CNS Lecture

8/3/2019 CNS Lecture

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Central Nervous System Agents

Chapters 6-24 and 27 in Goodman and Gilman(Look up each drug individually in the index)

Pp. 336 - 516 in Basic & Clinical Pharmacology by Katzung



I ntroduction - CNS

CNS = Central Nervous SystemBrain + Spinal ChordParallels Autonomic Nervous System

Not just Norepinephrine & AcetylcholineProblem: Numerous pathways use sameneurotransmitter!

Manipulating a diseased pathway also affectshealthy pathwaysCNS drugs NOTOR I OUS for causing side effects!



I ntroduction - CNS

Don t confuse CNS with the PNSPNS = Peripheral Nervous System

PNS Autonomic involuntary (i.e. cardiac & smooth muscle)

Sympathetic Fight or FlightParasympathetic

Somatic voluntary (i.e. skeletal muscle)

Pain & TouchPNS discussed in Pharmacology (Culver)



I ntroduction - CNS

SYMPATHETI C PARASYMPATHETI C

F rom: Clinical Pharmacology Made Ridiculously Simple, 2nd Ed., James Olson, MD, PhD.



Neurotransmitters - Brain

Monoamines (Catecholamines)Norepinephrine sympathetic transmitterDopamine

5-hydroxytryptamine (5-HT or Serotonin) Adrenergic : Refers to neurons that use catecholamines asneurotransmitters at a synapse when a nerve impulsepasses i.e. sympathetic fibers.

Acetylcholine parasympathetic transmitter

Gamma-amino butyric acid (GABA) - inhibitoryExcitatory amino acids (EAA) - glutamateOpioidsOther talk about as they come up.



Norepinephrine

1. a.a. tyrosine isconverted to L-dopawhich is thenhydroxylated toDopamine

&-hydroxylase convertsdopamine to norepi

3. Norepi release ± Ca 2+

4. Receptor binding (Alsosee #5 #7)

8. Catechol O-methyltransferase degradescatecholamines

9. Reuptake intopresynaptic neuron

10. Repackaging11. Degraded by

mitochondrial MAO12. Path for indirect

sympathomimetics

H O

H O

NH 2

OH

Catechol

amine



Dopaminergic Receptors

Storage vesicles

Dopamine

Postsynaptic Receptors

NH 2H O

H O

dopamine

Reuptake



Serotonin 5-HT

Tryptophan is hydroxylated anddecarboxylated to form 5-HTI n Neurons 5-HT is:

Stored in vesiclesReleasedTaken up by pre -synaptic neuronsRecycled or metabolized

5-HT released by inhibitory neuronsStimulates 5-HT 1, 5-HT 2, or 5-HT 3receptors

Antagonists: Depression, Attention Deficit Disorder (ADD), headaches, and nausea

NH 2

NH

H O

5-hy drox ytr y ptamine



Acetylcholine O N +

O

ace tylcholine

1. Choline acetyltransferasecatalyzes formation of

acetylcholine from choline andacetyl CoA

2. Storage in vesicles3. Ca 2+ stimulated release4. Receptor binding

Nicotinic

Muscarinic - CNS9. Reuptake and hydrolysis by

acetylcholine esterase10. Breakdown products recycled



Cholinergic Antagonists used primarilyto treat Parkinson s Disease .

Correct imbalance of acetylcholine anddopamine neurotransmissionI mbalance produced by degredation of dopaminergic nerves

No other major uses!

Acetylcholine



GABAI nhibitory amino acidSynthesized from glutamateStored in presynaptic vesicles for releaseBinds to GABA-A or GABA-B receptors

Receptors reside on two subunits of a four subunit complexThis regulates a chloride ion channel

GABA activation stimulates chloride influxHyperpolarizes the neuronMakes it more difficult to stimulate the neuron with excitatoryneurotransmitters

Benzodiazepines enhance GABA-A receptors ONLY!GABA enhancers (benzodiazepines, barbiturates ) used:

AnxietySeizures

Act as sedatives or muscle relaxants

O

O H

H 2 N

g amma aminobu tyric acid



Excitatory Amino Acids - EAAGlutamate and othersStimulation of EAA receptors increases cationconductance

I mportant in learning, memory, etc.Glutamate-induced toxicity implicated in

Alzheimer sHuntington s

StrokeEpilepsy

Amyotrophic Lateral Schlerosis (ALS)Drugs target decrease in glutamate toxicity

Riluzole - Rilutek ®



Opioiates & Opioids

Opiate receptors located along theperiaquiductal gray matterOpiate Receptor Agonists:

EndorphinsEnkephalinsDynorphins

Morphine and related compounds act on opiate receptors to relieve painI n times of stress & pain, endogenouspeptides act on opiate receptors



Sympathomimetic Actions

Direct

I ndirect

Mixed



Scheduled DrugsSchedule I

Drugs with a high abuse risk. These drugs have NO safe, acceptedmedical use in the United States.Ex. heroin, marijuana, LSD, PCP, and crack cocaine

Schedule II

Drugs with a high abuse risk, but also have safe and acceptedmedical uses in the United States. These drugs can cause severepsychological or physical dependence.Ex. morphine, cocaine, oxycodone (Percodan®), methylphenidate(Ritalin®), and dextroamphetamine (Dexedrine®)

Schedule III - VDrugs categorized as "prescription drugs . Schedule III drugs havesome potential for abuse, but less than I and II . The potential forabuse of Schedule IV drugs is less than Schedule III , and Schedule V is less than IV .Ex. acetaminophen with codeine (Tylenol® No.3), paregoric,hydrocodone with acetaminophen ( Vicodin®), diazepam( Valium®), alprazolam (Xanax®), propoxyphene (Darvon®), andpentazocine (Talwin®).



N

NN

N

O

O

CH 3

CH3

CH3

Caffeine

NoDoz® - 100-200 mg tablets, chewables and injectable

Indications: fatigue, drowsiness, adjunctive in analgesicpreparations, respiratory depression (injection), actopicdermatitis, obesity in combo with ephedrine, headache,treatment of excited or comatose alcoholic patients,postprandial hypotension

MOA: non-selective antagonist of adenosine receptors,increased cAMP via phosphodiesterase inhibition

Analeptics PNS stimulant

Can cause seizures in a dose-dependant manner!!!



& -Adrenergic Pathway:Second Messengers



SNH 2

OO

Modafinil - Provigil ®

Indications: Narcolepsy (p. 240 G&G)MOA: Unknown, similar tosympathomimetic agents

Racemic drug with differing half lives - oneenantiomer has 3X lifetime of others

Analeptics PNS stimulant

NO

NO

CH 3

HCl

Doxapram HCl - Dopram ®

Indications: postanesthesia drug inducedrespiratory depression or apnea due to drugsother than muscle relaxants, stimulation of druginduced CNS depression, COPD associated withacute hypercapnia (CO 2) , apnea of prematurity

MOA: stimulates peripheral carotid chemoreceptors ² increases tidal volume andrespiration rate, as dose is increased medullaryrespiratory centers are stimulated

Can cause seizures in a dose-dependant manner!!!



CNS Stimulants:Amphetamines

Simplest is 1-phenyl-2-aminopropaneCNS stimulant, anorectic, sympathomimetic actionsI ndications: ADHD (attention deficit hyperactivity disorder, narcolepsy)MOA: indirect-acting dopaminergic & noradrenergic agonist

Enhances release and prevents re-uptake of dopamineCan be attenuated by dopamine antagonists (chlorpromazine, haloperidol)

CNS effects: increased arousal and wakefulness mood alteration-increased confidence, ability to concentrate, exhilaration, euphoria;increased motor activity, anorexia, insomniaProlonged exposure can cause amphetamine psychosis

CH 3

NH3+H S O 4-

Racemic Amphetamine Su lfate

Dextroamphetamine Su lfate - Dexedrine ®

: Adderall ®



Dopaminergic Receptors

Storage vesicles

Dopamine

Postsynaptic Receptors

A mphetamines & Cocaine enhance release A ND hinder dopamine reuptake!

Enhances release



Amphetamines

Structure-Activity relationshipsFew derivatives retain pharmacologic activity.Fewer retain potency!Classes:

Aryl substitutionDeactivates CNS action

Amine substitution MOST AGENTS!Potency 1º> 2º> 3ºI ncrease in substituent size decrease in activity

Substitution at the E-carbonLoss or decrease in activity

Substitution at the K-carbonEphidrine & Pseudoephidrine are

F-hydroxyamphetamines

CH3

NH2

K-carbonR



CNS effects: increased arousal andwakefulness mood alteration-increasedconfidence, ability to concentrate,exhilaration, euphoria; increased motor activity, anorexia, insomnia

CV effects - similar to sympathomimeticamines

NO LONGER indicated for obesity andas an antidepressant due to highaddiction potential and CV side effects

Problems: addiction and tolerance, toxicpsychosis

Underlying psychosis, hypertension,angina, hyperthyroidism can beaggravated

Amphetamines

CH 3

NH2+HCl-CH 3

Methamphetamine HCl - Desoxyn ®

A mine substitution



CNS effects: increased arousal andwakefulness mood alteration-increasedconfidence, ability to concentrate,exhilaration, euphoria; increased motor activity, anorexia, insomnia

CV effects - similar to sympathomimeticamines: E-adrenergic effects

Indications: Decongestant

E phidrine MOR E effective thanpseudoephidrine. Pseudoephidrine

given to reduce side-effectsCAUTION: Use carefully with patientswith enlarged prostate, hypertension, or on MAO inhibitors

AmphetaminesCH 3

NHCH 3

OH

CH 3

NHCH 3

HO

Ephidrine Pse u doephidrine

Substitution at the K-carbon



NH

HOCH 3O

Methylphenidate - Ritalin ®

ON

NH 2

O

Pemoline - Cylert ®

Indications: ADHD , narcolepsy; unlabeled uses ± treatmentof depression in elderly, cancer and post-stroke patients, post-anesthesia related hiccups

MOA: mild CNS stimulant similar to amphetamines but withan unknown mechanism

Patient info: Take last dose prior to 6 pm to avoid insomnia,do not crush or chew SR products

NEW for 2002: Focalin ® ± dexmethylphenidate ± the (R,R¶)-(+) diastereomer that is more pharmacologically active

Indications: AD H D, narcolepsy ± 2 nd line agent

MOA: mild CNS stimulant similar to amphetamines butminimal sympathomimetic effects - may potentiatedopaminergic mechanisms

Patient info: Take single daily dose in the morning (insomnia)

Long-term effects of these drugs on children CNSdevelopment UNKNO W N!

Life threatening hepatic failure!

Amphetamine-like Drugs



-Cl+ H 2NO

Amphetamine-like Drugs

A tomoxetine hydrochloride - Strattera®

Indications: ADHD

MOA: Still under investigation. Thought to be a norepinephrinereuptake inhibitor . Increases the available stores of norepinephrinebelieved necessary for regulation of impulse control.

NEW for 2003 - First demonstrated effective in both adults and children

Metabolized extensively by CYP2D6 (7% caucasion, 2% AA slow met.)

Side effects: Dry mouth (21%), insomnia (16%), nausea (12%),dizziness (6%) + others.



Indications: short-term adjunct used in conjunction with caloricrestriction for exogenous obesity (< 8-12 weeks recommended)

MOA: S tim u late the satiety center in the hypothalamic and limbicregions of the brain prod u cing a loss of appetite

Two classes:

1. Amphetamine like analogs ± phenethylamines

2. Non-phenethylamines

Patient information: Best if taken on an empty stomach (exceptmazindol which can be taken with food to prevent GI upset), avoid

taking medication late in the day to avoid insomnia, do not crush or chew. NOT E : tolerance will occur if taken too frequently

Can produce psychological disturbances due to caloric restrictions:can lead to psychosis indistinguishable from schizophrenia, canlower seizure thresholds, NOT recommended if CV disease present- monitor BP in hypertensive patients continually

Anorexiants



CH 3

N CH 3

Benzphetamine HCl - Didrex ®

HCl

CH 3

N

CH 3

CH 3

O

HCl

Diethylpropion HCl - Ten u ate ®

25 and 50 mg tablets 1-3 times dailydepending on response

S hort-term weight loss

25 mg tablet tid one hour before

meals and midevening to overcomenight hunger if necessary

75 mg SR tablet once daily inmidmorning

Short-term weight loss

Anorexiants Amphetamine-like

A mine substitution



Dosing 8 mg tid 30 minutes prior to meals or 15 to 37.5mg as a single dose before breakfast or 10-14 hoursbefore sleeping

Recommended for obese patients based on body massindex (BMI = W eight (kg)/ H eight (# meters squared)):

>30 kg/meter sq or >27 kg/meter square in the

presence of other risk factors such as hypertension,diabetes, dyslipidemias

MOA: re u ptake inhibition of norepinephrine,serotonin, dopamine via metabolites of this dr u g

Monitor BP in hypertensive patients, dependence

possible, MD must be informed of any OTC¶s

CH 3CH3

NH3+Cl-

Phentermine - Ionamin ® , Fastin ® ,Zantryl ® , others

Cl

N

CH3

CH3

CH3

CH 3

S ib u tramine HCl - Meridia ®

Substitution at the E-carbon

Anorexiants Amphetamine-like



1 and 2 mg tablets 1-3 timesdaily depending on response

Take with meals to avoid GIdiscomfort

35 mg tablet or capsule bid or tid one hour before meals

105 mg SR capsule in themorning before breakfast

NN

OH

Cl

NHN

O

Cl

Mazindol - Mazanor ® , S anorex ®

NO

CH3CH3 H

Phendimetrazine tartrate - Plegine ® ,Bontril ® , Adipost ® , Dital ® , others

Anorexiants: Non-phenylethylamines

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CNS Lecture

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