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Mechanisms
(and some consequences)
of Drug Interactions
September 18, 2007
Frank F. Vincenzi
Learning Objectives
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•
Interaction
Object Drug
Precipitant Drug
Pharmacological
Antagonism
• Physiological
Antagonism
• Pharmacokinetic
Interaction
• Pharmacodynamic
Interaction
• Additive Effects
• Synergism
(potentiation)
• Adverse Drug Event
• Adverse Drug
Reaction
Definitions
• The effects of an OBJECT DRUG are altered by the
presence of another drug - the PRECIPITANT DRUG
• Operational Classifications of Drug Interactions (Hansten
& Horn)
– Class 1: Avoid (Risk >> benefit)
– Class 2: Usually avoid (alternatives or if benefit > risk)
– Class 3: Minimize risk (consider alternatives,
circumvent, monitor
– Class 4: No special precautions (risk << benefit)
– Class 5: No evidence of interaction
Definitions
• The effects of an OBJECT DRUG are altered by the
presence of another drug - the PRECIPITANT DRUG
• Operational Classifications of Drug Interactions
(ePocrates)
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Contraindicated
Avoid/use alternative
Monitor/modify treatment
Caution advised
A potentially lifesaving pharmacodynamic
drug interaction:
In a classic case of competitive
pharmacological antagonism, the respiratory
depressant effects of the opiate agonist,
heroin, are antagonized by the opiate
antagonist, naloxone (Narcan@).
A potentially lifesaving pharmacodynamic drug
interaction
Physiological antagonism
bronchoconstriction associated with
anaphylaxis (e.g., penicillin allergy) is
antagonized by epinephrine.
Histamine and other mediators act on certain
receptor(s) to cause bronchoconstriction.
Epinephrine acts on different receptors to
exert an opposite effect on the physiological
system.
Example of potentially lethal
pharmacodynamic drug interaction
(Class 1: Avoid Interaction)
• Amiodarone (Cordarone®) increases QTc interval
(ECG - QT interval corrected for heart rate) at
therapeutic concentrations
• So do:
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Disopyramide (Norpace®)
Procainamide (Pronestyl®)
Propafenone (Rhythmol)
Quinidine (Quinidex®)
Sotalol (Betapace®)
Example of potentially lethal
pharmacodynamic drug interaction
(Class 1: Avoid Interaction)
• Selegeline (Eldepryl®) (MAO inhibitor)
• Among others, avoid:
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Alpha agonists (all)
Opiates (all)
Selective serotonin reuptake inhibitors (all)
Tricyclic antidepressants (all)
Yohimbine
Example of potentially toxic or lethal
pharmacodynamic drug interaction
(Class 3: Caution advised, monitor)
• Morphine depresses respiration. Synergistic
depression of respiration may occur with:
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Anticholinergics
Antidepressants
Antihistamines
Antipsychotics
Barbiturates
Benzodiazepines
Ethanol
Muscle relaxants
Case: Wm. Unterexerciser
• 42 year old obese accountant; diagnosed with
sleep apnea after his wife complained of excessive
snoring
• Following surgical repair patient was monitored
with an oximeter in the recovery room
• In hospital room (no oximeter), several injections
of meperidine (Demerol®) gave little pain relief
• Injection of 10 mg of diazepam (Valium®) IV
provided relief and the patient went to sleep
• Several hours later the patient was found dead
William Osler was right!
• “The disease the patient has is less important than
the patient that has the disease”
• Some patients with sleep apnea have become
chronically desensitized to the accumulation of
carbon dioxide
• Opioids depress respiratory drive in part by
decreasing the sensitivity of the brain to the
accumulation of carbon dioxide
• A number of sleep apnea patients have died after
surgical repair when treated with opioids postoperatively.
Pharmacokinetic (dispositional) drug interaction:
changing the amount of target drug at its receptors
by altered drug absorption
• Binding drug in GI tract
– Antacids
– Cholestyramine
– Sucralfate
• Modification of GI pH
– Proton pump inhibitors, H2 antagonists, antacids
• Greatly reduce absorption of itraconazole or ketoconazole
• Induction or inhibition of P-glycoprotein (PGP)
Quinidine or verapamil inhibit PGP and increase the
absorption of digoxin.
Pharmacokinetic (dispositional) drug interactions:
altered drug abs/distribution and P-glycoprotein
• PGP: luminal membrane of epithelial cells in the gut,
blood-brain barrier kidney & placenta - also some
bacterial & cancer cells. PGP limits absorption from the
gut, access to the CNS, promotes secretion of drugs in
kidney tubules & protects the fetus.
• Substrates of PGP are many (lipid sol.). Some examples:
– Daunorubicin, digoxin, fexofenadine, paclitaxel,
rifampin, verapamil, vinblastine & vincristine
• Inhibitors of PGP on our drug list include:
– Amiodarone*, diltiazem, erythromycin, indinavir,
itraconazole, ketoconazole*, quinidine & verapamil
• Inducers of PGP include:
– Rifampin, St. John’s wort
P-glycoprotein is a product of the multidrug
resistance gene (MDR)
Pharmacokinetic (dispositional) drug interactions:
changing the amount of target drug at its receptors
by altered drug elimination
• Displacement from protein binding
– Increases glomerular filtration of small molecules
• Modification of tubular urine pH
– Sodium bicarbonate, ammonium chloride,
acetazolamide
• Induction or inhibition of P-glycoprotein (PGP)
– May change the amount of drug actively secreted by the
kidney tubules (see previous slide)
Pharmacokinetic (dispositional) drug interactions:
changing the amount of target drug at its receptors
by altered drug metabolism
• Theophylline (metabolized by CYP1A2 > CYP3A4)
– Most quinolone antibiotics inhibit 1A2)
• Ciprofloxacin (Cipro®)
– NOTE: Levofloxacin has little effect on CYP
– Most macrolide antibiotics inhibit 3A4
• Erythromycin (E-Mycin®)
– NOTE: azithromycin [Zithromax®] does not inhibit CYP3A4
•
(Class 2: Use only when benefits > risks)
Effect of a
component of
grapefruit juice
on felodipine
pharmacokinetics
OJ (solid), GJ (triangle),
furanocoumarin-free GJ (square)
Paine et al., 2006
Medication Errors, Adverse Drug Reactions and
Adverse Drug Events
Intercepted or no adverse outcome
Errors that result in harm to the patient
Approximately 20% are life-threatening
Unintended adverse reactions (un)/or expected
Adapted from Drug Therapy Topics 34 (7), 2005
Medication Errors: One Example
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106 cases of medication errors associated with
methotrexate were identified, including errors
resulting in deaths (24%) and other serious outcomes
(45%).
• The most common types of errors involved confusion
about the once-weekly dosage schedule (30%) and
other dosage errors (22%).
• Of the errors, 39 (37%) were attributable to the
prescriber, 21 (20%) to the patient, 20 (19%) to
dispensing, and 18 (17%) to administration by a
health care professional.
Moore et al., 2004, Medication Errors Associated With Methotrexate,
American Journal of Health-System Pharmacy Reported
SALAD
(Sound-Alike Look-Alike Drugs)
Pharmacist reported a potential error involving confusion
between INSPRA® (eplerenone), a selective aldosterone
receptor antagonist, and SPIRIVA® (tiotropium), an
inhalation powder indicated for bronchospasm associated
with COPD.
Physician ordered Spiriva® 25 mg PO daily. Since
Spiriva® is a powder for inhalation and shouldn't be
swallowed, the pharmacist called the physician who
verified intention was for Inspra® 25 mg PO daily.
Another SALAD Drug Example
Fluvoxamine (Luvox®)100 mg, was stocked in an
automated dispensing cabinet instead of flavoxate
(URISPAS® ) 100 mg.
The hospital is now labeling these medications as
fluvoxAMINE and flavoxATE.
One source of medication error now avoided
• Effective June 7, 2006 Washington State
law requires all prescriptions to be hand
printed, typewritten or electronically
generated.
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• Rxs in cursive are considered illegible
A note from official labeling of a new drug
• PALLADONE (hydromorphone extended-release)
comes in 12, 16, 24, and 32 mg capsules. This
drug should only be used in patients who are
already receiving opioid therapy and who require
a total daily dose of at least 12 mg of oral
hydromorphone or its equivalent. Palladone is
given daily but should NEVER be prescribed
using the abbreviation "Q.D." It is predictable that
if "Q.D." is misread as QID, the 4-fold overdose
of this potent narcotic could prove fatal to some
patients.
Limiting resident work hours does not
affect ADE rates
• Before or after weekly hours were limited to 80
hours per week there were no significant
differences in:
– Confirmed ADEs per 1000 patient days
– Preventable ADEs
Mycyk, Am J Health Syst Pharm 62(15):1592-1595, 2005
Some causes of preventable ADEs
• Drug interactions (4.6%)
• Excessive dosage (42%)
• Known drug allergies (1.5%)
• Patient identification errors (3.5%)
Adapted from Drug Therapy Topics 34 (7), 2005
Community Pharmacy Drug Interaction Software
• Identification of clinically relevant drug-drug interactions
(DDIs)
• Chain and HMO pharmacies in WA State (~half)
• Sensitivity, specificity and positive and negative predictive
values in detecting 16 well-established DDIs in six fictitious
patient profiles
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Sens (correctly identify DDI) [true pos/true pos+false neg]0.44-0.88
Spec (ignore non DDI) [true neg/true neg+false pos) 0.71-1.00
Pos pred value [true pos/true pos+false pos] 0.67-1.00
Neg pred value [true neg/true neg+false neg] 0.69-0.90
• Same software gave different results in different locations
• Failed to detect clinically relevant DDIs one-third of the time
• Suboptimal performance - not really reliable
Hazlet et al. J Am Pharm Assoc 41(2):200-204, 2001
PDA Software for Drug Interactions?
• Sensitivity, specificity and pos and neg predictive
values, speed to identify five important drug
interactions, ease of use
• Possible 800 points
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iFacts 777
Lexi-interact
Mosby’s Drug Consult 688
Mobile Micromedex 655
ePocrates 559
Barrons, Am J Health-Syst Pharm 61(4) 380-385, 2004
In-Hospital Errors
• July 27, 2004
• Nearly 195,000 people in the U.S. died each year as a
result of potentially avoidable medical errors in 2000,
2001, and 2002, according to a new study of 37 million
patient records released today.
• "The equivalent of 390 jumbo jets full of people are dying
each year due to likely preventable, in-hospital medical
errors.
• http://www.ghi.com/yourhealth/articles/102228.html
• If the CDC's annual list of leading causes of death included
medical errors, it would show up as number six, ahead of
diabetes, pneumonia, Alzheimer's disease and renal
disease.
Medication errors
• “The greatest single systemic factor
associated with medication errors is a
deficiency in the knowledge requisite to the
safe use of drugs.”
Peth, H.A., Medication errors in the emergency
department. A systems approach to minimizing
risk, Emerg.Med.Clin.N.Am. 21: 141-158, 2003
Drug Classes Associated with >= 5% Adverse Drug Events
Gurwitz et al., Am.J.Med., 118: 251-258, 2005
Adverse Drug Events in a Recent Study
Gurwitz et al., Am.J.Med., 118: 251-258, 2005