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PharmacologyPharmacology Drugs That Affect The:

Nervous System

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TopicsTopics Analgesics and antagonists

AnestheticsAnti-anxiety and sedative-hypnoticsAnti-seizure / anti-convulsants

C NS stimulators

PsychotherapeuticsANS/ P NS/SNS agents

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A colorful review of neurophysiology!

A colorful review of neurophysiology!

But f irs t...But f irs t...

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Ne

rvo us S ys te

mNe

rvo us S ys te

m

CNS PNS

SomaticAutonomic

ParasympatheticSympathetic

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Analg

esics

Analg

esics

Decrease in sensation of pain. C lasses:

Opioid.Agonist.Antagonist.Agonist-antagonist.

Non-opioids.Salicylates.

NSAIDs.Adjuncts.

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Opioids

Opioids

G eneric reference tomorphine-likedrugs/actions Opiate: derivative of opium

Prototype: morphine Morpheus: god of dreams

Act on endorphin

receptors: Mu (most important) Kappa

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A

ction

s of O

pioid Re

ce

ptors A

ction

s of O

pioid Re

ce

ptorsR esponse Mu Kappa

Analgesia

RespiratoryDepressionSedation

Euphoria

P hysical Dependence G I motility

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A

ction

s a tO

pioid Re

ce

ptors A

ction

s a tO

pioid Re

ce

ptorsD rugs Mu Kappa

P ure Agonists-morphine, codeine, meperidine (Demerol ),fentanyl (Sublimaze ), remifentanil (Ultiva ),

propoxyphene (Darvon ), hydrocodone (Vicodin ),oxycodone ( P ercocet )

Agonist Agonist

Agonist-Antagonist-nalbuphine (Nubaine ), butorphanol (Stadol )

Antagonist Agonist

P ure Antagonist-naloxone (Narcan )

Antagonist Antagonist

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G e n e

ral A

ction

s of O

pioidsG e n e

ral A

ction

s of O

pioids

AnalgesiaRespiratory depression

ConstipationUrinary retention

Cough suppressionEmesisIncreased I CP Indirect through C O2

retention

Euphoria/DysphoriaSedationMiosis P upil constriction P reload & afterload

Watch for hypotension!

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N

onN

on--

opioid An

alge

sicsopioid An

alge

sics

Salicylates Aspirin (Bayer ) * (prototype for class)

Non-Steroidal Anti-Inflammatory DrugsIbuprofen (Motrin, Advil )

P ropionic Acid derivative

Naproxen (Naprosyn

) Naproxen sodium (Aleve )All compete with aspirin for protein binding sites

Ketorolac (Toradol )

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N

S AID

Prope

r tie

sN

S AID

Prope

r tie

sD rug Fever Inflammation Pain

Aspirin

Ibuprofen

Acetaminophen

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A

spirin

Me

chan

ism of A

ction A

spirin

Me

chan

ism of A

ction

Inhibit synthesis of cyclooxygenase ( C OX) Enzyme responsible for synthesis of:

P rostaglandins P ain response Suppression of gastric acid secretion

P

romote secretion of gastric mucus and bicarbonate Mediation of inflammatory response P roduction of fever P romote renal vasodilation ( blood flow) P romote uterine contraction

Thromboxane A 2 Involved in platelet aggregation

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A

spirin

Eff e

cts A

spirin

Eff e

cts

G ood Pain relief

F ever Inflammation

Bad

G I ulceration: G astric acidity G I protection

Bleeding

Renal elimination Uterine contractionsduring labor

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A

ce

tamin

ophe n

(Tyle n

ol A

ce

tamin

ophe n

(Tyle n

ol

)) NSAID similar to aspirin

Only inhibits synthesis of C NS prostaglandins Does not have peripheral side effects of ASA:

G astric ulceration

P latelet aggregation Renal flow Uterine contractions

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A

ce

tamin

ophe n

Me

tabolism A

ce

tamin

ophe n

Me

tabolism

Acetaminophen Non-toxicmetabolites

Major Pathway

Minor Pathway

P-450

Toxicmetabolites

Non-toxicmetabolites

Induced byETOH

Glutathione

D epleted by ETOH &APAP overdose

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An es th

etics

An es th

etics

Loss of all sensation Usually with loss of consciousness propagation of neural impulses

G eneral anesthetics G ases

Nitrous oxide (Nitronox

), halothane, ether IVThiopental ( P entothal ), methohexital (Brevitol ),diazepam (valium), remifentanil (Ultiva )

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An ti An ti--a nx ie ty & S e da tivea nx ie ty & S e da tive --

hyp n otic D r ugshyp n otic D r ugs Sedation: anxiety & inhibitions

H ypnosis: instigation of sleep

Insomnia L atent period Wakenings

C lasses: Barbiturates Benzodiazepines Alcohol

Chemically different,Functionally similar

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Me

chan

ism of ac tion

Me

chan

ism of ac tion

Both promote the effectiveness of G ABAreceptors in the C NS Benzodiazepines promote only Barbiturates promote and (at high doses)

stimulate G ABA receptors

G ABA = chief C NS inhibitoryneurotransmitter P romotes hyperpolarization via C l- influx

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Be nz

odiaz e

pin e

sBe nz

odiaz e

pin e

s

Benzodiazepines

diazepam (Valium )midazolam (Versed )alprazolam (Xanax )lorazepam (Atiavan )

triazolam ( H alcion )

Non-benzo benzozolpidem (Ambien )

buspirone (Bus P ar )

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Barbi tura te

sBarbi tura te

sSubgroup Prototype Typical

Indication

Ultra-shortacting

thiopental(P entothol )

Anesthesia

Short acting secobarbital

(Seconal

)

Insomnia

L ong acting phenobarbital(L uminal )

Seizures

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Barbi tura te

sBarbi tura te

s amobarbital (Amytal )

pentobarbital (Nembutal )thiopental ( P entothal )

phenobarbital ( L uminal )

secobarbital (Seconal

)

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An

ti An

ti--s

eiz

ur e

Me

dica tion

sse

iz

ur e

Me

dica tion

s Seizures caused by hyperactive brain areas

Multiple chemical classes of drugs All have same approach Decrease propagation of action potentials

Na +, C a++ influx (delay depolarization/prolong

repolarization)C l- influx (hyperpolarize membrane)

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An

ti An

ti--S

eiz

ur e

Me

dica tion

sSe

iz

ur e

Me

dica tion

s

Benzodiazepines

diazepam (Valium)lorazepam (Ativan )

Barbiturates phenobarbital

(L uminal

)

Ion C hannel Inhibitorscarbamazepine(Tegretol )

phenytoin (Dilantin)Misc. Agents

valproic acid(Depakote)

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Io

n D

iffusionI

on

D

iffusion

Key to neurophysiologyDependent upon: C oncentration gradient Electrical gradient

Modified by: G ated ion channels

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W he r e D oe s D iffusio n Tak e the W he r e D oe s D iffusio n Tak e the Ion?Ion?

Exterior

Interior

K +

5 mM

C l-L ow

C l-H igh

K +

150 mM Na +

15 mM

Na +

150 mM

OU

T

IN

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A ction Po te n tial Compo n e n ts A ction Po te n tial Compo n e n ts

-50

-70

0

+30

Time (msec)

ThresholdP otential

Resting MembraneP otential

Na + equilibriumAction

P otential

Depolarization!

Hyperpolarized

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Me

mbran e

Pe

rme

abili tyMe

mbran e

Pe

rme

abili ty

-50

-70

0

+30

Time (msec)

ThresholdP otential

Resting MembraneP otential

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-50

-70

0

+30

Time (msec)

ThresholdP otential

Resting MembraneP otential

It getshyperpolarized!

What H appens to the Membrane If C l-

Rushes Into theC

ell During Repolarization?

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-50

-70

0

+30

Time (msec)

Itdecreases!

What H appens to the F requency of ActionP otentials If the Membrane G etsH yperpolarized?

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C linical C orrelation

Remember that it is the rate of action potential propagationthat determines neurologic function. Determined by frequency of action potentials.

W hat is a seizure? W hat would be the

effect on the membraneof Cl - influx

during a seizure? Hyperpolarization & seizureactivity!

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G amma A min o But yric A cid G amma A min o But yric A cid Re ce ptorsRe ce ptors G ABA

Receptor

Exterior

Interior

C l -

Hyperpolarized!

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G A

B A+

Bz

Comple xG A

B A+

Bz

Comple x

BzReceptor

G ABAReceptor

Exterior

Interior

C l -

P rofoundly Hyperpolarized!

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A r e You R e ady f or a Big A r e You R e ady f or a Big Su rpris e ?Su rpris e ?

Ma ny CNS drugs ac t on GABA Ma ny CNS drugs ac t on GABAre c eptors to effe c t the frequen c yre c eptors to effe c t the frequen c y

a nd dur a tion of ac tion potenti al s!a nd dur a tion of ac tion potenti al s!

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SN

S St imulan

tsSN

S St imulan

ts Two general mechanisms:

Increase excitatory neurotransmitter release Decrease inhibitory neurotransmitter release

Three classes:AmphetaminesMethylphendidateMethylxanthines

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A mph e tami n e s A mph e tami n e s

amphetaminemethamphetaminedextroamphetamine

(Dexedrine )

Side EffectsTachycardiaH ypertensionC onvulsionInsomnia

Psychosis

IndicationsDiet suppression F atigue

C oncentration

MOA:

promote release of norepinephrine,

dopamine

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Me

thylphe n

ida te

(R italin

Me

thylphe n

ida te

(R italin

)) Different structure than other stimulants

Similar mechanism Similar side effects

Indication: AD H D Increase ability to focus & concentrate

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Me

thylx

an

thin e

sMe

thylx

an

thin e

s

CaffeineTheophylline (Theo-Dur)Aminophylline

Mechanism of actionReversible blockade of adenosine receptors

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A pa tie n t is taki n g the ophylli n e a n d A pa tie n t is taki n g the ophylli n e a n d

be com e s tachycardic (SVT ). You w a n t to be com e s tachycardic (SVT ). You w a n t to give he r ad e n osi n e . Is the r e a n in te rac tion give he r ad e n osi n e . Is the r e a n in te rac tion you sho uld be a war e of ? How sho uld youyou sho uld be a war e of ? How sho uld you

al te

r your the

rapy?

al te

r your the

rapy?

Methylxanthines blocksadenosine receptors. A

typical dose of adenosinemay not be sufficient toachieve the desiredresult.

D ouble thedose!

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Ne ws You C a n Us eNe ws You C a n Us e

Source Amount of Caffeine

Coffee

BrewedInstant

40 180 mg/cup30 120 mg/cup

Decaffeinated C offee 2 - 5 mg/cup

Tea 20 110 mg/cup

C oke 40 60 mg/12 oz

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Psycho the rap e ut ic Psycho the rap e ut ic

Me dica tion sMe dica tion s Dysfunction related to neurotransmitter

imbalance. Norepinephrine. Dopamine. Seratonin.

G oal is to regulate excitory/inhibitoryneurotransmitters.

M onoamines

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An ti An ti--Psycho tic D r ugs Psycho tic D r ugs

(Ne urole ptics)(Ne urole ptics)

Schizophrenia L oss of contact with reality & disorganized

thoughts P robable cause: increased dopamine release Tx. Aimed at decreasing dopamine activity

Two ChemicalClasses:

Phenothiazines

chlorpromazine (Thorazine )

Butyrophenoneshaloperidol ( H aldol )

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O

the

r Use

s f or An

tipsycho ticsO

the

r Use

s f or An

tipsycho tics Bipolar depression

Tourettes Syndrome Prevention of emesisDementia (OBS)Temporary psychoses from other illness

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An

tipsycho tic MO A An

tipsycho tic MO A

Mechanism is similar Strength ([]) vs. P otency (oomph)

P henothiazines low potency Butyrophenones high potency

Receptor Antagonism Dopamine 2 in brain

Muscarinic cholinergic H istamine Norepi at alpha 1

T her a peuti c effec ts

Uninteded effe c ts

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An

tipsycho tic S ide

Eff e

cts An

tipsycho tic S ide

Eff e

cts G enerally short term

Extrapyramidal symptoms (E P S)

Anticholinergic effects (atropine-like) Dry mouth, blurred vision, photophobia, tachycardia,

constipation)

Orthostatic hypotension

SedationDecreased seizure thresholdSexual dysfunction

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Ex

trapyramidal S ymp tomsEx

trapyramidal S ymp tomsR eaction Onset Features

Acute dystonia H ours to 5 days Spasm of tongue, neck, face & back

P arkinsonism 5 30 days Tremor, shuffling gait, drooling,stooped posture, instability

Akathesia 5 60 days C ompulsive, repetitive motions;agitation

Tarditivedyskinesia

Months to years L ip-smacking, worm-like tonguemovement, fly-catching

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Tr e a tm e n t of EP STr e a tm e n t of EP S

L ikely caused by blocking centraldopamine 2 receptors responsible for movementAnticholinergic therapy rapidly effective diphenhydramine (Benadryl )

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An tipsycho tic A ge n ts An tipsycho tic A ge n ts

chlorpromazine (Thorazine)thioridazine (Mellaril)trifluoperazine (Stelazine)haloperidol ( H aldol)

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An tide pr e ssa n ts An tide pr e ssa n ts

L ikely cause: inadequate monoamine levelsTreatment options: Increasing NT synthesis in presynaptic end

bulb Increasing NT release from end bulb

Blocking NT reuptake by presynaptic end bulb

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Tricyclic An tide pr e ssa n ts Tricyclic An tide pr e ssa n ts

(TC A s)(TC A s) Block reuptake of both NE & serotonin

Enhance effects

Similar side effects to phenothiazines

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TC A S ide Eff e ctsTC A S ide Eff e cts

Orthostatic hypotensionSedationAnticholinergic effects

Cardiac toxicity Ventricular dysrythmias

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S e le ctive S e ro ton in Re uptak e S e le ctive S e ro ton in Re uptak e In hibi tors (SSR Is)In hibi tors (SSR Is)

Block only serotonin (not NE) reuptake Elevate serotonin levels

F ewer side effects than T C S No hypotension No anticholinergic effects No cardiotoxicity

Most common side effect Nausea, insomnia, sexual dysfunction

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Mon oami n e O x idas e In hibi tors Mon oami n e O x idas e In hibi tors

(M A O Is)(M A O Is) Monoamine oxidase

P resent in liver, intestines & MA releasingneurons

Inactivates monoamines Inactivates dietary tyramine in liver

Foods rich in tyramine: cheese & red wine

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M A O I S ide Eff e ctsM A O I S ide Eff e cts

C NS Stimulation Anxiety, agitation

Orthostatic hypotension H ypertensive C risis

F rom increased tyramine consumptionExcessive arteriole constriction, stimulation of heart

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M A O I & D ie tary Tyrami n eM A O I & D ie tary Tyrami n e

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An tide pr e ssa n t Me cha n ism An tide pr e ssa n t Me cha n ism

TC A s &SSR Is

Block He r e

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An tide pr e ssa n ts A ge n ts An tide pr e ssa n ts A ge n ts

TC Asimiprimine (Tofranil )

amitriptyline (Elavil )nortriptyline ( P amelor )

SSRIsfluoxetine ( P rozac )

paroxetine ( P axil )sertraline (Zoloft )

MAOIs phenelzine (Nardil )

Atypical Antidepressants bupropion (Wellbutrin )

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Parki n so ns D is e as eParki n so ns D is e as e

F ine motor control dependent upon balance between excitatory and inhibitory NT Acetylcholine = excitatory Dopamine =inhibitoryG ABA= inhibitory

C ontrol G ABArelease

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Parki n so ns D is e as eParki n so ns D is e as e

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Parki n so ns S ymp toms:Parki n so ns S ymp toms:

Similar to E P SDyskinesias Tremors, unsteady gait, instability

BradykinesiaAkinesia in severe cases

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Parki n so ns Tr e a tm e n tParki n so ns Tr e a tm e n t

Dopaminergic approach Release of dopamine [Dopamine] Dopamine breakdown

Cholinergic approach

Amount of A C h released Directly block A C h receptors

All treatment is symptomatic and temporary

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L e vodopaL e vodopa

Sinemet = levodopa + carbidopaIncrease central dopamine levelsSide effects: Nausea and vomiting Dyskinesia (~80% of population)

C ardiovascular (dysrythmias)

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L e vodopa Me cha n ismL e vodopa Me cha n ism

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O the r A ge n tsO the r A ge n ts

amantadine (Symmetrel ) release of dopamine from unaffected neurons

bromocriptine ( P arlodel ) Directly stimulated dopamine receptorsselegiline ( C arbex , Eldepryl )

MAOI selective for dopamine (MAO-B) benztropine ( C ogentin ) C entrally acting anticholinergic

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D r ugs Tha t A ff e ct the D r ugs Tha t A ff e ct the A

uton

omic Ne

rvo us S ys te

m A

uton

omic Ne

rvo us S ys te

m Word of Warning

C arefully review the A& P material &tables on pages 309 314 and 317 321!

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P N S D r ugsP N S D r ugs

Cholinergic Agonists & Antagonistis (Anticholinergics)

Based on response at nicotinic (N&M) &muscarinic receptors

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A ce tylcholi n e Re ce ptors A ce tylcholi n e Re ce ptors

Figure 9-8, page 313, Paramedic Care, V1

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Cholin e rgic A go n is tsCholin e rgic A go n is ts

SalivationL acrimationUrinationDefecationG astric motilityEmesis

Ch olinergic agents

cause SLUDGE !

HINT!T h ese effects are

predictable by knowing P NS p h ysiology (table 9-4)

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D ir e ct A ctin g Cholin e rgicsD ir e ct A ctin g Cholin e rgics

bethanechol (Urecholine) prototype Direct stimulation of A C h receptors

Used for urinary hesitancy and constipation

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In dir e ct A ctin g Cholin e rgicsIn dir e ct A ctin g Cholin e rgics

Inhibit C hE (cholinesterase) to prolong theduration of A C h stimulation in synapse

ReversibleIrreversible

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Re ve rsibl e ChE In hibi torsRe ve rsibl e ChE In hibi tors

neostigmine ( P rostigmine ) Myasthenia G ravis at nicotinic M receptors

C an reverse nondepolarizing neuromuscular blockade

physostigmine (Antilirium)

Shorter onset of action Used for iatrogenic atropine overdoses @

muscarinic receptors

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Irr e ve rsibl e ChE In hibi torsIrr e ve rsibl e ChE In hibi tors

Very rarely used clinicallyVery common in insecticides & chemicalweapons VX and Sarin gas C ause S L UD G E dammit and paralysis

Tx: atropine and pralidoxime (2- P AM ) Anticholinergics

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An ticholi n e rgics An ticholi n e rgics

Muscarinic antagonists Atropine

Ganglionic antagonists block nicotinic N

receptors T urns off the ANS! trimethaphan

(Arfonad ) H ypertensive crisis

Atropine Overdose Dry mouth, blurred

vision, anhidrosis

H ot as H ellBlind as a Bat

Dry as a BoneRed as a BeetMad as a H atter

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Ne urom usc ular Block e rsNe urom usc ular Block e rs

Nicotinic C holinergic Antagonists G iven to induce paralysis

Depolarizing succinylcholine (Anectin )

Nondepolarizing

tubocurarine fromcur

are rocuronium (Zemuron )

vecuronium (Norcuron )

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W ar n in g!W ar n in g!

Paralysis without loss of consciousness! MUST also give sedative-hypnotic

C ommon agents:fentanyl (Sublimaze )midazolam (Versed )

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S N S D r ugsS N S D r ugs

Predictable response based on knowledge of affects of adrenergic receptor stimulation

H INT: Know table 9-5, page 321Each receptor may be: Stimulated (sympathomimetic)

Inhibitied (sympatholytic)

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A lpha A lpha11

A go n is ts A go n is ts

Profound vasoconstriction Increases afterload & blood pressure when

given systemically Decreases drug absorption & bleeding when

given topically

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A lpha A lpha11

An tago n ism An tago n ism

Inhibits peripheral vasoconstriction Used for hypertension

prazosin (Minipress ) doxazosin ( C ardura ) phentolamine (Regitine )

Blocks alpha 1&2 receptors

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Be taBe ta11

A go n is ts A go n is ts

Increases heart rate, contractility, andconductivity

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Be ta An tago n is ts (Be ta An tago n is ts ( Block e rs)Block e rs)

F requently used Lower Blood P ressure Negative chronotropes & inotropes

Beta 1 Selective Blockadeatenolol (Tenormin )esmolol (Brevibloc )metoprolol ( L opressor )

Nonselective

propranolol (Inderal )labetalol (Normodyne ,Trandate )sotalol (Betapace )

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A dr e n e rgic Re ce ptor S pe cif icity A dr e n e rgic Re ce ptor S pe cif icity

Drug 1 2 1 2 DopaminergicEpinephrine

Ephedrine NorepinephrineP henylephrine

IsoproterenolDopamineDobutamine

terbutaline

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W e b Re so urc e sW e b Re so urc e s

Web based synaptic transmission project http://www.williams.edu/imput/index.html

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