Chapter 12 – Pharmacology of Stimulants

Cocaine
- Cultivated in South America
- 2 forms
o Base – low melting point and poor solubility  smoked and not injected
o Salt – high melting point and highly soluble  good for injection but not inhalation
- Additives
Inert – dextrose, lactose, starch
Active – lidocaine, procaine
- Can be heated in solvents to extract and purify to concentrations of 80-90% and converted to salt
form
- Crack- crackling sound made during heating process to convert salt form to “rocks”
o Can be smoked, inhaled or injected

Ephedrine and Pseudoephedrine

- Natural/plant-derived occurring alkaloids
- Same range of effect as cocaine and amphetamines
- Marketed as “safer”, “natural”, “herbal”

Khat
- Plant-derived  East Africa and Arabian peninsula
- 2 active chemicals
o Cathinones – similar to amphetamines
A. Synthetic cathinones aka. bath salts – mephedrone, methylone, MDPV

Synthetic Stimulants
- Amphetamines, methylphenidates
- D- or S-(+) isomers have 3-5x the CNS activity and 1/3 the half life of L- or R-(-) isomer.
- L-isomers have more peripheral alpha-activity
o D-methamphetamine is a potent CNS stimulant where as L-methamphetamine is used as
a decongestant in Vicks
- Strategies to mitigate abuse  extended release formulations, transdermal patches, and pro-drug
conversions
- Most common way is to get from friends and family
- Methamphetamines (desoxyephedrinbe) can also be synthesized wit standard chemical reactions
applied to legally available precursors

Clinical Uses
- Cocaine  legally available as schedule II as topical or local anesthetic, vasoconstrictor properties
(decongestants, bronchodilators)
- ADHD
- Appetite suppression
- Narcolepsy and excessive daytime sleepiness
- OTC stimulants  decongestion, bronchodilation, weight loss
- Adjunctive treatment in depression, for apathy & fatigue in dementia, elderly, HIV or other serious
medical conditions
- Ephedrine & phenylephrine used parenterally to counteract hypotension after spinal anesthesia
(urology and oBGYN)

*There is no evidence that medical use of stimulants at therapeutic doses in appropriately diagnosed
patients leads to a stimulant use disorder or increases the risk of serious adverse events.
Children receiving stimulant treatment for ADHD have no increased risk of developing a SUD

Stimulant Abuse
- Enhancement of cognitive and psychomotor effects  athletes
- 1 in 6 persons who use cocaine and 1 in 9 who use prescription stimulants for other than medical
purposes will develop a moderate–severe stimulant use disorder
- Increased risk with IV and inhaled use
- Stimulants prescribed for ADHD are misused by 10% of patients for whom there are prescribed
- Most common source of non-medical use of prescription stimulants us from friends and family
- Often combined IV with opioids for a better high than either one alone (cocaine+heroin =
speedballing)

Some History
- Naturally occurring plant alkaloids have been used for CNS stimulant effects for thousands of years
 leaves are chewed, brewed into teas etc.
o Continues to be used legally as such in Bolivia and Peru
- Cocaine isolated from coco leaf by German in 1860
- Amphetamines used in WWII to enhance performance of troops and factory workers

Epidemiology
- Cocaine is the 2nd most widely used illegal drug in USA after cannabis
- The 2015 NSDUH estimated that 38.7 million Americans (14.5% of the US population 12 years old or
older) had used cocaine at some time during their lifetime
- There were an estimated 968,000 new cocaine users in 2015 (37,000 [3.8%] by smoking), with a
mean age of 22 years.

Pharmacokinetics
- Inhalation – rapid absorption, reaches brain in 6-8 seconds
- IV – peak effect in 4-7 minutes
- Intranasal an oral  peak at 30-45 minutes
- Highest uptake of cocaine in striatum
- Cross placenta  umbilical cord blood, amniotic fluid, meconium
Metabolism
- Cocaine
o 95% of cocaine metabolized to benzoylecgonine
o 5% by CYP3A4 to norcocaine
- Methamphetamines often metabolized into active amphetamines
- Methylphenidate dose not appear as a positive amphetamine in UDS

Elimination
- Benzoylecgonine is the cocaine metabolite found in highest concentration in urine for several days
after cocaine use  this is what is reacts in a UDS

DDIs
- medications that also enhance catecholamine activity  cardiac arrythmia, hypertension, seizure,
cardiovascular collapse, death
- Should not be used within 2 weeks of MAOI use
- Alcohol used in conjunction with cocaine results in enhanced or prolonged cocaine effects, in part
because of formation of a new pharmacologically active compound, cocaethylene.
o Cocaethylene  similar action but less potent than cocaine; longer half life

Pharmacodynamics
- Increased energy, alertness, sociability, euphoria and elation, reduced fatigue, deceased need for
sleep, decreased appetite  described as “total body orgasm”
- Improve cognitive and psychomotor performance in subjects whose performance has been impaired
by fatigue, sleep deprivation, or alcohol, especially in tasks that require focused and sustained
attention.
- In those who are already fully awake and attentive  dysphoric states, anxiety, irritability, panic
attacks, interpersonal sensitivity, hypervigilance, suspiciousness, paranoia, grandiosity, impaired
judgment, and psychotic symptoms such as delusions and hallucinations

Psychosis

*Cocaine-induced psychosis may differ from acute schizophrenic psychosis in being marked by less
thought disorder and bizarre delusions and fewer negative symptoms such as alogia and inattention.

- Tactile hallucinations are especially typical of stimulant psychosis and include the sensation of
something (eg, insects) crawling under the skin (“formication,” “cocaine bugs”).
- Other behaviours  agitation, tremor, dyskinesia, and repetitive or stereotyped behaviors such as
picking at the skin or foraging for drug (punding)
- Tachycardia, mydriasis, diaphoresis, nausea

Chronic Effects
- Cognitive impairment lasting months after abstinence  visuomotor performance, attention,
inhibitory control, and verbal memory
- Decreased frontal grey matter volumes
- Psychotic syndrome lasting years after last drug use
Withdrawal
- “Crash”  depressed mood, anhedonia, fatigue, difficulty concentrating, increased total sleep and
rapid eye movement sleep duration (but with poor sleep quality)

CVS
- Stimulants act acutely on the cardiovascular system both directly (by increasing adrenergic activity
at sympathetic nerve terminals) and via the CNS to increase heart rate, blood pressure, and systemic
vascular resistance
- The resulting increase in myocardial oxygen demand, often accompanied by decreased coronary
blood flow (from vasospasm and vasoconstriction), may cause acute myocardial infarction, even in
young persons without atherosclerosis
- Cardiac arrythmias
- Cardiomyopathy and myocarditis

Other Effects
- No significant risk of seizures (Dr. Parran says otherwise)
- 2x increased risk of stroke
- Movement disorders  repetitive stereotyped behaviours, acute dystonia, choreoathetosis,
akathisia, orofacial dyskinesias, exacerbation of Tourette’s and tardive dyskinesia
- Increased risk of EPS but not akathisia when taking in combo with antipsychotics
- Effects on other organ system usually from ischemia and infarction from
vasoconstriction/vasospasm
- Rhinitis, perforated nasal septum, oropharyngeal ulcers
- Change in taste and smell are rare
- Acute effects  increases sexual interest
- Chronic use impairs sexual function

Pregnancy
- Prescription stimulants are FDA pregnancy category C
- Medical use by the mother of other prescription and OTC stimulants in appropriate doses usually
does not have clinically significant adverse effects on nursing infants.

- In utero exposure to cocaine, amphetamines, or methylphenidate has been associated with abruptio
placenta, placenta previa, still birth, premature rupture of membranes (smooth muscle contraction),
decreased head circumference, low birth weight, tremulousness, irritability, poor feeding, and
autonomic instability
- Long-term studies suggest that prenatal cocaine exposure is associated with small but statistically
significant impairments in sustained attention and behavioral self-regulation among preschool- and
school-aged children, and in language and memory among adolescents
 Neurobiology
- “Stimulants” enhance CNS (and peripheral sympathetic) activity by augmenting NA and DA
- Disrupt plasma membrane transporter proteins via 2 mechanisms
A. Reuptake blockers/”blockers” (cocaine, methylphenidate)  bind to the
extracellular face of transporter and inhibit the uptake of monoamine
neurotransmitters.
B. Transporter substrates/”releasers” (amphetamine and phentermine)
 they promote non-exocytotic release of cytoplasmic amine transmitters by
entering neurons and reversing the normal direction of transporter flux
 Disrupt monoamine storage by interacting with VMATs which increases
cytoplasmic concentration of transmitter molecules available for
transporter-mediated release.

- Tolerance to cardiovascular, hyperthermic, and lethal effects occurs even more quickly, sometimes
after just one or two exposures
- Tolerance to appetite-suppressing effects within several weeks of daily use, whereas the beneficial
effects in narcolepsy or ADHD remain over months of treatment
- Stimulant tolerance dissipates after 7-14 days of no exposure
- Releasers like amphetamine or methamphetamine produce substantial DA and 5HT neurotoxicity
via reactive oxygen species
- Chronic methamphetamine or methcathinone users have reduced density of dopamine transporters
in the brain (measured by PET) for at least 3 years after last use