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Unit 2 ©2014 Barkley & Associates
Advanced Pharmacology:Peripheral and Central Nervous System Agents
and PsychopharmacologyThomas W. Barkley, Jr., PhD, ACNP‐BC, FAANP
President, Barkley & Associateswww.NPcourses.com
andProfessor of Nursing
Director of Nurse Practitioner ProgramsCalifornia State University, Los Angeles
Robert Fellin, PharmD, BCPSFaculty, Barkley & Associates
Pharmacist, Cedars‐Sinai Medical CenterLos Angeles, CA
Unit 2 ©2014 Barkley & Associates
Nervous System• Central Nervous System (CNS)Receives and processes information Brain Spinal cord
• Peripheral Nervous System (PNS)
Transmits signals between the CNS and the rest of the body
Motor and sensory neurons Somatic Nervous System
Autonomic Nervous System
• Sympathetic (SNS)
• Parasympathetic (PNS)http://www.livescience.com/27975-human-body-system-the-nervous-system-infographic.html
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Autonomic Nervous System (ANS)
Physiology Review:
• Activities are not under direct conscious control
• Responsible for cardiac and smooth muscle (e.g., respiratory tract) activity, digestion as well as glandular secretion
• Divided into:
• Sympathetic System• Activated under conditions of stress (“fight or flight”)
• Parasympathetic System• Activated under nonstressful conditions (“rest and digest”)
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Autonomic Nervous System EffectsSympathetic (SNS) Parasympathetic (PNS)
Pupils Dilates Constricts
Tear glands No effect Stimulates
Salivary stimulation Inhibits Stimulates
Heart rate Increases Decreases
Arterioles Constricts Dilates
Bronchi Dilation Constricts
GI motility Inhibits Stimulates
Pancreas Inhibits Stimulates
Bladder Relaxes Contracts
Erection/Ejaculation Stimulates ejaculation Stimulates erection
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Unit 2 ©2014 Barkley & Associateshttp://www.yesselman.com/ans.jpg
Unit 2 ©2014 Barkley & Associates
SNS and PNS: Physiology ReviewTwo-neuron chain:
1. Presynaptic nerve (CNS) synapses to postsynaptic nerve connects to tissue or an organ
2. Presynaptic and postsynaptic neurons
are connected to each other at the ganglion
Presynaptic nerve: from the CNS to the ganglia
Postsynaptic nerve: from the ganglia to the tissues
(both are necessary for autonomic neurotransmission)
http://shp.by.ru/spravka/neurosci/synapse.gif
www.uspharmacist.com
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Neurotransmission Review
1.Synthesis of neurotransmitters (NTs)
2.Packaging of NTs in nerve cell axon (stored in axon terminal)
3.Stimulation of presynaptic nerve (release of NT)
4.Diffusion of NT (across synapse binds to post-synaptic membrane)
5.Activation of post-synaptic cell
6.Degradation/reuptake of NT
http://people.eku.edu/ritchisong/301images/Neurotransmission.gif
Unit 2 ©2014 Barkley & Associates
Major Neurotransmitters of the Autonomic Nervous System
• Released by Sympathetic Nervous System:
• Norepinephrine (NE)
• Epinephrine (Epi)
• Released by Parasympathetic Nervous System:
• Acetylcholine (Ach)
• Key Pharmacological Implications:
• Agents that increase NT release
• Agents that decrease NT degradation
• Receptor agonists and/or antagonists
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SNS/PNS Anatomy and Receptor TypesSNS PNS
Anatomy Origins Thoracic and lumbar Cranial and sacral
Receptor Types α1, α2, β1, β2 Nicotinic and muscarinic
http://instruct.uwo.ca/anatomy/530/autcont.gif
Unit 2 ©2014 Barkley & Associates
Autonomic Nervous System (ANS) =
Sympathetic Nervous System (SNS) +
Parasympathetic Nervous System (PNS)
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Sympathetic Nervous System (SNS)Major Mediators• Catecholamines:
• Metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO)• Epinephrine (Epi) and Norepinephrine (NE)
• Sympathomimetic• Sympathetic agonists (similar to Epi or NE)
• Sympatholytic• Sympathetic antagonist (blocks the effects of Epi or NE)
• Dopamine (DA):• Endogenous NT with sympathetic characteristics• Works at DA, α and β1 receptor sites
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Stimulation of SNS ReceptorsReceptor Select Agonist Action and Uses Stimulation Effects
α1• Smooth muscle contraction
• Mydriasis during eye exams
• Treatment of:
• Nasal congestion
• Hypotension
• Vasoconstriction
• Pupil dilation
• ↓ Secretions
• ↓ GI motility
α2• Smooth muscle contraction +
NT inhibition
• Treatment of hypertension (activation of receptors reduces the release of NE)
• ↓ CNS sympathetic outflow
• ↓ NE release
• ↓ Insulin release
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Stimulation of SNS Receptors
Receptor Select Agonist Action and Uses Stimulation Effects
β1• Heart muscle contraction
• Treatment of:
• Cardiac arrest
• Heart failure
• Shock
• ↑ Heart rate
• ↑ Cardiac output (CO)
• ↑ Stroke volume (SV)
• ↑ Cardiac automaticity
• ↑ Cardiac contractility
• ↑ Renin secretion
β2• Smooth muscle relaxation
• Treatment of:
• Asthma
• Premature contractions of labor
• Bronchial relaxation
• Uterine relaxation
• Vasodilation to skeletal muscle vessels
Unit 2 ©2014 Barkley & Associates
Adrenergic Agents (Sympathomimetics)
Select Examples Receptor Subtype Major Uses
Albuterol (Proventil; Ventolin) β2 • Asthma
Isoproterenol (Isuprel) β1: (↑ heart rate,
↑ contractility)
β2: (vasodilation, bronchodilation)
• Asthma
• Dysrhythmias
• Heart failure
Salmeterol (Serevent) β2 • Asthma
Terbutaline (Brethine) β2 • Asthma
• Slow uterine contractions
Epinephrine (Adrenalin) α & β • Cardiac arrest (↑ heart rate)
• Anaphylaxis (bronchodilation)
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Adrenergic Agents (Sympathomimetics - continued)
Select Examples Receptor Subtype Major Uses
Dobutamine (Dobutrex) β1 • Cardiac Stimulant
Clonidine (Catapres) α2 in CNS • Hypertension
Oxymetazoline (Afrin) α • Nasal congestion
Pseudoephedrine (Sudafed) α > β • Nasal congestion
Dopamine (Intropin) α1 & β1 • Shock
Norepinephrine (Levophed) α > β1 • Shock (vasoconstriction and
↑ heart rate)
Phenylephrine (Neo-Synephrine)
α1 ,α2 • Shock (vasoconstriction; causes reflex bradycardia)
• Nasal congestion
Unit 2 ©2014 Barkley & Associates
Adrenergic Blocking Agents (Sympatholytics/Sympathetic Antagonists)
Select Examples Receptor Subtype Major Uses
Atenolol (Tenormin) β1 specific* • Angina
• Hypertension
Timolol (Timoptic) Blocks β1 & β2 • Angina
• Glaucoma (↓ intraocular pressure)
• Hypertension
Prazosin (Minipress) Blocks α1 • BPH
• Hypertension
Tamsulosin (Flomax) Blocks α1 • BPH
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Adrenergic Blocking Agents (Sympatholytics/Sympathetic Antagonists –
continued)Select Examples Receptor Subtype Major Uses
Esmolol (Brevibloc) β1 specific* • Tachyarrhythmias
• Hypertension
Propranolol (Inderal) Blocks β1 & β2 • Dysrhythmias ( ↓ heart rate)
• Heart failure
• Hypertension
Metoprolol (Lopressor) β1 specific* • Hypertension
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Physiology Review:• Classic parasympathomimetic: acetylcholine (Ach)• Acetylcholine will bind to 2 types of receptors:
1. Nicotinic (ganglia)2. Muscarinic (organs)
• After binding to and activating the receptor, Ach is broken down by the enzyme, acetylcholine esterase (AchE)
• AChE metabolizes Ach into:• Choline• Acetate
• Nerve terminals can then take choline and acetate and re-synthesize Ach
• Parasympathetic effects = “cholinergic” effects
ParasympatheticNervous System (PNS)
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• Drugs can mimic the parasympathetic nervous system by either:
• Directly binding (direct-acting) to acetylcholine receptors
• Inhibiting acetylcholine esterase (AchE) – the enzyme that breaks acetylcholine (Ach) down
ParasympatheticNervous System (PNS)
Unit 2 ©2014 Barkley & Associates
Clinical Effects of MuscarinicReceptor Stimulation
• ↓ Heart rate• ↑ Gastric motility• ↑ Urination• ↑ Sweating• ↑ Salivation• ↑ Nasal secretions• ↑ Bronchial secretions• ↑ Bronchoconstriction• Miosis
• Direct-acting cholinergics (parasympathomimetics) bind to cholinergic receptors and produce a “rest and digest” response
• Select examples of direct-acting muscarinic agonists:• Pilocarpine (Isopto Carpine) –
glaucoma treatment• Bethanechol (Urecholine) – urinary
retention treatment
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Cholinesterase Inhibitors
Select Examples Primary Use
Donepezil (Aricept) Alzheimer’s disease
Galantamine (Razadyne) Alzheimer’s disease
Physostigmine (Antilirium) Reverses effects of anticholinergics*
Edrophonium (Tensilon) Dx. of myasthenia gravis
Pyridostigmine (Mestinon) Myasthenia gravis
• Indirect-acting parasympathomimetics inhibit the action of AchE
• “Cholinesterase inhibitors”
*has not been found to be safe and effective; drug product labeling has not been approved by the FDA
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Cholinergic Blockers (Anticholinergics/Muscarinic Antagonists)• ↑ Heart rate• ↓ Gastric motility (irritable bowel syndrome) • ↓ Gastric acid secretion (peptic ulcer disease)• ↓ Urination (incontinence)• ↓ Sweating• ↓ Salivation (anesthesia)• ↓ Nasal secretions• ↓ Bronchial secretions (anesthesia)• ↓ Bronchoconstriction [ipratropium bromide (Atrovent) dilates the
bronchi]• Mydriasis• Anticholinergic patient symptoms: “Blind as a bat, dry as a bone, red
as a beet, mad as a hatter, and hot as a hare”
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Select Examples Primary UsesIpratropium bromide (Atrovent) COPD
Atropine Bradycardia, ↓ secretions for anesthesia, diarrhea, urinary incontinence, others
Dicyclomine (Bentyl) Irritable bowel syndrome (IBS)
Propantheline (Pro-Banthine) IBS, urinary incontinence, neurogenic bladder
Scopolamine (Transderm-Scop) Motion sickness
Benztropine (Cogentin) Parkinson’s disease
Trihexyphenidyl (Artane) Parkinson’s disease
Cholinergic Blockers (Anticholinergics/Muscarinic Antagonists)
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Treating Parkinson’s DiseasePathophysiology Review:• Caused by decreased dopamine (DA)
transmission• Cholinergic transmission begins to dominate in
the brain as DA transmission is decreased
• Classic triad of findings:1. Tremor2. Rigidity3. Bradykinesias
• Treated by either:• Increasing dopamine transmission OR• Blocking cholinergic neurotransmission
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Unit 2 ©2014 Barkley & Associates
Dopaminergic AgentsAgents: Carbidopa/levodopa (Sinemet), Levodopa (Dopar)
MOA: Metabolized to dopamine in the CNS; stimulates dopamine receptors
Adverse
Effects:
GI upset, arrhythmias, dyskinesias, on-off and wearing-off phenomena, confusion, dizziness, headache, hallucinations
Comments: Use with carbidopa greatly diminishes required dosageUse with COMT/MAO-B inhibitors prolongs duration of effectSinemet is available as immediate release and sustained release
Unit 2 ©2014 Barkley & Associates
Dopamine AgonistsAgents: Bromocriptine (Parlodel), pramipexole (Mirapex), ropinirole
(Requip)
MOA: Stimulates dopamine receptorAdverse
Effects:
Nausea, vomiting, postural hypotension, dyskinesias, confusion, impulse control disorders, sleepiness
Comments: Can be used as monotherapy (mild disease) or in combination with SinemetPramipexole: adjust dose for renal dysfunctionRopinirole: many drug-drug interactionsContraindicated in patients with a history of psychotic illness or recent MI or active peptic ulceration
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Monoamine Oxidase Inhibitors
Agents: Rasagiline (Azilect), selegiline (Eldepryl)
MOA: Inhibits MOA, slows/prevents the breakdown of dopamine
Adverse
Effects:
Orthostatic hypotension, rash, weight loss, GI upset, arthralgia, ataxia, dyskinesia, headache
Comments: Adjunct therapy onlyRasagiline is more potent than selegilineMay cause serotonin syndromeMany drug interactions: avoid meperidine, tramadol, methadone, propoxyphene, cyclobenzaprine, OTC’sSerotonin syndrome: avoid TCA’s, SSRI’s
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COMT InhibitorsAgents: Entacapone (Comtan), tolcapone (Tasmar)MOA: Prolongs the action of levodopa by diminishing its peripheral
metabolismAdverse
Effects:
Diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, orange discoloration of the urine
Comments: Adjunct therapy with levodopa onlyReduce dose of levodopa by 30% upon initiation of treatmentTolcapone: liver toxicity, requires signed patient consent, monitor LFT’sEntacapone available as combination product with carbidopa/levodopa = Stalevo
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Amantadine (Symmetrel)
MOA: Unclear; may potentiate dopaminergic function by influencing the synthesis, release or reuptake of dopamine
Adverse
Effects:
Restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, confusion, headache, heart failure, postural hypotension, urinary retention, anorexia, nausea, constipation, dry mouth
Comments: Less efficacious than levodopaBenefit is limited as duration of efficacy may last only few weeksReduce dose for renal impairmentMay cause Livedo reticularis
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Anticholinergic Agents
Agents: Benztropine (Cogentin), biperiden (Akineton), diphenhydramine (Benadryl), trihexyphenidyl (Artane)
MOA: Antagonizes the effect of acetylcholine; decreases the imbalance between the acetylcholine and dopamine
Adverse
Effects:
Sedation, nausea, constipation, dry mouth, blurred vision, drowsiness, dizziness, tachycardia, hypotension, nervousness, urinary retention
Comments: May improve tremor and rigidity; have little effect on bradykinesiaIncrease dose gradually until benefit occursTaper dose when withdrawing therapy
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Treating Alzheimer’s DiseasePathophysiology Review:• Most common cause of dementia• Etiology is unknown; but patients lose ability to perform tasks that require
acetylcholine (Ach) as the transmitter• Ach is the a major NT within the hippocampus (responsible for learning and
memory)
• Classic Findings:1. Multiple cognitive defects characterized by both memory impairment and
one or more of the following:2. Aphasia (difficulty with speech)3. Apraxia (inability to perform a previously learned task)4. Agnosia (inability to recognize an object)5. Inability to plan, organize, sequence and make abstract differences
• Treatment:• Acetylcholinesterase inhibitors (Parasympathomimetics)
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Treating Alzheimer’s Disease: Acetylcholinesterase Inhibitors
• Donepezil hydrochloride (Aricept)
• Galantamine (Razadyne)
• Rivastigmine (Exelon)
• Associated with weight loss• Available as a transdermal patch
• Memantine (Namenda) – immediate release tablets to be discontinued as of 8/2014
• Tacrine (Cognex) – Discontinued 5/2012
• Associated with hepatotoxicity
• Many drug-drug interactions• Clinical benefit is modest and temporary
*Most ALL have GI side effects:• Nausea• Vomiting• Diarrhea
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Psychopharmacology
Drugs for mental illness,
Depression, anxiety, insomnia
Unit 2 ©2014 Barkley & Associates
CNS NeurotransmittersPhysiology Review:• Central nervous system (CNS)
neurotransmitters (NTs) are synthesized in axon terminals
• After nerve stimulation, NTs are released
• NTs diffuse and combine with central receptors resulting in an “effect”
• NTs are “turned off” by reuptake and/or enzymatic inactivation
• Major CNS NTs important to psychopharmacology include NE, 5-HT, Ach, DA, GABA, among others
http://www.unisverse.org/UNIScienceNet/Synapse.jpg
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CNS Neurotransmitters - continuedSelect Examples Comments
Acetylcholine (Ach)2 • Role in ensuring smooth, initiated movement
• Assists with cognitive function and memory
• Kept in balance with dopamine
Dopamine (DA)1 • Role in thought processes
• Assists with movement
• Kept in balance with acetylcholine
Gamma-amino butyric acid (GABA)
• Inhibitory NT
• Causes relaxation
Norepinephrine (NE)1 • Role in mood and well-being
Serotonin (5-HT)1 • Role in mood and well-being
• Facilitates motor activity1 Metabolized by monoamine oxidase (MOA) and catechol-o-methyl transferase (COMT)2 Metabolized by acetylcholinesterase (AChE)
Unit 2 ©2014 Barkley & Associates
Psychosis
Psychosis:• Symptom or feature of mental illness characterized by radical changes
in personality, impaired functioning and a distorted sense of objective reality• Delusions: false beliefs or ideas strongly held in spite of
invalidating evidence• Hallucinations: hearing, seeing or feeling things that are not
actually there• Illusions: erroneous, false perception of reality• Paranoia: unfounded or exaggerated distrust of others
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Psychosis: Schizophrenia
• Type of psychosis• The most common psychotic disorder• Characterized by severely impaired thinking, emotions and
behaviors • Patients are typically unable to filter sensory stimuli• May have enhanced perceptions of sounds, colors and
other features of the environment• Eventually become withdrawn and unable to take care of
ADLs high suicide risk
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Schizophrenia – continuedPathophysiology Review:• Genetics? Family history often positive
• Overproduction or over-activity of dopaminergic pathways in the basal nuclei (area of the brain responsible for motor activity)
• Symptoms associated with dopamine type 2 (D2) receptors
• All antipsychotic drugs act by entering dopaminergic synapses and competing with dopamine
• By blocking most D2 receptors, antipsychotic drugs decrease schizophrenia symptoms
http://www2.csusm.edu/DandB/Images/Antipsychotics.gif
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Schizophrenia – continued
Pharmacologic Management:
• Treatment reduces symptoms but does not provide a cure
• Little difference in terms of efficacy of all antipsychotic drugs but patients may tolerate one drug better than another
• Treatment recommendations from schizophrenia Patient Outcomes Research Team (PORT) were published in 2009
• Antipsychotic Drug Categories:
1. Conventional (Typical) Antipsychotics
• Phenothiazines (“Neuroleptics”; though all antipsychotic drugs may be referred to by this term)
2. Atypical Antipsychotics
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Phenothiazines: Conventional (Typical) Antipsychotic Drugs
Agents: Chlorpromazine, (Thorazine), fluphenazine (Prolixin), mesoridazine (Serentil), perphenazine (Trilafon), thioridazine (Mellaril), trifluoperazine (Stelazine)
MOA: Blockade of dopamine receptors >> serotonin receptors
AdverseEffects:
Sedation, drowsiness, dizziness, extra-pyramidal symptoms, QTc prolongation, photosensitivity, orthostatic hypotension, urinary retention, tardive dyskinesia, neuroleptic malignant syndrome
Comments: All block the excitement associated with “positive”schizophrenia symptomsNot all phenothiazines are created equalMany drug-drug interactions
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Nonphenothiazines: Conventional (Typical) Antipsychotic Drugs
Agents: Haloperidol (Haldol), loxapine (Loxitane), thiothixene(Navane), pimozide (Orap)
MOA: Blockade of dopamine receptors >> serotonin receptors
AdverseEffects:
Extra-pyramidal symptoms, sedation, drowsiness, dizziness, QTc prolongation, orthostatic hypotension, urinary retention, tardive dyskinesia, neuroleptic malignant syndrome, tremor
Comments: Alleviate “positive” schizophrenia symptomsEqually effective as phenothiazinesLess sedating than phenothiazinesReduce dose in liver impairment
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Antipsychotics: Adverse Effects1. Extrapyramidal symptoms
• Dystonias (head and neck)• Akathisia
• Restless, compulsive movements; constant pacing, etc.• Pseudo-Parkinsonism • Haloperidol (Haldol) > Chlorpromazine (Thorazine) > thioridazine
(Mellaril)2. Anticholinergic effects
• Dry mouth, blurred vision, urinary retention, tachycardia• Chlorpromazine (Thorazine) = thioridazine (Mellaril) > haloperidol
(Haldol)• [Agents that cause the MOST EPS cause the LEAST anticholinergic
effects]
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Antipsychotics: Adverse Effects1. Tardive dyskinesia
• Uncontrolled, bizarre, involuntary movements of the tongue, face, lip smacking, puffing cheeks, etc. due to hypersensitivity of DA receptors
4. Orthostatic hypotension5. Sedation – due to blocked H1 receptors centrally
• Chlorpromazine (Thorazine) = thioridazine (Mellaril) > haloperidol (Haldol)
6. Sexual dysfunction7. Neuroleptic malignant syndrome8. Agranulocytosis
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Atypical AntipsychoticsAgents: Aripiprazole (Abilify), asenapine (Saphris), clozapine (Clozaril),
iloperidone (Fanapt), lurasidone (Latuda), olanzapine (Zyprexa), paliperidone (Invega), quetiapine (Seroquel), risperidone (Risperdal), ziprasidone (Geodon)
MOA: Blockade of serotonin receptors > blockade of dopamine receptors
AdverseEffects:
Tachycardia, sedation, dizziness, headache, light-headedness, somnolence, anxiety, hostility, insomnia, nausea, dry mouth, constipation, akathisia, extrapyramidal symptoms, neuroleptic malignant syndrome, QTc prolongation, weight gain, diabetes
Comments: Improves both positive and negative symptomsMuch less EPS vs. typical antipsychoticsFewer side effects compared to typical antipsychoticsClozapine: monitor CBC, Clozaril National Registry
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Atypical AntipsychoticsAgent Weight Gain Risk of DM Hyperlipidemia
Aripiprazole Low Low Low
Asenapine Low Low Low
Clozapine High High High
Iloperidone Moderate Low Moderate
Lurasidone Low Low Low
Olanzapine High High High
Quetiapine Moderate Moderate Moderate
Risperidone Moderate Moderate Moderate
Ziprasidone Low Low Low
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Antidepressants• Depression – mood state characterized by diminished interest in
normal activity, fatigue, feelings of sadness and impaired concentration nearly every day• Psychodynamic causes• Cognitive causes• Biochemical theories
• Antidepressants work by either:• ↑ NE or 5-HT in the synapse by blocking reuptake OR by• Inhibiting degradation of 5-HT or NE by inhibition of monoamine
oxidase (MAO)
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Selective Serotonin Reuptake Inhibitors (SSRIs)
Agents: Citalopram (Celexa), escitalopram oxalate (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), vilazodone (Viibryd)
MOA: Highly selective blockade of serotonin
AdverseEffects:
Nausea, dry mouth, insomnia, somnolence, headache, anxiety, GI disturbances, dizziness, anorexia, fatigue, sexual dysfunction, suicidal ideation, serotonin syndrome, SJS
Comments: Generally considered as first line therapyMany applications: OCD, anxiety, PTSD, othersWell tolerated, but many drug-drug interactionsBlack Box Warning: increased risk of suicidal thinking/behaviorOnset of effect: 4-6 weeks
Unit 2 ©2014 Barkley & Associates
Serotonin-norepinephrine Reuptake Inhibitors (SNRIs)
Agents: Duloxetine (Cymbalta), Desvenlafaxine (Pristiq), venlafaxine (Effexor)
MOA: Moderately selective blockade of norepinephrine and serotonin
AdverseEffects:
Insomnia, nausea, dry mouth, constipation, hypertension, dizziness, somnolence, sweating, agitation, blurred vision, headache, tremor, vomiting, drowsiness, increased appetite, orthostatic hypotension, sexual dysfunction, suicidal ideation, serotonin syndrome
Comments: Other applications: pain disorders, fibromyalgiaSeveral drug-drug interactionsBlack Box Warning: suicidal thinking/behaviorWithdrawal syndrome if stopped abruptlyOnset of effect: 4-6 weeks
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Serotonin AntagonistsAgents: Nefazodone (Serzone), trazodone (Desyrel)
MOA: Inhibition of serotonin receptorAdverseEffects:
Insomnia, nausea, dry mouth, constipation, dizziness, somnolence, sweating, agitation, blurred vision, headache, tremor, vomiting, drowsiness, increased appetite, orthostatic hypotension, sexual dysfunction, suicidal ideation, serotonin syndrome, QTc prolongation
Comments: Several drug-drug interactionsBlack Box Warning: suicidal thinking/behaviorWithdrawal syndrome if stopped abruptlyOther applications: insomnia (trazodone)Onset of effect: 4-6 weeks
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Atypical AntidepressantsAgents: Bupropion (Wellbutrin), mirtazapine (Remeron)
MOA: Enhances norepinephrine and dopamine activity
AdverseEffects:
Insomnia, nausea, dry mouth, dizziness, somnolence, sweating, agitation, blurred vision, headache, tremor, vomiting, drowsiness, weight gain, orthostatic hypotension, sexual dysfunction, suicidal ideation, serotonin syndrome, seizures
Comments: Several drug-drug interactionsBlack Box Warning: suicidal thinking/behaviorWithdrawal syndrome if stopped abruptlyBupropion lowers the seizure thresholdOnset of effect: 4-6 weeks
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Tricyclic Antidepressants (TCAs)Agents: Amitriptyline (Elavil), amoxapine (Asendin), desipramine
(Norpramin), doxepin (Sinequan), imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), trimipramine (Surmontil)
MOA: Mixed and variable blockade of norepinephrine and serotonin
AdverseEffects:
Dry mouth, constipation, urinary retention, blurred vision, sedation, confusion, arrhythmias, insomnia, nausea, dizziness, somnolence, sweating, agitation, headache, tremor, vomiting, drowsiness, weight gain, orthostatic hypotension, sexual dysfunction, suicidal ideation
Comments: Several drug-drug interactionsOther applications: pain disorders, fibromyalgiaBlack Box Warning: suicidal thinking/behaviorOnset of effect: 4-6 weeks
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Monoamine Oxidase Inhibitors (MAOIs)
Agents: Isocarboxazid (Marplan), phenelzine (Nardil)
tranylcypromine (Parnate)MOA: Blockade of MAO-A and MAO-BAdverseEffects:
Dry mouth, constipation, urinary retention, blurred vision, sedation, confusion, arrhythmias, insomnia, nausea, anorexia, drowsiness, orthostatic hypotension, sexual dysfunction, serotonin syndrome, suicidal ideation
Comments: Reserved for depression unresponsive to other agentsMany drug-drug and drug-food (tyramine: HTN crisis) interactionsBlack Box Warning: suicidal thinking/behaviorOnset of effect: 4-6 weeks
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Agents for Anxiety/Insomnia• Anxiety: unpleasant feeling of
dread, apprehension or tension resulting from an unexpected threat to one’s feeling of self esteem or well being; may be a symptom in many disorders
• Sedative (anxiolytic): agent should reduce anxiety and exert a calming effect
• Insomnia: inability to fall asleep or remain asleep
• Hypnotic: produce drowsiness; induce sleep
• Antihistamines:• OTC agents: diphenhydramine
• Beta blockers: reduce tachycardia and other symptoms
• Antidepressants• SSRI’s• TCA’s• MAOI’s
• Barbiturates• Rarely used
• Antipsychotics (?)• Anti-seizure agents
• valproic acid (?)
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BenzodiazepinesAgents: Alprazolam (Xanax), lorazepam (Ativan), diazepam
(Valium), oxazepam (Serax)
MOA: Intensify the effect of GABAAdverseEffects:
Drowsiness, sedation, lethargy, ataxia, confusion
Comments: Preferred agent for insomnia caused by anxiety
Many other applications: seizures, EtOH withdrawal, adjunct to anesthesia, nausea
Adjust dose for liver/renal dysfunction
Some agents have active metabolites
Antidote: flumazenil (Romazicon)
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Serotonin Receptor AgonistAgents: buspirone (Buspar)
MOA: unknown mechanism of action; exhibits high affinity for serotonin receptors, moderate affinity for dopamine receptors
AdverseEffects:
nausea, dizziness, nervousness, headache, somnolence, tachycardia, heart failure, MI, CVA
Comments: Many drug-drug interactionsSlow onset of action (14 days)Adjust dose for liver or renal impairmentNot a controlled substance
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Hypnotics
Agents: Eszopiclone (Lunesta), zaleplon (Sonata), zolpidem(Ambien)
MOA: Enhance the effect of GABAAdverseEffects:
Taste disturbances, vomiting, diarrhea, dizziness , headache, somnolence, visual disturbances, fatigue
Comments: Rapid onsetZaleplon/zolpidem: short term use only (FDA)Several drug-drug interactionsAdjust dose for liver impairmentControlled substance: schedule IV
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Melatonin Receptor Agonist
Agents: Ramelteon (Rozerem)
MOA: Activates MT1 and MT2 receptors
AdverseEffects:
Nausea, dizziness, fatigue, insomnia, somnolence, depression, worsening, hallucinations, mania
Comments: Several drug interactionsDoes not appear to produce residual effects, rebound insomnia or withdrawal syndrome with prolonged useNot a controlled substance
Unit 2 ©2014 Barkley & Associates
Psychopharmacology
General summary:
1. ↑ DA transmission ↓ Parkinsonism
2. ↑ Ach improvement in cognitive function
3. ↓ DA transmission ↓ psychoses
4. ↑ GABA receptor stimulation ↓ anxiety
5. ↑ NE & ↑ 5-HT ↑ mood
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Bipolar Disorder• Previously referred to as “manic-depressive” disorder
• Bipolar I disorder: manic or mixed episode +/- depression• Bipolar II disorder: depression episode shifting w/ hypomanic episode• Cylcothymic disorder: fluctuations between hypomania and mild depression
• Characterized by:• Extreme opposite mood shifts, alternating from depression to mania• Grandiosity or inflated self-esteem• Talkativeness; flight of ideas• Increased goal-directed activity
• Causative Theories• Unknown• Genetics• NT imbalances• Stress
Unit 2 ©2014 Barkley & Associates
Bipolar Disorder – PharmacotherapyAgents: Lithium (Eskalith, Lithobid)
MOA: Influences the release, synthesis and reuptake of dopamine, norepinephrine and serotonin
AdverseEffects:
Headache, lethargy, fatigue, recent memory loss, nausea, vomiting, anorexia, abdominal pain, diarrhea, dry mouth, muscle weakness, hand tremors, leukocytosis, nephrogenic diabetes insipidus
Comments: Many drug-drug interactionsMonitor drug levelsTarget range: 0.6-1.4 mEq/LReduce dose in renal impairmentSalt (Na) affects lithium reabsorption in the kidney
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Anti-seizure Agents
Agents: Carbamazepine (Tegretol), lamotrigine (Lamictal), valproic acid (Depakote)
MOA: Unknown; not fully understood
AdverseEffects:
Dizziness, ataxia, somnolence, headache, nausea, diplopia, blurred vision, sedation, drowsiness, nausea, vomiting, prolonged bleeding time, SJS, Toxic epidermal necrolysis, bone marrow suppression
Comments: Many drug-drug interactionsMonitor drug levels: carbamazepine/valproic acidFDA labeled for bipolarOther anti-seizure agents ??
Unit 2 ©2014 Barkley & Associates
Antipsychotic Agents
Agents: aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine(Seroquel), risperidone (Risperdal), ziprasidone(Geodon)
MOA: blockade of serotonin receptors > blockade of dopamine receptors
AdverseEffects:
tachycardia, sedation, dizziness, headache, light-headedness, somnolence, anxiety, hostility, insomnia, nausea, dry mouth, constipation, akathisia, extrapyramidal symptoms, neuroleptic malignant syndrome, QTc prolongation, weight gain, diabetes
Comments: Effective as monotherapy or adjunct therapy
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Attention Deficit – Hyperactivity Disorder (ADHD)
• Characterized by a persistent pattern of inattention and/or hyperactivity
• Developmentally inappropriate behaviors
• Difficulty paying attention or focusing on tasks
• CNS Stimulants: traditional drugs to treat ADHD in children
• Classic drug: methylphenidate (Ritalin)
• Stimulate areas of the CNS
• Heighten awareness and increase focus
• May cause paradoxical hyperactivity
• Non CNS Stimulants: atomoxetine (Strattera)
• Clonidine, Antidepressants (?)
Unit 2 ©2014 Barkley & Associates
PharmacotherapyCNS Stimulants Comments
Dextroamphetamine (Dexedrine)D-and L-amphetamine racemic mixture (Adderall) Methylphenidate (Ritalin)Pemoline (Cyclert)
• SE = nervousness, restlessness, insomnia, irritability, euphoria, palpitations, others
Non CNS Stimulant
Atomoxetine (Strattera)Guanfacine XR (Intuniv)
• Headache, GI complaints (N, V, pain, anorexia)
• Dizziness, abdominal pain, fatigue• Less effective as monotherapy
compared to CNS stimulants
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Drugs for Seizures
• Due to hyperactivity of electrical conduction in the brain• Variety of causes (epilepsy, tumors, inflammation, trauma, others)• International Classification of Epileptic Seizure Nomenclature:
• Partial (focal): simple and complex• Generalized: absence, atonic, tonic-clonic
• MOA for drugs: • Potentiate GABA• Suppress Na influx across membranes • Suppress Ca influx
Unit 2 ©2014 Barkley & Associates
Anti-seizure Drugs – GABA Potentiaters
Barbiturates• Amobarbital (Amytal)• Pentobarbital (Nembutal)• Phenobarbital (Luminal)• Primidone (Mysoline)• Secobarbital (Seconal)
Benzodiazepines• Chlorazepate (Tranxene)• Clonazepam (Klonopin)• Diazepam (Valium)• Lorazepam (Ativan)
• *Status epilepticus
Miscellaneous• Ezogabine (Potiga)• Gabapentin (Neurontin)• Pregabalin (Lyrica)• Tiagabine (Gabitril)• Topiramate (Topamax)• Vigabatrin (Sabril)
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Anti-seizure Drugs – Na Influx Suppressants
• Diminish CNS activity by delaying an influx of Na across neuronal membranes
• Na channels are desensitized (not completely blocked)
• Hydantoins and Phenytoin-like Drugs
Unit 2 ©2014 Barkley & Associates
Anti-seizure Drugs – continued Hydantoins:• Fosphenytoin (Cerebyx)• Phenytoin (Dilantin)
• Requires loading dose• May cause toxicity r/t saturating
enzymes responsible for its metabolism
• Toxicity:• Sedation• Nystagmus• Ataxia• Hyperplasia• Stevens-Johnson syndrome/rashes• Peripheral neuropathy• Others
Phenytoin-like Agents:• Carbamezapine (Tegretol)• Felbamate (Felbatol)*• Lamotrigine (Lamictal)• Levetiracetam (Keppra)• Rufinamide (Banzel)• Valproic acid (Depakote)• Zonisamide (Zonegran)Other:• Lacosamide (Vimpat)
*not administered until a complete discussion of the risks; patient/ parent/guardian & the physician sign acknowledgment form
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Anti-seizure Drugs – Calcium Influx Suppressants
• Succinimides delay entry of Ca into neurons by blocking Ca channels, increasing the electrical threshold and reducing the likelihood that an action potential will be generated
• By raising the seizure threshold, succinimides keep neurons from firing too quickly, thus suppressing abnormal foci
• Generally, only effective against absence seizures• Succinimides:
• Ethosuximide (Zarontin)
• Methsuximide (Celontin)
Unit 2 ©2014 Barkley & Associates
Anti-seizure Drug Therapy1. Start with one drug
2. Increase dose until clinical effect or toxicity
3. Add a second drug, as needed
• Combination therapy
4. If able to discontinue, always taper
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Neuromuscular Disorders• Damage to the motor area of the cerebral cortex that controls
movement Stroke, spinal injury/trauma, neurodegenerative diseases,
dystonia• Muscle Spasms: involuntary contraction of the muscle or muscle
groups• Spasticity: continuous state of contraction of certain muscle groups• Pharmacologic therapy: Skeletal muscle relaxants, antispasmodics Neuromuscular blocking agents
Unit 2 ©2014 Barkley & Associates
Skeletal Muscle RelaxantsIndications: Muscle spasm, spasticity
Agents: Baclofen (Lioresal), carisoprodol (Soma), methocarbamol(Robaxin), tizanidine (Zanaflex)
MOA: Not fully understood; inhibits motor neurons within the CNS/spinal cord
Adverse
Effects:
Drowsiness, dizziness, dry mouth, sedation, ataxia, light-headedness, urinary retention, hypotension, bradycardia
Comments: Use lower initial dose in geriatrics
Reduce dose for liver or renal impairment
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Direct-acting AntispasmodicsIndications: Muscle spasm, spasticityAgents: OnabotulinumtoxinA (Botox, Dysport)
dantrolene (Dantrium)MOA: OnabotulinumtoxinA: blocks the release of acetylcholine from
cholinergic nerve terminalsdantrolene: interferes with the release of calcium in skeletal muscle
Adverse
Effects:
OnabotulinumtoxinA: anaphylaxis, headache, dysphagia, ptosis, local muscle weakness, pain, muscle tendernessdantrolene: muscle weakness, dizziness, hepatic necrosis
Comments: OnabotulinumtoxinA max dose: do not exceed 360 units in a 3-month interval; Botulinum toxin products are not interchangeableDantrolene max dose: 100 mg 4 times a day; monitor LFT’s
Unit 2 ©2014 Barkley & Associates
Neuromuscular Blocking AgentsIndications: facilitate intubation, prolonged relaxation for surgical
procedures, ease ventilationAgents: atracurium (Tracrium), cisatracurium (Nimbex), pancuronium
(Pavulon), rocuronium (Zemuron), vecuronium (Norcuron)
MOA: competitive antagonist at acetylcholine receptors, especially at neuromuscular junctions
Adverse
Effects:
apnea, cardiac arrest, cardiac dysrhythmia, hyperkalemia, hypersensitivity reaction, prolonged neuromuscular block, respiratory depression, rhabdomyolysis
Comments: Monitor: TOFAdjust dose for liver or renal impairmentNot all NMBA’s are alikeAdjunct therapy: prophylaxis for DVT, corneal abrasion decubitus ulcers
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Select Examples Onset Duration
Depolarizing:
Succinylcholine (Anectine) 30-60 sec 3-5 mins
Non-depolarizing:
Atracurium (Tracrium) 90 sec 30 mins or less
Cisatracurium (Nimbex) 60-90 sec 25-45 minutes
Pancuronium (Pavulon) 90 sec 90-100 mins
Rocuronium (Zemuron) 75 sec 45-70 mins
Vecuronium (Norcuron) 60 sec 30-40 mins
Neuromuscular Blocking Agents
Unit 2 ©2014 Barkley & Associates
The End