Title:  Stimulant Use and Cardiovascular Consequences

By Arthur Westover, MD, MSCS 5/30/2014

I.      Introduction

A.   Stimulants are one of five categories of drugs used to get a high

                        1.  Stimulants—increase arousal

                        2.  Depressants

                                    a.  ↓ brain activity/arousal (leading to lethargy, sleepiness)

                                    b.  ↓ anxiety

                                    c.  Examples:  alcohol & diazepam (Valium)

                        3.  Opioids

                                    a.  ↓ pain

                                    b.  ↓ gut motility and cough

                                    c.  Examples:  morphine, heroin, codeine

                        4.  Hallucinogens

                                    a.  ↑ sensory perception

                                    b.  Some have stimulant-like properties (e.g., LSD)

                                    c.  Examples:  LSD, mescaline, ecstasy

                        5.  Other drugs

                                    a.  Cannabis

                                    b.  Inhalants (e.g. gasoline, toluene)

B.  Stimulant misuse carries risks, especially in overdose:

            1.  Seizures

            2.  ↑ body temperature

            3.  Serious cardiovascular events

            4.  Death

C.  This lecture covers:

1.  Definition of stimulants and other drugs of misuse

                        2.  Rates of stimulant use

                        3.  Physiological effects of stimulants

                        4.  Cardiovascular consequences of high-dose stimulants

                        5.  Possible cardiovascular consequences of moderate-dose stimulants

D.  Stimulant misuse unrecognized by many docs, but is a major problem

II.  Description of stimulants

            A.  Multiple types of stimulants used on the street

                        1.  Cocaine (coke) & amphetamines (speed or uppers)

                                    a.  Cocaine comes in several forms

                                                1’.  Powder (cocaine hydrochloride) taken intranasally or  intravenous (IV)

                                                2’.  Crystalline (crack, rock)

                                                            a’.  More pure

                                                      b’.  Lower melting point

c’.  Smoked

b.  Amphetamines also in multiple forms

                                                1’.  Crystalline (“crystal meth”) usually smoked

2’.  Powder taken intranasally or IV

3’.  Tablets/capsules taken orally

B.   Stimulants are characterized by causing:

      1.  Euphoria

      2.  ↓ need for sleep

      3.  ↓ appetite

      4.  ↑ focus/attention

      5.  ↑ pulse, blood pressure (BP)

            C.  Cocaine and amphetamines have risks

                        1.  Overdose

                                    a.  Seizures

                                    b.  ↑ body temperature

                                    c.  ↑ BP

                                    d.  Heart arrhythmias

                                    e.  Can → death

                        2.  Cardiovascular effects

                                    a.  Low dose can cause ↓  heart rate1

                                    b.  High dose can ↑ heart rate and BP

            D.  Cocaine use is common

                        1.  ~40 million Americans 12+yo have lifetime use (2012)2

                        2.  ~5 million Americans 12+yo reported past-year use (2012)2

            E.  Amphetamine use is common

                        1.  ~12 million have lifetime use2

                        2.  ~1 million reported past-year use2

            F.  Rx Stimulant use increasing

                        1.  5 million insured users of stimulants in 2012

                        2.  Stimulant use increased from 2008 to 20123

                                    a.  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 illness

            A.  Clinical indications for use include:

                        1.  Attention Deficit Hyperactivity Disorder (ADHD)

                                    a.  Definition:  ↓attention and/or hyperactivity→ learning/behavior problems

                                    b.  Rates of ADHD

                                                1’.  Children

                                                            a’.  ~5% of ♂, ≤18 years of age4

                                                      b’. ~1.5% of ♀                                                    

                                                      c’.  11% of school age children diagnosed5:  overdiagnosis?

                                                2’.  Adults

a’.  ~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/day

                                                2’.  Amphetamine (Adderall); adult dose 15mg 2x/day

                        2.  Narcolepsy

                                    a.  Definition:  sudden disabling daytime sleepiness (fast onset dream sleep)

b.  Rate:  1 in 2000 persons7

c.  Daytime naps and medications are first-line therapy including:

            1’.  Methylphenidate (Ritalin); dose is usually 20mg 2x/day

            2’.  Amphetamine (Adderall); dose is usually 20mg 2x/day

                        3.  Obesity

                                    a.  >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 use

                        1.  Evidence is indirect and anecdotal; off-label use is likely frequent9

                        2.  Example uses:

                                    a.  Depressive symptoms

                                    b.  Dementia

                                    c.  Stroke recovery

                                    d.  “Neuroenhancement” (efforts to ↑ cognition)

                        3.  Use has risks but no clear evidence of benefit

                      4. Some risks noted above; more are given next section

IV.  Physiological effects of stimulants

            A.  Distinguishing "endogenous" vs. "exogenous" stimulants

                        1.  Endogenous stimulants

                                    a.  Body produces naturally

                                    b.  Examples:  epinephrine, norepinephrine, dopamine

                        2.  Exogenous stimulants

                                    a.  Referring to chemicals that are ingested

                                    b.  Examples include cocaine and amphetamine

            B.  Endogenous stimulants

                        1.  "Catecholamines" (comes from “catechol” =  plant product with stimulant properties)

                                    a.  Exist in nerve tissue throughout the body

                                    b.  Brain

                                    c.  Adrenal glands

                        2.  Exist as neurotransmitters

                                    a.  Epinephrine (called "adrenaline" in some countries)

                                    b.  Norepinephrine

                                    c.  Dopamine

            C.  Physiological effects

                        1.  Endogenous:  "fight or flight"

                        2.  Exogenous:  "hijack" the endogenous system

            D.  Fight or flight stress response

                        1.  ↑ heart rate

                        2.  ↑ release of glucose (energy)

                        3.  ↑ blood flow to skeletal muscles

                        4.  ↓ blood flow to many other parts of body

                        5.  ↓ digestion; dilation of the pupil

                        6.  ↓ salivation → dry mouth

            E.  How exogenous stimulants hijack the endogenous pathway

                        1.  Mechanism

                                    a.  Cause direct release of catecholamines

                                    b.  ↓ reputake of catecholamines from space between neurons

                        2.  Summary:  neuron is stuck in the stimulated position

            F.  Stimulant intoxication →

                        1.  CNS effects

                                    a.  Euphoria

                                    b.  ↓fatigue and ↑wakefulness

                                    c.  ↑ sex drive and prolonged orgasm

                                    d.  ↓appetite

                                    e.  ↑ energy

                                    f.  ↓distractibility (or ↑ attention focus)

                        2.  Peripheral effects

                                    a.  Hand tremor

                                    b.  Restlessness

                                    c.  ↑ muscle tension

                                    d.  ↑ body temperature

V.  Cardiovascular dangers associated with high-dose stimulants (i.e illicit/non-medical use)

            A.  Distinguishing between high and low dose stimulants

                        1.  High dose refers to illicit and non-medical use

                        2.  Low dose refers to medical use at prescribed doses

            B.  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 vessels

                        3.  Increased demand for oxygen

                        4.  Decreased perfusion (blood flow) to the heart muscle

                        5.  Clot (thrombus) formation through activation of platelets

                        6.  Arrhythmia (irregular heartbeat)

                        7. Inflammation of arteries to brain and heart (vasculitis)

            D.  Serious cardiovascular events from stimulants not uncommon

                        1.  A study reported 25% non-fatal MI in adults related to cocaine10

                        2.  3% sudden death may relate to cocaine 11

                        3.  2% bleeding-related strokes in adults related to amphetamines12

                        4.  3% aortic dissections in adults relate to cocaine and amphetamines13

            E.  Increased risk of serious cardiovascular events

                        1.  7x risk of non-fatal MI with cocaine use10

                        2.  3x risk of hemorrhagic stroke with amphetamine use12

                        3.  3x risk of aortic dissection with amphetamine use13

VI.  Possible cardiovascular dangers with low-dose prescribed stimulants

            A.  Mechanism

                        1.  Blood pressure

a.  Blood pressure ↑s with ↑ dose → ↑ mortality

b.  Stimulant medications ↑ BP by 2-4 mmHg14,15

                        2.  Heart rate                        

a. ↑ heart rate predicts ↑mortality 16

b.  Stimulants ↑  heart rate by 6 beats per minute14

                        3.  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 events

                                    a.  Linear relationship:  ↑ BP → increased stroke and myocardial infarction18

                                    b.  May not impact a specific individual, but important on population scale

            B.  Studies of the association between Rx stimulants and CV events

                        1.  Efficacy RCTs have been too small to observe a relationship

                        2.  Observational studies have been conducted in children & adults

            C.  Observational studies in children/adolescents

                        1.  20% increased hazard for CV ER visit19

                        2.  + ↑ risk sudden death20, 21

                        3.  No increased risk of heart attack, stroke, sudden death20

                        4.  Overall no ↑ risk serious child CV events21,22

            D.  Observational studies in adults

            1.  3x risk of transient ischemic attack (mini-stroke), but not stroke23

            2.  ~2x ↑ risk of sudden death/ventricular arrhythmia24

            3.  Overall no ↑ risk of serious adult CV events25

                        a.  Best & largest study of adults published

                        b.  Results subject to “healthy user bias”

                                    1'.  Stimulant users are generally healthier

                                    2'.  Stimulant users are more educated

                        c.  Median use only 4 months

            E.  What questions remain?

                        1.  Have we accounted for bias in the studies? 

                                    a.  Healthy user bias

                                    b.  Unmeasured variables (example:  lifestyle factors)

                        2.  Were high risk populations underrepresented?

                                    a.  Elderly

                                    b.  Adults with multiple cardiovascular risk factors

            F.  Public health considerations of serious cardiovascular events (stroke, heart attack, death)

                        1.  Baseline rate of serious cardiovascular events

a.  Children:  3 events per 100,000 person-years21

                                    b.  Adults: >70x higher than children (220  events per 100,000 person-years)25

                        2.  Any increased risk due to Rx stimulants would have more impact on adults

                                    a.  Children:  possible 2x risk = 6 per 100,000 person-years21

b.  Adults:  possible 2x risk = 440 per 100,000 person-years25

            G.  Government/organization-based  guidelines for Rx stimulants26

                        1.  US warned re: stimulant dangers starting in 2006

                        2.  Canada warned avoid use if heart disease/abnormalities in 2006

                        3.  Amer. Heart Assn: Rx stimulants < age 18  recommended

                                    a.  Careful health history

                                 b. Physical exam

                        4.  Amer Acad Peds: EKG reasonable but not mandatory before Rx stimulants

VII.  Conclusions

A.  Stimulants commonly misused

B.  Clinical use of prescribed stimulants is rapidly increasing

C.  Dangers associated with misuse of stimulants

D.  Cardiovascular safety has been a concern with prescribed use

            1.  Minimal concern with children

            2.  No definite risk established in adults, but safety signal present

            E.  Caution when prescribing to patients at high risk for CV events

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