Introduction 2011

Introduction 2011 South Brum VTS Welcome again!

The newNHS

Pharmacokinetics/dynamics • Excretion route • Liver • Kidney • Time to steady state (decay) • Absorption, distribution, metabolism and excretion • Digoxin half life 24-36 hours • Time to steady state = x 4-5 this, approx a week

Third order and ... • Phenytoin • Extensive protein binding... • Need to think about liver and • Erythromycin, anti-fungals, simvastatin, warfarin, theophyllines........... • Metformin and x-ray dyes

Nanomedicines • Human hair • RBC • Bacteria • Virus • Water molecule = 80,000nm = 7,000nm = 1,000nm = 100nm = 0.3nm 1nm = 10-9 m or 1 billionth of a metre. ‘Nano’ is derived from the Greek word for dwarf

Nanomedicines – the future? • Use carbon nanotubes to carry of protect molecules (ingested EPO or pancreatic beta cells protected by porous – 20nm holes – to allow glucose and insulin to cross, but not the immune molecules) • But biodegradability of nanoparticles • Biological availability

Genomics and Drug Response,Pharmacogenomics • Identification of biomarkers which help choose drugs, and doses • Research use giving insights into new agents • Terms • Allozyme • Gene cluster • Genomewide association study • Single nucleotide polymorphism

Pharmacogenomics and CV drugs • Narrow therapeutic index • warfarin • CYP2C9 and VKORC1 genotyping makes warfarin dosing safer (but is rarely used!) .........Economically, new drugs (direct thrombin inhibitor – dabigatran and factor Xa antagonists)? • Interest but not used • CYP2C19 is a genetically polymorphic, and is required to covert the prodrug clopidogrel – again not yet used

Pharmacogenomics and infectious disease • HLA –B* alleles and s/e with drugs • Carbamazipine and Stevens-Johnson syndrome • Response to Alfa interferon in Hep C • Flucloxacillin and an HIV drug with hepatitis

Pharmacogenomics and antineoplastic drugs • HER2 over-expression in breast cancer • EGF Receptor and gefitinib in NSC lung cancer • Mutation of BRAF in melanoma • Many other examples • ER • KRAS

Prescribing – advice from others – what do we do? Both Bean et al (2008)2 and, more recently, McKinnell et al (2011)4 concluded that nitrofurantoin should now be considered as a reasonable alternative for empirical treatment of uncomplicated UTI. Should it?

Should we, should it? Paper NEJM quote side effects of “between 3.5 and 40%” Macrobid has an overall score of 4.75. The effectiveness score is 6.50 and the side effect score is 6.25 Proloprim has an overall score of 9. The effectiveness score is 10 and the side effect score is 8. http://www.druglib.com/ratingsreviews

Keeping up-to-date – how can we do it? LABAs may improve survival better than tiotropium in older patients with COPD Beta-blockers associated with reduced mortality and exacerbations in patients with COPD Pragmatic Trials — Guides to Better Patient Care? Montelucast better than ICS in asthma?

How do we do it? • BMJ • BNF • npc - www.npc.co.uk/ • http://mtrac.co.uk/ • DTB • Colleagues • Medscape • No free lunch!

How do we do it?

In reality how do you do? • Don’t have to start many drugs to-day • Patient decision aids • Improves knowledge • Improves participation, without increasing worry • Patient find easier to make decisions • Smiley faces – Cate’s charts • Reduce risks not eliminate risks

Drugs Therapeutics Pharmacology • Gain agreement • Concordance (that requires connection, and patients say they don’t get ) • “nothing about me without me” Equity and excellence: liberating the NHS. 2010 • 1:3 in 10 care and 1:2 in 20 care would like to have greater involvement in decisions about their care Report of the national patient choice survey, England—September 2006. 2007. • Barber’s Boxes (1995) • Is it effective (POO! POEM rather than DOE) • Safety • Cost • Individual co/multimorbity

Effectiveness • Efficacy v Effective • Efficacy is DOE • Effective • Ie CURE aspirin + placebo v aspirin + clopid = 2/100 • 1/100 serious bleeding • Ie 1/100 “got good”! Would people really accept? • Glitazones (Rosi for 10 years)

CURE EFFECTS OF CLOPIDOGREL IN ADDITION TO ASPIRIN IN PATIENTS WITHACUTE CORONARY SYNDROMES WITHOUT ST-SEGMENT ELEVATION "The CURE findings demonstrate that clopidogrel on top of standard therapy including ASA (acetylsalicylic acid, or aspirin), provided early benefit to patients that continued long-term," said Dr. Salim Yusuf, Professor of Medicine and Director, McMaster University and principal investigator of the CURE trial. "These findings suggest that clopidogrel therapy should be started immediately and continued long-term in a broad group of high risk patients irrespective of other treatments they may receive."

CURE EFFECTS OF CLOPIDOGREL IN ADDITION TO ASPIRIN IN PATIENTS WITHACUTE CORONARY SYNDROMES WITHOUT ST-SEGMENT ELEVATION Conclusions The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel. (N Engl J Med 2001;345: 494-502.)

Cure

CURE in National Prescribing Centre • Number needed to prevent one of the composite events is 48 over 9 months • Composite of events were • Number needed to cause one of the recorded harmful events is 100 over 9 months

3 Cost • Effective – cost effective – affordable? The dilemma arises for two main reasons. First, recent decades have witnessed a flood of new, expensive medical technologies (drugs, imaging devices, surgical procedures) that are of varying degrees of value to patients. A few are true breakthroughs, with strong favourable effects on mortality and morbidity. Others make a meagre contribution, at best, to health outcomes. Moreover, technologies that may provide high value for carefully selected patients are often used indiscriminately for a much larger cohort of patients NEJM | August 17, 2011

Or, a current example vemurafenib for melanoma, just approved by FDA A new study showing that the chemotherapy drug vemurafenib can prolong the lives of people with malignant melanoma — the especially aggressive and dangerous form of skin cancer that kills about 8,700 Americans each year — has rightfully lifted the spirits of doctors and patients alike. But a close look at the numbers raises questions about the drug’s real-world impact. The study suggests that only one out of four patients with malignant melanoma will respond to the drug. For those who do respond, the benefits are uncertain, says Tim Turnham, executive director of the Melanoma Research Foundation. The study found that vemurafenib reduced the risk of death by 63% over six months compared with a standard treatment. That sounds impressive, but it’s impossible to predict how much time patients really bought themselves, Turnham says. A few patients may enjoy a few extra years of life thanks to the drug, but they will likely be the exception, not the rule. “This is not the breakthrough that we really need for this population,” he says. “There’s been a lot of hype in the news, but this is not a home run. It’s a really solid single.” An expensive single, at that. Vemurafenib will likely cost tens of thousands of dollars per year. (Turnham’s off-the-cuff guess is $50,000.)

Individual and co-morbidity

Patient factors • Monitoring • Interactions • Contraindications in real life (monitoring not done, amiodarone) • OTC / food interactions • 28% of hypertensive patients take β-blocker • Kronish IM, et al. Meta-Analysis: impact of drug class on adherence to antihypertensives. Circulation 2011;123:1611-21

Teplizumab - anti-CD3 antibody for recent DM1

Introduction 2011