528 Unit 2 PNS CNS Agents - MARKY - npcourses.com Handout Samples/Advanced... · Peripheral and Central Nervous System Agents ... Autonomic Nervous System ... Unit 2 ©2014 Barkley

1

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


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

2


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”)


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

3

Unit 2 ©2014 Barkley & Associateshttp://www.yesselman.com/ans.jpg


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

4


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


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

5


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


Autonomic Nervous System (ANS) =

Sympathetic Nervous System (SNS) +

Parasympathetic Nervous System (PNS)

6


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


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

7


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


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)

8


Adrenergic Agents (Sympathomimetics - continued)


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


Adrenergic Blocking Agents (Sympatholytics/Sympathetic Antagonists)


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

9


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


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)

10


• 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)


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

11


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


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”

12


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)


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

13


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


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

14


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


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

15


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


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

16


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)


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

17


Psychopharmacology

Drugs for mental illness,

Depression, anxiety, insomnia


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

18


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)


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

19


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


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

20


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


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

21


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


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]

22


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


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

23


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


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)

24


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


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

25


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


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

26


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


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

27


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 (?)


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)

28


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


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

29


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


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

30


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


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

31


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 ??


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

32


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 (?)


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

33


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


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)

34


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


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

35


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)


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

36


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


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

37


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


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

38


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


The End

Documents

528 Unit 2 PNS CNS Agents - MARKY - npcourses.com Handout Samples/Advanced... · Peripheral and Central Nervous System Agents ... Autonomic Nervous System ... Unit 2 ©2014 Barkley