No Slide Title

Report
Drug Reactions and
Interactions
in Myasthenia Gravis
Laurence Kinsella, M.D., F.A.A.N.
Professor of Neurology
Saint Louis University
Objectives
 Case presentation
 Review meds thought to worsen MG
 Review P450 drug interactions
75 yo M
 Presents with recurrent aspiration pneumonia to medicine
service.
 On exam, large lower eyelid ectropia, slurred speech,
trouble swallowing, generalized weakness
 Neurology consultant- “how long has your patient had
facial diplegia?”
 Tensilon test, NCS, antibodies confirm MG
 Begun on prednisone
 Developed acute respiratory failure, intubated
 Steroids reduced, slow steady improvement
Steroid Exacerbation
 Reported incidence 25-75%
 Mechanism poorly understood
 Low dose initiation every other day has been
recommended
 plasma exchange may limit steroid-induced weakness
Neurology 1972:22;603-610.
Lancet 1972:1;765-767.
N Engl J Med 1974;290:81-84.
Juel VC, Massey JM. Autoimmune Myasthenia Gravis: Recommendations for
Treatment and Immunologic Modulation. Curr Treat Options Neurol 2005;7:3-14.
Prednisolone (Prednisone)
 Effective, first line immunosuppressant for MG
 May be assoc with worsening weakness early, esp higher
doses
 42% patients begun on 40-80mg (1mg/kg) day developed
clinical worsening
 Main predictors of Steroid-induced weakness are:
 Older age
 Severe bulbar symptoms (diff swallowing, breathing)
 Low MG Severity Score
Bae JS, et al. Clinical predictors of steroid-induced exacerbation in
myasthenia gravis. J Clin Neuroscience 2006:13:1006-10.
Ten Drug Reactions
in Myasthenia Gravis
 Steroids (begun at high
doses)
 Azathioprine (Immuran)
 Anticholinesterase
inhibitors
(mestinon, tensilon)
 Neuromuscular Blockers
(Vecuronium)
 Botulinum toxin (Botox)
 IV Contrast
 Vaccinations
 Telithromycin (Ketek),
Zithromycin (Z-Pack)
 Quinolones (Cipro)
 Aminoglycosides
(tobramycin less than
gentamycin)
 Statins
Azathioprine (Immuran)
 Immunosuppressant
 Reduces T and B lymphocytes
 Used as steroid sparing agent
 Prodrug is converted to mercaptopurine, the active drug
 Mercaptopurine is deactivated by
Methyltransferase (TPMT)
Thiopurine S-
 Allergic Reaction within 14 days- fever, myalgia, flu-like symptoms
Sahasranaman S, et al.
Clinical pharmacology and pharmacogenetics of thiopurines
Eur J Clin Pharmacol (2008) 64:753–767
TPMT, Azathioprine, and Toxicity
 Enzyme is reduced in 10% of Caucasians
 need ½ dose
 Enzyme absent in .3% (1/300)
 need 1/10 dose
 Deficiency of enzyme may lead to bone marrow toxicity
(anemia, low WBC)
 Other idiosyncratic (allergic) reactions- pancreatitits,
hepatitis
Eur J Clin Pharmacol 2008: 64:753–767
Rheumatology. 2004; 43:13-18
TPMT Screening
 Recommended before starting Azathioprine
 TPMT testing available from many commercial labs
 Identifies patients with deficiency at risk for toxicity
 Monitor with weekly CBC x 1 month, biweekly for 2
months, then monthly
Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in
rheumatology patients receiving Azathioprine.
Rheumatology. 2004; 43:13-18
Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase
genotype predicts therapy-limiting severe toxicity from Azathioprine.
Ann Intern Med. 1998; 129:716-718
Azathioprine (AZA) and Drug
Interactions
Allopurinol (Zyloprim)
 Used for gout prevention
 Inhibits elimination of AZA
 May need lower doses of AZA
N Engl J Med 1972:286(13):730–731
 ACE inhibitors (Lisinopril)
 Anemia thought due to erythropoietin suppression
Transplantation 1993:56(3):585–589
 Warfarin (Coumadin)
 Inhibits action of warfarin
 Follow INR closely when stopping or starting AZA
Am J Med 1992: 92(2):217
Anticholinesterase Inhibitors
 Pyridostigmine (Mestinon), Edrophonium (Tensilon)
 reduces reuptake of acetylcholine, increasing amount
available in the neuromuscular junction.
 May be stand-alone agent in ocular myasthenia
 Side effects- nausea, diarrhea, abd cramps,
bronchospasm
 Doses >450mg day- may worsen weakness by
depolarization of NMJ- “Cholinergic Crisis”
 Usually seen in severe generalized MG with respiratory
weakness
Curr Treat Options Neurol 2005;7:3-14.
Lancet Neurol. 2009 May;8(5):475-90.
Neuromuscular Blockers
 Curare, vecuronium, botulinum toxin
 Leads to prolonged neuromuscular blockade
 Worsens and prolongs anesthetic paralysis and respiratory
paralysis
 Notify anesthesiologist of MG prior to surgery
 Botox should be avoided in MG (no matter how much you
hate the wrinkles)
IV Contrast
 Single case reports of weakness and respiratory paralysis
after contrast-enhanced CT scanning, etc.
 May occur in patients with severe generalized MG and
respiratory weakness
 In a careful review of 136 MG patients who received
contrast, the complication rate was 5.1%, similar to nonMG patients
 Caution is recommended, but IV contrast is not
contraindicated.
NEUROLOGY 1987;37:1400
Vaccinations
 Patients with disorders of the thymus may have less
protection from live (attenuated) virus vaccines
 Live virus vaccines should be avoided
 yellow fever, measles, rubella, mumps , some H1N1
 Flu shot, Pneumovax ok
 Consult your physician when travelling to Africa, other
locations endemic for yellow fever.
Muscle Nerve. 2009 Dec;40(6):947-51.
Antibiotics
 Zithromycin (Z-Pack)
 Telithromycin (Ketek)
 Levofloxacin (Levaquin)
 Ciprofloxacin (Cipro)
 Tetracyclines
 Aminoglycosides
 Gentamycin
 Tobramycin less of a
problem
 Tetracyclines bind calcium,
reduce Ach release
 Aminoglycosides interfere with
ACh release from presynaptic
terminal
 This leaves penicillins,
cephalosporins, metronidazole,
sulfa drugs as safest agents in
MG
The Pharmaceutical Journal 2006;277:703-706.
Statins
 Of 170 MG pts, 54 (31%) on statins reviewed.
 Myalgias noted in 13%, resolved after drug stopped.
 MG worsening in 11%, mainly oculobulbar
 Occurred within 1-16 weeks of statin treatment
 Safe for the majority, but vigilance is needed
Oh, S. Statins may aggravate MG. Muscle Nerve 2008;38:1101-1107.
Purvin V. Statin-Associated Myasthenia Gravis:
Medicine 2006;85:82-85.
Meriggioli M, Sanders DB.
Lancet Neurol. 2009 May;8(5):475-90
MG and Dentistry
 IV Lidocaine should be avoided
 Carbocaine may be safer theoretically
 Nitrous oxide OK
 Most dentistry involves local anesthetics, so few problems
are anticipated.
 A handout is available to bring to your dentist
Oral Surgery, Oral Medicine, Oral Pathology,
Oral Radiology, and Endodontology
2005;100:158-163
http://www.mgawpa.org/pdfs/Dentristy%20and%20Myasthenia%20GravisLH.pdf
Drug Effects often unclear
 MG can be exacerbated by
 infection
 was it the infection or the antibiotic?
 systemic illnesses
 thyroid disease
 Present in 11% with MG
 excessive heat
 exercise
 pregnancy
MG Drug Card
www.myasthenia.org
Why learn about
adverse drug reactions?
 6.7% (2.2 million) of hospitalized patients experience
adverse drug reactions
 Fatality rate 0.32%
 Fear of drug interactions or receiving the wrong drug are a
primary concern of hospitalized patients
Lazarou J. JAMA 1998
American Society of Health Systems Pharmacists. ASHP Patient Concerns National
Survey Research Report. 1999. Bethesda, MD.
Adverse Drug Interactions
2.2 million severe reactions/yr
7000 deaths/yr (institute of medicine)
Some claim 100,000+/yr
1.75 billion in increased medical costs
Largest reason for malpractice payouts
Lazarou J. JAMA 1998
Reported serious events vs outpatient
prescriptions, 1998-2005
Moore, T. J. et al. Arch Intern Med 2007;167:1752-1759.
Why so many ADRs?
 64% of patient visits result in Rx
 2.8 billion outpatient Rxs (10/person in US) in 2000
 ADRs increase dramatically over 4 medications
Jacubeit T. Agents Actions 1990.
What causes drug interactions?
 Age- >65 have 3 fold increase
 Polypharmacy
 Genetic variability in drug metabolism
 Lack of awareness of CYP450 system
 Protein binding site competition
 Esp. those with Renal failure
 Brown CS, US Pharmacist, 2000
Polypharmacy in the Elderly
 Average older person takes 4.5 prescription
medications and 2 OTC
 Average person aged 65-69 fills 13.6 rx/yr
 average person aged 80-84 fills 18.2 rx/yr
GAO, 1996
Senior Care Pharmacist, 2005
Potential Drug Interactions are Common
due to polypharmacy
 492 subjects over age 75 in Denmark
 Interviews w pt and GP, inspection of med cabinets
 87% use Rx, 72% OTC
 average 4.2 Rx meds, 2.5 OTC meds
 60% > 3, 34% > 5 meds
 31% used meds from 2 or more physicians
 Potential drug interactions seen in 15.3% of participants,
correl. with polypharmacy
Barat I, Andreasen F, Damsgaard EM. The consumption of drugs by 75-yearold individuals living in their own homes. European journal of clinical
pharmacology. 56(6-7):501-9, 2000 Sep.
Phase I Drug Oxidation
NADP +
Reduced
Oxidized
Fe
NADPH
Reductase
P450
Oxidized
Reduced
Drug
+
O2
Drug-OH
+
H2O
 Majority of drug interactions occur during phase 1 metabolism (oxidation,
hydroxylation, methylation)
 Phase 2 metabolism prepares the compound for elimination by making it water
soluble (i.e. glucuronidation)
Pharmacogenomics
 Drug therapies based upon genetic information
 6 p450 enzymes metabolize 95% of all drugs
 16 of the 27 (59%) most commonly cited drugs with ADR are
metabolized by P450 enzymes with genetic variants
 Genetic variation accounts for a majority of all adverse drug reactions
Phillips KA. Potential role of pharmacogenomics in reducing adverse drug
reactions: a systematic review. JAMA 2001;286:2270-79.
Pharmacogenetic Effect
of Cytochrome Genotypes
A. Poor metabolizer (PM)
no functioning alleles
B. Intermediate metabolizer (IM) Heterozygous
for normal and reduced activity allele.
C. Extensive metabolizer (EM)
2 functioning alleles- normal
D. Ultra Metabolizer (UM)
Greatly increased activity due to
3 or more alleles (2D6 only)
http://www.healthanddna.com/professional/pharmacogeneticsofpain.html
©
Genetics impact on drug metabolism:
copy number

Crixivan (indinavir) –an HIV/AIDs drug
Indinavir
Indinavir + St John’s Wort
Piscitelli SC. Lancet. 2000;355:547-548
Genetics impact on drug metabolism:
copy number

Pamelor (nortriptyline) manufactured by Novartis
PM
EM
Dalen P, et al. Clin Pharmacol Ther (1998).
P450 Enzyme System
 Located in liver, kidney, intestine, lungs, brain
 6 Individual enzymes metabolizing > 95% of all drugs:
 1A2, 2B6, 2C9, 2C19, 2D6, 3A4
www.fftc.agnet.org/library/image/tb159f1.html
Relative Importance of CYP 450
Enzymes
Evans WE, et al. Science 1999;286:487-91.
CYP1A2
 15% of all drugs metabolized by CYP1A2
 No genetic polymorphism
 Induced (rapid metabolism) by smoking tobacco
 Substrates  Warfarin, caffeine, benzos, SSRIs, Zyprexa, other antipsychotics,
theophylline
 Inhibitors  Fluvoxamine, quinolones, cimetidine
75 yo M with Seizures





Admitted 12/14 with COPD exacerbation.
Meds - theophylline 300 mg BID,
Begun on levaquin for pneumonia.
Developed confusion, ataxia, over next two days.
Seizure, encephalopathy 12/17.
 What caused the seizure?
Levaquin/theophylline interaction
 Theophylline is substrate of
CYP1A2
Theo levels
 Fluoroquinolones are inhibitor18
16
of CYP1A2.
14
12
 8.9 mg/dl (12/14)
10
 16.2 (12/17)
8
6
 6.2 (12/18) after
levaquin stopped, theo 4
2
held.
0
12
/1
8/
20
05
12
/1
7/
20
05
12
/1
6/
20
05
12
/1
5/
20
05
12
/1
4/
20
05
 Theo levels -
The Grapefruit Effect

Furanocoumarins in grapefruit inhibit 3A4

Reduces/eliminates first pass metabolism
Strong
Interaction
Moderate
Interaction
Weak Interaction
diazepam
buspirone
lovastatin
simvistatin
Nicardipine
felodipine
atorvastatin
vincristine
vinblastine
Sertraline
fexofenadine
omeprazole
guaifenesin
sildenafil
Center for Food-Drug Research and Education, University of Florida
Mnemonic: AVOID Mistakes

Allergies?

Vitamins and dietary supplements
 - grapefruit juice, St Johns Wort, tobacco, char-grilled meats

Old drugs and OTC?

Interactions risk?

Dependence?

Mendel: any family history of drug sensitivity
DDI- A Stepwise Approach
1. Take a medication history
 mnemonic - AVOID Mistakes
2. Identify high risk patients
>3 medications
red flag drugsanticonvulsants, SSRIs,
antifungals, quinolones,
digoxin, warfarin,
amiodarone
3. Check pocket reference
card (provided)
4. Consult pharmacist/ drug
specialist
5. Check computer programs
-www.epocrates.com
-medical letter drug
interaction program
www.fda.gov/cder/drug/drugReactions/default.htm
Drug interaction Card
www.drug-interactions.com
Websites on DDI, CYP450, and
drug transporting proteins

http://medicine.iupui.edu/flockhart

http://www.genemedrx.com/

Epocrates handheld

http://www.themedicalletter.com/

http://www.druginteractioninfo.org/

http://www.mhc.com/PGP/index.html

www.mhc.com/algortithms

http://mhc.daytondcs.com
Conclusions
1) Adverse Drug Effects may occur in MG by many mechanisms:
-Direct effect on muscle strength (Ketek, Botox, Quinine)
-Allergic/idiosyncratic reaction (Immuran)
-Genetic susceptibility (Immuran)
-Interactions with other drugs (Immuran, levaquin,)
-Unknown (steroid worsening, IV contrast)
2) Adverse effects are more likely in those with severe disease
3) Print and complete the Drug Avoidance Card avail on MGFA
website
4) Show the card to your doctor when receiving a new
medication
5) Ask “can this medicine interact with any of my others?”
6) When in doubt, call your neurologist before starting a new
medication
Questions from the
Audience?

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