Transcript PHL 322 ADHDnew (2)

Drugs Used In the Treatment of
Attention-Deficit/Hyperactivity Disorder
(ADHD)
Overview
• History of ADHD
• Definition & Features
• Etiological Factors
• Symptoms and Diagnosis: DSM-IV criteria
• Treatment
History of ADHD
Mid-1800s: Minimal Brain Damage
Mid 1900s: Minimal Brain Dysfunction
1960s: Hyperkinesia
1980: Attention-Deficit Disorder (ADD).
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With or Without Hyperactivity
1987: Attention Deficit Hyperactivity Disorder
1994-present: ADHD subtypes:
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Primarily Inattentive
Primarily Hyperactive
Combined Type
Definition & Features
• ADHD is a neurobehavioral developmental disorder affecting
about 3-5% of the world's population. It typically presents during
childhood, and is characterized by a persistent pattern of
impulsiveness and inattention, with or without a
component of hyperactivity.
• is a neurobehavioral developmental disorder affecting about 3-5% of the
world's population. It typically presents during childhood, and is
characterized by a persistent pattern of impulsiveness and inattention,
with or without a component of hyperactivity. ADHD occurs twice as
commonly in boys as in girls. Though previously regarded as a childhood
diagnosis, studies completed during the last few decades have shown that
ADHD often continues throughout adulthood - though generally with a
reduction in hyperactivity.
• The most common symptoms of ADHD are:
• Impulsiveness: a person who acts quickly without thinking things
through.
• Hyperactivity: a person who is unable to sit still.
• Inattention: a person who daydreams or seems to be in another world.
If Untreated ADHD Persists to Adulthood leading to:
- School underachievement---------------Career underemployment
- Impulsive actions---------------------------Impulsive life decisions
- Experimentation with
drugs, smoking, alcohol------------------substance use disorders
-Careless behaviour------------------------serious fatal traffic accidents
Adults with ADHD:
1. More likely to be suspended, expelled, or drop out of school.
2. Higher traffic citations.
3. Auto accidents.
4. Substance Abuse.
5. Unemployed, quit jobs, or get fired.
6. Increased divorce rates.
Cost to Society:
Health Care costs associated with ADHD are conservatively
estimated at $3.3 Billion annually
Causes of ADHD
1-Structural Differences in ADHD
2- Decrease Dopamine in the synaptic cleft
3- Genetic Origin in ADHD
4- Environmental factors in ADHD
5- Essential Fatty Acids Deficiency
1- Structural Differences:
1- Smaller Right cerebellar volume
(corrected for brain size]
2- Decreased prefrontal volume & activation
(Particularly Right hemisphere which cause
problems with focused attention)
3- Overall brain volume is 3% smaller in
ADHD
4- Decreased blood flow in certain parts of
the brain
2- Decrease Dopamine
in the synaptic cleft
1- Concentration of dopamine in a prefrontal
cortex plays a major role in motor control and
attention
2- Dopamine are received by different
dopamine receptor (DRD1-5) and re-uptake by
dopamine transporter (DAT) on pre-synaptic
neurons
3- Amount of dopamine depend on the:Availability of intra-vesicle Dopamine and
Sensitivity of DAT
4- In this case less dopamine in the
synaptic cleft induce ADHD
3- Genetic Origin:
Researchers believe that a large majority of ADHD arises from
a combination of various genes, many of which affect dopamine
transporters. Candidate genes include:
1- DAT1 (dopamine transporter gene)
2- DRD4 (dopamine receptor D4 gene)
3- DRD5
4- DBH (dopamine beta hydroxylase)
4- Environmental factors in ADHD:
Approximately 9-20 percent of the ADHD symptoms can be attributed to
environmental (nongenetic) factors. Environmental factors implicated
include alcohol and tobacco smoke exposure during pregnancy and lead
and mercury exposure after birth. Smoking relation to ADHD could be due
to nicotine causing hypoxia (lack of oxygen) in uterus. Complications during
pregnancy and birth—including premature birth—might also play a role.
1- Prenatal exposure to nicotine
Maternal smoking, second-hand exposure
2- Prenatal exposure to other neurotoxins
Lead, poly-biphenyls, etc
3- Prematurity
5- Essential Fatty Acids Deficiency:
Studies on Essential Fatty Acid levels in Attention Deficit Disorder
subjects vs. non- ADD ADHD subjects indicate that the ADHD groups had significantly
lower concentrations of key essential fatty acids than did the control groups, and about
40% of the ADHD group showed these signs of EFA deficiency:
• Increased thirst
• Frequent urination
• Dry skin
• Dry or brittle hair
Low levels of Omega 6 EFAs contributed to higher incidents of illness (colds, flu, etc.), and
deficits in Omega 3 EFAs contributed to problems with learning, behavior, sleep, and
temper. Preliminary evidence suggests that Omega-3/Omega-6 supplementation
reduces ADHD symptoms.
• ADHD Is Not Usually Caused by:
• - Too much TV
• - Food allergies
• - Excess sugar
• - Food additives
• NOR BY
• - Parents or poor home life
• - Teachers or poor Schools
Neurobiological
mechanisms
• PET scans measure the activity of various parts of the brain.
The image on the right illustrates glucose metabolism in the
brain of a person diagnosed with ADHD while doing an
assigned task. The image on the left illustrates glucose
metabolism in the brain of a normal subject when given that
same task. PET scan study found that global cerebral glucose
metabolism was 8% lower in medication-naive adults who
had been diagnosed as ADHD while children.
• In one study a delay in development of certain brain
structures by an average of three years occurred in ADHD
elementary school aged patients. The delay was most
prominent in the frontal cortex and temporal lobe, which
are believed to be responsible for the ability to control and
focus thinking. In contrast, the motor cortex in the ADHD
patients was seen to mature faster than normal, suggesting
that both slower development of behavioral control and
advanced motor development might be required for the
fidgetiness that characterize an ADHD diagnosis.
• The same laboratory had previously found involvement of
the "7-repeat" variant of the dopamine D4 receptor gene,
which accounts for about 30 percent of the genetic risk for
ADHD
Diagnosis of ADHD
• Based on the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV ) three types of ADHD are classified:
1. ADHD Predominantly Inattentive Type
2. ADHD, Predominantly Hyperactive-Impulsive Type
3. ADHD, Combined Type
DSM-IV: The Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric
Association provides a common language and standard criteria for the classification of mental disorders
Diagnosis of ADHD
• Based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV )
three types of ADHD are classified:
• ADHD Predominantly Inattentive Type: if criterion 1A is met but criterion 1B is
not met for the past six months
• ADHD, Predominantly Hyperactive-Impulsive Type: if Criterion 1B is met but
Criterion 1A is not met for the past six months.
• ADHD, Combined Type: if both criteria 1A and 1B are met for the past 6 months
• The terminology of ADD expired with the revision of the most current version of
the DSM. Consequently, ADHD is the current nomenclature used to describe the
disorder as one distinct disorder which can manifest itself as being a primary
deficit resulting in hyperactivity/impulsivity (ADHD, predominately hyperactiveimpulsive type) or inattention (ADHD predominately inattentive type) or both
(ADHD combined type).
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DSM-IV criteria
I. Either A or B:
• A. Six or more of the following symptoms of inattention have been present for at least 6 months to a point
that is disruptive and inappropriate for developmental level:
1. Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other
activities.
2. Often has trouble keeping attention on tasks or play activities.
3. Often does not seem to listen when spoken to directly.
4. Often does not follow instructions and fails to finish schoolwork, chores, or duties in the workplace (not
due to oppositional behavior or failure to understand instructions).
5. Often have trouble organizing activities.
6. Often avoids, dislikes, or doesn't want to do things that take a lot of mental effort for a long period of
time (such as schoolwork or homework).
7. Often loses things needed for tasks and activities (e.g. toys, school assignments, pencils, books, or tools).
8. Is often easily distracted.
9. Often forgetful in daily activities.
• B. Six or more of the following symptoms of hyperactivity-impulsivity have been
present for at least 6 months to an extent that is disruptive and inappropriate for
developmental level:
• Hyperactivity:
1. Often fidgets with hands or feet or squirms in seat.
2. Often gets up from seat when remaining in seat is expected.
3. Often runs about or climbs when and where it is not appropriate (adolescents or
adults may feel very restless).
4. Often has trouble playing or enjoying leisure activities quietly.
5. Is often "on the go" or often acts as if "driven by a motor".
6. Often talks excessively.
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Impulsiveness:
Often blurts out answers before questions have been finished.
Often has trouble waiting one's turn.
Often interrupts or intrudes on others (e.g., butts into conversations or games).
II. Some symptoms that cause impairment were present before age 7 years.
III. Some impairment from the symptoms is present in two or more settings (e.g.
at school/work and at home).
• IV. There must be clear evidence of significant impairment in social, school, or
work functioning.
• V. The symptoms do not happen only during the course of a Pervasive
Developmental Disorder, Schizophrenia, or other Psychotic Disorder. The
symptoms are not better accounted for by another mental disorder (e.g. Mood
Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder).
Methods of treatment
• Methods of treatment often involve some combination of medications, behavior
modifications, life style changes, and counseling.
• 1- Behavioral Treatments:
• Many believe that concepts such as, self-regulation, self-monitoring, and effortful
control are at the center of the functional impairments regarding ADHD. There
are Cognitive-Behavioral interventions designed to improve these areas and
boost self-efficacy, social competence, and emotional control, which can affect
attention and self-regulation. One such program is the Challenge Software
Program. This program uses media in the form of interactive videos and games to
grab and hold an inattentive child's attention and engage them in the process
quickly. The program also offers measurable Pre and Post outcomes to illustrate
improvement.
• Family therapy has shown little benefit in the treatment of ADHD. Education to
help parents understand ADHD has shown short term benefits.
2- Pharmacological Treatment:
• 1- First line treatment (Stimulant Medications):
• Stimulant medications are the most clinically and cost effective method of
treating ADHD. Stimulants have 80 % response rate. No significant differences
between the various drugs in terms of efficacy or side effects have been found.
About 70% of children improve after being treated with stimulants. Medications,
however, are not recommended for pre-school children with ADHD. Stimulants, in
the short term, have been found to be safe in the appropriately selected patient
and appear well tolerated over 5 years of treatment.
• Long term safety, however, has not been determined. There are no randomized
controlled trials assessing the harms or benefits of treatment beyond two years.[8]
The American Heart Association and the American Academy of Pediatrics feels
that it is prudent to carefully assess children for heart conditions before treating
them with stimulant medications. The FDA has added black box warning to some
ADHD medications. Amphetamines have warnings about potential for abuse,
drug dependence, and sudden death.
1-Amphetamine
• Amphetamine and dextroamphetamine, together with methamphetamine and
methylphenidate, comprise a group of drugs with very similar pharmacological
properties. They are substrates for the neuronal uptake transporters for noradrenaline,
serotonin and dopamine, and cause release of these mediators producing the acute
effects described below. With prolonged use, they are neurotoxic, causing degeneration
of amine-containing nerve terminals and eventually cell death. This effect is probably due
to the accumulation of reactive metabolites of the parent compounds within the nerve
terminals. Amphetamine, and related drugs such as methamphetamine are a group of
drugs that act by increasing levels of norepinephrine, serotonin, and dopamine in the
brain. It includes prescription CNS drugs commonly used to treat attention-deficit
disorder (ADD) and attention-deficit hyperactivity disorder (ADHD) in adults and
children. It is also used to treat symptoms of traumatic brain injury and the daytime
drowsiness symptoms of narcolepsy and chronic fatigue syndrome. Initially it was more
popularly used to diminish the appetite and to control weight.
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The main central effects of amphetamine-like
drugs are
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locomotor stimulation
euphoria and excitement
stereotyped behaviour
anorexia.
• In addition, amphetamines have peripheral sympathomimetic actions such as:
. producing a rise in blood pressure
. Inhibition of gastrointestinal motility.
• In experimental animals, amphetamines cause increased alertness and
locomotor activity, and increased grooming; they also increase aggressive
behaviour. With large doses of amphetamines, stereotyped behaviour
occurs. This consists of repeated actions, such as licking, gnawing, rearing
or repeated movements of the head and limbs. These activities are
generally inappropriate to the environment, and with increasing doses of
amphetamine they take over more and more of the behaviour of the
animal. These behavioural effects are evidently produced by the release
of catecholamines in the brain, because pretreatment with 6hydroxydopamine, which depletes the brain of both noradrenaline and
dopamine, abolishes the effect of amphetamine, as does pretreatment
with α-methyltyrosine, an inhibitor of catecholamine biosynthesis.
Similarly, tricyclic antidepressants and monoamine oxidase inhibitors
potentiate the effects of amphetamine, presumably by blocking amine
reuptake or metabolism.
• Amphetamine-like drugs cause marked anorexia, but with continued administration this effect
wears off in a few days and food intake returns to normal.
• In humans, amphetamine causes euphoria; with intravenous injection, this can be so intense as
to be described as 'orgasmic'. Subjects become confident, hyperactive and talkative, and sex
drive is said to be enhanced. Fatigue, both physical and mental, is reduced by amphetamine, and
many studies have shown improvement of both mental and physical performance in fatigued,
although not in well-rested, subjects. Mental performance is improved for simple tedious tasks
much more than for difficult tasks, and amphetamines have been used to improve the
performance of soldiers, military pilots and others who need to remain alert under extremely
fatiguing conditions.
• It has also been in vogue as a means of helping students to concentrate before and during
examinations, but the improvement caused by reduction of fatigue can be offset by the
mistakes of overconfidence.
• Clinical uses:
1. Appetite suppressant
2. ADHD
3. Narcolepsy and chronic fatigue syndrome
4. Treatment-resistant depression
• Along with methylphenidate, amphetamine is one of the standard
treatments for ADHD. Beneficial effects for ADHD can include:
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Improved impulse control
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Improved concentration
• Decreased sensory over stimulation
• Decreased irritability and decreased anxiety.
• Amphetamines are sometimes used to augment anti-depressant therapy in
treatment-resistant depression.
• As appetite suppressants in humans and weight loss is still approved in
some countries, but is regarded as obsolete and dangerous in others
because of its tendency to cause pulmonary hypertension, which can be so
severe as to necessitate heart-lung transplantation.
Adverse effects:
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Cardiovascular:
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Vasoconstriction
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Tachycardia
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Palpitation
Ear, nose, and throat:
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Decongestant
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Xerostomia
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Mydriasis
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Relaxation of ciliary muscle
Eye:
Gastrointestinal:
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Decreased secretions
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Decreased peristalsis
Genitourinary:
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Urinary retention
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Erectile dysfunction
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Decrease in appetite/weight loss
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Euphoria
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Insomnia
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Visual disturbance
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Aggressiveness
Others:
Amphetamines Summary:
• The main effects are:
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increased motor activity
euphoria and excitement
anorexia
with prolonged administration, stereotyped and psychotic behaviour.
• Effects are due mainly to release of catecholamines, especially noradrenaline and dopamine.
• Stimulant effect lasts for a few hours and is followed by depression and anxiety.
• Tolerance to the stimulant effects develops rapidly, although peripheral sympathomimetic effects
may persist.
• Amphetamines may be useful in treating narcolepsy, and also (paradoxically) to control
hyperkinetic children (ADHD). They are no longer used as appetite suppressants because of the
risk of pulmonary hypertension.
• Amphetamine psychosis, which closely resembles schizophrenia, can develop after prolonged use.
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Contraindications
CNS Stimulants
Agitated states
Patients with a history of drug abuse
Glaucoma
MAOI use
• Stimulants such as amphetamines elevate cardiac output and blood pressure making them dangerous for
use by patients with a history of heart disease or hypertension. Also, patients with a history of drug
dependence or anorexia should not be treated with amphetamines due to their addictive and appetite
suppressing properties. Amphetamines can cause a life-threatening complication in patients taking MAOI
antidepressants. Amphetamine is not suitable for patients with a history of glaucoma.
• Amphetamines have also been shown to pass through into breast milk. Because of this, mothers taking
medications containing amphetamines are advised to avoid breastfeeding during their course of treatment.
2- Methylphenidate
• Methylphenidate (MPH) is a prescription stimulant commonly used to treat Attention-deficit
hyperactivity disorder, or ADHD. It is also one of the primary drugs used to treat the daytime
drowsiness symptoms of narcolepsy and chronic fatigue syndrome. The drug is seeing early use to
treat cancer-related fatigue.[4] Brand names of drugs that contain methylphenidate include Ritalin
(Ritalina, Rilatine, Attenta, Methylin, Penid, Rubifen.
• Mechanism of action:
• The means by which methylphenidate affects people diagnosed with ADHD are not well
understood. Some researchers have theorized that ADHD is caused by a dopamine imbalance in
the brains of those affected. Methylphenidate is a norepinephrine and dopamine reuptake
inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain
by partially blocking the dopamine transporter (DAT) that removes dopamine from the synapses.
This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic
neuron, increasing the amount of dopamine in the synapse. It also stimulates the release of
dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine
release after a stimulus, increasing the salience of stimulus. The stimulants do not work
paradoxically. They stimulate portions of the brain that are underactive by increasing dopamine
and norepinephrine in the striatum and prefontal cortex. An alternate explanation which has
been explored is that the methylphenidate affects the action of serotonin in the brain.
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Indications
ADHD
Narcolepsy
Treatment-resistant depression
Appetite suppressant
Antidepressant augmentation
Methylphenidate is a central nervous system (CNS) stimulant, reducing
impulsive behavior, and facilitating concentration on work and other
tasks. Adults who have ADHD often report that methylphenidate
increases their ability to focus on tasks and organize their lives.
Side effects:
-1Cardiovascular: Arrhythmia or increase in blood pressure
2- Endocrinal:
Appetite loss
3- Eye:
Blurred vision
4- Gastrointestinal:
Nausea/vomiting, abdominal pain
5- Musculoskeletal:
Muscle twitches
6- Neurological: Insomnia, drowsiness, dizziness, headache
7- Psychological: Psychosis (abnormal thoughts or hallucinations)
Contraindications:
• Use of tricyclic antidepressants: (e.g. desipramine), as
methylphenidate may dangerously increase their plasma
concentrations, leading to potential toxic reactions (mainly,
cardiovascular effects).
• Use of MAO Inhibitors:, such as phenelzine (Nardil) or
tranylcypromine (Parnate), and certain other drugs. methylphenidate
should not be given to patients who suffer from the following
conditions: Severe Arrhythmia, Hypertension or Liver damage.
suspected risks to health:
• In a 2005 study, only "minimal effects on growth in height and weight
were observed" after 2 years of treatment. "
• In February 2005, a team of researchers from The University of Texas
M. D. Anderson Cancer Center led by R.A. El-Zein announced that a
study of 12 children indicated that methylphenidate may be
carcinogenic.
3- Methamphetamine
• Methamphetamine , also known as methylamphetamine, Nmethylamphetamine or desoxyephedrine, is a psychostimulant and
sympathomimetic drug. It is a member of the family of phenylethylamines.
The dextrorotatory (S-isomer) dextromethamphetamine can be prescribed
to treat attention-deficit hyperactivity disorder, though unmethylated
amphetamine is more commonly prescribed. Narcolepsy and obesity can
also be treated by the aforementioned isomer under the brand name
Desoxyn. It is considered a second line of treatment, used when
amphetamine and methylphenidate cause the patient too many side
effects. It is only recommended for short term use (~6 weeks) in obesity
patients because it is thought that the anorectic effects of the drug are
short lived and produce tolerance quickly, whereas the effects on CNS
stimulation are much less susceptible to tolerance. It is also used illegally
for weight loss and to maintain alertness, focus, motivation, and mental
clarity for extended periods of time, and for recreational purposes.
• Methamphetamine enters the brain and triggers a cascading release of norepinephrine,
dopamine and serotonin. To a lesser extent methamphetamine acts as a dopaminergic
and adrenergic reuptake inhibitor and in high concentrations as a monamine oxidase
inhibitor (MAOI). Since it stimulates the mesolimbic reward pathway, causing euphoria
and excitement, it is prone to abuse and addiction. Users may become obsessed or
perform repetitive tasks such as cleaning, hand-washing, or assembling and
disassembling objects. Withdrawal is characterized by excessive sleeping, eating, and
depression-like symptoms, often accompanied by anxiety and drug-craving. Users of
methamphetamine sometimes take sedatives such as benzodiazepines as a means of
easing their "come down".
• Methamphetamine has the potential to cause addiction. An addiction to
methamphetamine typically occurs when a person begins to use the drug as a stimulant,
because of its enhancing effects on pleasure and sex, alertness and ability to
concentrate. Over time, however, the effectiveness decreases, and users find that they
need to take higher doses to get the same results.
Pharmacology
• Methamphetamine is a potent central nervous system stimulant which affects neurochemical
mechanisms responsible for regulating heart rate, body temperature, blood pressure, appetite,
attention, mood and responses associated with alertness or alarm conditions. The acute physical
effects of the drug closely resemble the physiological and psychological effects of an epinephrineprovoked fight-or-flight response, including increased heart rate and blood pressure,
vasoconstriction (constriction of the arterial walls), bronchodilation, and hyperglycemia
(increased blood sugar). Users experience an increase in focus, increased mental alertness, and
the elimination of fatigue, as well as a decrease in appetite.
• The methyl group is responsible for the potentiation of effects as compared to the related
compound amphetamine, rendering the substance on the one hand more lipid soluble and easing
transport across the blood brain barrier, and on the other hand more stable against enzymatic
degradation by MAO. Methamphetamine causes the norepinephrine, dopamine and
serotonin(5HT) transporters to reverse their direction of flow. This inversion leads to a release of
these transmitters from the vesicles to the cytoplasm and from the cytoplasm to the synapse
(releasing monoamines in rats with ratios of about NE:DA = 1:2, NE:5HT= 1:60), causing increased
stimulation of post-synaptic receptors. Methamphetamine also indirectly prevents the reuptake
of these neurotransmitters, causing them to remain in the synaptic cleft for a prolonged period
(inhibiting monoamine reuptake in rats with ratios of about: NE:DA = 1:2.35, NE:5HT = 1:44.5).
• Methamphetamine is a potent neurotoxin, shown to cause dopaminergic
degeneration. High doses of methamphetamine produce losses in several
markers of brain dopamine and serotonin neurons. Dopamine and
serotonin concentrations, dopamine and 5HT uptake sites, and tyrosine
and tryptophan hydroxylase activities are reduced after the administration
of methamphetamine. It has been proposed that dopamine plays a role in
methamphetamine induced neurotoxicity because experiments which
reduce dopamine production or block the release of dopamine decrease
the toxic effects of methamphetamine administration. When dopamine
breaks down it produces reactive oxygen species such as hydrogen
peroxide. It is likely that the oxidative stress that occurs after taking
methamphetamine mediates its neurotoxicity. It has been demonstrated
that a high ambient temperature increases the neurotoxic effects of
methamphetamine.
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Indications:
Attention deficit hyperactivity disorder
Extreme obesity
Narcolepsy
Methamphetamine addicts may lose their teeth abnormally quickly, a condition known as "meth mouth".
This effect is not caused by any corrosive effects of the drug itself, which is a common myth. According to the
American Dental Association, meth mouth "is probably caused by a combination of drug-induced
psychological and physiological changes resulting in xerostomia (dry mouth), extended periods of poor oral
hygiene, frequent consumption of high calorie, carbonated beverages and tooth grinding and clenching."
Similar, though far less severe symptoms have been reported in clinical use of other amphetamines, where
effects are not exacerbated by a lack of oral hygiene for extended periods.
• Like other substances which stimulate the sympathetic nervous system, methamphetamine causes
decreased production of acid-fighting saliva and increased thirst, resulting in increased risk for tooth decay,
especially when thirst is quenched by high-sugar drinks.
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2- Second Line Treatment (Non-Stimulant
Medications):
1- Atomoxetine (Strattera):
- Mode of Action: prevents the reuptake of norepinephrine
- Recently associated with increased suicide
2- Bupropion (Wellbutrin): Discussed in antidepressants
3- Venlafaxine (Effexor XR ): Discussed in antidepressants
4- TCADs (Tofranil): Discussed in antidepressants
3- Third line treatment:
- Minimal use
- Too many side effects
1- Clonidine
2- Guanfacine