Pharmacology 8:00 am - Dr
Pharmacology 8:00-10:00 a.m. A Longhorn Production
Tuesday November 28, 2000
Dr. Machu/Dr. McMahon
STIMULANTS/NONOPIOD DRUGS OF ABUSE
SYMPATHOMIMETIC AMINES
A. Amphetamine (d, l or d)
i. D = dextrorotatory, l = levorotatory form
ii. L form has more cardiovascular effects than the d form
iii. Prepared in the d from or as a racemic mixture of both d and l
B. Methamphetamine (Ritalin()
C. Methylphenidate
D. Pemoline
E. Cocaine – although it is a stimulant, it is not used clinically as one
AMPHETAMINE
A. Has been around since the 1920s
B. Sold OTC until the 1950s – abuse dropped dramatically after regulation
C. Extensive use in WWII – solders injected them to stay awake and alert for days at a time
D. Used by truck drivers to fight fatigue
METHAMPHETAMINE
A. Solid form – “crystal or ice” – smoked (as opposed to amphetamine which is injected or taken orally) for rapid onset due to the huge surface area of the lung. The effects can be felt in 5-10 seconds.
B. Very popular due to rapidity of onset and the fact that it is a “cleaner high” – methamphetamine’s effects are more central than peripheral
C. Still has a high potential for abuse
PLEASURABLE EFFECTS
A. Mood elevation/euphoria – intensely pleasurable euphoric feeling particularly when smoked
B. Increased confidence
C. Increased physical performance – many athletes abuse it for this reason
D. Increased speed at performing repetitive tasks – however accuracy does not improve
E. Increased wakefulness and alertness
F. Reduced feelings of fatigue
CLINICALLY RELEVANT EFFECTS
A. Increased attentiveness, vigilance, concentration – we will focus on AD/HD (see below) today since it is one of the main uses of stimulants in the US
B. Reduction of narcoleptic episodes - there are far fewer people with narcolepsy than AD/HD
C. Anorexia
D. Mood elevation – sometimes used as an anti-depressant
MECHANISM OF ACTION
A. Inhibition of DA/NE/5-HT uptake
i. DA is affected the most and then NE. 5-HT is least affected and only at higher concentrations
ii. Noncompetitive inhibitors of pumps that remove up to 85% of these biogenic amines from the synapse (major action). As a result, these neurotransmitters stay in the synapse longer.
B. Enhances calcium independent release of catecholamines – reverses the same pump that takes catecholamines up into the neuron. This is a minor effect of amphetamines because in neuronal function, calcium induced neurotransmitter release following depolarization is more important.
C. Weak inhibition of monoamine oxidase (MAO)
D. Stimulation of 5-HT receptors – whether or not this is clinically relevant is uncertain
STIMULANT ACTION: DA
A. Euphoria, dependence liability, sleep antagonism, increased concentration, motor stimulation, psychosis, increased respiration
STIMULANT ACTION: NE
A. Euphoria, sleep antagonism, anorexia, respiratory stimulation
STIMULANT ACTION: 5-HT
A. Euphoria, anorexia, anxiety, psychosis (maybe)
ATTENTION DEFICIT/HYPERACTIVITY DISORDER
A. One of the main uses of stimulants in this country
B. Clinical phenomena vs. disease state
i. We don’t understand the neurological dysfunction that is behind AD/HD. We do, however, see the symptoms in patients.
C. Persistent pattern of inattention that may be accompanied by hyperactivity and impulsivity
i. Patient is a kid that has difficulty concentrating
ii. Easily distracted and looks like his/her mind is elsewhere
iii. Lack of attention to detail with a tendency to lose important things (e.g. homework)
iv. Lack of organizational skills
v. Apparent restlessness with excessive talking
vi. Poor social skills, low self esteem, tendency to get frustrated, poor compliance
vii. Learning disabilities
D. Most common psychiatric disorder in children:
i. 5-10% elementary kids
ii. 3-7% elementary school kids receive stimulants
iii. 90% of those receiving stimulants receive methylphenidate (Ritalin()
E. Predominantly in males
i. 9:1 males in the clinic
ii. 4:1 males in epidemiologic studies
F. Only a small percentage has an identifiable disorder that causes AD/HD (e.g. Fragile X Syndrome and Fetal Alcohol Syndrome). In most cases, the underlying cause of AD/HD cannot be found
G. Large percentage have co-morbid behavioral disorder(s) (e.g. learning disorders, conduct disorders, Tourette’s Syndrome and chronic tics)
H. Heritable factors are important however psychosocial and environmental factors (e.g. children eating an excessive amount of sugar) are NOT important in causing AD/HD.
I. Outcomes:
i. 30%: developmental delay but as they reach adulthood they outgrow their AD/HD with no more problems
ii. 40%: continual display – some form of the disease (e.g. concentration problems) into adulthood
iii. 30%: developmental decay with serious psychopathology – substance abuse or another serious type of psychiatric disorder
J. One putative cause – reduction in DA in brain-orbitofrontal cortex. Must be part of the mechanism since stimulants relieve symptoms. Also, in PET scans of children with AD/HD, activation of orbitofrontal cortex is diminished but returns to normal upon administration of stimulants.
K. Stimulant Treatment:
i. In children: big improvement: 30-50%, some improvement: 70-80%
ii. In adults: only variable success
iii. Some patients are refractory to stimulants: guanfacine/clonidine, TCA’s and valproic acid sometimes help these children
L. Side effects of Treatment
i. Insomnia, anorexia
a. Tolerance develops quickly, so insomnia and anorexia are not experienced for long
b. Dose is given in the morning to combat insomnia
ii. Growth suppression – temporary, overall stature and weight is not affected
iii. Exacerbation of any underlying mania or psychosis
iv. Toxic psychosis – rare
M. Treatment
i. Methylphenidate (Ritalin() – 90% of AD/HD children receive this
a. Children: BID dosing, ................
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