edema (Lasix), Aspirin, time passed since onset of symptoms.
b. It should be taken into account that patient takes Lasix as a diuretic. GTN is known to interact with Furosenamide which is present in Lasix. If he continues to take Lasix while taking GTN, he might have clinically ineffective concentration of GTN. If he is allergic to nitrates and if he is still offered GTN it may trigger anaphylactic shock instead of lowering his heart attack symptoms. If he is taking Sildenafil (Viagra), it might lower his BP to dangerously low level. GTN could exhibit interaction with aspirin.
c. The most important risk benefit factor to consider is how much time has passed since onset of his symptoms. As it has been demonstrated that the majority of patients that demonstrated improvement following treatment with GTN received the drug within hours of onset of symptoms (Flaherty, et. al. 1983). So it makes sense to give the patient GTN, only if his symptoms are ongoing. If he has known allergies to nitrates the use of GTN would not make sense. GTN interact with Lasix and Aspirin, so it should be realized that intake of GTN might lower active concentrations of both drugs. It will have to be determined whether some decrease of diuretic activity is acceptable in order to control the heart attack symptoms.
d. If the patient has taken slidenafil, the use of GTN will have to be avoided. However to answer the effect of interaction of GTN with lasix and aspirin, their use might be suspended for a brief time. The dose of GTN should be high enough to overcome the effect of drug interactions.
Flaherty, J. T., Becker, L. C., Bulkley, B. H., Weiss, J. L, Kallman, C. H., Silverman, K. J. and Weisfeldt, J. L.(1983). A randomized prospective trial of IV nitroglycerin in patients with acute myocardial infarction. Circulation, 68, pp. 576–58
http://www. nlm. nih. gov/medlineplus/druginfo/meds/a601086. html
http://www. mayoclinic. com/health/drug-information/DR602937/DSECTION= before-using
8.
The first reference identified is a meta analysis study that measured the effectiveness of a anti-platelet agent as opposed to a placebo control or compared the efficacy of two anti-platelets. This meta analysis involved 287 studies with 135 000 patients where antiplatelet therapy was compared to control while, 77 000 patients were participants in comparison study of different antiplatelet drugs. The analyses of data from various studies demonstrated that Aspirin exhibits protection in most types of patient at increased risk of acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, STEMI. Being a meta analysis patients were evaluated over different time periods. (Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71–86.)
The second study was a 2 by 2 factorial design analysis. 25000 patients were assigned to low or high dose clopidogrel or low (75-100 mg) or high dose aspirin (300-350 mg aspirin daily). The patients were observed on day 30and cardiovascular death, myocardial infarction, or stroke were the outcomes analyzed. Patients suffering from acute coronary syndrome did not exhibit difference in outcome between the lower or higher aspirin dose. High dose aspirin was involved in bleeding complication. ( CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Eikelboom JW, Fox KA, Granger CB, Jolly S, Joyner CD, Rupprecht HJ, Widimsky P, Afzal R, Pogue J, Yusuf S. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010 Sep 2; 363(10): 930-42. doi: 10. 1056/NEJMoa0909475. )
b. Aspirin exhibits better activity as a preventive long term treatment strategy as opposed to use for acute treatment.
9.
.
Fig 2. Metabolic activation of Clopidogrel
a. Clopidogrel is a prodrug that needs to be metabolized in order to carry out anti-platelet mechanism. Almost 85% of clopidogrel is metabolized by the action of esterase to carboxylic acid inactive form. However, about 15% of the prodrug gets metabolized, primarily by CYP2C19 and also by CYP1A2, 2B6 and 3A 4enzymes in a two step activation process. Following intestinal absorption, clopidogrel gets metabolized to 2-Oxo clopidogrel, while the active metabolite formed after the second metabolic step has actual structure unknown.
b. The active metabolite of clopidogrel binds to the ADP receptors on platelets and interferes with ADP binding. This interference of ADP-ADP receptor interaction inhibits the proper activation of the GP IIb/IIIa receptors. As a result, platelets cannot stick together or to fibrinogen molecules. This then results in inhibition of platelet aggregation.
10. Clopidogrel is a pro-drug that requires metabolic activation by CYP450 enzymes. The primary metabolic enzyme involved in activation of Clopidogrel(plavix) is CYP2C19. Any pharmacological agent that can inhibit the activity of CYP2C19 and other enzymes involved in this metabolic activation will lower available effective concentration of Clopidogrel.
Proton pump inhibitors such as omeprazole can inhibit the activity of CYP2C19, lowering the efficacy of clopidogrel. A clinical study evaluated the effectiveness of clopidogrel when given in combination with various PPI. It was demonstrated that PPI such as omeprazole and esomeprazole reduced the effectiveness of clopidogrel. This was a randomized crossover study performed on healthy subjects. The effect was pharmacokinetic and reduction in clopidogrel activity was observed due to inhibition of activation pathway. The study limitation was that a higher than usually prescribed dose of omeprazole was used (80 mg as opposed to 20 and 40 mg commonly indicated for GERD). (Frelinger AL 3rd, Lee RD, Mulford DJ, Wu J, Nudurupati S, Nigam A, Brooks JK, Bhatt DL, Michelson AD. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol. 2012 Apr 3; 59(14): 1304-11.).
A second study was identified that evaluated the efficacy of using clopidogrel in combination with aspirin as opposed to using aspirin alone in patients with ischemic stroke or high risk transient ischemic stroke. This study recruited 5170 patients within hours of being admitted for ischemic stroke. The follow up was done at 90 days when it was observed that clopidogrel and aspirin combination regimen is better than aspirin alone in reducing the risk of stroke and does not increase hemorrhage risk in patients after TIA. This study involved a large sample size with robust statistical analysis. The improvement in stroke risk reduction was 4%, due to synergistic pharmacodynamic drug combination. (Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013 Jul 4; 369(1): 11-9.) doi: 10. 1056/NEJMoa1215340. Epub 2013 Jun 26.
Metoclopramide
11.
a. Metoclopramide is 13-30% plasma protein bound. It is primarily bound to albumin.
b. Unbound fraction would be 70-87%.
c. Since it has been identified that metoclopramide binds to albumin primarily. Lowering of plasma albumin concentration will increase the available amount of clopidogrel to carry out its anti-emetic activity.
12. a. The volume of distribution is high 3. 53 L. kg-1
b. The blood volume is 15L. This means that the Volume of distribution is high.
c. This suggests that metoclopramide is present at higher concentration in tissues than in plasma. It is not bound to plasma proteins as much.
13. Metoclopramide is excreted 20-30% in the urine as unchanged drug and 50-60% as metabolites. 5% is also excreted by feces.
14. a. Metoclopramide undergoes first pass hepatic metabolism by the liver.
b. One of the principal metabolites of metoclopramide is monodeethylmetoclopramide, N-dealkylation product. It is also excreted as conjugated form. It is also excreted as glucuronide and sulphate metabolites
c. It is metabolized by the cytochrome P450 (CYP) pathway. It is mainly metabolized via the CYP2D6 isoform and to a lesser degree by CYP3A and CYP1A2 enzymes. Interestingly, metoclopramide is not only as a substrate for CYP2D6, but also a competitive inhibitor of the enzyme. It is excreted mainly through the kidneys. (figure 3 below)
Figure 3. Metabolic pathway of Metoclopromide
15. Plasma concentration-time data was found to fit a two compartment model with a mean half-life of 4. 55 h±0. 80 h. The clearance value was 0. 53±0. 191 · kg−1h−1. This suggests that the drug occurs at higher concentrations in tissues than in plasma, and that its clearance is perhaps limited by liver blood flow rather than liver metabolic capacity.
The total plasma clearance value was (10. 9 + 1. 5 ml min-‘ kg-‘) and it approximates to the liver plasma flow.
Cl = F. Dose/AUC = 0. 693x Varea/t(1/2) {total systemic clearance}
CL(hepatic clearance) = Q * E
E= Extraction ratio and Q= total hepatic flow
CL (renal clearance) = urine flow x urine concentration/Plasma concentration
16.
metoclopramide has absolute oral bioavailability of 80 + 15. 5%
The lower bioavailability was due to first pass effect, not GI absorption. It was completely absorbed from GI tract.
17. The factor that primarily affects the clearance of drug is the patient’s age. Elderly patients are likely to develop tardive dyskinesia. Clopidogrel which has been demonstrated to inhibit CYP450 enzyme may affect the metabolism and clearance of metoclopramide.
18. Howard has lower than average albumin concentration. Since metoclopramide is mainly albumin bound a low albumin concentration will result in elevated level of available metoclopramide. In addition metoclopramide is associated with tardive dyskinesia. His Maxalon or metoclopramide dose should be kept at 10 mg or lower.
Fass, R., Pieniaszek, H. J., Thompson, J. R(2009). Pharmacokinetic comparison of orally-disintegrating metoclopramide with conventional metoclopramide tablet formulation in healthy volunteers. Aliment Pharmacol Ther (3): 301-6.
Campbell, M., Bateman, D. N, Davies, D. N (1992). Pharmacokinetic optimisation of antiemetic therapy. Clin Pharmacokinet. 23(2): 147-60. (these 2 are post 1990)
Bateman DN, Kahn C, Mashiter K, Davies DS (1978). Pharmacokinetic and concentration-effect studies with intravenous metoclopramide. Br J Clin Pharmacol; 6(5): 401-7. This is from 1978 but very useful
References
Antithrombotic Trialists’ Collaboration (2002). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71–86.
Bateman DN, Kahn C, Mashiter K, Davies DS (1978). Pharmacokinetic and concentration-effect studies with intravenous metoclopramide. Br J Clin Pharmacol; 6(5): 401-7.
Campbell, M., Bateman, D. N, (1992). Pharmacokinetic optimisation of antiemetic therapy. Clin Pharmacokinet, 23(2): 147-60.
CURRENT-OASIS 7 Investigators, Mehta, S. R., Bassand, J. P., Chrolavicius, S., Diaz, R., Eikelboom, J. W., Fox, K. A., Granger, C. B., Jolly, S., Joyner, C. D., Rupprecht, H. J., Widimsky, P., Afzal, R., Pogue, J.& Yusuf , S.(2010). Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. Sep 2; 363(10): 930-42. doi: 10. 1056/NEJMoa0909475.
Eggertsen, R., Andreasson, A.& Andrén, L (2007).. Effects of treatment with a commercially available St John’s Wort product (Movina) on cholesterol levels in patients with hypercholesterolemia treated with simvastatin. Scand J Prim Health Care. Sep; 25(3): 154-9.
Fass, R., Pieniaszek, H. J., Thompson, J. R(2009). Pharmacokinetic comparison of orally-disintegrating metoclopramide with conventional metoclopramide tablet formulation in healthy volunteers. Aliment Pharmacol Ther (3): 301-6. doi: 10. 1111/j. 1365-2036. 2009. 04045. x. Epub 2009 May 18.
Flaherty, J. T., Becker, L. C., Bulkley, B. H., Weiss, J. L, Kallman, C. H., Silverman, K. J. and Weisfeldt, J. L.(1983). A randomized prospective trial of IV nitroglycerin in patients with acute myocardial infarction. Circulation, 68 . 576–588
Frelinger, A. L. 3rd, Lee, R. D., Mulford, D. J., Wu, J., Nudurupati, S., Nigam, A., Brooks, J. K., Bhatt, D. L.& Michelson, A. D. (2012). A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll CardiolApr 3; 59(14): 1304-11
Larson, M. K., Ashmore, J. H., Harris, K. A., Vogelaar, J. L., Pottala, J. V., Sprehe, M., Harris, W. S.(2008). Effects of omega-3 acid ethyl esters and aspirin, alone and in combination, on platelet function in healthy subjects. Thrombosis and homeostasis. 100(4): 634-41
Lis D, Bennett G, Lambert, D. &Robson, M. K. (1984). A preliminary double-blind study of IV nitroglycerin in acute myocardial infarction. Intensive Care Med, 10, pp. 179–184
Mangano, D. T., Layug, E. L., Wallace, A. & Tateo, I (1996). for the Multicenter Study of Perioperative Ischemia Research Group. Effect of Atenolol on Mortality and Cardiovascular Morbidity after Noncardiac Surgery. N Engl J Med; 335: 1713-1721DOI: 10. 1056/NEJM199612053352301
Nieminen, T. H., Hagelberg, N. M., Saari, T. I., Neuvonen, M., Laine, K., Neuvonen, P. J., Olkkola, K. T(2010). St John’s wort greatly reduces the concentrations of oral oxycodone. Eur J Pain. Sep; 14(8): 854-9
Söderberg, L., Löfdal, K. C., Andersson, M. L., Gustafsson, L. L .(2013). Cytochrome p450-mediated changes in oxycodone pharmacokinetics/pharmacodynamics and their clinical implications. Drugs. May; 73(6): 533-43
Wang, Y., Wang, Y., Zhao, X., Liu, L., Wang, D., Wang, C., Wang, C., Li, H., Meng, X., Cu, i L., Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC; CHANCE Investigators (2013). Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. Jul 4; 369(1): 11-9
Yin, O. Q, Tomlinson, B., Waye, M. M., Chow, A. H., Chow, M. S. (2004). Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics, 14(12): 841-50
www. studyblue. com (beta blocker mechanism fig)
www. ncbi. nlm. nih. gov/pubmed (Search engine for the primary literature)
www. herbmed. org for information on the natural supplements
www. american college of cardiology. org (figure on metabolism of clopidogrel