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

Introduction - CNS


CNS = Central Nervous System

  

Brain + Spinal Chord Parallels Autonomic Nervous System Not just Norepinephrine & Acetylcholine

Problem: Numerous pathways use same neurotransmitter!



Manipulating a diseased pathway also affects healthy pathways CNS drugs NOTORIOUS for causing side effects!

Introduction - CNS


Don t confuse CNS with the PNS



PNS = Peripheral Nervous System Autonomic

 

PNS


involuntary

(i.e. cardiac & smooth muscle)

Sympathetic Fight or Flight Parasympathetic

Somatic


voluntary

(i.e. skeletal muscle)

Pain & Touch

PNS discussed in Pharmacology (Culver)

Introduction - CNS

SYMPATHETIC

PARASYMPATHETIC

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

Neurotransmitters - Brain


Monoamines (Catecholamines)
   

Norepinephrine sympathetic transmitter Dopamine 5-hydroxytryptamine (5-HT or Serotonin) Adrenergic: Refers to neurons that use catecholamines as neurotransmitters at a synapse when a nerve impulse passes i.e. sympathetic fibers.

    

Acetylcholine parasympathetic transmitter Gamma-amino butyric acid (GABA) - inhibitory Excitatory amino acids (EAA) - glutamate Opioids Other talk about as they come up.

OH HO NH2

Norepinephrine
1. a.a. tyrosine is converted to L-dopa which is then hydroxylated to Dopamine &-hydroxylase converts dopamine to norepi Norepi release Ca2+ Receptor binding (Also see #5 #7)

amine
HO

Catechol

 3. 4.

8.

Catechol O-methyl transferase degrades catecholamines 9. Reuptake into presynaptic neuron 10. Repackaging 11. Degraded by mitochondrial MAO 12. Path for indirect sympathomimetics

Dopaminergic Receptors
HO

Storage vesicles

HO

NH2

dopamine

Dopamine Reuptake

Postsynaptic Receptors

HO

Serotonin


5-HT

NH2

Tryptophan is hydroxylated and N H decarboxylated to form 5-HT 5-hydroxytryptamine In Neurons 5-HT is:
   

Stored in vesicles Released Taken up by pre-synaptic neurons Recycled or metabolized

 

5-HT released by inhibitory neurons Stimulates 5-HT1, 5-HT2, or 5-HT3 receptors Antagonists: Depression, Attention Deficit Disorder (ADD), headaches, and nausea

Acetylcholine
O

N+

acetylcholine

1.

Choline acetyltransferase catalyzes formation of acetylcholine from choline and acetyl CoA 2. Storage in vesicles 3. Ca2+ stimulated release 4. Receptor binding Nicotinic Muscarinic - CNS 9. Reuptake and hydrolysis by acetylcholine esterase 10. Breakdown products recycled

Acetylcholine


Cholinergic Antagonists used primarily to treat Parkinson s Disease.



Correct imbalance of acetylcholine and dopamine neurotransmission Imbalance produced by degredation of dopaminergic nerves No other major uses!

GABA
   

H2N OH

gamma aminobutyric acid Inhibitory amino acid Synthesized from glutamate Stored in presynaptic vesicles for release Binds to GABA-A or GABA-B receptors
 

Receptors reside on two subunits of a four subunit complex This regulates a chloride ion channel Hyperpolarizes the neuron Makes it more difficult to stimulate the neuron with excitatory neurotransmitters

GABA activation stimulates chloride influx

 

 

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

Anxiety Seizures Act as sedatives or muscle relaxants

Excitatory Amino Acids - EAA

 

 

Glutamate and others Stimulation of EAA receptors increases cation conductance Important in learning, memory, etc. Glutamate-induced toxicity implicated in
    

Alzheimer s Huntington s Stroke Epilepsy Amyotrophic Lateral Schlerosis (ALS) Riluzole - Rilutek

Drugs target decrease in glutamate toxicity



Opioiates & Opioids



Opiate receptors located along the periaquiductal gray matter Opiate Receptor Agonists:
  

Endorphins Enkephalins Dynorphins

Morphine and related compounds act on opiate receptors to relieve pain In times of stress & pain, endogenous peptides act on opiate receptors

Sympathomimetic Actions
Direct

Indirect

Mixed

Scheduled Drugs


Schedule I
 

Drugs with a high abuse risk. These drugs have NO safe, accepted medical use in the United States. Ex. heroin, marijuana, LSD, PCP, and crack cocaine Drugs with a high abuse risk, but also have safe and accepted medical uses in the United States. These drugs can cause severe psychological or physical dependence. Ex. morphine, cocaine, oxycodone (Percodan), methylphenidate (Ritalin), and dextroamphetamine (Dexedrine) Drugs categorized as "prescription drugs . Schedule III drugs have some potential for abuse, but less than I and II. The potential for abuse 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), and pentazocine (Talwin).

Schedule II


Schedule III - V


Analeptics
O H3 C O N

PNS stimulant

NoDoz - 100-200 mg tablets, chewables and injectable

CH3 N

N N CH3 Caffeine

Indications: fatigue, drowsiness, adjunctive in analgesic preparations, respiratory depression (injection), actopic dermatitis, 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

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

&-Adrenergic Pathway:Second Messengers

Analeptics
O N
O

PNS stimulant

HCl
N CH3

Indications: postanesthesia drug induced respiratory depression or apnea due to drugs other than muscle relaxants, stimulation of drug induced CNS depression, COPD associated with acute hypercapnia (CO2) , apnea of prematurity MOA: stimulates peripheral carotid chemoreceptors increases tidal volume and respiration rate, as dose is increased medullary respiratory centers are stimulated Indications: Narcolepsy (p. 240 G&G)

Doxapram HCl - Dopram

S O

NH2 O

MOA: Unknown, similar to sympathomimetic agents Racemic drug with differing half lives - one enantiomer has 3X lifetime of others

Modafinil - Provigil

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

CNS Stimulants:Amphetamines
CH3 NH3+HSO4-

Racemic Amphetamine Sulfate : Adderall Dextroamphetamine Sulfate - Dexedrine

   

Simplest is 1-phenyl-2-aminopropane CNS stimulant, anorectic, sympathomimetic actions Indications: ADHD (attention deficit hyperactivity disorder, narcolepsy) MOA: indirect-acting dopaminergic & noradrenergic agonist
 

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

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

Dopaminergic Receptors

Storage vesicles

Enhances release Dopamine

Postsynaptic Receptors

Amphetamines & Cocaine enhance release AND hinder dopamine reuptake!

Amphetamines
K-carbon R

CH3

NH2
   

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


Aryl substitution


Deactivates CNS action

Amine substitution
 

MOST AGENTS!
decrease in activity

Potency 1> 2> 3 Increase in substituent size Loss or decrease in activity

Substitution at the E-carbon



Substitution at the K-carbon



Ephidrine & Pseudoephidrine are F-hydroxyamphetamines

Amphetamines
CH3 NH2+HClCH3

Methamphetamine HCl - Desoxyn

CNS effects: increased arousal and wakefulness mood alteration-increased confidence, ability to concentrate, exhilaration, euphoria; increased motor activity, anorexia, insomnia CV effects - similar to sympathomimetic amines NO LONGER indicated for obesity and as an antidepressant due to high addiction potential and CV side effects Problems: addiction and tolerance, toxic psychosis Underlying psychosis, hypertension, angina, hyperthyroidism can be aggravated

Amine substitution

Amphetamines
CH3 NHCH3 OH HO CH3 NHCH3

CNS effects: increased arousal and wakefulness mood alteration-increased confidence, ability to concentrate, exhilaration, euphoria; increased motor activity, anorexia, insomnia CV effects - similar to sympathomimetic amines: E-adrenergic effects Indications: Decongestant Ephidrine MORE effective than pseudoephidrine. Pseudoephidrine given to reduce side-effects CAUTION: Use carefully with patients with enlarged prostate, hypertension, or on MAO inhibitors

Ephidrine

Pseudoephidrine

Substitution at the K-carbon

Amphetamine-like Drugs
HN CH3O OH Methylphenidate - Ritalin

Indications: ADHD, narcolepsy; unlabeled uses treatment of depression in elderly, cancer and post-stroke patients, postanesthesia related hiccups MOA: mild CNS stimulant similar to amphetamines but with an 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
O N O NH2 Cylert

Indications: ADHD, narcolepsy 2nd line agent MOA: mild CNS stimulant similar to amphetamines but minimal sympathomimetic effects - may potentiate dopaminergic mechanisms Patient info: Take single daily dose in the morning (insomnia) Long-term effects of these drugs on children CNS development UNKNOWN! Life threatening hepatic failure!

Pemoline -

Amphetamine-like Drugs
O -Cl+H2N

Atomoxetine hydrochloride - Strattera

Indications: ADHD MOA: Still under investigation. Thought to be a norepinephrine reuptake inhibitor. Increases the available stores of norepinephrine believed 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.

Anorexiants
Indications: short-term adjunct used in conjunction with caloric restriction for exogenous obesity (< 8-12 weeks recommended) MOA: Stimulate the satiety center in the hypothalamic and limbic regions of the brain producing a loss of appetite Two classes: 1. 2. Amphetamine like analogs phenethylamines Non-phenethylamines

Patient information: Best if taken on an empty stomach (except mazindol 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. NOTE: tolerance will occur if taken too frequently Can produce psychological disturbances due to caloric restrictions: can lead to psychosis indistinguishable from schizophrenia, can lower seizure thresholds, NOT recommended if CV disease present - monitor BP in hypertensive patients continually

Anorexiants
CH3 N CH3

Amphetamine-like
25 and 50 mg tablets 1-3 times daily depending on response Short-term weight loss

HCl

Benzphetamine HCl - Didrex

Amine substitution
O
CH3 N

HCl

CH3

25 mg tablet tid one hour before meals and midevening to overcome night hunger if necessary 75 mg SR tablet once daily in midmorning Short-term weight loss

CH3 Diethylpropion HCl - Tenuate

Anorexiants
Substitution at the E-carbon
NH3+ClH3C CH3

Amphetamine-like

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

Phentermine - Ionamin, Fastin, Zantryl, others

CH3 H3 C N H3C H3 C

Recommended for obese patients based on body mass index (BMI = Weight (kg)/Height (# meters squared)): >30 kg/meter sq or >27 kg/meter square in the presence of other risk factors such as hypertension, diabetes, dyslipidemias

Cl

Sibutramine HCl - Meridia

MOA: reuptake inhibition of norepinephrine, serotonin, dopamine via metabolites of this drug Monitor BP in hypertensive patients, dependence possible, MD must be informed of any OTCs

Anorexiants: Non-phenylethylamines
Cl OH N N Mazindol - Mazanor, Sanorex Cl

1 and 2 mg tablets 1-3 times daily depending on response

O HN N

Take with meals to avoid GI discomfort

O H3C N H3C H Plegine,

35 mg tablet or capsule bid or tid one hour before meals 105 mg SR capsule in the morning before breakfast

Phendimetrazine tartrate Bontril, Adipost, Dital, others