Pharmacology of CNS Stimulants PDF Fall 2024

PHM 736 Fall 2024 Lunawati Bennett MS; PhD; PharmD; FACN For I know the plan I have for you declared the Lord, plan to prosper you and not to harm you to give you hope and future. Then you will call upon ME and come and pray to ME, and I will listen to you. You will seek ME and find ME whe...

PHM 736 Fall 2024 Lunawati Bennett MS; PhD; PharmD; FACN For I know the plan I have for you declared the Lord, plan to prosper you and not to harm you to give you hope and future. Then you will call upon ME and come and pray to ME, and I will listen to you. You will seek ME and find ME when you search ME with all your heart. Jeremiah 29: 11-13  ADD-attention deficit disorders  M1- muscarinic  ADHD- attention deficit hyperactive  H1- histamine disorders  5HT- serotonin ▪ MAOI- monoamine oxidase  NE- norepinephrine inhibitors  DA- dopamine ▪ MAO- monoamine oxidase ▪ CV- cardiovascular ▪ MOA- mechanism of action ▪ OROS- oral osmotic controlled ▪ DDI- drug -drug interactions delivery ▪ ADRs- adverse drug reactions ▪ GABA- gamma amino butyric acid ▪ OCD-obsessive compulsive disorder ▪ TCA- tricyclic anti depressant ▪ BBW- black box warning Generic Name Trade Name Type Bupropion HCL Wellbutrin ® Antidepressant, ADHD Amitriptyline HCL Elavil ® TCA, antidepressant Clonidine HCl Catapres®, Kapvay ®  2 agonist Amphetamine+dextroamphetamine Adderall ® CII stimulant Ritalin®, Methylin®, Methylphenidate HCL Metadate®, Concerta ® CII stimulant Lisdexamfetamine Vyvance ® CII stimulant Atomoxetine HCl Straterra® non- CII stimulant Modafinil Provigil ® C IV stimulant You are responsible for underlined ADRs, drug names of each class, and brand names At the end of this lecture and after studying the material, the student should be able to : 1. Identify sign/problems of ADHD and how psychostimulants can improve ADHD problems 2. Compare and contrast psychostimulants and psychomimetics using known drugs 3. Identify MOA, ADRs, BBW (if any) and component of Adderall XR®, Concerta®, Vyvance®, Ritalin LA®, and Dexedrine spansule ® 4. Identify ADRs, contraindication and management of overdose of psychostimulants 5. Identify MOA, ADRs, BBW, and DDI of atomoxetine 6. Identify MOA, ADR and use of alpha 2 agonists 7. Identify MOA , characteristics, ADR of modafinil and other drug for treatment of narcolepsy 1. Psychostimulants: for moderate to severe ADHD Methylphenidate, amphetamine, dextroamphetamine, lisdexamphetamine 2. Antidepressants : second line therapy Imipramine, Desipramine, Nortriptyline, Bupropion 3. Anti hypertensives: to treat aggressive behavior Clonidine, Guanfacine 4. Atomoxetine (Strattera®)- non psychostimulant 5. Modafinil (Provigil ®) – off label use. Also use for narcolepsy 6. Antipsychotics: for comorbid aggression, or resistant disorder Aripripazole, haloperidol, Olanzapine, Risperidone 7. Lithium, Valproate, carbamazepine: for explosive behavior, aggression, impulsivity   Improve Core Symptoms: inattention, impulsivity, hyperactivity  Can also improve other symptoms: non-compliance, impulsive aggression, social interactions, academic efficiency and accuracy, family dynamics What is the difference between psychomotor stimulants and psychomimetics ? Psychomotor stimulant: ____________________________________________ Psychomimetic: ____________________________________________________ Psycho Stimulants t1/2 dosing____  Adderall XR ® (amphetamine+dextro) 10 hr 10-30mg  Desoxyn ® (methamphetamine) 4 -5 hr 10-25 mg  Dexedrine Spansule ® (dextroampetamine SR) 7 hr 5-15 mg  Dexedrine ® (dextroamphetamine) 5 hr 5-14mg  Vyvanse ®(lisdexamfetamine) 10-12 hr 30-70 mg  Metadate CD ® (methylphenidate ER) 8 hr 20-60 mg  Concerta ®(methylphenidate ER) 9-10 hr 18-72mg  Ritalin LA® (methylphenidate ER) 7-8 hr 10-60 mg  Methylin ER ® (methylphenidate ER) 6 hr 20-30 mg  Focalin ®(dexmethylphenidate) 4 hr 2.5-15 mg  Focalin XR ® dexmethylphenidate) 8 hr 5-20mg  Daytrana ® (Methylphenidate patch ) 12 hr 10-30 mg  Quillivant XR ® (methylphenidate)-powder 5 hr 20-60 mg  MOA: Promote release of NE, DA, 5-HT from nerve terminals  catecholamine in the synaptic (inhibit reuptake), inhibit the action of MAO Absorption: kidney, lungs & brain. High Vd Metabolism: deamination (inactive), B-hydroxylation (active) demethylation (methamphetamine become amphetamine) Excretion: urine metabolites or unchanged. Reabsorption depends on pH of the urine Effects: Euphoria, ↑ confidence, ↑ alertness, ↑ mental/physical abilities, improved self-esteem ( if withdrawal have opposite effects) ✓ The euphoria caused by amphetamine is 4-6 hr, which is 4-8 times longer than cocaine  ADRs: insomnia, dizziness, headache, confusion,  seizure (if have history of seizure), exacerbation of mixed/mania episodes in bipolar disorders ____________, ___________, ________, _________,_____, _____ bronchodilation, pulmonary edema, pulmonary hypertension, ↓ urine volume, new or worse behavior and thought problems Monitor: height, weight, symptoms improvement, mood worsening, CV Methamphetamines have stronger CNS action than amphetamine, but amphetamines have more potent effect than methamphetamine on cardiac ADRs such as : chest pain, BP, HR, MI may occur with overdose, tachycardia with PVC (premature ventricular contractions) MOA: Block NE and DA reuptake into presynaptic neurons, NE and DA release from nerve terminals, Inhibit the action of MAO  Indications: ADD/ADHD, narcolepsy (excessive sleepiness)  Unlabeled indication: depression in elderly and medically ill  Use with caution in bipolar, DM, HTN,  Should be taken 30-45 minutes before meal  Don’t take with alcohol. Less irritability, anxiety or anorexia effect than amphetamine  ADRs: same as methamphetamine  Monitor: height, weight Golan et al, 2012  Prodrug, Lisdexamfetamine =L-lysine-d-amphetamine that is converted to d- ampehtamine. ▪ Drug become active when metabolized in the GI tract that break down L lysine→ releasing the active drug, d-amphetamine ADR: BP BBW: serious cardiovascular sudden death, MI, stroke (in pts with preexisting cardiac problem) Advantages: less abuse potential, less drug blood level fluctuations, longer onset of effects, can’t be injected or snorted DDI: monoamine oxidase inhibitor (MAOI), opioid, sympathomimetics Need 14 days of wash out period after MAOI use Contraindication of using stimulants ✓ agitated states (may aggravate symptoms), ✓ cardiovascular disease, glaucoma, moderate to severe hypertension, and hyperthyroidism ✓ concomitant use with MAOI or within less than 14 days of use ( can cause hypertensive crisis ) Treatment of overdose amphetamine, methylphenidate, cocaine Hypertension: IV phentolamine or PO doxazosin Tachycardia: IV β-blocker or verapamil Hyperthermia: cooling blanket, dantrolene Seizures: IV diazepam or phenytoin Agitation: IV benzodiazepine (diazepam) Hydration: with IV fluids to prevent renal damage ADRS Management strategy Wt loss,  appetite Give high calorie meals Stomachache Give with meal,  dose Insomnia Give dose earlier in the day, consider giving guanfacine, clonidine , melatonin at bed times Rebound symptoms Use longer acting stimulant, atomoxetine, or anti-depressant HTN, pulse fluctuation  dose, change medication Hallucination d/c stimulant, reassess diagnosis, mood stabilizer or antipsychotic maybe needed Irritable Assess comorbid condition, mood stabilizer or antipsychotic maybe needed Dipiro et al, 2011 Tricyclic anti-depressants (TCA) ▪ Drugs: Imipramine, desipramine, nortriptyline ▪ MOA: inhibit 5 HT and NE reuptake, block M1, 1, H1 receptors ▪ Second line alternative for 10-20% of pts who are unresponsive to psychostimulants ▪ Maximal benefits are primarily observed in depressed or angry patients ▪ Potential for lethal overdose. Need for screening labs and EKG. ▪ ADRs: sedation, dizziness, constipation, heart block, weight gain Bupropion (Wellbutrin ®) MOA:  presynaptic release of NE and DA Use: antidepressant, smoking cessation, ADHD ADRs: anorexia, insomnia MOA: selectively inhibit re-uptake of norepinephrine  Does not exacerbate tics. Full effect may not be seen until 6-8 weeks  ADRs: ↓ appetite, nausea, ↓weight, somnolence,__________, ____________, fatique, mood changes, liver damage, ________________  DDI: MAOI, alcohol, 2 agonist, CNS depressants, CP2D6 inhibitor  Protein binding: 98%  Metabolism: hepatic via CYP2D6 and CYP2C19 (no dose adjustment in renal but adjustment in hepatic ) Excretion : urine 80%, feces 17%  t1/2: 5 hr, up to 24 hr in poor metabolizer of CYP2D6 17 BBW: risk of suicidal ideation of Atomoxetine (2 of 2) MOA: stimulate 2 in brain. In presynapse: inhibit NE release. In Postsynapse:  blood flow in prefrontal context (memory). ✓ Clonidine (Catapres ®, Kapvay®-ER ) t1/2- 12 hr ✓ Guanfacine (Tenex®, Intuniv®-ER)- longer acting; less sedating than clonidine t1/2 -18 hr ADR: sedation, hypotension (should be withdrawn slowly to avoid rebound HTN) bradycardia, HA, fatigue, tremor, sweating, anxiety ▪ Transdermal patches may enhance compliance. ▪ Pregnancy C Indication: ▪ Benefit in hyper-aroused pts, extremely overactive ,and pts with overactive or irritable, impulsive, aggressive conduct disorders ▪ Used at bedtime to counteract insomnia effects of stimulants. ▪ Tourette’s syndrome , tic disorder DDI: CYP3A4 substrate, inducer or inhibitor CYP2D6 inhibitor (paroxetine, fluoxetine) Need 14 days wash out period with MAOI  Condition of excessive daytime Drugs: sleepiness; sudden daytime “sleep 1. Dextroamphetamine, attacks” due to poor control of normal Methylphenidate sleep wake cycles.  The sleep attacks last a few seconds to 2. Modafinil, armodafinil several minutes.  Cataplexy (sudden loss of muscle tone) 3. Sodium Oxybate and sleep paralysis  Sleep quality is poor, but can fall asleep 4. H3 antagonist while at work, school or in the middle of conversation 5. Dopamine and norepinephrine reuptake  Treatment: psycho stimulants inhibitor (DNRI) MOA: mechanism unclear. May decrease GABA, not altering NE nor DA Methylphenidate or amphetamine: widespread CNS activation Modafinil works in discrete brain regions, with specific receptors  It is not a typical stimulant and is often described as a "wakefulness promoting agent“ to improve "alertness" and reducing excessive sleepiness, narcolepsy, sleep apnea  Off-label use for ADHD.  Class: IV ADR: rash can be life threatening, anxiety, headache, agitation, aggressive, confused, or excited, fever, nausea, vomiting, diarrhea chills, cough, sore throat, and body aches, mood or mental, changes, numbness, tingling, or burning pain in hands, arms, or feet Armodafinil (Nuvigil ®)- R isomer of modafanil- similar profile like modafinil MOA: derivative of GABA Indication: narcolepsy with cataplexy  Help with sleep at night, and use with stimulants during daytime This is “date rape” drug (CI, illicit use).  Require REMS program to unsure only used by pts- class: CIII Contraindication: sedative hypnotic, alcohol Warning: depression, suicide, psychosis, anxiety, sleep walking ADR: dizziness, confusion ,nausea MOA: Block histamine subtype 3  It works as inverse agonist Indications: adult patients with excessive daytime sleepiness associated with narcolepsy Contraindication: severe hepatic impairment ADRs: insomnia, nausea, anxiety, headache, and QT prolongation Harvey RA, Champe PC, 2012  MOA: dopamine and norepinephrine reuptake inhibitor (DNRI)  Indications: adult with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea  Contraindication: use with monoamine oxidase inhibitor (MAOI) or within 14 days of d/c  ADRs: headache, nausea,  BP and heart rate, anxiety, psychiatric symptoms,  appetite https://sunosihcp.com/mechanism-of-action 1) Straterra  (______________) is useful as ______________ stimulant, works by _______________. Can cause ____________, ________________, __________________, __________________, ________,  2) Clonidine (Catapres®, Kapvay ®) works as ______________, causing ________________. It cause ________ blood flow in cortex, thus _____ memory.  It is useful for ______________, _______________. Should be given at ______________. It can cause ____________, ___________, ___________ ✓ Dipiro et al. Pharmacotherapy: A Pathophysiologic Approach, 8th ed. 2011 ✓ RxPrep Course book NAPLEX 2020 edition. ✓ ADHD Practice Parameters. J Am Acad Child Adolesc Psychiatry. 1997;36:85S. ✓ Greenhill LL, et al. J Am Acad Child Adolesc Psychiatry. 1999;38:503-512. ✓ Various internet sources as cited ✓ Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 14th edition Editors: Brunton, Hilal-Dandan, Knollmann. Publisher: McGraw-Hill, 2023 ✓ Katzung BG et al. Basic & Clinical Pharmacology. 15th ed. 2021  FYI Wednesday, January 21, 2009 What children say about taking their ADD drugs “When I take my medication, it is like my teacher is in my head” “On my medicine I feel calm, without it I’m in hyperspace” “Before I was looking through a door that had frosted glass, but now it is all clear” https://www.youtube.com/watch?v= 5GBMS7WPFSs by: David Gutierrez, staff writer  A specific neuroanatomic, physiologic, biochemical or psychologic origin that has not been identified, despite extensive investigations o Boys are identified to have more of hyperactive-impulsive and inattentive type disorder in comparison to girls. Some have learning disabilities, neurological signs, or Tourette’s disorder. As they grow older can become OCD  75% of child / adolescent with ADHD cases continue to adulthood  Signs: Lack of social skills, unpopular, need to be first; Needs are imperative, now, can not wait; Problem in writing, reversal of letters  3 components of treatment: education interventions, psychosocial interventions, pharmacotherapeutic interventions ▪ Establish a treatment program that recognizes ADHD as a chronic condition ▪ Specify appropriate target outcomes to guide management ▪ Prescribe stimulant medication and/or behavior therapy to improve target outcomes in children with ADHD ▪ If the treatment program has not met target outcomes, evaluate: ✓ Original diagnosis ✓ Use of all appropriate treatments ✓ Adherence to the treatment plan ✓ Presence of coexisting conditions ▪ Using information from parents, teachers, and the child, follow-up to evaluate target outcomes and adverse effects Parent and Child Interviews ▪ Consider using DSM-IV symptoms checklist ▪ General Past Medical History with attention, from birth History , due to trauma ▪ ‘Onset’ before 7 years of age? ▪ Specific queries about Family History of ADHD, other psychiatric disorders, neurologic disorders and psychosocial adversity, Social History, Developmental History ▪ Medications ( RX, OTC, illicit substances), ▪ Parent completed rating scales; ▪ Target questions to ascertain 2 or more settings for functional impairment School-Related Assessment ▪ Obtain reports of behavior, learning, attendance, grades and test scores ▪ Psychoeducational testing is indicated to assess intellectual ability and to learning disabilities ▪ Teacher completed rating scales  DEX- dextroamphetamine  DMPH- dexmethylphenidate  MPH- methylphenidate  MXA-mixed amphetamine salt  TCA-tricyclic antidepressant Dipiro et al., 2011 1. Fish oil  Omega 3 FA  If use with evening primrose oil (omega 6 FA)- may improve cognitive function and behavior in children. Need to take 6 capsules 2. St. John’s wort  May inhibit reuptake of NE, DA, 5HT  DDI: CYP3A4 and CYP2C9 inducers 3. Ginkgo  May have neuroprotective effect  DDI: warfarin. ADRs: GI, HA, dizziness 4. S-adenosyl L methionine (SAMe)  Endogenous substance made from L-methionine and ATP produce in liver. May increase NE, DA, 5HT in brain  ADR: ND, heartburn, dry mouth