CHAPTER 2 Anatomy/ Pharmacokinetics/Addiction

Pharmacokinetics

How Drugs Get to the Brain

Distribution

Metabolism/Elimination

Half Life – Steady State

PharmacodynamicsReceptor model

ReceptorAction

Dose-Response

Introduction to the Nervous SystemsAll nervous systems consist of specialized

nerve cells called neurons.Neurons are responsible for conducting the

homeostatic functions of the brain and other nervous systems by receiving and sending information

Sending and receiving information is an electrochemical process

CNS Organization

Old Brain/New BrainOld Brain

Brain StemCerebellumMidbrain (includes Limbic System)

Regulates PhysiologyBasic Emotions-cravingsSurvival memoriesMost frequently involved in addiction

Old Brain/New BrainNew Brain

Cerebrum/Cerebral cortexProcessing centerData from old brain

CNS - Spinal CordSpinal CordOrganizing and modulating motor impulsesCarrying sensory input (e.g. pain)Autonomic control of vital functionsCarrying sensory information

CNS - Brain StemBrain StemResponsible for conduction of all impulse

between spinal cord and brain (both directions)MedullaPonsMidbrain

CNS - Brain StemBrain StemRegulation of vital functions (breathing, heart

rate, BP, GI, sleep, wakefulness)Behavior alteringAttentionArousal

CNS - CerebellumCerebellumMovementPosture

CNS - MidbrainHypothalamus – integration of the

autonomic system, pituitary, emotion, hormonal systems

Subthalamus – motor controlLimbic system – Reward/Reinforcement

PathwayIntegrate emotion, reward behavior with motor

and autonomic functions Amygdala Hippocampus

CNS - MidbrainHypothalamus and Limbic SystemInteract to regulate

EmotionEmotional expression

Important Site for Psychoactive DrugsDopamine-rich reward centers

Ventral tegmental area Median forebrain bundle Nucleus accumbens

CNS - Cerebrum

CNS - CerebrumVisionHearingSpeechSensory PerceptionEmotion

NeuronSoma – Cell bodyDendrites – receptorsAxon - transmitter

Neurons

Transfer of Messages by NeuronsThe receiving region of the neuron is

affected by a chemical message that either excites or inhibits

If the message is excitatory, an impulse moves from the receiving region of the neuron down the axon to the sending region, the terminal, and chemical messengers, neurotransmitters, are released

Transfer of Messages by NeuronsThe neurotransmitters travel and attach to

receiving proteins called receptors on the target cells.

Activation of receptors by neurotransmitters causes a change in the activity of the target cell; the target cells can be other neurons or cell that make up organs, muscles, or glands

Sending Messages by Neurons

Sending Messages by Neurons

Neurons

Neurons are highly versatile and can send discrete excitatory or inhibitory messages to their target cells

Neurons are distinguished by the type of neurotransmitter they release

Neurotransmitters represent a wide variety of chemical substancesExample: dopamine and pleasure center

Drug ReceptorsThe chemical messengers from glands and

neurons exert their effects by interacting with special protein regions in membranes called receptors.

Receptors only interact with molecules that have specific configurations

Drug Receptors

Drug ReceptorsAgonists are substances or drugs that

stimulate receptorsAntagonists are substances or drugs that

attach to receptors and prevent them from being activated

Drug Receptors

NeuronPresynaptic

Synaptic vesicles Store neurotransmitters Release – mediated by Calcium ions

Synaptic Cleft – space between axon and dendrite (or target cell)

NeuronPostsynaptic

Protein receptorsNeurotransmitters from axon activate cell

NeuronTermination of Synaptic Transmission

Enzymes in synaptic cleft destroy free neurotransmitters

Neurotransmitters re-absorbed by receptors on presynaptic cell for re-use

Common Neurotransmitters

Drug ActionPsychoactive Drugs

mimic neurotransmitters – or –Stimulate release of neurotransmitter(s) – or-Inhibit release/action of neurotransmitters

Drug ActionDrugs must leave the circulatory system to

get to the site of actionBlood-Brain BarrierPlacental Barrier

Blood-Brain BarrierCapillaries of the brain are difficult to

penetrateSurvival response to prevent poisons from

having easy access to the brainLipid sheathLipid solubility major factor in crossing the

blood-brain barrier

Placental BarrierEasy to penetrateDesigned to allow small molecules to cross

into fetus, prevent large molecules (e.g. proteins) from crossing

What mother takes, fetus takesFetal metabolism may not be developed

NeurotransmittersAcetylcholine

Memory/learningSensory processingNeuromuscular/neurotransmissionBehavioral arousalAttentionEnergy conservationMoodREM Sleep

NeurotransmittersCatecholamines

DopamineNorepinephrineEpinephrine – peripheral nervous systemCNS Sensory processingCerebellar functionSleep, mood, learning, memory, anxietyReuptake from cleftBound inactivated by MAO enzymes

NeurotransmittersCatecholamines

Norepinephirne Brain Stem - Alerting, focusing, orienting response,

positive reward, analgesiaDopamine

Hypothalamus - Hormone regulation Brain Stem - Movement (Parkinsonism) Midbrain, Cerebral Cortex, Limbic System – central

reward pathway. Linked to continued use of most drugs of abuse

NeurotransmittersSerotonin

Emotional processingMoodAppetite, sleepPain processingHallucinationsReflex regulationBrain Stem – Pons, medulla, cerebral cortex,

hypothalamus, limbic systemEffect opposite DopamineSSRI

NeurotransmittersAmino Acids

GlutamateAspartateMemoryMain excitatory and inhibitory functions in

CNS and PNS

NeurotransmittersGABA – gamma aminobutyric acid

Major inhibitory transmitter for CNSCerebral cortex, cerebellum Neurotransmitters

PeptidesOpioid peptides

Endorphins – 16-30 amino acids Enkephalins – 5 amino acids Mu receptor – analgesic, reinforcement

Pain perception Reward Emotional stability, energetic “highs” Acupuncture

Substance P Pain transmission – peripheral to spinal cord/brain

PhysiologyTolerance

Metabolic Systems adapt to drug, requiring increasing amounts to be used for effect

Desensitization of neuronsLearned behaviorCross Tolerance – similar drugs

Physiological DependenceCells change to require the presence of

substance

Psychological DependenceReward/Reinforcement – Limbic System

Turn on the “More”Turn off the “StopCraving – can have physical manifestations

Social PressuresHabituation – associated activities

AddictionContinued use in spite of known negative

consequencesCompulsion to useWithdrawal

FORMS OF ACCEPTABLE DRUG USE IN AMERICATHERAPEUTIC DRUG USE

DIAGNOSISRELIEF OF SYMPTOMSCURE DISEASEDRUG EFFECT EXPECTED TO BE DIRECT,

RELIABLE AND PREDICTABLESTRICT AND EXPLICIT DIRECTIONS FOR

USETHERAPEUTIC FAILURE OR TOXICITY -

FAILURE TO COMPLY WITH RULES

FORMS OF ACCEPTABLE DRUG USE IN AMERICARELIGIOUS DRUG USE

RELIGIOUS RITUAL PROTECTED BY TABOONO INTENT TO CONSUME INTOXICATING

AMOUNTFOCUS ON HIGH MORAL STANDARDS AND

CONSIDERATION OF NATURE AND ONE’S FELLOW MAN

FORMS OF ACCEPTABLE DRUG USE IN AMERICACULTURAL DRUG USE

NORMAL, COMMONPLACE BEHAVIORPERSPECTIVE OF PSYCHOACTIVE DRUG

EXPOSURECULTURAL LIMIT ON DOSE AND PATTERN

OF USECOFFEE, TEA

FORMS OF ACCEPTABLE DRUG USE IN AMERICASOCIAL DRUG USE

LOW-DOSE ALCOHOLLEGAL AGEIN COMPANY OF OTHERSEXPECT MILD PSYCHOACTIVE EFFECTEXPECTATION THAT INDIVIDUALS WILL ACT

RESPECTABLY AND SENSIBLY

ACCEPTABLE SOCIAL DRUG USESOCIAL MORES AND CUSTOMS DEFINE

ACCEPTABLE PATTERNSUSE OF SOCIALLY-SANCTIONED DRUGS BY

THOSE OF LEGAL AGEACCOUNTABILITY FOR ACTIONSEXPECT INCREASED SOCIAL

INTERACTIONS“SOCIALIZATION” NOT “ADDICTION”

ACCEPTABLE SOCIAL DRUG USESOCIAL MORES AND CUSTOMS DEFINE

ACCEPTABLE PATTERNSUSE OF SOCIALLY-SANCTIONED DRUGS BY

THOSE OF LEGAL AGEACCOUNTABILITY FOR ACTIONSEXPECT INCREASED SOCIAL

INTERACTIONS“SOCIALIZATION” NOT “ADDICTION”

STAGES OF DRUG USESTARTING POINTREWARD VS. CONSEQUENCES OF USECONTINUED AND INCREASED USEPSYCHOLOGICAL DEPENDENCE

CRAVINGPREOCCUPATION WITH USECHANGING LIFESTYLES

STAGES OF DRUG USETOLERANCE INCREASESNEGATIVE CONSEQUENCES INCREASEPHYSICAL DEPENDENCERELAPSE

VARIABLES CONTRIBUTING TO DRUG RESPONSE

ROUTE OF DOSEADMINISTRATION

SETTING

DRUG EFFECTSET

OTHER DRUGS IN BIOCHEMICAL COMBINATION AVAILABILITY

Theories of AddictionDisease Model

Chronic, progressive, relapsing, incurable and potentially fatal condition Hereditary predisposition Environment Triggered by substance

Theories of AddictionBehavioral/Environmental

Significant stresses can cause a person to seek relief via drug(s) Abuse Anger Peer pressure PTSD-like

Theories of AddictionAcademic

Adaptation to substance at physiologic and cellular level

Exemplified by: Tolerance Physiological dependence Withdrawal Psychological dependence

Theories of AddictionDiathesis-Stress

Combination of the above

Factors in AddictionHeredity

Predisposition to addictionTwin studiesAddiction associated genes

EnvironmentIncreased stressors increase likelihood of

abuse/addictionShapes normative behavior

Factors in AddictionPsychoactive Drugs

Change brain chemistryInterfere with normal neurotransmitter

functionIncreased frequency of use increases riskCan cause permanent damage (e.g.

amphetamines, alcohol)

Factors in AddictionOther Behaviors

“Compulsive Behaviors” can act similarly to drugs to trigger addiction Gambling Eating Sex Shopping Video games Internet

SummaryAddiction is complex, but can be thought of,

in simple terms, as compulsive behavior in spite of negative consequences

Once a person becomes an addict, change is difficult and not totally under the person’s control