Sympathomimetics

Chapter 8
KINS 401
DR. MARC COOK
Department of Kinesiology (NC A&T)
 Lecture Objectives

• Learn how sympathomimetics work.

• Distinguish between peripheral and centrally acting
sympathomimetics.
• Learn the medical conditions for which sympathomimetics are used.
• Appreciate the issues associated with attention deficit and
hyperactivity disorder.
• Understand how ephedrine and related drugs affect athletic
performance.
• Appreciate how exercise may be a useful adjuvant therapy for ADHD.
• Contemplate the ongoing debate over whether drugs like
pseudoephedrine should be banned from competition.
 Introduction
• Sympathomimetics are a class of drugs that stimulate the
sympathetic nervous system (adrenergic agonists). They include:
 They include amphetamines and ephedra

• Sympathomimetics have diverse mechanisms, with some drugs

having agonist activity and others indirectly increasing the activity of
norepinephrine and epinephrine.
• They also vary in their access to the central nervous system, so some
drugs largely affect peripheral responses, whereas others can
profoundly change behavior.
• Since the drugs mimic adrenergic activity, and exercise and stress
also involve adrenergic responses, the exercise pharmacology of
these drugs explores whether they provide competitive advantage
and the negative effects they may exert on the cardiovascular
system.
 Types of sympathomimetics
• Drugs that mimic the actions of:
 norepinephrine (through adrenergic receptors
at post-synaptic sites),
 epinephrine (released from the adrenal gland
following stress or intense exercise),
 and possibly dopamine (active mostly in the
central nervous system)

• Characterized as specific (as with β-2

agonists) or general (having epinephrine-like
effects).
• Some of these drugs have agonist activity,
and some have indirect mechanisms for
increasing levels of endogenous
catecholamines.
• Examples of indirectly acting drugs include
those that:
1. block reuptake of neurotransmitters at the
pre-synaptic membrane,
2. drugs that displace neurotransmitters from
their storage sites, and Figure: Osmosis.org - sympathomimetics
3. drugs that inhibit metabolic inactivation of the
neurotransmitters.
Use of Sympathomimetics – variety of conditions
• Epinephrine: drug of choice during emergencies involving anaphylactic
shock (a severe allergic reaction involving swelling, respiratory distress,
and circulation collapse):
 Can be injected intramuscularly or subcutaneously (e.g., EpiPen).
 Used as a pressor agents (agents that cause the constriction of blood
vessels), usually in a clinical setting.
• Used as decongestants, appetite suppressants, weight control, and asthma
(β-2 agonists like albuterol).
• Effects on CNS: Sympathomimetics are prescribed for narcolepsy, attention
deficit / hyperactivity disorder (ADHD), and some types of sleep disorders.
 Ritalin (amphetamine): used for ADHD, narcolepsy, depression, and cocaine
addiction.
 Methamphetamines: Were a first drug prescribed in the 1950s for weight-loss
because it suppresses appetite.
 Frequently abused or used illegally

• Usage and abuse can increase blood pressure significantly

Sympathomimetics Discussed in this Chapter
 Ephedrine and related drugs
• Ephedra is a naturally occurring plant alkaloid. Active ingredient is Ephedrine
 primarily as part of herbal therapy (Chinese medicine) for alleviating cold symptoms.

• Ephedrine releases norepinephrine from storage sites in sympathetic neurons.

 Adverse side effects: including increased blood pressure, arrhythmias, psychosis, seizure, and
death.
 Pseudoephedrine, one of several compounds related to ephedrine, is less potent, requiring about
three times the dose to be equipotent (depending on the response being measured). Other
common drugs related to ephedra include phenylephrine and phenylpropanolamine.
• Common OTC decongestants, such as Sudafed, contain pseudoephedrine. which has
limited or very weak agonist activity.
 Mechanism of action: displacing norepinephrine from pre-synaptic terminals, resulting in a
contraction of vascular smooth muscle in the nasal passages. Oral and nasal sprays.
 Vasoconstriction decreases blood flow in nasal passages, thereby decreasing inflammation,
swelling, and mucus production.
• Newer formulations of OTC decongestants are replacing pseudoephedrine with
phenylephrine.
 The primary reason for the change is that pseudoephedrine can be converted into
methamphetamine illegally, and new laws require that products with pseudoephedrine be sold in
limited amounts and require an identification check.
 Potential Deadly Effects of Ephedra
• Report of heat stress/stroke/death in athletes using ephedra containing products
but causation was circumstantial.
• In the summer of 2001, an overweight and out-of-shape Korey Stringer, an offensive
lineman for the Minnesota Vikings, died from apparent heat stroke. He had been
fasting to lose weight and had a supplement called Ripped Fuel in his locker. This
supplement contained ephedra and caffeine. Although it was reported that ephedra
was not detected upon autopsy, it is not clear that it was actually tested. Stringer
had been ill and vomiting the night before the practice that led to his overheating
and death.
• February of 2003, when a pitcher for the Baltimore Orioles died from apparent heat
exhaustion early in training camp in Florida.
 He died the day after his body temperature reached 108 degrees. He was known to have
high blood pressure and some abnormal liver activity. To lose weight, he had been on a
liquid diet and was taking an ephedra-containing supplement called Xenadrine RFA-1. The
coroner’s report suggested that ephedrine could have been a factor in his death.
• The FDA banned ephedra in 2004, and it was removed from many OTC
supplements. Internet sale of herbal extracts claiming to contain ephedra for weight
loss still exists, but these products are not regulated and the contents are not
guaranteed
Amphetamine and Related Sympathomimetics
• Amphetamine causes release of neurotransmitters from nerve terminals
similar to that caused by ephedrine. Unlike ephedrine, amphetamine readily
enters the CNS, causing a stimulant effect on mood and alertness.
 Amphetamine also interferes with reuptake of norepinephrine by the norepinephrine
transporter (NET) in the pre-synaptic membrane  elevated and prolonged levels of
norepinephrine at the synapse, causing increased norepinephrine-dependent
signaling.
 Amphetamines may similarly affect dopamine synapses, which could contribute to
the elevated mood, wakefulness, appetite suppression, and pleasure responses many
feel when taking these drugs. Dopamine antagonists can suppress some of
amphetamine’s effects, suggesting the involvement of both norepinephrine and
dopamine pathways.
• Methamphetamine has an even greater CNS effect than amphetamine,
probably because it can more easily pass through the blood–brain barrier.
Methylphenidate (Ritalin), prescribed for ADHD, is related to the amphetamine
family.
 It also interferes with neurotransmitter reuptake and recycling and has abuse
potential.
 Other drugs include Atomoxetine (more selective for norepinephrine reuptake and
lacks the abuse potential);
Pharmocokinetic concerns
• During exercise, the blood level of epinephrine increases markedly, as
do levels of dopamine, norepinephrine, and serotonin.
 The sympathetic response includes shifting metabolism to mobilize energy
reserves, activating sweat glands, and stimulating K+ reuptake by skeletal
muscle.
 Under most conditions, the blood–brain barrier excludes systemic
catecholamines from entering the CNS. However, under conditions of high stress
or intense exercise, the blood levels of catecholamines can become high enough
that some will cross the barrier and exert an effect centrally.
• Ephedrine-Related Drugs: Urine concentrations of pseudoephedrine
peaks about 4 hours after dosing and 70% of compounds are secreted
unchanged by the kidneys.
• Amphetamines: readily absorbed from the small intestine and reach
maximum levels in the blood in one to two hours and can be detected in
the urine for up to 48 hours.
 Addicts need to take more as they develop tolerance, but the side effects
become more pronounced: increased blood pressure (increased vasoconstriction
and peripheral resistance) and reduced heat distribution  increased body
temperature
Pharmacodynamic Concerns 1
• Ephedrine and Related Drugs: Ephedra (the herbal supplement) and
ephedrine (the active component) have been studied for weight loss
and athletic performance.
 short-term weight loss was possible with ephedrine but that long-term
weight loss or improved athletic performance was not.
 Ephedrine with caffeine was shown to increase Power performance
(Wingate testing) but the side effects (cardiovascular health, psychiatric
symptoms, seizures, and death) are not worth consumption in athletes.
• OTC drugs (decongestants): oral doses of pseudoephedrine or
phenylpropanolamine have little effect on strength, energy
metabolism, or oxygen consumption.
• Phenylpropanolamine can increase blood pressure but no ergogenic
effects on exercise performance.
 Increased risk of stroke in some individuals
Pharmacodynamic Concerns 2
• Amphetamines and Related Drugs
• The centrally acting stimulants, such as amphetamine, reduce fatigue
and enhance performance.
 Amphetamines increase time to exhaustion during treadmill running,
cycling, and distance running. As expected, amphetamines increase heart
rate and blood pressure, redistribute blood to muscle, and mobilize energy
substrates.
 The increase in time to exhaustion is related to amphetamine’s ability to
decrease fatigue.
• Subjects receiving methylphenidate cycled 32% longer and, at the
point where the placebo trial terminated, had higher power output.
 They also had greater oxygen consumption, heart rate, ventilatory volume,
and blood lactate. These results suggest that we exercise with a centrally
controlled reserve and that amphetamine-like drugs allow access to this
reserve, thereby delaying fatigue.
Exercise vs. Drug for ADHD
• Exercise increases noradrenergic and dopaminergic signaling in
regions of the brain that have some overlap with the regions affected
by ADHD.
 The centrally acting stimulants and intense exercise probably share
overlapping yet distinct mechanisms
• Aerobic exercise
 increased the effectiveness of methylphenidate on clinical symptoms of
adolescents with ADHD
 beneficial for various executive functions, response time, attention, and
behavior in ADHD patients
• Exercise produces physical, mental, and emotional benefits without
problematic side effects. Timing and dosing strategies that include
both drugs and exercise will require optimization, but there is
significant support for exercise being an adjunct therapy in controlling
ADHD (especially because of medication side effects).
Health Risks 1
• At recommended doses of sympathomimetics for decongestant use, a
mild and general adrenergic effect would be noted.
• During endurance training, endogenous epinephrine probably
supersedes the drug effect and its weak agonist activity.
• Blood pressure can rise to very high levels during weightlifting; use of
high levels of these drugs is not recommended, since it could
augment the rise in blood pressure.
• Phenylpropanolamine can cause hemorrhage in normal individuals,
especially with a 100 mg dose. These drugs are not recommended for
use by hypertensives or diabetics.
Health Risks 2
• Centrally acting stimulants increase blood pressure and can cause left
ventricular hypertrophy with prolonged use.
• Physical and psychological dependence (i.e., addiction) are possible
with both amphetamine and cocaine.
• These drugs also cause issues with the body’s cooling ability and can
lead to heat exhaustion.
• Cocaine can significantly increase heart rate and blood pressure,
producing a serious health risk (as evident from the deaths of
basketball player Len Bias or football player Don Rogers and the many
others who have died from cocaine abuse).
PES Watch
• Because sympathomimetics have possible ergogenic effects, they have
doping potential. Stimulants like amphetamine and cocaine, usually
obtained illegally, are on the WADA Prohibited List.
 The weaker, mostly systemic acting derivatives of ephedra were moved from the
Prohibited List to the Monitored List around 2004.
• One report published after the changes in 2004 suggested improved times
in a 1,500-meter run following pseudoephedrine use at three times the
recommended dose.
 Pseudoephedrine was put back on the WADA Prohibited List in 2010, with a
urinary threshold of 150 μg/ml. This threshold should allow for the therapeutic
use of pseudoephedrine at 60 mg every four to six hours (240 mg per day max;
Deventer, Van Eenoo, Baele, et al. 2009) so they aren’t completely banned by
the NCAA or NHL.
• Most of the CNS stimulants are Schedule II Controlled Substances and
require a prescription. They are on the WADA Prohibited List and banned by
Olympic committees. The NCAA will offer a drug exemption to qualified
individuals with diagnosed ADHD.
 Conclusion
• Sympathomimetics are a diverse group of drugs that have
adrenergic properties.
• The ephedrine derivatives are used to alleviate cold
symptoms. The centrally acting stimulants are powerful drugs
that have abuse potential. However, some of these drugs are
useful in treating ADHD.
• Exercise affects areas of the brain that are also targets for
these stimulants and is encouraged as a helpful supplement to
drug therapy for ADHD.