Transcript No Slide Title
Drug Reactions and Interactions in Myasthenia Gravis
Laurence Kinsella, M.D., F.A.A.N.
Professor of Neurology Saint Louis University
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 facial diplegia?” “how long has your patient had Tensilon test, NCS, antibodies confirm MG Begun on prednisone Developed acute respiratory failure, intubated Steroids reduced, slow steady improvement
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.
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.
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
Immunosuppressant Reduces T and B lymphocytes Used as steroid sparing agent Prodrug is converted to mercaptopurine, the active drug Mercaptopurine is deactivated by Thiopurine S Methyltransferase (TPMT) 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
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
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.
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)
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 non MG patients Caution is recommended, but IV contrast is not contraindicated.
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.
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.
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
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 Pharmacist s. 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-year old individuals living in their own homes. European journal of clinical pharmacology. 56(6-7):501-9, 2000 Sep.
Phase I Drug Oxidation
NADP + NADPH Reduced Reductase Oxidized Oxidized Fe P450 Reduced Drug + O 2 Drug-OH + H 2 O
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)
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
Intermediate metabolizer (IM) Heterozygous for normal and reduced activity allele .
Extensive metabolizer (EM) 2 functioning alleles- normal
Ultra Metabolizer (UM) Greatly increased activity due to 3 or more alleles (2D6 only)
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
Relative Importance of CYP 450 Enzymes
Evans WE, et al. Science 1999;286:487-91.
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?
Theophylline is substrate of CYP1A2 Fluoroquinolones are inhibitor of CYP1A2.
Theo levels -
8.9 mg/dl (12/14)
6.2 (12/18) after levaquin stopped, theo held.
6 4 2 0 Theo levels 12 /1 4/ 20 05 12 /1 5/ 20 05 12 /1 6/ 20 05 12 /1 7/ 20 05 12 /1 8/ 20 05
The Grapefruit Effect
Furanocoumarins in grapefruit inhibit 3A4 Reduces/eliminates first pass metabolism Strong Interaction diazepam buspirone lovastatin simvistatin Moderate Interaction Nicardipine felodipine atorvastatin vincristine vinblastine Weak Interaction Sertraline fexofenadine omeprazole guaifenesin sildenafil
Center for Food-Drug Research and Education, University of Florida
Mnemonic: AVOID Mistakes
V itamins and dietary supplements - grapefruit juice, St Johns Wort, tobacco, char-grilled meats I O nteractions risk?
D M ld drugs and ependence?
endel: any family history of drug sensitivity
DDI- A Stepwise Approach
1. Take a medication history 3. Check pocket reference mnemonic AVOID M istakes 2. Identify high risk patients 4. Consult pharmacist/ drug specialist >3 medications 5. Check computer programs red flag drugs anticonvulsants, SSRIs, antifungals, quinolones, digoxin, warfarin, amiodarone 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
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) 5) Show the card to your doctor when receiving a new medication Ask “can this medicine interact with any of my others?” 6) When in doubt, call your neurologist before starting a new medication