Amphetamines - Recommendations for Appropriate Use

transcript

AmphetaminesPresented by Alexis Polles, MD

For the MS Medical AssocciationMay 23-28, 2013Sandestin

Disclosures

None to disclose Non-approved use of amphetamine for

“performance enhancement” and others will be mentioned. These are not currently FDA recommended uses of these substances.

Outline

Amphetamine – structure, function, mechanism of action, effects, uses, contraindications

Amphetamine – abuse Specific Disease Applications

Narcolepsy ADD/ADHD

Note: Many slides contain information for your review and may not be discussed in detail in order to conserve time. You may contact me for any questions at agpolles@comcast.net or 601-520-4814.

Amphetamines: recommendations for appropriate use

Objectives:1.To educate prescribers about controlled substance scheduling.

2.To educate prescribers about the pharmacology of amphetamines

3.To educate prescribers about the indications for the proper use of psychostimulants

4.To educate prescribers about discontinuation and tapering strategies

Description

Amphetamine is a stimulant that is now primarily used to treat narcolepsy and attention-deficit hyperactivity disorder. It is also used recreationally as a club drug and as a performance enhancer.

The name amphetamine is derived from its chemical name alpha-methylphenethylamine.

Initially, amphetamine was more popularly used to diminish the appetite and to control weight.

Because of the widespread use of amphetamines as a treatment for narcolepsy and ADD/ADHD, prescription amphetamines are subject to diversion and are one of the most frequently- abused drugs in high schools and colleges.

Norepinephrine(Noradrenaline)

Amphetamine

Methamphetamine

Methylphenidate(RitalinTM)

Brand Names

Brand names of the medications that contain, or metabolize into, amphetamine include "Adderall", "Dexedrine", "Dextrostat", "Desoxyn", "ProCentra", "Vyvanse", and "Benzedrine" in the past.

Adderall(dextroamphetamine/amphetamine)-High Abuse Potential, DependencyAvoid prolonged tx, may lead to drug dependence; potential for non-therapeutic use or distribution to others; prescribe/dispense sparingly; serious cardiovascular adverse events and sudden death reported w/ misuse Adult Dosing: Dosage forms: 5,7.5,10,12.5,15,20,30 ADHD [5-40 mg/day PO div qd-tid] Start: 5 mg PO qam or bid, incr. 5 mg/day qwk; Info: give divided doses at 4-6h intervals; doses >40 mg/day

rarely more effective narcolepsy [5-60 mg/day PO div qd-tid] Start: 10 mg PO qam, incr. 10 mg/day qwk; Info: give divided doses at 4-6h intervals renal dosing [not defined] hepatic dosing [not defined]

Peds Dosing : Dosage forms: 5,7.5,10,12.5,15,20,30 ADHD [3-5 yo] Dose: 2.5-40 mg/day PO div qd-tid; Start: 2.5 mg PO qam, incr. 2.5 mg/day qwk; Info: give divided doses at 4-6h intervals; doses

>40 mg/day rarely more effective [>6 yo] Dose: 5-40 mg/day PO div qd-tid; Start: 5 mg PO qam or bid, incr. 5 mg/day qwk; Info: give divided doses at 4-6h intervals; doses >40 mg/day rarely more effective

narcolepsy [6-12 yo] Dose: 5-60 mg/day PO div qd-tid; Start: 5 mg PO qam, incr. 5 mg/day qwk; Info: give divided doses at 4-6h intervals [>12 yo]

Dose: 5-60 mg/day PO div qd-tid; Start: 10 mg PO qam, incr. 10 mg/day qwk; Info: give divided doses at 4-6h intervals Metabolism: liver; CYP450: 2D6 substrate; Info: active metabolites Excretion: urine; Half-life 9-14h; Info: pH-dependent excretion

XR: Peds Dosing . Dosage forms: 5,10,15,20,25,30 ER ADHD [6-12 yo] Dose: 10 mg PO qam; Start: 5-10 mg PO qam, incr. 5-10 mg/day qwk; Max: 30 mg/day; Info: may convert from IR to ER at

same total daily dose qam [13-17 yo] Dose: 10-20 mg PO qam; Start: 10 mg PO qam, incr. 10 mg/day qwk; Max: 40 mg/day; Info: may convert from IR to ER at same total daily dose qam; doses >20 mg/day rarely more effective

renal dosing [not defined] hepatic dosing [not defined] Metabolism: liver; CYP450: 2D6 substrate; Info: active metabolites Excretion: urine; Half-life 9-14h; Info: pH-dependent excretion

Vyvanse(lisdexamfetamine)-Epocrates Online

Adult Dosing . Dosage forms: 20,30,40,50,60,70 ADHD [30 mg PO qam] Max: 70 mg/day; Info: may incr. dose 10-20 mg/day qwk; use lowest effective

dose renal dosing [not defined] hepatic dosing [not defined]

Peds Dosing . Dosage forms: 20,30,40,50,60,70 ADHD [6-17 yo] Dose: 30 mg PO qam; Max: 70 mg/day; Info: may incr. dose 10-20 mg/day qwk; use

lowest effective dose renal dosing[not defined] hepatic dosing [not defined] Metabolism: liver; CYP450: 2D6 (weak) inhibitor; Info: prodrug converted to dextroamphetamine Excretion: urine 96%, feces 0.3%; Half-life: <1h, 12h (dextroamphetamine); Info: pH-dependent

excretion

High Abuse Potential, Dependency: high abuse potential; avoid prolonged tx, may lead to drug dependence; potential for non-therapeutic use or distribution to others; prescribe/dispense sparingly; serious cardiovascular adverse events and sudden death reported w/ misuse

From Medline Release

November 16, 2010 — The US Food and Drug Administration (FDA) has approved lisdexamfetamine dimesylate capsules (Vyvanse; Shire Pharmaceuticals, Inc) for the treatment of attention deficit hyperactivity disorder (ADHD) in adolescents aged 13 to 17 years.

FDA approval was based on data from a double-blind, 4-week (emphasis mine), randomized, forced-dose escalation study of 314 adolescents showing that lisdexamfetamine doses of 30, 50, and 70 mg/day significantly improved ADHD symptoms relative to placebo, as evaluated using the ADHD Rating Scale-IV.

DEA Schedule

In the United States, amphetamine and methamphetamine are Schedule II drugs, classified as CNS (central nervous system) stimulants.

A Schedule II drug is classified as one that has a high potential for abuse, has a currently-accepted medical use and is used under severe restrictions, and has a high possibility of severe psychological and physiological dependence.

Historical Amphetamine was synthesized in 1887 by Lazar Edeleanu at

the University of Berlin. It was one of a series of compounds related to the plant derivative Ephedrine, which had been purified two years previously.

No medical use was found for Amphetamine until the 1900s, when it was introduced in most of the world in the form of the pharmaceutical Benzedrine. This drug was used by the militaries of several nations, especially the air forces, to fight fatigue and increase alertness among servicemen.

After decades of reports of abuse, the FDA banned Benzedrine inhalers, and limited amphetamines to prescription use in 1959, but illegal use became common.

Historical

The related compound methamphetamine was first synthesized from ephedrine in Japan in 1893 by chemist Nagayoshi Nagai.

In 1919, crystallized methamphetamine was synthesized by Akira Ogata via reduction of ephedrine using red phosphorus and iodine.

The German military was notorious for their use of methamphetamine in World War II.

Endogenous amphetamines

Amphetamine has been found to have several endogenous analogues; that is, molecules of a similar structure found naturally in the brain.

l-Phenylalanine and β-Phenethylamine are two examples, which are formed in the peripheral nervous system as well as in the brain itself.

These molecules are thought to modulate levels of excitement and alertness, among other related affective states.

Hypotheses of How Amphetamine Affects Dopamine The most widely studied neurotransmitter with regard to

amphetamine action is dopamine (DA). DA is highly active in numerous reward pathways of the brain. Amphetamine increases the concentrations of dopamine in the

synaptic cleft. The specific mechanisms by which amphetamine affects

dopamine concentrations have been studied extensively. One theory emphasizes amphetamine’s actions on the vesicular

level: Amphetamine increases concentrations of dopamine in the cytosol of the pre-synaptic neuron.

The other focuses on the role of the dopamine transporter DAT: Amphetamine may interact with DAT to induce reverse transport of dopamine from the presynaptic neuron into the synaptic cleft.

Storage

Synthesis

Precursor

Release

Reuptake

Degradation

Synaptic Cleft

= vesicle = neurotransmitters= receptor

Hypotheses of How Amphetamine Affects Serotonin and Glutamate Amphetamine has been found to exert similar effects on

serotonin as on dopamine in particular regions of the brain, such as the mesocorticolimbic projection.

Recent studies additionally postulate that amphetamine may indirectly alter the behavior of glutamatergic pathways. Increased extracellular concentrations of serotonin may thus modulate the excitatory activity of glutamatergic neurons.

Dopamine Neurotransmission

VTA/SNVTA/SNnucleus accumbensnucleus accumbens

frontalcortexfrontalcortex

00100100200200300300400400500500600600700700800800900900

1000100011001100

00 11 22 33 44 5 hr5 hrTime After AmphetamineTime After Amphetamine

AMPHETAMINEAMPHETAMINE

100100

150150

200200

00 6060 120120 180180Time (min)Time (min)

EmptyEmptyBoxBox FeedingFeeding

Di Chiara et al.Di Chiara et al.

FOODFOOD

0100200300400500600700800900

10001100

0 1 2 3 4 5 hr

Time After Amphetamine

% of Basal Release

DADOPACHVA

Accumbens AMPHETAMINE

0 1 2 3 4 5 hrTime After Cocaine

% of Basal Release

DADOPACHVA

AccumbensCOCAINE

0 1 2 3 4 5hrTime After Morphine

% of Basal Release Accumbens

0.51.02.510

Dose (mg/kg)

MORPHINE

0 1 2 3 hrTime After Nicotine

% of Basal Release

AccumbensCaudate

NICOTINE

Di Chiara and Imperato, PNAS, 1988

Effects of Drugs on Dopamine Release

Amphetamine Tolerance Tolerance is developed rapidly in amphetamine abuse,

therefore increasing the amount of the drug that is needed.

Short term tolerance can be caused by depleted levels of neurotransmitters within the vesicles available for release into the synaptic cleft following subsequent reuse (tachyphylaxis).

Short term tolerance typically lasts 2-3 days, until neurotransmitter levels are fully replenished.

Prolonged overstimulation of dopamine may eventually cause the receptors to downregulate in order to compensate for increased levels of dopamine within the synaptic cleft.

EffectsCentral:Short term use: euphoria, anxiety, increased libido, alertness, concentration, energy, self-esteem, self-confidence, sociability, grandiosity, excessive feelings of power and invincibility (mimics mania), repetitive and obsessive behaviors, paranoia, and with high doses, amphetamine psychosis can occur.

Other central effects include insomnia, irritability, weakness, tremor, confusion, delirium, panic states and suicidal tendencies.

Chronic use: Can produce psychosis, mood changes,chronic irritability.

The anorectic effect of amphetamine is due to direct action in the feeding center located In the lateral hypothalamus.

Effects

Peripheral:

Cardiovascular effects: palpitations, tachyarrthymias, hypertension acute coronary ischemia and cardiovascular collapse can occur.

GI effects: Nausea, vomiting, abdominal cramps and diarrhea.

Contraindications Amphetamine elevates cardiac output and blood pressure

making it dangerous for use by patients with a history of heart disease or hypertension.

Amphetamine can cause a life-threatening complication in patients taking MAOI antidepressants.

The use of amphetamine and amphetamine-like drugs is contraindicated in patients with narrow-angle glaucoma or anatomically narrow angles. Like other sympathomimetic amines, amphetamine can induce transient mydriasis.

These agents should also be avoided in patients with other forms of glaucoma, as mydriasis may occasionally increase intraocular pressure.

Amphetamine has been shown to pass through into breast milk. Because of this, mothers taking amphetamine are advised to avoid breastfeeding during their course of treatment.

Withdrawal effects

Withdrawal symptoms of amphetamine primarily consist of mental fatigue, mental depression and an increased appetite.

Symptoms may last for days with occasional use and weeks or months with chronic use, with severity dependent on the length of time and the amount of amphetamine used.

Withdrawal symptoms may also include anxiety, agitation, excessive sleep, vivid or lucid dreams, deep REM sleep and suicidal ideation.

Detection in body fluids Amphetamine is frequently measured in urine as part of drug

abuse programs, etc.

Techniques such as immunoassay may cross-react with a number of sympathomimetics drugs, so chromatographic methods specific for amphetamine should be employed to prevent false positive results.

Yep, alkalinizing your system does increase amphetamine absorption/decrease degradation. In addition to sodium bicarbonate you can use Tums (calcium carbonate) as well -- the combo works nicely, and has the added benefit of settling the stomach.

Unfortunately, you should have SOME antioxidants around (to reduce neurotoxicity), and alpha lipoic acid (as well as vitamin c --both are acidic, obviously), is the best antioxidant. I try and take it a few hours before doing any stimulants, as well as several hours into the stimulant use. You can also take non-acidic antioxidants like vitamin E and selenium.

Excretion of amphetamine is pH dependent

Food for thought: “First Do No Harm.”

Science has generated muchevidence showing that…

prolonged drug use changesthe brain in fundamentaland long-lasting ways

Specific Disease Application: Narcolepsy

Diagnostic criteria for Narcolepsy

A. Irresistible attacks of non-refreshing sleep that occur daily over at least 3 months.

B. The presence of one or both of the following: (1) cataplexy (i.e., brief episodes of sudden bilateral loss of muscle tone, most

often in association with intense emotion)

(2) recurrent intrusions of elements of rapid eye movement (REM) sleep into the transition between sleep and wakefulness, as manifested by either hypnopompic or hypnagogic hallucinations or sleep paralysis at the beginning or end of sleep episodes

C. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or another general medical condition.

Hypnopompic hallucination: A vivid dreamlike hallucination that occurs as one is waking up. The opposite of an hypnagogic hallucination, which occurs as one is falling asleep.

Specific Disease Application: ADHD

ADHD Tidbits

Its symptoms can be difficult to differentiate from other disorders.

ADHD and its diagnosis and treatment have been considered controversial since the 1970s.The controversies have involved clinicians, teachers, policymakers,

parents and the media. Topics include the actuality of the disorder, its causes, and the use of stimulant medications in its treatment.

Most healthcare providers accept that ADHD is a genuine disorder with debate in the scientific community centering mainly around how it is diagnosed and treated.

American Academy of Pediatrics Guidelines for Treating ADHD Set specific, appropriate target goals to guide therapy.

Start medication and non-pharmacologic therapy.

When treatment has not met the target goals, re-evaluate the original diagnosis, the possible presence of other conditions, and how well the treatment plan has been implemented.

Follow-up regularly with the doctor to check on goals, results, and any side effects of medications. During these check-ups, information should be gathered from parents, teachers, and the child.

ADHD or Stimulant Seeking? Prevalence of ADHD worldwide is 5.2% Prevalence in the US is 9.5%

Riddle MA, et al. J Am Acad Child Adoles Psychiatry. 2013; 52:264-278

How Do Know It’s ADHD?

AACAP guidelines for ADHD diagnosis Symptoms at home, school, other settings Report of patient, parent, teachers, coaches History since childhood (before age 12) Rule out other disorders Use validated diagnostic tools

Give the diagnosis the time it deserves

ADHD vs. SUD Diagnosis

Do symptoms co-occur with substance use? If yes, then additional symptoms may be a

consequence of substance use rather than ADHD Did ADHD symptoms begin before or after

regular substance abuse? Is there a temporal relationship of symptoms

with other comorbidities?

The Dilemma: Are we preventing drug addiction in kids with ADHD or are we contributing to it? About half the large studies to date

indicate that early recognition and treatment reduces later rates of addiction. However…….

In a 13 year prospective study which looked at adult cocaine users, it was found that those individuals who used Ritalin for ADHD between one and ten years of age had a percentage of cocaine abuse twice that of those who had been diagnosed with ADHD but had not utilized Ritalin. Though use of Ritalin may not explain all reasons someone may begin to utilize drugs, there is a correlation between length of use of Ritalin and later drug use.

Russell A. Barkley, PhD,et al. (2003). "Does the Treatment of Attention-Deficit/Hyperactivity Disorder With Stimulants Contribute to Drug Use/Abuse? A 13-Year Prospective Study". PEDIATRICS. 2003 Vol. 111 No. 1: pp. 97-109

Early ADHD Treatment Linked to Lower Risk for Substance Use Disorders until age 18 Information sourced from NEJM Journal Watch Researchers conducted an industry-supported, prospective,

longitudinal study. Participants were followed for a mean of 4 years until a mean age of 16. There were three groups: 327 ADHD patients treated with stimulants (85% male), 61 untreated ADHD patients (59% male), and 211 healthy controls (41% male).

Untreated patients had a significantly higher risk for SUDs than treated patients (hazard ratio, 1.91). Younger age at beginning stimulants was associated with lower risk for SUDs — until age 18, after which SUD risk increased. Controlling for oppositional defiant disorder, conduct disorder, and sex did not affect the results.

A study limitation is that by the end of the study, participants were typically still younger than the mean age (20 years) for onset of SUDs (Arch Gen Psychiatry 2005; 62:593). Barbara Geller, MD reviewing Groenman AP et al. Br J Psychiatry 2013 Jul 11.

ADHD Treatments Not Working for Most Young ChildrenSOURCE: Johns Hopkins Medicine, news release, Feb. 11, 2013

N=186, 3-5 year olds

For six years, researchers tracked the severity of the three primary ADHD symptoms: inattention, hyperactivity and impulsivity.

2/3 were on stimulant medications

90% continued to have symptoms

62% of kids on meds. Vs 58% with no meds. had “significant hyperactivity and impulsivity”

65% on meds. Vs 62% no meds. had “serious inattention”

The study was funded by the U.S. National Institute of Mental Health and published online Feb. 11 in the Journal of the American Academy of Child & Adolescent Psychiatry.

Adult ADHD:

About 4 percent of adults (General Population) have attention deficit hyperactivity disorder (ADHD). (About half of kids with ADHD still have it in adulthood.) If you are an addict, the percentages go way up.

Though you may have strong urges to help the person somehow, please do not prescribe stimulants to alcoholics or addicts thinking it will improve their chances for cessation of substance abuse.

A diagnosis can be important. Adults with ADHD tend to have lower incomes as well as higher rates of accidents, unplanned pregnancies, and substance abuse than those without it.

The Challenges ADD is very difficult to diagnose

There is no distinct profile on testing, most of what is used in adults is self-report, and even sophisticated testing can be “fooled”

Expectancy effects on self-report of symptoms and treatment (with stimulants) are large

Because a person likes having more energy and can “get more done” on stimulants, it does not mean they have ADD.

Most experienced practitioners, if they are brutally honest with themselves, will probably admit that they are not completely sure about the diagnosis in adults.

The best predictor of the likely diagnosis of ADD is the patient deciding they have it.

ADD symptoms and personality traits are difficult to differentiate.

People want a quick fix.

Non-Disease Unapproved Use “Performance Enhancement”

Performance-enhancing use Amphetamine is used by some college (est. 25% +) and high-school

students as a study and test-taking aid. Adults use it to improve their ability to work when fatigued, and some give them to their children to give the children a supposed edge.

Amphetamine has been, and is still, used by militaries around the world.

Amphetamine is also used by some professional, collegiate, and high school athletes for its strong stimulant effect.

Amphetamine use has historically been especially common among Major League Baseball players; the league banned the use of amphetamine in 2006. The ban is enforced through periodic drug-testing.

Amphetamine was formerly in widespread use by truck drivers to combat symptoms of somnolence and to increase their concentration during driving, especially in the decades prior to the signing by former president Ronald Reagan of Executive Order 12564, which initiated mandatory random drug testing of all truck drivers and employees of other DOT-regulated industries.

Don't Give ADHD Meds to Undiagnosed Kids, Experts Urge Neurologists say some doctors are prescribing these drugs as a way to boost school performance By Barbara Bronson Gray

HealthDay Reporter WEDNESDAY, March 13 (HealthDay News) -- Some people call it "brain doping" or "meducation." Others label the problem "neuroenhancement." Whatever the term, the American Academy of Neurology has published a position paper criticizing the practice of prescribing "study drugs" to boost memory and thinking abilities in healthy children and teens.

Amphetamines - Recommendations for Appropriate Use

Health & Medicine