Essentials of ADHD Medications: From Mechanisms of Action...
1
Specifics About Stimulant Drug Formulations gelatin capsule two different types of beads amphetamine Spansules, a type of formulation used for am- phetamine, are also referred to as the two-bead system. Two different types of beads are con- tained in a gelatin capsule. While the gelatin capsule dissolves quickly in water, the two beads dissolve at different speeds, thereby allowing for a longer duration of action of the drug. This theoretically leads to a constant release of the drug, a constant stimulation of DA receptors, and thus a steady-state DA release. A prodrug is a pharmacologically inactive compound, that needs to be metabolized by the body to become active. A prodrug there- fore increases oral bioavailability. Lisdexamfet- amine is a prodrug of dextroamphetamine and becomes active only after it has been con- verted to dextroamphetamine and l-lysine in the intestinal tract. This formulation allows for once-daily dosing, and minimizes the potential of abuse and diversion as this formulation may be less abusable than other stimulants. lisdexamfetamine gelatin capsule The osmotic controlled-release oral delivery system (OROS) is one formulation of methyl- phenidate. Once swallowed, the outer coating that is laced with methylphenidate quickly dis- integrates thereby releasing the first “dose” or “mini-burst” of methylphenidate. The internal insoluble capsule is divided into three com- partments: the first one contains the lowest concentration of the drug; the second one con- tains the highest concentration of the drug; and the third compartment contains molecules that expand with water, resulting in the third compartment pushing out the drug through the small hole on the opposite side. opening first compartment: low concentration of methylphenidate second compartment: high concentration of methylphenidate coating: methylphenidate, binders semipermeable rigid membrane third compartment: mixture of triacetin, cellulose acetate, hypromellose, polyethylene glycol, polyethylene oxides The patch is one formulation used for the de- livery of racemic methylphenidate. In this case, the drug is released through a micropore mem- brane controlling drug release. It then passes through the adhesive layer and diffuses through the skin to enter the bloodstream. It normally takes up to two hours for patients to feel the effects of the drug. Thus it is important to remove the patch a few hours before bed- time. First-pass metabolism is not extensive with the patch, resulting in notably higher exposure to the drug than after oral dosing. skin impermeable covering membrane capillary adhesive methylphenidate Dosing Information and Main Side Effects of ADHD Medications Characteristics of ADHD Drug Formulations These tables give an overview of the different ADHD drug formulations, including the brand names of the various medications, and the ages for which they are approved. *not currently available, approval pending Amphetamine Formulations Formulation Immediate-release d-amphetamine (Dexedrine) Immediate-release d, l-amphetamine (Adderall) Sustained-release d-amphetamine (Dexedrine Spansule) Extended-release d, l-amphetamine(mixed AMP salts) (Adderall XR) Lisdexamfetamine dimesylate (Vyvanse) Profile 2nd dose at lunch; low risk for insomnia unless dosed at night 2nd dose at lunch; low risk for insomnia unless dosed at night No lunch dosing; low risk for insomnia unless dosed at night Continued effects into evening Breakfast dosing; risk of insomnia if dosed in afternoon Approval Age 3 to 16 Age 3 to 12 Age 3 to 16 Age 6 to 12, Age 13 to 17 and adults Age 6 to 12 and adults Duration 3–6-hr 5-hr 6–9-hr Max plasma concentration at 7-hr Peak at 3.5 hrs 10–12-hr Non-Stimulant Drug Formulations Formulation Atomoxetine (Strattera, Attentin) Guanfacine immediate-release (Tenex) Guanfacine extended- release (Intuniv*) Bupropion (Wellbutrin IR, SR, XR, Zyban) Modafinil (Provigil) Armodafinil (Nuvigil) Clonidine (Duraclon, Catapres) Profile Dosing 1X or 2X a day; morning and late afternoon Multiple dosing (3X per day), somnolence is frequent Morning dosing; somnolence observed when dose is increased Dosing differs with formulation Once-daily dosing Once-daily dosing, may have longer duration of action than modafinil Morning and night dosing, sedation is common Approval Age 6 to 18 and adults Children and adolescents; effective in adults, but not FDA-approved for ADHD Children and adolescents; effective in adults, but not FDA-approved for ADHD Effective in adults, but not FDA-approved for ADHD Efficacious in children and adolescents, but not FDA- approved for ADHD Not studied in or FDA- approved for ADHD Effective in children, but not FDA-approved for ADHD Half-life ~5-hr ~17-hr ~14–18-hr 10–17-hr 15-hr (after multiple dosing) 15-hr 12–16-hr Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu- lar adverse effects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous- ness, irritability, overstimulation, tremor, dizziness Side Effects Dosing Approved For: Attention deficit hyperactivity disorder in children and adults (approved ages vary based on formularies); narcolepsy Dosage Range: Oral: up to 2 mg/kg/day in children 6 and older, with maximum of 60 mg/day; in adults usually 20–30 mg/day, can use up to 40–60 mg/day; transdermal: 10–30 mg/9hrs Formulation: 5, 10, and 20 mg immediate-release tablets; 2.5, 5, and 10 mg immediate-release chewable tablets; 5 mg/mL and 10 mg/5 mL oral solution; 10 and 20 mg older sustained-release tablets; 10, 20, 30, and 40 mg newer sustained-release capsules; 18, 27, 36, and 54 mg newer sustained-release tablets; 27 mg/12.5 cm 2 (10 mg/9hrs); 41.3 mg/18.75 cm 2 (15 mg/9hrs); 55 mg/25 cm 2 (20 mg/9hrs) and 82.5 mg/37 cm 2 (30 mg/9hrs) transdermal patch Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu- lar adverse effects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous- ness, irritability, overstimulation, tremor, dizziness Side Effects Dosing Approved For: Attention deficit hyperactivity disorder in children ages 6–17, and in adults (extended-release formulation) Dosage Range: Immediate-release (IR): 2.5–10 mg twice a day; extended-release (ER): 5–20 mg Formulation: 2.5, 5, and 10 mg tablets; 5, 10, and 20 mg extended-release capsules DAT NET D-Methylphenidate D,L-Methylphenidate Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu- lar adverse effects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous- ness, irritability, overstimulation, tremor, dizziness Side Effects Dosing Approved For: ADHD in children ages 3–16 (immediate-release formulation); ADHD in children ages 6–17 and in adults (extended-release formulation); narcolepsy Dosage Range: 5–40 mg/day (divided doses for immediate-release tablet, once-daily morning dose for extended-release tablet) Formulation: 5, 7.5, 10, 12.5, 15, 20, and 30 mg double-scored immediate-release tablets; 5, 10, 15, 20, 25, and 30 mg extended-release tablets Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu- lar adverse effects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous- ness, irritability, overstimulation, tremor, dizziness Side Effects DAT NET VMAT D,L-Amphetamine DAT NET VMAT DAT NET VMAT Increased heart rate and hypertension, orthostatic hypotension, rare severe liver damage, rare suicidality, rare induction of hypomania, sedation especially in children Side Effects Dosing Approved For: Attention deficit disorder in adults and children over 6, treatment- resistant depression Dosage Range: For children up to 70 kg: start at 0.5 mg/kg/day, then increase to 1.2 mg/kg/day after 3 days, max dose is 100 mg/day or 1.4 mg/kg/day, whichever is less For children and adults over 70 kg: start at 40 mg/day and increase to 80 mg/day after 3 days, max dose is 100 mg Formulation: 10, 18, 25, 40, 60, 80, and 100 mg capsules Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu- lar adverse effects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous- ness, irritability, overstimulation, tremor, dizziness Side Effects Dosing Approved For: Attention deficit hyperactivity disorder in children ages 6–12 and in adults Dosage Range: 30–70 mg/day Formulation: 20, 30, 40, 50, 60, and 70 mg capsules Atomoxetine DRI NRI Rare seizures, induction of mania and suicidality Side Effects Dosing Approved For: Major depressive disorder and nicotine addiction Dosage Range: Bupropion: 225–450 mg in 3 divided doses (150 mg maximum single dose); SR: 200–450 mg in 2 divided doses (200 mg maximum single dose); XL: 150–450 mg once/day (450 mg max dose) Formulation: 75, 100 mg tablets; SR: 100, 150, and 200 mg tablets; XL: 150 and 300 mg tablets Sinus bradycardia; atrioventricular block; during withdrawal, hypertensive encephalopathy, cerebrovascular accidents, and death (rare); notable side effects include dry mouth, dizziness, constipation, and sedation Side Effects Dosing Approved For: Hypertension Dosage Range: 0.2–0.6 mg/day in divided doses Formulation: 0.1, 0.2, and 0.3 mg scored tablets; 0.1 mg/24hrs; 0.2 mg/24hrs; 0.3 mg/24hrs topical form (7 day administration); 100 and 500 mg/mL injection Bupropion NRI Serious or life-threatening rash, including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), transient EKG ischemic changes in patients with mitral valve prolapse or left ventricular hypertrophy, can activate hypomania, suicidality Side Effects Dosing Approved For: Narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD) Dosage Range: 200 mg/day in the morning, doses up to 400 mg/day have been well-tolerated Formulation: 100 and 200 mg (scored) tablets Sinus bradycardia; hypotension; side effects include sedation, dizziness, dry mouth, constipation Side Effects Dosing Approved For: Hypertension (immediate-release formulation); extended-release formulation is not yet available, approval pending Dosage Range: 1–2 mg/day Formulation: 1, 2, and 3 mg immediate-release tablets 2A Modafinil imidazoline 2C 2B 2A DAT NET VMAT D-Amphetamine Lisdexamfetamine Clonidine Guanfacine DAT NET DAT NET B NET blocked in PFC: NE increases “normal” NE diffusion “normal” DA diffusion “normal” DA diffusion NET blockade increases NE diffusion NET blockade increases DA diffusion Normal DA release in PFC: No DAT, diffuses to NET A NET C NET blocked in PFC: DA increases DA neuron NE neuron There are many NETs, and only very few DATs, in the prefrontal cortex (PFC). Due to greater diffusion, released DA in the PFC can exert its actions further away (A). In the PFC, atomoxetine primarily raises NE levels and increases its diffusion radius by blocking NET (B). As NET also takes up DA, NET blockade in the PFC will also increase synaptic DA, further enhancing its diffusion. Thus in the PFC, atomoxetine increases both NE and DA. Methylphenidate works at the dopamine (DAT) and norepinephrine transporter (NET) by blocking the reuptake of both dopamine (DA) or norepinephrine (NE) into the terminal. Methylphenidate basically freezes the transporter in time, preventing DA (and NE) reuptake and thus lead- ing to increased synaptic availability of DA and NE. Unlike amphetamine, methylphenidate is a non-competitive inhibitor, and is not itself taken up into the DA or NE terminal via the transporter. When DAT is saturated by methylphenidate in the nucleus accumbens this can lead to euphoria, reward, reinforcement, and continued abuse. methylphenidate methylphenidate DA neuron NE neuron Amphetamine is a competitive inhibitor at DAT (1), NET, and the vesicular monoamine transporter (VMAT). After being taken up into the DA termi- nal via DAT (2), amphetamine is packaged into vesicles (3). At high levels, it will displace DA from the vesicles into the terminal (4), which will lead to DA being expelled from the terminal via two mechanisms: the opening of channels allowing for a massive DA dumping into the synapse (5) and the reversal of DAT (6). This fast release of DA can lead to euphoria. 1 = competitive inhibition 2 = DAT transport of amphetamine DAT DAT DAT DAT amphetamine 3 = VMAT transport of amphetamine 5 = high DA opens channel and spills out 6 = high DA reverse transports DA out 4 = amphetamine displacement of dopamine DAT DAT DAT DAT VMAT DAT DAT DAT DAT DAT DAT DAT DAT ATPase 1 2 4 4 4 4 4 4 5 5 6 6 3 3 3 2 Alpha2 adrenergic receptors are present in high concentrations in the PFC, but low concentrations in the nucleus accumbens. There are three forms of alpha2 receptors: alpha2A, 2B, and 2C. The most prevalent subtype in the PFC is the alpha2A receptor, and it is the receptor most likely involved in ADHD. In ADHD, clonidine (a nonselective alpha2 ago- nist) and guanfacine (a selective alpha2A agonist) stimulate postsynap- tic receptors, thus normalizing NE signaling. The lack of action at postsyn- aptic DA receptors parallels their lack of abuse potential. D1 + + + + + + 2B 2C 2A NE neuron DA neuron sedation hypotension sedation sedation hypotension guanfacine clonidine imidazoline receptor NET 2A D2 prefrontal cortex Unlike atomoxetine, bupropion also directly affects DA levels by inhibit- ing DAT. Thus in the PFC, bupropion leads to increased NE (A) and DA diffusion (B) via inhibition of NET. Bupropion, however, also leads to increases in DA levels in the striatum and nucleus accumbens due to its inhibition of DAT. This then leads to increased DA diffusion in the nucleus accumbens as well. C NDRI action in striatum: DAT blockade and increases DA DAT DAT blockade increases DA diffusion B “normal” DA diffusion “normal” DA diffusion NET blockade increases DA diffusion A NE neuron DA neuron DA neuron “normal” NE diffusion NET blockade increases NE diffusion The exact mechanism of action of the wake-promoting agent modafinil and armodafinil remains unknown. Modafinil is hypothesized to selec- tively activate neurons within the wake promoter tuberomammillary nucleus and the lateral hypothalamus, thus leading to the release of histamine and orexin. Modafinil likely binds to the DA transporter, and acts as a weak to moderate DAT inhibitor depending on the drug concen- trations. Modafinil, which is not formally approved to treat ADHD, is a scheduled substance, considered less abusable than methylphenidate or amphetamine. D2 DA DA reuptake pump modafinil armodafinil increase in tonic firing, downstream increase in HA and activation of wake-related circuits + + + + Mechanisms of Action of ADHD Medications This poster is supported by an educational grant from Shire Pharmaceuticals Inc. Dosing Approved For: Attention deficit hyperactivity disorder in children ages 3–16; narcolepsy Dosage Range: 5–40 mg/day (divided doses for tablet, once-daily morning dose for spansule capsule); ages 3–5: initial 2.5 mg/day; increase by 2.5 mg each week Formulation: 5, 10, and 15 mg spansule capsule; 5 (scored) and 10 mg tablet Essentials of ADHD Medications: From Mechanisms of Action to Dosing Information Essentials of ADHD Medications: From Mechanisms of Action to Dosing Information Disclosure of Off-Label Use This educational poster includes discussion of products that are not currently labeled for such use by the FDA. Please consult the product prescribing information for full disclosure of labeled uses. Methylphenidate Formulations Formulation Immediate-release racemic (Ritalin, Methylin, generic IR) Immediate-release d-methylphenidate (Focalin) Sustained-release racemic (Ritalin SR, Methylin SR, Metadate ER, generic SR) Time-release beads racemic (Metadate CD) SODAS microbeads racemic (Ritalin LA) OROS technology racemic (Concerta) SODAS microbeads d-methylphenidate (Focalin XR) Methylphenidate transdermal patch (multipolymeric adhesive) (Daytrana) Profile 2nd dose at lunch; low risk for insomnia unless dosed at night 2nd dose at lunch; effective at ½ racemic dose with longer duration of action 2nd dose at lunch; low risk for insomnia unless dosed at night Less risk for insomnia than OROS Less risk for insomnia than OROS Continued effects into evening Once-daily dose in the morning Application on hip 2 hrs before effect is desired; wear for approx. 9 hrs Approval Age 6 to 12 Age 6 to 17 Age 6 to 15 Age 6 to 15 Age 6 to 12 Age 6 to 17 and adults Age 6 to 17 and adults Age 6 to 12 Peak, Duration Early peak, 2–4-hr duration Early peak, 4–8-hr duration Early peak, 4-hr duration Strong early peak, 8-hr duration Two strong peaks (early and after 4 hrs), 8–12-hr duration Small early peak, 12-hr duration Two peaks (after 1.5 and 6.5 hrs), 12–16-hr duration One peak at 7–10 hrs, 12-hr duration
Transcript of Essentials of ADHD Medications: From Mechanisms of Action...
Speci�cs About Stimulant Drug Formulations
gelatin capsule
two differenttypes of beads
amphetamine
Spansules, a type of formulation used for am-phetamine, are also referred to as the two-bead system. Two di�erent types of beads are con-tained in a gelatin capsule. While the gelatin capsule dissolves quickly in water, the two beads dissolve at di�erent speeds, thereby allowing for a longer duration of action of the drug. This theoretically leads to a constant release of the drug, a constant stimulation of DA receptors, and thus a steady-state DA release.
A prodrug is a pharmacologically inactive compound, that needs to be metabolized by the body to become active. A prodrug there-fore increases oral bioavailability. Lisdexamfet-amine is a prodrug of dextroamphetamine and becomes active only after it has been con-verted to dextroamphetamine and l-lysine in the intestinal tract. This formulation allows for once-daily dosing, and minimizes the potential of abuse and diversion as this formulation may be less abusable than other stimulants.
lisdexamfetamine
gelatin capsule
The osmotic controlled-release oral delivery system (OROS) is one formulation of methyl-phenidate. Once swallowed, the outer coating that is laced with methylphenidate quickly dis-integrates thereby releasing the �rst “dose” or “mini-burst” of methylphenidate. The internal insoluble capsule is divided into three com-partments: the �rst one contains the lowest concentration of the drug; the second one con-tains the highest concentration of the drug; and the third compartment contains molecules that expand with water, resulting in the third compartment pushing out the drug through the small hole on the opposite side.
opening
first compartment:low concentration of methylphenidate
second compartment:high concentration of methylphenidate
coating: methylphenidate,binders
semipermeablerigid membrane
third compartment:mixture of triacetin,cellulose acetate,hypromellose,polyethylene glycol,polyethylene oxides
The patch is one formulation used for the de-livery of racemic methylphenidate. In this case, the drug is released through a micropore mem-brane controlling drug release. It then passes through the adhesive layer and di�uses through the skin to enter the bloodstream. It normally takes up to two hours for patients to feel the e�ects of the drug. Thus it is important to remove the patch a few hours before bed-time. First-pass metabolism is not extensive with the patch, resulting in notably higher exposure to the drug than after oral dosing.
skin
impermeablecoveringmembrane
capillary
adhesive
methylphenidate
Dosing Information and Main Side E�ects of ADHD MedicationsCharacteristics of ADHD Drug Formulations
These tables give an overview of the di�erent ADHD drug formulations, including the brand names of the various medications, and the ages for which they are approved. *not currently available, approval pending
Amphetamine Formulations
Formulation
Immediate-released-amphetamine(Dexedrine)
Immediate-released, l-amphetamine(Adderall)
Sustained-released-amphetamine(Dexedrine Spansule)
Extended-released, l-amphetamine(mixedAMP salts) (Adderall XR)
Lisdexamfetaminedimesylate (Vyvanse)
Pro�le
2nd dose at lunch; lowrisk for insomniaunless dosed at night
2nd dose at lunch; lowrisk for insomniaunless dosed at night
No lunch dosing; lowrisk for insomniaunless dosed at night
Continued e�ects intoevening
Breakfast dosing; risk ofinsomnia if dosed inafternoon
Approval
Age 3 to 16
Age 3 to 12
Age 3 to 16
Age 6 to 12,Age 13 to 17and adults
Age 6 to 12 and adults
Duration
3–6-hr
5-hr
6–9-hr
Max plasmaconcentration
at 7-hr
Peak at 3.5 hrs10–12-hr
Non-Stimulant Drug Formulations
Formulation
Atomoxetine(Strattera, Attentin)
Guanfacineimmediate-release(Tenex)
Guanfacine extended-release (Intuniv*)
Bupropion (Wellbutrin IR,SR, XR, Zyban)
Moda�nil (Provigil)
Armoda�nil (Nuvigil)
Clonidine (Duraclon,Catapres)
Pro�le
Dosing 1X or 2X aday; morning and lateafternoon
Multiple dosing (3X perday), somnolence isfrequent
Morning dosing;somnolence observedwhen dose is increased
Dosing di�ers withformulation
Once-daily dosing
Once-daily dosing, mayhave longer duration ofaction than moda�nil
Morning and nightdosing, sedation iscommon
Approval
Age 6 to 18and adults
Children and adolescents;e�ective in adults, but notFDA-approved for ADHD
Children and adolescents;e�ective in adults, but notFDA-approved for ADHD
E�ective in adults, but notFDA-approved for ADHD
E�cacious in children andadolescents, but not FDA-approved for ADHD
Not studied in or FDA-approved for ADHD
E�ective in children, but notFDA-approved for ADHD
Half-life
~5-hr
~17-hr
~14–18-hr
10–17-hr
15-hr(after multiple
dosing)
15-hr
12–16-hr
Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu-lar adverse e�ects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous-ness, irritability, overstimulation, tremor, dizziness
Side Effects
Dosing
Approved For:Attention de�cit hyperactivity disorder in children and adults (approved ages vary based on formularies); narcolepsy
Dosage Range:Oral: up to 2 mg/kg/day in children 6 and older, with maximum of 60 mg/day; in adults usually 20–30 mg/day, can use up to 40–60 mg/day; transdermal: 10–30 mg/9hrs
Formulation:5, 10, and 20 mg immediate-release tablets; 2.5, 5, and 10 mg immediate-release chewable tablets; 5 mg/mL and 10 mg/5 mL oral solution; 10 and 20 mg older sustained-release tablets; 10, 20, 30, and 40 mg newer sustained-release capsules; 18, 27, 36, and 54 mg newer sustained-release tablets; 27 mg/12.5 cm2 (10 mg/9hrs); 41.3 mg/18.75 cm2 (15 mg/9hrs); 55 mg/25 cm2 (20 mg/9hrs) and 82.5 mg/37 cm2 (30 mg/9hrs) transdermal patch
Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu-lar adverse e�ects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous-ness, irritability, overstimulation, tremor, dizziness
Side Effects
Dosing
Approved For:Attention deficit hyperactivity disorder in children ages 6–17, and in adults (extended-release formulation)
Dosage Range:Immediate-release (IR): 2.5–10 mg twice a day; extended-release (ER): 5–20 mg
Formulation:2.5, 5, and 10 mg tablets; 5, 10, and 20 mg extended-release capsules
DAT
NET
D-Methylphenidate
D,L-Methylphenidate
Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu-lar adverse e�ects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous-ness, irritability, overstimulation, tremor, dizziness
Side Effects
Dosing
Approved For:ADHD in children ages 3–16 (immediate-release formulation); ADHD in children ages 6–17 and in adults (extended-release formulation); narcolepsy
Dosage Range:5–40 mg/day (divided doses for immediate-release tablet, once-daily morning dose for extended-release tablet)
Formulation:5, 7.5, 10, 12.5, 15, 20, and 30 mg double-scored immediate-release tablets; 5, 10, 15, 20, 25, and 30 mg extended-release tablets
Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu-lar adverse e�ects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous-ness, irritability, overstimulation, tremor, dizziness
Side Effects
DAT
NET
VMAT
D,L-Amphetamine
DAT
NET
VMAT
DAT
NET
VMAT
Increased heart rate and hypertension, orthostatic hypotension, rare severe liver damage, rare suicidality, rare induction of hypomania, sedation especially in children
Side Effects
Dosing
Approved For:Attention de�cit disorder in adults and children over 6, treatment-resistant depression
Dosage Range:For children up to 70 kg: start at 0.5 mg/kg/day, then increase to 1.2 mg/kg/day after 3 days, max dose is 100 mg/day or 1.4 mg/kg/day, whichever is lessFor children and adults over 70 kg: start at 40 mg/day and increase to 80 mg/day after 3 days, max dose is 100 mg
Formulation:10, 18, 25, 40, 60, 80, and 100 mg capsules
Psychotic episodes, seizures, palpitations, tachycardia, hypertension, rare activation of (hypo)mania, or suicidal ideation (controversial), cardiovascu-lar adverse e�ects, sudden death in patients with preexisting cardiac structural abnormalities, insomnia, headache, exacerbation of tics, nervous-ness, irritability, overstimulation, tremor, dizziness
Side Effects
Dosing
Approved For:Attention de�cit hyperactivity disorder in children ages 6–12 and in adults
Dosage Range:30–70 mg/day
Formulation:20, 30, 40, 50, 60, and 70 mg capsules
Atomoxetine
DRI
NRI
Rare seizures, induction of mania and suicidality
Side Effects
Dosing
Approved For:Major depressive disorder and nicotine addiction
Dosage Range:Bupropion: 225–450 mg in 3 divided doses (150 mg maximum single dose); SR: 200–450 mg in 2 divided doses (200 mg maximum single dose); XL: 150–450 mg once/day (450 mg max dose)
Formulation:75, 100 mg tablets; SR: 100, 150, and 200 mg tablets; XL: 150 and 300 mg tablets
Sinus bradycardia; atrioventricular block; during withdrawal, hypertensive encephalopathy, cerebrovascular accidents, and death (rare); notable side e�ects include dry mouth, dizziness, constipation, and sedation
Side Effects
Dosing
Approved For:Hypertension
Dosage Range:0.2–0.6 mg/day in divided doses
Formulation:0.1, 0.2, and 0.3 mg scored tablets; 0.1 mg/24hrs; 0.2 mg/24hrs; 0.3 mg/24hrs topical form (7 day administration); 100 and 500 mg/mL injection
Bupropion
NRI
Serious or life-threatening rash, including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), transient EKG ischemic changes in patients with mitral valve prolapse or left ventricular hypertrophy, can activate hypomania, suicidality
Side Effects
Dosing
Approved For:Narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD)
Dosage Range:200 mg/day in the morning, doses up to 400 mg/day have been well-tolerated
Formulation:100 and 200 mg (scored) tablets
Sinus bradycardia; hypotension; side e�ects include sedation, dizziness, dry mouth, constipation
Side Effects
Dosing
Approved For:Hypertension (immediate-release formulation); extended-release formulation is not yet available, approval pending
Dosage Range:1–2 mg/day
Formulation:1, 2, and 3 mg immediate-release tablets
2A
Moda�nil
imidazoline
2C
2B
2ADAT
NET
VMAT
D-Amphetamine Lisdexamfetamine Clonidine Guanfacine
DAT
NET
DAT
NET
B
NET blocked in PFC:NE increases
“normal”NE diffusion “normal”
DA diffusion
“normal”DA diffusion
NET blockadeincreases NEdiffusion
NET blockadeincreases DAdiffusion
Normal DA release in PFC:No DAT, diffuses to NET
A
NET
C
NET blocked in PFC:DA increases
DAneuron
NEneuron
There are many NETs, and only very few DATs, in the prefrontal cortex (PFC). Due to greater di�usion, released DA in the PFC can exert its actions further away (A). In the PFC, atomoxetine primarily raises NE levels and increases its di�usion radius by blocking NET (B). As NET also takes up DA, NET blockade in the PFC will also increase synaptic DA, further enhancing its di�usion. Thus in the PFC, atomoxetine increases both NE and DA.
Methylphenidate works at the dopamine (DAT) and norepinephrine transporter (NET) by blocking the reuptake of both dopamine (DA) or norepinephrine (NE) into the terminal. Methylphenidate basically freezes the transporter in time, preventing DA (and NE) reuptake and thus lead-ing to increased synaptic availability of DA and NE. Unlike amphetamine, methylphenidate is a non-competitive inhibitor, and is not itself taken up into the DA or NE terminal via the transporter. When DAT is saturated by methylphenidate in the nucleus accumbens this can lead to euphoria, reward, reinforcement, and continued abuse.
methylphenidatemethylphenidate
DA neuron NE neuron
Amphetamine is a competitive inhibitor at DAT (1), NET, and the vesicular monoamine transporter (VMAT). After being taken up into the DA termi-nal via DAT (2), amphetamine is packaged into vesicles (3). At high levels, it will displace DA from the vesicles into the terminal (4), which will lead to DA being expelled from the terminal via two mechanisms: the opening of channels allowing for a massive DA dumping into the synapse (5) and the reversal of DAT (6). This fast release of DA can lead to euphoria.
1 = competitive inhibition2 = DAT transport of amphetamine
DAT
DAT
DAT
DAT
amphetamine
3 = VMAT transport of amphetamine
5 = high DA opens channel and spills out6 = high DA reverse transports DA out
4 = amphetamine displacement of dopamine
DAT
DAT
DAT
DAT
VMAT
DAT
DAT
DAT
DAT
DAT
DAT
DAT
DAT
ATPase
1
2
4
4
44
44
5
5
6
6
3
3
3
2
Alpha2 adrenergic receptors are present in high concentrations in the PFC, but low concentrations in the nucleus accumbens. There are three forms of alpha2 receptors: alpha2A, 2B, and 2C. The most prevalent subtype in the PFC is the alpha2A receptor, and it is the receptor most likely involved in ADHD. In ADHD, clonidine (a nonselective alpha2 ago-nist) and guanfacine (a selective alpha2A agonist) stimulate postsynap-tic receptors, thus normalizing NE signaling. The lack of action at postsyn-aptic DA receptors parallels their lack of abuse potential.
D1+
+
++
++
2B 2C
2A
NEneuron
DAneuron
sedationhypotension
sedation
sedationhypotension
guanfacine clonidine
imidazolinereceptor
NET
2A D2
prefrontal cortex
Unlike atomoxetine, bupropion also directly a�ects DA levels by inhibit-ing DAT. Thus in the PFC, bupropion leads to increased NE (A) and DA di�usion (B) via inhibition of NET. Bupropion, however, also leads to increases in DA levels in the striatum and nucleus accumbens due to its inhibition of DAT. This then leads to increased DA di�usion in the nucleus accumbens as well.
C
NDRI action in striatum:DAT blockade and increases DA
DAT
DAT blockadeincreases
DA diffusion
B
“normal”DA diffusion
“normal”DA diffusion
NET blockadeincreases
DA diffusion
A
NEneuron
DAneuron
DAneuron
“normal”NE diffusion
NET blockadeincreases NEdiffusion
The exact mechanism of action of the wake-promoting agent moda�nil and armoda�nil remains unknown. Moda�nil is hypothesized to selec-tively activate neurons within the wake promoter tuberomammillary nucleus and the lateral hypothalamus, thus leading to the release of histamine and orexin. Moda�nil likely binds to the DA transporter, and acts as a weak to moderate DAT inhibitor depending on the drug concen-trations. Moda�nil, which is not formally approved to treat ADHD, is a scheduled substance, considered less abusable than methylphenidate or amphetamine.
D2
DA
DAreuptake pump
modafinilarmodafinil
increase in tonic firing,downstream increase in HAand activation of wake-relatedcircuits
+
+
+
+
Mechanisms of Action of ADHD Medications
This poster is supported by an educational grant from Shire Pharmaceuticals Inc.
Dosing
Approved For:Attention de�cit hyperactivity disorder in children ages 3–16; narcolepsy
Dosage Range:5–40 mg/day (divided doses for tablet, once-daily morning dose for spansule capsule); ages 3–5: initial 2.5 mg/day; increase by 2.5 mg each week
Formulation:5, 10, and 15 mg spansule capsule; 5 (scored) and 10 mg tablet
Essentials of ADHD Medications: From Mechanisms of Action to Dosing InformationEssentials of ADHD Medications: From Mechanisms of Action to Dosing Information
Disclosure of O�-Label Use This educational poster includes discussion of products that are not currently labeled for such use by the FDA.
Please consult the product prescribing information for full disclosure of labeled uses.
Methylphenidate Formulations
Formulation
Immediate-releaseracemic (Ritalin, Methylin,generic IR)
Immediate-released-methylphenidate(Focalin)
Sustained-releaseracemic (Ritalin SR,Methylin SR, MetadateER, generic SR)
Time-release beadsracemic (Metadate CD)
SODAS microbeadsracemic (Ritalin LA)
OROS technologyracemic (Concerta)
SODAS microbeads d-methylphenidate(Focalin XR)
Methylphenidatetransdermal patch(multipolymericadhesive) (Daytrana)
Pro�le
2nd dose at lunch; lowrisk for insomnia unlessdosed at night
2nd dose at lunch;e�ective at ½ racemicdose with longerduration of action
2nd dose at lunch; lowrisk for insomnia unlessdosed at night
Less risk for insomniathan OROS
Less risk for insomniathan OROS
Continued e�ects intoevening
Once-daily dose in themorning
Application on hip 2hrs before e�ect isdesired; wear forapprox. 9 hrs
Approval
Age 6 to 12
Age 6 to 17
Age 6 to 15
Age 6 to 15
Age 6 to 12
Age 6 to 17and adults
Age 6 to 17and adults
Age 6 to 12
Peak, Duration
Early peak, 2–4-hrduration
Early peak, 4–8-hrduration
Early peak, 4-hrduration
Strong early peak, 8-hr duration
Two strong peaks(early and after 4hrs), 8–12-hrduration
Small early peak,12-hr duration
Two peaks (after1.5 and 6.5 hrs),12–16-hr duration
One peak at 7–10hrs, 12-hr duration
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