CAM Therapies in Hepatology .pdf

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn CAM Therapies in Hepatology, incl. Interactions with Conventional Medicines Class Third Enter subtitle here (24pt, Arial Regular) Pharmacy...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn CAM Therapies in Hepatology, incl. Interactions with Conventional Medicines Class Third Enter subtitle here (24pt, Arial Regular) Pharmacy Enter date: 25.06.13 Course Liver & Kidney Lecturer Dr. James Barlow  Learning outcomes Following this lecture, students should be able to: Describe the active principles, mode of action and evidence base of common phytotherapies that are used by patients for hepatoprotective properties, most notably milk thistle Recognise that CAM interventions may result in interactions with conventional drugs Describe the common mechanisms through which drug interactions occur Discuss the phytochemical profile of St John’s Wort products in the context of drug interactions Discuss the phytochemical profile of grapefruit in the context of drug interactions  CAM therapies in hepatology Few studies specifically evaluate CAM use in hepatology However, in one study of over 600 adults with liver disease, 41% had used CAM in the prior year (vs 33% without) CAM was used more commonly for anxiety or depression, fatigue, and substance use Most common modalities encountered are herbs and supplements Some of these substances are actually potentially hepatotoxic ! Many patients are on multi-drug regimens, so CAM interactions are possible Historically herbalists and other CAM therapists promoted ‘liver detoxification’ as a general approach to disease treatment, so hepato- and gastro-active herbs were commonly used for all conditions – In Ireland today, the most commonly encountered such herb is milk thistle  Milk thistle Origins Silybum marianum O CH2OH HO O OMe O Constituents Mixture of flavonolignans OH OH OH O Silybin Mode of action Claimed antihepatotoxic effect Complex mode of action – Inhibition of toxin binding and activation? – Enhanced glutathione and protein synthesis?  Milk thistle Applications Mild hypolipidaemic effect Tx of hepatitis, cirrhosis ?? 400mg daily treatment dose typically used Valid specialist (non-CAM) use to treat the toxic effects of certain fungi Efficacy? Positive findings usually reported in terms of improvement in LFTs, e.g. aminotransferases – Is this a valid clinical outcome?  Milk thistle: evidence base? Cochrane hepato-biliary group review with meta-analyses of randomized clinical trials conclusions (2005): – Ineffective for various disorders of the liver (viral, steatosis, alcoholic) – Safe and well tolerated – However, end-point was all-cause mortality ?! – Findings largely based on one trial, of short duration Cochrane (2007) further questioned the beneficial effects of milk thistle for patients with alcoholic and/or hepatitis B or C virus liver diseases Commission E considers it safe and effective for ‘toxic liver damage and for supportive treatment in chronic inflammatory liver disease and hepatic cirrhosis’  Liver disorders : use of bitters Traditional use, largely unsupported by evidence-base Examples include: Artichoke Leaf Bitter sesquiterpene lactone Cynaropicrin Anti-hepatotoxic, cholagogue, ↓cholesterol Traditionally uses: bloating, constipation, abdominal pain, vomiting, IBS Gentian Fermented roots & rhizomes of Gentiana lutea Bitter compounds – Gentiopicroside (a seco-iridoid) O O – Amarogentin Stimulation of bitter receptors O → promotes salivation & → Appetite stimulant ? Traditional used to treat poor appetite, bloating, jaundice O-Glu Gentiopicroside  Traditional herbs for Liver disorders Dandelion Origins Rhizome and root of Taraxacum officinale Constituents Up to 25% of inulin and other (FOS) saccharides Polyphenols & terpenes Traditional uses Hepatic stimulant, diuretic, tonic and anti-rheumatic Mode of action largely unknown Efficacy Historical uses have some support through in vitro / animal studies Little or no research in clinic  Traditional herbs for Liver disorders Turmeric Origins Rhizome of Curcuma domestica Constituents Curcuminoids (phenolic diaryl heptanoids) e.g. curcumin Uses (mostly traditional) Antihepatotoxic, anti-inflammatory – Some interesting results in IBD/GI disorders Antispasmodic Hypoglycaemic Hypocholesterolaemic Mode of action 7C chain Inhibits several transcription factors of interest as potential anticancer drug lead  Overview of drug interactions Mechanisms of interaction – Pharmacodynamic (PD) May occur when constituents of herbal products have either synergistic or antagonist activity in relation to a conventional drug Concentration-dependent activity of a therapeutic molecule is altered at the site of action at the drug-receptor level – Pharmacokinetic (PK) Result from alteration of ADME of a conventional drug by an herbal product Interactions of herbal & conventional medicines need to be considered as carefully as those of conventional drug-drug interactions!  Useful resources Mosby’s Handbook of Drug-Herb and Drug-Supplement Interactions (c. 35 Euro) ISBN 0-323-02014-3 Library √ Stockley’s Herbal Medicine Interactions (c. 50 STG) ISBN: 978 0 85369 760 2  Particular risk groups for drug interactions Patients with chronic disease, who use multiple medications—particularly those with a narrow therapeutic range Patients with genetic variance in drug metabolism Patients with impaired organ function Patients at either end of the age spectrum  EVIDENCE-BASED DRUG–HERBAL INTERACTIONS Sources Known or suspected pharmacologic activity Data derived from in vitro or animal studies Isolated case reports lacking full information Usefulness of such information ? Fully documented case reports (see rubric) In vivo studies Clinical trials RUBRIC FOR EVALUATION OF HERBAL– DRUG INTERACTIONS  Interactions Many interactions are potential Many are harmless or clinically insignificant However some can be serious Undeclared use of herbal medicines can be a cause of toxicity or ineffectiveness of conventional therapy REPORT suspected interactions involving herbals, just as you would with ‘conventional’ medicines!! https://www.hpra.ie/homepage/about-us/report- an-issue/human-adverse-reaction-form Major hepatic P450 enzymes Main sites of localization of P-glycoprotein  St. John's Wort Active principles hypericins and hyperforin Inhibition of MAOI not clinically relevant – Probably does not interact with foods that contain tyramine May ↑ levels of serotonin, dopamine and norepinephrine ? Should not be used with prescription antidepressants: Mild serotonin syndrome with SSRIs (sertaline, paroxetine, nefazodone)  St John's Wort Hyperforin is a potent INDUCER of: CYP3A4 CYP2E1 P-glycoprotein (also Hypericin) Lowers blood concentrations of several drugs, e.g. Cyclosporin Tacrolimus Amitriptyline Digoxin Indinavir Warfarin Theophylline Irinotecan COC Failure of therapy: – Contraceptive failure – Organ rejection – Viral load increase in HIV ST JOHNS WORT – INDINAVIR INTERACTION St Johns Wort - Tacrolimus interaction St Johns Wort – Irinotecan interaction  Grapefruit juice INHIBITOR of : 1. Small Intestinal CYP3A4 Effect can persist for 3+ days after last glass Mechanism-based inhibition 2. P-glycoprotein and influx transporters Compounds responsible ? – most concentrated in peel Furanocoumarins – Bergamottin and 6',7'-dihydroxybergamottin 1. Flavonoids (now considered less important as inhibitors) – Naringin and naringenin Grapefruit components  FC activation Irreversibly binds to CYP apoprotein Eliminates enzymatic activity O O O OR O O O O O O O O H OR OR Furanoepoxide intermediate γ-Ketoenal intermediate Variability in juices (study of 14 brands) Naringin (174 - 1492 µmol/L) Bergamottin (1.0 - 36.6 µmol/L) 6′,7′-di(OH)BG (0.22 - 52.5 µmol/L) Flavedo = outer coloured peel Albedo = inner peel  Grapefruit juice >80 Drugs affected (increased levels) Anticoagulants (apixaban, rivoraxaban) Antiarrhythmics (amiodarone, propafenone, dronedarone) Ca2+ channel blockers (verapamil, amlodipine, felodipine, nifedipine, nicardipine) Drugs that act on the CNS (carbamazepine, pimozide, quetiapine, buspirone, triazolam) Cytotoxics (nilotinib, sunitinib, lapatanib) Immunosuppressants (ciclosporin, tacrolimus, sirolimus) Statins (atorvastatin, simvastatin) Blood concentration–time profile for cyclosporin in subject 1 after ingestion of cyclosporine with water, grapefruit juice, or Seville orange juice (Note 6',7'-dihydroxybergamottin occurs in both juices to a similar degree)  Grapefruit: also potential of reducing drug exposure levels? 2013: flavonoids implicated as inhibitors of organic anion transporting polypeptide (OATP)-mediated absorptive uptake in the intestine : An opposite effect to that of inhibiting PgP! Reported examples with citrus juices: Fexofenadine, aliskiren, celiprolol Interaction in this case is short-lived & reversible Avoid by separating juice from food by 4h