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Rational Use of Drugs for Key Conditions - part 1b

HealthMasters Live Webinar Series

Giselle Cooke

on 27 February 2013

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Transcript of Rational Use of Drugs for Key Conditions - part 1b

1. When drug therapy is inappropriate 3. When to prioritise drugs over
complementary or natural medicines Cardiovascular Disorders Arteriosclerosis
Cardiomyopathy Rational Use of Drugs for Key Conditions - Part 1b Masterclass presented by Dr Giselle Cooke Where an underlying cause of condition can be treated
Where there is a proven effective and safer diet, lifestyle or complementary medicine intervention
When natural medicine is a superior choice Arteriosclerosis Hypertension Cardiomyopathy Treat underlying conditions first:
Elevated LDL cholesterol,triglycerides
Endarteritis - inflammation/infection

Modify gene expression:
Lipoprotein (a)
Apolipo A1/B

When Statin prescription is irrational
& should be avoided, increased cancer risk for efficacy, ethical practice
& best clinical outcomes Rational Drug Prescribing

Positive ionotropic agents Treat underlying conditions :
ad/renal disease, obesity, inactivity, stress, insomnia, magnesium deficiency, stimulants (caffeine)

Nutritional solutions - Magnesium, fish oil, fruits, vegetables, nuts, garlic, olive oilm, green tea, dark chocolate, cocoa
Supplements - CoQ10, quercetin, vitamin C
Herbal Solutions - antihypertensives, nervines, hypnotics

Bio-identical hormones : melatonin

Drugs should not be first choice for
Tailored herbal medicines coupled with nutritional supplements
Exercise program, especially yoga
Dietary management to reduce fat mass, blood volume
Sleep hygiene
Biofeedback, e.g. RESPeRATE
Releasing stress & emotional tension. e.g. NET, somatic integration psychotherapy ALTERNATIVE TREATMENTS FOR CARDIOMYOPATHY Dietary management of dyslipidaemias
Supplementation : omega-3 fatty acids, Alpha-linolenic acid (ALA), lecithin, gugulipids, policosanol, cod liver oil, coenzyme Q10, beta-sitosterol,

Herbal/food solutions : Garlic, artichoke, oat bran, barley, psyllium, cocoa

Key targeted solutions : Bergamet
The role of exercise
Genetic predisposition - enhancing genes Treat underlying conditions:
hypertension & valvular heart disease
metabolic disorders, e.g. thyroid disease, diabetes, haemochromatosis
Influenza prevention/early management of viral illnesses, e.g. coxsackie virus

Avoid cardiotoxic agents - alcohol,
cortisol, chemotherapy drugs, cocaine,
tricyclic antidepressants

Optimise coenzyme Q10 status - avoid statin drugs unless essential Integrative management of hypertension ("Hypertension Review", Dr Tim Ewer, JIM 2010)
Nutritional support for cardiac muscle, valves
Graded exercise program
Avoidance of alcohol, caffeine Cardiomyopathy drug treatment:
angiotensin-converting enzyme (ACE) inhibitors
angiotensin receptor blockers
beta blockers
digoxin (Lanoxin)
diuretics 2. When complementary or natural medicines can be integrated with drug therapy
for best clinical outcomes Arteriosclerosis Hypertension Cardiomyopathy Dietary management + natural medicines for correcting lipid profile +
exercise to improve circulation +
Statin drugs + CoQ10 if indicated Antihypertensive drugs + magnesium, omega-3 fatty acids + coenzyme Q10 +
meditation, sleep hygiene, exercise Coenzyme Q10, omega-3 fatty acids +
prescription drugs + exercise +
possible valvular repair surgery Prevention and treatment of arteriosclerosis

Antiplatelet drugs Drug therapy for hypertension:
thiazide diuretics
beta blockers
angiotensin-converting enzyme (ACE) inhibitors
angiotensin II receptor blockers (ARBs)
calcium channel blockers
renin inhibitors IN SUMMARY 1. Always seek to treat the underlying condition or contributing factors first
in any CVS condition

2. Integrated protocols can produce better outcomes for management of chronic CVS conditions, while minimising drug side effects

3. Life-saving drug treatments should be prioritised in urgent and serious cases Melatonin secreted by the pineal gland plays an important role in the regulation of blood pressure (BP) and its administration reduces hypertension both in animals and humans.
There are two experimental models of melatonin-deficient hypertension: one induced by pinealectomy and another by continuous 24 hour exposure to light.
Both models cause melatonin deficiency and prevent darkness-mediated nocturnal melatonin secretion and are associated with increased BP and myocardial, vascular and renal dysfunction.
These models also lead to neurohumoral activation of the renin-angiotensin system, sympathetic nervous system, adrenocorticotrophin-glucocorticoid axis and cause insulin resistance. Together, these alterations contribute to rise in blood pressure by vasoconstrictive or circulatory fluid volume overload.
The light induced hypertension model mimics the melatonin deficiency in patients with insufficient nocturnal BP decline, in those who have night shift or who are exposed to environmental light pollution. For this reason, this model is useful in development of antihypertensive drugs.

Simko F, Reiter RJ, Pechanova O, Paulis L. Experimental models of melatonin-deficient hypertension. Front Biosci. 2013 Jan 1;18:616-25. Statins are not "wonder drugs" for all
New Scientist 15 June 2004 by Philip Cohen
The cholesterol-lowering "wonder" drugs known as statins may be less wondrous for people with two genetic variations.

Nearly 70% of the population have genetic features which make statins an average of 20% less effective at lowering cholesterol levels, found Daniel Chasman of Harvard Medical School in Boston, US and his colleagues.

Statin therapy is used by millions of people to reduce their risk of heart disease.

The researchers now plan to study whether those 70% of statin takers end up having more heart attacks and cardiovascular disease due to their weak response to the drug. Their work is the latest example of pharmacogenetics, a field that aims to tailor medical treatment to each person's individual genetic background. Considering the complexity of mitochondria, it is not surprising that the pathogenesis of adverse drug events often develop on drug-induced mitochondrial injury.
Drug induced mitochondrial toxicity can occur through several mechanisms, such as depletion of mtDNA (e.g. NRTI), inhibition of fatty acid beta-oxidation (e.g. valproic acid), opening of the mitochondrial permeability transition pore (e.g. anthracyclines), formation of mitochondrial oxidative stress and depletion of mitochondrial glutathione pool (e.g. acetaminophen), uncoupling of electron transport from ATP synthesis (e.g. tamoxifen) and inhibition of mitochondrial electron transport chain complexes (e.g. simvastatin). This review focuses on the mitochondrial toxicity of drugs in general and explains the practical relevance of these adverse drug events according to specific drugs (metformin, statins, acetaminophen, valproic acid).
Furthermore the significance of mitotropic micronutrients such as coenzyme Q10, L-carnitine and glutathione in the prevention and management ofdrug-induced mitochondrial injury is discussed.

Gröber U. Mitochondrial toxicity of drugs. Med Monatsschr Pharm. 2012 Dec;35(12):445-56. There is an increasing global trend in cardiometabolic disorders being a leading cause of morbidity and mortality. Adverse dietary habits and sedentary lifestyles contribute to cardiovascular disease (CVD) and diabetes mellitus (DM). Dietary nutrients in nuts have attracted attention in recent literature due to their beneficial effects on CVD by attenuating lipid profiles, inflammation and oxidative stress.
There is well-established evidence of the pharmacological properties of micronutrients that render them therapeutically effective in chronic inflammatory diseases. Although caution should be exercised in using antioxidant supplementation, antioxidant foods as dietary components play an important role in the management of cardiometabolic disorders.
There is documented evidence of disease-modifying effects of nutritional compounds with anti-inflammatory and antioxidant effects. They have specific applications in ameliorating oxidative stress- induced inflammatory diseases such as DM and CVD. It is relevant that dietary components that influence risk of DM, have similar effects on inflammatory biomarkers of cardiovascular risk.
Polyphenolic compounds such as flavonoids, isoflavones, phenolic acids and lignan contribute to increased plasma antioxidant capacity, decreased oxidative stress markers and reduced total and LDL cholesterol. They modulate genes associated with metabolism, stress defence, detoxification and transporter proteins. Their antioxidant and anti-inflammatory actions have specific applications for pathologies associated with chronic low-grade systemic inflammation that underpins progression of DM and CVD. Mechanisms involved depend on the structure of the compound, redox status of the inflammatory milieu and other interactions.
Bioactive phytochemicals play an important therapeutic role in attenuating oxidative damage induced by metabolic syndrome associated with atherogenic dyslipidaemia and a pro-inflammatory, pro-thrombotic state, at a sub-cellular level. It would be critical to formulate optimal proportions and their combinations for therapeutic efficacy, based on synergistic interactions. Some of these mechanisms and potential actions are discussed.

Soory M. Nutritional antioxidants and their applications in cardiometabolic diseases. Infect Disord Drug Targets. 2012 Oct;12(5):388-401. Aging is very often associated with magnesium (Mg) deficit. Total plasma magnesium concentrations are remarkably constant in healthy subjects throughout life, while total body Mg and Mg in the intracellular compartment tend to decrease with age.
Dietary Mg deficiencies are common in the elderly population. Other frequent causes of Mg deficits in the elderly include reduced Mg intestinal absorption, reduced Mg bone stores, and excess urinary loss. Secondary Mg deficit in aging may result from different conditions and diseases often observed in the elderly (i.e. insulin resistance and/or type 2 diabetes mellitus) and drugs (i.e. use of hypermagnesuric diuretics).
Chronic Mg deficits have been linked to an increased risk of numerous preclinical and clinical outcomes, mostly observed in the elderly population, including HYPERTENSION, stroke, atherosclerosis, ischemic heart disease, cardiac arrhythmias, glucose intolerance, insulin resistance, type 2 diabetes mellitus, endothelial dysfunction, vascular remodeling, alterations in lipid metabolism, platelet aggregation/thrombosis, inflammation, oxidative stress, cardiovascular mortality, asthma, chronic fatigue, as well as depression and other neuropsychiatric disorders.
Both aging and Mg deficiency have been associated to excessive production of oxygen-derived free radicals and low-grade inflammation. Chronic inflammation and oxidative stress are also present in several age-related diseases, such as many vascular and metabolic conditions, as well as frailty, muscle loss and sarcopenia, and altered immune responses, among others. Mg deficit associated to aging may be at least one of the pathophysiological links that may help to explain the interactions between inflammation and oxidative stress with the aging process and many age-related diseases.

Barbagallo M, Belvedere M, Dominguez LJ. Magnesium homeostasis and aging. Magnes Res. 2009 Dec;22(4):235-46. Epidemiological and clinical studies suggest that consumption of omega (-3) polyunsaturated fatty acids (PUFA) contributes to the reduction of cardiovascular mortality through different mechanisms including modulation of cellular metabolic functions, gene expression and beneficial effects on lipid profile or blood pressure.
The analysis of different studies suggests that high doses -3 PUFA ( ≥ 3 g/day) produces a small but significant decrease in blood pressure, especially systolic blood pressure, in older and hypertensive subjects; however, the evidence is not consistent among different studies.
-3 polyunsaturated fatty acids consumption might have a place in the control of patients with mild hypertension before starting drug treatment and of those who prefer changes of lifestyles like diet.

Cabo J, Alonso R, Mata P. Omega-3 fatty acids and blood pressure. Br J Nutr. 2012 Jun;107 Suppl 2:S195-200 Studies have shown that coenzyme Q10 deficiency is associated with cardiovascular disease.
Hypertension is a commonly measured surrogate marker for non-fatal and fatal cardiovascular endpoints such as heart attacks and strokes.
Clinical trials have suggested that coenzyme Q10 supplementation can effectively lower blood pressure (BP).

Three clinical trials with a total of 96 participants were evaluated for the effects of coenzyme Q10 on blood pressure compared to placebo.
Treatment with coenzyme Q10 in subjects with systolic BP (SBP) > 140 mmHg or diastolic BP (DBP) > 90 mmHg resulted in mean decreases in SBP of 11 mmHg (95% CI 8, 14) and DBP of 7 mmHg (95% CI 5, 8).

Due to the possible unreliability of some of the included studies, it is uncertain whether or not coenzyme Q10 reduces blood pressure in the long-term management of primary hypertension.

Ho MJ, Bellusci A, Wright JM. Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. Cochrane Database Syst Rev. 2009 Oct 7;(4) We aimed to determine the effect of supplementation with coenzyme Q10 on conventional therapy of children with cardiac failure due to idiopathic dilated cardiomyopathy.
In a prospective, randomized, double-blinded, placebo-controlled trial, we randomized 38 patients younger than 18 years with idiopathic dilated cardiomyopathy to receive either coenzyme Q10, chosen for 17 patients, or placebo, administered in the remaining 21. Echocardiographic systolic and diastolic function parameters were determined for every patient at baseline, and after 6 months of supplementation.
After 6 months supplementation, 10 patients randomized to receive coenzyme Q10 showed improvements in the grading of diastolic function, this being significantly more than that achieved by those randomized to the placebo group.
The mean score for the index of cardiac failure index for those receiving coenzyme Q10 was also lower than the control group.
Our results, therefore, indicate that administration of coenzyme Q10 is useful in ameliorating cardiac failure in patients with idiopathic dilated cardiomyopathy through its significant effect on improving diastolic function.

Kocharian A, Shabanian R, Rafiei-Khorgami M, Kiani A, Heidari-Bateni G. Coenzyme Q10 improves diastolic function in children with idiopathic dilated cardiomyopathy. Cardiol Young. 2009 Sep;19(5):501-6. The beneficial effects of regular physical activity on cardiovascular health are well established, with convincing evidence of improvements in blood pressure, lipid profile and overall mortality.
Conversely, individuals with pre-existing congenital, inherited or acquired heart conditions may experience functional cardiac deterioration or sudden death during even moderate exertion.
Exclusion from high-level sporting activity may be mandated in some cases, and pre-participation screening of competitive athletes plays an important role in the identification of such individuals.
The issue of screening is complicated by the fact that physiological cardiovascular adaptation in healthy athletes, including modest left ventricular hypertrophy and biventricular cavity dilatation, may create a diagnostic overlap with pathological conditions such as hypertrophic cardiomyopathy.
Furthermore, much interest has focused recently on the possibility of irreversible cardiac remodeling in a proportion of veteran endurance athletes, with the potential for arrhythmogenesis and adverse cardiac events.

Zaidi A, Sharma S. Exercise and heart disease: from athletes and arrhythmias to hypertrophic cardiomyopathy and congenital heart disease. Future Cardiol. 2013 Jan;9(1):119-36.
Drug-induced valvular heart disease (DIVHD) was first described in the 1960s.
Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described.
Drugs used for the treatment of Parkinson's disease and endocrine diseases, like hyperprolactinemia, may also induce VHD. More recently, the use of 3,4-methylendioxymetamphetamine (MDMA, 'Ecstasy') and benfluorexhave been found to be associated with DIVHD.
Although some of these drugs were withdrawn from the market, several cases of patients requiring valve surgery even years after the cessation of therapy have been reported.
DIVHD is not infrequent, may be severe, and has been described in association with several drugs. Even after drug cessation, long-term implications of this type of VHD may persist.
The present review underlines the need for a careful evaluation of the associated clinical and echocardiographic risk factors to allow early recognition so as not to delay appropriate management.

Cosyns B, Droogmans S, Rosenhek R, Lancellotti P. Drug-induced valvular heart disease. Postgrad Med J. 2013 Mar;89(1049):173-8
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