1. STIMULANT USE AND CARDIOVASCULAR CONSEQUENCES Arthur Westover, MD, MSCS UT Southwestern Medical Center © AMSP1

2. Classes of drugs Stimulants Depressants (alcohol, diazepam) Opioids (morphine, heroin) Hallucinogens (LSD) Others (e.g., cannabis, inhalants) © AMSP2

3. Stimulant misuse carries risks Overdose –Seizures –↑ body temp –CV events –Death © AMSP3

4. This lecture covers Description of stimulants Patterns of stimulant use Physiological effects of stimulants Cardiovascular (CV) effects at high doses Possible effects of low/moderate doses © AMSP4

5. This lecture covers Description of stimulants Patterns of stimulant use Physiological effects of stimulants Cardiovascular (CV) effects at high doses Possible effects of low/moderate doses © AMSP5

6. Types of stimulants Cocaine –Powder –Crystalline (“crack”) Amphetamines –Powder –Crystalline (“crystal meth”) –Tablets/capsules © AMSP 6

7. Stimulants Characterized by: –Euphoria –↓ Need for sleep –↓ Appetite –↑ Focus/attention © AMSP7

8. Dangers of stimulant misuse ↑ BP Grand mal seizures ↑ Pulse Arrhythmias ↑ Body temperature © AMSP8

9. This lecture covers Description of stimulants Patterns of stimulant use Physiological effects of stimulants Cardiovascular (CV) effects w/ high doses Possible effects of low/moderate doses © AMSP9

10. Rates of illicit use (US) Cocaine (12+yo in 2012) –~40 million lifetime –~5 million past-year Amphetamines –~12 million lifetime –~1 million past-year © AMSP10

11. Increased Rx use in US 5 million insured users in 2012 Stimulant use ↑’d from 2008 to 2012 –Children: ↑ 19% –Adults: ↑ 53% –Women 26-34yr: ↑ 85% © AMSP11

12. Prescription (Rx) amphetamines FDA approved indications –Attention Deficit Hyperactivity Disorder –Narcolepsy –Obesity Off-label use © AMSP12

13. Attention Deficit Hyperactivity Disorder Definition: ↓attention ± hyperactivity→ learning/behavior problems Rates of ADHD –Children (≤18yo) 5% ♂ taking stimulants 1.5% ♀ –Adults (18-44yo) 5% ♂ meet ADHD criteria, 3% ♀ A lower percentage are treated © AMSP13

14. ADHD Treatment Stimulants first-line: –Methylphenidate (Ritalin) 20mg 3x/day –Amphetamine (Adderall) 15mg 2x/day © AMSP14

15. Narcolepsy Definition: –Sudden disabling daytime sleepiness –Fast onset dream sleep Rate: 1 in 2000 persons Treatment: daytime naps and medications –Methylphenidate (Ritalin) 20mg 2x/day –Amphetamine (Adderall) 20mg 2x/day © AMSP15

16. Obesity Definition: Body Mass Index ≥ 30 Rate: > 1/3 rd US adults Treatment with stimulants : –Dextroamphetamine (Dexedrine) –Methamphetamine (Desoxyn) –Benzphetamine (Didrex) Uncommon: –↓ Weight only seen first 3 weeks and returns –Safer options (example: orlistat [Xenical]) © AMSP16

17. Off-label use Likely frequent; anecdotal evidence Example conditions: –Depressive symptoms –Dementia –Stroke recovery –“Neuroenhancement” (↑ cognition?) Risks present No clear benefit © AMSP17

18. This lecture covers Description of stimulants Patterns of stimulant use Physiological effects of stimulants Cardiovascular (CV) effects at high doses Possible effects of low/moderate doses © AMSP18

19. Endogenous vs. Exogenous Endogenous stimulants –Body produces naturally –Example: norepinephrine Exogenous stimulants –Chemicals that are ingested –Examples: cocaine, amphetamine © AMSP19

20. Endogenous stimulants “Catecholamines” –Nerve tissue –Brain –Adrenal glands Exist as neurotransmitters –Epinephrine (i.e. adrenaline) –Norepinephrine –Dopamine © AMSP20

21. Physiological effects Endogenous: “Fight or flight” Exogenous: “Hijack” endogenous © AMSP21

22. Fight or flight Stress response –↑ Heart rate –↑ Release of glucose (energy) –↑ Blood flow to skeletal muscles –↓ Blood flow to other parts of body –↓ Digestion; dilation of the pupil –↓ Salivation → dry mouth © AMSP22

23. Hijack endogenous Mechanism : –Direct release of catecholamine –↓ Reuptake from space between neurons Neuron stuck in stimulated position © AMSP 23

24. Stimulant intoxication CNS effects – Euphoria, ↑wakefulness –↑ Sex drive –↓Appetite, ↑ energy Peripheral effects –Hand tremor, restlessness –↑ Muscle tension –↑ body temperature © AMSP 24

25. This lecture covers Description of stimulants Patterns of stimulant use Physiological effects of stimulants Cardiovascular (CV) effects at high doses Possible effects of low/moderate doses © AMSP25

26. Cardiovascular dangers High dose stimulants –Illicit use –Non-medical use Low dose stimulants –Medical use –Prescribed doses © AMSP 26

27. High dose stimulant CV problems Stroke –Ischemic –Hemorrhagic Heart attack Sudden cardiac death Aortic dissection (tearing of the aorta) © AMSP 27

28. Mechanisms of CV problems Vasospasm arteries in brain/heart ↑ BP → bleeding ↑ Oxygen demand ↓ Perfusion heart muscle ↑ Clots from activation of platelets Arrhythmia Inflammation arteries brain/heart © AMSP 28

29. Serious CV events Cocaine –25% non-fatal MI in adults (18-45yo) –3% sudden death Amphetamines –2% bleeding-related strokes in adults Cocaine and Amphetamines –3% aortic dissections in adults © AMSP 29

30. Risk of serious CV events Cocaine: 7x ↑ non-fatal MI Amphet: 3x ↑ hemorrhagic stroke Amphet: 3x ↑ aortic dissection © AMSP 30

31. Mechanisms of low-dose CV dangers Blood pressure ↑ 2-4 mm Hg Heart rate ↑ 6 beats/min QT Prolongation → arrhythmias → death © AMSP 31

32. BP and CV events Linear relationship Important on population scale © AMSP 32 Psaty et al., 2001 ≤ 125 mmHg >160 mmHg

33. CV events & Rx stimulants Efficacy RCT too small Observational studies: –Children –Adults © AMSP 33

34. Studies in children 20% ↑ risk of CV ER visit + ↑ risk sudden death Best: NO ↑ risk serious CV events –Cooper et al., NEJM 2011 © AMSP 34

35. Studies in adults 3x ↑ “mini-stroke” (not stroke) ~2x ↑ sudden death/ventricular arrhythmia © AMSP 35

36. Studies in adults Best: no ↑ serious CV events ? Selection bias: –Users healthier –More educated Median use 4 months © AMSP 36 Habel et al., JAMA 2011

37. Remaining questions Other variables (e.g. lifestyle factors) High risk populations underrepresented? –Elderly –Adults with multiple CV risk factors © AMSP 37

38. Public health considerations Baseline rates of serious CV events –Children: 3/100,000 person-years –Adults: 220/100,000 person-years Doubling risk? –Children: 6/100,000 person-years –Adults: 440/100,000 person-years © AMSP 38

39. Government regs of Rx stimulants 2006 US: avoid use if heart disease American Heart Association: –< age 18 –Careful health history –Physical exam American Academy Pediatrics: –EKG not mandatory © AMSP 39

40. Conclusions Stimulants commonly misused Rx stimulants: use increasing Dangers associated with misuse CV safety: a concern with Rx use –Children: minimal concern –Adults: no definite risk; safety signal present Caution Rx’ing to high risk CV patients © AMSP 40