cns lecture
TRANSCRIPT
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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
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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!
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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)
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I ntroduction - CNS
SYMPATHETI C PARASYMPATHETI C
F rom: Clinical Pharmacology Made Ridiculously Simple, 2nd Ed., James Olson, MD, PhD.
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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.
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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
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Dopaminergic Receptors
Storage vesicles
Dopamine
Postsynaptic Receptors
NH 2H O
H O
dopamine
Reuptake
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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
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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
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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
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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
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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 ®
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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
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Sympathomimetic Actions
Direct
I ndirect
Mixed
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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®).
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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!!!
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& -Adrenergic Pathway:Second Messengers
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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!!!
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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 ®
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Dopaminergic Receptors
Storage vesicles
Dopamine
Postsynaptic Receptors
A mphetamines & Cocaine enhance release A ND hinder dopamine reuptake!
Enhances release
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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
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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
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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
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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
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-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.
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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
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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
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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
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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