Pharmacologypharmacologypharmacology

PharmacologyPharmacologyPharmacology

DrugsDrugs ThatThat AffectAffect The:The: NervousNervous SystemSystem TopicsTopicsTopics

•• Analgesics Analgesics andand antagonistsantagonists •• Anesthetics Anesthetics •• Anti-anxiety Anti-anxiety andand sedative-hypnoticssedative-hypnotics •• Anti-seizure Anti-seizure // anti-convulsantsanti-convulsants •• CNS CNS stimulatorsstimulators •• Psychotherapeutics Psychotherapeutics •• ANS/PNS/SNS ANS/PNS/SNS agentsagents ButButBut first...first...first...

AA colorfulcolorful reviewreview ofof neurophysiology!neurophysiology! NervousNervousNervous SystemSystemSystem

CNSCNS PNSPNS

AutonomicAutonomic SomaticSomatic

SympatheticSympathetic ParasympatheticParasympathetic AnalgesicsAnalgesicsAnalgesics

•• Decrease Decrease inin sensationsensation ofof pain.pain. •• Classes: Classes: –– Opioid. Opioid. •• Agonist. Agonist. •• Antagonist. Antagonist. •• Agonist-antagonist. Agonist-antagonist. –– Non-opioids. Non-opioids. •• Salicylates. Salicylates. •NSAIDs.•NSAIDs. •• Adjuncts. Adjuncts. OpioidsOpioidsOpioids

•• Generic Generic reference reference to to morphine-likemorphine-like drugs/actionsdrugs/actions –– Opiate: Opiate: derivative derivative of of opium opium •• Prototype: Prototype: morphine morphine –– Morpheus: Morpheus: god god of of dreams dreams •• Act Act onon endorphinendorphin receptors:receptors: –– Mu Mu (most (most important) important) –– Kappa Kappa ActionsActionsActions ofofof OpioidOpioidOpioid ReceptorsReceptorsReceptors

Response Mu Kappa Analgesia ;; Respiratory ; Depression Sedation ;; Euphoria ; Physical Dependence ; ⇓ GI motility ;; ActionsActionsActions atatat OpioidOpioidOpioid ReceptorsReceptorsReceptors

Drugs Mu Kappa Pure Agonists Agonist Agonist -morphine, codeine, meperidine (Demerol®), fentanyl (Sublimaze®), remifentanil (Ultiva®), propoxyphene (Darvon®), hydrocodone (Vicodin®), oxycodone (Percocet®) Agonist-Antagonist Antagonist Agonist -nalbuphine (Nubaine®), butorphanol (Stadol®) Pure Antagonist Antagonist Antagonist -naloxone (Narcan®) GeneralGeneralGeneral ActionsActionsActions ofofof OpioidsOpioidsOpioids

•• Analgesia Analgesia •• Euphoria/Dysphoria Euphoria/Dysphoria •• Respiratory Respiratory depressiondepression •Sedation•Sedation • Constipation • Constipation •• Miosis Miosis • Urinary retention • Urinary retention –– Pupil Pupil constrictionconstriction • Cough suppression • Cough suppression •• ⇓⇓PreloadPreload && afterloadafterload •Emesis •Emesis –– Watch Watch forfor •Increased•Increased ICPICP hypotension!hypotension! – Indirect through CO – Indirect through CO22 retentionretention NonNonNon-opioid--opioidopioid AnalgesicsAnalgesics Analgesics

•• Salicylates Salicylates –– Aspirin Aspirin (Bayer(Bayer®®)) ** (prototype(prototype forfor class)class) •• Non-Steroidal Non-Steroidal Anti-InflammatoryAnti-Inflammatory DrugsDrugs •• Ibuprofen Ibuprofen (Motrin®,(Motrin®, AdvilAdvil®®)) –– Propionic Propionic Acid Acid derivative derivative •• Naproxen Naproxen (Naprosyn(Naprosyn®®)) •• Naproxen Naproxen sodiumsodium (Aleve(Aleve®®)) •• All All competecompete withwith aspirinaspirin forfor proteinprotein bindingbinding sitessites –– Ketorolac Ketorolac (Toradol (Toradol®®)) NSAIDNSAIDNSAID PropertiesPropertiesProperties

Drug Fever Inflammation Pain

Aspirin ;;;

Ibuprofen ;;;

Acetaminophen ;; AspirinAspirinAspirin MechanismMechanismMechanism ofofof ActionActionAction

•• Inhibit Inhibit synthesissynthesis ofof cyclooxygenasecyclooxygenase (COX)(COX) –– Enzyme Enzyme responsibleresponsible forfor synthesissynthesis of:of:

Prostaglandins Thromboxane A Prostaglandins Thromboxane A22 –Pain–Pain response response –Involved–Involved in in platelet platelet –Suppression–Suppression of of gastric gastric acid acid secretion secretion –aggregation–aggregation –Promote–Promote secretion secretion of of gastric gastric mucus mucus and and bicarbonate bicarbonate –Mediation–Mediation of of inflammatory inflammatory response response –Production–Production of of fever fever –Promote–Promote renal renal vasodilation vasodilation ( (⇑⇑bloodblood flow) flow) –Promote–Promote uterine uterine contraction contraction AspirinAspirinAspirin EffectsEffectsEffects

GoodGood BadBad •• Pain Pain reliefrelief •• GI GI ulceration:ulceration: •• ⇓⇓FeverFever –– ⇑⇑GastricGastric acidity acidity – ⇓ GI protection •• ⇓⇓InflammationInflammation – ⇓ GI protection •• ⇑⇑BleedingBleeding •• ⇓⇓RenalRenal eliminationelimination •• ⇓⇓UterineUterine contractionscontractions duringduring laborlabor AcetaminophenAcetaminophenAcetaminophen (Tylenol(Tylenol(Tylenol®®®)))

•• NSAID NSAID similarsimilar toto aspirinaspirin •• Only Only inhibitsinhibits synthesissynthesis ofof CNSCNS prostaglandinsprostaglandins –Does–Does notnothavehave peripheralperipheral sideside effectseffects ofof ASA:ASA: •• Gastric Gastric ulcerationulceration •• ⇓⇓PlateletPlatelet aggregation aggregation •• ⇓⇓RenalRenal flowflow •• ⇓⇓UterineUterine contractions contractions AcetaminophenAcetaminophenAcetaminophen MetabolismMetabolismMetabolism

Major Pathway Non-toxic AcetaminophenAcetaminophen Non-toxic metabolitesmetabolites

InducedInduced byby Depleted by ETOH & ETOH Depleted by ETOH & ETOH APAPAPAP overdoseoverdose P-450

ToxicToxic Glutathione Non-toxicNon-toxic metabolitesmetabolites metabolitesmetabolites

Minor Pathway AnestheticsAnestheticsAnesthetics

•• Loss Loss ofof allall sensationsensation –– Usually Usually withwith lossloss ofof consciousnessconsciousness ––⇓⇓propagationpropagation ofof neuralneural impulsesimpulses •• General General anestheticsanesthetics –Gases–Gases •• Nitrous Nitrous oxideoxide (Nitronox(Nitronox®®),), halothane, halothane, ether ether –IV–IV •• Thiopental Thiopental (Pentothal(Pentothal®®),), methohexital methohexital (Brevitol (Brevitol®®),), diazepamdiazepam (valium®),(valium®), remifentanilremifentanil (Ultiva (Ultiva®®)) AnestheticsAnestheticsAnesthetics

•Local•Local –– Affect Affect onon areaarea aroundaround injectioninjection –– Usually Usually accompaniedaccompanied byby epinephrineepinephrine •• Lidocaine Lidocaine (Xylocaine(Xylocaine®®),), topical topical cocaine cocaine AntiAntiAnti-anxiety--anxietyanxiety &&& SedativeSedativeSedative--- hypnotichypnotichypnotic DrugsDrugsDrugs •• Sedation: Sedation: ⇓⇓anxietyanxiety && inhibitionsinhibitions •• Hypnosis: Hypnosis: instigationinstigation ofof sleepsleep •• Insomnia Insomnia –– ⇑⇑LatentLatent periodperiod –– ⇑⇑WakeningsWakenings •• Classes: Classes: – Barbiturates – Barbiturates ChemicallyChemically different, different, –– Benzodiazepines Benzodiazepines FunctionallyFunctionally similar similar –– Alcohol Alcohol MechanismMechanismMechanism ofofof actionactionaction

•• Both Both promotepromote thethe effectivenesseffectiveness ofof GABAGABA receptorsreceptors inin thethe CNSCNS –– Benzodiazepines Benzodiazepines promotepromote onlyonly –– Barbiturates Barbiturates promotepromote andand (at(at highhigh doses)doses) stimulatestimulate GABAGABA receptorsreceptors •• GABA GABA == chiefchief CNSCNS inhibitoryinhibitory neurotransmitterneurotransmitter –– Promotes Promotes hyperpolarizationhyperpolarization viavia ⇑⇑ClCl--influxinflux BenzodiazepinesBenzodiazepinesBenzodiazepines vs.vs.vs. BarbituratesBarbituratesBarbiturates Criteria BZ Barb. Relative Safety High Low Maximal CNS depression Low High Respiratory Depression Low High Suicide Potential Low High Abuse Potential Low High Antagonist Available? Yes No BenzodiazepinesBenzodiazepinesBenzodiazepines

BenzodiazepinesBenzodiazepines “Non-benzo“Non-benzo benzo” benzo” •• diazepam diazepam (Valium(Valium®®)) •• zolpidem zolpidem (Ambien (Ambien®®)) •• midazolam midazolam (Versed (Versed®®)) •• buspirone buspirone (BusPar (BusPar®®)) •• alprazolam alprazolam (Xanax (Xanax®®)) •• lorazepam lorazepam (Atiavan (Atiavan®®)) •• triazolam triazolam (Halcion (Halcion®®)) BarbituratesBarbituratesBarbiturates

Subgroup Prototype Typical Indication Ultra-short thiopental Anesthesia acting (Pentothol®) Short acting secobarbital Insomnia (Seconal®) Long acting phenobarbital Seizures (Luminal®) BarbituratesBarbituratesBarbiturates

•• amobarbital amobarbital (Amytal (Amytal®®)) •• pentobarbital pentobarbital (Nembutal(Nembutal®®)) •• thiopental thiopental (Pentothal(Pentothal®®)) •• phenobarbital phenobarbital (Luminal (Luminal ®®)) •• secobarbital secobarbital (Seconal (Seconal®®)) AntiAntiAnti-seizure--seizureseizure MedicationsMedicationsMedications

•• Seizures Seizures causedcaused byby hyperactivehyperactive brainbrain areasareas •• Multiple Multiple chemicalchemical classesclasses ofof drugsdrugs –– All All havehave samesame approachapproach –– Decrease Decrease propagationpropagation ofof actionaction potentialspotentials •• ⇓⇓NaNa++,, CaCa++++influxinflux (delay(delay depolarization/prolongdepolarization/prolong repolarization)repolarization) •• ⇑⇑ClCl--influxinflux (hyperpolarize (hyperpolarize membrane) membrane) AntiAntiAnti-Seizure--SeizureSeizure MedicationsMedicationsMedications

BenzodiazepinesBenzodiazepines IonIon ChannelChannel InhibitorsInhibitors •• diazepam diazepam (Valium®)(Valium®) •• carbamazepine carbamazepine ® •• lorazepam lorazepam (Ativan (Ativan®®)) (Tegretol(Tegretol®)) BarbituratesBarbiturates •• phenytoin phenytoin (Dilantin®) (Dilantin®) •• phenobarbital phenobarbital Misc.Misc. AgentsAgents (Luminal(Luminal®®)) •• valproic valproic acid acid (Depakote®)(Depakote®) IonIonIon DiffusionDiffusionDiffusion

•• Key Key toto neurophysiologyneurophysiology •• Dependent Dependent upon:upon: –– Concentration Concentration gradientgradient –– Electrical Electrical gradientgradient •• Modified Modified by:by: –– ‘Gated ‘Gated ionion channels’channels’ WhereWhereWhere DoesDoesDoes DiffusionDiffusionDiffusion TakeTakeTake thethethe Ion?Ion?Ion?

NaNa++ KK++ ClCl-- 150150 mMmM 55 mMmM HighHigh Exterior

II OO II NN UU NN TT Interior

NaNa++ KK++ ClCl-- 1515 mMmM 150150 mMmM LowLow ActionActionAction PotentialPotentialPotential ComponentsComponentsComponents

Na++equilibrium Depolarization!Depolarization! Na equilibrium ActionAction PotentialPotential

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l a i t n e t o P What Happens to the Frequency of Action Potentials If the Membrane Gets Hyperpolarized? e n a r b m e M ClinicalClinical CorrelationCorrelation

•• Remember Remember that that it it is is the the rate rate of of action action potential potential propagation propagation thatthat determinesdetermines neurologicneurologic function.function. –– Determined Determined by by frequency frequency of of action action potentials. potentials.

WhatWhat wouldwould bebe thethe WhatWhat isis aa seizure?seizure? effecteffect onon thethe membranemembrane of ⇑ Cl--influx of ⇑ Cl influx Hyperpolarization & duringduring aa seizure?seizure? ⇓ seizure activity! ClCl - - GammaGammaGamma AminoAminoAmino ButyricButyricButyric AcidAcidAcid ReceptorsReceptors Receptors GABAGABA ReceptorReceptor

Exterior Hyperpolarized!Hyperpolarized!

Interior ClCl - - GABA+BzGABA+BzGABA+BzComplexComplex Complex BzBz GABAGABA ReceptorReceptor ReceptorReceptor

ProfoundlyProfoundly Exterior Hyperpolarized!Hyperpolarized!

Interior AreAreAre YouYouYou ReadyReadyReady forforfor aaa BigBigBig Surprise?Surprise?Surprise?

ManyMany CNSCNS drugsdrugs actact onon GABAGABA receptorsreceptors toto effecteffect thethe frequencyfrequency andand durationduration ofof actionaction potentials!potentials! SNSSNSSNS StimulantsStimulantsStimulants

•• Two Two generalgeneral mechanisms:mechanisms: –– Increase Increase excitatoryexcitatory neurotransmitterneurotransmitter releaserelease –– Decrease Decrease inhibitoryinhibitory neurotransmitterneurotransmitter releaserelease

•• Three Three classes:classes: •• Amphetamines Amphetamines •• Methylphendidate Methylphendidate •• Methylxanthines Methylxanthines AmphetaminesAmphetaminesAmphetamines amphetamineamphetamine MOA:MOA: methamphetaminemethamphetamine promotepromote releaserelease ofof dextroamphetaminedextroamphetamine norepinephrine,norepinephrine, (Dexedrine(Dexedrine®®)) dopaminedopamine IndicationsIndications SideSide EffectsEffects •Diet•Diet suppressionsuppression •Tachycardia•Tachycardia ••⇓⇓FatigueFatigue •Hypertension•Hypertension ••⇑⇑ConcentrationConcentration •Convulsion•Convulsion •Insomnia•Insomnia •Psychosis•Psychosis MethylphenidateMethylphenidateMethylphenidate (Ritalin(Ritalin(Ritalin®®®)))

•• Different Different structurestructure thanthan otherother stimulantsstimulants –– Similar Similar mechanismmechanism –– Similar Similar sideside effectseffects •• Indication: Indication: ADHDADHD –– Increase Increase abilityability toto focusfocus && concentrateconcentrate MethylxanthinesMethylxanthinesMethylxanthines

•Caffeine•Caffeine •• Theophylline Theophylline (Theo-Dur®) (Theo-Dur®) •• Aminophylline Aminophylline MechanismMechanism ofof actionaction •• Reversible Reversible blockadeblockade ofof adenosineadenosine receptorsreceptors AAA patientpatientpatient isisis takingtakingtaking theophyllinetheophyllinetheophylline andandand becomesbecomesbecomes tachycardictachycardictachycardic (SVT).(SVT).(SVT). YouYouYou wantwantwant tototo givegivegive herherher adenosine.adenosine.adenosine. IsIsIs theretherethere ananan interactioninteractioninteraction youyouyou shouldshouldshould bebebe awareawareaware of?of?of? HowHowHow shouldshouldshould youyouyou alteralteralter youryouryour therapy?therapy?therapy?

MethylxanthinesMethylxanthines blocksblocks adenosineadenosine receptors.receptors. AA typicaltypical dosedose ofof adenosineadenosine DoubleDouble thethe maymay notnot bebe sufficientsufficient toto dose!dose! achieveachieve thethe desireddesired result.result. NewsNewsNews YouYouYou CanCanCan UseUseUse………

Source Amount of Caffeine

Coffee •Brewed 40 – 180 mg/cup •Instant 30 – 120 mg/cup Decaffeinated Coffee 2 - 5 mg/cup

Tea 20 – 110 mg/cup

Coke 40 – 60 mg/12 oz PsychotherapeuticPsychotherapeuticPsychotherapeutic MedicationsMedicationsMedications •• Dysfunction Dysfunction relatedrelated toto neurotransmitterneurotransmitter imbalance.imbalance. –– Norepinephrine. Norepinephrine. –– Dopamine. Dopamine. Monoamines –Seratonin.–Seratonin. •• Goal Goal isis toto regulateregulate excitory/inhibitoryexcitory/inhibitory neurotransmitters.neurotransmitters. AntiAntiAnti-Psychotic--PsychoticPsychotic DrugsDrugsDrugs (Neuroleptics)(Neuroleptics)(Neuroleptics) •• Schizophrenia Schizophrenia –– Loss Loss ofof contactcontact withwith realityreality && disorganizeddisorganized thoughtsthoughts –– Probable Probable cause:cause: increasedincreased dopaminedopamine releaserelease –– Tx. Tx. AimedAimed atat decreasingdecreasing dopaminedopamine activityactivity

•• PhenothiazinesPhenothiazines ® TwoTwo ChemicalChemical •• chlorpromazinechlorpromazine (Thorazine (Thorazine ®)) Classes:Classes: •• ButyrophenonesButyrophenones ® •• haloperidol haloperidol (Haldol (Haldol®)) OtherOtherOther UsesUsesUses forforfor AntipsychoticsAntipsychoticsAntipsychotics

•• Bipolar Bipolar depressiondepression •• Tourette’s Tourette’s Syndrome Syndrome •• Prevention Prevention ofof emesisemesis •• Dementia Dementia (OBS)(OBS) •• Temporary Temporary psychosespsychoses fromfrom otherother illnessillness AntipsychoticAntipsychoticAntipsychotic MOAMOAMOA

•• Mechanism Mechanism isis similarsimilar •• Strength Strength ([])([]) vs.vs. PotencyPotency (‘oomph’)(‘oomph’) –– Phenothiazines Phenothiazines –– low low potencypotency –– Butyrophenones Butyrophenones – – high high potency potency •• Receptor Receptor AntagonismAntagonism – Dopamine in brain – Dopamine22 in brain Therapeutic effects –– Muscarinic Muscarinic cholinergic cholinergic –– Histamine Histamine Uninteded effects – Norepi at alpha – Norepi at alpha11 AntipsychoticAntipsychoticAntipsychotic SideSideSide EffectsEffectsEffects

•• Generally Generally shortshort termterm •• Extrapyramidal Extrapyramidal symptomssymptoms (EPS)(EPS) •• Anticholinergic Anticholinergic effectseffects (atropine-like)(atropine-like) –– Dry Dry mouth,mouth, blurredblurred vision,vision, photophobia,photophobia, tachycardia,tachycardia, constipation)constipation) •• Orthostatic Orthostatic hypotensionhypotension •Sedation•Sedation •• Decreased Decreased seizureseizure thresholdthreshold •• Sexual Sexual dysfunctiondysfunction ExtrapyramidalExtrapyramidalExtrapyramidal SymptomsSymptomsSymptoms

Reaction Onset Features

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

Parkinsonism 5 – 30 days Tremor, shuffling gait, drooling, stooped posture, instability

Akathesia 5 – 60 days Compulsive, repetitive motions; agitation

Tarditive Months to years Lip-smacking, worm-like tongue dyskinesia movement, ‘fly-catching’ TreatmentTreatmentTreatment ofofof EPSEPSEPS

•• Likely Likely causedcaused byby blockingblocking centralcentral dopamine receptors responsible for dopamine22 receptors responsible for movementmovement •• Anticholinergic Anticholinergic therapytherapy rapidlyrapidly effectiveeffective –– diphenhydramine diphenhydramine (Benadryl (Benadryl®®)) AntipsychoticAntipsychoticAntipsychotic AgentsAgentsAgents

•• chlorpromazine chlorpromazine (Thorazine®)(Thorazine®) •• thioridazine thioridazine (Mellaril®) (Mellaril®) •• trifluoperazine trifluoperazine (Stelazine®) (Stelazine®) •• haloperidol haloperidol (Haldol®)(Haldol®) AntidepressantsAntidepressantsAntidepressants

•• Likely Likely cause:cause: inadequateinadequate monoaminemonoamine levelslevels •• Treatment Treatment options:options: –– Increasing Increasing NTNT synthesissynthesis inin presynapticpresynaptic end end bulbbulb –– Increasing Increasing NTNT releaserelease fromfrom endend bulbbulb –– Blocking Blocking NTNT ‘reuptake’‘reuptake’ by by presynapticpresynaptic end end bulbbulb TricyclicTricyclicTricyclicAntidepressantsAntidepressants Antidepressants (TCAs)(TCAs)(TCAs) •• Block Block reuptakereuptake ofof bothboth NENE && serotoninserotonin –– Enhance Enhance effects effects •• Similar Similar sideside effectseffects toto phenothiazinesphenothiazines TCATCATCA SideSideSide EffectsEffectsEffects

•• Orthostatic Orthostatic hypotensionhypotension •• Sedation Sedation •• Anticholinergic Anticholinergic effectseffects •• Cardiac Cardiac toxicitytoxicity –– Ventricular Ventricular dysrythmiasdysrythmias SelectiveSelectiveSelective SerotoninSerotoninSerotonin ReuptakeReuptakeReuptake InhibitorsInhibitorsInhibitors (SSRIs)(SSRIs)(SSRIs) •• Block Block onlyonly serotoninserotonin (not(not NE)NE) reuptakereuptake –– Elevate Elevate serotoninserotonin levelslevels •• Fewer Fewer sideside effectseffects thanthan TCSTCS –– No No hypotensionhypotension –– No No anticholinergicanticholinergic effects effects –– No No cardiotoxicitycardiotoxicity •• Most Most commoncommon sideside effecteffect –– Nausea, Nausea, insomnia,insomnia, sexualsexual dysfunctiondysfunction MonoamineMonoamineMonoamine OxidaseOxidaseOxidaseInhibitorsInhibitors Inhibitors (((MAOIs)MAOIsMAOIs)) •• Monoamine Monoamine oxidaseoxidase –– Present Present inin liver,liver, intestinesintestines && MAMA releasingreleasing neuronsneurons –– Inactivates Inactivates monoaminesmonoamines –– Inactivates Inactivates dietarydietary tyraminetyramine in in liverliver •• Foods Foods rich rich in in tyramine: tyramine: cheese cheese & & red red wine wine MAOIMAOIMAOI SideSideSide EffectsEffectsEffects

•• CNS CNS StimulationStimulation –– Anxiety, Anxiety, agitationagitation •• Orthostatic Orthostatic hypotensionhypotension •• Hypertensive Hypertensive CrisisCrisis –– From From increasedincreased tyraminetyramine consumption consumption •• Excessive Excessive arteriole arteriole constriction, constriction, stimulation stimulation of of heart heart MAOIMAOIMAOI &&& DietaryDietaryDietary TyramineTyramineTyramine AntidepressantAntidepressantAntidepressant MechanismMechanismMechanism

TCAs & SSRIs Block Here AntidepressantsAntidepressantsAntidepressants AgentsAgentsAgents

TCAsTCAs MAOIsMAOIs ® •• imiprimine imiprimine (Tofranil (Tofranil®®)) •• phenelzine phenelzine (Nardil (Nardil®)) •• amitriptyline amitriptyline (Elavil (Elavil®®)) •• nortriptyline nortriptyline (Pamelor (Pamelor®®)) AtypicalAtypical AntidepressantsAntidepressants SSRIsSSRIs •• bupropion bupropion (Wellbutrin (Wellbutrin®®)) •• fluoxetine fluoxetine (Prozac (Prozac®®)) •• paroxetine paroxetine (Paxil (Paxil®®)) •• sertraline sertraline (Zoloft (Zoloft®®)) ParkinsonParkinsonParkinson’s’’ss DiseaseDiseaseDisease

•• Fine Fine motormotor controlcontrol dependentdependent uponupon balancebalance betweenbetween excitatoryexcitatory andand inhibitoryinhibitory NTNT –– Acetylcholine Acetylcholine == excitatoryexcitatory Control GABA release –– Dopamine Dopamine =inhibitory=inhibitory GABA=GABA= inhibitoryinhibitory ParkinsonParkinsonParkinson’s’’ss DiseaseDiseaseDisease ParkinsonParkinsonParkinson’s’’ss Symptoms:Symptoms:Symptoms:

•• Similar Similar toto EPSEPS •• Dyskinesias Dyskinesias –– Tremors, Tremors, unsteadyunsteady gait,gait, instabilityinstability •• Bradykinesia Bradykinesia •• Akinesia Akinesia in in severesevere casescases ParkinsonParkinsonParkinson’s’’ss TreatmentTreatmentTreatment

•• Dopaminergic Dopaminergic approachapproach ––⇑⇑ReleaseRelease ofof dopaminedopamine ––⇑⇑[Dopamine][Dopamine] ––⇓⇓DopamineDopamine breakdownbreakdown •• Cholinergic Cholinergic approachapproach ––⇓⇓AmountAmount ofof AChACh releasedreleased –– Directly Directly blockblock AChACh receptorsreceptors •• All All treatmenttreatment isis symptomaticsymptomatic andand temporarytemporary LevodopaLevodopaLevodopa

•• Sinemet Sinemet ® ® = = levodopalevodopa + + carbidopacarbidopa •• Increase Increase centralcentral dopaminedopamine levelslevels •• Side Side effects:effects: –– Nausea Nausea andand vomitingvomiting –– Dyskinesia Dyskinesia (~80% (~80% ofof population)population) –– Cardiovascular Cardiovascular (dysrythmias)(dysrythmias) LevodopaLevodopaLevodopaMechanismMechanism Mechanism OtherOtherOther AgentsAgentsAgents

•• amantadine amantadine (Symmetrel (Symmetrel®®)) ––⇑⇑releaserelease ofof dopaminedopamine fromfrom unaffectedunaffected neuronsneurons •• bromocriptine bromocriptine (Parlodel (Parlodel®®)) –– Directly Directly stimulatedstimulated dopaminedopamine receptorsreceptors •• selegiline selegiline (Carbex (Carbex®®,, EldeprylEldepryl®®)) –– MAOI MAOI selectiveselective forfor dopaminedopamine (MAO-B)(MAO-B) •• benztropine benztropine (Cogentin (Cogentin®®)) –– Centrally Centrally actingacting anticholinergicanticholinergic DrugsDrugsDrugs ThatThatThat AffectAffectAffect thethethe AutonomicAutonomicAutonomic NervousNervousNervous SystemSystemSystem

WordWord ofof WarningWarning CarefullyCarefully reviewreview thethe A&PA&P materialmaterial && tablestables onon pagespages 309309 –– 314 314 andand 317317 –– 321! 321! PNSPNSPNS DrugsDrugsDrugs

•• Cholinergic Cholinergic –– Agonists Agonists && AntagonistisAntagonistis (Anticholinergics) (Anticholinergics) – Based on response at nicotinic & – Based on response at nicotinic(N&M)(N&M) & muscarinicmuscarinic receptors receptors AcetylcholineAcetylcholineAcetylcholine ReceptorsReceptorsReceptors

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

SSalivationalivation Cholinergic agents Lacrimation cause SLUDGE! Lacrimation UUrinationrination HINT! DDefecationefecation These effects are GGastricastric motilitymotility predictable by knowing EEmesismesis PNS physiology (table 9-4) DirectDirectDirect ActingActingActing CholinergicsCholinergicsCholinergics

•• bethanechol bethanechol (Urecholine) (Urecholine) prototypeprototype –– Direct Direct stimulationstimulation ofof AChACh receptorsreceptors –– Used Used forfor urinaryurinary hesitancyhesitancy andand constipationconstipation IndirectIndirectIndirect ActingActingActing CholinergicsCholinergicsCholinergics

•• Inhibit Inhibit ChEChE (cholinesterase)(cholinesterase) toto prolongprolong thethe durationduration ofof AChACh stimulationstimulation inin synapsesynapse •• Reversible Reversible •• Irreversible Irreversible ReversibleReversibleReversible ChEChEChE InhibitorsInhibitorsInhibitors

•• neostigmine neostigmine (Prostigmine (Prostigmine®®)) – Myasthenia Gravis at nicotinic receptors – Myasthenia Gravis at nicotinicMM receptors –– Can Can reversereverse nondepolarizingnondepolarizing neuromuscular neuromuscular blockadeblockade •• physostigmine physostigmine (Antilirium®) (Antilirium®) –– Shorter Shorter onsetonset ofof actionaction –– Used Used forfor iatrogeniciatrogenic atropineatropine overdosesoverdoses @@ muscarinicmuscarinic receptors receptors IrreversibleIrreversibleIrreversible ChEChEChE InhibitorsInhibitorsInhibitors

•• Very Very rarelyrarely usedused clinicallyclinically •• Very Very commoncommon inin insecticidesinsecticides && chemicalchemical weaponsweapons –– VX VX andand SarinSarin gas gas –– Cause Cause SLUDGESLUDGE dammitdammit and and paralysisparalysis •• Tx: Tx: atropineatropine andand pralidoximepralidoxime (2-PAM (2-PAM®®)) –– Anticholinergics Anticholinergics AnticholinergicsAnticholinergicsAnticholinergics

•• Muscarinic Muscarinic •• Atropine Atropine OverdoseOverdose antagonists antagonists –– Dry Dry mouth,mouth, blurredblurred –– Atropine Atropine vision,vision, anhidrosisanhidrosis •• Ganglionic Ganglionic antagonists antagonists – block nicotinic – block nicotinicNN Hot as Hell receptorsreceptors Hot as Hell –– TurnsTurns off off the the ANS! ANS! BlindBlind as as a a Bat Bat –– trimethaphan trimethaphan DryDry asas aa BoneBone ® (Arfonad(Arfonad®)) RedRed as as a a Beet Beet • Hypertensive crisis • Hypertensive crisis MadMad as as a a Hatter Hatter NeuromuscularNeuromuscularNeuromuscular BlockersBlockersBlockers

•• Nicotinic Nicotinic CholinergicCholinergic AntagonistsAntagonists –– Given Given toto induceinduce paralysisparalysis •• Depolarizing Depolarizing –– succinylcholine succinylcholine (Anectin (Anectin®®)) •• Nondepolarizing Nondepolarizing –– tubocurarine tubocurarine from from curarecurare –– rocuronium rocuronium (Zemuron (Zemuron®®)) –– vecuronium vecuronium (Norcuron (Norcuron®®)) Warning!Warning!Warning!

•• Paralysis Paralysis withoutwithout lossloss ofof consciousness!consciousness! –– MUST MUST alsoalso givegive sedative-hypnoticsedative-hypnotic –– Common Common agents:agents: •• fentanyl fentanyl (Sublimaze(Sublimaze®®)) •• midazolam midazolam (Versed (Versed®®)) SNSSNSSNS DrugsDrugsDrugs

•• Predictable Predictable responseresponse basedbased onon knowledgeknowledge ofof affectsaffects ofof adrenergicadrenergic receptorreceptor stimulationstimulation •• HINT: HINT: KnowKnow tabletable 9-5,9-5, pagepage 321321 •• Each Each receptorreceptor maymay be:be: –– Stimulated Stimulated (sympathomimetic)(sympathomimetic) –– Inhibitied Inhibitied (sympatholytic) (sympatholytic) AlphaAlphaAlpha111 AgonistsAgonistsAgonists

•• Profound Profound vasoconstrictionvasoconstriction –– Increases Increases afterloadafterload && bloodblood pressurepressure whenwhen givengiven systemicallysystemically –– Decreases Decreases drugdrug absorptionabsorption && bleedingbleeding whenwhen givengiven topicallytopically AlphaAlphaAlpha111 AntagonismAntagonismAntagonism

•• Inhibits Inhibits peripheralperipheral vasoconstrictionvasoconstriction –– Used Used forfor hypertensionhypertension –– prazosin prazosin (Minipress (Minipress®®)) –– doxazosin doxazosin (Cardura (Cardura®®)) –– phentolamine phentolamine (Regitine (Regitine®®)) • Blocks alpha receptors • Blocks alpha1&21&2 receptors BetaBetaBeta111 AgonistsAgonistsAgonists

•• Increases Increases heartheart rate,rate, contractility,contractility, andand conductivityconductivity BetaBetaBeta AntagonistsAntagonistsAntagonists (((βββ Blockers)Blockers)Blockers)

•• Frequently Frequently usedused •• Lower Lower BloodBlood PressurePressure •• Negative Negative chronotropeschronotropes & & inotropesinotropes

Beta Selective Blockade Nonselective Beta11 Selective Blockade Nonselective •• atenolol atenolol (Tenormin (Tenormin®®)) •• propranolol propranolol (Inderal (Inderal®®)) •• esmolol esmolol (Brevibloc (Brevibloc®®)) •• labetalol labetalol (Normodyne (Normodyne®®,, ® •• metoprolol metoprolol (Lopressor (Lopressor®®)) TrandateTrandate®)) •• sotalol sotalol (Betapace (Betapace®®)) AdrenergicAdrenergicAdrenergic ReceptorReceptorReceptor SpecificitySpecificitySpecificity

Drug α1 α2 β1 β2 Dopaminergic Epinephrine Ephedrine Norepinephrine Phenylephrine Isoproterenol Dopamine Dobutamine terbutaline WebWebWeb ResourcesResourcesResources

•• Web Web basedbased synapticsynaptic transmissiontransmission projectproject –– http://www.williams.edu/imput/index.html http://www.williams.edu/imput/index.html ThankThankThank You!You!You!

•• To To TempleTemple CollegeCollege EMSEMS ProfessionsProfessions forfor permissionpermission toto useuse theirtheir materialsmaterials