The War on Drugs THE BAS ICS O

The War on Drugs THE BAS ICS O F P HARMACO LOG Y AND THE USE OF MEDICATIONS IN MEDIC INE

Disclosures v. I am a medical student v. This session is not intended to give you a diagnosis or replace going to see your health care professional v. No samples

What we will discuss v. A brief history of pharmacy v. How drugs work: Drug mechanisms v. Pharmacokinetics v. Pharmacodynamics v. Drug interactions v. Evidence based medicine v. The opioid crisis

Pop Quiz 1. What is pharmacology? 2. What are pharmacokinetics? 3. What is a ligand? 4. What are the ADME processes? 5. True or False: With increased number of medications comes an increased risk of drug interactions. 6. True or False: Supervised injection sites decrease the annual number of lethal overdoses.

Definitions v. Pharmacology is the science of drugs including their origin, composition, pharmacokinetics, therapeutic use, and toxicology v. Pharmacy is the art, practice, or profession of preparing, preserving, compounding , and dispensing medical drugs v. Therapeutics is the application of pharmacology to the treatment of disease

History

History v. Paleolithic era – Treatment based on observation and instinct v. Babylonia (2600 B. C)- Earliest known record of practice of the art of the apothecary v. Egypt- Papyrus Ebers (1500 BC) contained 811 drug recipes derived from plants, animals, and minerals v. Ancient Greece ◦ King Mithridates VI of Pontus the father of toxicology ◦ Terra Sigillata is the first trademarked drug ◦ Pedanios Discorides (first century A. D) writes Herbarium De Meteria Medica which is used until the 1600 s

History Medieval Pharmacy ◦ Pharmacy and medicine are extensions of the church ◦ The advancement of chemistry begin in the Islamic world Middle Ages o Medicine and Pharmacy are separated o 1618 the first London Pharmacopoeia is written 18 th and 19 th Century o o o Advances in chemistry and the ability to isolate compounds Heroic medicine Drugs start to be used to treat symptoms Germ theory by Louis Pasteur and Robert Koch at the end of the 19 th century Pierre Paul Emile Roux develops the diptheria anti-toxin

History The 20 th century ◦ Drug receptor theory emerges(1907 Ehrlich proposes existence of chemoreceptors) ◦ Alexander Flemming discovers Penicillium mold hindered the growth of staphylococci in 1928 but Florey and Chain isolate the antibiotic and commercial production begins ◦ Golden age of pharmaceuticals: Streptomycin(1945), Benedryl(1946), Chlortetracycline(1948), Chlorampheicol(1949) ◦ After 1960 focus on chronic and hereditary illness

Pharmacodynamics v. The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of their actions and effects with their chemical structure v. Pharmacological effect v. Drug-Receptor Theory: Drugs act by binding to specific receptors, either in or on cells, to change their biochemical or biophysical activity and thus their cellular function

Example: Antihypertensives Aliskerin targets renin ACEi target angiotensin converting enzyme ARBs bind to angiotensin receptors https: //www. youtube. com/watch? v=b Y 6 IWVg. FCr. Q From: CARDIOVASCULAR-RENAL DRUGS Basic & Clinical Pharmacology, 13 e, 2015 Date of download: 12/8/2016 Copyright © 2016 Mc. Graw-Hill Education. All rights reserved.

Metformin v. Full explanation of the mechanism of action is not known v. Their primary effect is to activate the enzyme AMP-activated protein kinase and reduce hepatic glucose production

Pharmacokinetics v. The study of the movement of drugs in the body, including the process of absorption, distribution, localization in tissues, biotransformation, and excretion v. How much? How often? How long? What form? v. ADME processes

ADME Processes A-Absorption: D-Distribution: M-Metabolism: E-Excretion:

Absorption v. A-Absorption: Movement of the drug from the site of administration into the blood Influencing factors • Concentration gradient • Size • Lipid solubility/p. H v. Bioavailability is the fraction of drug that reaches circulation unchanged v. IV vs. Oral

Absorption-influence of p. H Example: Piroxicam v. An NSAID prescribed to relieve arthritis pain v. It is a weakly acidic drug v. Common side effects include nausea, indigestion, heartburn v. Heart burn is commonly treated with TUMS(antacid) which increase stomach p. H and thus decrease absorption of a weakly acidic drug

Distribution D-Distribution: The process by which the drug reversibly leaves the blood stream and reaches the site of action(receptors) Influencing Factors • • • Concentration gradient Drug size Lipid solubility/p. H Blood flow Protein binding

Distribution-influence of protein binding v. Drugs reversibly bind to plasma proteins to varying degrees depending on the drug v. The more a drug is protein bound the less it is available to reach its target v. The amount of plasma protein changes with different physiological states v. Example-CKD • Phenytoin is 90% bound to albumin • Digoxin tissue biding is decreased • Both have increased availability in the setting of CKD

The Blood Brain Barrier v. A diffusion barrier essential for normal functioning of the CNS v. Extensive tight junctions v. Limits the paracellular flux of hydrophilic molecules from the blood to brain

Focused ultrasound BBB disruption v. Lipid-encased perfluorocarbon gas microbubbles injected intravenously along with drug v. Transcranial delivery of lowfrequency ultrasound waves which results in disruption of BBB v. It has been used in one patient to target a malignant brain tumor

Metabolism v. The irreversible biotransformation of a drug v. Primarily in the liver v. The goal is to make the drug more water soluble so it can be excreted through the urine or bile v. Phase I: Cytochrome P 450 enzyme family increases water solubility of the drug v. Phase II: Various non-P 450 liver enzymes ensures that metabolite is ready for renal excretion v. Influences • • Liver function Route of administration Disease state Age

Metabolism in action: Prodrugs v. A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent v. Example: Codeine is converted to morphine via O-demethylation • The reaction is catalyzed by CYP 2 D 6 • Genetic variations in this gene lead to variable effects of codeine CYP 2 D 6 Morphine

Excretion v The irreversible loss of a drug from the body v. Primarily through the kidneys v. Some excretion occurs through the biliary system v. Enterohepatic recycling • Example: OCP and antibiotics

Summary Pharmacodynamics are the mechanism by which drugs work Pharmacokinetics is how the body effects the drug Both need to be understood in order to use drugs appropriately and effectively

Polypharmacy

Canadian adverse events study Procedures or events to which AE were related v. AE incidence of 7. 5% v 37% are preventable v 20% result in death Surgical Drugs Clinical Management Diagnostic Medical Other System Events Fracture Anesthetic Obstectric

Polypharmacy The elderly account for 13% of the population but 33% of prescriptions About 35% of American seniors are on more than 5 medications On the rise 1995 -2010 in Scotland the proportion of adults prescribed more than 10 medications tripled Prevalence of polypharmacy increased from 54%-67% between 1998 and 2003

Polypharmacy Problems associated with polypharmacy v. Increased fall risk v. Decreased compliance v. Increased use of prescription drugs is associated with decreased ability to carry out activities of daily living v. Excessive polypharmacy (10≥drugs) is an indicator of increased mortality (Jyrkkä, 2012) v. With increased number of drugs comes an increased risk of DDI

Polypharmacy and Adverse Drug Reactions

Drug Interactions Drug-Food Drug-Disease Drug-Drug Pharmacokinetic Absorption p. H, Chelation, binding, GI motility, P-gp Distribution Protein binding Pharmacodynamic Metabolism CYP p 450 induction or inhibition Excretion Renal transporters, P-gp

Drug-Drug

Drug-Drug Interactions v. Drug-Drug interactions account for around a sixth of all adverse drug reactions v. Many potential DDI but only a small number are clinically relevant v. Three mechanisms • Pharmaceutical interaction • Pharmacokinetic interaction • Pharmacodynamic interaction v. Example: Paroxetine and Tamoxifen • Paroxetine inhibits CYP 450 2 D 6 • Tamoxifen is a prodrug: it is converted from to endoxifen by CYP 450 2 D 6

Common Drug-Drug Interactions Drug Combination Adverse events Warfarin and aspirin GI bleeding NSAIDs and aspirin GI adverse effects Warfarin and interacting drugs Bleeding (GI and non-GI) Diuretic combinations Renal failure Diuretics and ACE inhibitors Renal failure Digoxin and interacting drugs Digoxin toxicity

Drug-Food

Drug-Food Interactions Drug-Food Pharmacodynamic: Warfarin and leafy greens Pharmacokinetic: Grape fruit juice and atorvastatin

Drug Checkers https: //www. drugs. com/drug_interac tions. php

Pharma. Net v. Province-wide network that links all BC pharmacies to a central set of data systems v. Every prescription in B. C is entered into Pharma. Net v. Accessible by B. C pharmacists, community health practitioners, emergency departments, hospitals and designated mental health facilities, providers of medical devices and supplies

Pharma. Net v. Information stored on Pharma. Net • Demographic information • Medication hx including all prescriptions, reported non-prescription drugs, reported drug allergies • Claims information v. Not stored on Pharma. Net • Drugs received in hospital • Drugs received through the BC Cancer Agency, Center for Excellence in HIV/AIDS, Transplant society, Renal Agency • Samples received

Pharma. Net v. Improves safety by allowing authorized health care practitioners to access information about all prescription medications dispensed anywhere in BC v. Allows for quick identification and warning about potentially harmful medication interactions and accidental duplications of prescriptions v. Privacy concerns v. Only as good as the patient’s history

Which drug is right for you? EVIDENCE BASED MEDICINE

Evidence Based Medicine v. The integration of best research evidence with clinical expertise and patient values v. The goal is to prevent inappropriate discrepancies in practice and improve patient care by providing the most effective treatment v. Economic advantages

Evidence Based medicine

Evidence Based medicine The integration of best research evidence with clinical expertise and patient values The goal is to prevent inappropriate discrepancies in practice and improve patient care by providing the most effective treatment

Barriers to evidence based medicine v. A lack of evidence v. An abundance of evidence v. Critical appraisal of the evidence v. Integration of critical appraisal with clinical expertise v. Patient overload v. Time constraints v. Financial barriers

Evidence based medicine and statistics v. Likelihood ratio is the likelihood that a given test result would be expected in a patient with target disorder compared to the likelihood that same result would be expected in a patient without the target disorder v. Number needed to treat is the number of patients who need to be treated to prevent one additional bad outcome v. Relative Risk is the ratio of the probability of an event occurring in an exposed group to the probability of the event occurring in a comparison group v. Confidence intervals give an estimated range of values which is likely to include an unknown population parameter, the estimated range being calculated from a given set of sample data

A few examples of evidence based medicine

The fentanyl crisis

Diabetes Prevention Research question ◦ Does a lifestyle intervention or treatment with metformin, a biguanide antihyperglycemic agent, prevent or delay the onset of diabetes? ◦ Do these two interventions differ in effectiveness? ◦ Does their effectiveness differ according to age, sex, or race or ethnic group? Method ◦ N=3234 from 1996 to 1999 randomly assigned individuals over the age of 25 at high risk of developing diabetes to placebo, metformin, intensive lifestyle intervention Outcome ◦ Diagnosis of diabetes Interventions ◦ Metformin 850 mg daily then twice daily ◦ Intensive lifestyle intervention

Diabetes Prevention Results Lifestyle intervention: 6. 9 NNT Metformin: 13. 9 NNT

Another Example Heart Failure

Antihypertensives in Heart Failure ACEi ◦ SOLDV-T 16% reduction in mortality compared to placebo ◦ CONSENSUS-I 27% reduction in mortality compared to Placebo ◦ Overview of Randomized Trials of Angiotensin-Converting Enzyme Inhibitors on Mortality and Morbidity in Patients With Heart Failure JAMA 1995; 273: 1450 -1456 statistically significant reduction in total mortality odds ratio 0. 77 CI 0. 67 -0. 88

Fig 3 Standard pair-wise meta-analysis of β blockers and effect on mortality in chronic heart failure. © 2013 by British Medical Journal Publishing Group Saurav Chatterjee et al. BMJ 2013; 346: bmj. f 55

The opioid crisis A BRIEF ASIDE BUT A VERY RELEVANT TOPIC

But first… A some what long winded but good explanation of how opioids work https: //www. youtube. com/watch? v=Aq. Do 4 Li. Kz-c

Opioid crisis http: //www. theglobeandmail. com/news/investigations/oxycontin/article 33448409/

Opioid Crisis How we got to now v 1992 Purdue Pharma files Canadian Patent No. 2, 098, 738 for Oxy. Contin v. Opioid prescription rates have been steadily increasing since 2000(Oxy. Cotin added to formulary) o o o 10209 defined daily doses per million population a day 2001 -2003 30 540 in 2012 -2014 Evidence suggests levels of NMPOU as well as PO-related morbidity and mortality correlate strongly with the total of PO volume dispensed in the population v. Between 200 -2008 long term opioid users in BC has increased from 2 -2. 4% v About 18500 person increase v. Canada has the second highest rate of opioid use in defined daily doses and highest overall when considering morphine equivalents v. By 2010 1/5 Canadian have reported use of pain relievers in previous year v 23% increase in high-dose opioid dispensing from 2006 -2011 v 2012 Oxycotin is no longer available in Canada v. Increased prevalence of Fentanyl on the street

Opioid crisis Why Canada? ◦ ◦ High PO dispensing rates Weak prescribing guidelines Lack of evidence Large pharmaceutical influence

Opioid Crisis v. Not all Chronic Pain patient’s develop a drug addiction ◦ ◦ 3. 27% develop a drug addiction 0. 19% develop a drug addiction if preselected against previous history for addiction 11. 5% develop ADRB(eg. Early refill, stolen medications) 0. 59% develop ADRB if preselected

Evidence based solutions Naloxone ◦ ◦ ◦ ◦ An opioid antagonist that reverses the effects of opioids Take Home Naloxone started in 2012 in BC 125 documented overdoes reversals 2012 -2014 “Not only does it not increase the amount of drugs used, but people who have been trained are more safety conscious and are at less risk of an overdose, ” says Buxton. 2016 naloxone becomes over the counter “Take home” naloxone: what does the evidence base tell us? (2015): May reduce overdose deaths Are take-home naloxone program effective? Systematic review utilizing application of the Bradford Hill criteria (2016): Take home naloxone reduces overdose mortality among program users and the community and has a low rate of adverse events https: //www. youtube. com/watch? v=e 73 MRb_Sb_k

Evidence based solutions

Evidence based solutions Supervised injection sites 75 articles reviewed (most are from Vancouver or Sydney) Outcomes ◦ ◦ ◦ No death by overdose ever reported within SIS 35% decrease in number of lethal overdoses in vicinity of SIS (2 -12 OD deaths/yr avoided) 68% fewer OD related ambulance calls during SIS operating hours 69% reduced likelihood of syringe sharing No direct evidence of decreased viral transmission but 8% increase in condom use and increase in injection site infection treatment Odds ratio=1. 32 for dependence care Decrease in public injections and drug injecting associated litter No increase in crime or trafficking in SIS vicinity No increase in number of drug users nor relapse rates No decrease in number of drug users who started methadone Over 10 years predicted cost savings of $14 million, gain 920 years of life, avoidance of 1191 new HIV infections and 54 new HCV infections

Pop Quiz 1. What is pharmacology? 2. What are pharmacokinetics? 3. What is a ligand? 4. What are the ADME processes? 5. True or False: With increased number of medications comes an increased risk of drug interactions. 6. True or False: Supervised injection sites decrease the annual number of lethal overdoses.

Questions

Methadone Quick how it works