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What are the core symptoms of Attention Deficit Hyperactivity Disorder (ADHD)?
Inattention, Hyperactivity, Impulsivity
What is the mechanism of action (MOA) of Atomoxetine?
Selective norepinephrine reuptake inhibitor
What is the prevalence of diagnosed ADHD in children from 2007 to 2011?
increased 28%
The non-pharmacologic therapy includes behavioral interventions and _______.
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What is the primary MOA of Guanfacine and Clonidine?
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What neurotransmitters does cocaine block the reuptake of?
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What is the first-line pharmacologic therapy for ADHD?
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Controlled substances for ADHD treatment are classified as Schedule I.
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Which of the following is a xanthine?
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What are anorexiant/anti-obesity agents primarily related to?
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The stimulant mechanism of action derives from its structural similarity to neurotransmitters, DA and NE, and to a lesser extent _______.
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What is the primary adverse effect of amphetamine?
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What characterizes neuromuscular blockers?
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What was the first known neuromuscular blocking drug?
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Amphetamine is ______% excreted unchanged.
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What are the potential effects of prolonged use of amphetamines?
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The structure of a depolarizing NM blocking agent is _______
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What is the MOA of Methylphenidate?
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Non-depolarizing agents have a more _______ structure.
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Which of the following describes Lisdexamfetamine?
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What is one example of a depolarizing neuromuscular blocker?
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What is a common feature of non-depolarizing neuromuscular blockers?
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Methamphetamine has a lower abuse potential than dextroamphetamine.
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Non-depolarizing blockers utilize two types of bulky __________.
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R2 = CH3 introduces asymmetry and allows penetration of the _______.
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What is the significance of the β-OH in the structure of Phenylethylamines?
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Which type of muscle relaxants are used to reduce spasticity in painful conditions?
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Study Notes
Attention Deficit Hyperactivity Disorder (ADHD)
- Core symptoms include inattention, hyperactivity, and impulsivity
- 80% genetic in origin
- Implicated Systems: Dopaminergic and adrenoceptor alpha 2 genes
- The prevalence of diagnosed ADHD in children increased 28% from 2007 to 2011
Non-Pharmacologic Therapy
- First-line interventions PRIOR to medication trails:
- Behavioral Interventions
- Structured Limit-Setting
- Parent training
- Dietary Interventions:
- Iron + Zn supplements (known deficiency)
- Omega-3 FISH OIL supplements (with or without primrose (omega 6))
- Avoid red/orange food dye in lunch meat/hotdogs
- Avoid allergenic foods
- Avoid sugar/artificial sweeteners
Behavioral Interventions
- Preschool and School Age (6-11 yrs):
- Parent /Family Education on ADHD
- Training on behavioral modification
- Classroom mgmt. instruction for teachers
- Adolescent:
- Breakup homework into short segments
- Structured schedule organizer (to-do lists)
- Adolescent and Adult:
- ADHD specific cognitive behavioral therapy (think before acting)
- Metacognitive therapy (2h/week for 12 weeks)
Pharmacologic Therapy
- Stimulants:
- First line
- Controlled (schedule II)
- Non-stimulants:
- Second line
- NOT controlled agents
- Often used as adjuncts to stimulants, can be used alone
Amphetamine
- Inhibits actions of DAT, NET, and SERT in staitum & prefrontal cortex
- Inhibits vesicular monoamine transporter 2 (VMAT2) = Inhibits translocation of DA and NE from the cytosol into storage vesicles
- Increases DA and NE concentration in the synapse
- Inhibits MAO = Risk for SS and Hypertensive Crisis
- A racemic (±) mixture:
- Dextro (D-) 4X more potent than levo (L-)
Amphetamine Adverse Effects
- Common:
- Decreased appetite
- Tachycardia
- Weight loss
- Insomnia
- Headache and irritability
- Jitteriness
- Rare/Prolonged Use:
- Dysphoria
- A Zombie-like state
- Priapism
- Hypertension
- Psychosis (especially with prolonged use)
Amphetamine Metabolism
- 30%-40% excreted unchanged
- Alkaline urine = Decreases elimination
- Acidic urine = Increases elimination
Lisdexamfetamine
- Lysine amide derivative
- Pro-drug = Hydrolysis in RBCs to D-amphetamine
- Hydrolysis = SLOW release = SLOW onset = LONGER Duration
- Less abuse potential & smoother Peak/Trough effect
Methamphetamine
- N-methyl analog of dextroamphetamine
- Exhibits increased central effects than dextroamphetamine
- Exhibits decreased peripheral effects than dextroamphetamine
- Increased abuse potential
Ephedrine and Pseudoephedrine
- β-OH analogues of methamphetamine
- Ephedrine used in Chinese medicine for millennia
- Dietary supplements with ephedrine now banned in the US
- Pseudoephedrine used as a precursor to make meth
Methylphenidate
- MOA = same as amphetamines
- Also inhibits MAO
- Two chiral centers = four isomers
- Only threo used clinically since erythro has greater side effects
- D threo isomer causes the effect
- Can get just d isomer = dexmethylphenidate
SAR Of Phenylethylamines
- Amine substituent (R1):
- A cationic amine is essential for adrenoceptor binding. The size of the substituent influences which receptor subtype(s) will be stimulated.
- R1 = H: Preferential α-agonist action; used predominantly as vasoconstrictors.
- R1 = CH3: Nonselective agonist action; used predominantly for their α-agonist action.
- More R1 = more β action, less α
- α-Carbon substituent (R2):
- R2 = CH3: α-Carbon substituents introduce asymmetry. R and S isomers exist. Penetration of the blood–brain barrier occurs if no phenolic hydroxyls are present. Stimulation of central α1- receptors results in sleeplessness, agitation, restlessness, and anorexia (appetite suppression).
- β-Carbon substituent (R3):
- R3 = OH: A β-OH introduces asymmetry. R and S isomers exist. A β-OH slows, but does not stop, CNS penetration.
- R3 = H: CNS penetration in nonphenolic compounds is significantly enhanced, especially when R1 and/or R2 is/are CH3.
ADHD stimulants
- Atomoxetine is a selective norepinephrine reuptake inhibitor
- Guanfacine and clonidine are presynaptic alpha2A-agonists
Xanthines
- Xanthines act as non-selective adenosine receptor antagonists
- Caffeine produces central vasoconstrictive effects
Narcoleptics
- Psychostimulants are used to improve wakefulness in narcolepsy and other conditions
- Psychostimulants can lead to an increase in blood pressure and heart rate
- The mechanism of action of psychostimulants in narcolepsy is not fully known
Anorexiant / Anti-obesity Agents
- Anorexiant/anti-obesity agents have no primary effect on the appetite brain center
- Anorexiant/anti-obesity agents suppress appetite through CNS stimulation
- Phentermine is the only anorexiant/anti-obesity agent that is not chiral
- Dextroisomers of chiral anorexiant/anti-obesity agents exhibit psychostimulant and anorexiant activity
- Larger N-substitutions on phenethylamines lead to more beta action and less alpha action
Skeletal Muscle Relaxants
- There are two therapeutic groups of skeletal muscle relaxants
- Neuromuscular blockers
- Spasmolytics
Neuromuscular blockers
- Used during surgery and in the ICU to produce muscle paralysis
- Primarily used as an adjunct during general anesthesia
- Used to optimize surgical conditions and facilitate endotracheal intubation
- Used to relax skeletal muscles during abdominal surgery
- Muscles of the limbs, chest, and abdomen are affected first
- Muscles supporting respiration are affected last
- Decrease the dose of general anesthetic required, surgical risk, and post-operative recovery time
Tubocurarine
- The first known neuromuscular blocking drug
- Used by South American tribes in 1510
- Structure was initially misassigned
- Two types of neuromuscular blockers:
- Depolarizing
- Non-depolarizing
Neuromuscular Blockers SAR
- Depolarizing neuromuscular blockers have a flexible structure
- Non-depolarizing neuromuscular blockers have a more rigid structure
Depolarizing Neuromuscular Blockers
- Succinylcholine is the only known depolarizing neuromuscular blocker
- Succinylcholine is a dimer of acetylcholine
- Succinylcholine causes initial muscle fasciculation before relaxation
Non-Depolarizing Neuromuscular Blockers
- Non-depolarizing neuromuscular blockers have one of two types of bulky, semi-rigid ring systems:
- Isoquinoline derivatives
- Steroid derivatives
- Non-depolarizing neuromuscular blockers have one or two quaternary nitrogens
- They are poorly lipid soluble
- They have limited entry into the CNS
- They are competitive nACh antagonists
Non-Depolarizing Neuromuscular Blockers: Non-Steroid Derivatives
- Atracurium
- Cisatracurium
Non-Depolarizing Neuromuscular Blockers: Steroid Derivatives
- Steroid derivatives
Neuromuscular Blocker Physicochemical and Pharmacokinetic Properties
- They have a fast onset, short duration, and short half life
- They are not absorbed orally
- They are well distributed following IM or IV administration
- They are too polar to enter the CNS
- They have a duration of action limited by ester hydrolysis
- Their metabolites may show some activity
- 3-hydroxy metabolites of steroid muscle relaxants have 40-80% of the potency of the parent compound
- The 3-hydroxy metabolite has a longer half life than the parent compound
Spasmolytics
- They are centrally acting muscle relaxants
- They reduce spasticity in a variety of painful conditions:
- Chronic back pain
- Painful fibromyalgic conditions
- Spinal injury
- Cerebral palsy
- Multiple sclerosis
- Stroke
- Acute spasm due to muscle injury
- No SAR for spasmolytics is discussed
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