CNS Stimulants and Muscle Relaxants PDF

CNS Stimulants and Muscle Relaxants Nate Daniels, Ph.D. Union University College of Pharmacy November 18, 2022  Reading Roche VF, Zito SW, Lemke TL, and Williams DA. Foye’s Principles of Medicinal Chemistry, 8th Edition (2019). Wolters Kluwer. pp....

CNS Stimulants and Muscle Relaxants Nate Daniels, Ph.D. Union University College of Pharmacy November 18, 2022  Reading Roche VF, Zito SW, Lemke TL, and Williams DA. Foye’s Principles of Medicinal Chemistry, 8th Edition (2019). Wolters Kluwer. pp. 225-226, 294-302, 408-412, 1564-1565 Katzung BG, Vanderah TW. Basic & Clinical Pharmacology, 15th Edition (2021). McGraw-Hill. Chapter 9 and 27 2  Learning Objectives Describe the MOA of stimulants and muscle relaxants discussed Discuss the SAR of key drug classes where presented Identify clinically significant physiochemical and pharmacokinetic properties of stimulants and muscle relaxants discussed Discuss, with chemical structures, the clinically significant metabolism of stimulants and muscle relaxants discussed and how that affects their activity 3  Course Goal Learn the knowledge in this class to help prepare you to be able to best show love to patients 4  Lecture Outline ADHD stimulants Overview of ADHD Therapies for ADHD SAR of Phenylethylamines Non-ADHD stimulants Muscle relaxants Neuromuscular blockers Spasmolytics 5  Attention Deficit Hyperactivity Disorder (ADHD) Core symptoms include Inattention; Hyperactivity and Impulsivity 80% genetic in origin Implicated Systems: Dopaminergic and adrenoceptor alpha 2 genes Environmental factors can play a significant role The prevalence of diagnosed ADHD in children _________ increased 28% from 2007 to 2011 Debate in the literature about whether it is over-diagnosed ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 6  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 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 7  Behavioral Interventions Age Behavioral Interventions Preschool and - Parent /Family Education on ADHD - Training on behavioral modification School Age (6-11 yrs) - 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) ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 8  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 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 9  Pharmacologic Therapy The stimulant mechanism action of amphetamine derives from its structural similarity to the neurotransmitters, DA and NE, and to a lesser extent 5-HT since it has the arylethylamine moiety in common Drugs that mimic the actions of epinephrine or norepinephrine have traditionally been called sympathomimetic drugs ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 10  Amphetamine _______ inhibit actions of DAT, NET, and SERT in striatum & prefrontal cortex Inhibits vesicular monoamine transporter 2 (VMAT2) = Inhibits translocation of DA and NE from A racemic (±) mixture the cytosol into storage vesicles Dextro (D-) 4X more Increases DA and NE potent than levo (L-) concentration in the synapse Inhibits MAO = Risk for SS and Hypertensive crisis ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 11  Amphetamine Adverse Effects Adverse effects are due to its MOA Common - Decreased appetite, tachycardia, weight loss, insomnia, headache and irritability, and jitteriness Rare/Prolonged Use - Dysphoria, a Zombie-like state, priapism, hypertension, and psychosis especially with prolonged use ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 12  Amphetamine Metabolism Amphetamine is 30%-40% excreted _________ unchanged Alkaline urine = Decreases elimination Acidic urine = Increases elimination ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 13  Lisdexamfetamine no methyl- group Dextroamphetamine = dextro (d-) isomer of amphetamine More potent isomer Aka S isomer Hydrolysis pro drug no effect this has effect Lisdexamfetamine D-amphetamine 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 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 14  Methamphetamine methyl- group N-methyl analog of dextroamphetamine Aka what people ask me about when they find out I'm a chemist Exhibits ______ inc central effects than dextroamphetamine Exhibits _______ dec peripheral effects than dextroamphetamine Increased abuse potential ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 15  Ephedrine and Pseudoephedrine β-OH analogues of methamphetamine Ephedrine used in Chinese medicine for S,R-(+)-Ephedrine R,S-(-)-Ephedrine millennia Dietary supplements with ephedrine now banned in the US Pseudoephedrine used S,S-(+)-pseudoephedrine R,R-(-)-pseudoephedrine as a precursor to make meth ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 16  Methylphenidate MOA = same as amphetamines Also inhibits MAO Two chiral centers = four isomers Only threo used clinically since erythro has greater dexmethylphenidate side effects D threo isomer causes the effect Can get just d isomer = dexmethylphenidate EP2651892B1 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 17  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 Essentials of Foye’s Principles of Medicinal Chemistry, 2017 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 18  SAR of Phenylethylamines 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). Essentials of Foye’s Principles of Medicinal Chemistry, 2017 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 19  SAR of Phenylethylamines 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. Essentials of Foye’s Principles of Medicinal Chemistry, 2017 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 20  Nonstimulant Drugs for ADHD Atomoxetine MOA = selective NE reuptake inhibitor Selective because of the methyl in the 2 position of the aryl ring Guanfacine and clonidine MOA = presynaptic alpha2A-agonist ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 21  Lecture Outline ADHD stimulants Overview of ADHD Therapies for ADHD SAR of Phenylethylamines Non-ADHD stimulants Muscle relaxants Neuromuscular blockers Spasmolytics 22  Cocaine Blocks reuptake of NE, 5-HT & DA Reinforcing & stimulant effects of cocaine primarily due to blockade of DA reuptake Amphetamine-like psychological effect that is shorter and more intense than amphetamine Very addictive ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 23  Xanthines Caffeine Theophylline Theobromine Xanthine MOAs = ________ non-selective adenosine receptor antagonist Caffeine has central vasoconstrictive effects ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 24  Narcoleptics Psychostimulants used primarily to improve wakefulness in narcolepsy and some other conditions Can be associated with increases in blood pressure and heart rate, although these are usually mild Mechanism of action is not fully known ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 25  Anorexiant/Anti-obesity Agents No primary effect on the appetite brain center; rather, its appetite- suppressant action appears to be secondary to CNS stimulation Chiral compounds (except phentermine) with the dextro isomer exhibiting the psychostimulant and anorexiant activity Remember from phenethylamine SAR that _______ Bigger N substituent = Essentials of Foye’s Principles of Medicinal Chemistry, 2017 more β action, less α ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 26  msucle relaxents neuromusclar blocker spasmolytics non-polarizing depolarizing steroid isopquinolines  Lecture Outline ADHD stimulants Overview of ADHD Therapies for ADHD SAR of Phenylethylamines Non-ADHD stimulants Muscle relaxants Neuromuscular blockers Spasmolytics 27  Skeletal Muscle Relaxants Two different therapeutic groups Neuromuscular blockers Interfere with transmission at the neuromuscular end plate and lack central nervous system (CNS) activity Spasmolytics “centrally acting” muscle relaxants ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 28  Neuromuscular blockers Used during surgical procedures and in the intensive care unit (ICU) to produce muscle paralysis Used primarily as adjuncts during general anesthesia to optimize surgical conditions and to facilitate endotracheal intubation in order to ensure adequate ventilation Relax skeletal muscles during abdominal surgery Muscles of limbs, chest, abdomen affected first Respiration affected last Decrease dose of general anesthetic, risk of surgery, and postanesthetic recovery time ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 29  Neuromuscular blockers Tubocurarine was the first known neuromuscular blocking drug Reported as early as 1510 when indigenous tribes of South America were found using it Structure was originally misassigned as having two quaternary ammonium salts Two types of Neuromuscular blockers Depolarizing Non-depolarizing Essentials of Foye’s Principles of Medicinal Chemistry, 2017 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 30  Neuromuscular blockers SAR Depolarizing NM blocking agent has a _______ flexible structure connecting the two quaternary heads Nondepolarizing agents have a more _______ rigid structure with the quaternary and protonated heads being part of bulky groups rigid flexible Essentials of Foye’s Principles of Medicinal Chemistry, 2017 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 31  Depolarizing Neuromuscular blockers One depolarizing neuromuscular blocker = Succinylcholine Dimer of acetylcholine MOA: nACh agonist Causes initial muscle fasciculation before relaxation Basic & Clinical Pharmacology, 2021 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 32  Non-Depolarizing Neuromuscular blockers Conceal the “double-acetylcholine” structure in one of two types of bulky, semi-rigid ring systems Isoquinoline derivatives Steroid derivatives Common feature = one or two quaternary nitrogens Poorly lipid soluble Limits entry into the CNS MOA: competitive nACh antagonists ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 33  Non-Depolarizing Neuromuscular blockers nonsteroids Atracurium Cisatracurium steroids Essentials of Foye’s Principles of Medicinal Chemistry, 2017 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 34  Physicochemical, and Pharmacokinetic Properties fast onset, short duration, short half life used in hospital ICU/ surgical setting _____ NOT absorbed orally, but are well distributed following IM or IV administration Too polar to enter the CNS (charged quaternary amine) Essentials of Foye’s Principles of Medicinal Chemistry, 2017 ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 35  Physicochemical, and Pharmacokinetic Properties Duration of action is limited usually by haptic hydrolysis of the esters present in these drugs although often, the metabolites show partial activity With steroidal muscle relaxants 3-hydroxy metabolites are usually 40-80% as potent as the parent Can be an issue if parent compound is administered for several days in the ICU setting The 3-hydroxy metabolite may accumulate and will be on exam cause prolonged paralysis because it has a longer half-life than the parent compound ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 36  Spasmolytics _______ centrally acting muscle relaxants Used to 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 Not SAR to discuss here  ADHD Stimulants > Non-ADHD Stimulants > Muscle Relaxants 37