Pharmacology

Drugs That Affect The: Nervous System

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

But first...

A colorful review of neurophysiology!

Nervous System
CNS PNS

Autonomic

Somatic

Sympathetic

Parasympathetic

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

Non-opioids.
Salicylates. NSAIDs. Adjuncts.

Opioids
Generic reference to morphine-like drugs/actions
Opiate: derivative of opium

Prototype: morphine
Morpheus: god of dreams

Act on endorphin receptors:

Mu (most important) Kappa

Actions of Opioid Receptors

Response
Analgesia Respiratory Depression Sedation Euphoria Physical Dependence GI motility

Mu

Kappa

Actions at Opioid Receptors

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

Mu
Agonist

Kappa
Agonist

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

-naloxone (Narcan)

Antagonist Agonist Antagonist Antagonist

General Actions of Opioids

Analgesia Respiratory depression Constipation Urinary retention Cough suppression Emesis Increased ICP
Indirect through CO2 retention

Euphoria/Dysphoria Sedation Miosis

Pupil constriction

Preload & afterload

Watch for hypotension!

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

Non-Steroidal Anti-Inflammatory Drugs

Ibuprofen (Motrin, Advil)
Propionic Acid derivative

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

Ketorolac (Toradol)

NSAID Properties
Drug
Aspirin Ibuprofen Acetaminophen

Fever

Inflammation Pain

Aspirin Mechanism of Action

Inhibit synthesis of cyclooxygenase (COX)
Enzyme responsible for synthesis of:
Prostaglandins
Pain response Suppression of gastric acid secretion Promote secretion of gastric mucus and bicarbonate Mediation of inflammatory response Production of fever Promote renal vasodilation ( blood flow) Promote uterine contraction

Thromboxane A2
Involved in platelet aggregation

Aspirin Effects
Good Pain relief Fever Inflammation Bad GI ulceration:
Gastric acidity GI protection

Bleeding Renal elimination Uterine contractions during labor

Acetaminophen (Tylenol)
NSAID similar to aspirin Only inhibits synthesis of CNS prostaglandins
Does not have peripheral side effects of ASA:
Gastric ulceration Platelet aggregation Renal flow Uterine contractions

Acetaminophen Metabolism
Major Pathway Acetaminophen Non-toxic metabolites Depleted by ETOH & APAP overdose

Induced by ETOH
P-450 Toxic metabolites Minor Pathway

Glutathione

Non-toxic metabolites

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

General anesthetics
Gases
Nitrous oxide (Nitronox), halothane, ether

IV
Thiopental (Pentothal), methohexital (Brevitol), diazepam (valium), remifentanil (Ultiva)

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

Anti-anxiety & Sedativehypnotic Drugs

Sedation: anxiety & inhibitions Hypnosis: instigation of sleep Insomnia
Latent period Wakenings

Classes:
Barbiturates Benzodiazepines Alcohol

Chemically different, Functionally similar

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

GABA = chief CNS inhibitory neurotransmitter

Promotes hyperpolarization via Cl- influx

Benzodiazepines vs. Barbiturates

Criteria
Relative Safety

BZ

Barb.

High Low

Maximal CNS depression

Respiratory Depression

Low High
Low High

Suicide Potential
Abuse Potential Antagonist Available?

Low High
Low High Yes No

Benzodiazepines
Benzodiazepines diazepam (Valium) midazolam (Versed) alprazolam (Xanax) lorazepam (Atiavan) triazolam (Halcion) Non-benzo benzo zolpidem (Ambien) buspirone (BusPar)

Barbiturates
Subgroup
Ultra-short acting Short acting Long acting

Prototype
thiopental (Pentothol) secobarbital (Seconal) phenobarbital (Luminal)

Typical Indication
Anesthesia Insomnia Seizures

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

Anti-seizure Medications
Seizures caused by hyperactive brain areas Multiple chemical classes of drugs
All have same approach Decrease propagation of action potentials
Na+, Ca++ influx (delay depolarization/prolong repolarization) Cl- influx (hyperpolarize membrane)

Anti-Seizure Medications
Benzodiazepines diazepam (Valium) lorazepam (Ativan) Barbiturates phenobarbital (Luminal) Ion Channel Inhibitors carbamazepine (Tegretol) phenytoin (Dilantin) Misc. Agents valproic acid (Depakote)

Ion Diffusion
Key to neurophysiology Dependent upon:
Concentration gradient Electrical gradient

Modified by:
Gated ion channels

Where Does Diffusion Take the Ion?

Na+ 150 mM K+ 5 mM ClHigh Exterior I N O U T

Interior
Na+ 15 mM K+ 150 mM ClLow

Action Potential Components

Depolarization! Action Potential
+30 0

Na+ equilibrium

Threshold Potential

-50 -70

Hyperpolarized

Resting Membrane Potential

Time (msec)

Membrane Permeability
+30 0

Threshold Potential

-50 -70

Resting Membrane Potential Time (msec)

What Happens to the Membrane If ClRushes Into the Cell During Repolarization?

+30 0

It gets hyperpolarized!

Threshold Potential

-50 -70

Resting Membrane Potential Time (msec)

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

It decreases!

-50 -70

Time (msec)

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

What is a seizure? What would be the effect on the membrane of Cl- influx Hyperpolarization & during a seizure?
seizure activity!

Cl -

Gamma Amino Butyric Acid Receptors GABA

Receptor

Exterior

Hyperpolarized!

Interior

Cl -

GABA+Bz Complex
Bz Receptor GABA Receptor

Profoundly Hyperpolarized!

Exterior

Interior

Are You Ready for a Big Surprise?

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

SNS Stimulants
Two general mechanisms:
Increase excitatory neurotransmitter release Decrease inhibitory neurotransmitter release

Three classes:
Amphetamines Methylphendidate Methylxanthines

Amphetamines
amphetamine methamphetamine dextroamphetamine (Dexedrine) Indications Diet suppression Fatigue Concentration MOA: promote release of norepinephrine, dopamine Side Effects Tachycardia Hypertension Convulsion Insomnia Psychosis

Methylphenidate (Ritalin)
Different structure than other stimulants
Similar mechanism Similar side effects

Indication: ADHD
Increase ability to focus & concentrate

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

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

Double the dose!

News You Can Use

Source
Coffee Brewed Instant Decaffeinated Coffee Tea Coke

Amount of Caffeine

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

20 110 mg/cup 40 60 mg/12 oz

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

Monoamines

Goal is to regulate excitory/inhibitory neurotransmitters.

Anti-Psychotic Drugs (Neuroleptics)

Schizophrenia
Loss of contact with reality & disorganized thoughts Probable cause: increased dopamine release Tx. Aimed at decreasing dopamine activity Two Chemical Classes:

Phenothiazines
chlorpromazine (Thorazine )

Butyrophenones
haloperidol (Haldol)

Other Uses for Antipsychotics

Bipolar depression Tourettes Syndrome Prevention of emesis Dementia (OBS) Temporary psychoses from other illness

Antipsychotic MOA
Mechanism is similar Strength ([]) vs. Potency (oomph)
Phenothiazines low potency Butyrophenones high potency

Receptor Antagonism
Dopamine2 in brain Muscarinic cholinergic Histamine Norepi at alpha1 Therapeutic effects Uninteded effects

Antipsychotic Side Effects

Generally short term Extrapyramidal symptoms (EPS) Anticholinergic effects (atropine-like)
Dry mouth, blurred vision, photophobia, tachycardia, constipation)

Orthostatic hypotension Sedation Decreased seizure threshold Sexual dysfunction

Extrapyramidal Symptoms
Reaction
Acute dystonia Parkinsonism Akathesia Tarditive dyskinesia

Onset
Hours to 5 days 5 30 days 5 60 days Months to years

Features
Spasm of tongue, neck, face & back Tremor, shuffling gait, drooling, stooped posture, instability Compulsive, repetitive motions; agitation Lip-smacking, worm-like tongue movement, fly-catching

Treatment of EPS
Likely caused by blocking central dopamine2 receptors responsible for movement Anticholinergic therapy rapidly effective
diphenhydramine (Benadryl)

Antipsychotic Agents
chlorpromazine (Thorazine) thioridazine (Mellaril) trifluoperazine (Stelazine) haloperidol (Haldol)

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

Tricyclic Antidepressants (TCAs)

Block reuptake of both NE & serotonin
Enhance effects

Similar side effects to phenothiazines

TCA Side Effects

Orthostatic hypotension Sedation Anticholinergic effects Cardiac toxicity
Ventricular dysrythmias

Selective Serotonin Reuptake Inhibitors (SSRIs)

Block only serotonin (not NE) reuptake
Elevate serotonin levels

Fewer side effects than TCS

No hypotension No anticholinergic effects No cardiotoxicity

Most common side effect

Nausea, insomnia, sexual dysfunction

Monoamine Oxidase Inhibitors (MAOIs)

Monoamine oxidase
Present in liver, intestines & MA releasing neurons Inactivates monoamines Inactivates dietary tyramine in liver
Foods rich in tyramine: cheese & red wine

MAOI Side Effects

CNS Stimulation
Anxiety, agitation

Orthostatic hypotension Hypertensive Crisis

From increased tyramine consumption
Excessive arteriole constriction, stimulation of heart

MAOI & Dietary Tyramine

Antidepressant Mechanism
TCAs & SSRIs Block Here

Antidepressants Agents
TCAs
imiprimine (Tofranil) amitriptyline (Elavil) nortriptyline (Pamelor )

MAOIs
phenelzine (Nardil)

Atypical Antidepressants
bupropion (Wellbutrin)

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

Parkinsons Disease
Fine motor control dependent upon balance between excitatory and inhibitory NT
Acetylcholine = excitatory Dopamine =inhibitory GABA= inhibitory
Control GABA release

Parkinsons Disease

Parkinsons Symptoms:
Similar to EPS Dyskinesias
Tremors, unsteady gait, instability

Bradykinesia Akinesia in severe cases

Parkinsons Treatment
Dopaminergic approach
Release of dopamine [Dopamine] Dopamine breakdown

Cholinergic approach
Amount of ACh released Directly block ACh receptors

All treatment is symptomatic and temporary

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

Levodopa Mechanism

Other Agents
amantadine (Symmetrel)
release of dopamine from unaffected neurons

bromocriptine (Parlodel)
Directly stimulated dopamine receptors

selegiline (Carbex, Eldepryl)

MAOI selective for dopamine (MAO-B)

benztropine (Cogentin)
Centrally acting anticholinergic

Drugs That Affect the Autonomic Nervous System

Word of Warning Carefully review the A&P material & tables on pages 309 314 and 317 321!

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

Acetylcholine Receptors

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

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

Salivation Lacrimation Urination Defecation Gastric motility Emesis

Direct Acting Cholinergics

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

Indirect Acting Cholinergics

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

Reversible ChE Inhibitors

neostigmine (Prostigmine)
Myasthenia Gravis at nicotinicM receptors Can reverse nondepolarizing neuromuscular blockade

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

Irreversible ChE Inhibitors

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

Tx: atropine and pralidoxime (2-PAM)

Anticholinergics

Anticholinergics
Muscarinic antagonists Atropine Overdose
Atropine

Ganglionic antagonists
block nicotinicN receptors Turns off the ANS! trimethaphan (Arfonad)
Hypertensive crisis

Dry mouth, blurred vision, anhidrosis

Hot as Hell Blind as a Bat Dry as a Bone Red as a Beet Mad as a Hatter

Neuromuscular Blockers
Nicotinic Cholinergic Antagonists
Given to induce paralysis

Depolarizing
succinylcholine (Anectin)

Nondepolarizing
tubocurarine from curare rocuronium (Zemuron) vecuronium (Norcuron)

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

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

Alpha1 Agonists
Profound vasoconstriction
Increases afterload & blood pressure when given systemically Decreases drug absorption & bleeding when given topically

Alpha1 Antagonism
Inhibits peripheral vasoconstriction
Used for hypertension prazosin (Minipress) doxazosin (Cardura) phentolamine (Regitine)
Blocks alpha1&2 receptors

Beta1 Agonists
Increases heart rate, contractility, and conductivity

Beta Antagonists ( Blockers)

Frequently used Lower Blood Pressure Negative chronotropes & inotropes
Beta1 Selective Blockade atenolol (Tenormin) esmolol (Brevibloc) metoprolol (Lopressor) Nonselective propranolol (Inderal) labetalol (Normodyne, Trandate) sotalol (Betapace)

Adrenergic Receptor Specificity

Drug
Epinephrine Ephedrine Norepinephrine Phenylephrine Isoproterenol Dopamine Dobutamine terbutaline

Dopaminergic

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