the autonomic nervous system - prehospital medicine · autonomic nervous system functions: ......

The Autonomic Nervous SystemThe Autonomic Nervous System

Autonomic Nervous SystemAutonomic Nervous System

Functions:Functions:

Without conscious effort, Without conscious effort,

Continuously.Continuously.

Controls:Controls:

Activities in smooth & cardiac muscles and Activities in smooth & cardiac muscles and sweat glands.sweat glands.

Nervous SystemNervous SystemNervous System

Central N.S.

brain &spinal cord

Peripheral N.S.AfferentDivision (information in)

EfferentDivision

(orders out)

Somatic System

(skeletal muscles)

AutonomicsystemSympathetic Parasympathetic

Presenter

Presentation Notes

Nervous system divided into two main divisions: Central Nervous System ( CNS ) – brain & spinal cord. Peripheral Nervous System ( PNS ) Afferent ( sensory ) Efferent ( effector ) – Somatic system – skeletal muscle. Autonomic system – regulates smooth & cardiac muscle. Sympathetic Parasympathetic – cranial & spinal nerves.

Components of the ANSComponents of the ANS

The autonomic component is divided The autonomic component is divided anatomically into:anatomically into:

the nerve fibers that innervate target organs the nerve fibers that innervate target organs or tissues or tissues

and nerve fibers that innervate the adrenal and nerve fibers that innervate the adrenal medulla that causes the release of substances medulla that causes the release of substances called catecholamines that act upon the ANS.called catecholamines that act upon the ANS.

Autonomic Nervous SystemAutonomic Nervous System

The Autonomic System can be influenced or The Autonomic System can be influenced or manipulated in two ways:manipulated in two ways:

by hormones that are circulated through the blood stream by hormones that are circulated through the blood stream ((ieie. ADH);. ADH);

and by the stimulation or blocking of nerve impulses. An and by the stimulation or blocking of nerve impulses. An example is the transmission impulses from receptors in the example is the transmission impulses from receptors in the carotid sinus and aortic arch to control B/P.carotid sinus and aortic arch to control B/P.

Both play important roles in the reflex regulation of the Both play important roles in the reflex regulation of the systemsystem. .

Sympathetic NeuronsSympathetic Neurons

Sympathetic neurons exit the spinal cord Sympathetic neurons exit the spinal cord via the thoracic vertebrae and lumbar via the thoracic vertebrae and lumbar vertebrae. For this reason the vertebrae. For this reason the sympathetic division is sometimes called sympathetic division is sometimes called the the thoracolumbarthoracolumbar division.division.

Sympathetic DivisionSympathetic Division

Presenter

Presentation Notes

Sometimes, you will hear the sympathetic nervous system referred to as the thoraco-lumbar system because of where the preganglionic neurons leave the spinal cord ( all thoracic and upper 2 or 3 lumbar ). The preganglionic nerves synapse at the ganglia, where a neurotransmitter passes on the impulse to the postganglionic axons which then innervate the target organ or tissue, thus causing a response. ( Short ) Preganglionic neurons arise from the thoracic & lumbar regions ( lateral horn of the spinal cord ) and synapse in ganglia. ( Long ) Postganglionic axons extend to effector organs and glands. Adrenal medulla secretes catecholamines.

Parasympathetic NeuronsParasympathetic Neurons

The parasympathetic system is also termed the The parasympathetic system is also termed the CranialCranial--SacralSacral system because of the location system because of the location on the spinal cord that these nerves are located. on the spinal cord that these nerves are located.

PreganglionicPreganglionic fibres arise from neurons in the fibres arise from neurons in the midbrain midbrain –– medulla & pons medulla & pons –– and the sacral area and the sacral area of he spinal cord. of he spinal cord.

The Vagus ( X ) nerve carries about The Vagus ( X ) nerve carries about ¾¾ of all of all Parasympathetic fibres.Parasympathetic fibres.

Parasympathetic DivisionParasympathetic Division

Presenter

Presentation Notes

They, too, synapse at a ganglia and pass on their impulses to the postganglionic nerves to their effector organ or tissue. ( Long ) Preganglionic fibers arise from the cranial & sacral areas. ( Short ) Postganglionic fibers innervate effector organs and glands.

Anatomy

• Sympathetic

• Parasympathetic

- “thoracolumbar”- T1-L3 (F, F, F)

- “craniosacral”- brainstem &S2-S4 (R & D)

Actions: Sympathetic vs. Actions: Sympathetic vs. ParasympatheticParasympathetic

Site Sympathetic Sympathetic ParasympatheticParasympathetic

Eye Dilate Constrict

Trachea/ BronchiTrachea/ Bronchi DilateDilate Constrict, increase Constrict, increase secretionssecretions

HeartHeart Increase HR, Increase HR, contractilitycontractility

Decrease rate, Decrease rate, contractilitycontractility

GI TractGI Tract Decrease GI MotilityDecrease GI Motility Increase MotilityIncrease Motility

Blood Supply to Blood Supply to MusclesMuscles

IncreasedIncreased No effectNo effect

Blood Supply to Blood Supply to Skin/Mucous Skin/Mucous MembranceMembrance/GI Tract/GI Tract

ConstrictConstrict No effectNo effect

ExceptionsExceptions

All systems dual innervation (both sympathetic and parasympathetic fibres).

Exceptions:

Adrenal medulla

Sweat glands and piloerector muscles

Ventricles of Heart

ALL ARE SYMPATHETIC INNERVATION ONLY

Structure of a typical neuronStructure of a typical neuron

Axon End Terminal; Meet Axon End Terminal; Meet DendriteDendrite

Slide #3 (BASIC)

Actual PhotographActual Photograph

Neurons and NeurotransmittersNeurons and Neurotransmitters

Two of the most frequently discussed Two of the most frequently discussed neurotransmitters:neurotransmitters:

Epinephrine and NorepinephrineEpinephrine and Norepinephrine

binds to:binds to:

alpha (alpha (11 22 ))

beta (beta (11 2 2 ))--note NE binds B1 onlynote NE binds B1 only

AcetylcholineAcetylcholine

nicotinic

muscarinic

Other NeurotransmittersOther Neurotransmitters

serotoninserotonin (5(5--HT)HT)

melatoninmelatonin

GlutamateGlutamate

gamma gamma aminobutyricaminobutyric acidacid (GABA), (GABA), aspartateaspartate

glycineglycine

histaminehistamine

AdenosineAdenosine, , ATPATP, , GTPGTP, and their derivatives , and their derivatives

http://en.wikipedia.org/wiki/Serotonin

http://en.wikipedia.org/wiki/Melatonin

http://en.wikipedia.org/wiki/Glutamate

http://en.wikipedia.org/wiki/Gamma_aminobutyric_acid



http://en.wikipedia.org/wiki/Aspartate

http://en.wikipedia.org/wiki/Glycine

http://en.wikipedia.org/wiki/Histamine

http://en.wikipedia.org/wiki/Adenosine

http://en.wikipedia.org/wiki/Adenosine_triphosphate

http://en.wikipedia.org/wiki/Guanosine_triphosphate

Neurotransmitters send chemical messages.

Presenter

Presentation Notes

Slide 7: The synapse and synaptic neurotransmission Describe the synapse and the process of chemical neurotransmission. As an electrical impulse arrives at the terminal, it triggers vesicles containing a neurotransmitter, such as dopamine (in blue), to move toward the terminal membrane . The vesicles fuse with the terminal membrane to release their contents (in this case, dopamine). Once inside the synaptic cleft (the space between the 2 neurons) the dopamine can bind to specific proteins called dopamine receptors (in pink) on the membrane of a neighboring neuron. This is illustrated in more detail on the next slide.

NorepinephrineNorepinephrine

The major postganglionic neurotransmitter The major postganglionic neurotransmitter of the SNS.of the SNS.

It is produced from building blocks that It is produced from building blocks that are present in the end terminal of the are present in the end terminal of the neuron.neuron.

Adrenal medulla: 80% NE

EPI

Presenter

Presentation Notes

Tyrosine----------DOPA DOPA------------Dopamine Transport of dopamine into vesicles Dopamine---------Norepinephrine In adrenal medulla, 80% of norepinephrine is converted into epinephrine.

Storage and ReleaseStorage and Release

Neurotransmitters are Neurotransmitters are taken up for storage taken up for storage at terminal endings of at terminal endings of nerves.nerves.

Nerve impulse Nerve impulse prompts prompts exocytosisexocytosis of of vesicles containing vesicles containing neurotransmitter.neurotransmitter.

ExocytosisExocytosis

NorepinephrineNorepinephrine

Following its use as a neurotransmitter, Following its use as a neurotransmitter, Norepinephrine is removed by:Norepinephrine is removed by:

Reuptake into the terminal nerve ending by Reuptake into the terminal nerve ending by active transport active transport –– 5050--80%. 80%.

Na+,K+Na+,K+--ATPaseATPase is the pump responsible for this reuptake. is the pump responsible for this reuptake.

Pump inhibited by cocaine, Pump inhibited by cocaine, TCAsTCAs..

Diffusion away from the nerve endings into the Diffusion away from the nerve endings into the surrounding body fluids.surrounding body fluids.

Destruction by enzymes such as MAO & COMT.Destruction by enzymes such as MAO & COMT.

Synthesis of AcetylcholineSynthesis of Acetylcholine

Acetylcholine is the major preganglionic Acetylcholine is the major preganglionic neurotransmitter of both the SNS and PNS and neurotransmitter of both the SNS and PNS and is the neurotransmitter of the postganglionic is the neurotransmitter of the postganglionic side of the PNS. side of the PNS.

It is also the neurotransmitter for the somatic It is also the neurotransmitter for the somatic system with striated skeletal muscle.system with striated skeletal muscle.

The only exception to this is the The only exception to this is the neurotransmitter for the neurotransmitter for the pilomotorpilomotor and sweat and sweat glands innervated by the SNS. Acetylcholine is glands innervated by the SNS. Acetylcholine is the neurotransmitter responsible at this end the neurotransmitter responsible at this end also, not Norepinephrine. This distinction is also, not Norepinephrine. This distinction is important when you start to study important when you start to study toxidromestoxidromes. .

Synthesis of AcetylcholineSynthesis of Acetylcholine

The process of synthesizing acetylcholine The process of synthesizing acetylcholine requires a catalyst to enable the reaction to requires a catalyst to enable the reaction to occur. occur.

This enzyme is This enzyme is cholinecholine acetyltransferaseacetyltransferase. .

On the opposite end, when acetylcholine is On the opposite end, when acetylcholine is broken down, it requires cholinesterase to broken down, it requires cholinesterase to facilitate the process. facilitate the process.

Acetyl coenzyme A binds with Acetyl coenzyme A binds with cholinecholine in the in the presence of catalyst presence of catalyst cholinecholine acetyltransferaseacetyltransferase to form acetylcholine.to form acetylcholine.

Acetylcholine is brokenAcetylcholine is broken--down by down by cholinesterase.cholinesterase.

ANS ReceptorsANS Receptors

The parasympathetic system is The parasympathetic system is referred to as the cholinergic referred to as the cholinergic system system –– this is because the major this is because the major neurotransmitter for the PNS is neurotransmitter for the PNS is acetylcholine.acetylcholine.

So why is the sympathetic system So why is the sympathetic system called the adrenergic system?called the adrenergic system?

There are two major receptors in the There are two major receptors in the PNS:PNS:

ANS ReceptorsANS Receptors

MuscarinicMuscarinic which are in the postganglionic PNS which are in the postganglionic PNS on the target end organs.on the target end organs.

NicotinicNicotinic, which are in the preganglionic side of , which are in the preganglionic side of both the SNS and the PNS.both the SNS and the PNS.

Some of the drugs that we administer affect Some of the drugs that we administer affect these receptors specifically: atropine blocks these receptors specifically: atropine blocks muscarinic receptors specifically and other muscarinic receptors specifically and other agents (curare) block nicotinic receptors in agents (curare) block nicotinic receptors in skeletal muscleskeletal muscle

Receptors ( I )Receptors ( I )

Adrenergic ( SNS ):Adrenergic ( SNS ):

11

blood vesselsblood vessels

constrictionconstriction

22

11

heartheart

HR, contractility, & HR, contractility, & conduction conduction

22

bronchial/vascular s.m.bronchial/vascular s.m.

dilationdilation

Cholinergic ( PNS ):Cholinergic ( PNS ):

Muscarinic:Muscarinic:

endend--organs organs ( Parasympathetic )( Parasympathetic )

stimulate accordinglystimulate accordingly

Nicotinic:Nicotinic:

gangliaganglia

stimulate poststimulate post-- ganglion neuronganglion neuron

musclesmuscles

stimulate contractionstimulate contraction

alpha ( alpha (

) and beta ( ) and beta (

) ) Receptors:Receptors:Alpha ReceptorsAlpha Receptors

Alpha 1Alpha 1 receptors:receptors:

Found predominately outside of the heart & major Found predominately outside of the heart & major organs.organs.

Influence smooth muscle found in the peripheral Influence smooth muscle found in the peripheral vasculature, intestinal tract and eyes.vasculature, intestinal tract and eyes.

Alpha 1:Alpha 1:

Vasoconstriction, pupil dilation, intestinal relaxation, Vasoconstriction, pupil dilation, intestinal relaxation, etc.etc.

Alpha ReceptorsAlpha Receptors

Alpha 2Alpha 2 receptors:receptors:

Act as a mediator of neurotransmitter production Act as a mediator of neurotransmitter production –– as neurotransmitter is released from the neuron, as neurotransmitter is released from the neuron, receptor sites on the neuron become filled receptor sites on the neuron become filled –– when when sufficient numbers have been occupied, a message sufficient numbers have been occupied, a message is sent to reduce or turnis sent to reduce or turn--off the production of off the production of neurotransmitter neurotransmitter –– this is sometimes referred to as this is sometimes referred to as a feedback loop mechanism.a feedback loop mechanism.

Alpha 2:Alpha 2:

Preganglionic receptor that regulates the release of Preganglionic receptor that regulates the release of neurotransmitter through a feedback loop.neurotransmitter through a feedback loop.

alpha ( alpha (


) ) Receptors:Receptors:

Beta ReceptorsBeta Receptors

Beta 1Beta 1 receptors:receptors:

Found in the heart Found in the heart –– stimulation or stimulation or excitement of these receptors leads to an excitement of these receptors leads to an increase in heart rate (chronotropic), in force increase in heart rate (chronotropic), in force of contraction (of contraction (inotropicinotropic), and rate of nerve ), and rate of nerve impulse conduction (impulse conduction (dromotropicdromotropic).).

alpha ( alpha (


) ) Receptors:Receptors:

alpha ( alpha (


) ) Receptors:Receptors:Beta ReceptorsBeta Receptors

Beta 2Beta 2 receptors:receptors:

Found primarily in the pulmonary smooth muscle lining the Found primarily in the pulmonary smooth muscle lining the lower airways of the lungs and in the peripheral vasculature lower airways of the lungs and in the peripheral vasculature –– it is also thought that beta 2 cells in the liver regulate the it is also thought that beta 2 cells in the liver regulate the release of glycogen stores.release of glycogen stores.

Beta 2:Beta 2:

Primarily bronchodilation and peripheral vasodilation with Primarily bronchodilation and peripheral vasodilation with increased glycogen release.increased glycogen release.

IF you have trouble remembering where the beta 1 and beta 2 IF you have trouble remembering where the beta 1 and beta 2 receptors are located, receptors are located,

then just think of 1 heart = beta 1; and 2 lungs = beta 2.then just think of 1 heart = beta 1; and 2 lungs = beta 2.

Before We ContinueBefore We Continue

Pharmacology ofPharmacology of Synaptic TransmissionSynaptic Transmission

Drugs that facilitate a neurotransmitterDrugs that facilitate a neurotransmitter’’s s effects are called effects are called agonistsagonists; drugs that ; drugs that reduce a neurotransmitterreduce a neurotransmitter’’s effect are s effect are called called antagonistsantagonists

Drugs act upon one or more of the steps Drugs act upon one or more of the steps in neurotransmitter action; the exact in neurotransmitter action; the exact mechanism varies from drug to drugmechanism varies from drug to drug


For example, For example, cocainecocaine is a catecholamine is a catecholamine agonist that acts by blocking the reuptake agonist that acts by blocking the reuptake of dopamine and norepinephrineof dopamine and norepinephrine


By contrast, By contrast, valiumvalium is a GABA agonist is a GABA agonist that acts by increasing the binding of that acts by increasing the binding of GABA to its receptorGABA to its receptor

GABA is an inhibitory neurotransmitter (itGABA is an inhibitory neurotransmitter (it’’s s receptor allows Clreceptor allows Cl-- in, hyperpolarizing, in, hyperpolarizing, IPSPsIPSPs))


AtropineAtropine and and curarecurare are both ACh are both ACh antagonists;antagonists;

atropine blocks atropine blocks muscarinemuscarine receptors, not receptors, not allowing acetylcholine to bind allowing acetylcholine to bind

whereas curare paralyzes by blocking nicotinic whereas curare paralyzes by blocking nicotinic receptors, not allowing acetylcholine to bindreceptors, not allowing acetylcholine to bind

ToxicologyToxicology

DefinitionsDefinitions

ToxidromeToxidrome: a set of signs and symptoms : a set of signs and symptoms induced by ingestion of a toxic substance.induced by ingestion of a toxic substance.

Toxicology: The science of poisons, : The science of poisons, including their source, chemical including their source, chemical composition, action, tests, and antidotes.composition, action, tests, and antidotes.

ToxicodynamicsToxicodynamics: the study of the effects : the study of the effects of the toxic substance at the molecular of the toxic substance at the molecular level.level.

Major Toxic SyndromesMajor Toxic Syndromes

Cholinergic/AnticholinesteraseCholinergic/Anticholinesterase

AnticholinergicAnticholinergic

HallucinogenicHallucinogenic

OpiateOpiate

Sedative/hypnoticSedative/hypnotic

SympathomimeticSympathomimetic

Drug WithdrawalDrug Withdrawal

Presenter

Presentation Notes

Identify the Major Toxidromes to the students. For some students, this may be the first opportunity that they have had to hear these terms.

Cholinergic & Cholinergic & AnticholinesteraseAnticholinesterase

Organophosphate Organophosphate insecticides are examples insecticides are examples of cholinesterase of cholinesterase inhibitors.inhibitors.

Muscarinic signs and Muscarinic signs and symptoms may be symptoms may be remembered by using remembered by using one of the following one of the following mnemonicsmnemonics::

DUMBBELSDUMBBELS SLUDGESLUDGE

Presenter

Presentation Notes

Cholinergic Drugs Indirect Acting Cholinergic Stimulating Agents: Acetylcholine Esterase Inhibitors: Indirect stimulation of cholinergic nerves occurs by inhibiting the cholinesterase enzyme, thus permitting a build up of acetylcholine on the nerve receptor sites. As a result, acetylcholine increases in quantity with successive nerve impulses so that large amounts of acetylcholine can accumulate and repetitively stimulate receptors. Acetylcholine Stimulation: Cholinesterase inhibitors act indirectly by preventing the enzyme from hydrolyzing (inactivating) acetylcholine at the receptor site. This inhibition permits the buildup of acetylcholine and results in more intensive and prolonged activation of the receptor site. The effects of cholinergic stimulation include: vasodilattion of blood vessels; slower heart rate; constriction of bronchioles and reduced secretion of mucus in the respiratory tract; intestinal cramps; secretion of salvia; sweat and tears; and constriction of eye pupils. Acetylcholine Inhibitors - Toxic Poisons The main agents in this class are poisons such as organophosphate insecticides and nerve gases. �Organophosphorus pesticides and Carbamate pesticides �Organophosphorus warfare nerve agents: Sarin, Soman, Tabun


DDiarrheaiarrhea

UUrinationrination

MMiosisiosis

BBronchorrhearonchorrhea

BBradycardiaradycardia

EEmesismesis

LLacrimationacrimation

SSalivationalivation

SSalivationalivation

LLacrimationacrimation

UUrinationrination

DDefecationefecation

GG.I. Cramps.I. Cramps

EEmesismesis

Presenter

Presentation Notes

Organophosphate such as Sarin interacts with cholinesterase, thus preventing it from doing what it is suppose to: breaking down acetylcholine. Now, since acetylcholine is being built up, the receptors nerves get fired off repeatedly thereby causing the muscles, organs and, glands to be overstimulated. If death occurs, it is caused by asphyxia resulting from respiratory failure. Other nerve gases are Tabun, Soman, and VX. VX is the most toxic and long lasting of the nerve gases.


Nicotinic signs can be remembered Nicotinic signs can be remembered using the using the MTWHFMTWHF mnemonic :mnemonic :

MMydriasisydriasisTTachycardiaachycardiaWWeaknesseaknessHHypertension/Hypoglycemiaypertension/HypoglycemiaFFasiculationsasiculations

Presenter

Presentation Notes

The molecule pralidoxime is a useful antidote for intoxication with cholinesterase inhibitors such as the organophosphates. Pralidoxime, has been shown to regenerate functional AChE from the phosphorylated form, thereby reversing the effects of the organophosphates. The pralidoxime oxygen attacks the phosphorous atom of the nerve agent, freeing it from the AChE active site. The molecule removes the inhibitor from the active site in the form of an oxime phosphonate. Atropine also is used to block responses due to excess acetylcholine. In addition, valium often is given as an antidote in conjunction with atropine to counteract seizures which may develop due to elevated levels of acetylcholine.


Central signs may include:Central signs may include:-- CConfusiononfusion-- CConvulsionsonvulsions-- CComaoma

AnticholinergicsAnticholinergics

-- TCATCA-- AntihistaminesAntihistamines-- Belladonna alkaloids Belladonna alkaloids

(atropine/scopolamine)(atropine/scopolamine)-- MushroomsMushrooms-- AntipsychoticsAntipsychotics

-- OTC sleep meds.OTC sleep meds.

-- OTC cold meds.OTC cold meds.

-- ScopolamineScopolamine

-- Jimson WeedJimson Weed

Presenter

Presentation Notes

Pathophysiology: Substances with anticholinergic properties competitively antagonize acetylcholine muscarinic receptors; this predominantly occurs at peripheral (eg, heart, salivary glands, sweat glands, GI tract, GU tract) postganglionic parasympathetic muscarinic receptors. Anticholinergic substances minimally compete with acetylcholine at other sites (eg, autonomic ganglia). Central nervous system (CNS) manifestations result from central cortical and subcortical muscarinic receptor antagonism. The degree of CNS manifestation is related to the drug’s ability to cross the blood-brain barrier. Anticholinergic syndrome results from the inhibition of muscarinic cholinergic neurotransmission. Clinical manifestations are caused by CNS effects, peripheral nervous system effects, or both.

Anticholinergic ToxidromesAnticholinergic Toxidromes

Red As A BeetRed As A Beet

Hot as a HareHot as a Hare

Mad as A HatterMad as A Hatter

Dry as a BoneDry as a Bone

Blind as a BatBlind as a Bat

AnticholinergicsAnticholinergics Signs include:Signs include:

Peripheral:Peripheral:-- flushed skin flushed skin -- mydriasis mydriasis -- hyperpyrexia hyperpyrexia -- dry skin & mucous dry skin & mucous

membranes membranes -- thirstthirst-- urinary retentionurinary retention

Central:Central:-- anxiety, confusionanxiety, confusion-- agitationagitation-- dysphagiadysphagia-- deliriumdelirium-- ataxiaataxia-- lethargylethargy-- respiratory failurerespiratory failure-- coma, deathcoma, death

Presenter

Presentation Notes

The Peripheral signs have been ordered to parallel the ‘Alice in Wonderland’ presentation. Red as a beetFlushed Blind as a batDilated pupils Hot as a hareDon’t sweat ( ACh sites – both sites for sweat glands ) Dry as a boneNo secretions Mad as a hatterCNS delirium ( Hallucinate – small people )


Vital signs:Vital signs:

Increased pulse, increased respiratory Increased pulse, increased respiratory rate, increased B/P, increased temp.rate, increased B/P, increased temp.

These patients have many of the same signs These patients have many of the same signs as seen in as seen in sympathomimeticsympathomimetic & withdrawal.& withdrawal.

It is useful to note that these patients It is useful to note that these patients dondon’’t sweat or have bowel sounds.t sweat or have bowel sounds.

SympathomimeticsSympathomimetics

CocaineCocaine

MethamphetamineMethamphetamine

Methylphenidate Methylphenidate (Ritalin) (Ritalin)


HypertensionHypertension

TachycardiaTachycardia

Psychomotor AgitationPsychomotor Agitation

HyperthermiaHyperthermia

DiaphoresisDiaphoresis

MydriasisMydriasis

Causes of Adrenergic StateThink I’m not SAD

Sympathomimetics AnticholinergicsDrug withdrawal Hallucinogens

OpiatesOpiates

MiosisMiosis

Respiratory depressionRespiratory depression

BradycardiaBradycardia

HypotensionHypotension

SedationSedation

Decreased GI motilityDecreased GI motility

HypothermiaHypothermia

Pulmonary edemaPulmonary edema

SeizuresSeizures

NarcoticsNarcotics

Narcotics:Narcotics:-- Heroin, Morphine, Codeine, Heroin, Morphine, Codeine,

MeperidineMeperidine

Signs may include:Signs may include:-- CNS depressionCNS depression-- Respiratory depressionRespiratory depression-- Pulmonary edemaPulmonary edema-- HypotensionHypotension-- Miosis ( except Demerol )Miosis ( except Demerol )-- SeizuresSeizures

Presenter

Presentation Notes

Narcotics. Opioids cause a release of endorphins, which bind to the opioid receptors in the brain, producing a feeling of pleasure. Opioid abuse includes both medicinal and illegal drugs. Heroin, for example, is a highly addictive opioid that can be injected, inhaled, or smoked. It metabolizes to morphine, and users describe an immediate rush or euphoric feeling because the drug quickly passes into the brain. Illegal narcotics, however, are not the only problem. Abuse of prescription drugs such as oxycodone HCl (OxyContin) and hydrocodone bitartrate (Vicodin) is also high Regardless of the type of narcotic, an overdose will produce an opioid toxidrome effect, which includes miosis (pinpoint pupils), respiratory depression, and CNS depression. An overdose of heroin, for example, can result in apnea, bradycardia, decreased muscle reflexes, hypotension, and coma. Naloxone HCl (Narcan) is used to reverse the CNS and respiratory depressive effects of narcotic drugs.

NarcoticsNarcotics

Miosis seen in approximately 90% of Narcotic Miosis seen in approximately 90% of Narcotic O.D. , unless hypoxic or mixed overdose O.D. , unless hypoxic or mixed overdose (exceptions are Demerol and Talwin). (exceptions are Demerol and Talwin).

If vomiting occurs with these patients, good If vomiting occurs with these patients, good chance of aspiration. chance of aspiration.

NonNon--cardiogenic pulmonary edema can be an cardiogenic pulmonary edema can be an extremely rapid onset, is usually fulminatingextremely rapid onset, is usually fulminating..

Longer half/life than Longer half/life than narcannarcan

Presenter

Presentation Notes

Remember to reinforce the half-life of the competitive narcotic antagonist versus the narcotic, hence, the implications in patient care, capacity and consent! Heroin – Cocaine speedballs: If you use Naloxone to competitively reverse the narcotic, you could have unopposed alpha stimulation from the cocaine.

BarbituatesBarbituates

Barbituates:Barbituates:Phenobarbital Long lastingPhenobarbital Long lastingButabarbitalButabarbital IntermediateIntermediateSecobarbitalSecobarbital Short actingShort acting

Overdose:Overdose:

No antidoteNo antidote

Skin Skin bullaebullae presentationpresentation

Presenter

Presentation Notes

Review the three categories of Barbituates from the Rx Medications Lecture according to their longevity. Some others: AmbarbitalAmytal PentobarbitalNembutal SecobarbitalSeconal Pent/SecoTuinal PentathalThiopental

Narcotic Overdose: Special Narcotic Overdose: Special casescases

Pupils largePupils large

MeperedineMeperedine (Demerol)(Demerol)

LomotilLomotil

Narcan may not work:Narcan may not work:

FentanylFentanyl

Rigid chest syndromeRigid chest syndrome

Long acting agentsLong acting agents

methadonemethadone

MSMS--ContinContin

OxycontinOxycontinJanis Joplin

Narcotic Overdose: Narcotic Overdose: Atypical toxicity seenAtypical toxicity seen

SeizuresSeizures

MeperedineMeperedine (Demerol)(Demerol)

Tramadol (Ultram) Tramadol (Ultram)

Pentazocine (Talwin)Pentazocine (Talwin)

ProxypheneProxyphene (Darvocet)(Darvocet)

Ventricular Ventricular arrythmiasarrythmias

ProxypheneProxyphene (Darvocet)(Darvocet)

Serotonin syndromeSerotonin syndrome

MeperedineMeperedine

DextromorphanDextromorphan

Narcotic WithdrawalNarcotic Withdrawal

Vital Signs:Vital Signs:

Increased respiratory rate, increased Increased respiratory rate, increased pulse, increased B/P, increased temp.pulse, increased B/P, increased temp.

Signs may include:Signs may include:-- AgitationAgitation-- YawnYawn-- VomitingVomiting-- Cold turkey skinCold turkey skin-- Normal mental statusNormal mental status

Narcotic WithdrawalNarcotic Withdrawal

Cholinergic + +Cholinergic + +

Progression of signs & symptoms:Progression of signs & symptoms:

Yawn, Yawn, lacrimationlacrimation, , rhinnorhearhinnorhea, diaphoretic, , diaphoretic, restless, insomnia.restless, insomnia.

Mydriasis, Mydriasis, goosebumpsgoosebumps, aching, nausea., aching, nausea.

Anorexia, vomiting, diarrhea, ( after 2 Anorexia, vomiting, diarrhea, ( after 2 --3 3 days ).days ).

DishevelledDishevelled appearance, fever, increased B/P.appearance, fever, increased B/P.

Toxins and their AntidotesToxins and their Antidotes

AcetaminophenAcetaminophen NN--acetylcysteineacetylcysteine

Physostigmine

AtropineAtropine(muscarinic effects)(muscarinic effects)

PralidoximePralidoxime(nicotinic effects)(nicotinic effects)


AnticholinesterasesAnticholinesterases//CholinergicsCholinergics


BenzodiazepinesBenzodiazepines

BotulismBotulism

BetaBeta--blockersblockers

Calcium channel blockersCalcium channel blockers

Carbon monoxideCarbon monoxide

Cyanide, NitritesCyanide, Nitrites

FlumazenilFlumazenil

BotulinumBotulinum antitoxinantitoxin

GlucagonGlucagon

CalciumCalcium

Hyperbaric OHyperbaric O 22 , O, O 22

Sodium Sodium thiosulfatethiosulfate


EthanolEthanol

MethyleneMethylene blueblue

NaloxoneNaloxone

NaHCO3NaHCO3

Vitamin KVitamin K

MethanolMethanol

MethemoglobinMethemoglobin

OpioidsOpioids

TricyclicTricyclic antidepressantsantidepressants

Warfarin Warfarin

Pupillary ReactionsPupillary Reactions

Drugs that can Drugs that can cause Miosis:cause Miosis:

Narcotics Narcotics ( except Demerol )( except Demerol )

Cholinergic & Cholinergic & AnticholinesteraseAnticholinesterase OrganophosphatesOrganophosphates

PhencyclidinePhencyclidine ( PCP )( PCP )

MushroomsMushrooms

PhenothiazinesPhenothiazines

Drugs that can Drugs that can cause Mydriasis:cause Mydriasis:



Drug withdrawalDrug withdrawal

DemerolDemerol


Presenter

Presentation Notes

Now look at the various Toxidromes according to certain clinical findings.

Drugs that can cause Drugs that can cause Pulmonary EdemaPulmonary Edema

Drugs that cause pulmonary edema:Drugs that cause pulmonary edema:

-- SalicylatesSalicylates-- Narcotics ( especially Heroin )Narcotics ( especially Heroin )-- Carbon monoxideCarbon monoxide-- Sedative Sedative -- hypnoticshypnotics-- OrganophosphatesOrganophosphates

ToxidromesToxidromes

If patient presents If patient presents with:with:

pinpoint pupilspinpoint pupils

CNS depressionCNS depression

respiratory respiratory depressiondepression

Think NarcoticsThink Narcotics


dilated pupilsdilated pupils

dry skindry skin

decreased GI decreased GI motilitymotility

dysrhythmiasdysrhythmias

↑↑

respirations, pulse, respirations, pulse, B/P, temperatureB/P, temperature

Think Think Anticholinergic Anticholinergic SyndromeSyndrome

Presenter

Presentation Notes

Now look at the various Toxidromes according to common clinical findings.



pinpoint pupilspinpoint pupils

sweatingsweating

increased secretions increased secretions -- SLUDGESLUDGE

increased GI motilityincreased GI motility

Think Cholinergic SyndromeThink Cholinergic Syndrome


If patient presents with:If patient presents with:

pallorpallor

diaphoresisdiaphoresis

nausea / vomiting / diarrheanausea / vomiting / diarrhea

hyperadrenergichyperadrenergic ( SNS ) ( SNS )

↑↑

respirations, pulse, B/P, temperaturerespirations, pulse, B/P, temperature

bowel sounds present bowel sounds present Think Think Sympathomimetic / Drug WithdrawalSympathomimetic / Drug Withdrawal

3,4 3,4 MethylenedioxymethamphetamineMethylenedioxymethamphetamine

OverviewOverview

Stimulant/hallucinogenStimulant/hallucinogen

19501950’’ss--armyarmy

19701970’’s therapy tools therapy tool

Route of admin.Route of admin.

DoseDose

5050--100mg/tablet100mg/tablet

Effective dose is Effective dose is 11--2mg/kg2mg/kg

Onset 30Onset 30--60 min.60 min.

Effects last 3Effects last 3--4 hours4 hours

Effects of EcstasyEffects of Ecstasy


MydriasisMydriasis

HypertensionHypertension


Muscle CrampsMuscle Cramps

HallucinationsHallucinations

SweatingSweating

DehydrationDehydration

But Wait, ThereBut Wait, There’’s Mores More

RhabdomyolysisRhabdomyolysis

Cardiac ArrhythmiasCardiac Arrhythmias

CVAsCVAs

SeizuresSeizures

ComaComa

DeathDeath

Ecstasy destroys neurons.

Presenter

Presentation Notes

Slide 17: Long-term Effects in Monkeys A very important experiment was performed in monkeys to determine if Ecstasy can actually damage neurons. Monkeys were given Ecstasy twice a day for 4 days (control monkeys were given saline). One group of monkeys’ brains were removed 2 weeks later for analysis and another group of monkeys lived for an additional 7 years before their brains were removed. Scientists examined the brains for the presence of serotonin. This slide shows the presence of serotonin in neurons of the neocortex from 3 typical monkeys. On the left, the monkey who did not receive any Ecstasy had a lot of serotonin (in pink) in the neocortex. Two weeks after a monkey received Ecstasy, most of the serotonin was gone (point to the middle panel), suggesting that the serotonin neuron terminals were destroyed (there was no destruction of the serotonin cell bodies arising back in the brainstem). Point to the right hand panel and show students that this damage appeared to be long-term because 7 years later there was some recovery, but it was not complete (in fact the pattern of regrowth of serotonin terminals was abnormal– point out one of the areas where the pink lines are running sideways). Scientists found similar changes in limbic areas of the brain such as the hippocampus and amygdala. The monkey experiments are an important reminder that humans may suffer the same fate, although this still remains to be demonstrated. Tell the students how difficult it is to do this same kind of experiment in humans because it requires removing pieces of the brain to look for the loss of the serotonin neurons. Image courtesy of Dr. GA Ricaurte, Johns Hopkins University School of Medicine

Treatment PearlsTreatment Pearls

CC--spinespine

ABCsABCs


IV fluidsIV fluids

CoolingCooling

Cause of most Cause of most fatalities?fatalities?

Physiology ofEcstasy

End Terminal and VesiclesEnd Terminal and Vesicles

Receptors & ReReceptors & Re--uptakeuptake

Presenter

Presentation Notes

This is a model of a typical brain cell, or neuron. Your brain contains billions of brain cells. A brain cell consists of a cell body, which stores the DNA, dendrites which receive chemical signals from other cells, and an axon, which carries an electrical signal from the cell body to the axon terminals. The axon terminals contain chemicals, called "neurotransmitters," which are released in order for the cell to communicate with nearby cells. Serotonin is a neurotransmitter, and some brain cells have axons that contain only serotonin. These are called "serotonin neurons." Other brain cells produce and release different neurotransmitters, like dopamine or norepinephrine, and some produce and release more than one neurotransmitter. However, your serotonin cells only produce and release serotonin. Here you can see how the axon terminals, which contain serotonin, lie very close to the dendrites of other, nearby neurons. Notice the gap between the axon terminal of the serotonin neuron and the dendrites of the next neuron. This gap is called the "synapse" and is where the serotonin gets released. Soon we will look at the synapse up close, and see what happens when ecstasy causes large amounts of serotonin to be released there. But first, let's look at how serotonin cells are distributed throughout your brain. Moving in a little closer to the synapse, we can see some serotonin molecules floating around. We also see some serotonin reuptake transporters on the membrane of the axon terminal, as well as receptors on the dendrite of the nearby neuron. In order to understand how MDMA works in the brain, and why it produces the effects it does, you need to know what these reuptake transporters and receptors do. But first, just for the fun of it, let's look at an actual photograph of a synapse...

Serotonin/Receptor BindingSerotonin/Receptor Binding

Presenter

Presentation Notes

Serotonin Receptors: The primary reason for Ecstasy's subjective effects. On the other side of the synapse, attached to the membrane of the dendrite, are these things called receptors. There are receptors for many neurotransmitters. Let's say the magenta-colored ones are serotonin receptors and the green ones are for dopamine. Notice how a serotonin molecule can easily fit into the serotonin receptor, but not into the dopamine receptors (or any other type of receptor for that matter). This is because serotonin recepters are designed specifically for serotonin molecules. When a serotonin molecule attaches to a receptor, which is called receptor binding, the receptor sends chemical information down the dendrite to the cell body of the neuron. The cell body then decides, based on the information from all its recepters put together, whether or not to fire an electrical impulse down its own axon. If a critical amount of receptor binding occurs then the axon will fire, causing the release of other neurotransmitters into other synapses. This is how your brain communicates, and something like this is happening in your brain at a normal pace all the time. Research has shown that your mood is influenced in part by the amount of serotonin receptor binding. When you are happy, it is likely that you have more serotonin receptors activated. Positive events in your life (like falling in love, perhaps) cause greater serotonin release, increasing receptor binding. So does taking ecstasy. After a little while the serotonin molecule will detach ("unbind") from the recepter and float back into the synapse. When this happens, the receptor stops sending chemical signals to the cell body, and it waits for another serotonin molecule to come along. (Those yellow things on the membrane of the axon terminal are serotonin reuptake transporters. Don't worry about them just yet.)

GimmeGimme an an ““E!E!””

Presenter

Presentation Notes

When you take Ecstasy, the vesicles release enormous amounts of serotonin into the synapse. This significantly increases serotonin receptor binding (more serotonin in the synapse means a greater chance for some of them to bind to the receptors). This increased receptor activity leads to significant changes in the brain's electrical firing and is primarily responsible for the MDMA experience (i.e. empathy, happiness, increased sociableness, enhanced sensation of touch, etc.). Notice also that there is some dopamine in the synapse as well (the blue things). MDMA also causes dopamine release (from dopamine cells), but lets not discuss that yet. Keep it in the back of your mind (no pun intended) because it will come up later when we get into neurotoxicity. For now, just notice that the dopamine receptors have also been activated. The effects of a normal dose of ecstasy last about four to six hours. We will be looking at what happens in the brain during the various stages of an ecstasy experience, as well as some changes that may occur in the brain after long-term, frequent use. But now let's take a look at the "reuptake transporters" (those yellow "H" looking things). To understand how ecstasy works over time in the brain, it is important to know what these things do.

Serotonin Reuptake Serotonin Reuptake TransportersTransporters

Presenter

Presentation Notes

Along with binding to the dendritic recepters, serotonin molecules also bind to "reuptake transporters" on the axon's membrane. These transporters take the molecule and transport it back into the axon terminal. They are sometimes called "pumps" and can be thought of as a revolving door. The serotonin enters one side, and the door spins around pushing it out the other side. We have shown here four reuptake pumps in various stages of transporting serotonin. Imagine them spinning and transporting serotonin from the synapse back into the axon. Reuptake transporters reduce the amount of serotonin in the synapse. Keep in mind that these are one-way doors. Serotonin doesn't go through them the other direction. It can only be released into the synapse from the vesicles. As the reuptake pumps are pulling the serotonin back into the axon, some of this serotonin makes its way back into the vesicles, where the MDMA may cause it to be released again. However, some of it gets broken down by Monoamine Oxidase. We show this in the next slide.

Monoamine Monoamine OxidaseOxidase

Presenter

Presentation Notes

Approximately three hours into your ecstasy experience your serotonin transporters have removed much of the serotonin from the synapse, but there is still plenty around to activate the receptors, so you still feel the desired effects of the drug. Pretty soon, however, the reuptake transporters will remove most of the serotonin from the synapse, and you will start coming down. We said in the last slide that some of the serotonin finds its way back into the receptor where the MDMA causes it to be released again. This is true, but notice the hammers inside the axon. This is "monoamine oxidase" (MAO), an enzyme that breaks down serotonin (serotonin is a monoamine, remember). After your reuptake pumps remove the serotonin, MAO breaks most of it down. MAO doesn't really look like a hammer, but thinking of it as a hammer that smashes up serotonin molecules is a good way to remember what it does. Notice too that the dopamine receptors are also still activated as well.

DonDon’’t Bring Me Downt Bring Me Down

Presenter

Presentation Notes

First, notice that the number of activated serotonin receptors has been reduced because there is less serotonin in the synapse. This means you should be starting to feel somewhat normal again. Also, the uptake pumps are still removing serotonin from the synapse, as usual, and MAO is still doing its job breaking it down. Notice that the dopamine levels in the synapse haven't lowered as much as the serotonin. This is because dopamine replenishes itself much more quickly than serotonin. Notice also that there is a lot less serotonin in your vesicles, and this is mainly why you come down. Simply put, there's no more serotonin left to be released. The MDMA may still be around trying to make your vesicles release more, but there isn't enough there. In about four hours, Ecstasy has used up most of your serotonin. You could take more Ecstasy at this point, which a lot of people do. However, this usually doesn't work. You can't just take more ecstasy to regain the ecstasy feeling. Why? Because the ecstasy feeling is really a "serotonin feeling" and you currently don't have enough serotonin left. (It takes time for your brain to build up more, which we will be discussing soon.) Of course, if you took a lower-than-normal dose, you may not have released most of your serotonin, in which case you may feel the effects come on again if you take more. However, you cannot keep doing this repeatedly all night long. There will come a point (sooner rather than later) when you have depleted your serotonin levels so much that taking more Ecstasy will not work.

Depressed? You Bet!Depressed? You Bet!

Presenter

Presentation Notes

Depending on how much MDMA you took, you may end up depleting so much of your serotonin that fewer receptors are activated than before you took ecstasy, when you were in a normal brain state. This is what causes the "ate up" feeling that a lot of users experience when they come down. You can become very depressed at this point, feeling extremely non-social, tired and irritable. Some people at this point are tempted to take more Ecstasy, because the contrast between how they were feeling an hour earlier and how they feel now is so extreme. But when they take more, it doesn't work. While it may give the user a little more energy (i.e increase the speediness), they won't recapture the empathy and other desirable MDMA effects. Remember, Ecstasy releases (and then depletes) the serotonin that you already have. It doesn't cause more serotonin to be created. Your brain needs time in order to rebuild its serotonin levels. This could take up to two weeks. As expected, the larger the dose the greater the serotonin depletion and the longer it takes for your brain to replenish it. Can these lowered serotonin levels cause depression? Yes. There are a few pharmacological reasons why MDMA use can lead to temporary yet prolonged periods of depression. Perpetually low serotonin levels resulting from weekly MDMA use is one of these reasons. If you take ecstasy on a regular basis, you may be releasing and depleting your serotonin before it has a chance to fully replenish itself. This means you will be operating on lower-than-normal serotonin levels most of the time, and this can lead to depression. Another reason you can get depressed has to do with "receptor downgrading," which we will be discussing soon. How does your brain make serotonin in the first place, and why does it take so long for it to replenish its stores after they have been depleted by MDMA? Let's take a look . . .

Funny, I crave turkeyFunny, I crave turkey

Presenter

Presentation Notes

Your serotonin brain cells produce serotonin when an amino acid called 5-Hydroxy-Tryptophan (5-htp) enters the cell and comes into contact with an enzyme called decarboxylese. The 5-htp enters the cell directly through the cell's membrane. It does not have to go through the reuptake transporters, the way previously-released serotonin must. Once in the axon, decarboxylase turns the 5-htp into serotonin, where it enters the vesicles (the vesicles are not shown in this diagram). In other words, after the serotonin is made inside the cell, it moves to the terminal where it is stored in the vesicles ready to be released into the synapse when the time comes. There's usually plenty of decarboxylase in your cells, but the amount of 5-htp you have can vary depending on your diet. 5-htp is synthesized in your body from another amino acid called tryptophan, which is contained in many foods. A diet high in tryptophan-containing proteins can increase the amount of 5-htp in your brain, and thus help your brain build serotonin more quickly. Normally it takes a long time for your brain to build serotonin. Why? One reason is that tryptophan must go through a number of metabolic changes before it is turned into 5-htp. Another reason is simply that your brain was not made to make serotonin very quickly. Normally, it doesn't need to, because serotonin is not usually released in very large quantities. As a comparison, dopamine is released in larger quantities under normal circumstances, and your brain is thus built to replenish dopamine much more quickly. Researchers say that the dopamine system is "robust" in this sense, while the serotonin system is "delicate." Some ecstasy users take 5-htp supplements to restore their depleted serotonin levels more quickly.

Receptor DownReceptor Down--regulationregulation

Presenter

Presentation Notes

The brain is built to adapt to changing circumstances. One of the ways your brain adapts is through the up-and-down regulation of receptors. What this means is that if your serotonin receptors get hyper-activated by serotonin molecules, they may retreat into the membrane of the dendrite, essentially shutting themselves down for a while. One theory says they do this in order to avoid getting damaged from over-stimulation. Another theory says that it is just a way for your brain to maintain a balanced, normal state. Whichever one of these theories is true, it has been proven conclusively that serotonin receptors will down-regulate over time if bombarded with large amounts of serotonin. This may lead to depression, even after your brain serotonin levels have been restored, because the serotonin cannot bind to downregulated receptors. Many ecstasy users we have interviewed have reported periods of depression lasting months or even a year or more following a period of heavy use. Keep in mind, however, that most evidence of MDMA-induced depression is anecdotal, based on reports by MDMA users. Since many people experience depression it is difficult to know for sure whether the depression experienced by MDMA users is really related to their MDMA use. While MDMA is known to reduce serotonin levels, serotonin levels varies greatly among healthy, non-depressed, non-MDMA users. Until more research is done, we cannot know for sure whether MDMA users actually have a greater risk of experiencing depression than non-users.

NeurotoxicityNeurotoxicity--Current TheoryCurrent Theory

Presenter

Presentation Notes

The current theory The most current theory of how MDMA causes neurotoxic damage in laboratory animals goes like this: After MDMA depletes serotonin, the reuptake transporters are left vacant and exposed. When this happens, dopamine enters the transporter and gets taken up into the serotonin axon, where it isn't supposed to be. Studies have shown that dopamine itself is toxic to serotonin cells. But if that weren't enough, MAO comes along and breaks it down into hydrogen peroxide, which is also toxic to the cell. (Yes, the same hydrogen peroxide they put in hair bleach!) The hydrogen peroxide then "oxidizes" certain parts of the cell which don't normally get oxidized ("oxidize," as used here, basically means to break down with oxygen). Researchers sometimes refer to this as oxidative stress, and a number of studies have looked at anti-oxidants like Vitamin-C as a possible agent to prevent MDMA's neurotoxicity (see our section about pre-loading on our neurotoxicity page for more info on this). Once again . . . To re-cap we have (1) serotonin depletion causing the uptake transporters to become empty. Then (2) dopamine, which exists in higher levels in the synapse now, enters the uptake transporter. (3) This dopamine is broken down by MAO into hydrogen peroxide. (4) The dopamine is toxic to the cell and so is the hydrogen peroxide, by producing oxidative stress. How did they come up with this theory? And is there evidence for it? The researchers who first devised this theory (Jon E. Sprague, Shannon L. Everman and David E. Nichols) called it an "integrated hypothesis." They looked at a decade worth of MDMA research and tried to put the pieces together. They came up with this theory in the summer of 1997 and it was published in 1998. To date, it is still the dominant theory of how MDMA causes axon damage in laboratory animals, and would most likely apply to humans as well, should neurotoxic damage in humans be proven conclusively. Technical details Below are some rather techincal explanations of how they came up with this theory. If you're not interested in such detail, go on to the next slide. Looking at past studies of MDMA neurotoxicity, it is clear that dopamine plays a crucial role. For example, in 1988, it was discovered that pre-treating rats with a-methyl-p-tyrosine, a substance which inhibits the synthesis of dopamine, prevents MDMA neurotoxicity (Stone et al.). Also, in 1990 a study showed that if you destroy all of the rat's dopamine terminals before giving them MDMA (thus eliminating all their dopamine), they sustain no serotonin axon loss (Schmidt et al.). Furthermore, in the same year they also discovered that if you give the rats L-DOPA, a dopamine precursor, they sustain more neurotoxic damage when given MDMA. And another study in 1991 demonstrated a linear correlation between the amount of dopamine release and the extent of MDMA-induced axon loss in rats (Nash and Nichols). In 1987 researchers discovered that MDMA itself releases dopamine (Schmidt et al., Steele et al.). Then they discovered in 1996 that serotonin release also increases dopamine release (Gudelsky and Nash). It does this because one of the serotonin receptors (receptor 2A), when activated by serotonin, stimulates the synthesis and release of dopamine (Nash; Schmidt et al., 1990). Also, drugs which block the 2A-receptor have been shown to reduce extracellular dopamine levels. They also discovered that dopamine actually can get uptaken into the serotonin terminal (Faraj et al, 1994) and that the terminal dose, in fact, contain a type of MAO known to metabolize dopamine (MAO-B). To further support the theory, in 1995 they discovered that MAO-B inhibitors (L-deprenyl or MDL-72974) reduce neurotoxic damage in rats given 40mg/kg of MDMA.

ShrinkageShrinkage

How Ecstasy WorksHow Ecstasy Works

Presenter

Presentation Notes

We've been neglecting this question for a long time, because we didn't want to present too much information all at once, and there wasn't any pressing need early on to show this. However, we'll show you now. MDMA enters the serotonin axon terminal by going through the uptake transporters! Researchers say MDMA has a greater affinity for the transporter than serotonin (just like prozac does). This means that the MDMA will be the first thing to get into the axon terminal. Once there, it interacts with the vesicle, causing it to pour it's serotonin into the synapse. The important thing to be aware of is that the MDMA does its thing only after entering the serotonin axon terminal via the uptake transporters. This is important, as we will soon see.

Transporter Working BackwardsTransporter Working Backwards

Presenter

Presentation Notes

MDMA Makes the Serotonin Transporters Work In Reverse! A new theory is gaining wider acceptance among researchers about exactly how MDMA causes serotonin to be released into the synapse after it enters the axon. It is no longer assumed that the MDMA somehow interacts with the vesicle, ausing it to pour its serotonin into the synapse. Rather, the MDMA is thought to make the transporters work backwards, transporting serotonin from inside the axon to the synapse! Here's the theory: Once the MDMA enters the transporter, it falls off inside the axon terminal, and leaves the transporter in such a state that a serotonin molecule now binds to the place where the MDMA fell off. The transporter then spins around and deposits the serotonin molecule into the synapse, where another MDMA molecule binds to where this serotonin molecule used to be. This all happens through a four-step process: MDMA is released from the transporter into the axon when the transporter undergoes a change in "configuration." (The transporter is basically a group of proteins that can change configuration, or "shape." Depending on its configuration, certain molecules are more likely to bind to it. This is called "affintity." When a molecule with a high affinity binds to a transporter, it changes the transporter's configuration, which eventually causes the molecule to unbind or "fall off," possibly on the other side. This is what makes the transporter capable of "transporting" molecules between the synapse and the axon.) The transporter now has the correct configuration to attract and bind cytoplasmic serotonin inside the axon. The bound serotonin is then transported out of the presynaptic cell, and when the transporter changes configuration again, the serotonin falls off into the synapse. The transporter is now in the correct configuration to attract more MDMA in the synapse, and the whole process is repeated. Remember, serotonin is produced inside the axon (through the conversion of 5-htp), and under normal circumstances it enters the vesicles, which release it, over time, into the synapse. The reuptake transporters then bring some of the serotonin back into the axon, where it enters the vesicles again and is recycled. On MDMA, however, most of the serotonin enters the synapse directly through the reuptake transporters (in the opposite direction from what is normal). So now let's go back to a previous slide and look at your brain on ecstasy again.

End ResultEnd Result

Ecstasy + Prozac = Nothing!Ecstasy + Prozac = Nothing!

Presenter

Presentation Notes

Prozac has a greater affinity for the reuptake trasnporter than MDMA and serotonin both. Most people on Prozac don't feel much when they take ecstasy, because the ecstasy cannot get into the serotonin axon terminal in order to release the serotonin. The ecstasy does cause some dopamine release, as well as norepinephrine, so the user will feel a little something. But the primary effects will be largely inhibited. Of course, this depends on how much Prozac the person is on, and how big of a dose of MDMA the person takes. Someone on a low dose of Prozac (10mg) will feel more effect than someone on a high dose (40mg). Someone who takes a low dose of MDMA (60mg) will feel less than someone who takes a high dose (150mg).

Which one is Real?Which one is Real?

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TimelineTimeline

3000 BC3000 BC--Coca chewing Coca chewing practiced in S. Americapracticed in S. America

1500s Incan coca 1500s Incan coca plantations controlled by plantations controlled by SpanishSpanish

15751575--Labourers in Labourers in Spanish silver mines Spanish silver mines chewed cocachewed coca

1855 Cocaine extracted 1855 Cocaine extracted from coca leavesfrom coca leaves

1862 Merck produces 1862 Merck produces ¼¼ pound of cocainepound of cocaine

1884 Freud advocates 1884 Freud advocates use to treat variety of use to treat variety of conditionsconditions

1884 Merck produces 1884 Merck produces 3179 pounds of cocaine3179 pounds of cocaine

1886 Merck produces 1886 Merck produces 158352 pounds158352 pounds

TimelineTimeline

1886 Coca Cola 1886 Coca Cola introducedintroduced

1901 Coca Cola removes 1901 Coca Cola removes coca from their coca from their forumulaforumula

1910 First reports of 1910 First reports of nasal damage in literaturenasal damage in literature

1912 US government 1912 US government reports 5000 cocaine reports 5000 cocaine related fatalities/yearrelated fatalities/year

The Harrison Narcotics The Harrison Narcotics Act of 1914 banned Act of 1914 banned nonprescriptionnonprescription use of use of cocainecocaine--containing containing products products

19201920--1970 cocaine use 1970 cocaine use diminishesdiminishes

1970 Cocaine becomes 1970 Cocaine becomes schedule II substanceschedule II substance

1984 One kg costs 1984 One kg costs $25000$25000

Norepinephrine Everywhere!Norepinephrine Everywhere!

2525--100mg/line100mg/line

CocaCoca--Cola had Cola had 80mg/bottle80mg/bottle

Cocaine EffectsCocaine Effects

Think Think hyperadrenergichyperadrenergic

Blocks reuptake of Blocks reuptake of norepinephrinenorepinephrine

Stimulates release of Stimulates release of norepinephrine, norepinephrine, dopamine and dopamine and serotoninserotonin

Side EffectsSide Effects

CVACVA


rhabdomyolysisrhabdomyolysis

MIMI

CADCAD


Route Onset Peak Effect (min)

Duration (min)

Half-Life (min)

Inhalation 7 s 1-5 20 40-60

IV 15 s 3-5 20-30 40-60

Nasal 3 min 15 45-90 60-90

Oral 10 min 60 60 60-90

Onset of EffectsOnset of Effects

plus

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More than 38 pharmacologically active substances have reportedly been used with cocaine; alcohol and nicotine are the most common. Although alcohol and nicotine are individually well known for their potential sequelae, their use with cocaine may acutely increase morbidity and mortality risks. Between 30% and 60% of individuals who take cocaine combine it with alcohol. Clinical data indicate that the concurrent use of alcohol and cocaine is associated with increased mortality and morbidity from cardiovascular complications, hepatotoxicity, and behaviors leading to personal injury. In 74% of cocaine-related fatalities in the United States, another drug, usually ethanol, had been co-ingested. The addition of alcohol to cocaine increases the risk of sudden death 25-fold. The concomitant use of alcohol and cocaine results in the in vivo formation of a third active compound of toxicologic importance, namely, ethylbenzoylecgonine, commonly known as cocaethylene. Although its behavioral pharmacology and psychomotor stimulant effects are similar to those of cocaine, its toxicity is greater. The plasma half-life of cocaethylene is longer than that of cocaine, and inferential evidence suggests that the lethal dose to kill 50% of subjects (LD50) is lower. Almost most cocaine metabolism involves serum cholinesterase, some of the drug is metabolized in the liver by carboxylesterases. In the presence of alcohol, a nonspecific carboxylesterase catalyses ethyl transesterification of cocaine to cocaethylene; cocaine is the rate-limiting substrate in this reaction. Cocaethylene can be detected in urine and blood within 100 minutes after a person uses alcohol and intranasal cocaine. Whereas the half-life of cocaine is approximately 40 minutes, the half-life of cocaethylene is 2.5 hours, which may explain why cocaine-related symptoms can continue for some time after cocaine is last used. The human brain, heart, liver, and placenta bind cocaine and cocaethylene. As with cocaine, cocaethylene binds to dopamine and norepinephrine transporters and inhibits catecholamine reuptake (primarily norepinephrine) into synaptosomes. The increased "high" reported with concurrent use of alcohol and cocaine may be the result of the additive effect of cocaine and cocaethylene. Yet another reason may be the relationship between these substances and serotonin. The binding of serotonin by cocaine may modulate the high and may be the cause of the dysphoric effects of cocaine. Cocaethylene, which is 40 times less potent than cocaine in binding to the serotonin receptor, does not share this negative property. In dog studies, cocaethylene was a more potent precipitant of convulsions and cause of lethality than cocaine. Cocaethylene blocks sodium channels more potently than cocaine. Although the toxic level of cocaethylene in humans is not known, the LD50 in mice was 93 mg/kg for cocaine versus 60 mg/kg for cocaethylene. The process of cocaethylene formation continues for several hours; this may explain why sudden deaths may occur 6-12 hours after cocaine ingestion. Cocaethylene, which is ultimately metabolized to benzoylecgonine, is not the only factor augmenting the effects of cocaine with ethanol (Rose, 1994). Consumption of ethanol before cocaine use also increases the bioavailability of cocaine. Signs et al present an exception to the weight of the literature in a study based on 57 ED patients who tested positive for both alcohol and cocaine. In these patients, systolic and diastolic BP, heart rate, and body temperature did not significantly differ between those testing positive for both alcohol and cocaine and drug-free control subjects. This may be because chronic cocaine users reportedly develop tolerance to the cardiovascular effects of the drug. Sign et al concluded that the incidence of serious cardiovascular complications resulting from simultaneous use of cocaine and ethanol does not appear to be significantly higher than that observed in patients using only cocaine, only ethanol, or no drug.

MethamphetamineMethamphetamine

Figure 1 www.dea.gov

First synthesized 1887

Initial application 1920s as nasal decongestant (Benzedrine)

WW II used as stimulant

Popular with students and truckers in the 1950’s (Dexedrine)

Schedule II in 1971

Off-white/pinkish or yellowish powder, 5-20% purity

MethamphetamineMethamphetamine--An OverviewAn Overview

MethamphetamineMethamphetamine--An OverviewAn Overview

StimulantStimulant

Effects last up to 12 hours (cocaine 20 min)Effects last up to 12 hours (cocaine 20 min)

Ice, crystal meth (ephedrine reduction) Average dose 50 Ice, crystal meth (ephedrine reduction) Average dose 50 –– 200 mg200 mg

Onset of actionOnset of action

Oral: 30Oral: 30--60 min60 min

Nasal: 15Nasal: 15--20 min20 min

Inhaled or injected: 1Inhaled or injected: 1--3 min3 min

Elimination halfElimination half--life and duration of action: 4 life and duration of action: 4 –– 6 hours6 hours

White, yellow, light brown, dark brown powderWhite, yellow, light brown, dark brown powder

Whiter is cleanerWhiter is cleaner

Pills, capsules, injected, smokedPills, capsules, injected, smoked

Methamphetamine UsersMethamphetamine Users

TweakersTweakers

Long time, habitual meth Long time, habitual meth usersusers

Attempt to maintain Attempt to maintain steady state of meth in steady state of meth in their bloodstreamtheir bloodstream

May be sleep deprivedMay be sleep deprived

Frustrated, unpredictable Frustrated, unpredictable and dangerousand dangerous

May appear May appear ““supersuper-- exaggerated normalexaggerated normal””

TweakersTweakers

Eyes clear, speech concise, movements briskEyes clear, speech concise, movements brisk

Eyes look normal but on close exam may be moving Eyes look normal but on close exam may be moving 10X faster than normal may appear to roll10X faster than normal may appear to roll

Movements may be exaggerated (Movements may be exaggerated (overstimulatedoverstimulated))

Thought process scattered, paranoidThought process scattered, paranoid

Requires little provocation to react violently, may be Requires little provocation to react violently, may be hallucinatinghallucinating

Items Found in LabsItems Found in Labs

Lab glasswareLab glassware

Heat sourceHeat source

Red phosphorusRed phosphorus-- striker striker plates/road flaresplates/road flares

Starter fluid (ether)Starter fluid (ether)

Muriatic/hydrochloric Muriatic/hydrochloric acidacid--hardware storeshardware stores

Sodium hydroxide (lye): Sodium hydroxide (lye): "Drano" "Drano"

Sulfuric acid: battery acid Sulfuric acid: battery acid or drain cleanersor drain cleaners

Anhydrous ammoniaAnhydrous ammonia-- farmerfarmer’’s cos co--opop

Coleman fuelColeman fuel

Other solvents and Other solvents and containerscontainers

Toluene: paint thinnerToluene: paint thinner

Methanol: gas tank antiMethanol: gas tank anti-- freezefreeze

Iodine crystalsIodine crystals

Lithium: camera batteriesLithium: camera batteries

Methamphetamine ProductionMethamphetamine Production

Cold MethodCold Method

ephedrine (ephedrine (sudafedsudafed))

Mix with water, denatured alcohol, methanol or Mix with water, denatured alcohol, methanol or other solvent.other solvent.

Add iodine, red phosphorus (Add iodine, red phosphorus (phogenephogene gas) and gas) and water, heat to boiling 6water, heat to boiling 6--8 hours8 hours

red red phorphorusphorphorus, lye, lye

ether, toluene or Coleman fuel.ether, toluene or Coleman fuel.

Cold MethodCold Method

Nazi MethodNazi Method

Heat the Heat the ephedrine/pseudoephephedrine/pseudoeph edrine mixture in a edrine mixture in a dish on a heat source.dish on a heat source.

Explosion riskExplosion risk

sodium metal, lithium sodium metal, lithium wirewire

anhydrous ammoniaanhydrous ammonia

Signs of UsageSigns of Usage

Think Think hyperadrenergichyperadrenergic!!

BradycardiaBradycardia??

AtherosclerosisAtherosclerosis

SeizuresSeizures


Long Term UsageLong Term Usage

Depletion in the neurons of these Depletion in the neurons of these neurotransmitters, especially dopamine, neurotransmitters, especially dopamine, can have permanent effects in the braincan have permanent effects in the brain

SlownessSlowness

ParkinsonParkinson’’s like movement disorderss like movement disorders-- tremor tremor and rigidityand rigidity

Thinking problemsThinking problems



Placental vasoconstrictionPlacental vasoconstriction

Cooling techniquesCooling techniques

Decrease BP=Decrease ICPDecrease BP=Decrease ICP

HistoryHistory

19601960’’s s anaestheticanaesthetic--issuesissues

19801980’’s bodybuildings bodybuilding--issuesissues

19901990’’s ravess raves--issuesissues

How it WorksHow it Works

Naturally Naturally occuringoccuring

GABA in brainGABA in brain

Dopamine responseDopamine response-- dose dependantdose dependant

HghHgh in ratsin rats

Dose Dependant EffectsDose Dependant Effects

10mg/kg10mg/kg--amnesia, amnesia, drowsinessdrowsiness

20mg/kg20mg/kg--sleep, delta sleep, delta waveswaves

5050--70mg/kg70mg/kg-- hypnosis, comahypnosis, coma

Note: no analgesia or Note: no analgesia or muscle relaxationmuscle relaxation


Manage airway Manage airway appropriatelyappropriately

NarcanNarcan??

BradycardiaBradycardia

HypotensionHypotension

Watch for Watch for myoclonusmyoclonus

HallucinogensHallucinogens

MescalineMescaline

http://www.mescaline.com/synth/index.htm

DISSOCIATIVE DRUGSDISSOCIATIVE DRUGSKetamineKetaminePhenycyclidinePhenycyclidine (PCP)(PCP)PhenylcyclohexylpyrolidinePhenylcyclohexylpyrolidine (PHP)(PHP)

Acts on all six neurotransmitter systemsActs on all six neurotransmitter systems

AnticholinergicAnticholinergic: dry skin, : dry skin, miosismiosis Dopaminergic/AdrenergicDopaminergic/Adrenergic:agitation:agitation, delusions, delusionsOpioidOpioid:pain:pain perception alterationsperception alterationsSerotinergicSerotinergic: perceptual changes: perceptual changesGABA receptor inhibitionGABA receptor inhibition: excitation: excitation

TreatmentTreatment

HaloperidolHaloperidol

PresynapticPresynaptic dopamine antagonistdopamine antagonist

Shifts the dopamineShifts the dopamine--acetylcholine activity ratio in acetylcholine activity ratio in the limbic systemthe limbic system

Therefore can counteract the dopamine stimulation Therefore can counteract the dopamine stimulation and cholinergic antagonism of the drugand cholinergic antagonism of the drug

PCPPCP

http://www.biopsychiatry.com/phencyclidine/index.html

UsageUsage

First tried in humansFirst tried in humans

Never mindNever mind……..what ..what about using it to about using it to neuter fluffy?neuter fluffy?

ActionsActions

11--5 minutes for onset5 minutes for onset

3030--45 minutes duration of effect45 minutes duration of effect

Provides analgesia and Provides analgesia and anaesthesiaanaesthesia

KK--holehole


Watch the Watch the laryngospasmlaryngospasm

Minimize tactile stimulation to diminish Minimize tactile stimulation to diminish psychosispsychosis

Watch for transient spikes in BPWatch for transient spikes in BP

Jimson WeedJimson Weed

Jimson Weed

DextromethorphanDextromethorphan

Stages of Stages of AnaesthesiaAnaesthesia

Drowsiness, confusion, analgesiaDrowsiness, confusion, analgesia

Euphoria, excitement, spontaneous muscle Euphoria, excitement, spontaneous muscle movements, hallucinationsmovements, hallucinations

Loss of consciousnessLoss of consciousness

Negative Side EffectsNegative Side Effects

FrostbiteFrostbite

Malignant HyperthermiaMalignant Hyperthermia

Does not combine with hemoglobinDoes not combine with hemoglobin

Injuries from fallingInjuries from falling

the autonomic nervous system - prehospital medicine · autonomic nervous system functions: ......

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