Pharmacology Pharmacology Drugs Drugs That That Affect Affect The: The: Nervous Nervous System System

Topics Topics •• •• •• •• •• •• ••

Analgesics Analgesics and and antagonists antagonists Anesthetics Anesthetics Anti-anxiety Anti-anxiety and and sedative-hypnotics sedative-hypnotics Anti-seizure Anti-seizure // anti-convulsants anti-convulsants CNS CNS stimulators stimulators Psychotherapeutics Psychotherapeutics ANS/PNS/SNS ANS/PNS/SNS agents agents

But But first... first...

A A colorful colorful review review of of neurophysiology! neurophysiology!

Nervous Nervous System System CNS CNS

PNS PNS

Autonomic Autonomic

Sympathetic Sympathetic

Parasympathetic Parasympathetic

Somatic Somatic

Analgesics Analgesics •• ••

Decrease Decrease in in sensation sensation of of pain. pain. Classes: Classes: –– Opioid. Opioid. •• Agonist. Agonist. •• Antagonist. Antagonist. •• Agonist-antagonist. Agonist-antagonist.

–– Non-opioids. Non-opioids. •• Salicylates. Salicylates. •• NSAIDs. NSAIDs. •• Adjuncts. Adjuncts.

Opioids Opioids •• Generic Genericreference referenceto to morphine-like morphine-like drugs/actions drugs/actions

–– Opiate: Opiate:derivative derivativeof ofopium opium

•• Prototype: Prototype:morphine morphine

–– Morpheus: Morpheus:god godof ofdreams dreams

•• Act Acton onendorphin endorphin receptors: receptors: –– ––

Mu Mu(most (mostimportant) important) Kappa Kappa

Actions Actions of of Opioid Opioid Receptors Receptors Response

Mu

Kappa

Analgesia

;

;

Respiratory Depression Sedation

;

Euphoria

;

Physical Dependence

;

⇓ GI motility

;

;

;

;

Actions Actions at at Opioid Opioid Receptors Receptors Drugs

Mu

Kappa

Pure Agonists

Agonist

Agonist

-morphine, codeine, meperidine (Demerol®), fentanyl (Sublimaze®), remifentanil (Ultiva®), propoxyphene (Darvon®), hydrocodone (Vicodin®), oxycodone (Percocet®)

Agonist-Antagonist -nalbuphine (Nubaine®), butorphanol (Stadol®) Pure Antagonist -naloxone (Narcan®)

Antagonist Agonist Antagonist Antagonist

General General Actions Actions of of Opioids Opioids •• •• •• •• •• •• ••

Analgesia Analgesia Respiratory Respiratory depression depression Constipation Constipation Urinary Urinary retention retention Cough Cough suppression suppression Emesis Emesis Increased Increased ICP ICP –– Indirect Indirectthrough throughCO CO22 retention retention

•• •• ••

Euphoria/Dysphoria Euphoria/Dysphoria Sedation Sedation Miosis Miosis –– Pupil Pupilconstriction constriction

•• ⇓⇓ Preload Preload & & afterload afterload –– Watch Watchfor for hypotension! hypotension!

Non -opioid Analgesics Non-opioid Analgesics •• Salicylates Salicylates –– Aspirin Aspirin (Bayer (Bayer®® )) ** (prototype (prototype for for class) class)

•• Non-Steroidal Non-Steroidal Anti-Inflammatory Anti-Inflammatory Drugs Drugs ® •• Ibuprofen Ibuprofen(Motrin®, (Motrin®,Advil Advil®))

–– Propionic PropionicAcid Acidderivative derivative ® •• Naproxen Naproxen(Naprosyn (Naprosyn®)) ® •• Naproxen Naproxensodium sodium(Aleve (Aleve®)) •• All Allcompete competewith withaspirin aspirinfor forprotein proteinbinding bindingsites sites

–– Ketorolac Ketorolac (Toradol (Toradol®®))

NSAID NSAID Properties Properties Drug

Fever

Inflammation Pain

Aspirin

;

;

;

Ibuprofen

;

;

;

Acetaminophen

;

;

Aspirin Aspirin Mechanism Mechanism of of Action Action •• Inhibit Inhibit synthesis synthesis of of cyclooxygenase cyclooxygenase (COX) (COX) –– Enzyme Enzyme responsible responsible for for synthesis synthesis of: of: Prostaglandins Prostaglandins

–Pain –Painresponse response –Suppression –Suppressionof ofgastric gastricacid acidsecretion secretion –Promote –Promotesecretion secretionof ofgastric gastricmucus mucusand andbicarbonate bicarbonate –Mediation –Mediationof ofinflammatory inflammatoryresponse response –Production –Productionof offever fever –Promote –Promoterenal renalvasodilation vasodilation(⇑ (⇑blood bloodflow) flow) –Promote –Promoteuterine uterinecontraction contraction

Thromboxane ThromboxaneAA22 –Involved –Involvedininplatelet platelet –aggregation –aggregation

Aspirin Aspirin Effects Effects Good Good •• Pain Pain relief relief •• ⇓⇓ Fever Fever •• ⇓⇓ Inflammation Inflammation

Bad Bad •• GI GI ulceration: ulceration:

–– ⇑⇑Gastric Gastricacidity acidity –– ⇓⇓GI GIprotection protection

•• •• ••

⇑⇑ Bleeding Bleeding ⇓⇓ Renal Renal elimination elimination ⇓⇓ Uterine Uterine contractions contractions during during labor labor

® Acetaminophen (Tylenol Acetaminophen (Tylenol®))

•• ••

NSAID NSAID similar similar to to aspirin aspirin Only Only inhibits inhibits synthesis synthesis of of CNS CNS prostaglandins prostaglandins –– Does Does not not have have peripheral peripheral side side effects effects of of ASA: ASA: •• Gastric Gastriculceration ulceration •• ⇓⇓Platelet Plateletaggregation aggregation •• ⇓⇓Renal Renalflow flow •• ⇓⇓Uterine Uterinecontractions contractions

Acetaminophen Acetaminophen Metabolism Metabolism Major Pathway Non-toxic Non-toxic metabolites metabolites

Acetaminophen Acetaminophen Induced Inducedby by ETOH ETOH P-450 Toxic Toxic metabolites metabolites Minor Pathway

Depleted Depletedby byETOH ETOH& & APAP APAPoverdose overdose Glutathione

Non-toxic Non-toxic metabolites metabolites

Anesthetics Anesthetics •• Loss Loss of of all all sensation sensation

–– Usually Usually with with loss loss of of consciousness consciousness –– ⇓⇓ propagation propagation of of neural neural impulses impulses

•• General General anesthetics anesthetics –– Gases Gases

®®), halothane, ether •• Nitrous oxide (Nitronox Nitrous oxide (Nitronox ), halothane, ether

–– IV IV

®®), methohexital (Brevitol®®), •• Thiopental (Pentothal Thiopental (Pentothal ), methohexital (Brevitol ), ® diazepam diazepam(valium®), (valium®),remifentanil remifentanil(Ultiva (Ultiva®))

Anesthetics Anesthetics •• Local Local –– Affect Affect on on area area around around injection injection –– Usually Usually accompanied accompanied by by epinephrine epinephrine ® •• Lidocaine Lidocaine(Xylocaine (Xylocaine ®),),topical topicalcocaine cocaine

Anti -anxiety & Anti-anxiety & Sedative Sedative-hypnotic hypnotic Drugs Drugs •• •• ••

Sedation: Sedation: ⇓⇓ anxiety anxiety & & inhibitions inhibitions Hypnosis: Hypnosis: instigation instigation of of sleep sleep Insomnia Insomnia –– ⇑⇑Latent Latentperiod period –– ⇑⇑Wakenings Wakenings

•• Classes: Classes:

–– Barbiturates Barbiturates –– Benzodiazepines Benzodiazepines –– Alcohol Alcohol

Chemically Chemicallydifferent, different, Functionally Functionallysimilar similar

Mechanism Mechanism of of action action •• Both Both promote promote the the effectiveness effectiveness of of GABA GABA receptors receptors in in the the CNS CNS –– Benzodiazepines Benzodiazepines promote promote only only –– Barbiturates Barbiturates promote promote and and (at (at high high doses) doses) stimulate stimulate GABA GABA receptors receptors

•• GABA GABA == chief chief CNS CNS inhibitory inhibitory neurotransmitter neurotransmitter –– Promotes Promotes hyperpolarization hyperpolarization via via ⇑⇑ Cl Cl-- influx influx

Benzodiazepines Benzodiazepines vs. vs. Barbiturates Barbiturates 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

Benzodiazepines Benzodiazepines Benzodiazepines Benzodiazepines ®®) •• diazepam (Valium diazepam (Valium ) ®®) •• midazolam (Versed midazolam (Versed ) •• alprazolam alprazolam (Xanax (Xanax®®)) •• lorazepam lorazepam (Atiavan (Atiavan®®)) •• triazolam triazolam (Halcion (Halcion®®))

“Non-benzo “Non-benzo benzo” benzo” ®®) •• zolpidem (Ambien zolpidem (Ambien ) ®®) •• buspirone (BusPar buspirone (BusPar )

Barbiturates Barbiturates Subgroup

Prototype

Typical Indication

Ultra-short acting

thiopental (Pentothol®)

Anesthesia

Short acting

secobarbital (Seconal®)

Insomnia

Long acting

phenobarbital (Luminal®)

Seizures

Barbiturates Barbiturates •• •• •• •• ••

®®) amobarbital (Amytal amobarbital (Amytal ) ®®) pentobarbital (Nembutal pentobarbital (Nembutal ) ®®) thiopental (Pentothal thiopental (Pentothal ) ®®) phenobarbital (Luminal phenobarbital (Luminal ) ®®) secobarbital (Seconal secobarbital (Seconal )

Anti -seizure Medications Anti-seizure Medications •• ••

Seizures Seizures caused caused by by hyperactive hyperactive brain brain areas areas Multiple Multiple chemical chemical classes classes of of drugs drugs –– All All have have same same approach approach –– Decrease Decrease propagation propagation of of action action potentials potentials

++, Ca++ •• ⇓⇓Na Na , Ca++influx influx(delay (delaydepolarization/prolong depolarization/prolong repolarization) repolarization) •• ⇑⇑Cl influx(hyperpolarize (hyperpolarizemembrane) membrane) Cl-influx

Anti -Seizure Medications Anti-Seizure Medications Benzodiazepines Benzodiazepines •• diazepam diazepam (Valium®) (Valium®) ®®) •• lorazepam (Ativan lorazepam (Ativan ) Barbiturates Barbiturates •• phenobarbital phenobarbital ®®) (Luminal (Luminal )

Ion Ion Channel Channel Inhibitors Inhibitors •• carbamazepine carbamazepine (Tegretol (Tegretol®®)) •• phenytoin phenytoin (Dilantin®) (Dilantin®) Misc. Misc. Agents Agents •• valproic valproic acid acid (Depakote®) (Depakote®)

Ion Ion Diffusion Diffusion •• ••

Key Key to to neurophysiology neurophysiology Dependent Dependent upon: upon: –– Concentration Concentration gradient gradient –– Electrical Electrical gradient gradient

•• Modified Modified by: by: –– ‘Gated ‘Gated ion ion channels’ channels’

Where Where Does Does Diffusion Diffusion Take Take the the Ion? Ion? + Na Na+ 150 150mM mM

KK++ 55mM mM

Cl ClHigh High

Exterior II NN

++ Na Na 15 15mM mM

O O UU TT KK++ 150 150mM mM

II NN

Interior -Cl Cl Low Low

Action Action Potential Potential Components Components Membrane Potential (mV)

Depolarization! Depolarization!

+ Na Na+equilibrium equilibrium

Action Action Potential Potential

+30 0

Threshold Threshold Potential Potential

-50 -70

Hyperpolarized Hyperpolarized

Time (msec)

Resting RestingMembrane Membrane Potential Potential

0

Na + Influx

+30

K+ Efflux

Membrane Potential (mV)

Membrane Membrane Permeability Permeability

Threshold Threshold Potential Potential

-50 -70

Resting RestingMembrane Membrane Potential Potential Time (msec)

0

Na + Influx

+30

K+ Efflux

Membrane Potential (mV)

-What Happens to the Membrane If Cl What Happens to the Membrane If Cl Rushes Rushes Into Into the the Cell Cell During During Repolarization? Repolarization?

It It gets gets hyperpolarized! hyperpolarized!

Threshold Threshold Potential Potential

-50 -70

Resting RestingMembrane Membrane Potential Potential Time (msec)

Membrane Potential (mV)

What What Happens Happens to to the the Frequency Frequency of of Action Action Potentials Potentials IfIf the the Membrane Membrane Gets Gets Hyperpolarized? Hyperpolarized? +30 0

It It decreases! decreases!

-50 -70

Time (msec)

Clinical Clinical Correlation Correlation •• Remember Rememberthat thatititisisthe therate rateof ofaction actionpotential potentialpropagation propagation that thatdetermines determinesneurologic neurologicfunction. function. –– Determined Determinedby byfrequency frequencyof ofaction actionpotentials. potentials.

What What What isis aa seizure? seizure? What would would be be the the effect effect on on the the membrane membrane -- influx of ⇑ Cl of ⇑ Cl influx Hyperpolarization & during during aa seizure? seizure? ⇓ seizure activity!

Cl Cl -

Gamma Gamma Amino Amino Butyric Butyric Acid Acid Receptors Receptors GABA GABA Receptor Receptor

Exterior

Hyperpolarized! Hyperpolarized! Interior

Cl Cl -

GABA+Bz GABA+Bz Complex Complex

Bz Bz Receptor Receptor

GABA GABA Receptor Receptor

Profoundly Profoundly Hyperpolarized! Hyperpolarized!

Exterior

Interior

Are Are You You Ready Ready for for aa Big Big Surprise? Surprise?

Many CNS drugs act on GABA receptors to effect the frequency and duration of action potentials!

SNS SNS Stimulants Stimulants •• Two Two general general mechanisms: mechanisms:

–– Increase Increase excitatory excitatory neurotransmitter neurotransmitter release release –– Decrease Decrease inhibitory inhibitory neurotransmitter neurotransmitter release release

•• Three Three classes: classes:

•• Amphetamines Amphetamines •• Methylphendidate Methylphendidate •• Methylxanthines Methylxanthines

Amphetamines Amphetamines amphetamine amphetamine methamphetamine methamphetamine dextroamphetamine dextroamphetamine ®®) (Dexedrine (Dexedrine )

MOA: MOA: promote promote release release of of norepinephrine, norepinephrine, dopamine dopamine

Indications Indications •Diet •Diet suppression suppression •⇓ •⇓ Fatigue Fatigue •⇑ •⇑ Concentration Concentration

Side Side Effects Effects •Tachycardia •Tachycardia •Hypertension •Hypertension •Convulsion •Convulsion •Insomnia •Insomnia •Psychosis •Psychosis

® Methylphenidate (Ritalin Methylphenidate (Ritalin®))

•• Different Different structure structure than than other other stimulants stimulants –– Similar Similar mechanism mechanism –– Similar Similar side side effects effects

•• Indication: Indication: ADHD ADHD –– Increase Increase ability ability to to focus focus & & concentrate concentrate

Methylxanthines Methylxanthines •• Caffeine Caffeine •• Theophylline Theophylline (Theo-Dur®) (Theo-Dur®) •• Aminophylline Aminophylline Mechanism Mechanism of of action action •• Reversible Reversible blockade blockade of of adenosine adenosine receptors receptors

AA patient patient is is taking taking theophylline theophylline and and becomes becomes tachycardic tachycardic (SVT). (SVT). You You want want to to give give her her adenosine. adenosine. Is Is there there an an interaction interaction you you should should be be aware aware of? of? How How should should you you alter alter your your therapy? therapy? Methylxanthines Methylxanthines blocks blocks adenosine adenosine receptors. receptors. A A typical typical dose dose of of adenosine adenosine may may not not be be sufficient sufficient to to achieve achieve the the desired desired result. result.

Double Double the the dose! dose!

News … News You You Can Can Use Use… Source

Amount of Caffeine

Coffee •Brewed •Instant Decaffeinated Coffee

40 – 180 mg/cup 30 – 120 mg/cup 2 - 5 mg/cup

Tea

20 – 110 mg/cup

Coke

40 – 60 mg/12 oz

Psychotherapeutic Psychotherapeutic Medications Medications •• Dysfunction Dysfunction related related to to neurotransmitter neurotransmitter imbalance. imbalance. –– Norepinephrine. Norepinephrine. –– Dopamine. Dopamine. –– Seratonin. Seratonin.

Monoamines

•• Goal Goal isis to to regulate regulate excitory/inhibitory excitory/inhibitory neurotransmitters. neurotransmitters.

Anti -Psychotic Drugs Anti-Psychotic Drugs (Neuroleptics) (Neuroleptics) •• Schizophrenia Schizophrenia –– Loss Loss of of contact contact with with reality reality & & disorganized disorganized thoughts thoughts –– Probable Probable cause: cause: increased increased dopamine dopamine release release –– Tx. Tx. Aimed Aimed at at decreasing decreasing dopamine dopamine activity activity Two Two Chemical Chemical Classes: Classes:

•• Phenothiazines Phenothiazines ••

® chlorpromazine chlorpromazine(Thorazine (Thorazine ®))

••

haloperidol haloperidol(Haldol (Haldol®))

•• Butyrophenones Butyrophenones®

Other Other Uses Uses for for Antipsychotics Antipsychotics •• •• •• •• ••

Bipolar Bipolar depression depression Tourette’s Tourette’s Syndrome Syndrome Prevention Prevention of of emesis emesis Dementia Dementia (OBS) (OBS) Temporary Temporary psychoses psychoses from from other other illness illness

Antipsychotic Antipsychotic MOA MOA •• ••

Mechanism Mechanism isis similar similar Strength Strength ([]) ([]) vs. vs. Potency Potency (‘oomph’) (‘oomph’) –– Phenothiazines Phenothiazines––low lowpotency potency –– Butyrophenones Butyrophenones––high highpotency potency

•• Receptor Receptor Antagonism Antagonism

–– Dopamine Dopamine22in inbrain brain –– Muscarinic Muscariniccholinergic cholinergic –– Histamine Histamine –– Norepi Norepiatatalpha alpha1 1

Therapeutic effects Uninteded effects

Antipsychotic Antipsychotic Side Side Effects Effects •• •• ••

Generally Generally short short term term Extrapyramidal Extrapyramidal symptoms symptoms (EPS) (EPS) Anticholinergic Anticholinergic effects effects (atropine-like) (atropine-like)

•• •• •• ••

Orthostatic Orthostatic hypotension hypotension Sedation Sedation Decreased Decreased seizure seizure threshold threshold Sexual Sexual dysfunction dysfunction

–– Dry Drymouth, mouth,blurred blurredvision, vision,photophobia, photophobia,tachycardia, tachycardia, constipation) constipation)

Extrapyramidal Extrapyramidal Symptoms Symptoms 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 dyskinesia

Months to years

Lip-smacking, worm-like tongue movement, ‘fly-catching’

Treatment Treatment of of EPS EPS •• Likely Likely caused caused by by blocking blocking central central dopamine receptors responsible responsible for for dopamine22 receptors movement movement •• Anticholinergic Anticholinergic therapy therapy rapidly rapidly effective effective ®®) –– diphenhydramine (Benadryl diphenhydramine (Benadryl )

Antipsychotic Antipsychotic Agents Agents •• •• •• ••

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

Antidepressants Antidepressants •• ••

Likely Likely cause: cause: inadequate inadequate monoamine monoamine levels levels Treatment Treatment options: options: –– Increasing Increasing NT NT synthesis synthesis in in presynaptic presynaptic end end bulb bulb –– Increasing Increasing NT NT release release from from end end bulb bulb –– Blocking Blocking NT NT ‘reuptake’ ‘reuptake’ by by presynaptic presynaptic end end bulb bulb

Tricyclic Tricyclic Antidepressants Antidepressants (TCAs) (TCAs) •• Block Block reuptake reuptake of of both both NE NE & & serotonin serotonin –– Enhance Enhanceeffects effects

•• Similar Similar side side effects effects to to phenothiazines phenothiazines

TCA TCA Side Side Effects Effects •• •• •• ••

Orthostatic Orthostatic hypotension hypotension Sedation Sedation Anticholinergic Anticholinergic effects effects Cardiac Cardiac toxicity toxicity –– Ventricular Ventricular dysrythmias dysrythmias

Selective Selective Serotonin Serotonin Reuptake Reuptake Inhibitors Inhibitors (SSRIs) (SSRIs) •• Block Block only only serotonin serotonin (not (not NE) NE) reuptake reuptake –– Elevate Elevate serotonin serotonin levels levels

•• Fewer Fewer side side effects effects than than TCS TCS –– No No hypotension hypotension –– No No anticholinergic anticholinergic effects effects –– No No cardiotoxicity cardiotoxicity

•• Most Most common common side side effect effect

–– Nausea, Nausea, insomnia, insomnia, sexual sexual dysfunction dysfunction

Monoamine Monoamine Oxidase Oxidase Inhibitors Inhibitors ((MAOIs) MAOIs) •• Monoamine Monoamine oxidase oxidase –– Present Present in in liver, liver, intestines intestines & & MA MA releasing releasing neurons neurons –– Inactivates Inactivates monoamines monoamines –– Inactivates Inactivates dietary dietary tyramine tyramine in in liver liver •• Foods Foodsrich richin intyramine: tyramine:cheese cheese& &red redwine wine

MAOI MAOI Side Side Effects Effects •• CNS CNS Stimulation Stimulation –– Anxiety, Anxiety, agitation agitation

•• ••

Orthostatic Orthostatic hypotension hypotension Hypertensive Hypertensive Crisis Crisis –– From From increased increased tyramine tyramine consumption consumption •• Excessive Excessivearteriole arterioleconstriction, constriction,stimulation stimulationof ofheart heart

MAOI MAOI & & Dietary Dietary Tyramine Tyramine

Antidepressant Antidepressant Mechanism Mechanism TCAs & SSRIs Block Here

Antidepressants Antidepressants Agents Agents TCAs TCAs •• •• ••

® imiprimine imiprimine(Tofranil (Tofranil®)) ® amitriptyline amitriptyline(Elavil (Elavil®)) ® nortriptyline nortriptyline(Pamelor (Pamelor ®))

SSRIs SSRIs •• •• ••

® fluoxetine fluoxetine(Prozac (Prozac®)) ® paroxetine paroxetine(Paxil (Paxil®)) ® sertraline sertraline(Zoloft (Zoloft®))

MAOIs MAOIs ®®) •• phenelzine (Nardil phenelzine (Nardil )

Atypical Atypical Antidepressants Antidepressants ® •• bupropion bupropion(Wellbutrin (Wellbutrin®))

Parkinson ’s Disease Parkinson’s Disease •• Fine Fine motor motor control control dependent dependent upon upon balance balance between between excitatory excitatory and and inhibitory inhibitory NT NT –– Acetylcholine Acetylcholine == excitatory excitatory –– Dopamine Dopamine =inhibitory =inhibitory GABA= GABA= inhibitory inhibitory

Control GABA release

Parkinson ’s Disease Parkinson’s Disease

Parkinson ’s Symptoms: Parkinson’s Symptoms: •• ••

Similar Similar to to EPS EPS Dyskinesias Dyskinesias –– Tremors, Tremors, unsteady unsteady gait, gait, instability instability

•• ••

Bradykinesia Bradykinesia Akinesia Akinesia in in severe severe cases cases

Parkinson ’s Treatment Parkinson’s Treatment •• Dopaminergic Dopaminergic approach approach –– ⇑⇑ Release Release of of dopamine dopamine –– ⇑⇑ [Dopamine] [Dopamine] –– ⇓⇓ Dopamine Dopamine breakdown breakdown

•• Cholinergic Cholinergic approach approach –– ⇓⇓ Amount Amount of of ACh ACh released released –– Directly Directly block block ACh ACh receptors receptors

•• All All treatment treatment isis symptomatic symptomatic and and temporary temporary

Levodopa Levodopa •• •• ••

Sinemet Sinemet ® ® == levodopa levodopa ++ carbidopa carbidopa Increase Increase central central dopamine dopamine levels levels Side Side effects: effects: –– Nausea Nausea and and vomiting vomiting –– Dyskinesia Dyskinesia (~80% (~80% of of population) population) –– Cardiovascular Cardiovascular (dysrythmias) (dysrythmias)

Levodopa Levodopa Mechanism Mechanism

Other Other Agents Agents ®®) •• amantadine (Symmetrel amantadine (Symmetrel )

–– ⇑⇑ release release of of dopamine dopamine from from unaffected unaffected neurons neurons

®®) •• bromocriptine (Parlodel bromocriptine (Parlodel )

–– Directly Directly stimulated stimulated dopamine dopamine receptors receptors ®®, Eldepryl®®) •• selegiline (Carbex selegiline (Carbex , Eldepryl )

–– MAOI MAOI selective selective for for dopamine dopamine (MAO-B) (MAO-B) ®®) •• benztropine (Cogentin benztropine (Cogentin )

–– Centrally Centrally acting acting anticholinergic anticholinergic

Drugs Drugs That That Affect Affect the the Autonomic Autonomic Nervous Nervous System System Word Word of of Warning Warning Carefully Carefully review review the the A&P A&P material material & & tables tables on on pages pages 309 309 –– 314 314 and and 317 317 –– 321! 321!

PNS PNS Drugs Drugs •• Cholinergic Cholinergic –– Agonists Agonists & & Antagonistis Antagonistis (Anticholinergics) (Anticholinergics) –– Based & Based on on response response at at nicotinic nicotinic(N&M) (N&M) & muscarinic muscarinic receptors receptors

Acetylcholine Acetylcholine Receptors Receptors

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

Cholinergic Cholinergic Agonists Agonists Cholinergic agents cause SLUDGE! HINT! These effects are predictable by knowing PNS physiology (table 9-4)

Salivation Salivation Lacrimation Lacrimation Urination Urination Defecation Defecation Gastric Gastric motility motility Emesis Emesis

Direct Direct Acting Acting Cholinergics Cholinergics •• bethanechol bethanechol (Urecholine) (Urecholine) prototype prototype –– Direct Direct stimulation stimulation of of ACh ACh receptors receptors –– Used Used for for urinary urinary hesitancy hesitancy and and constipation constipation

Indirect Indirect Acting Acting Cholinergics Cholinergics •• Inhibit Inhibit ChE ChE (cholinesterase) (cholinesterase) to to prolong prolong the the duration duration of of ACh ACh stimulation stimulation in in synapse synapse •• Reversible Reversible •• Irreversible Irreversible

Reversible Reversible ChE ChE Inhibitors Inhibitors ®®) •• neostigmine (Prostigmine neostigmine (Prostigmine )

–– Myasthenia Myasthenia Gravis Gravis at at nicotinic nicotinicMM receptors receptors –– Can Can reverse reverse nondepolarizing nondepolarizing neuromuscular neuromuscular blockade blockade

•• physostigmine physostigmine (Antilirium®) (Antilirium®) –– Shorter Shorter onset onset of of action action –– Used Used for for iatrogenic iatrogenic atropine atropine overdoses overdoses @ @ muscarinic muscarinic receptors receptors

Irreversible Irreversible ChE ChE Inhibitors Inhibitors •• ••

Very Very rarely rarely used used clinically clinically Very Very common common in in insecticides insecticides & & chemical chemical weapons weapons –– VX VX and and Sarin Sarin gas gas –– Cause Cause SLUDGE SLUDGE dammit dammit and and paralysis paralysis

®®) •• Tx: atropine and pralidoxime (2-PAM Tx: atropine and pralidoxime (2-PAM )

–– Anticholinergics Anticholinergics

Anticholinergics Anticholinergics •• Muscarinic Muscarinic antagonists antagonists –– Atropine Atropine

•• Ganglionic Ganglionic antagonists antagonists –– block blocknicotinic nicotinicNN receptors receptors –– Turns Turnsoff offthe theANS! ANS! –– trimethaphan trimethaphan ®®) (Arfonad (Arfonad )

•• Hypertensive Hypertensivecrisis crisis

•• Atropine Atropine Overdose Overdose –– Dry Drymouth, mouth,blurred blurred vision, vision,anhidrosis anhidrosis Hot Hotas asHell Hell Blind Blindas asaaBat Bat Dry Dryas asaaBone Bone Red Redas asaaBeet Beet Mad Madas asaaHatter Hatter

Neuromuscular Neuromuscular Blockers Blockers •• Nicotinic Nicotinic Cholinergic Cholinergic Antagonists Antagonists –– Given Given to to induce induce paralysis paralysis

•• Depolarizing Depolarizing –– succinylcholine succinylcholine (Anectin (Anectin®®))

•• Nondepolarizing Nondepolarizing –– tubocurarine tubocurarine from from curare curare –– rocuronium rocuronium (Zemuron (Zemuron®®)) –– vecuronium vecuronium (Norcuron (Norcuron®®))

Warning! Warning! •• Paralysis Paralysis without without loss loss of of consciousness! consciousness! –– MUST MUST also also give give sedative-hypnotic sedative-hypnotic –– Common Common agents: agents: ® •• fentanyl fentanyl(Sublimaze (Sublimaze®)) ®®) •• midazolam (Versed midazolam (Versed )

SNS SNS Drugs Drugs •• Predictable Predictable response response based based on on knowledge knowledge of of affects affects of of adrenergic adrenergic receptor receptor stimulation stimulation •• HINT: HINT: Know Know table table 9-5, 9-5, page page 321 321 •• Each Each receptor receptor may may be: be: –– Stimulated Stimulated (sympathomimetic) (sympathomimetic) –– Inhibitied Inhibitied (sympatholytic) (sympatholytic)

Alpha Alpha11 Agonists Agonists •• Profound Profound vasoconstriction vasoconstriction –– Increases Increases afterload afterload & & blood blood pressure pressure when when given given systemically systemically –– Decreases Decreases drug drug absorption absorption & & bleeding bleeding when when given given topically topically

Alpha Alpha11 Antagonism Antagonism •• Inhibits Inhibits peripheral peripheral vasoconstriction vasoconstriction –– Used Used for for hypertension hypertension –– prazosin prazosin (Minipress (Minipress®®)) –– doxazosin doxazosin (Cardura (Cardura®®)) –– phentolamine phentolamine (Regitine (Regitine®®)) •• Blocks receptors Blocksalpha alpha1&2 1&2 receptors

Beta Beta11 Agonists Agonists •• Increases Increases heart heart rate, rate, contractility, contractility, and and conductivity conductivity

Beta β Blockers) Beta Antagonists Antagonists ((β Blockers) •• •• ••

Frequently Frequently used used Lower Lower Blood Blood Pressure Pressure Negative Negative chronotropes chronotropes & & inotropes inotropes

Beta Beta11Selective SelectiveBlockade Blockade ® •• atenolol atenolol(Tenormin (Tenormin®)) ®®) •• esmolol (Brevibloc esmolol (Brevibloc ) ® •• metoprolol metoprolol(Lopressor (Lopressor®))

Nonselective Nonselective ® •• propranolol propranolol(Inderal (Inderal®)) ®®, •• labetalol (Normodyne labetalol (Normodyne , ®®) Trandate Trandate ) ® •• sotalol sotalol(Betapace (Betapace®))

Adrenergic Adrenergic Receptor Receptor Specificity Specificity Drug Epinephrine Ephedrine Norepinephrine Phenylephrine Isoproterenol Dopamine Dobutamine terbutaline

α1

α2

β1

β2

Dopaminergic

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

Thank Thank You! You! •• To To Temple Temple College College EMS EMS Professions Professions for for permission permission to to use use their their materials materials