W HICH EXPLAINS A PERSON WHOSE CAFFEINE USE MAKES THEM SLEEPY ? A.T HEY HAVE WEAK CYP1A2 B.T HEY...
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Transcript of W HICH EXPLAINS A PERSON WHOSE CAFFEINE USE MAKES THEM SLEEPY ? A.T HEY HAVE WEAK CYP1A2 B.T HEY...
UW BIOLOGY OF ADDICTION UNIT IV: STIMULANTS
LECTURE 18: AMPHETAMINES
LT FOR LESSON 18: AMPHETAMINESAFTER SUCCESSFULLY COMPLETING THIS LESSON YOU WILL BE ABLE TO:
• TO UNDERSTAND WHAT AMPHETAMINES ARE, WHERE WE FIND THEM, HOW WE USE THEM
• TO UNDERSTAND HOW AMPHETAMINES WORK AT THE LEVEL OF THE MOLECULE, THE NEURON, THE BRAIN, AND BEHAVIOR.
• TO UNDERSTAND THE REWARD PATHWAY AND HOW THESE PARTICULAR DRUGS STIMULATES IT.
• TO BE ABLE TO RELATE THE PROPERTIES OF AMPHETAMINES (IN PARTICULAR TOLERANCE) TO OVERDOSE POTENTIAL.
• TO CONSIDER THE IMPACT OF SMALL CHEMICAL CHANGES (METHYL GROUPS) ON DRUG POTENCY.
• TO UNDERSTAND HOW DRUGS HAVE IMPACT ON BOTH CENTRAL AND PERIPHERAL NERVOUS SYSTEMS AND THE IMPACTS OF PERIPHERAL NERVOUS SYSTEM STIMULATION.
• TO BE ABLE TO RELATE THESE INTERACTING MOLECULES WITH THE GENES THAT ENCODE THEM AND DEVELOP AN UNDERSTANDING OF HOW GENETIC DIFFERENCES CAN INFLUENCE DRUG EXPERIENCE.
• TO BE ABLE TO WEIGH RISKS AND BENEFITS OF THIS DRUG IN A KNOWLEDGEABLE WAY THAT ASSISTS IN WISE DECISION MAKING.
PREVIOUSLY LEARNED…
COCAINE AND CAFFEINE, BUT NOT NICOTINE….
A. CAUSE VASOCONSTRICTION
B. STIMULATE THE REWARD PATHWAY
C. BIND ANTAGONISTICALLY TO BRAIN MOLECULES
D. IMPACT RECYCLING TRANSPORTERS
E. ARE METABOLIZED BY CYP 450 ENZYMES
F. LEAD TO DEPENDENCE (AND RESULTANT WITHDRAWAL SYMPTOMS)
WHICH EXPLAINS A PERSON WHOSE CAFFEINE USE MAKES THEM SLEEPY?
A. THEY HAVE WEAK CYP1A2
B. THEY HAVE STRONG CYP1A2
C. THEIR ADENOSINE PRODUCTION IS EXCESSIVELY STRONG
D. THEIR ADENOSINE RECEPTORS BIND CAFFEINE AS AN AGONIST
AMPHETAMINES ARE….Amphetamine – general category
WHAT IS AMPHETAMINE? WHY DO WE USE AMPHETAMINES?
THEY ARE USED TO TREAT ADHD, NARCOLEPSY, AND OBESITY
• TABLET/CAPSULE
• DEXTROAMPHETAMINE
• RITALIN
• ADDERALL
• FENFLURAMINE/PHENTERMINE
• FENPHEN
• MANY OBESITY MARKETED MEDICATIONS ARE NO LONGER ETHICAL TO PRESCRIBE BASED ON THE ADDICTIVE NATURE OF THE DRUGS
HOW ABOUT HERBAL STIMULANTS?
” Catha edulis” active ingredient – cathine (cathidine)
HydroxycutMetabalife
FDA – 50+ deaths, high blood pressure, stroke, heart attack, one death
NOT regulated• Packaged
as food supplement to avoid regulation,
• inaccurate dosage info…
WHAT ARE AMPHETAMINES? TOC
Q: METHAMPHETAMINE IS AN DEXTROAMPHETAMINE WITH AN ADDED METHYL GROUP. DO YOU THINK IT'S EFFECTS MORE CLOSELY RESEMBLE CATHINE OR EPHEDRA?
A: ONE COULD ARGUE EITHER WAY: IF IT'S JUST THE METHYLS, THEN CATHINE MIGHT BE A BETTER MATCH.
BUT IT ALSO HAS A =O INSTEAD OF A HYDROXYL. IF THAT IS IMPORTANT, THEN EPHEDRA IS A BETTER MATCH.
Q: IF AMPHETAMINES FOLLOW THE SAME RULE AS XANTHINES WITH REGARD TO THE NUMBER OF METHYLS, WHICH AMPHETAMINE IS MOST POTENT - DEXTROAMPHETAMINE, EPHEDRA, OR CATHINE?
A: EPHEDRA
HOW ARE AMPHETAMINES ADMINISTERED?
Orally• Ephedra & cathine• Pills/CapsulesSmokedInsufflatedIntravenous
AMPHETAMINE DOSAGE?
DOSAGE DEPENDS ON USE AND METHOD OF ADMINISTRATION:
• THERAPEUTIC DOSAGES VARY
• PHYSICIANS OFTEN START BY PRESCRIBING 5 MG PER DAY
• DOSAGE CAN GO AS HIGH AS 60 MG PER DAY
• INCREASE DUE TO TOLERANCE WITH LONG TERM USE
INJECTING AMPHETAMINE INTRAVENOUSLY WILL:
A. HURT!
B. SPEED DELIVERY TO THE BRAIN
C. RESULT IN GREATER ADDICTION
D. EXPOSE A USER TO BLOOD-BORNE PATHOGENS
E. ALL OF THE ABOVE
AMPHETAMINE DOSAGEED50= 5– 60 mg orally
Lethal dose
Effective dose
Few exposures Regular exposures
Dosag
e
Initial TI of 100 is common long-time users often are taking in a dose that is only different from the LD by a factor of 10
AMPHETAMINE DOSAGE & TOLERANCE
TOLERANCE HAPPENS BECAUSE OF :
• INCREASES IN METABOLIC ENZYME
• DECREASES IN RECEPTOR BINDING
Q: WHICH MECHANISM WOULD ACCOUNT FOR THE RAPID TOLERANCE THAT LEADS TO DECREASING IMPACT WHILE BLOOD LEVEL OF AMPHETAMINE IS STILL INCREASING? A: DECREASING RECEPTOR BINDING. IT CAN’T BE INCREASING METABOLIC ENZYME - BECAUSE THE AMPHETAMINE LEVEL WOULD DECREASE IF METABOLIC ENZYME DECREASED.
AMPHETAMINE METABOLISM?
CYP2D6
HO
Half life ~ 1 hour
dextro-amphetamine
hydroxy-amphetamine
HOW DO AMPHETAMINES WORK ON A CELL?
Endogenousamphetamine
NH
2
Produce alertnessActivate the sympathetic nervous systemTreat narcolepsy, fatigue, obesity, ADHD
EuphoriantActivate the Reward Pathway
LONG TERM EFFECTS ON NEURON
Receptor density
Post-synaptic membrane density
PMID 14686913
Study suggests rewiring or change in the brain of someone who used Ritalin• Might increases probability of
having drug addiction
Why? • Reuptake transporters could be e
back to pre-Ritalin efficient state• Cells have been permanently
changed by Ritalin use
Natural euphoric events are less rewarding
ADDICTION?
REWARD PATHWAY STIMULATED…A LOT
• BLOCKS DOPAMINE REUPTAKE
• BLOCKS NOREPINEPHRINE REUPTAKE
• ELEVATED DOPAMINE RELEASE
ADMINISTRATION IS A KEY
• INSUFFLATION, INHALATION & INJECTION DELIVER THE DRUG TO THE BRAIN RAPIDLY
• THE ONSET OF THE HIGH IS SO RAPID THAT THE INTENSITY IS VERY GREAT
ADDICTION?MANY EXPERTS RATE METHAMPHETAMINE AS AN EQUAL TO NICOTINE IN ADDICTIVENESS.
• SOME SAY MORE
• FOCUS ON THE QUICKNESS OF COMPULSIVE USE OR THE LENGTHS AN ADDICT WILL GO TO FOR A "FIX"
• OTHERS SAY LESS
• FOCUS ON THE SUCCESS RATE OF BREAKING THE ADDICTION CYCLE
TOC
Q: COME UP WITH TWO REASONS FOR METHAMPHETAMINE BEING MORE ADDICTIVE THAN DEXTRO AMPHETAMINE. (DIAGRAM ABOVE HAS A HINT)
A: SPEEDIER TO THE BRAIN (INJECTED) &
EXTRA METHYL GROUP MAKES IT MORE INTENSE
BENEFITS? DO AMPHETAMINES DO ANY GOOD?
THERAPEUTIC USES FOR AMPHETAMINES INCLUDE TREATMENT OF NARCOLEPSY, OBESITY, AND ADHD.
• IT HAS BEEN SHOWN THAT INDIVIDUALS WITH ADHD HAVE LESS DOPAMINE AVAILABLE PROBABLY DUE TO OVERACTIVE DOPAMINE RECYCLERS
In the ADHD subject above• less red area= less dopamine
receptor occupancy• suggests less dopamine
availability• Thus inhibiting dopamine
recycling might diminish the deficit in focusing
BENEFITS? DO AMPHETAMINES DO ANY GOOD?• IN TERMS OF TREATING NARCOLEPSY OR OBESITY
BOTH WAKEFULNESS AND APPETITE SUPPRESSION ARE EXPERIENCED ON AMPHETAMINES.
• IN THE 1970'S DEXTRO-AMPHETAMINE "CHEWS" WERE WIDELY AVAILABLE OTC
• USED COMMONLY BY MANY TRYING TO LOSE WEIGHT NOT EFFECTIVE FOR LONG TERM WEIGHT LOSS
• ALSO OBSERVED TO HAVE AN ADDICTIVE PROPERTY.
• MANY WEIGHT-LOSS AMPHETAMINES HAVE BEEN REMOVED FROM THE MARKET DUE TO SERIOUS CARDIAC RISK
BENEFITS? DO AMPHETAMINES DO ANY GOOD?
ALERTNESS
• "BENEFIT" AMONG PEOPLE WHO WANT TO/ NEED TO STAY AWAKE
• EX- TRUCK DRIVERS
• METH WAS HEAVILY USED AMONG SOLDIERS IN WORLD WAR II
• ABILITY TO PUT OFF EXHAUSTION
• ABILITY TO MAKE A PERSON MORE COMFORTABLE TAKING SERIOUS RISK
HARMS ASSOCIATED WITH AMPHETAMINE USE?
HERBAL AMPHETAMINES CAN ALSO BE DANGEROUS
• EPHEDRA WAS A COMMON INGREDIENT IN ENERGY DRINKS & PERFORMANCE ENHANCING DRUGS
• RESULTED IN THE DEATH OF ONE MLB PITCHER, STEVE BETCHLER
• EPHEDRA BECAME THE FIRST FDA BANNED HERBAL SUPPLEMENT IN 2004
• EPHEDRA ACCOUNTED FOR APPROXIMATELY 1% OF THE SALES OF ALL HERBAL SUPPLEMENTS
• 64% OF THE SERIOUS SIDE EFFECTS
HARMS ASSOCIATED WITH AMPHETAMINE USE?
HARMS ASSOCIATED WITH AMPHETAMINE USE?STIMULATES THE SYMPATHETIC NERVOUS SYSTEM ANXIOUS, OVERWHELMED, WORRIED
• AMPHETAMINES & NOREPINEPHRINE HAVE SIMILAR CHEMICAL STRUCTURES
• AMPHETAMINES CAN HAVE A SERIOUS PSYCHOLOGICAL HEALTH RISK
• DO HAVE THE POTENTIAL TO PUSH A BORDERLINE PSYCHOTICS OVER THE BRINK.
• BRING ON SYMPTOMS THAT WERE LURKING BUT NOT FULLY EXPRESSED.
HARMS ASSOCIATED WITH AMPHETAMINE USE?• STUDIES SUGGESTS THAT NEURONS
RESPOND TO AMPHETAMINE USE AND EXCESS DOPAMINE STIMULATION BY REMODELING THE NEURONAL WIRING (PMID 14686913)
• THIS REWIRING CAN LOOK DIFFERENTLY
• IT CAN MEAN A LOSS OF RECEPTORS ON DENDRITES OR PERMANENT LOSS OF DENDRITES.
• CONNECTIONS THAT ARE NORMALLY PRESENT CAN BE LOST DUE TO OVERSTIMULATION.
HARMS ASSOCIATED WITH AMPHETAMINE USE? LONG TERM USE-
SEVERAL STUDIES SHOW LONG-TERM DAMAGE TO THE BRAIN & LOSS OF BRAIN CELLS AMONG LONG TERM METH USERS
• LOOKED AT BRAIN DAMAGE BY INDICATED BY THE PRESENCE OF NEURON-MADE CHEMICALS WHICH ARE REDUCED
• EX> N-ACETYLASPARTATE (NAA) IS REDUCED
• BRAIN DAMAGE CAN ALSO BE DETECTED BY ASSAYING FOR CHEMICALS MADE BY GLIAL CELLS IN RESPONSE TO NEURON DAMAGE.
• CHOLINE AND MYOINOSITOL ARE INCREASED
• GLIAL-MADE CHEMICALS THAT HAVE BEEN SHOWN TO BE INCREASED WITH NEURON DAMAGE
• THESE ARE INCREASED IN METHAMPHETAMINE-EXPOSED CELLS.
METHAMPHETAMINE AND BRAIN LOSS
Media/meth/meth.jpg
Limbic – 11% loss of tissue
Hippocampus – 8% loss of tissue
Subjects studied:• ~ 30 years old• 4 grams per week for 10
years-Smoked • 22 people, 21 controls
Increases seen in glial proteins that respond to neuron injury
HARMS ASSOCIATED WITH AMPHETAMINE USE? TOCQ: WHAT ROLE DO NEURO GLIA HAVE IN THE STORY OF DRUGS AND BRAIN DAMAGE?
A: NEUROGLIAL CELLS HELP PROTECT NEURONS FROM DAMAGE BY MANUFACTURING RESTORATIVE PROTEINS.
Q: SOME STUDIES SUGGEST THAT THERE ARE CORROSIVE INGREDIENTS IN METH THAT LEAD TO DENTAL PROBLEMS, OTHERS SUGGEST THAT THESE PROBLEMS RESULT FROM ONE OF THE OTHER SIDE EFFECTS LISTED. WHICH IS THAT?
A: DENTAL DECAY CAN COME FROM POOR NUTRITION ASSOCIATED WITH METH USE.
Q: EPHEDRA IS “HERBAL”. MANY THEREFORE CLAIM IT IS NATURAL AND HAS NO RISK. FOR THIS AND MANY OTHER REASONS, COMPANIES MARKET AND SOLD EPHEDRA AS A FOOD SUPPLEMENT. FOOD SUPPLEMENTS DO NOT HAVE TO GO THROUGH RIGOROUS SAFETY TESTING THAT DRUGS DO. HOW, THEN, CAN THEY BE DETERMINED TO BE UNSAFE?
A: FOOD SUPPLEMENTS ARE DETERMINED TO BE UNSAFE IF THEY ARE ASSOCIATED WITH A LOT OF COMPLAINTS RELATING TO POOR HEALTH.
INDIVIDUAL EXPERIENCES MAY VARY
• PRIOR AMPHETAMINE USE CAN IMPACT INDIVIDUAL EXPERIENCE
• AMPHETAMINE TOLERANCE HAPPENS RAPIDLY ESPECIALLY AN INCREASE IN THERAPEUTIC DOSE
• THE TYPICAL THERAPEUTIC INDEX FOR AMPHETAMINES VARIED FROM 10 TO 100.
• THAT RANGE IS MUCH LARGER THAN CAN BE ACCOUNTED FOR OR EXPECTED BASED ON OTHER CONTRIBUTORS LIKE:
• METABOLIC ROBUSTNESS
• HOW HEALTHY THE USER IS
• THERAPEUTIC DOSE RISES QUICKLY WITH MINIMAL INCREASE IN LD.
• INITIALLY A NEW USER HAS A HIGH TI (100) BUT AS THEIR DOSE INCREASES, THE TI NARROWS TO 10.
INDIVIDUAL EXPERIENCES MAY VARY
DEATH CAN OCCUR MORE EASILY IN PEOPLE WHO HAVE ATTEMPTED TO QUIT BUT "FALL OFF THE WAGON"
• IF A PERSON RELAPSES S/HE CAN’T RETURN TO THE SAME DOSAGE THEY WERE PREVIOUSLY USING
• BODY IS NO LONGER USED TO METABOLIZING THE DRUG EFFICIENTLY
INDIVIDUAL EXPERIENCES MAY VARY
GENES THAT INFLUENCE AMPHETAMINE EXPERIENCE
• DIFFERENCES IN THE CARTPT GENE ARE KNOWN TO ALTER ONE'S RESPONSE TO AMPHETAMINE.
• THE DAT GENE & THE GENE THAT ENCODES CYP2D6 WILL ALSO INFLUENCE OUR RESPONSE TO THE DRUG
• A GENE THAT PRODUCES GLIAL FACTOR DERIVED GROWTH FACTOR HAS ALSO BEEN SHOWN TO INFLUENCE AMPHETAMINE RESPONSE
ERS FOR LESSON 18: AMPHETAMINES
REQUIRED READINGS
LISKA - SECTION 7.6 - 7.11 AND QUESTIONS 8 – 12
WEB SITES
• HTTP://LEARN.GENETICS.UTAH.EDU/CONTENT/ADDICTION/DRUGS/MOUSE.HTML
• HTTP://WWW.NIDA.NIH.GOV/INFOFACTS/METHAMPHETAMINE.HTML
• HTTP://WWW.DRUGABUSE.GOV/DRUGPAGES/METHAMPHETAMINE.HTML
• HTTP://ARCHIVES.DRUGABUSE.GOV/MEETINGS/WIRED.HTML
(MEETING ABSTRACT ABOUT STUDIES LOOKING AT AMPHETAMINE-CAUSED BRAIN REWIRING)