Download The War on Drugs

The War on Drugs
T HE BA S I CS OF P HA R M ACOLOGY A N D T HE U S E OF M E DI CATIONS I N
M E DI CI NE
Disclosures
I am a medical student
This session is not intended to give you a diagnosis or replace going to see your health care
professional
No samples
What we will discuss
A brief history of pharmacy
How drugs work: Drug mechanisms
Pharmacokinetics
Pharmacodynamics
Drug interactions
Evidence based medicine
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
Pharmacology is the science of drugs including their origin, composition, pharmacokinetics,
therapeutic use, and toxicology
Pharmacy is the art, practice, or profession of preparing, preserving, compounding , and
dispensing medical drugs
Therapeutics is the application of pharmacology to the treatment of disease
History
History
Paleolithic era – Treatment based on observation and instinct
Babylonia (2600 B.C)- Earliest known record of practice of the art of the apothecary
Egypt- Papyrus Ebers (1500 BC) contained 811 drug recipes derived from plants, animals, and
minerals
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
1600s
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
18th and 19th Century
o
o
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 19th century
Pierre Paul Emile Roux develops the diptheria anti-toxin
History
The 20th century
◦ Drug receptor theory emerges(1907 Ehrlich proposes existence of chemoreceptors)
◦ Alexander Flemming discovers Penicillium mold hindered the growth of staphylococci in1928 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
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
Pharmacological effect
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
Y6IWVgFCrQ
From: CARDIOVASCULAR-RENAL DRUGS
Basic & Clinical Pharmacology, 13e,
2015
Date of download: 12/8/2016
Copyright © 2016 McGraw-Hill Education. All rights reserved.
Metformin
Full explanation of the mechanism of action is not known
Their primary effect is to activate the enzyme AMP-activated protein kinase and reduce hepatic
glucose production
Pharmacokinetics
The study of the movement of drugs in the body in the body, including the process of
absorption, distribution, localization in tissues, biotransformation, and excretion
How much? How often? How long? What form?
ADME processes
ADME Processes
A-Absorption:
D-Distribution:
M-Metabolism:
E-Excretion:
Absorption
A-Absorption: Movement of the drug from the site of administration into the blood
Influencing factors
• Concentration gradient
• Size
• Lipid solubility/pH
Bioavailability is the fraction of drug that reaches circulation unchanged
IV vs. Oral
Absorption-influence of pH
Example: Piroxicam
An NSAID prescribed to relieve arthritis pain
It is a weakly acidic drug
Common side effects include nausea, indigestion, heartburn
Heart burn is commonly treated with TUMS(antacid) which
increase stomach pH 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/pH
Blood flow
Protein binding
Distribution-influence of protein binding
Drugs reversibly bind to plasma proteins to varying degrees
depending on the drug
The more a drug is protein bound the less it is available to
reach its target
The amount of plasma protein changes with different
physiological states
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
A diffusion barrier essential for
normal functioning of the CNS
Extensive tight junctions
Limits the paracellular flux of
hydrophilic molecules from the blood
to brain
Focused
ultrasound BBB
disruption
Lipid-encased perfluorocarbon
gas microbubbles injected
intravenously along with drug
Transcranial delivery of lowfrequency ultrasound waves which
results in disruption of BBB
It has been used in one patient
to target a malignant brain tumor
Metabolism
The irreversible biotransformation of a drug
Primarily in the liver
The goal is to make the drug more water soluble so it can be excreted through the urine or bile
Phase I: Cytochrome P450 enzyme family increases water solubility of the drug
Phase II: Various non-P450 liver enzymes ensures that metabolite is ready for renal excretion
Influences
•
•
•
•
Liver function
Route of administration
Disease state
Age
Metabolism in action: Prodrugs
A compound that, on administration, must undergo chemical conversion by metabolic
processes before becoming an active pharmacological agent
Example: Codeine is converted to morphine via O-demethylation
• The reaction is catalyzed by CYP 2D6
• Genetic variations in this gene lead to variable effects of codeine
Codeine
CYP 2D6
Morphine
Excretion
 The irreversible loss of a drug from the
body
Primarily through the kidneys
Some excretion occurs through the biliary
system
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
AE incidence of 7.5%
Procedures or events to which AE were related
37% are preventable
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
Increased fall risk
Decreased compliance
Increased use of prescription drugs is associated with decreased ability to carry out activities of
daily living
Excessive polypharmacy (10≥drugs) is an indicator of increased mortality (Jyrkkä, 2012)
With increased number of drugs comes an increased risk of DDI
Polypharmacy and Adverse Drug
Reactions
Drug Interactions
Drug Interactions
Drug-Food
Drug-Disease
Drug-Drug
Pharmacokinetic
Absorption
pH, Chelation,
binding, GI
motility, P-gp
Distribution
Protein binding
Pharmacodynamic
Metabolism
CYP p450
induction or
inhibition
Excretion
Renal transporters,
P-gp
Drug-Drug
Drug-Drug Interactions
Drug-Drug interactions account for around a sixth of all adverse drug reactions
Many potential DDI but only a small number are clinically relevant
Three mechanisms
• Pharmaceutical interaction
• Pharmacokinetic interaction
• Pharmacodynamic interaction
Example: Paroxetine and Tamoxifen
• Paroxetine inhibits CYP450 2D6
• Tamoxifen is a prodrug: it is converted from to endoxifen by CYP450 2D6
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_interact
ions.php
PharmaNet
Province-wide network that links all BC
pharmacies to a central set of data systems
Every prescription in B.C is entered into
PharmaNet
Accessible by B.C pharmacists, community
health practitioners, emergency departments,
hospitals and designated mental health facilities,
providers of medical devices and supplies
PharmaNet
Information stored on PharmaNet
• Demographic information
• Medication hx including all prescriptions, reported non-prescription drugs, reported drug allergies
• Claims information
Not stored on PharmaNet
• Drugs received in hospital
• Drugs received through the BC Cancer Agency, Center for Excellence in HIV/AIDS, Transplant society,
Renal Agency
• Samples received
PharmaNet
Improves safety by allowing authorized health care practitioners to access information about
all prescription medications dispensed anywhere in BC
Allows for quick identification and warning about potentially harmful medication interactions
and accidental duplications of prescriptions
Privacy concerns
Only as good as the patient’s history
Which drug is right for
you?
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
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
A lack of evidence
An abundance of evidence
Critical appraisal of the evidence
Integration of critical appraisal with clinical expertise
Patient overload
Time constraints
Financial barriers
Evidence based medicine and statistics
Likelihood ratio is the likelihood that a given test result would be expected in a patient with
target disorder compared to the likelihood that that same result would be expected in a patient
without the target disorder
Number needed to treat is the number of patients who need to be treated to prevent one
additional bad outcome
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
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.f55
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=AqDo4LiKz-c
Opioid crisis
http://www.theglobeandmail.com/news/investigations/oxycontin/article33448409/
Opioid Crisis
How we got to now
1992 Purdue Pharma files Canadian Patent No. 2,098,738 for OxyContin
Opioid prescription rates have been steadily increasing since 2000(OxyCotin 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
Between 200-2008 long term opioid users in BC has increased from 2-2.4%
 About 18500 person increase
Canada has the second highest rate of opioid use in defined daily doses and highest overall when considering morphine equivalents
By 2010 1/5 Canadian have reported use of pain relievers in previous year
23% increase in high-dose opioid dispensing from 2006-2011
2012 Oxycotin is no longer available in Canada
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
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=e73MRb_Sb_k
Evidence based solutions
Evidence based solutions
Supervised injection sites
75 articles reviewed (most are from Vancouver or Sydney)
Outcomes
◦
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◦
◦
◦
◦
◦
◦
◦
◦
◦
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