Title: Stimulant Use and Cardiovascular Consequences



Title: ?Stimulant Use and Cardiovascular ConsequencesBy Arthur Westover, MD, MSCS 5/30/2014IntroductionStimulants are one of five categories of drugs used to get a high1. Stimulants—increase arousal2. Depressantsa. ↓ brain activity/arousal (leading to lethargy, sleepiness)b. ↓ anxietyc. Examples: alcohol & diazepam (Valium)3. Opioidsa. ↓ painb. ↓ gut motility and coughc. Examples: morphine, heroin, codeine4. Hallucinogensa. ↑ sensory perceptionb. Some have stimulant-like properties (e.g., LSD)c. Examples: LSD, mescaline, ecstasy5. Other drugsa. Cannabisb. Inhalants (e.g. gasoline, toluene)B. Stimulant misuse carries risks, especially in overdose:1. Seizures2. ↑ body temperature3. Serious cardiovascular events4. DeathC. This lecture covers:1. Definition of stimulants and other drugs of misuse2. Rates of stimulant use3. Physiological effects of stimulants4. Cardiovascular consequences of high-dose stimulants5. Possible cardiovascular consequences of moderate-dose stimulantsD. Stimulant misuse unrecognized by many docs, but is a major problem II. Description of stimulantsA. Multiple types of stimulants used on the street1. Cocaine (coke) & amphetamines (speed or uppers)a. Cocaine comes in several forms1’. Powder (cocaine hydrochloride) taken intranasally or intravenous (IV)2’. Crystalline (crack, rock)a’. More pure b’. Lower melting pointc’. Smokedb. Amphetamines also in multiple forms1’. Crystalline (“crystal meth”) usually smoked2’. Powder taken intranasally or IV3’. Tablets/capsules taken orallyStimulants are characterized by causing: 1. Euphoria 2. ↓ need for sleep 3. ↓ appetite4. ↑ focus/attention 5. ↑ pulse, blood pressure (BP)C. Cocaine and amphetamines have risks1. Overdosea. Seizuresb. ↑ body temperaturec. ↑ BPd. Heart arrhythmiase. Can → death2. Cardiovascular effectsa. Low dose can cause ↓ heart rate1b. High dose can ↑ heart rate and BPD. Cocaine use is common1. ~40 million Americans 12+yo have lifetime use (2012)22. ~5 million Americans 12+yo reported past-year use (2012)2E. Amphetamine use is common1. ~12 million have lifetime use22. ~1 million reported past-year use2F. Rx Stimulant use increasing1. 5 million insured users of stimulants in 20122. Stimulant use increased from 2008 to 20123a. Use by children ↑ by 19%b. Use by adults ↑ by 53%c. Use by women 26-34 years old ↑ 85%III. Amphetamines also prescribed to treat illnessA. Clinical indications for use include:1. Attention Deficit Hyperactivity Disorder (ADHD)a. Definition: ↓attention and/or hyperactivity→ learning/behavior problemsb. Rates of ADHD1’. Childrena’. ~5% of ♂, ≤18 years of age4 b’. ~1.5% of ♀ c’. 11% of school age children diagnosed5: overdiagnosis?2’. Adultsa’. ~5% of ♂, age 18-44 6 meet criteria (less diagnosed & treated)b’. ~3% of ♀, age 18-44 c. Stimulants are part of ADHD treatment including:1’. Methylphenidate (Ritalin); adult dose 20mg 3x/day2’. Amphetamine (Adderall); adult dose 15mg 2x/day2. Narcolepsya. Definition: sudden disabling daytime sleepiness (fast onset dream sleep)b. Rate: 1 in 2000 persons7c. Daytime naps and medications are first-line therapy including:1’. Methylphenidate (Ritalin); dose is usually 20mg 2x/day2’. Amphetamine (Adderall); dose is usually 20mg 2x/day3. Obesitya. >1/3rd US adults are obese (definition: Body Mass Index ≥ 30)8 b. Stimulants → ↓ appetite c. Stimulants used in Rx weight loss include:1’. Dextroamphetamine (Dexedrine)2’. Methamphetamine (Desoxyn)3’. Benzphetamine (Didrex)d. Use in weight loss relatively rare due to:1’. Other pharmacological options that are safer (e.g.,orlistat [Xenical])2’. ↓ weight only seen first ~ 3 weeks and returns1 B. Off-label use1. Evidence is indirect and anecdotal; off-label use is likely frequent92. Example uses:a. Depressive symptomsb. Dementiac. Stroke recoveryd. “Neuroenhancement” (efforts to ↑ cognition)3. Use has risks but no clear evidence of benefit 4. Some risks noted above; more are given next sectionIV. Physiological effects of stimulantsA. Distinguishing "endogenous" vs. "exogenous" stimulants1. Endogenous stimulantsa. Body produces naturallyb. Examples: epinephrine, norepinephrine, dopamine2. Exogenous stimulantsa. Referring to chemicals that are ingestedb. Examples include cocaine and amphetamineB. Endogenous stimulants1. "Catecholamines" (comes from “catechol” = plant product with stimulant properties)a. Exist in nerve tissue throughout the bodyb. Brainc. Adrenal glands2. Exist as neurotransmittersa. Epinephrine (called "adrenaline" in some countries)b. Norepinephrinec. DopamineC. Physiological effects1. Endogenous: "fight or flight"2. Exogenous: "hijack" the endogenous systemD. Fight or flight stress response1. ↑ heart rate2. ↑ release of glucose (energy)3. ↑ blood flow to skeletal muscles4. ↓ blood flow to many other parts of body5. ↓ digestion; dilation of the pupil6. ↓ salivation → dry mouthE. How exogenous stimulants hijack the endogenous pathway1. Mechanisma. Cause direct release of catecholaminesb. ↓ reputake of catecholamines from space between neurons2. Summary: neuron is stuck in the stimulated positionF. Stimulant intoxication →1. CNS effectsa. Euphoriab. ↓fatigue and ↑wakefulnessc. ↑ sex drive and prolonged orgasmd. ↓appetitee. ↑ energyf. ↓distractibility (or ↑ attention focus)2. Peripheral effectsa. Hand tremor b. Restlessnessc. ↑ muscle tensiond. ↑ body temperatureV. Cardiovascular dangers associated with high-dose stimulants (i.e illicit/non-medical use)A. Distinguishing between high and low dose stimulants1. High dose refers to illicit and non-medical use2. Low dose refers to medical use at prescribed dosesB. High dose cocaine & amphetamines ↑ risk cardiovascular problems including:1. Stroke (both ischemic and hemorrhagic)2. Heart attack (i.e. myocardial infarction or MI) 3. Sudden cardiac death (sudden pulseless condition leading to death)4. Aortic dissection (tearing of the aorta)C. Mechanisms 1. Vasospasm (constriction) of arteries in brain and heart 2. Increased BP → bleeding from blood vessels3. Increased demand for oxygen4. Decreased perfusion (blood flow) to the heart muscle5. Clot (thrombus) formation through activation of platelets6. Arrhythmia (irregular heartbeat)7. Inflammation of arteries to brain and heart (vasculitis)D. Serious cardiovascular events from stimulants not uncommon1. A study reported 25% non-fatal MI in adults related to cocaine102. 3% sudden death may relate to cocaine 113. 2% bleeding-related strokes in adults related to amphetamines124. 3% aortic dissections in adults relate to cocaine and amphetamines13E. Increased risk of serious cardiovascular events1. 7x risk of non-fatal MI with cocaine use102. 3x risk of hemorrhagic stroke with amphetamine use123. 3x risk of aortic dissection with amphetamine use13VI. Possible cardiovascular dangers with low-dose prescribed stimulants A. Mechanism1. Blood pressurea. ?Blood pressure ↑s with ↑ dose → ↑ mortalityb. Stimulant medications ↑ BP by 2-4 mmHg14,152. Heart ratea. ↑ heart rate predicts ↑mortality 16b. Stimulants ↑ heart rate by 6 beats per minute143. QT Prolongation17 a. QT interval: time heart takes to make next beat b. ↑ in QT interval ↑ risk arrhythmias c. ↑ risk sudden death as heart loses coordination of beats 4. Large epidemiological studies have linked increases to BP to CV eventsa. Linear relationship: ↑ BP → increased stroke and myocardial infarction18b. May not impact a specific individual, but important on population scaleB. Studies of the association between Rx stimulants and CV events1. Efficacy RCTs have been too small to observe a relationship2. Observational studies have been conducted in children & adultsC. Observational studies in children/adolescents1. ?20% increased hazard for CV ER visit192. + ↑ risk sudden death20, 21 3. No increased risk of heart attack, stroke, sudden death204. Overall no ↑ risk serious child CV events21,22D. Observational studies in adults1. 3x risk of transient ischemic attack (mini-stroke), but not stroke232. ~2x ↑ risk of sudden death/ventricular arrhythmia243. Overall no ↑ risk of serious adult CV events25a. Best & largest study of adults published b. Results subject to “healthy user bias”1'. Stimulant users are generally healthier2'. Stimulant users are more educatedc. Median use only 4 monthsE. What questions remain?1. Have we accounted for bias in the studies? a. Healthy user biasb. Unmeasured variables (example: lifestyle factors)2. Were high risk populations underrepresented?a. Elderlyb. Adults with multiple cardiovascular risk factorsF. Public health considerations of serious cardiovascular events (stroke, heart attack, death)1. Baseline rate of serious cardiovascular eventsa. Children: 3 events per 100,000 person-years21b. Adults: >70x higher than children (220 events per 100,000 person-years)252. Any increased risk due to Rx stimulants would have more impact on adultsa. Children: possible 2x risk = 6 per 100,000 person-years21b. Adults: possible 2x risk = 440 per 100,000 person-years25G. Government/organization-based guidelines for Rx stimulants261. US warned re: stimulant dangers starting in 20062. Canada warned avoid use if heart disease/abnormalities in 20063. Amer. Heart Assn: Rx stimulants < age 18 recommendeda. Careful health history b. Physical exam4. Amer Acad Peds: EKG reasonable but not mandatory before Rx stimulantsVII. ConclusionsA. Stimulants commonly misusedB. Clinical use of prescribed stimulants is rapidly increasingC. Dangers associated with misuse of stimulantsD. Cardiovascular safety has been a concern with prescribed use1. Minimal concern with children2. No definite risk established in adults, but safety signal presentE. Caution when prescribing to patients at high risk for CV eventsReference List1. Schuckit M. Drug and Alcohol Abuse: A Clinical Guide to Diagnosis and Treatment. 6th ed. Springer; 2005.2. Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings and Detailed Tables. Substance Use and Mental Health Services Administration. 10-2-2013. Available at: . Accessed April 8, 2011.3. Turning Attention to ADHD: U.S. Medication Trends for Attention Deficit Hyperactivity Disorder. The Express Scripts Lab. 2014. Available at: . Accessed April 8, 2011.4. Zuvekas SH, Vitiello B. Stimulant medication use in children: a 12-year perspective. Am J Psychiatry. 2012;169:160-166.5. 2011-2012 National Survey of Children's Health. CDC. 2013. Available at: . Accessed April 8, 2011.6. Kessler RC, Adler L, Barkley R et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163:716-723.7. Thorpy M. Therapeutic advances in narcolepsy. Sleep Med. 2007;8:427-440.8. Ogden, CL, Carroll, MD, Kit, BK, and Flegal, KM. Prevalence of Obesity in the United States, 2009–2010. Centers for Disease Control and Prevention. 2012. Available at: . Accessed April 8, 2011.9. Radley DC, Finkelstein SN, Stafford RS. Off-label Prescribing Among Office-Based Physicians. Archives of Internal Medicine. 2006;166:1021-1026.10. Qureshi AI, Suri MF, Guterman LR, Hopkins LN. Cocaine use and the likelihood of nonfatal myocardial infarction and stroke: data from the Third National Health and Nutrition Examination Survey. Circulation. 2001;103:502-506.11. Lucena J, Blanco M, Jurado C et al. Cocaine-related sudden death: a prospective investigation in south-west Spain. European Heart Journal. 2010;31:318-329.12. Westover AN, McBride S, Haley RW. Stroke in young adults who abuse amphetamines or cocaine: A population-based study of hospitalized patients. Archives of General Psychiatry. 2007;64:495-502.13. Westover AN, Nakonezny PA. Aortic dissection in young adults who abuse amphetamines. American Heart Journal. 2010;160:315-321.14. Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. European Neuropsychopharmacology. 2013;23:534-541.15. Wilens TE, Hammerness PG, Biederman J et al. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2005;66:253-259.16. Cooney MT, Vartiainen E, Laatikainen T, Juolevi A, Dudina A, Graham IM. Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women. Am Heart J. 2010;159:612-619.17. Reimherr FW, Williams ED, Strong RE, Mestas R, Soni P, Marchant BK. A double-blind, placebo-controlled, crossover study of osmotic release oral system methylphenidate in adults with ADHD with assessment of oppositional and emotional dimensions of the disorder. J Clin Psychiatry. 2007;68:93-101.18. Psaty BM, Furberg CD, Kuller LH et al. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. Arch Intern Med. 2001;161:1183-1192.19. Winterstein AG, Gerhard T, Shuster J, Johnson M, Zito JM, Saidi A. Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2007;120:e1494-e1501.20. Schelleman H, Bilker WB, Strom BL et al. Cardiovascular Events and Death in Children Exposed and Unexposed to ADHD Agents. Pediatrics. 2011;127:1102-1110.21. Cooper WO, Habel LA, Sox CM et al. ADHD Drugs and Serious Cardiovascular Events in Children and Young Adults. New England Journal of Medicine. 2011;365:1896-1904.22. Almut GW, Tobias G, Paul K et al. Cardiovascular safety of central nervous system stimulants in children and adolescents: population based cohort study. BMJ. 2012;345.23. Holick CN, Turnbull BR, Jones ME, Chaudhry S, Bangs ME, Seeger JD. Atomoxetine and cerebrovascular outcomes in adults. J Clin Psychopharmacol. 2009;29:453-460.24. Schelleman H, Bilker WB, Kimmel SE et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169:178-185.25. Habel LA, Cooper WO, Sox CM et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306:2673-2683.26. Westover A, Halm E. Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review. BMC Cardiovascular Disorders. 2012;12:41. ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download